Dr. Nirao Shah is a Professor of Psychiatry and Behavioral Sciences and of Neurobiology at Stanford University. After completing his medical training, Nirao was a graduate student at Caltech, where he identified mechanisms that control differentiation of stem cells that give rise to the peripheral nervous system. For his post-graduate fellowship at Columbia University, Nirao developed genetic approaches to identify neural pathways that regulate social behaviors. In his own laboratory, his research has elaborated on such approaches to identify genes and neurons that control different aspects of social interactions. Nirao’s findings have provided insights into how our brains enable social interactions in health, and they are relevant to understanding mechanisms underlying behavioral manifestations of autism, dementia, mood disorders, and PTSD.
Director of Neurosciences Graduate Program, School of Medicine (2019 - Present)
Honors & Awards
Scholar in Neuroscience, Ellison Medical Foundation (2012)
Byers Award, UCSF (2010)
Pioneer Award, NIH (2009)
Young Investigator Award, NARSAD (2009)
Mallinckrodt Scholar, Edward Mallinckrodt, Jr. Foundation (2008)
Kavli Fellow, German American Frontiers of Science Foundation (2006)
Alfred P. Sloan Fellow, Sloan Foundation (2005)
Scholar, McKnight Endowment Fund for Neuroscience (2005)
Career Award in Biomedical Sciences, Burroughs Wellcome Fund (2000)
Fellow, Jane Coffin Childs Memorial Fund for Medical Research (1997)
Fellow, Columbia University, Neural Circuits & Behavior (2003)
Ph.D., Caltech, Stem Cells (1997)
Clinical Internship, Seth G.S. Medical College & K.EM. Hospital, Mumbai, Medicine (1991)
M.B.,B.S., Seth G.S. Medical College & K.EM. Hospital, Mumbai, Medicine (1990)
David Anderson, Nirao Shah. "United States Patent 6,001,654 Methods for differentiating neural stem cells to neurons or smooth muscle cells using TGF-ß super family growth factors", Caltech, Dec 14, 1999
Current Research and Scholarly Interests
We study how our brains generate social interactions that differ between the sexes. Such gender differences in behavior are regulated by sex hormones, experience, and social cues. Accordingly, we are characterizing how these internal and external factors control gene expression and neuronal physiology in the two sexes to generate behavior. We are also interested in understanding how such sex differences in the healthy brain translate to sex differences in many neuro-psychiatric illnesses.
Doctoral Dissertation Reader (AC)
Luke Brezovec, Lucas Encarnacion-Rivera, Ellen Gingrich, Josh Head, Neil Khosla, Ethan Richman
Postdoctoral Faculty Sponsor
Lele Cui, Dan Landayan, Vinicius Miessler de Andrade Carvalho, Sakura Tanaka, Yichao Wei, Renzhi Yang
Doctoral Dissertation Advisor (AC)
Chung-ha Davis, Leonardi Gozali
Graduate and Fellowship Programs
Endocrinology (Fellowship Program)
A neural circuit for male sexual behavior and reward.
Male sexual behavior is innate and rewarding. Despite its centrality to reproduction, a molecularly specified neural circuit governing innate male sexual behavior and reward remains to be characterized. We have discovered a developmentally wired neural circuit necessary and sufficient for male mating. This circuit connects chemosensory input to BNSTprTac1 neurons, which innervate POATacr1 neurons that project to centers regulating motor output and reward. Epistasis studies demonstrate that BNSTprTac1 neurons are upstream of POATacr1 neurons, and BNSTprTac1-released substance P following mate recognition potentiates activation of POATacr1 neurons through Tacr1 to initiate mating. Experimental activation of POATacr1 neurons triggers mating, even in sexually satiated males, and it is rewarding, eliciting dopamine release and self-stimulation of these cells. Together, we have uncovered a neural circuit that governs the key aspects of innate male sexual behavior: motor displays, drive, and reward.
View details for DOI 10.1016/j.cell.2023.07.021
View details for PubMedID 37572660
Hypothalamic neurons that mirror aggression.
Social interactions require awareness and understanding of the behavior of others. Mirror neurons, cells representing an action by self and others, have been proposed to be integral to the cognitive substrates that enable such awareness and understanding. Mirror neurons of the primate neocortex represent skilled motor tasks, but it is unclear if they are critical for the actions they embody, enable social behaviors, or exist in non-cortical regions. We demonstrate that the activity of individual VMHvlPR neurons in the mouse hypothalamus represents aggression performed by self and others. We used a genetically encoded mirror-TRAP strategy to functionally interrogate these aggression-mirroring neurons. We find that their activity is essential for fighting and that forced activation of these cells triggers aggressive displays by mice, even toward their mirror image. Together, we have discovered a mirroring center in an evolutionarily ancient region that provides a subcortical cognitive substrate essential for a social behavior.
View details for DOI 10.1016/j.cell.2023.01.022
View details for PubMedID 36796363
Oxytocin receptor is not required for social attachment in prairie voles.
Prairie voles are among a small group of mammals that display long-term social attachment between mating partners. Many pharmacological studies show that signaling via the oxytocin receptor (Oxtr) is critical for the display of social monogamy in these animals. We used CRISPR mutagenesis to generate three different Oxtr-null mutant prairie vole lines. Oxtr mutants displayed social attachment such that males and females showed a behavioral preference for their mating partners over a stranger of the opposite sex, even when assayed using different experimental setups. Mothers lacking Oxtr delivered viable pups, and parents displayed care for their young and raised them to the weanling stage. Together, our studies unexpectedly reveal that social attachment, parturition, and parental behavior can occur in the absence of Oxtr signaling in prairie voles.
