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or mitotically arrested neuronal of speech. Whilst there is no progenitors. The clinical findings doubt that each MCPH gene can Primer in MCPH support the hypothesis affect size significantly, they are that neuronal progenitors are more maybe better viewed as modulators vulnerable than other cell types of . And it is for this reason The hypothalamus to mutations in genes encoding that the study of these genes may centrosome proteins. eventually lead us to discover the Clifford B. Saper1,3,* chance change(s) that have led to the and Bradford B. Lowell2,3 What has MCPH got to do with the emergence of the massive parallel evolution of human intelligence? processor that is the . The hypothalamus is one of the It has been suggested that small, oldest and smallest parts of the cumulative changes in MCPH- Where can I find out more? brain, constituting just 4 gm of associated genes have collectively led Bazzi, H., and Anderson, K.V. (2014). Acentriolar the 1400 gm of adult human brain mitosis activates a p53-dependent apoptosis to the increase in human brain size. pathway in the mouse embryo. Proc. Natl. weight. And yet this tiny area There is a clear relationship between Acad. Sci. USA 111, E1491–E1500. contains highly conserved neural Bond, J., Roberts, E., Mochida, G.H., measurable intelligence and brain Hampshire, D.J., Scott, S., Askham, J.M., circuitry that controls basic life size within and between Springell, K., Mahadevan, M., Crow, Y.J., functions: these include energy other mammals. Broadly speaking, Markham, A.F., et al. (2002). ASPM is a major , from feeding through determinant of cerebral cortical size. Nat. herbivores have smaller than Genet. 32, 316–320. , metabolic control, and predators and scavengers. Also, Bond, J., Roberts, E., Springell, K., Lizarraga, energy expenditure; fluid and S.B., Scott, S., Higgins, J., Hampshire, D.J., nearly all conditions in which the Morrison, E.E., Leal, G.F., Silva, E.O., et al. electrolyte balance, from drinking brain is substantially reduced in size (2005). A centrosomal mechanism involving through fluid absorption and lead to intellectual disability (despite CDK5RAP2 and CENPJ controls brain size. excretion; , from Nat. Genet. 37, 353–355. physical abilities often being normal). Chavali, P.L., Putz, M., and Gergely, F. (2014). choice of environment through Humans are regarded (by humans!) as Small organelle, big responsibility: the role heat production and conservation, of centrosomes in development and disease. having the greatest cognitive abilities Philos. Trans. R. Soc. Lond. B Biol. Sci. 369. and responses; wake- amongst animals, and have proven Chen, J.F., Zhang, Y., Wilde, J., Hansen, K.C., Lai, cycles and emergency responses themselves remarkably adaptable F., and Niswander, L. (2014). Microcephaly to in the environment; and disease gene Wdr62 regulates mitotic to different conditions on Earth and progression of embryonic neural stem cells reproduction, from reproductive hence have spread far beyond their and brain size. Nat. Commun. 5, 3885. control through mating, Cox, J., Jackson, A.P., Bond, J., and Woods, C.G. ancestral geographical origins. But (2006). What primary microcephaly can tell pregnancy, birth, and suckling. In this none of this proves that a larger brain us about brain growth. Trends Mol. Med. 12, Primer, we will give an overview of the is a cleverer brain, although inherently 358–366. structure of the hypothalamus, and Kaindl, A.M., Passemard, S., Kumar, P., this might make ! Kraemer, N., Issa, L., Zwirner, A., Gerard, B., outline what we know about how that For most MCPH-associated genes Verloes, A., Mani, S., and Gressens, P. (2010). relates to its functional circuitry. Many roads lead to primary autosomal there is evidence for evolutionary recessive microcephaly. Prog. Neurobiol. 90, selection and change during the 363–383. Overview of the hypothalamus monkey/ape/human lineage, as seen Marthiens, V., Rujano, M.A., Pennetier, C., The hypothalamus develops Tessier, S., Paul-Gilloteaux, P., and Basto, R. for genes involved in fertility and (2013). Centrosome amplification causes from the most anterior end of the immunity. Taken together it has been microcephaly. Nat. Cell Biol. 15, 731–740. developing . Most of it is Novorol, C., Burkhardt, J., Wood, K.J., Iqbal, A., speculated that multiple alterations Roque, C., Coutts, N., Almeida, A.D., He, J., derived from the ventral part of the in MCPH genes (and presumably in Wilkinson, C.J., and Harris, W.A. (2013). , but its most rostral other genes with which they interact) Microcephaly models in the developing component, the , zebrafish retinal neuroepithelium point to an have led to the threefold increase in underlying defect in metaphase progression. develops from the telencephalon. brain size between chimpanzees (our Open Biol. 3, 130065. In the adult brain, however, it is Roberts, E., Hampshire, D.J., Pattison, L., closest relatives) and us. The other Springell, K., Jafri, H., Corry, P., Mannon, J., impossible to distinguish these evolutionary change that is thought Rashid, Y., Crow, Y., Bond, J., et al. (2002). components. to be related to human brain size is Autosomal recessive primary microcephaly: an The hypothalamus is most easily analysis of locus heterogeneity and phenotypic the loss of the masseter muscle gene variation. J. Med. Genet. 