Volume 94, No. 3 September 2019 THE QUARTERLY REVIEW of Biology

INVISIBLE DESIGNERS: BRAIN EVOLUTION THROUGH THE LENS OF PARASITE MANIPULATION

Marco Del Giudice Department of Psychology, University of New Mexico Albuquerque, New Mexico 87131 USA e-mail: [email protected]

keywords behavior, brain evolution, hormones, neurobiology, parasite-host interactions, parasite manipulation

abstract The ability of parasites to manipulate host behavior to their advantage has been studied extensively, but the impact of parasite manipulation on the evolution of neural and endocrine mechanisms has re- mained virtually unexplored. If selection for countermeasures has shaped the evolution of nervous sys- tems, many aspects of neural functioning are likely to remain poorly understood until parasites—the brain’s invisible designers—are included in the picture. This article offers the first systematic discussion of brain evolution in light of parasite manipulation. After reviewing the strategies and mechanisms employed by parasites, the paper presents a taxonomy of host countermeasures with four main categories, namely: restrict access to the brain; increase the costs of manipulation; increase the complexity of signals; and increase robustness. For each category, possible examples of countermeasures are explored, and the likely evolutionary responses by parasites are considered. The article then discusses the metabolic, com- putational, and ecological constraints that limit the evolution of countermeasures. The final sections offer suggestions for future research and consider some implications for basic neuroscience and psycho- pharmacology. The paper aims to present a novel perspective on brain evolution, chart a provisional way forward, and stimulate research across the relevant disciplines.

Introduction topic in biology (Hughes et al. 2012; Adamo HE ability of some parasites to manip- 2013; Mehlhorn 2015a; Poulin and Maure T ulate their hosts’ behavior is a growing 2015; Heil 2016), and has become a staple

The Quarterly Review of Biology, September 2019, Vol. 94, No. 3 Copyright © 2019 by The University of Chicago Press. All rights reserved. 0033-5770/2019/9403-0001$15.00

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8073.proof.3d 249 Achorn International 06/27/19 01:01 250 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 of popular science (McAuliffe 2016; Simon It is worth quoting some passages: “There 2018). From “zombieants”to “kamikazecrick- are two ways hosts can protect themselves ets” and “mind-controlling wasps,” the parade from behavior attack. One way is to kill or in- of behavior-altering parasites and their vic- capacitate the causal pathogen. The other tims offers riveting examples of how nervous way is to counter the manipulation itself, systems can be hijacked to serve the interests either by making behavior control systems of hostile organisms. Despite its sensational less vulnerable to attack, or by recalibrating qualities, behavioral manipulation is not a things to accommodate the manipulation. rarity in nature: the list of manipulating or- Immunologists study the first kind of de- ganismsislongandincludesviruses,bacteria, fense; next to nothing is known about the protozoa, fungi, helminths (parasitic worms), other kind [...]. How much of our neural and insects such as wasps and flies (Hughes complexity is a necessary defense against ma- et al. 2012; Mehlhorn 2015a; Poulin and nipulative invaders? How much of the enor- Maure 2015). Just as important, behavior- mous redundancy is to provide system level altering strategies have a remarkably deep functionality if part of the system is attacked? evolutionary history. Parasites have attempted How much of the complex process of wiring to control their hosts’ behavior for hundreds a brain during development is to prevent of millions of years (Adamo 2013). Host ma- pathogen re-wiring?” (Read and Braithwaite nipulation has evolved independently at least 2012:195). The authors predicted that these 20 times; fossilized ants show that present- questions would soon become central to be- day manipulation strategies by fungi and hel- havioral biology and neuroscience. Instead, minths were already well established around parasites have continued to claim the spot- 30–50 million years ago, suggesting that they light, and the fascinating issue of how the originated much earlier (see Poulin 2010; brain protects itself from manipulation has Hughes 2014). been left unaddressed. Research on behavioral manipulation has focused almost exclusively on the evolution of parasites and their strategies. This includes Overview the specific biochemical mechanisms em- In this paper, I begin to systematically ex- ployed by parasites (e.g., Adamo 2012, 2013; plore the question of how parasite manipula- Perrot-Minnot and Cézilly 2013; Herbison tion may have shaped the evolution of brain 2017; Libersat et al. 2018), the evolutionary mechanisms. I start by reviewing the strate- trajectories that lead to manipulation (e.g., gies employed by parasites that target the Poulin 2010; Thomas et al. 2012; Loreto et al. central nervous system and related endo- 2018), and the corresponding tradeoffs (e.g., crine pathways. I then present a taxonomy Poulin et al. 2005; Roitberg 2012). What has of possible countermeasures to manipula- been almost entirely neglected is the effect tion, and consider the likely evolutionary re- of parasites on the evolution of their hosts’ sponses by parasites (Table 1).Abroad range nervous and endocrine systems. Millions of of potential countermeasures are discussed, years of attacks by manipulating organisms from the more plausible (e.g., increasing the must have exerted a powerful selective pres- complexity and metabolic costs of molecular sure on brain evolution in animals. If so, pre- signals)tothemore speculative(e.g.,employ- sent-day nervous systems should embody a ing individualized “signatures” to protect variety of countermeasures to manipulation signaling pathways from eavesdropping and accumulated through a long coevolutionary intrusion). For each hypothetical strategy, I history—possibly reaching all the way down consider what neural and endocrine mecha- to some of themost basic,ubiquitousfeatures nisms might implement it in the real world of neural functioning. and look for possible examples in the litera- This crucial observation was made by Read ture. This section has a deliberate exploratory and Braithwaite (2012) in an afterword to a character: the goal is not to demonstrate that book chapter, but—to my knowledge—has not a given mechanism works—fully or in part— been followed up in the literature until now. as a countermeasure to manipulation, but to

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TABLE 1 Ataxonomyofcountermeasuresagainstbehavioralmanipulation Host countermeasures Possible examples Possible responses by parasites

Restrict access to the brain Blood-brain barrier as physical defense Cross/bypass the barrier Blood-brain barrier as chemical defense Target weak spots in the barrier Loss of molecular entry points Target influx/efflux mechanisms Decoy molecules Find new molecular entry points Avoid decoy molecules Increase manipulation costs Metabolically costly signals Cost-sharing Toxic signaling molecules (dopamine, nitric Indirect attacks, genomic manipulation oxide, antimicrobial peptides) Detoxification, antimicrobial resistence Increase signal complexity Diversification of signals/receptors Indirect attacks, genomic manipulation Co-transmission Increase manipulation complexity Convergent signaling Pulsatile signaling Individualized signatures Increase robustness Passive: redundancy, modularity Target core regulatory processes (“knots”) Reactive: negative feedback, specialized Target vulnerable feedback loops detection/interference mechanisms Proactive: immune-activated countermea- Target/escape detection mechanisms sures, preemptive compensation Target/escape immune responses Increase manipulation strength

Each type of countermeasure is followed by possible examples of neurobiological mechanisms and evolutionary responses by parasites.

single out promising candidates for further measures” can persist indefinitely if they have investigation. Next, I discuss the constraints become embedded into basic neural pro- that limit the evolution of countermeasures cesses. Mapping what Read and Braithwaite in the hosts. I suggest that metabolic, com- called the “ghost of manipulations past” putational, and ecological considerations (Read and Braithwaite 2012:195) is going to contribute to explain why complex “manip- require a great deal of reverse engineering, ulation syndromes” are mostly observed in modeling, and comparative analysis. Finally, small animals such as ants and snails, and why I consider some implications for basic neuro- there are no established examples of adap- science and psychopharmacology. My goal tive behavior manipulation in our species. in this paper is not to provide definitive an- In the following section I advance sugges- swers but to open up a new area of research, tions for research on this topic. No doubt, chart a provisional way forward, and stimu- identifying host countermeasures in the in- late responses from researchers across the tricate workings of the brain is a formidable relevant disciplines. task. Some antiparasite adaptations may have originally evolved with different functions; others may have been recruited and exapted Hijacking the Brain: Parasite in the service of different goals. Others still Manipulation Strategies may have become useless over time—either Controlling behavior requires the coordi- because they were successfully thwarted by nated action of multiple systems, including parasites, or because they proved so effective neural and hormonal mechanisms but also that parasites were forced to take a different sensory and motor organs. Each node in evolutionary route. Such “frozen counter- the control network is also a potential target

8073.proof.3d 251 Achorn International 06/27/19 01:01 252 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 for manipulation. Since the topic of this pa- fected by spiny-headed worms become at- per is brain evolution, I restrict my focus to tracted by light (positive phototaxis), and the central nervous system (CNS) and the when the water is disturbed they do not re- major endocrine pathways that relay signals spond by escaping; instead, they swim to between the brain and the rest of the body. I the surface and cling to a solid object, thus do not discuss the strategies of parasites that becoming easy prey for birds. When Califor- take direct control of the host’s muscles (as nia killifish are infected by the fluke it has been suggested in the case of the ant- Euhaplorchis californiensis, they begin to dis- infecting fungus Ophiocordyceps unilateralis; play atypical swimming behaviors—such as Fredericksen et al. 2017); target sensory re- jerky, conspicuous movements and sudden ceptors; and indirectly affect behavior by swims to the surface—that attract bird pred- depleting energetic reserves, castrating/ster- ators (Adamo 2002, 2013; Lafferty and Shaw ilizing the host, or altering sex determina- 2013). The abdomen of tropical ants infected tion (see Adamo 2012; Lafferty and Shaw by the roundworm Myrmeconema neotropicum 2013). Also excluded is manipulation through turns from black to bright red; the ants then sensory cues and signals, as practiced by climb into patches of red berries and raise brood parasites in birds (e.g., cuckoos; Lang- their abdomen to mimic a fruit, thus attract- more and Spottiswoode 2012) and social par- ing the frugivorous birds that serve as the par- asites in insects (e.g., beetles that parasitize asite’s final host (Yanoviak et al. 2008; for ant colonies; Grüter et al. 2018). Before ad- more examples see Poulin 2010; Lafferty dressing specific mechanisms, however, it is and Shaw 2013; Mehlhorn 2015b). useful to briefly consider the functions of In addition to trophic transmission, para- manipulation from the perspective of para- sites can move between hosts through skin sites. When they hijack the host’s nervous contact, bodily fluids (e.g., saliva, blood), or system, what kinds of behaviors are they at- excretions (e.g., vomit, feces), and indirectly tempting to produce, and why? through animal vectors (e.g., mosquitoes). For vector-borne parasites, a way to facilitate transmission is to alter the behavior of the functions of behavior manipulation vector so it will visit more hosts in the same amount of time (e.g., a mosquito may suck Transmission blood from more individuals, spending a The first and most frequently studied func- shorter time on each). This is what happens tion of manipulation is to increase the prob- to mosquitoes infected with malaria Plasmo- ability of transmitting the parasite. This can dium, although it is still unclear whether the take a number of distinct forms depending behavioral change is a targeted manipula- on the parasite’s life cycle and transmission tion by the parasite or a compensatory re- route. In trophic transmission, an intermedi- sponse by the host (Cator et al. 2013; Heil ate host is manipulated to make it more sus- 2016). Rabies viruses offer a remarkable ex- ceptible to predation by the definitive host ample of facilitation in a directly transmitted (Lafferty 1999). To this end, a parasite may parasite. In the acute phase, the symptoms of reduce the host’s avoidance and antipred- rabies combine increased production of in- ator behaviors, or even replace avoidance fected saliva, aversion to water (which further with attraction. A classic example is proto- concentrates the saliva), and unpredictable zoan Toxoplasma gondii: infected rats lose bouts of aggressive biting that transmit the vi- their innate aversion to the odor of cats— rus to the victims (Hemachudha et al. 2013; the definitive host—and may even become Jackson 2013). In principle, sexually trans- attracted to it (this phenomenon has been mitted parasites can spread more effectively dubbed “feline attraction”; Berdoy et al. by manipulating aspects of the host’s sex- 2000; Ingram et al. 2013; Kaushik et al. 2014). ual behavior, including frequency of mat- Alternatively or in addition, parasites may in- ing, mate choice selectivity, attractiveness to duce behaviors that actively lure predators potential mates, and specific copulatory be- toward the host. Gammarid crustaceans in- haviors. Although there have been initial