View details for DOI 10.1016/j.neuron.2022.12.011
View details for PubMedID 36708707
A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior.
Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.
View details for DOI 10.1016/j.cell.2021.12.031
View details for PubMedID 35065713
Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior.
Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with 3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.
View details for DOI 10.1016/j.cell.2019.10.025
View details for PubMedID 31735496
Evolution of Mechanisms that Control Mating in Drosophila Males.
2019; 27 (9): 2527
Genetically wired neural mechanisms inhibit mating between species because even naive animals rarely mate with other species. These mechanisms can evolve through changes in expression or function of key genes in sensory pathways or central circuits. Gr32a is a gustatory chemoreceptor that, in D.melanogaster, is essential to inhibit interspecies courtship and sense quinine. Similar to D.melanogaster, we find that D.simulans Gr32a is expressed in foreleg tarsi, sensorimotor appendages that inhibit interspecies courtship, and it is required to sense quinine. Nevertheless, Gr32a is not required to inhibit interspecies mating by D.simulans males. However, and similar to its function in D.melanogaster, Ppk25, a member of the Pickpocket family, promotes conspecific courtship in D.simulans. Together, we have identified distinct evolutionary mechanisms underlying chemosensory control of taste and courtship in closely related Drosophila species.
View details for DOI 10.1016/j.celrep.2019.04.104
View details for PubMedID 31141679
Limbic Neurons Shape Sex Recognition and Social Behavior in Sexually Naive Males.
Sexually naive animals have to distinguish between the sexes because they show species-typical interactions with males and females without meaningful prior experience. However, central neural pathways in naive mammals that recognize sex of other individuals remain poorly characterized. We examined the role of the principal component of the bed nucleus of stria terminalis (BNSTpr), a limbic center, in social interactions in mice. We find that activity of aromatase-expressing BNSTpr (AB) neurons appears to encode sex of other animals and subsequent displays of mating in sexually naive males. Silencing these neurons in males eliminates preference for female pheromones and abrogates mating success, whereas activating them even transiently promotes male-male mating. Surprisingly, female AB neurons do not appear to control sex recognition, mating, or maternal aggression. In summary, AB neurons represent sex of other animals and govern ensuing social behaviors in sexually naive males.
View details for PubMedID 30712868
- Neural control of sexually dimorphic social behaviors CURRENT OPINION IN PHYSIOLOGY 2018; 6: 89–95
Molecular mechanisms underlying sexual differentiation of the nervous system.
Current opinion in neurobiology
2018; 53: 192–97
A long-standing goal in developmental neuroscience is to understand the mechanisms by which steroid sex hormones pattern the mammalian central nervous system along male or female pathways to enable subsequent displays of sexually dimorphic behaviors. In this article, we review recent advances in understanding the epigenetic and transcriptional mechanisms mediating sexual differentiation of the brain in mammals, flies, and worms. These studies suggest a model of sexual differentiation wherein master regulators of sex determination initiate a cascade of sexually dimorphic gene expression that controls development of neural pathways and behavioral displays in a strikingly modular manner. With these advances in molecular genetics, it is now feasible to disassemble different components of sexually dimorphic social behaviors without disrupting other behavioral interactions. Such experimental tractability promises rapid advances in this exciting field.
View details for PubMedID 30316066
Identification of a motor-to-auditory pathway important for vocal learning.
Learning to vocalize depends on the ability to adaptively modify the temporal and spectral features of vocal elements. Neurons that convey motor-related signals to the auditory system are theorized to facilitate vocal learning, but the identity and function of such neurons remain unknown. Here we identify a previously unknown neuron type in the songbird brain that transmits vocal motor signals to the auditory cortex. Genetically ablating these neurons in juveniles disrupted their ability to imitate features of an adult tutor's song. Ablating these neurons in adults had little effect on previously learned songs but interfered with their ability to adaptively modify the duration of vocal elements and largely prevented the degradation of songs' temporal features that is normally caused by deafening. These findings identify a motor to auditory circuit essential to vocal imitation and to the adaptive modification of vocal timing.
View details for DOI 10.1038/nn.4563
View details for PubMedID 28504672
Social Control of Hypothalamus-Mediated Male Aggression.
2017; 95 (4): 955–70.e4
How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male's territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression.
View details for PubMedID 28757304
View details for PubMedCentralID PMC5648542
Molecular and neural control of sexually dimorphic social behaviors
CURRENT OPINION IN NEUROBIOLOGY
2016; 38: 89-95
Sexually reproducing animals exhibit sex differences in behavior. Sexual dimorphisms in mating, aggression, and parental care directly contribute to reproductive success of the individual and survival of progeny. In this review, we discuss recent advances in our understanding of the molecular and neural network mechanisms underlying these behaviors in mice. Notable advances include novel insights into the sensory control of social interactions and the identification of molecularly-specified neuronal populations in the brain that control mating, aggression, and parental behaviors. In the case of the latter, these advances mark a watershed because scientists can now focus on discrete neural pathways in an effort to understand how the brain encodes these fundamental social behaviors.