39, 718–721. defined from its ventral surface. It MYH16 following the evolutionary Rujano, M.A., Sanchez-Pulido, L., Pennetier, C., is bounded anteriorly by the optic le Dez, G., and Basto, R. (2013). The fixation of a premature nonsense microcephaly protein Asp regulates chiasm, laterally by the optic tracts, mutation, allowing the young human neuroepithelium morphogenesis by controlling and posteriorly by the mammillary skull to be able to grow more easily, the spatial distribution of myosin II. Nat. Cell body. It is surrounded by the Biol. 15, 1294–1306. but this relationship still remains to be Thornton, G.K., and Woods, C.G. (2009). Primary vessels of the circle of Willis. The proven. There is no such clear major microcephaly: do all roads lead to Rome? hypothalamus is symmetrically Trends Genet. 25, 501–510. change in an MCPH-associated gene Woods, C.G., Bond, J., and Enard, W. (2005). duplicated on each side of the that would make it ‘the’ candidate to Autosomal recessive primary microcephaly brain, with the in the explain a stepwise increase in human (MCPH): a review of clinical, molecular, and midline forming a boundary between evolutionary findings. Am. J. Hum. Genet.76 , versus ape brain size. It is worth 717–728. the two sides. For most functions, noting, however, that there are only only the activity of one side of the 1 4 amino acid differences between Cambridge Institute for Medical Research, hypothalamus is required. Cambridge University, Addenbrookes man and mouse in the 714-amino- Hospital, Cambridge, UK. 2UMR144, CNRS, The hypothalamus is usually acid FOXP2 protein and these are Institute Curie, Paris, France. divided from rostral to caudal into thought to have led to the acquisition *E-mail: [email protected] thirds (Figure 1). The rostral part, the Current Vol 24 No 23 R1112

the paraventricular and the adjacent lateral hypothalamic area, with smaller numbers in the . Individual pre- autonomic project to AC DHA multiple levels of the spinal cord, PVH DMH where they are thought selectively to innervate neurons of a particular M DLPO N type. Selective physiological stimuli, PHA P MPO such as or lipopolysaccharide, O LHA AHA VMH stimulate expression of cFos protein in limited subsets of these neurons

SUM (arcuate and dorsal paraventricular, VLPO SCN SON ARC T respectively), suggesting that I OC M these pre-autonomic neurons are N N F MAM organized along functional, rather than strictly anatomical, lines. There are three sets of endocrine Preoptic area Tuberal hypothalamus Posterior hypothalamus outputs from the hypothalamus. The Current Biology magnocellular system consists of large neurons in the supraoptic and Figure 1. An overview of the hypothalamus. paraventricular nuclei that express This figure and the ones that follow are enlargements of the area shown by the box in the inset at the upper right, projected against a midsagittal section of a rat brain. The relative locations of the either or . hypothalamus and its nuclei shown here are very similar in other mammals, including humans. These are actually secretory The most rostral part of the hypothalamus, overlaying the , is the preoptic area neurons, whose traverse the (left). The tuberal portion (center) overlays the (infundibulum, INF). The stalk to end along blood hypothalamus (right) overlays the mammillary bodies. AC, anterior commissure; AHA, anterior vessels in the posterior pituitary hypothalamic area; ARC, arcuate nucleus; DHA, dorsal hypothalamic area; DLPO, dorsolateral gland, where they provide these preoptic area; DMH, dorsomedial nucleus; LHA, lateral hypothalamic area; MAM, mammillary nuclei; MNPO, ; MPO, medial preoptic area; OC, optic chiasm; PHA, systemically for the entire posterior hypothalamic area; PVH, paraventricular hypothalamic nucleus; SCN, suprachiasmatic body. The parvicellular system nucleus; SON, ; SUM, supramammillary nucleus; TMN, tuberomammillary nu- comprises smaller neurons in the cleus; VLPO, ventrolateral preoptic nucleus; VMH, ventromedial nucleus. wall of the third ventricle, including many in the medial part of the preoptic area, lies above the optic , which