8073.proof.3d 252 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 253 reports of manipulation by sexually trans- the parasite’s strategy turns out to benefitthe mitted parasites, the evidence is still scant and host under particular conditions. For exam- the topic remains understudied (see Adamo ple, trophic parasites should be selected to 2014; Heil 2016). enhance the intermediate host’s antipredator behaviors (and hence survival) until they are ready to be transmitted to the definitive host Movement (Parker et al. 2009). There is evidence that, Another common goal of manipulation is in the early phase of the infection, spiny- to make the host move to a different habitat, headed worms protect their gammarid hosts one that is favorable to the parasite or its off- by making them less susceptible to preda- spring. Typically, the new habitat is used for tion (Dianne et al. 2011). Other condition- sexual reproduction or the release of infec- ally helpful parasites may increase their tive propagules (e.g., spores or cysts; see Pou- host’s mating success or help prevent infec- lin 2010; Moore 2013; Mehlhorn 2015b). tions by other and potentially more harmful Grasshoppers and crickets infected by horse- parasites (see Fellous and Salvaudon 2009; hair worms begin to seek out water and Weinersmith and Earley 2016). The net ef- eventually jump into it, releasing the adult fect on the host’s fitness is still likely to be parasite—whichcanthencompleteitsrepro- negative in most cases, but may turn positive ductive cycle—and usually dying in the pro- if ecological conditions put a premium on cess (Poulin 2010; Mehlhorn 2015b). Bees the specific phenotype induced by the para- infected by larvae of the parasitoid fly Apo- site. For example, heightened antipredator cephalus borealis fly far away from their hive, behaviors may provide a net benefit if pre- die, and release the larvae as these are ready dation risk is especially severe; enhanced im- to pupate (Core et al. 2012). munity from other parasites may be a crucial advantage under high pathogen threat (see Weinersmith and Earley 2016). Protection Less intuitively, parasites may also use the host as a “bodyguard” to protect their off- mechanisms of behavior manipulation spring during critical developmental stages. The most obvious target of behavior ma- This is most commonly seen in parasitoid in- nipulation is an animal’s brain. Parasites can sects.Forexample,braconidwasplarvaegrow penetrate inside the brain and attack it from inside caterpillars, feeding on the host’s tis- within or secrete neuroactive compounds sues. After the larvae exit to pupate, the dying that will reach the brain through circulation. caterpillar remains coiled on the cocoons In both cases, they need to get past the that contain the pupae and begins to per- blood-brain interface and its defenses. Al- form violent head-thrashing movements. The ternatively, a parasite may take an indirect movements keep away potential predators route and target endocrine organs such as and increase the survival of the pupae. Other the thyroid, gonads, or various components wasps parasitize spiders, and manipulate of the immune system. The hormones pro- them into weaving special “cocoon webs” to duced by these organs modulate brain func- protect the developing pupae (Gonzaga et al. tion and can powerfully affect behavior. 2017; these and other examples of body- The same applies to the cytokines secreted guard manipulation are reviewed in Maure by immune cells such as macrophages and et al. 2013). lymphocytes. Again, the parasite may lodge itself inside an organ or manipulate it from the outside. Endocrine systems are not just a conditionally helpful parasites potential target for hijacking: parasites can The strategies that promote the fitness of eavesdrop on the host’s hormonal signals to parasites generally reduce that of the hosts— gain precious information about the state of not infrequently to the point of killing them. the organism and respond adaptively. For Still, manipulation may have a silver lining if example, enteric pathogens such as Escheri-

8073.proof.3d 253 Achorn International 06/27/19 01:01 254 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 chia coli and Salmonella enterica can sense in- nipulation (Adamo 2013). At the same time, creases in stress-related catecholamines (such immune reactions normally function to ben- as epinephrine and norepinephrine), and re- efitthehost;thismakesit hard to conclusively spond by accelerating growth and expressing demonstrate that a given behavioral symptom virulence factors (Roshchina 2010; Stevens is in the interest of the parasite (Herbison 2010; Neuman et al. 2015). Likewise, many 2017). Most of the putative examples come sexually transmitted microbes regulate their from invertebrates. When it infects its snail growth in response to sex hormone levels host, the fluke Trichobilharzia ocellata induces (Jahoor et al. 2010). In addition to hor- secretion of a cytokine that suppresses egg mones, peripheral nerves that relay informa- laying; the energy diverted from reproduc- tion to the CNS are vulnerable pathways that tion can then be used to support the para- canbeexploitedtoindirectlymodulatebrain site’s growth (de Jong-Brink et al. 2001). A function. Even more circuitously, some para- few hours before emerging from caterpillars, sites may affect the host’s behavior by manip- the larvae of parasitoid wasps secrete com- ulating its microbiota—including mutualists pounds that raise octopamine levels and sup- and commensal microorganisms (e.g., gut press their host’s feeding and locomotion; microbes) that may enjoy privileged chan- although the mechanism is not fully under- nels of influence and communication with stood, there are reasons to think that immu- the host (Dheilly et al. 2015; more on this nological manipulation is involved (Adamo below). 2005, 2013; but see Herbison 2017 for a skep- When a parasite gains access to the brain tical perspective). In gammarids infected by oranotherendocrineorgan,thesimplest way various species of helminths, the changes in to affect the host’s behavior is to physically serotonergic transmission induced by the destroy part of the organ’s tissue (Lafferty parasites (see below) seem to be partly me- and Shaw 2013). Although this strategy can diated by neuroinflammation, through the produce gross behavioral alterations, it car- release of cytokines and nitric oxide (Helluy ries a high risk of prematurely killing the 2013). Abundant cytokines and nitric oxide host and is not well suited to yield subtle or are also released when toxoplasma cysts in- coordinated changes. Unsurprisingly, then, fect the brain of the host; but as in most other parasiteshaveevolvedastrikingvarietyofbio- vertebrate examples, it is unclear whether the chemical means of manipulation. For ease immune reactions triggered by the parasite of presentation, these mechanisms can be are part of an adaptive manipulation strategy grouped into three overlapping categories: (see Herbison 2017). immunological, neuropharmacological, and geno- When parasites secrete substances that mic/proteomic (Adamo 2013; Herbison 2017). directly affect the nervous system, they are The immunological route is indirect but said to engage in neuropharmacological ma- potentially very effective. The immune sys- nipulation (Adamo 2012, 2013). The typical tem enjoys extensive crosstalk with the brain targets are neurotransmitters and neuromod- through cytokines and autonomic nerves, and ulators—most notably serotonin, dopamine, powerfully modulates behavior in response octopamine (an invertebrate analogue of nor- to infections—by affecting the animal’sover- epinephrine), opioids, vasopressin, and ni- all activity levels, sleeping patterns, feeding tric oxide (Perrot-Minnot and Cézilly 2013). andfoodpreferences,aswellasabroadrange Note that the standard distinction between of social behaviors (including mating; see neurotransmitters and neuromodulators is Adamo 2014). By triggering or suppressing only heuristic: “classic” neurotransmitters specific immune responses, parasites can ex- such as dopamine and serotonin can also ploit the associated behavioral changes to diffuse out of the synapse and exert modula- their advantage. Since the immune system tory effects (see Gutiérrez 2009; Leng 2018). is designed to detect and react to parasites Neuroactive hormones (e.g., sex and stress and to modulate a range of neural and behav- hormones) can also be used to influence the ioral processes in the host, one could say that host’s behavior. By directly modulating brain immune pathways are preadapted for ma- function, parasites can potentially achieve

8073.proof.3d 254 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 255 highly specificchangesandbringaboutnovel expression in the medial amygdala, a neu- behavioralpatterns(incontrast,immunolog- rochemical alteration that seems to play a ical manipulations can only exploit the host’s key role in the onset of “feline attraction” evolved responses to infection). Neurotrans- (Adamo 2013; Vyas 2015a,b; Heil 2016). This mitters and hormones are highly conserved is another example of how behavioral manip- across species; their phylogenetic stability ulation may require the coordinated exploi- facilitates the evolution of specialized mech- tation of multiple neurobiological systems. anisms of biochemical offense. Unsurpris- To survive and reproduce within their hosts, ingly, neuropharmacological manipulation many parasites rely on mechanisms that mod- is very common and has been documented ify gene expression and protein synthesis in in dozens of species (see Perrot-Minnot and the host’s cells. For example, viruses may in- Cézilly 2013). duce the hosts to synthesize viral proteins by Sometimes, alteration of a single key neu- supplying strands of messenger RNA or di- rotransmitter triggers an entire “syndrome” rectly insert copies of their genes into the of coordinated behaviors that can be ex- host’s DNA (retroviruses). Both protozoan ploited by the parasite. By increasing the and helminth parasites release vesicles con- synthesis of serotonin, helminths that para- taining small noncoding RNAs, which can reg- sitize gammarids produce a suite of behav- ulate gene expression by host cells in myriad ioral changes that include reduced activity ways (e.g., Buck et al. 2014; Cheeseman and levels, positive phototaxis, and impaired es- Weitzman 2015; Linhares-Lacerda and Mor- cape behaviors (Perrot-Minnot et al. 2014). rot 2016; Bayer-Santos et al. 2017). All of these In other cases, the parasite secretes a mix- genomic/proteomic means of manipulation ture of molecules that target multiple bio- can be used to influence behavior. Caterpil- chemical systems at once. The best-known lars infected by the virus Lymantria dispar example is that of parasitoid jewel wasps, nucleopolyhedrovirus climb to elevated posi- which use cockroaches as food supply for tions before dying and rupturing, thus spread- the developing larvae. These wasps inject a ing large amounts of infectious particles on venomous “cocktail” directly into the brains the ground. To produce this behavior, the of the cockroaches (ganglia). After the injec- virus induces the host to synthesize a virally tion, the cockroach engages in vigorous self- encoded enzyme; in turn, the enzyme inacti- cleaning for about 30 minutes, while the vates a key hormone that regulates circadian wasp leaves in search of a suitable nest. When cycles of climbing and descending (Hoover the wasp returns, grooming has given way to et al. 2011). Crickets and grasshoppers in- a lethargic state; the cockroach lets the wasp fected by hairworms show similar profiles of bite off its antennae, obediently follows it to altered protein expression in the CNS, sug- the nest, and remains immobile as the larvae gesting some kind of coordinated genomic/ are deposed in its body. To achieve this ma- proteomic manipulation (Biron et al. 2005, nipulation feat, jewel wasps rely on a mixture 2006; Herbison 2017). of molecules that includes dopamine, octo- Clearly, the distinction between genomic/ pamine receptor antagonists, and opioid ag- proteomic mechanisms and the other cate- onists (Libersat and Gal 2014). Dopamine is gories reviewed in this section is a fuzzy one: also one of the main biochemical targets of in many cases, parasites target gene expres- toxoplasma. As is common in microbial para- sion to manipulate the host’s immune system sites, toxoplasma cysts do not directly secrete or modulate the activity of neurotransmit- dopamine into the host’s brain; instead, they ters, neuromodulators, and neuroactive hor- release a key enzyme in the synthesis of do- mones. Conversely, changes in immune and pamine (tyrosine hydroxylase) to increase its neurochemical profiles may lead to altera- production by infected neurons (Gaskell et al. tions in gene expression. For example, there 2009; Adamo 2012, 2013). In male rodents, is evidence that elevated testosterone in rats toxoplasma also invades the testes, where it infected by toxoplasma triggers epigenetic stimulates the production of testosterone. modifications in the vasopressin gene, lead- Elevated testosterone increases vasopressin ing to increased expression of this neuromod-