View details for DOI 10.1016/j.conb.2016.04.015
View details for Web of Science ID 000379556700015
View details for PubMedID 27162162
View details for PubMedCentralID PMC4985614
Retinofugal Projections from Melanopsin-Expressing Retinal Ganglion Cells Revealed by Intraocular Injections of Cre-Dependent Virus
2016; 11 (2)
To understand visual functions mediated by intrinsically photosensitive melanopsin-expressing retinal ganglion cells (mRGCs), it is important to elucidate axonal projections from these cells into the brain. Initial studies reported that melanopsin is expressed only in retinal ganglion cells within the eye. However, recent studies in Opn4-Cre mice revealed Cre-mediated marker expression in multiple brain areas. These discoveries complicate the use of melanopsin-driven genetic labeling techniques to identify retinofugal projections specifically from mRGCs. To restrict labeling to mRGCs, we developed a recombinant adeno-associated virus (AAV) carrying a Cre-dependent reporter (human placental alkaline phosphatase) that was injected into the vitreous of Opn4-Cre mouse eyes. The labeling observed in the brain of these mice was necessarily restricted specifically to retinofugal projections from mRGCs in the injected eye. We found that mRGCs innervate multiple nuclei in the basal forebrain, hypothalamus, amygdala, thalamus and midbrain. Midline structures tended to be bilaterally innervated, whereas the lateral structures received mostly contralateral innervation. As validation of our approach, we found projection patterns largely corresponded with previously published results; however, we have also identified a few novel targets. Our discovery of projections to the central amygdala suggests a possible direct neural pathway for aversive responses to light in neonates. In addition, projections to the accessory optic system suggest that mRGCs play a direct role in visual tracking, responses that were previously attributed to other classes of retinal ganglion cells. Moreover, projections to the zona incerta raise the possibility that mRGCs could regulate visceral and sensory functions. However, additional studies are needed to investigate the actual photosensitivity of mRGCs that project to the different brain areas. Also, there is a concern of "overlabeling" with very sensitive reporters that uncover low levels of expression. Light-evoked signaling from these cells must be shown to be of sufficient sensitivity to elicit physiologically relevant responses.
View details for DOI 10.1371/journal.pone.0149501
View details for Web of Science ID 000371223400060
View details for PubMedID 26895233
Genetic dissection of neural circuits underlying sexually dimorphic social behaviours
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
2016; 371 (1688)
The unique hormonal, genetic and epigenetic environments of males and females during development and adulthood shape the neural circuitry of the brain. These differences in neural circuitry result in sex-typical displays of social behaviours such as mating and aggression. Like other neural circuits, those underlying sex-typical social behaviours weave through complex brain regions that control a variety of diverse behaviours. For this reason, the functional dissection of neural circuits underlying sex-typical social behaviours has proved to be difficult. However, molecularly discrete neuronal subpopulations can be identified in the heterogeneous brain regions that control sex-typical social behaviours. In addition, the actions of oestrogens and androgens produce sex differences in gene expression within these brain regions, thereby highlighting the neuronal subpopulations most likely to control sexually dimorphic social behaviours. These conditions permit the implementation of innovative genetic approaches that, in mammals, are most highly advanced in the laboratory mouse. Such approaches have greatly advanced our understanding of the functional significance of sexually dimorphic neural circuits in the brain. In this review, we discuss the neural circuitry of sex-typical social behaviours in mice while highlighting the genetic technical innovations that have advanced the field.
View details for DOI 10.1098/rstb.2015.0109
View details for Web of Science ID 000369065000002
View details for PubMedID 26833830
Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output
2015; 4 (11): 857-866
The ventromedial hypothalamic nucleus (VMH) regulates energy homeostasis as well as social and emotional behaviors. Nearly all VMH neurons, including those in the sexually dimorphic ventrolateral VMH (VMHvl) subregion, release the excitatory neurotransmitter glutamate and use the vesicular glutamate transporter 2 (Vglut2). Here, we asked how glutamatergic signaling contributes to the collective metabolic and behavioral responses attributed to the VMH and VMHvl.Using Sf1-Cre and a Vglut2 floxed allele, Vglut2 was knocked-out in SF-1 VMH neurons (Vglut2 (Sf1-Cre) ). Metabolic and neurobehavioral assays were carried out initially on Vglut2 (fl/fl) and Vglut2 (Sf1-Cre) mice in a mixed, and then in the C57BL/6 genetic background, which is prone to hyperglycemia and diet induced obesity (DIO).Several phenotypes observed in Vglut2 (Sf1-Cre) mice were largely unexpected based on prior studies that have perturbed VMH development or VMH glutamate signaling. In our hands, Vglut2 (Sf1-Cre) mice failed to exhibit the anticipated increase in body weight after high fat diet (HFD) or the impaired glucose homeostasis after fasting. Instead, there was a significant sex-dependent attenuation of DIO in Vglut2 (Sf1-Cre) females. Vglut2 (Sf1-Cre) males also display a sex-specific loss of conditioned-fear responses and aggression accompanied by more novelty-associated locomotion. Finally, unlike the higher anxiety noted in Sf1 (Nestin-Cre) mice that lack a fully formed VMH, both male and female Vglut2 (Sf1-Cre) mice were less anxious.Loss of VMH glutamatergic signaling sharply decreased DIO in females, attenuated aggression and learned fear in males, and was anxiolytic in males and females. Collectively, our findings demonstrate that while glutamatergic output from the VMH appears largely dispensable for counter regulatory responses to hypoglycemia, it drives sex-dependent differences in metabolism and social behaviors and is essential for adaptive responses to anxiety-provoking stimuli in both sexes.
