Available online at www.sciencedirect.com ScienceDirect Escalated aggression in animal models: shedding new light on mesocorticolimbic circuits 1,2 3 2 Klaus A Miczek , Aki Takahashi , Kyle L Gobrogge , 2 4 Lara S Hwa and Rosa MM de Almeida Recent developments promise to significantly advance the molecules for adaptive vs. excessive, maladaptive aggres- understudied behavioral and neurobiology of aggression: (1) sive behavior in several animal models [5,6 ,7,8 ]. Animal models that capture essential features of human violence and callousness have been developed. These models What is aggression in excess? range from mice that have been selectively bred for short attack Ethological studies of aggression focus on the distal and latencies, monogamous prairie voles, and glucocorticoid- proximal causes, the ontogenetic and phylogenetic origins compromised rats to rodents and non-human primates that of aggressive behavior [9]. This framework for adaptive escalate their aggression after consuming or when withdrawing species-typical aggressive behavior allows for the assess- from alcohol. (2) Optogenetic stimulation and viral vector- ment of maladaptive and excessive aggression. based approaches have begun to identify overlapping and distinctive neural microcircuits and intracellular molecules for When aggressive behavior escalates to maladaptive levels adaptive vs. excessive, maladaptive aggressive behavior in in rodents [10–12], it is operationally defined by: several rodent models. Projections from hypothalamic and mesencephalic neurons to the medial prefrontal cortex contain (1) Low provocation threshold, short latency to initiate microcircuits that appear pivotal for the escalation of attack; aggression. (2) High rate; (3) High intensity, leading to significant tissue damage; Addresses (4) Lack of species-normative behavioral structure (i.e. 1 Departments of Pharmacology, Psychiatry and Neuroscience, Tufts threats are deficient in conveying signaling inten- University, Boston, MA 02111, USA 2 tions, and lack of context, critical features of the Department of Psychology, Tufts University, Medford, MA 02155, USA 3 Laboratory of Behavioral Neuroendocrinology, University of Tsukuba, opponent such as age, sex, or locale are misjudged); Tsukuba, Japan (5) Atypically long aggressive bursts; 4 UFRGS, Porto Alegre, RS, Brazil (6) Insensitivity to long-term consequences; (7) Disregard of appeasement signals. Corresponding author: Miczek, Klaus A ([email protected]) Current Opinion in Behavioral Sciences 2015, 3:90–95 The presently available animal models attain face validity This review comes from a themed issue on Social behavior by implementing isomorphic signs and symptoms of excessive aggression, but their phylogenetic and ontoge- Edited by Molly J Crockett and Amy Cuddy netic development can only be inferred (i.e. low construct For a complete overview see the Issue and the Editorial validity). Available online 5th March 2015 http://dx.doi.10.1016/j.cobeha.2015.02.007 Animal models of maladaptive, pathological 2352-1546/# 2015 Elsevier Ltd. All rights reserved. aggression Selective breeding and ethological models for escalated aggression Escalated aggressive behavior with pathological features is evident in mouse and rat strains that are selectively bred for high aggression [1]. Direct comparisons of inde- Two significant developments during the last decade pendent selection experiments identified SAL (short have enhanced our understanding of the brain mecha- attack latency) mice [13] as the strain displaying the most nisms of excessive aggressive behavior. First, recent compelling abnormal and pathological forms of attack advances in preclinical research have led to animal mod- [14]. In addition to escalated aggression, SAL mice, els of aggression that capture the salient features of acts of derived from wild-trapped rodent colonies, are also char- human violence and callousness [1–4]. Second, novel acterized by low heart rate, glucocorticoids, brain seroto- neurobiological methods such as optogenetics and viral nin levels, and reuptake transporter activity, but elevated vector-based approaches have begun to identify over- serotonin-1A autoreceptor activity relative to other high- lapping and distinctive microcircuits and intracellular aggression mouse lines [15]. Current Opinion in Behavioral Sciences 2015, 3:90–95 www.sciencedirect.com Optogenetics and escalated aggression in animal models Miczek et al. 91 The prairie vole (Microtus ochrogaster) has recently effects in mice, rats, and monkeys [20–29]. Considerably emerged as a viable animal model for investigating the less is known about the neurobiology of escalated aggres- neurobiology of escalated aggression and violence [16], sive behavior that emerges during withdrawal