are believed to paraventricular nucleus and in the chiasm and includes the median and play a role in regulating arcuate nucleus. These neurons ventrolateral preoptic nuclei, the as well as responses. send axons to the floor of the third medial and lateral preoptic areas, The role of the hypothalamus is ventricle at the emergence of the and the . It essentially integrative, meaning pituitary stalk, or , contains key integrative circuitry for that it brings together a range of where they secrete releasing or thermoregulation, fever, electrolyte sensory inputs necessary to make release-inhibiting hormones into the balance, wake-sleep, circadian important decisions about basic life hypophysial portal vessels. These rhythms, and sexual behavior. functions. It then compares those are loops in the floor of The middle part is the tuberal inputs to basic setpoints, that is, the median eminence, which then hypothalamus, and the pituitary stalk ideal levels for parameters such as form veins that bring the blood (infundibulum) emerges from the body temperature, blood sodium carrying the releasing hormones to ventral surface of this central region. and levels, and various the anterior , where The tuberal hypothalamus includes hormone levels. The hypothalamus they control the secretion of pituitary the anterior and lateral hypothalamic then activates autonomic, endocrine, hormones such as , areas and the dorsomedial, and behavioral responses that try adrenocorticotropic hormone, ventromedial, paraventricular, to maintain the body at the key stimulating hormone, growth supraoptic, and arcuate nuclei. setpoints () or overcome hormone, and . The third The tuberal hypothalamus contains a (allostasis). route for hypothalamic control of the integrative circuitry for feeding, is by autonomic but output circuitry for sexual Key outputs of the hypothalamus innervation of the endocrine glands; behavior, aggressiveness, and The hypothalamus controls the for example, autonomic innervation many autonomic and endocrine autonomic via of the pancreas contributes to responses. The posterior part a set of neurons that directly regulating secretion of and of the hypothalamus includes innervates both the parasympathetic . the mammillary bodies and the and sympathetic preganglionic The hypothalamic control of areas above them, such as the neurons, as well as various cell behavior is more complex. While tuberomammillary, supramammillary, groups in the that control it was once thought that the and posterior hypothalamic nuclei. autonomic reflexes. These pre- hypothalamus contains ‘centers’ for This region provides intense autonomic neurons are mainly feeding, aggressive behavior, and so outputs to the system and located in the parvicellular part of on, which can activate fully formed Magazine R1113 behaviors, current thought suggests Stress that it contains circuits that increase AC DHA PB the likelihood that the animal will PVH DMH engage in certain behaviors. For Skin temp example, in a hungry animal there M DLPO N Brown adipose is an increase in wakefulness and PHA P MPO AHA LHA Vasoconstriction locomotor activity that increases the O VMH likelihood of the animal encountering PGE2 RPa . By facilitating circuitry for SUM licking, chewing, and swallowing, VLPO SCN SON ARC T and enhancing pleasurable I OC M N N responses to the sensory stimuli F MAM (taste, smell, texture, temperature) of food ingestion, the hypothalamus Current Biology can drive a relatively complex behavior such as feeding. Figure 2. A schematic drawing of the hypothalamic pathways involved in thermoregulation For the remainder of this Primer, (black). we will focus on a few responses The remainder of the hypothalamus (gray) is shown as in Figure 1, for orientation. The parabra- where important parts of the circuitry chial nucleus (PB), which provides thermoreceptor inputs from the skin, and the raphe pallidus have recently been discovered, as nucleus (RPa), which provides output to sympathetic preganglionic neurons that control brown examples of how the hypothalamus adipose thermogenesis and arterial vasoconstrictor heat dissipation, are located in the brain- works. stem, but for the sake of scale are shown here just to the right of the hypothalamus. PGE2, E2. See text for details. Thermoregulation and fever The median preoptic nucleus, in turn innervate sympathetic preoptic area also sends axons to the located in the midline along the preganglionic neurons that activate raphe pallidus. Lesions involving both anterior wall of the third ventricle brown adipose (causing the median and dorsolateral preoptic (Figure 2), is a key site for integrating thermogenesis) and neurons that populations, but not either one thermal inputs from both the skin cause vasoconstriction