8073.proof.3d 255 Achorn International 06/27/19 01:01 256 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 ulator in the medial amygdala (Vyas 2015a,b; gut microbiota are also associated with levels Herbison 2017). of hunger- and metabolism-related hormones Viruses possess sophisticated abilities of such as leptin, ghrelin, and neuropeptide Y. genomic manipulation, and some macropar- Besides releasing hormonal signals and tox- asites (e.g., wasps) have evolved to exploit vi- ins, microorganisms that colonize the gut of ruses as intermediate vectors to alter their vertebrates may stimulate the vagus nerve host’s behavior. The relationship is symbi- (for example, with adrenergic chemicals) to otic: the virus provides the biochemical tools deliver signals directly to the brain (Cryan for manipulation, while at the same time it and Dinan 2012; Alcock et al. 2014; Sherwin employs the macroparasite as a delivery de- et al. 2016). vice (Dheilly et al. 2015; Herbison 2017). Based on these data and studies showing The best-studied example is that of parasit- associations between the microbiota and var- oid wasps that use lady beetles as bodyguards ious aspects of behavior, some authors have to incubate their eggs. When the developed suggested that gut microbes manipulate the larva exits the abdomen to spin a cocoon host for their own benefit. There is some ex- and pupate, the lady beetle enters a phase perimental evidence that the composition of of paralysis with tremors—a phase that lasts the gut microbiota modulates food choice until the adult wasp emerges from the co- in the fruit fly Drosophila melanogaster, in ways coon. The cause of the paralysis is not a com- that favor the dominant species of bacteria pound secreted by the larva, but a symbiotic (e.g., by inducing aversion to protein or at- virus (Dinocampus coccinellae paralysis virus) traction to carbohydrates; Wong et al. 2017; injected by the wasp along with the eggs. Yuval 2017). Alcock et al. (2014) considered The virus infects the lady beetle’s CNS and the possibility that similar scenarios may play triggers paralysis at the appropriate time; in- out in humans, and speculated that gut mi- triguingly, the mechanism used to produce crobes may affect food preferences, patterns the paralysis seems to exploit the host’s own of hunger and satiety, and even obesity risk. immune response, making this an instance To illustrate, one of their predictions is that of immunological manipulation by proxy increased microbial diversity should limit (Dheilly et al. 2015). theabilityofindividual speciestomanipulate the host, leading to fewer cravings and more satiety. manipulation by mutualists Despite these promising leads, the evidence and commensals that the microbiota has consistent effects on To end this section, it is worth considering behavior is still relatively weak. Establishing the possibility that the host’s behavior may the causal direction of correlations is chal- be manipulated not just by parasites but also lenging,and there arejustified concernswith by mutualists and commensals, notably the the replicability of findings in this area (For- gut microbiota. Clearly, gut microbes have sythe et al. 2016; Hooks et al. 2018). What is the biochemical potential for manipulation more, evolutionary scenarios involving gut and a privileged relationship with the host. microbes are not a straightforward extension Some of them can produce neurotransmit- of those involving exploitative parasites, and ters such as γ-aminobutyric acid (GABA), face additional theoretical problems (John- acetylcholine, epinephrine, norepinephrine, son and Foster 2018). The gut microbiota dopamine, and serotonin; and may be able comprises a large number of species and to modulate the permeability of the blood- strains that compete with one another for brain barrier (BBB) by secreting specificpro- space and resources. If one of them were to teins, thus increasing the penetration of evolve the ability to manipulate the host’s neuroactive substances into the CNS (Cryan behavior, it would have to pay the full cost and Dinan 2012; Sherwin et al. 2016). Like of manipulation but share the benefits with enteric pathogens, they can sense and re- its nonmanipulative counterparts, thus grant- spond to fluctuations in the host’s catechol- ing them a competitive advantage. Unless amines (Rumbaugh 2007). Changes in the special conditions apply, selection should

8073.proof.3d 256 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 257 limit the evolution of this kind of strategy; nedy 2008; Rodgers 2010; Kennedy and Rod- and, if this is the case, the behavioral effects gers 2019; Masocha and Kristensson 2019). of the microbiota might be best explained as Other data suggest that this parasite may by- byproducts of local competition for growth pass the BBB entirely, and penetrate through (for details see Johnson and Foster 2018). the blood-cerebrospinal fluid barrier in the In summary, manipulation by mutualists and choroid plexus—asiteofintensecellulartraf- commensals is an intriguing possibility, but ficking where leukocytes enter the CNS— the underlying logic is still poorly understood and/or in the circumventricular organs (Mogk and the phenomenon has yet to be convinc- et al. 2017; Kennedy and Rodgers 2019). ingly demonstrated across species. This illustrates the principle that parasites should evolve to target the inevitable “weak spots” in the barrier, which include passages Securing the Brain: Possible Host for cranial nerves (e.g., the olfactory nerve; Countermeasures Masocha and Kristensson 2012) and several restrict access to the brain regions of relatively high permeability (e.g., around the pineal gland and the median em- The Blood-Brain Barrier inence of the hypothalamus; Daneman and as a Physical Defense Prat 2015). A first line of defense against behavior- altering parasites is to keep them out of the CNS. Naturally, the benefits of restricting The Blood-Brain Barrier access to the brain also apply to pathogens as a Chemical Defense that do not adaptively manipulate behavior, Another key function of the BBB is to but may damage the brain and produce det- regulatethefluxofneurotransmitters/neuro- rimental neurological symptoms. In verte- modulators, hormones, and other molecules brates and some invertebrates (including from the blood to the brain and vice versa. crustaceans and insects), the BBB provides The brief summary that follows is based on an important layer of physical security (Da- studies of mammals such as rats, dogs, and neman and Prat 2015; see Abbott 1992). Par- humans, even though several BBB mecha- asites have a number of options: they can nisms are surprisingly conserved in both ver- manufacture behavior-altering substances tebrates and invertebrates (see DeSalvo et al. and release them in the blood; invade other 2014; Hindle and Bainton 2014; Hindle et al. endocrine organs and manipulate hormone 2017; Saili et al. 2017). For some molecules secretion; take the immunological route by such as serotonin and steroid hormones, the activating specificimmuneresponses;orcross flux is bidirectional; other molecules only the barrier to reach the brain. flow from the blood to the brain (influx) as, Many parasites—from viruses and bacte- for example, insulin and thyroid hormone. ria to helminths—have evolved the ability to The molecules that are only transported out penetrate or bypass the BBB (see Feustel of the brain (efflux) include GABA, gluta- et al. 2012; Masocha and Kristensson 2012). mate, norepinephrine, dopamine, and the do- An interesting case study is the protozoan Try- pamine metabolite homovanillic acid (HVA). panosoma brucei, the agent of sleeping sick- There are also active transporters that expel ness (Lundkvist et al. 2004; Mogk et al. 2017). a variety of toxins and other foreign sub- There is still considerable uncertainty on stances (xenobiotics), as well as metaboliz- how this parasite manages to enter the CNS ing enzymes that inactivate them (Ohtsuki (Kennedy and Rodgers 2019). Trypanosoma 2004; Banks 2012; Zhao et al. 2015; Saili stimulates the release of various cytokines by et al. 2017). By clearing neuroactive mole- lymphocytes and neurons; the same cyto- cules such as dopamine and GABA, the BBB kines (including IFN-γ) facilitate the passage probably contributes to regulate neurotrans- of immune cells from the blood to the brain, mission(Ohtsuki2004).Atthesametime,the a mechanism that may be exploited by the constant efflux of neurotransmitters and xe- parasite to cross the barrier (Grab and Ken- nobiotics protects the brain from neurophar-

8073.proof.3d 257 Achorn International 06/27/19 01:01 258 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 macological manipulationbycompoundsre- edge, the potential implications of parasite- leased in the blood, either by parasites driven glycan evolution for brain physiology lodged outside the CNS or by gut microbes and function have yet to be explored. and other mutualists/commensals. Recent experimental work shows that it is possible to chemically alter behavior without crossing Decoy Molecules the barrier, by modulating the activity of ef- fl To prevent parasites from infecting their ux transporters (Hindle et al. 2017). Al- cells, hosts can evolve decoy surface mole- though there is considerable literature on cules—molecules that mimicthoseexploited how parasites manage to cross the barrier to by parasites, but fail to perform the same get inside the brain (e.g., Masocha and Kri- function or even trigger a defensive response stensson 2012; Mogk et al. 2017), the ques- when bound. This is one of the many forms tion of how manipulation from the outside of “molecular deception” that may take place may have contributed to shape the biochem- between parasites and hosts (Massey and ical functions of the barrier has received little Mishra 2018). A well-studied example of decoy if any attention. molecules in humans is carcinoembryonic antigen-related cell adhesion 3 (CEACAM3), Loss of Molecular Entry Points which mimics the cell adhesion molecule and immune inhibitory receptor CEACAM1 To recognize and invade the host cells, (Zimmermann 2019). Several bacterial and many parasites make use of surface mole- fungal pathogens bind CEACAM1 in order cules. In particular, the layer of glycans (poly- to attach to host cells, penetrate them, and/ saccharides) that envelopes cell membranes or modulate innate immune responses. Gran- is a common target for attack (see Gagneux ulocytes express CEACAM3, which has a sim- et al. 2017). Parasites can mimic the com- ilar structure but induces phagocytosis of position of host glycans to escape immune the parasites that bind it. In the resulting detection, synthesize toxins that bind to spe- fi coevolutionary race, CEACAM1 is selected ci c glycans expressed by the host, or exploit to avoid binding to parasites, parasites are glycans as attachment and entry points into fl selected to selectively bind CEACAM1 while the host cells. Con ict with parasites may ex- avoiding CEACAM3, and CEACAM3 is se- plain why glycans tend to evolve rapidly, and — lected to counteract the resulting binding often through loss of function since loss of loss (Zimmermann 2019). Unsurprisingly, a particular glycan may eliminate a point of CEACAM3 is one of the fastest-evolving genes pathogen entry or pathogen action (Springer in the human genome; moreover, CEACAM3 and Gagneux 2013; Schnaar et al. 2014). homologues from various primate species An especially intriguing case is that of N- bind preferentially to host-specific parasites acetylneuraminic acid (Neu5Ac) and N- (Adrian et al. 2019). The case of CEACAM3 glycolylneuraminic acid (Neu5Gc), two sialic illustrates the logic of this countermeasure, acids that cap membrane glycans in verte- and raises the question of whether the sur- brates. Neu5Ac is converted into Neu5Gc by fi face molecules expressed by cells in the CNS aspeci c enzyme, and the two are expressed include decoys specialized against brain-tar- in variable proportions across different spe- geting parasites. A possible example is the cies and tissues. The ability to synthesize neural cell adhesion molecule NCAM-120, Neu5Gc has been lost independently by hu- which may function as a decoy receptor for mans, several other mammals, birds, and the rabies virus (see Hotta et al. 2007). platypuses (Springer and Gagneux 2013; Gag- neux et al. 2017); but even vertebrates that express high levels of Neu5Gc in bodily tis- increase the costs of manipulation sues show extremely low amounts of this mol- ecule in the brain. There is recent evidence Metabolically Costly Signals that suppression of Neu5Gc protects the brain In principle, the most direct way to con- from bacterial toxins that use it as a binding trol the host’s behavior is to hijack signaling site (Naito-Matsui et al. 2017). To my knowl- pathways by directly releasing neuroactive