View details for DOI 10.1016/j.molmet.2015.09.001
View details for Web of Science ID 000367447300010
View details for PubMedID 26629409
Specification of Select Hypothalamic Circuits and Innate Behaviors by the Embryonic Patterning Gene Dbx1
2015; 86 (2): 403-416
The hypothalamus integrates information required for the production of a variety of innate behaviors such as feeding, mating, aggression, and predator avoidance. Despite an extensive knowledge of hypothalamic function, how embryonic genetic programs specify circuits that regulate these behaviors remains unknown. Here, we find that in the hypothalamus the developmentally regulated homeodomain-containing transcription factor Dbx1 is required for the generation of specific subclasses of neurons within the lateral hypothalamic area/zona incerta (LH) and the arcuate (Arc) nucleus. Consistent with this specific developmental role, Dbx1 hypothalamic-specific conditional-knockout mice display attenuated responses to predator odor and feeding stressors but do not display deficits in other innate behaviors such as mating or conspecific aggression. Thus, activity of a single developmentally regulated gene, Dbx1, is a shared requirement for the specification of hypothalamic nuclei governing a subset of innate behaviors. VIDEO ABSTRACT.
View details for DOI 10.1016/j.neuron.2015.03.022
View details for Web of Science ID 000353410000010
View details for PubMedID 25864637
Medial Amygdalar Aromatase Neurons Regulate Aggression in Both Sexes
2015; 10 (4): 453-462
Aromatase-expressing neuroendocrine neurons in the vertebrate male brain synthesize estradiol from circulating testosterone. This locally produced estradiol controls neural circuits underlying courtship vocalization, mating, aggression, and territory marking in male mice. How aromatase-expressing neuronal populations control these diverse estrogen-dependent male behaviors is poorly understood, and the function, if any, of aromatase-expressing neurons in females is unclear. Using targeted genetic approaches, we show that aromatase-expressing neurons within the male posterodorsal medial amygdala (MeApd) regulate components of aggression, but not other estrogen-dependent male-typical behaviors. Remarkably, aromatase-expressing MeApd neurons in females are specifically required for components of maternal aggression, which we show is distinct from intermale aggression in pattern and execution. Thus, aromatase-expressing MeApd neurons control distinct forms of aggression in the two sexes. Moreover, our findings indicate that complex social behaviors are separable in a modular manner at the level of genetically identified neuronal populations.
View details for DOI 10.1016/j.celrep.2014.12.040
View details for Web of Science ID 000349404100001
View details for PubMedID 25620703
Representing Sex in the Brain, One Module at a Time
2014; 82 (2): 261-278
Sexually dimorphic behaviors, qualitative or quantitative differences in behaviors between the sexes, result from the activity of a sexually differentiated nervous system. Sensory cues and sex hormones control the entire repertoire of sexually dimorphic behaviors, including those commonly thought to be charged with emotion such as courtship and aggression. Such overarching control mechanisms regulate distinct genes and neurons that in turn specify the display of these behaviors in a modular manner. How such modular control is transformed into cohesive internal states that correspond to sexually dimorphic behavior is poorly understood. We summarize current understanding of the neural circuit control of sexually dimorphic behaviors from several perspectives, including how neural circuits in general, and sexually dimorphic neurons in particular, can generate sexually dimorphic behaviors, and how molecular mechanisms and evolutionary constraints shape these behaviors. We propose that emergent themes such as the modular genetic and neural control of dimorphic behavior are broadly applicable to the neural control of other behaviors.
View details for DOI 10.1016/j.neuron.2014.03.029
View details for Web of Science ID 000334506800005
View details for PubMedID 24742456
Striatal Cholinergic Interneurons Drive GABA Release from Dopamine Terminals
2014; 82 (1): 63-70
Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.
View details for DOI 10.1016/j.neuron.2014.01.023
View details for Web of Science ID 000333804800008
View details for PubMedID 24613418
Complex Chemosensory Control of Female Reproductive Behaviors
2014; 9 (2)
Olfaction exerts a profound influence on reproductive physiology and behavior in many animals, including rodents. Odors are recognized by sensory neurons residing in the main olfactory epithelium (MOE) and the vomeronasal organ (VNO) in mice and many other vertebrates. The relative contributions of the MOE and VNO in the display of female behaviors are not well understood. Mice null for Cnga2 or Trpc2 essentially lack odor-evoked activity in the MOE and VNO, respectively. Using females mutant for one or both of Cnga2 and Trpc2, we find that maternal care is differentially regulated by the MOE and VNO: retrieval of wandering pups requires the MOE and is regulated redundantly by the VNO whereas maternal aggression requires both sensory epithelia to be functional. Female sexual receptivity appears to be regulated by both the MOE and VNO. Trpc2 null females have previously been shown to display male-type mounting towards other males. Remarkably, we find that females double mutant for Cnga2 and Trpc2 continue to mount other males, indicating that the disinhibition of male-type sexual displays observed in Trpc2 null females does not require chemosensory input from a functional MOE. Taken together, our findings reveal a previously unappreciated complexity in the chemosensory control of reproductive behaviors in the female mouse.