of superficial alone, cause an elevation of body and from thermosensitive neurons vascular beds (thus reducing heat temperature by about 2oC. Acute within the brain, such as neurons loss through the skin). These two inhibition of either site also causes a in the preoptic region that respond actions cause an increase in body rise in body temperature, suggesting to brain temperature. The warm- temperature. that both produce inhibition of the and cold-sensing neurons in the The median preoptic nucleus raphe pallidus at baseline, but that spinal cord project to adjacent contains GABAergic neurons that either one can compensate for the warm- and cold-responsive sites in inhibit the raphe pallidus. These loss of the other in the case of a the lateral parabrachial nucleus in neurons express EP3 receptors for chronic lesion. the pons. The parabrachial nucleus prostaglandin E2. During immune is a relay station for transferring stimulation, for example by systemic Feeding and energy metabolism many types of ascending visceral administration of lipopolysaccharide, Attention was first focused on the sensory information derived from prostaglandin E2 is produced by role of the hypothalamus in feeding the spinal and cranial nerves to endothelial cells in the preoptic area, and metabolism by the dramatic the hypothalamus, and for much and acts on the EP3 receptors in the demonstration in the 1930s and descending feedback from the median preoptic nucleus to cause an 1940s of massive hyperphagia and hypothalamus back to the autonomic elevation of body temperature (fever). after large lesions centered reflex and motor cell groups. Lesions of the median preoptic on the ventromedial nucleus, and The median preoptic nucleus nucleus or deleting EP3 receptors hypophagia and inanition after sends descending output to two from just that site prevent such large lesions of the adjacent lateral key sites for controlling body fever responses; however, rats and hypothalamus. Such efforts led to the temperature (Figure 2). One site mice with such lesions still show an view that there were hypothalamic consists of a cluster of glutamatergic elevation of body temperature when ‘centers’ controlling satiety and neurons along the dorsal border they are stressed (for example, by . However, problems in of the dorsomedial nucleus (this handling or placing them in a new replicating these findings in studies site is sometimes called the dorsal cage). This appears to be due to using smaller, cell-specific lesions hypothalamic area, but other authors stress circuitry accessing the dorsal made it difficult to identify the do not distinguish it from the rest of hypothalamic neurons, as lesions in cellular substrates of the effects. the dorsomedial nucleus). Activation this area or eliminating the vesicular This situation changed dramatically of these dorsal hypothalamic glutamate 2 transporter from these with the demonstration that the neurons causes an increase in neurons prevents stress . mutation in ob/ob mice, which have body temperature. Both the median On the other hand, lesions of the genetic obesity, is in the gene for preoptic nucleus and dorsal median preoptic nucleus do not leptin, a hormone made by white hypothalamic area in turn innervate affect baseline body temperature. A fat cells when there is adequate a third key site, the raphe pallidus second population of neurons in the substrate available. When fat stores nucleus. The raphe pallidus neurons more caudal part of the dorsolateral are low due either to fasting, adipose Current Biology Vol 24 No 23 R1114

Motivation induced by caloric depletion. Motor and arousal cortex Manipulation of POMC neurons, autonomic in contrast, generally produces pattern generators opposite effects — but the effects AC DHA take longer to occur. PVH Parabrachial nucleus DMH The actions of AgRP and POMC neurons are brought about by M DLPO projections to other brain sites, N Nucleus of the PHA one notable structure being the P MPO O paraventricular nucleus (Figure 3). AHA LHA VMH MC4R-expressing neurons, a subset Gastrointestinal of the neurons in this complex neural SUM visceral sensation VLPO SCN SON AgRP POMC ARC hub, play a major role in mediating T I the effects of the OC M N N system on hunger. The MC4R- F Leptin MAM expressing neurons responsible for Current Biology regulating energy expenditure, on the other hand, appear to be located elsewhere, possibly in the spinal Figure 3. A schematic drawing of the hypothalamic pathways involved in regulation of feeding cord or the hindbrain. Because AgRP (solid lines, pathways that promote feeding; dashed lines, POMC pathways that inhibit feeding). The remainder of the hypothalamus (gray) is shown as in Figure 1, for orientation. The nucleus