8073.proof.3d 258 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 259 substances such as neurotransmitters, neuro- signaling pathway—including second mes- modulators, and hormones. In some cases, sengers that transduce and amplify the sig- entire suites of coordinated behaviors can be nals relayed by receptors (Adamo 2013; Heil evoked by raising the levels of key neuro- 2016; Herbison 2017). Indirect forms of transmitters such as serotonin and dopamine, neuropharmacological manipulation are the either in the brain as a whole or in strategi- norm, but there are exceptions: one is the cally picked regions. To counteract this type venom of jewel wasps, which contains sig- of attack, the host can raise the metabolic nificant amounts of dopamine and/or dopa- cost for the parasite, by increasing the amount mine-like substances (Libersat and Gal 2014; of substance required to produce the same Herbison 2017). The exception is telling be- behavioral effect. In principle, this can be cause the size disparity between wasps and achieved by: lowering the concentration of cockroaches is minimal; this makes it meta- receptors; expressing receptors with lower bolically feasible for the wasp to synthesize binding affinity to the signaling molecule; large quantities of neuroactive compounds. altering the signaling pathway downstream It is also relevant that the wasp injects the of receptors to make it less sensitive (that is, venom directly into the cockroach’s brain, requiring the activation of more receptors literally breaking through the BBB and its for the same effect); and metabolizing or chemical defenses. clearing the signaling molecule at a faster Several authors have pointed out that, in rate. Note that—besides their other poten- all likelihood, indirect manipulation strate- tial side effects—these countermeasures are gies have evolved to avoid the cost of syn- also expensive for the host, as they increase thesizing signaling molecules (e.g., Adamo the cost of internal signaling. However, the 2012, 2013; Heil 2016). What has not been host usually enjoys the advantage of a larger discussed is the possibility that the physio- size and higher metabolic capacity, and the logical parameters that determine the cost additional costs may be minimal or even neg- of signaling (e.g., receptor density/sensitiv- ligible from the host’s perspective. If the ity, clearance/breakdown rates, transduction marginal fitness costs of synthesizing larger mechanisms) have themselves evolved so as quantities of neuroactive substances are much topreventmoredirectformsofmanipulation. steeper for the parasite, the host can effec- Since present-day instances of manipulation tively defend itself against direct hijacking. are mostly of the indirect kind, selection to In response to escalating costs, parasites increase the costs of signaling would have have two main options. First, they can infect peaked a long time ago, possibly in the early the host in larger numbers to share the addi- stages of brain evolution. Assuming that cost- tional metabolic costs (Weinersmith et al. increasing countermeasures evolved as hy- 2014; Gopko et al. 2017). Second, they can pothesized here, are they still relevant to evolve indirect manipulation mechanisms understanding brain function in living or- that act upstream or downstream of the ex- ganisms? Paradoxically, if those countermea- pensive signal. And, indeed, this is what hap- sures were so effective that they forced most pens in the majority of known cases. Instead parasites to adopt indirect strategies, they of directly synthesizing neuroactive mole- would have rendered themselves obsolete, cules, parasites tend to upregulate the syn- eventually becoming a net cost without any thesis of endogenous substances by the host; countervailing benefits. If so, they may have an example is toxoplasma, which increases been selected out owing to the relentless pres- the host’s production of dopamine and tes- sure for efficiency (Sterling and Laughlin tosterone. Another strategy is to interfere 2015). This fate is most likely for easily re- with metabolism and clearance mechanisms; versible parameters such as receptor density. for instance, wasp larvae raise octopamine lev- On the other hand, some costly mechanisms els in parasitized caterpillars by secreting that originally evolved as countermeasures substances that retard the breakdown of this may have become so entrenched that they hormone (see Adamo 2012, 2013). Parasites are hard or impossible to eliminate by incre- may also alter the expression of the host’s re- mental changes. At present, these scenarios ceptors, or target downstream nodes in the remain speculative but suggest a novel, in-

8073.proof.3d 259 Achorn International 06/27/19 01:01 260 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 triguing perspective on the economy of neu- gen species (RNS; Guix et al. 2005; Moncada ral and hormonal signaling. and Bolaños 2006; Calabrese et al. 2007). RNS have a range of powerful antimicrobial effects, both alone and in synergy with ROS Toxic Signaling Molecules (Fang 2004; Jones et al. 2010). To compli- Increasing the energetic demands of sig- cate the story, many bacteria synthesize nitric naling is not the only way to impose costs on oxide endogenously as a defense against anti- parasites. An even more direct strategy would biotics. The protective qualities of nitric ox- be to employ toxic molecules as chemical ide—a molecule that “seems to be playing signals. In principle, this countermeasure for both teams” (Patel and Crane 2010: achieves two goals at once: it turns the brain 235)—stem from its ability to directly detox- into an inhospitable environment for manip- ify certain antibiotic compounds,suppress the ulative parasites, and forces them to synthe- ROS-producing reactions that mediate anti- size dangerous substances that may hinder biotic toxicity, and/or activate the expression their survival and reproduction. If the fitness of antioxidant enzymes (Gusarov et al. 2009; costs are sufficiently large, toxic signals can Patel and Crane 2010). work as deterrents against direct hijacking. Of course, the use of dopamine and nitric Among classic neurotransmitters, dopa- oxide as signaling molecules is very ancient, mine is the most likely candidate as a toxic and the same applies to its possible history signal. Dopamine molecules are unstable and as a host countermeasure. Still, it is notewor- tend to oxidate spontaneously, yielding highly thy that so many of the behaviors that para- reactive quinones that can damage proteins, sites attempt to manipulate are mediated DNA, and other macromolecules. Moreover, or regulated by these molecules (see Adamo dopamine metabolism produces reactive ox- 2013; Perrot-Minnot and Cézilly 2013; Mehl- ygen species (ROS) and induces oxidative horn 2015b). The synthesis of dopamine in stress in dopaminergic neurons (Stokes et al. the brain is highly localized, which may 1999). In total, synthesizing and storing do- contribute to make this neurotransmitter a pamine is hazardous, but even breaking it promising manipulation target. At the same down involves a potential risk of damage. In- time, the restricted distribution of dopami- deed, some species of green algae exploit the nergic neurons may itself be linked to the toxicity of dopamine to repel marine herbi- toxicity of dopamine. There is evidence that vores and avoid being eaten by them (Van several enzymes involved in the synthesis and Alstyne et al. 2006). Serotonin is often used metabolism of dopamine, nitric oxide, and by yeast and bacteria as a communication other neurotransmitters in animals originate and synchronization signal, but only a few from bacteria, and were acquired through species of microbes (including some gut sym- horizontal gene transfer (Iyer et al. 2004). bionts) have the ability to synthesize or me- Animals have a long history of co-opting tabolize dopamine (Roshchina 2010). microbes (and/or their genes) to combat Nitric oxide is a versatile molecule with other microbial species (see Thompson multiple physiological roles, including im- 2013:Chapters 5–6). It would be interesting munity(particularlyinflammation)andvaso- to know if the original functions of dopa- dilation. It is employed as a neuromodulator mine in bacteria included chemical defense in the CNS, where it contributes to regulate and/or offense against other microbes. neural plasticity, sleep, feeding, thermoreg- The scope for toxic signals becomes even ulation, and reproduction (Calabrese et al. broader if one considers the rich variety of 2007; Garthwaite 2008). A chemically unsta- modulatory peptides. Many neuropeptides ble free radical, nitric oxide has the potential with modulatory and endocrine functions to cause molecular damage and interfere have a chemical structure very similar to that with cellular respiration. Unsurprisingly, it of antimicrobial peptides involved in im- has antimicrobial properties; and in the pres- mune defense (Brogden et al. 2005). More ence of ROS, it forms a number of highly directly, there is experimental evidence that toxic compounds, including reactive nitro- several neuropeptides that are also involved

8073.proof.3d 260 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 261 in immunity—including substance P, neu- same logic applies to neural transmission ropeptide Y, and neurokinin A—have anti- and hormonal pathways. microbial properties against bacteria, yeast, Withtheevolution ofcomplexcodes,basic and protozoa (El Karim et al. 2008; Augus- neuropharmacological manipulations that tyniak et al. 2012). The standard interpreta- increase or decrease the concentration of a tion of these findings is that, on top of their single neuroactive molecule should become signaling functions, neuropeptides contrib- ineffective. Injecting serotonin in gammarid ute to protect the brain from pathogens crustaceans is sufficient to reproduce the full (e.g., El Karim et al. 2008). The complemen- syndrome caused by helminth infection (Per- tary hypothesis I am suggesting is that these rot-Minnot et al. 2014); but increasing the peptides may have been adopted as signal- availability of dopamine in the brain of ro- ing molecules in the CNS precisely because of dents fails to evoke the “feline attraction” in- their antimicrobial effects, as a countermea- duced by toxoplasma—if anything, it seems sure against neuropharmacological hijack- to prompt avoidance behaviors rather than ing by parasites. This possibility is broadly approach (Eskow Jaunarajs et al. 2011; see consistent with phylogenetic analyses sug- Adamo 2012, 2013). Even though toxoplas- gesting that, across mammalian evolution, ma’s mechanism of action is still incompletely molecules with immune-specific functions understood, it is obviously more complex than have been gradually recruited for expression simply boosting dopaminergic transmission in the nervous system (Castillo-Morales et al. in the host. For example, this parasite may 2014). relyonthejoint actionof dopamineandother molecules (such as testosterone and vaso- pressin) and/or the patterned release of do- increase the complexity of signals pamine-increasing enzymes. From a computational perspective, neuro- Naturally, complexity does not come for active substances function as internal signals free. To begin, the host faces the metabolic that transmit information between neurons, expense of producing the signal and main- between different networks within the brain, taining the additional biochemical machin- and between the brain and other organs and ery, such as receptors and enzymes. As noted tissues. Parasites can hijack a signaling path- earlier, metabolic costs are likely to be dis- way by producing new signals or corrupting proportionately more severe for parasites, existing ones; in either case, they need to which tend to be much smaller than their “break” the code employed by the host. The hosts and have vastly lower energetic re- same applies to parasites that eavesdrop on sources (see Lafferty and Kuris 2002). Even the host’s chemical signals. Since complex more importantly, increasing the complex- communication codes are harder to mimic ity of a system to prevent a certain type of and subvert, the host can increase the perturbation tends to create new points of complexity of signals as a countermeasure fragility. For example, each additional com- against manipulation—a strategy that has ponent (e.g., a receptor or neuromodulator) been termed defensive complexity by Chastain creates new opportunities for failure and et al. (2012). Using evolutionary modeling malfunction, and opens up new windows of these authors showed that, as internal signals vulnerability (e.g., deleterious mutations, in- become more elaborate, the time required to terference with other pathways). Potentially break the code and evolve effective manipu- complex interactions among multiple com- lation strategies tends to increase steeply— ponents can amplify local failures into cata- in certain cases, exponentially so. This means strophic events; and although the system may that the host can potentially gain the upper be rendered more secure against direct hi- hand in the conflict, forcing the parasite to jacking, it may also become more vulnerable resort to other means of manipulation. Al- to other forms of attack (e.g., genomic ma- though Chastain et al. (2012) developed nipulation). Such robustness-fragility tradeoffs their model to explain the evolution of sig- are pervasive in biological systems, and tend naling within the immune system, the exact to drive up the complexity of organisms over