View details for DOI 10.1371/journal.pone.0090368
View details for Web of Science ID 000332396200180
View details for PubMedID 24587340
Turning ON Caspases with Genetics and Small Molecules
REGULATED CELL DEATH PT A: APOPTOTIC MECHANISMS
2014; 544: 179-213
Caspases, aspartate-specific cysteine proteases, have fate-determining roles in many cellular processes including apoptosis, differentiation, neuronal remodeling, and inflammation (for review, see Yuan & Kroemer, 2010). There are a dozen caspases in humans alone, yet their individual contributions toward these phenotypes are not well understood. Thus, there has been considerable interest in activating individual caspases or using their activity to drive these processes in cells and animals. We envision that such experimental control of caspase activity can not only afford novel insights into fundamental biological problems but may also enable new models for disease and suggest possible routes to therapeutic intervention. In particular, localized, genetic, and small-molecule-controlled caspase activation has the potential to target the desired cell type in a tissue. Suppression of caspase activation is one of the hallmarks of cancer and thus there has been significant enthusiasm for generating selective small-molecule activators that could bypass upstream mutational events that prevent apoptosis. Here, we provide a practical guide that investigators have devised, using genetics or small molecules, to activate specific caspases in cells or animals. Additionally, we show genetically controlled activation of an executioner caspase to target the function of a defined group of neurons in the adult mammalian brain.
View details for DOI 10.1016/B978-0-12-417158-9.00008-X
View details for Web of Science ID 000341414700009
View details for PubMedID 24974291
Genetic and Neural Mechanisms that Inhibit Drosophila from Mating with Other Species
2013; 154 (1): 89-102
Genetically hard-wired neural mechanisms must enforce behavioral reproductive isolation because interspecies courtship is rare even in sexually naïve animals of most species. We find that the chemoreceptor Gr32a inhibits male D. melanogaster from courting diverse fruit fly species. Gr32a recognizes nonvolatile aversive cues present on these reproductively dead-end targets, and activity of Gr32a neurons is necessary and sufficient to inhibit interspecies courtship. Male-specific Fruitless (Fru(M)), a master regulator of courtship, also inhibits interspecies courtship. Gr32a and Fru(M) are not coexpressed, but Fru(M) neurons contact Gr32a neurons, suggesting that these genes influence a shared neural circuit that inhibits interspecies courtship. Gr32a and Fru(M) also suppress within-species intermale courtship, but we show that distinct mechanisms preclude sexual displays toward conspecific males and other species. Although this chemosensory pathway does not inhibit interspecies mating in D. melanogaster females, similar mechanisms appear to inhibit this behavior in many other male drosophilids.
View details for DOI 10.1016/j.cell.2013.06.008
View details for Web of Science ID 000321327900012
View details for PubMedID 23810192
Neural control of sexually dimorphic behaviors
CURRENT OPINION IN NEUROBIOLOGY
2013; 23 (3): 330-338
All sexually reproducing animals exhibit gender differences in behavior. Such sexual dimorphisms in behavior are most obvious in stereotyped displays that enhance reproductive success such as mating, aggression, and parental care. Sexually dimorphic behaviors are a consequence of a sexually differentiated nervous system, and recent studies in fruit flies and mice reveal novel insights into the neural mechanisms that control these behaviors. In the main, these include a diverse array of novel sex differences in the nervous system, surprisingly modular control of various stereotyped dimorphic behavioral routines, and unanticipated sensory and central modulation of mating. We start with a brief overview to provide the appropriate conceptual framework so that the advances made by the newer studies discussed subsequently can be fully appreciated. We restrict our review to reporting progress in understanding the basis of mating and aggression in fruit flies and mice.
View details for DOI 10.1016/j.conb.2013.04.005
View details for Web of Science ID 000320750000007
View details for PubMedID 23680385
Sexually Dimorphic Neurons in the Ventromedial Hypothalamus Govern Mating in Both Sexes and Aggression in Males
2013; 153 (4): 896-909
Sexual dimorphisms in the brain underlie behavioral sex differences, but the function of individual sexually dimorphic neuronal populations is poorly understood. Neuronal sexual dimorphisms typically represent quantitative differences in cell number, gene expression, or other features, and it is unknown whether these dimorphisms control sex-typical behavior exclusively in one sex or in both sexes. The progesterone receptor (PR) controls female sexual behavior, and we find many sex differences in number, distribution, or projections of PR-expressing neurons in the adult mouse brain. Using a genetic strategy we developed, we have ablated one such dimorphic PR-expressing neuronal population located in the ventromedial hypothalamus (VMH). Ablation of these neurons in females greatly diminishes sexual receptivity. Strikingly, the corresponding ablation in males reduces mating and aggression. Our findings reveal the functions of a molecularly defined, sexually dimorphic neuronal population in the brain. Moreover, we show that sexually dimorphic neurons can control distinct sex-typical behaviors in both sexes.
View details for DOI 10.1016/j.cell.2013.04.017
View details for Web of Science ID 000318844000017
View details for PubMedID 23663785
Generation of Induced Pluripotent Stem Cells from the Prairie Vole
2012; 7 (5)
The vast majority of animals mate more or less promiscuously. A few mammals, including humans, utilize more restrained mating strategies that entail a longer term affiliation with a single mating partner. Such pair bonding mating strategies have been resistant to genetic analysis because of a lack of suitable model organisms. Prairie voles are small mouse-like rodents that form enduring pair bonds in the wild as well as in the laboratory, and consequently they have been used widely to study social bonding behavior. The lack of targeted genetic approaches in this species however has restricted the study of the molecular and neural circuit basis of pair bonds. As a first step in rendering the prairie vole amenable to reverse genetics, we have generated induced pluripotent stem cell (IPSC) lines from prairie vole fibroblasts using retroviral transduction of reprogramming factors. These IPSC lines display the cellular and molecular hallmarks of IPSC cells from other organisms, including mice and humans. Moreover, the prairie vole IPSC lines have pluripotent differentiation potential since they can give rise to all three germ layers in tissue culture and in vivo. These IPSC lines can now be used to develop conditions that facilitate homologous recombination and eventually the generation of prairie voles bearing targeted genetic modifications to study the molecular and neural basis of pair bond formation.