neurons also release GABA and NPY, of the solitary tract and the parabrachial nucleus, which provide visceral sensory input to the which, like AgRP, are inhibitory, not hypothalamus, and the motor and autonomic pattern generators responsible for licking, chew- all of these actions of AgRP neurons ing, swallowing, etc. are located in the brainstem, but for the sake of scale are shown here are necessarily brought about by just to the right of the hypothalamus. The nucleus accumbens and cortical and limbic areas, action on MC4Rs. responsible for motivation, arousal, and food selection, are located in the rostral to Cues other than leptin also the hypothalamus, but are shown here above it. See text for details. provide inputs that regulate feeding and metabolism. These tissue lipodystrophy, or uncontrolled nucleus and use -MSH to activate include visceroceptive inputs insulin-deficient diabetes, leptin melanocortin-4 receptors (MC4R) (food taste, presence of food in levels fall, hunger is increased and located in the paraventricularα nucleus the , signaled energy expenditure is reduced. and elsewhere. Leptin also acts on a by cranial nerves VII, IX, and X), Leptin acts on specific receptors second population of neurons in the olfactory cues, hormones (such that are concentrated in the arcuate, medial part of the arcuate nucleus. as ghrelin, a made by the dorsomedial, ventromedial and These neurons, which contain agouti- stomach that signals lack of food, premammillary nuclei — the part of related protein (AgRP) as well as or , made by the the hypothalamus that was ablated GABA and Y (NPY), are pancreas and the gut wall that signals by the ventromedial nucleus lesions. inhibited by leptin. the presence of food), and central These profoundly influential studies AgRP is a natural inverse agonist neurons that are sensitive to the definitively established that of the MC4R, and the POMC and levels of certain metabolites, such as and body weight are under intense AgRP neurons project to many glucose. In addition, there are likely biological control, as opposed to of the same targets. Fasting and/ to be important inputs from forebrain “willpower” or lack thereof, and that or leptin deficiency coordinately circuits that deal with reward, neurons in the hypothalamus are key activates AgRP neurons and inhibits motivation, and decision-making. to this control. POMC neurons; feeding and leptin How MC4R-expressing neurons These observations focused repletion, on the other hand, do the engaged by AgRP and POMC attention on specific neuronal opposite. As might be expected, neurons ultimately provide feedback circuits that were either activated POMC and AgRP neurons have to circuits that control hunger is or suppressed by leptin, and which opposite effects on their downstream presently unknown. Of particular therefore would play a role in target neurons, as well as behavior interest is how the circuits engaged regulation of feeding and energy and metabolism. These state- by these MC4R-expressing neurons metabolism. Many of the actions dependent changes in AgRP and regulate the reward value of of leptin, as well as other factors POMC activities then bring food and related cues, modulate that regulate energy metabolism, about homeostatically appropriate motivation, and ultimately affect are brought about by the activation changes in hunger and energy decision making. The substrates of the melanocortin system expenditure. Indeed, optogenetic and of this dialog present some of the (Figure 3). Melanocortin neurons chemogenetic studies have shown biggest questions for the field. contain pro-opiomelanocortin that experimental activation of AgRP Previously, complexities within the (POMC), the precursor for neurons dramatically stimulates brain made such topics essentially -melanocyte stimulating hormone hunger and decreases energy unapproachable. Fortunately, ( -MSH), -endorphin, and other expenditure, even in animals that are this has changed with the recent .α POMC neurons in nutritionally replete. Chemogenetic development of Cre-recombinase- theα hypothalamusβ are mainly located inhibition of AgRP neurons, on enabled tools which make possible, in the lateral part of the arcuate the other hand, attenuates hunger in conjunction with neuron-specific Magazine R1115

Cre-expressing mice, cell-specific Basal forebrain manipulation of neural activity and Wake cortex precise cell-to-cell mapping of connectivity. These approaches AC DHA are allowing investigators to follow PVH the ‘labeled lines’ of information as DMH they course through and beyond DLPO the hypothalamus, and are starting M N LHA to reveal discrete, highly specific PHA P MPO wiring diagrams that underlie O hypothalamic regulation of feeding AHA VMH and metabolism.