8073.proof.3d 261 Achorn International 06/27/19 01:01 262 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 evolutionary time (Kitano 2004, 2007; Alder- as cannabinoids and substance P (Gutiér- son and Doyle 2010; see Del Giudice and rez 2009; Hökfelt 2009; Trudeau et al. 2009; Crespi 2018). Tritsch et al. 2016). Since different mole- cules have different timescales of action, co- transmission can be employed to regulate fi Diversi cation, Co-transmission, neural activity (and behavior) in remarkably and Convergent Signaling sophisticated ways. For example, the fast excit- One way to increase the complexity of atory action of glutamate may support short- chemical signaling is to expand the set of term learning, whereas the slow inhibitory molecules used for transmission and the re- action of serotonin may sustain motivation ceptors that bind to those molecules. The over the long term (Fischer et al. 2015). In variety ofneuromodulators inanimals is stag- the roundworm Caenorhabditis elegans, glu- gering; most notably, there are more than tamate promotes food search, while the co- 100 distinct neuropeptides and several hun- released peptide NLP-1 initiates a negative dred neuropeptide receptors (Hökfelt 2009; feedback response that eventually terminates Jékely et al. 2018). Even simple physiologi- the foraging behavior (Nusbaum et al. 2017). cal mechanisms may be modulated by doz- The possible functions of co-transmission ens of molecules, with partially overlapping include more accurate modulation of the functions and the potential for complex in- postsynaptic response; more precise timing teractions. A classic example is the pyloric of action; increased flexibility through state- component of the crustacean stomatogastric dependent patterns with opposite or com- system, which is regulated by over 30 neuro- plementary effects; and the opportunity for modulators despite its apparently straightfor- a neuron to target different signals to differ- ward pumping/filtering function (Selverston ent neurons within a complex circuit (see 2007; see also Nusbaum et al. 2017). This Tritsch et al. 2016; Nusbaum et al. 2017). abundanceofsignalsmayproviderobustness However, it is also the case that combined through redundancy, or allow for precise signals are harder to mimic, making the sys- fine-tuning of the control system; the possi- tem less vulnerable to hijacking. There are bility that it partly reflects defensive complex- well-studied cases in which the combined ac- ity against parasites has yet to be explored. tion of two or more molecules is required to Footprints of defensive complexity might fully express a particular behavior: for ex- also be found in the evolution of receptors ample, egg laying in C. elegans is jointly con- for neurotransmitters and neuropeptides, trolled by serotonin and the neuropeptide which have an intricate phylogenetic history NLP-3 (Brewer et al. 2018). To take control of duplication, diversification, convergence, of egg laying, a hypothetical parasite would and loss of function (see Yamamoto and Ver- have to secrete the correct combination of nier 2011; Katz and Lillvis 2014). molecules, possibly in a specific concentra- The availability of multiple neuromodu- tion and temporal pattern. In the sea slug lators makes it possible to increase complex- Aplysia, the cholinergic neurons that control ity by signaling with combinations of molecules. feedingco-releasetwodifferentpeptideswith This principle is well illustrated by co-transmis- synergistic effects (Jékely et al. 2018). More sion (or co-release), whereby a single neuron re- generally, convergent signaling is a common leases more than one neuroactive molecule. feature of neuropeptides. Particularly in ar- Far from being a rarity, co-transmission has eas of the brain that control major hormonal turned out to be widespread in nervous sys- systems, the same neuron receives input from tems (Gutiérrez 2009; Nusbaum et al. 2017). multiple peptides that modulate the effect of Most commonly, monoaminergic neurons one another: as a result, the signal is not en- (which release dopamine, serotonin, epineph- coded by individual peptides but by their rine, or norepinephrine) also release excit- specific combination (Jékely et al. 2018). Al- atory/inhibitory neurotransmitters (glutamate, though this strategy permits high levels of GABA) or modulatory neuropeptides such flexibility and context-dependence, it may

8073.proof.3d 262 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 263 also contribute to protect key signaling path- systematically, both across related species and ways from manipulative parasites. across an individual’s life stages (see Crock- ford 2003 for a detailed review of variation in thyroid hormones). Pulsatile Signaling What is the functional rationale of pul- A striking feature of many hormones and satile signaling? Researchers have pointed neuromodulators is that they are not secreted out that the discrete format of pulses may continuously, but in timed pulses. Different make them more resistant to noise, as com- molecules have different secretion periods, pared with graded concentration changes. ranging from minutes (e.g., insulin, oxytocin) Moreover, pulsed signals can encode more to hours (e.g., melatonin, anterior pituitary information by exploiting both frequency hormones, gonadal and adrenal steroids; (timing of pulses) and amplitude modula- Veldhuisetal.2008).Thefeedbackloopsthat tion (amount released per pulse). Some mod- give rise to pulsatile secretion can be rather els also suggest that pulsatile secretion can complex, and may be regulated by multiple also be more energy efficient than continu- excitatory and inhibitory mechanisms that ous release (Walker et al. 2010; Faghih et al. integrate inputs from the same cell, other 2015). In summary, pulsatile signaling has cells, and other organs through hormone re- no shortage of potential advantages. An ad- ceptors (see Veldhuis et al. 2008; Lightman ditional possibility that has been overlooked and Conway-Campbell 2010; Leng 2018). so far is that pulsed signals—whatever their Crucially, it is often the case that brief pulses original function—may have become wide- produce stronger physiological and behav- spread in internal communications because ioral effects than exposure to constantly ele- they are an effective countermeasure against vated levels of the same signaling molecule. hijacking by parasites. To begin, releasing a For example, estrogen administration to fe- pulse of a neuroactive substance demands a male rats requires about 48 hours to produce concentrated metabolic effort over a brief the maximal behavioral response, but two brief period of time (regardless of the long-term estrogen pulses a few hours apart are just as energeticefficiency of thesystem). Even more effective as 24 hours of hormonal priming importantly, microbes would have to syn- (see Pfaff et al. 2004). In many instances, chronize their activity in time—which would constant elevation does not just fail to elicit a require additional computational and meta- strong response but leads to inhibition or de- bolic resources—and do so with the correct sensitization. For example, steady-state levels frequency: pulses that are too slow or too of gonadotropin releasing hormone (GnRH) fast would fail to elicit a strong response, or suppress the hypothalamic-pituitary-gonadal may even bring about the opposite effect. Al- axis instead of stimulating it (Pfaff et al. though pulsatile codes are not impossible to 2004). break, from the standpoint of manipulative The decoding of pulsatile patterns takes parasites they are significantly more challeng- place in receiving cells, from the activation ing than their analog counterparts. of receptors to the regulation of gene expres- sion. These processes may be “tuned” to a spe- cific frequency so that both slower and faster Individualized Signatures pulses fail to produce the maximal response Defensive complexity works by slowing (Lightman and Conway-Campbell 2010); or down the evolution of effective manipula- may exhibit different responses to different tive signals in the parasite population. Like- frequencies (for example, slower GnRH wise, the evolution of manipulation would pulses favor secretion of follicle-stimulating be hampered if each individual host used a hormone in the pituitary, whereas faster somewhat different version of the same basic pulses favor luteinizing hormone; see Leng molecular code—for example, variations in 2018). Interestingly, frequency and ampli- the combination of neuromodulators and/ tude patterns for the same molecule may vary or receptors, or in the optimal frequency

8073.proof.3d 263 Achorn International 06/27/19 01:01 264 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 of pulsatile signals. Selection for counter- ent combinations of receptors, and so on measures can be expected to favor a certain (Anderson et al. 2016; Leng 2018). It is easy amount of stochastic variation in the pa- to see how selection for countermeasures rameters of neural and hormonal signaling, may lead to release or even amplify existing leading to the development of individual- sources of stochastic variation, instead of ized “signatures.” In principle, microbes can buffering or correcting them through cana- evolve within a host and converge on its indi- lization processes (see Debat and David vidual code thanks to their short generation 2001; Dworkin 2005; Hiesinger and Hassan time (Spottiswoode and Busch 2019); how- 2018). At the same time, genetic and devel- ever, the distinctive features of behavioral opmental noise are often deleterious, and manipulation dramatically reduce the effec- the potential benefits of decanalization must tiveness of this process. In many common be weighed against the inevitable costs (in- scenarios (including trophic transmission and cluding loss of robustness in molecular path- bodyguard manipulations), the manipula- ways; see Salathé and Soyer 2008). One tion strategy undergoes one selective event shouldnotethatadaptivestochasticvariation per individual host (e.g., successful versus expressed as a countermeasure to parasites unsuccessful predation), irrespective of the should look very similar to nonadaptive var- parasite’s replication rate prior to the event. iation due to imperfect buffering and can- Other types of transmission (e.g., sexual trans- alization; thus, devising empirical tests of mission) allow for multiple selection events this hypothesis is going to be particularly within the same individual host (e.g., one challenging. per copulation); but as the parasite becomes more adapted to the unique physiology of the current host, it inevitably becomes less increase robustness adapted to that of the next (a partial excep- Despitemultiplelayersofpreventivecoun- tion would apply to parasites that are prefer- termeasures, a parasite may still be able to entially transmitted between relatives). gain access to the brain, break the signaling This hypothesis is clearly speculative but code (or bypass signaling through genomic not implausible; it is consistent with the idea or immunological means), and carry out a that biological systems employ randomness manipulative attack. The host’s problem is as a cryptographic device in order to pro- now one of damage control: the goal is to tect information flows from detection and maintain the functionality of behavior in the exploitation (Krakauer 2017). The use of face of the parasite’s attack (Salathé and stochastic signatures for self/nonself rec- Soyer 2008; Foster 2011). In this section I dis- ognition has been documented in various cuss some potential strategies that the host biological systems under selection by para- can use to increase the brain’s ability to with- sites, including the major histocompatibility stand perturbations—that is, its robustness (see complex (MHC) in the vertebrate immune Kitano 2004; Krakauer 2006; Alderson and system, polymorphic egg markings in birds Doyle 2010; Flack et al. 2012). For conve- targeted by brood parasites, and olfactory nience, I distinguish between passive strategies signatures against social parasites in insect that make the brain’s architecture intrinsi- colonies (Summers et al. 2003; Spottiswoode cally resistant to manipulation and damage; and Busch 2019). reactive strategies that actively respond to The complexity of signaling pathways pro- manipulation attempts; and proactive strate- vides abundant opportunities for stochastic gies that are deployed before manipulation deviations, including genetic and epigenetic occurs. Some of the mechanisms I review mutations as well as developmental noise. are nonspecific: although they can function In fact, even individual neurons that secrete as countermeasures to manipulation, they the samemolecule (e.g.,oxytocin) within the also protect the brain against other sources brain of a single individual are not com- of damage, malfunction, and noise—for ex- pletely alike—each shows a slightly different ample, nonmanipulative pathogens, strokes, pattern of activity, expresses slightly differ- seizures, and chemical imbalances caused