View details for DOI 10.1371/journal.pone.0038119
View details for Web of Science ID 000305338500089
View details for PubMedID 22675440
Modular Genetic Control of Sexually Dimorphic Behaviors
2012; 148 (3): 596-607
Sex hormones such as estrogen and testosterone are essential for sexually dimorphic behaviors in vertebrates. However, the hormone-activated molecular mechanisms that control the development and function of the underlying neural circuits remain poorly defined. We have identified numerous sexually dimorphic gene expression patterns in the adult mouse hypothalamus and amygdala. We find that adult sex hormones regulate these expression patterns in a sex-specific, regionally restricted manner, suggesting that these genes regulate sex typical behaviors. Indeed, we find that mice with targeted disruptions of each of four of these genes (Brs3, Cckar, Irs4, Sytl4) exhibit extremely specific deficits in sex specific behaviors, with single genes controlling the pattern or extent of male sexual behavior, male aggression, maternal behavior, or female sexual behavior. Taken together, our findings demonstrate that various components of sexually dimorphic behaviors are governed by separable genetic programs.
View details for DOI 10.1016/j.cell.2011.12.018
View details for Web of Science ID 000300225000025
View details for PubMedID 22304924
Restriction of Transient Receptor Potential Vanilloid-1 to the Peptidergic Subset of Primary Afferent Neurons Follows Its Developmental Downregulation in Nonpeptidergic Neurons
JOURNAL OF NEUROSCIENCE
2011; 31 (28): 10119-10127
Primary afferent "pain" fibers (nociceptors) are divided into subclasses based on distinct molecular and anatomical features, and these classes mediate noxious modality-specific contributions to behaviors evoked by painful stimuli. Whether the heat and capsaicin receptor transient receptor potential vanilloid-1 (TRPV1) is expressed heterogeneously across several sensory populations, or is selectively expressed by a unique nociceptor subclass, however, is unclear. Here we used two lines of Trpv1 reporter mice to investigate the primary afferent expression of TRPV1, both during development and in the adult. We demonstrate, using Cre-induced lineage tracing, that during development TRPV1 is transiently expressed in a wide range of dorsal root ganglion neurons, and that its expression is gradually refined, such that TRPV1 transcripts become restricted to a specific subset of peptidergic sensory neurons. Finally, the remarkable sensitivity that is characteristic of these reporter mice revealed an innervation of central and peripheral targets by TRPV1+ primary afferents in the adult that is considerably more extensive than has previously been appreciated.
View details for DOI 10.1523/JNEUROSCI.1299-11.2011
View details for Web of Science ID 000292699600002
View details for PubMedID 21752988
Trpv1 Reporter Mice Reveal Highly Restricted Brain Distribution and Functional Expression in Arteriolar Smooth Muscle Cells
JOURNAL OF NEUROSCIENCE
2011; 31 (13): 5067-5077
The heat and capsaicin receptor, TRPV1, is required for the detection of painful heat by primary afferent pain fibers (nociceptors), but the extent to which functional TRPV1 channels are expressed in the CNS is debated. Because previous evidence is based primarily on indirect physiological responses to capsaicin, here we genetically modified the Trpv1 locus to reveal, with excellent sensitivity and specificity, the distribution of TRPV1 in all neuronal and non-neuronal tissues. In contrast to reports of widespread and robust expression in the CNS, we find that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus. We confirm hypothalamic expression in the mouse using several complementary approaches, including in situ hybridization, calcium imaging, and electrophysiological recordings. Additional in situ hybridization experiments in rat, monkey, and human brain demonstrate that the restricted expression of TRPV1 in the CNS is conserved across species. Outside of the CNS, we find TRPV1 expression in a subset of arteriolar smooth muscle cells within thermoregulatory tissues. Here, capsaicin increases calcium uptake and induces vasoconstriction, an effect that likely counteracts the vasodilation produced by activation of neuronal TRPV1.
View details for DOI 10.1523/JNEUROSCI.6451-10.2011
View details for Web of Science ID 000288938200032
View details for PubMedID 21451044
Control of masculinization of the brain and behavior
CURRENT OPINION IN NEUROBIOLOGY
2011; 21 (1): 116-123
Sex steroid hormones exert a profound influence on the sexual differentiation and function of the neural circuits that mediate dimorphic behaviors. Both estrogen and testosterone are essential for male typical behaviors in many species. Recent studies with genetically modified mice provide important new insights into the logic whereby these two hormones coordinate the display of sexually dimorphic behaviors: estrogen sets up the masculine repertoire of sexual and territorial behaviors and testosterone controls the extent of these male displays.
View details for DOI 10.1016/j.conb.2010.09.014
View details for Web of Science ID 000288876100016
View details for PubMedID 20970320
The Androgen Receptor Governs the Execution, but Not Programming, of Male Sexual and Territorial Behaviors
2010; 66 (2): 260-272
Testosterone and estrogen are essential for male behaviors in vertebrates. How these two signaling pathways interact to control masculinization of the brain and behavior remains to be established. Circulating testosterone activates the androgen receptor (AR) and also serves as the source of estrogen in the brain. We have used a genetic strategy to delete AR specifically in the mouse nervous system. This approach permits us to determine the function of AR in sexually dimorphic behaviors in males while maintaining circulating testosterone levels within the normal range. We find that AR mutant males exhibit masculine sexual and territorial displays, but they have striking deficits in specific components of these behaviors. Taken together with the surprisingly limited expression of AR in the developing brain, our findings indicate that testosterone acts as a precursor to estrogen to masculinize the brain and behavior, and signals via AR to control the levels of male behavioral displays.