VLPO SUM Sleep and wakefulness SCN SON ARC T A hypothalamic circuit for sleep I OC M and wakefulness was first proposed N N MAM by in 1946, when he F showed that lesions of the preoptic area caused insomnia in rats, while Current Biology lesions of the posterior hypothalamus at the mammillary level caused excessive sleepiness. He proposed Figure 4. A schematic drawing of the hypothalamic pathways involved in the regulation of sleep and wakefulness (black). that neurons in the posterior The remainder of the hypothalamus (gray) is shown as in Figure 1, for orientation. The basal hypothalamus promote wakefulness, forebrain and cerebral cortex, which are rostral to the hypothalamus, are illustrated above the and that they might be inhibited by hypothalamus, for the sake of scale in this drawing. See text for details. preoptic neurons that promote sleep. Several groups of neurons in the whose axons pass through the that occur during the normal wake posterior half of the hypothalamus . Ventrolateral period. Narcolepsy is one of the few that promote wakefulness have been preoptic neurons have been found to neurological disorders that is known discovered over the last thirty years, be inhibited by many of the arousal to occur due to loss of a single including histaminergic neurons in system , such . the , as , , and (or hypocretin) neurons in the lateral acetylcholine. This mutual inhibition Social responses: sex versus hypothalamic area, and glutamatergic between the ventrolateral preoptic neurons in the supramammillary nucleus and the arousal systems The search for the structural basis of region (Figure 4). Each of these cell provides the conditions for a flip-flop sexual behavior was aided by early groups has extensive and diffuse switch. This is a type of switch that studies that demonstrated that the direct projections to the cerebral is built into electrical circuits when medial preoptic nucleus contains cortex which are believed to be the designer wants the switch to be neurons that are responsive to excitatory. In addition, arousal- bistable — stable in either the fully sex , and that it is sexually promoting neurons in the brainstem, on or fully off position — but to avoid dimorphic, being larger and having including noradrenergic (locus intermediate states. This relationship more neurons in males than in female coeruleus), serotonergic (dorsal insures rapid transitions from one rodents. Subsequent studies showed and median raphe), dopaminergic state to the other, and is thought to that individual neurons in the medial (ventral matter), explain the relatively rapid transitions preoptic nucleus fire during sexual cholinergic (pedunculopontine and most animals make between waking stimulation and that lesions of this lateral dorsal tegmental muclei), and and sleeping states. area disrupt both male and female glutamatergic (parabrachial nucleus) The orexin neurons, in the lateral sexual behavior. The outputs of the components, all pass through the hypothalamus, are thought to medial preoptic nucleus include a lateral hypothalamus and project play a particularly important role major projection to the ventrolateral directly to the cerebral cortex, in stabilizing this switch. These part of the ventromedial nucleus contributing to the waking state. neurons have potent descending of the hypothalamus (Figure 5). Sleep-promoting neurons have projections to the other components Lesions in this latter site prevent been identified in the ventrolateral of the arousal system, which they both male (mounting) and female preoptic and median preoptic nuclei potentiate. Thus, while the orexin (lordosis) sexual behavior. Both (Figure 4). Lesions of the ventrolateral neurons are firing, it is very difficult the medial preoptic nucleus and preoptic nucleus, in particular, for the ventrolateral preoptic neurons the ventromedial nucleus have cause rodents to lose as much as to overcome the wake system, and strong projections to the lateral 50% of total sleep. Ventrolateral a waking state is stabilized. Animals periaqueductal gray matter that are preoptic neurons contain the or people who lack the orexin thought to mediate the motor and inhibitory neurotransmitters GABA neurons suffer from the disorder autonomic patterns associated with and , are most active during known as narcolepsy, in which they sexual behavior. sleep, and innervate most of the have excessive sleepiness, marked Studies of aggressiveness in components of the arousal system by overwhelming sleep attacks animals have also focused on the Current Biology Vol 24 No 23 R1116