8073.proof.3d 264 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 265 by any number of internal or external fac- that the system as a whole maintains a degree tors (including deleterious mutations). Pin- of functionality even if one of the compo- pointing the role of parasites in the evolution nents fails. On the other hand, if a specialized of those mechanisms is not going to be an module fails the organism may completely easy task. More intriguingly, a manipula- lose the ability to perform the corresponding tion perspective suggests that the brain may function—another example of robustness- contain as yet undiscovered robustness mech- fragility tradeoffs (see above; Kitano 2007). anisms that are specifically targeted to para- The fact that most parasites show little or no site intrusions. anatomical specificity when they attack the brain (Adamo 2012, 2013) might be viewed as a response to the modularity and redun- Passive Robustness dancy of behavioral processes. The architecture of a system is an impor- Although redundancy and modularity in- tant factor in its ability to withstand pertur- crease a system’s robustness, they also make bations. Redundancy and modularity are two it harder to coordinate the activity of multi- common properties of biological systems ple components with rapidity and efficiency. that contribute to increase their robustness For example, if different aspects of behavior (see Kitano 2004; Krakauer 2006; Alderson (e.g., foraging, mating, and predator avoid- and Doyle 2010; Flack et al. 2012). When ance) were controlled by modularized bio- multiple components perform identical or chemical pathways with limited crosstalk, overlapping tasks, the system becomes more parasites would need to separately hijack each resistant to damage and failure. For exam- of the pathways in order to manipulate the ple, heat avoidance (negative thermotaxis) host’s behavior. However, behavioral coordi- in C. elegans is controlled by three distinct nation would also become significantly more types of thermosensory neurons, which re- difficult for the host. A common design solu- spond in different combinations to different tion to balance robustness and controllabil- environmental conditions. This functional ity is the “bow-tie” architecture, in which overlap allows C. elegans to successfully avoid multiple, partially modularized pathways con- heat damage even following the loss of one verge on a small hub of shared processes that neuron type (Beverly et al. 2011). In the ver- link their inputs and outputs (Csete and tebrate hypothalamic-pituitary-gonadal axis, Doyle 2004; Kitano 2004). Individual path- the release of follicle-stimulating hormone ways can evolve and function in relative inde- is initiated by GnRH but regulated by sev- pendence from one another, but the shared eral peptides that have both stimulatory and core—the “knot” of the bow tie—permits inhibitory effects (Leng 2018). As noted ear- rapid and efficient control of the system as a lier, robustness through partial redundancy whole. The concept of bow-tie architectures is a plausible benefit of complex neuropep- has been applied to the organization of cell tide signaling, in which multiple neuromodu- signaling, metabolism, and immunity (Csete lators converge on the same neuron (Jékely and Doyle 2004; Kitano 2004; Kitano and et al. 2018). Mathematical models show that Oda 2006). Bow-tie architectures are not when signaling networks evolve under threat immune from robustness-fragility tradeoffs: of interference by parasites they tend to be- while the knot confers robustness on the sys- come more redundant; at the same time, par- tem, it also becomes a vulnerable target. asites select for robust connection patterns Thus, parasites can be expected to concen- that can withstand the loss of any individual trate their manipulation attempts on core molecule (Salathé and Soyer 2008). biochemicalprocessesthatregulatemultiple Modularity can also promote robustness pathways at once (Kitano and Oda 2006). by decoupling the functions of different And, indeed, parasites tend to target neuro- components (functional modularity) and/or transmitters such as dopamine and seroto- separating them in space (anatomical modu- nin, ubiquitous second messengers like cyclic larity). In modular systems, the effect of per- adenosine monophosphate (cAMP), or key turbations can be contained and isolated, so transcription factors such as NF-jBand

8073.proof.3d 265 Achorn International 06/27/19 01:01 266 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 c-Myc (Adamo 2013; Perrot-Minnot et al. and respond in flexible, strategic ways (see 2014; Cheeseman and Weitzman 2015; Her- Weinersmith and Earley 2016; Massey and bison 2017). Mishra 2018). The first question to ask is: How can the brain detect a manipulation attempt? When parasites hijack a signaling Reactive Robustness pathway and significantly alter its activity, Negative feedback is arguably the most ba- they should typically induce a compensatory sic form of reactive robustness (Kitano 2004; response in the feedback mechanisms that Krakauer 2006; Alderson and Doyle 2010; stabilize the pathway (unless they also man- Khammash 2016). Feedback-regulated sys- age to disrupt the feedback channels; see tems are homeostatic: perturbations that above). If this is the case, unusual activation move the system away from the set point are patterns of neural and endocrine feedback detected and corrected with adjustments in mechanisms (e.g., atypically large or sudden the opposite direction, potentially very rap- responses) may be interpreted as potential idly if the feedback loop has high “gain” cues of ongoing manipulation. Other detec- (that is, if deviations from the set point elicit tion mechanisms may be subtler and more a strong compensatory response; see Bech- attuned to indirect forms of manipulation— hoefer 2005; Frank 2018). Negative feedback for example, intracellular probes may moni- is a general strategy for robustness, and a tor key second messengers and transcription pervasive feature of neural and endocrine factors for anomalous changes in their activ- systems at all levels of analysis (e.g., Pfaff et al. ity, or sense the presence of specific mole- 2004; Davis 2006; Del Giudice et al. 2018; cules produced by the parasite. Leng 2018). Even the BBB may contribute Once a potential manipulation attempt to the feedback regulation of brain neuro- has been detected, various adaptive responses chemistry by modulating the efflux of neuro- are possible. A straightforward option is to transmitters such as dopamine, serotonin, directly counteract the biochemical mecha- and GABA (see above). From the host’s per- nisms employed by parasites. For example, spective, signaling pathways can be made the expression of noncoding RNAs in host more resistant to neuropharmacological ma- cells responds to cues of infection and in- nipulation through stiffer feedback regula- flammation, and contributes to regulate mul- tion. The price to pay is loss of flexibility: as tiple immune-related genes. Intriguingly, the system becomes more effective in block- noncoding RNA expression partly depends ing external interferences, it also becomes on the specific pathogen infecting the host slower and less adaptable (Bechhoefer 2005). (Duval et al. 2017; zur Bruegge et al. 2017). In addition, higher feedback gain makes the Unsurprisingly, host RNAs are themselves system more robust against slow perturba- targeted by parasites because of their immu- tions but increasingly unstable against rapid noregulatory activity (Duval et al. 2017; zur fluctuations—a point of fragility that can be Bruegge et al.2017). Some of these RNA mol- exploited by parasites to affect the host’s be- ecules may interfere with the messenger and havior (Csete and Doyle 2002; Kitano 2007). noncoding RNAs injected by the parasite, More generally, feedback-regulated systems initiate epigenetic changes that counteract are particularly vulnerable to noise coming their activity, or even regulate the expres- from sensors (Bechhoefer 2005); thus, para- sion of the parasite’s own genes. The fact sites may attempt to disrupt homeostasis by that some noncoding RNAs in the host are targeting the receptors and cellular path- strongly induced by parasite-derived mole- ways that receive and relay feedback signals. cules is usually interpreted as evidence of Negative feedback is a basic building block parasite manipulation (for a recent exam- of robust systems; it is also a general purpose ple involving toxoplasma see Menard et al. strategy with little functional specificity. More 2018). However, it is also possible that cer- sophisticated forms of reactive robustness can tain host RNAs function as components of be implemented by specialized mechanisms molecular mechanisms that detect and adap- designed to detect manipulation attempts tively respond to manipulative attacks. In

8073.proof.3d 266 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 267 mammals, a large fraction of noncoding RNA Proactive Robustness is specifically expressed in brain cells, and our understanding of its many functions is By definition, reactive mechanisms wait still very patchy (Briggs et al. 2015). Some for evidence that a manipulation attempt brain-expressed RNAs may contribute to re- may be taking place. The logic of proactive active robustness against behavior-altering robustness is to anticipate the parasite and parasites, as either “sensors” or interference deploy countermeasures even before manip- mechanisms. ulation occurs. Proactive processes may op- On a more macroscopic level, the host erate on different time scales. In the short may adjust the parameters of feedback mech- term, the brain may use nonspecific cues of anisms (e.g., increase feedback gain, lower immune activity (e.g., inflammatory cyto- the set point) to constrain the response of kines) as a warning sign that a parasite is signaling pathways that might have been hi- invading the body, and respond with preven- jacked, thus dampening the effects of the tive measures to make manipulation more parasite’s manipulative effort. If signals are difficult. Information about the activity of the carried by partially redundant pathways, the immune system reaches the brain through brain may respond by silencing or attenuat- multiple routes: both cytokines and leuko- ing the suspicious pathway—effectively switch- cytes can cross the BBB, and inflammatory ing its internal communications to safer and signals are relayed by the vagus nerve and plausibly intact channels. These countermea- other afferent neural pathways (Quan and sures do not need to be centrally coordinated Banks 2007; Capuron and Miller 2011). It and may be implemented via self-organizing is well established that inflammation modu- processes (e.g., signaling pathways may auto- lates brain neurochemistry; specifically, in- matically readjust or temporarily “shut off” flammatory signals induce substantial changes if their activity patterns become consistent in the activity of major signaling pathways, with a hijacking attempt). Such active coun- including the synthesis and metabolism of termeasures would have costs and undesir- serotonin and dopamine (e.g., Capuron and able side effects; in particular, any defensive Miller 2011; Baganz and Blakely 2013). On shift toward tighter regulation and lower the standard view, these neurobiological re- redundancy of signals can be expected to sponses bring about sickness behavior—leth- compromise the flexibility of the organism’s argy, loss of appetite, sleepiness, and so on behavior. Moreover, manipulation detection (McCusker and Kelley 2013). It is also possi- mechanisms are costly and can themselves ble that one of their functions is to prevent become targets of parasite attacks, thus intro- manipulation, for instance, by tightening the ducing new points of fragility into the system. feedback regulation of key pathways or re- The brain’s reactive robustness may con- ducing the activity of vulnerable mechanisms. tribute to explain why, at least in some in- Intriguingly, even some aspects of sickness stances, it has proven difficult to reproduce behavior might be interpreted as proactive the behaviors induced by parasites by simply countermeasures: to give just one example, altering the level of key signaling molecules. lethargy may thwart behavioral manipulations Some apparently “paradoxical” effects—e.g., designed to transport the parasite to a differ- increasingdopaminemakesratsmorefearful ent habitat. The activation of decoy receptors rather than less—are consistent with the exis- and the expression of noncoding RNAs can tence of compensatory mechanisms that get also be used as warning cues of impending triggered by sudden, anomalous changes in manipulation attempts. In some cases, these brain biochemistry. What I am suggesting is mechanisms can be so specific that they per- that those mechanisms may be more than mit accurate recognition of the invading par- general purpose homeostatic devices (e.g., asite, allowing the host to deploy a tailored Adamo 2013); instead, some of their features response. may be specifically designed to detect and re- On a longer time scale, recurrent infec- spond to parasite intrusions (for a similar ar- tions by the same parasite over evolutionary gument see Weinersmith and Earley 2016). time may lead organisms to preemptively

8073.proof.3d 267 Achorn International 06/27/19 01:01 268 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 compensate for the manipulative effects of (which are also energetically expensive; see that parasite. To illustrate, consider a hypo- Sterling and Laughlin 2015; Faisal and Neis- thetical animal targeted by a serotonin- habouri 2017). It follows that animals with increasing parasite. If infection is so com- smaller metabolic budgets should be more mon and predictable that it can be treated limited in their ability to evolve effective de- as an expected feature of the environment, fenses against parasites. But energy avail- the host may evolve lower levels of serotonin ability is not the only factor in play. A small as a proactive countermeasure (in turn, this body size means that the maximum size of would select for stronger manipulation by the brain is also severely limited; the problem the parasite, setting the stage for reciprocal is exacerbated in animals that fly or jump escalation). A downside of preemptive strat- and thus need to minimize total body weight. egies is evolved dependence (de Mazancourt In turn, miniaturized nervous systems face et al. 2005): if brain physiology and behavior tremendous computational constraints (Ni- are designed to function optimally when the ven and Ferris 2012). Smaller neurons gen- parasite is present, the absence of the parasite erate more spontaneous noise, and cannot will lead to inappropriate or fitness-reducing host enough mitochondria to sustain high behaviors (Weinersmith and Earley 2016; see firing frequencies. Smaller axons transmit also Johnson and Foster 2018). When a para- information more slowly and less accurately; site is common but the frequency and inten- at the same time, error correction strategies sity of infection varies across generations, are hard to implement because they require the host species should not evolve fixed phys- higher energetic expenditures and/or more iological adjustments, but plastic responses complex neural circuits (Niven and Ferris triggered by cues of infection. Weinersmith 2012; Zylberberg et al. 2016; Faisal and and Earley (2016) provide a detailed discus- Neishabouri 2017). Body temperature is an- sion of these and other scenarios. other relevant factor. Somewhat counter- intuitively, the noise introduced by random action potentials increases at lower temper- Constraints on the Evolution atures; as a consequence, cold-blooded ani- of Countermeasures mals cannot afford to reduce the size of axons At various points in the preceding sections, as much as warm-blooded animals can (Fai- I have noted that the evolution of manipula- sal and Neishabouri 2017). tion strategies is constrained by their meta- It follows that the brains of small, cold- bolic and computational costs (see Adamo blooded animals must rely on relatively sim- 2013; Herbison 2017). In fact, I have argued ple computations, and may not be able to that hosts may increase the costs of neural afford sophisticated countermeasures to ma- and hormonal signaling precisely as a strat- nipulation. For example, insect brains em- egy against parasite manipulation. I now look ploy many computation-saving shortcuts for at the other side of the coin, and consider perception and decision-making, and use a how the same factors constrain the evolution small number of “command” neurons to con- of effective countermeasures by the hosts. I trol complex behavioral patterns (Sterling then discuss the lack of documented exam- and Laughlin 2015). In contrast, animals ples of adaptive behavior manipulation in with larger (and warmer) brains can evolve our own species. multiple layers of protection and consider- able amounts of redundancy. This plausibly contributes to explain why the most striking metabolic and computational instances of complex behavioral manipula- constraints tion involve insects (e.g., ants), small crusta- Most of the countermeasures examined in ceans (e.g., gammarids), and mollusks (e.g., this paper require the host to invest in higher snails). The same considerations may explain metabolic expenditures, additional neural why direct manipulation of neurotransmit- machinery (which is costly to build and main- ter levels can have such divergent outcomes tain), and/or more complex computations in different species. Injecting serotonin in