View details for DOI 10.1016/j.neuron.2010.03.024
View details for Web of Science ID 000277308200011
View details for PubMedID 20435002
Estrogen Masculinizes Neural Pathways and Sex-Specific Behaviors
2009; 139 (1): 61-72
Sex hormones are essential for neural circuit development and sex-specific behaviors. Male behaviors require both testosterone and estrogen, but it is unclear how the two hormonal pathways intersect. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. We demonstrate extensive sexual dimorphism in the number and projections of aromatase-expressing neurons. The masculinization of these cells is independent of AR but can be induced in females by either testosterone or estrogen, indicating a role for aromatase in sexual differentiation of these neurons. We provide evidence suggesting that aromatase is also important in activating male-specific aggression and urine marking because these behaviors can be elicited by testosterone in males mutant for AR and in females subjected to neonatal estrogen exposure. Our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.
View details for DOI 10.1016/j.cell.2009.07.036
View details for Web of Science ID 000270388600016
View details for PubMedID 19804754
A genetic approach to dissect sexually dimorphic behaviors
HORMONES AND BEHAVIOR
2008; 53 (5): 627-637
It has been known since antiquity that gender-specific behaviors are regulated by the gonads. We now know that testosterone is required for the appropriate display of male patterns of behavior. Estrogen and progesterone, on the other hand, are essential for female typical responses. Research from several groups also indicates that estrogen signaling is required for male typical behaviors. This finding raises the issue of the relative contribution of these two hormonal systems in the control of male typical behavioral displays. In this review we discuss the findings that led to these conclusions and suggest various genetic strategies that may be required to understand the relative roles of testosterone and estrogen signaling in the control of gender-specific behavior.
View details for DOI 10.1016/j.yhbeh.2007.12.012
View details for Web of Science ID 000256283100004
View details for PubMedID 18313055
Abnormal social behaviors in mice lacking Fgf17
GENES BRAIN AND BEHAVIOR
2008; 7 (3): 344-354
The fibroblast growth factor family of secreted signaling molecules is essential for patterning in the central nervous system. Fibroblast growth factor 17 (Fgf17) has been shown to contribute to regionalization of the rodent frontal cortex. To determine how Fgf17 signaling modulates behavior, both during development and in adulthood, we studied mice lacking one or two copies of the Fgf17 gene. Fgf17-deficient mice showed no abnormalities in overall physical growth, activity level, exploration, anxiety-like behaviors, motor co-ordination, motor learning, acoustic startle, prepulse inhibition, feeding, fear conditioning, aggression and olfactory exploration. However, they displayed striking deficits in several behaviors involving specific social interactions. Fgf17-deficient pups vocalized less than wild-type controls when separated from their mother and siblings. Elimination of Fgf17 also decreased the interaction of adult males with a novel ovariectomized female in a social recognition test and reduced the amount of time opposite-sex pairs spent engaged in prolonged, affiliative interactions during exploration of a novel environment. After social exploration of a novel environment, Fgf17-deficient mice showed less activation of the immediate-early gene Fos in the frontal cortex than wild-type controls. Our findings show that Fgf17 is required for several complex social behaviors and suggest that disturbances in Fgf17 signaling may contribute to neuropsychiatric diseases that affect such behaviors.
View details for DOI 10.1111/j.1601-183X.2007.00357.x
View details for Web of Science ID 000254611500010
View details for PubMedID 17908176
- Behavioural neurobiology - Females can also be from Mars NATURE 2007; 448 (7157): 999-1000
Nursing behavior: Remembrance of things past
2006; 16 (19): R842-R844
Successful suckling is vital to the survival of mammalian newborns. In many mammals, nursing behavior is triggered by maternally derived odors. Such odors may also promote the learned association of odorant cues present in the environment during nursing.
View details for DOI 10.1016/j.cub.2006.09.001
View details for Web of Science ID 000241273000015
View details for PubMedID 17027479
Deficits in sexual and aggressive behaviors in Cnga2 mutant mice
2005; 8 (12): 1660-1662
Odors detected by the vomeronasal organ or the main olfactory epithelium (MOE) trigger social behaviors in many animals. It is unknown whether MOE neurons detect cues that initiate mating or aggression. We demonstrate that mice lacking functional CNGA2 (cyclic nucleotide-gated channel alpha2), which is required for odor-evoked MOE signaling, fail to mate or fight, suggesting a broad and essential role for the MOE in regulating these behaviors.
View details for DOI 10.1038/nn1589
View details for Web of Science ID 000233576200012
View details for PubMedID 16261133
Visualizing sexual dimorphism in the brain
2004; 43 (3): 313-319
Sexually dimorphic behaviors are likely to involve neural pathways that express the androgen receptor (AR). We have genetically modified the AR locus to visualize dimorphisms in neuronal populations that express AR. Analysis of AR-positive neurons reveals both known dimorphisms in the preoptic area of the hypothalamus and the bed nucleus of the stria terminalis as well as novel dimorphic islands in the basal forebrain with a clarity unencumbered by the vast population of AR-negative neurons. This genetic approach allows the visualization of dimorphic subpopulations of AR-positive neurons along with their projections and may ultimately permit an association between neural circuits and specific dimorphic behaviors.