from pro- using advanced genetic tools to reveal the neural mecha- longed exposure to alcohol. nisms mediating maladaptive and excessive agonistic behavior [17]. Ethologically, mating induces intense fatal One hypothesis links the rewarding effects of alcohol and forms of offensive attack behavior directed toward both its underlying neural mechanisms to those of aggressive male and female conspecifics but not toward their familiar behavior originates from the mescorticolimbic dopami- female partner (i.e. selective aggression) in the wild; this nergic circuit [30–34]. A second hypothesis focuses on the can be modeled under well-controlled laboratory condi- considerable evidence for the anxiolytic effects of alcohol tions [5,18]. In pair-bonded males parvocellular vasopres- that may reduce the fear of the stranger (i.e. xenophobia) sin neurons in the nucleus circularis and medial and thereby disinhibit aggressive behavior [11]. Third, supraoptic nucleus are activated during aggression [18] the pro-aggressive effects of alcohol may stem from and release their contents in the anterior hypothalamic misperceived threatening stimuli [35]. How can animal nucleus, activating vasopressin-V1a-type receptors models best examine the face validity of these alternative (V1aRs) to facilitate selective aggression toward novel hypotheses for better understanding the aggression-esca- females but not toward their female partner [5]. Two lating effects of alcohol? weeks of sociosexual experience induces structural plas- ticity of V1aRs to mediate selective aggression, while viral-vector-mediated gene transfer of V1aR into the Neurobiological mechanisms of aggression in anterior hypothalamic nucleus, of sexually naı¨ve males excess recapitulates pair bonding-induced aggression [5]. Fur- Pharmacological studies of monoamines, glutamate/ thermore, low dose (1 mg/kg, i.p.) repeated treatment GABA, and neuropeptides with the psychostimulant d-amphetamine in bonded One of the most intriguing hypotheses relating the be- and unmated males produces vicious attacks toward both havioral and neural mechanisms underlying alcohol- familiar and unfamiliar females [5]. heightened aggressive behavior postulates shared neural mechanisms for escalated alcohol consumption and ag- The unambiguous qualitatively and quantitatively esca- gression. Considerable evidence suggests that neural lated forms of aggression in a relatively small number of activity in mesencephalic-limbic-cortical loops is required individuals convey face validity to human violence. Dys- for preferring alcohol over other commodities, seeking functions in serotonin and neuropeptide neurotransmis- out the opportunity to self-administer alcohol, working to sion in selectively bred and feral aggressive rodents obtain alcohol, and resisting the negative consequences of translate well to impulsively aggressive and violent be- alcohol consumption [36–42]. Abundant data identify the havior in humans. intact ascending monoaminergic pathways as necessary for the reinforcing effects of alcohol. Several ionophoric Excessive aggression in the hypoglucocorticoid rat receptors in monoaminergic, GABA-ergic and glutama- model tergic cells are activated by alcohol at millimolar concen- Hypoarousal during violence as indexed by low glucocor- trations [43]. Neuropeptides such as corticotrophin ticoid production, heart rate and skin conductance in releasing factor, neuropeptide Y and opioid peptides patients with antisocial personality disorder and conduct modulate the monoaminergic, GABA-ergic and glutama- disorder can be modeled in adrenalectomized rats that are tergic networks that mediate the reinforcing and reward- maintained by low-level glucocorticoid replacement ther- ing effects of alcohol [42,44]. apy [2,19]. This model captures the ‘callous-unemotional’ hallmark of Conduct Disorder by the display of dysfunc- There is growing support for the hypothesis that the tional attack targeting, the absence of social signaling and neural mechanisms mediating alcohol’s reinforcing reduced autonomic activation. effects overlap or interact with those that are responsible for aggressive and violent acts which in themselves func- Alcohol-heightened aggression tion as reinforcers. Pharmacological antagonism of dopa- From a pharmacological perspective, aggressive behavior mine D1 and D2 receptors in the nucleus accumbens can be escalated either by low acute alcohol doses or diminishes the seeking of the opportunity to fight [33,45]. during withdrawal from prolonged exposure to repeated Direct neurochemical assays reveal increased dopamine high alcohol doses, presumably based on separate neural release in the nucleus accumbens of rats that consume mechanisms. Further pharmacological studies of alcohol- alcohol