8073.proof.3d 268 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 269 gammarids successfully mimics the effects of of individual immunity only increase the sur- helminth infection (for this and other ex- vival of a single organism, and may be se- amples see Perrot-Minnot and Cézilly 2013); lected against if their cost detracts from but raising dopamine in rats fails to repro- investment in group-beneficial adaptations duce the symptoms of toxoplasma, and in (Cotter and Kilner 2010). A similar tradeoff fact seems to favor the opposite behaviors may exist in the evolution of countermea- (see Adamo 2013). sures to manipulation. Consider a trophic Although parasites can evolve subtler and parasite that is relatively rare, kills the in- more indirect means of manipulation, their fected individual through predation, but is computational capabilities are ultimately lim- notdirectlytransmittedtoothercolonymem- ited by their size. As the size and complexity bers. In this case, the benefits of expensive of the host’s brain increase relative to the par- countermeasures would mainly accrue to asite, the disparity may become so extreme the individual, with relatively little impact that the host is able to “outcompute” its ad- on the colony. All else being equal, the scope versary, making complex manipulations ef- for the evolution of countermeasures against fectively impossible. The parasite may still be the parasite should be more constrained if able to alter the host’s behavior in nonspe- the host is eusocial (Hughes 2012). In prin- cific ways (e.g., sickness, brain damage), but ciple, this hypothesis can be tested empiri- is unable to induce the kind of coordinated cally by comparing patterns of manipulation pattern required for trophic transmission or and countermeasures among related species bodyguard manipulation. Although this ar- with different social systems. Even in noneu- gument is admittedly speculative, it is consis- social animals, the costs and benefits of indi- tent with the fact that complex behavioral vidual defense may vary depending on the manipulations have not been documented life history of a species and the sex and life in larger, warm-blooded animals (see Laf- stage of a particular individual (see Cotter ferty and Kuris 2002). and Kilner 2010).

other constraints behavioral manipulation in humans Besides energetic and computational re- With their large, complex, and energeti- sources, many other factors can constrain the cally expensive brains, humans seem unlikely evolution of host countermeasures. Generally targets for adaptive behavioral manipula- speaking, selection for enhanced protection tions. Moreover, our extended life history will not occur if infection is sufficiently rare and prolonged investment in brain develop- (e.g., the parasite is uncommon), the cost ment (Kaplan et al. 2007) suggests that we of manipulation is sufficiently low (e.g., the should invest in mechanisms that protect host dies only after reproduction), and/or our hard-won “neural capital” from deterio- the cost of effective countermeasures is suf- ration and external attacks. Modern humans ficiently high. In turn, the balance between have few predators and very low predation costs and benefits depends on the specific rates, making trophic transmission an un- outcomes of manipulation and the host’s workable option. On the other hand, preda- ecology and life history. tion—for example, by felines such as leopards An interesting example in this regard is and tigers, raptors such as hawks and eagles, provided by eusocial species (including many or reptiles such as snakes and crocodiles— species of ants, bees, and wasps), which are has been a significant pressure throughout characterized by group living in colonies and primate evolution (Hart 2007). Indeed, there reproductive division of labor. In eusocial is evidence that our hominid ancestors were species, nonreproductive individuals are rel- prey as much as predators; even present-day atively expendable, and there are strong se- hunter-gatherers are not immune from the lective pressures to protect other members risk of being killed and eaten by snakes of the colony from parasite infections (social (e.g., pythons) and other large animals (see immunity; see Meunier 2015). Mechanisms Hart and Sussman 2009; Headland and

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Greene 2011). Although our long life span sion from an individual to another. In light may diminish the potential benefits of tro- of our intense sociality and flexible mating phic strategies (Lafferty and Kuris 2002), it patterns, social and sexual behaviors are the is possible that our brains (and some of our most likely candidates for adaptive manipu- present-day parasites) carry the traces of a lation. Several authors have speculated that past in which transmission through preda- sexually transmitted pathogens may influ- tion was a reality (Libersat et al. 2018). An ence a person’s sexual attractiveness and/or intriguing study by Poirotte et al. (2016) sug- behavior so as to maximize their transmis- gested that toxoplasma-infected chimpanzees sion, for example, by increasing sexual desire develop attraction to leopard urine; however, or inducing behaviors that favor promiscu- this finding is based on a very small sample ous mating (Cochran et al. 2000; Nesse and and must be regarded as anecdotal until Foxman 2011; Heil 2016; Miller and Fleisch- replicated. man 2016; Sarafin et al. 2018). This hypoth- Alternatively, we could be susceptible to esis is fascinating, but has yet to be tested manipulation as an incidental byproduct, if empirically. As noted earlier, arguments for parasites adapted to trophic transmission in adaptive manipulation by gut microbes in other animals happened to have similar ef- our species (e.g., Alcock et al. 2014) are still fects on our brain mechanisms. In line with largely speculative; if supported, they will this scenario, some researchers have found indicate another plausible source of manip- evidence that toxoplasma infection in hu- ulative pressures. At present, the best-docu- mans leads to permanent alterations in mented behavioral syndrome in humans is personality and behavior—for example, in- the one induced by the rabies virus. The creased risk-taking, impulsivity, and extraver- symptoms of “furious rabies”—hydropho- sion; reduced cognitive concentration and bia, extreme salivation, exaggerated reactiv- novelty seeking; and higher suspiciousness ity to stimuli, agitation—are similar to those in males, but lower suspiciousness in females observed in other infected animals (Susilawa- (reviewed in Flegr 2013). Unfortunately, re- thi et al. 2012). However, human-to-human search on this topic tends to suffer from transmission is exceedingly rare (Hanlon and methodological limitations, including un- Childs 2013), suggesting that the symptoms constrained multiple testing (with the pos- of rabies in our species are more likely to sibility of cherry-picking) and inconsistent be nonadaptive byproducts. There are many measures across studies (see Martinez et al. other parasites that affect human behavior, 2018). More recently, some large-sample including poliovirus (the agent of poliomy- studies have yielded interesting if somewhat elitis) and the sleeping sickness protozoan scattered findings, namely increased risk of T. brucei. However, so far there is no evidence self-harm in women (Pedersen et al. 2012); that the behavioral effects of these pathogens higher scores on some aggression and im- represent adaptive manipulations (for a ten- pulsivity measures, with possible differences tative argument about the possible parasite by sex (Cook et al. 2015); no effects on per- benefits of hypersomnia see Lundkvist et al. sonality, but lower performance on some 2004). cognitive measures (Sugden et al. 2016); In total, it is fair to conclude that—if one and higher levels of entrepreneurial behav- excludes simple symptoms such as coughing iors (an indirect manifestation of risk-taking; and scratching—there are no established ex- Johnson et al. 2018). Taken at face value, amples of adaptive behavioral manipulation these data are consistent with the idea that in humans. This can be partly explained by toxoplasma alters human neurobiology as a our (current) place in the food chain and byproduct of manipulation in other species, long life span. Another possibility is that our causing subtle behavioral changes but no brain is so large, complex, and secured by dramatic modifications of personality. multiple layers of countermeasures that it ex- Even if humans are not a vehicle for tro- ceeds the capabilities of parasites. The main phic transmission, parasites may attempt to piece of evidence against this hypothesis is control behavior to facilitate direct transmis- the ability of the rabies virus to induce a co-

8073.proof.3d 270 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 271 ordinated (if nonadaptive) behavioral syn- manifestations of cognitive ability—often fa- drome in infected people. Assuming that hu- vors the evolution of wasteful, costly mecha- mans are not victims of behavior-altering nisms rather than maximally efficient ones parasites, does it mean that defenses against (Miller 2000; Kuijper et al. 2012). Sexual se- manipulation have become useless in our lection may also decrease the robustness of species? This is a complex question that will some traits, precisely to turn them into reli- require a complex answer and much addi- able indicators of health and genetic quality tional evidence. It is certainly possible that (see Geary 2015). our brain and endocrine systems contain On this background, evolutionary con- “frozen” countermeasures that evolved at a flictsbetweenparasitesandhostsareanother time when parasite manipulation was a strong potential source of inefficiency. In general, selection pressure, became embedded in neu- competitive interactions push the evolution ral processes, and persist today even if they no of biological mechanisms away from simple longer serve their original function. In fact, optimization goals (Foster 2011), and may some of those ancient mechanisms may have escalate into wasteful “arms races” in which been recycled and modified to perform novel organisms spend large amounts of resources functions, as is the ruleinbrain evolution (An- just to keep ahead of the adversary (Sum- derson 2010). mers et al. 2003). Other scholars have noted that host-parasite conflicts may select for en- hanced robustness (Salathé and Soyer 2008; Implications for Neuroscience Foster 2011). In this paper, I have argued and Psychopharmacology thatrobustnessmechanismsareonlyonetype of countermeasure; other possible responses implications for basic neuroscience include defensive increases in complexity, es- In the quest to reverse engineer the brain, calating costs of signaling, toxic signaling neuroscientists confront some hard ques- molecules, and more. Each of these counter- tions about the evolved design of neural sys- measures has unique implications for under- tems. To what extent are brain mechanisms standing the evolution of brain function. For optimized for their tasks? Are they efficient example, selection for defensive complexity and streamlined or wasteful and redundant? tends to produce complex signals that are On one hand, there is mounting evidence intricate and hard to decode—for parasites, that neural systems, from synapses and neu- but also for the neuroscientists who study rons to whole brain networks, are relent- them. The fact that the chemical codes em- lessly optimized to process information with ployed by neurons and endocrine cells are maximum energetic efficiency (e.g., Ster- exceedingly difficult to decipher may turn ling and Laughlin 2015). On the other hand, out to be a specificdesignfeature,ratherthan there are important biological forces that just a reflection of their complex functions work against selection for efficiency. Evolu- (Chastain et al. 2012). tion is a wasteful process that “tinkers” with Another intriguing possibility is that mech- what is available at any given time, and can anisms that initially evolved as countermea- never escape the constraints of previous his- sures may have been co-opted and exapted tory; for all of its ability to produce effective to serve other functions, unrelated to the orig- and finely tuned adaptations, natural selec- inal conflict (Foster 2011). For example, a tion is also bound to leave behind a legacy of defensive increase in signaling complexity suboptimal solutions, design compromises, (e.g., receptor duplication and divergence) and inefficiencies (e.g., Marcus 2009). The may enhance the flexibility of neural signal- fact that brains are exposed to accidents and ing, and serve as a springboard for the evolu- malfunctions inevitably gives rise to trade- tion of novel behavioral patterns. A useful offs between efficiency and robustness (see analogy is that of military research, which— Del Giudice and Crespi 2018); less intui- under the pressure of ongoing or potential tively, sexual selection for behavioral traits— war—generates a multitude of new technol- from courtship displays such as bird songs to ogies that are later adopted for everyday