functions are extraordinarily Cortical and limbic behavioral arousal robust, redundant, and complex, Olfactory and Motor as one might imagine for circuitry hormonal cues pattern AC DHA generators on which the life of the animal depends. The differentiation of PVH DMH hypothalamic circuitry into hundreds, perhaps thousands of chemically, M DLPO connectionally, and functionally N PHA distinct cell populations stands in P MPO LHA PAG stark contrast to the cerebral cortex, O AHA VMH which hosts a range of complex vl functions using a small number of SUM cell types and neurotransmitters, and VLPO SCN SON ARC T a highly stereotyped architecture I OC M which is similar from one cortical N N MAM F column and area to the next, despite the extensive variations in function. Current Biology The differences in computational power between the cerebral cortex Figure 5. A schematic drawing of the hypothalamic pathways involved in the regulation of ag- of a mouse and a human is largely gressive vs. sexual behavior toward a conspecific animal (black). due to the number of such columnar The remainder of the hypothalamus (gray) is shown as in Figure 1, for orientation. For ease of processing units and distinct cortical illustration, olfactory cues which largely come from the medial and hormonal cues areas, and their interconnections. such as sex steroids, which enter the brain directly, are shown above the paraventricular nu- Conversely, the similarity in the basic cleus. Cortical and limbic areas that process visual and other sensory cues and contribute to life functions between a mouse behavioral arousal during either activity are shown above the hypothalamus. The per- iaqueductal gray matter (PAG) activates brainstem and spinal pattern generators responsible and a human has resulted in the for motor and autonomic responses associated with either sexual and aggressive behaviors; conservation of a large number of all of these are shown just to the right of the hypothalamus. See text for explanation. VMHvl, very specific hypothalamic neuronal ventrolateral part of the ventromedial nucleus. circuits. The availability of genetic tools for manipulating those circuits ventromedial nucleus as playing remain to be elucidated. In addition, in mice is likely to give us critical an important role in coordinating they must have interactions that insights into how the same circuits in aggressive attack behaviors. Recent allow activation of sexual response humans shape our lives. studies have shown that overlapping to profoundly inhibit aggressive populations of neurons in the response. The resolution of these Further reading ventrolateral part of the ventromedial questions and many others about Anderson, D.J. (2012). Optogenetics, sex, nucleus of male mice show cFos how these two systems interact and violence in the brain: implications for psychiatry. Biol. Psychiatry 71, 1081–1089. activation during both aggressive would be facilitated by the Morrison, S.F. (2011). 2010 Carl Ludwig encounters (with an intruder male) development of molecular tools Distinguished Lectureship of the APS Neural and during sexual encounters (with that differentiated between the two Control and Autonomic Regulation Section: Central neural pathways for thermoregulatory a female mouse). Interestingly, populations of neurons. cold defense. J. Appl. Physiol. 110, at least some of these neurons 1137–1149. Morrison, S.F., Madden, C.J., and Tupone, D. were activated initially under both Conclusions (2014). Central neural regulation of brown scenarios, but later continued to fire Our experience over the last thermogenesis and energy only with one or the other type of few years has indicated that the expenditure. Cell Metab. 19, 741–756. Morton, G.J., Meek, T.H., and Schwartz M.W. encounter. Neurons that responded hypothalamus is composed of myriad (2014). Neurobiology of food intake in health to male intruders continued to fire at very specific circuits which are and disease. Nat. Rev. Neurosci. 15, 367–378. Saper, C.B., and Stornetta, R.L. (2014). Central high rates during the encounter, but devoted to important life functions. autonomic system. In: The Rat Nervous those responding to females tended The examples above are just a small System, Third Edition, G. Paxinos, ed. (San to decrease firing as the encounter sampling of some of the prominent Diego: Elsevier Academic Press), in press. Saper, C.B. (2012). Hypothalamus. In: The Human progressed. Optogenetic activation circuits that have come to light in Nervous System, Second Edition. J.K. Mai of neurons in the same region caused the last few years. This wealth of and G. Paxinos, eds. (Amsterdam: Elsevier), pp. 548–583. male mice to attack other mice of new data is due in part to the fact Saper, C.B., Fuller, P.M., Pedersen, N.P., Lu, J., both sexes, as well as inanimate that so many of the hypothalamic and Scammell, T.E. (2010). Sleep state objects. But during a sexual circuits have distinct peptide switching. Neuron 68, 1023–1042. Saper, C.B., Romanovsky, A.A., and Scammell, T.E. encounter, the same stimulation neurotransmitters, which allow us (2012). Neural circuitry engaged by would not provoke attack. to manipulate and map specific during the sickness syndrome. 15, These observations suggest that populations of neurons using modern Nat. Neurosci. 1088–1095. these ventromedial nucleus neurons, tools such as conditional knockouts, which gate two polar opposite cell-specific mapping tools, and 1Department of Neurology, 2Division of 3 types of social interactions, must chemo- and optogenetics. Endocrinology, Program in Neuroscience, Beth Israel Deaconess Medical Center and share many of the same inputs. The picture that is emerging, Harvard Medical School, Boston MA 02215, However, they must have distinct however, is that the regulatory USA. sets of output pathways, and these circuits that control basic life *E-mail: [email protected]