8073.proof.3d 271 Achorn International 06/27/19 01:01 272 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 use. The key point of the analogy is that the effects and their decline over time (see Fava research and design costs of high-risk inno- and Offidani 2011; Fornaro et al. 2019). It is vations are often prohibitive; the logic of worth considering the possibility that at least conflict justifies large-scale investments that some of these reactive mechanisms may be would be unsustainable in a peacetime econ- specifically designed to detect and respond omy. Likewise, conflict with parasites may to parasite intrusions. If so, standard pharma- fuel the evolution of complex or expensive cological treatments may unwittingly mimic a adaptations that would not evolve otherwise, parasite attack and trigger specialized defen- because their large “R&D costs” would ex- sive responses. Intriguingly, some undesirable ceed the initial fitness benefits for the host. “side effects” of the drugs (e.g., behavioral ri- gidity, loss of motivation) might be best understood as costly yet adaptive features— implications for psychopharmacology that is, adaptive in the original context of Using psychoactive drugs to treat psychiat- parasite manipulation, but potentially detri- ric symptoms is an attempt to alter behavior mental in the evolutionarily novel context of by pharmacological means. This is also what psychiatric treatment. manipulative parasites do—even though, in A manipulation perspective may contrib- the case of psychiatric treatment, the goal ute to explain when and why drugs fail, but is to benefit the patient (Massey and Mishra also help researchers devise more effective 2018). If the human brain contains evolved treatments. On point, Adamo (2013) con- countermeasures to manipulation, the impli- trasted the ways in which parasites and neu- cations for psychopharmacology could be roscientists use biochemical manipulations profound. I now briefly discuss some of these to alter behavior in animals. She argued that implications, using depression as a running parasites can teach two useful lessons to neu- example. roscientists. The first is that parasites tend to A persistent obstacle in the development of attack multiple mechanisms at once instead psychoactive drugs is that stable behavioral of focusing on one specific pathway. This changes are difficult to bring about in a reli- pattern is to be expected in light of counter- able fashion. The acute effects of drugs of measures such as robustness and defensive abuse such as heroin and cocaine are intense complexity, and may explain why the behav- but short-lived, and wash out within hours; ioral changes induced by parasites are of- in contrast, psychiatric drugs like antidepres- ten remarkably stable, or even permanent. sants must alleviate symptoms for months In the domain of psychopharmacology, one or years on end in order to be useful. Not implication is that using multiple drugs to only do antidepressants take weeks to start treat a single disorder—for example, depres- working, they also tend to induce tolerance sion—may enhance the reliability and long- in patients. The buildup of tolerance to anti- term efficacy of the treatment. This approach depressants can be gradual, but about 10– is known as combination therapy when the 20% of patients experience a sudden, rapid drugs have similar functions but different loss of effectiveness (tachyphylaxis) during mechanisms of action (e.g., two or more an- which symptoms reemerge quickly after the tidepressants) or augmentation therapy when initial remission (Fornaro et al. 2019; Kinrys the main drug (for example, an antidepres- et al. 2019). sant) is supplemented with molecules that The mechanism responsible for tolerance target different systems (e.g., antipsychotics, to antidepressants (and most other drugs) anxiolytics, or hormones such as testoster- are still poorly understood. Researchers have one). Combination/augmentation therapies argued that continued administration of the for depression and other mood disorders drug may trigger compensatory mechanisms have yielded promising results against treat- at the level of receptors and/or cellular trans- ment resistance and tachyphylaxis, but are duction pathways; similar feedback processes still underresearched (Ionescu et al. 2015; could explain the delayed onset of the drug Kinrys et al. 2019). There are also concerns

8073.proof.3d 272 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 273 about the cumulative effects of multiple drugs enhance the efficacy of drugs, by delivering on the risk for other conditions (e.g., kidney them in strategically timed patterns. disorders; Nestsiarovich et al. 2019). A manip- ulation perspective may help to understand more clearly why some combinations of mol- Suggestions for Future Research ecules work better or worse than others, and Rethinking behavior manipulation from offer insights into the best attack strategy. the standpoint of the host’s nervous system If core signaling pathways turn out to be raises many fascinating questions and hy- strongly protected against hijacking, it might potheses, which at this point are necessarily pay off to take indirect routes, sidestepping speculative. Because the hypotheses I ad- the obvious candidate mechanisms and fo- vance in this paper bear on a variety of dis- cusing on the vulnerable nodes of the sys- ciplines and research areas—each with its tem (e.g., the knots of biochemical bow-tie own specialized tools and techniques—it is structures). hard to offer general guidelines for testing The second lesson discussed by Adamo them. Here I propose some heuristics and (2013) is that parasites often eschew signal- examples of how this perspective can be ing molecules and their receptors, and in- used to extend current thinking in the rele- stead target genes and proteins that are not vant disciplines. For example, major efforts directly involved in signaling. One of the most are underway in molecular neurobiology and common indirect strategies employed by par- immunology to elucidate the roles of gly- asites is to target the immune system. This is cans, noncoding RNAs, cell adhesion mol- also a relatively novel, active research topic ecules, and other mechanisms involved in in the treatment of depression. The current parasite-host conflicts. The set of possible in- therapeutic approach is straightforward: in terpretations of findings in these areas could light of the finding that at least some depres- be expanded to include host countermea- sion subtypes are associated with elevated in- sures against manipulation. To illustrate, one flammation biomarkers, anti-inflammatory might entertain the idea that noncoding drugs may be used to treat depressive symp- RNAs whose expression is strongly induced toms. The results of clinical trials have been by specific pathogens may be part of spe- promising, but heterogeneous and still ten- cialized detection and response mechanisms tative in many respects (Köhler et al. 2014; (see above). Serendipity will obviously play a Köhler-Forsberg and Benros 2018; Pfau major role in future discoveries, but this can et al. 2018). A closer look at the mechanisms only happen if researchers are aware that employed by parasites to alter immune func- the question exists in the first place. tioning is likely to suggest other, more sophis- In other cases, some modeling and simula- ticated avenues for intervention. tion work will be necessary before empirical Finally, the novel idea that pulsatile signal- tests can be designed and carried out. This ing may have evolved as a countermeasure is especially true of hypotheses about the is particularly intriguing in relation to phar- origin of ancient, ubiquitous mechanisms— macological treatments. At present, most such as pulsatile signaling, the use of anti- psychiatric drugs are used to bring about a microbial compounds as neurotransmitters/ sustained increase (or decrease) in the brain neuromodulators, or co-transmission and con- concentration of certain signaling molecules, vergent signaling in the nervous system. These for example, serotonin or dopamine. Unfor- mechanisms are highly conserved across spe- tunately, this might be exactly the kind of cies, cannot be significantly altered by short- simple manipulation that pulsatile signals are term selection, and may not be amenable to designed to thwart. Modern delivery tech- experimental manipulations. Evolutionary nologies can be used to release drugs in models would help determine if they can pulses rather than continuously (Davoodi benefit the host in the presence of parasites, et al. 2018). Framing pulsatile signaling as delimit the conditions at which they do, and a code to break may indicate new ways to evaluate the strength of the resulting selec-

8073.proof.3d 273 Achorn International 06/27/19 01:01 274 THE QUARTERLY REVIEW OF BIOLOGY Volume 94 tion pressures in the context of other po- and that of parasite strategies and responses tential advantages (e.g., metabolic efficiency, (Table 1). Also, patterns of molecular di- flexibility). Crucially, formal models may sug- versity can provide indirect cues to the ex- gest unique predictions that are hard or im- istence of host-parasite conflicts and arms possible to derive from the verbal statement races (Summers et al. 2003; see also Massey of a hypothesis. In the future, it should also and Mishra 2018). become feasible to combine evolutionary “Natural experiments” in which a parasite models of fitness costs and benefits with de- is introduced or removed from the host’s tailed mechanistic models of parasite bio- environment can be quite informative, al- chemistry (e.g., metabolic network models; though they are limited to the more rapidly see Imam et al. 2015; Zhang and Hua 2016). evolvable aspects of host countermeasures. Present-day metabolic models—which are For example, I speculated that hosts may am- only available for a few model species, such as plify genetic and/or developmental stochas- E. coli—incorporate information about hun- ticity to generate individualized signatures in dreds or thousands of genes and intracellular their signaling pathways. This strategy should reactions. Among other things, they can be entail nontrivial costs for the host, and may used to predict the effects of antimicrobial be quickly reversed (via tighter canalization) substances on the metabolism and growth as soon as it is no longer beneficial. As an rate of bacteria (e.g., Li et al. 2016). analogy, there is evidence that birds rapidly Naturally, comparative research is a crucial lose variability in egg markings when they source of evidence to investigate the evolu- escape brood parasitism (Lahti 2005; see tion of host countermeasures. Related species Spottiswoode and Busch 2019). or populations may be targeted by different Finally, countermeasure hypotheses can behavior-altering parasites with different strat- be explored with a variety of experimental egies, experience infection at different rates, designs. Experimental evolution is an espe- or face different sets of constraints (e.g., en- cially promising method in this regard. In a ergy, temperature, size, life history). At least recent study, Hafer-Hahmann (2019) sub- in some instances, it may be possible to map jected the parasitic flatworm Schistocephalus these ecological variables onto differences solidus to selection for enhanced versus re- in the expression of hypothetical counter- duced manipulation strength, finding high measures. Examples include the biochemi- heritability and a rapid response to selection. cal parameters that affect the costs of neural A similar approach could be applied to hosts or hormonal signaling (e.g., effective con- with short generation times, either by di- centrations, receptor expression, clearance rectly selecting for/against resistance to ma- rates); CNS-expressed glycans and surface nipulation or by introducing/removing the molecules when the parasite manipulates the parasite from the host’s environment. Other host from within the brain; or the regulation relevant designs include neurobiological of influx/efflux through the BBB, particu- studies in which the action of a parasite is larly when the parasite resides in the host’s mimicked to study the host’s response, and body and releases neuroactive substances in brain lesion or gene knockout studies in the circulation. Other useful comparisons which putative countermeasures are inacti- could be made between host populations vated or impaired. that coexist with the same parasite, but show different levels of susceptibility to manipu- lation—or, symmetrically, different strains Conclusion of a parasite that vary in their ability to ma- Throughout their long history, brains have nipulate the same host species. If compara- been battlegrounds between hosts and para- tive molecular data are available for both sites for the control of the host’s behavior. the host and the parasite, it may be possible The unrelenting pressure exerted by para- to reconstruct the coevolutionary process, sites must have shaped the evolution of ner- and explore the temporal links between the vous and endocrine systems at all levels, with evolution of putative host countermeasures important consequences even for animals

8073.proof.3d 274 Achorn International 06/27/19 01:01 September 2019 BRAIN EVOLUTION AND PARASITE MANIPULATION 275 that are not (or no longer) manipulation tar- visible, but one can already tell that it leads gets. If this is true, many aspects of neurobi- to strange and interesting places. ology are destined to remain mysterious or poorly understood until parasites—the brain’s invisible designers—are finally included in the picture. This is not a simple task, and acknowledgments one can anticipate that researchers will face My warmest thanks to Gregory Cochran, Steve Gangestad, plenty of false starts and dead ends. At the Adam Safron, Peter Todd, and Kelly Weinersmith for same time, there are good reasons for curios- sharing their expertise and offering thought-provoking ity and excitement. The road ahead is barely feedback during the writing of this paper.

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