View details for Web of Science ID 000223156900006
View details for PubMedID 15294140
Integration of multiple instructive cues by neural crest stem cells reveals cell-intrinsic biases in relative growth factor responsiveness
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1997; 94 (21): 11369-11374
Growth factors can influence lineage determination of neural crest stem cells (NCSCs) in an instructive manner, in vitro. Because NCSCs are likely exposed to multiple signals in vivo, these findings raise the question of how stem cells would integrate such combined influences. Bone morphogenetic protein 2 (BMP2) promotes neuronal differentiation and glial growth factor 2 (GGF2) promotes glial differentiation; if NCSCs are exposed to saturating concentrations of both factors, BMP2 appears dominant. By contrast, if the cells are exposed to saturating concentrations of both BMP2 and transforming growth factor beta1 (which promotes smooth muscle differentiation), the two factors appear codominant. Sequential addition experiments indicate that NCSCs require 48-96 hrs in GGF2 before they commit to a glial fate, whereas the cells commit to a smooth muscle fate within 24 hr in transforming growth factor beta1. The delayed response to GGF2 does not reflect a lack of functional receptors; however, because the growth factor induces rapid mitogen-activated protein kinase phosphorylation in naive cells. Furthermore, GGF2 can attenuate induction of the neurogenic transcription factor mammalian achaete-scute homolog 1, by low doses of BMP2. This short-term antineurogenic influence of GGF2 is not sufficient for glial lineage commitment, however. These data imply that NCSCs exhibit cell-intrinsic biases in the timing and relative dosage sensitivity of their responses to instructive factors that influence the outcome of lineage decisions in the presence of multiple factors. The relative delay in glial lineage commitment, moreover, apparently reflects successive short-term and longer-term actions of GGF2. Such a delay may help to explain why glia normally differentiate after neurons, in vivo.
View details for Web of Science ID A1997YA93000055
View details for PubMedID 9326616
- Regulatory mechanisms in stem cell biology CELL 1997; 88 (3): 287-298
Cell lineage determination and the control of neuronal identity in the neural crest
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
1997; 62: 493-504
The molecular mechanisms underlying the determination of neuronal identity in the vertebrate peripheral nervous system are only just beginning to come into focus. Many of these mechanisms, such as the involvement of cascades of bHLH transcription factors and lateral inhibition via the Notch-Delta system, appear to have been conserved from Drosophila (Ghysen et al. 1993; Jan and Jan 1993). The way in which these genetic circuits are controlled by instructive growth factors, and the manner in which they lead to expression of a particular neuronal identity, is far from clear. This process is being elucidated by studies of neurogenesis in the peripheral autonomic lineage, which is arguably the best-understood neurogenic lineage in vertebrates. Emerging evidence is beginning to suggest that neuronal diversity within the autonomic and sensory lineages may be generated by related, but distinct, mechanisms. All autonomic progenitors express a common bHLH protein, MASH1, which appears to be induced by members of the BMP2 subfamily secreted by the tissues to which these progenitors migrate. Additional signals may then act on these progenitors in different locations to induce the expression of other transcription factors, which act in conjunction with MASH1 to specify the final phenotypes of the different autonomic neuron subtypes (sympathetic, parasympathetic, and enteric). Although different classes of autonomic neurons develop in very different locations within the body, different classes of sensory neurons are located together in dorsal root ganglia. The finding that distinct but related subtypes of bHLH proteins, the neurogenins, are expressed by different classes of sensory neuron precursors early in development suggests that sensory neuron diversity, in contrast to autonomic neuron diversity, may be pre-specified at or before the time neural crest cells begin their emigration from the neural tube.
View details for Web of Science ID 000073570200055
View details for PubMedID 9598383
Alternative neural crest cell fates are instructively promoted by TGF beta superfamily members
1996; 85 (3): 331-343
How growth factors influence the fate of multipotent progenitor cells is not well understood. Most hematopoietic growth factors act selectively as survival factors, rather than instructively as lineage determination signals. In the neural crest, neuregulin instructively promotes gliogenesis, but how alternative fates are determined is unclear. We demonstrate that bone morphogenic protein 2 (BMP2) induces the basic-helix-loop-helix protein MASH1 and neurogenesis in neural crest stem cells. In vivo, MASH1+ cells are located near sites of BMP2 mRNA expression. Some smooth muscle differentiation is also observed in BMP2. A related factor, transforming growth factor beta1 (TGFbeta1), exclusively promotes smooth muscle differentiation. Like neuregulin, BMP2 and TGFbeta1 act instructively rather than selectively. The neural crest and hematopoietic systems may therefore utilize growth factors in different ways to generate cellular diversity.
View details for Web of Science ID A1996UK14000007
View details for PubMedID 8616889
The cellular function of MASH1 in autonomic neurogenesis
1995; 15 (6): 1245-1258
Using primary cultures and immortalized multipotential stem cell lines derived from wild-type and Mash1 mutant neural crest cells, we have analyzed the cellular function of MASH1 in autonomic neurogenesis. We present evidence for the existence of a precursor expressing MASH1 and neuronal markers such as neurofilament, neuron-specific tubulin, and tetanus toxin receptor. This cell has a nonneuronal morphology. Differentiation of this precursor to neurons that express markers such as SCG10, peripherin, and neuron-specific enolase is dependent upon MASH1 function. These data imply that the differentiation of autonomic neurons from uncommitted neural crest cells occurs in several sequential steps. Moreover, they suggest that MASH1 does not commit multipotent cells to a neural fate, like its Drosophila achaete-scute counterparts, but rather promotes the differentiation of a committed neuronal precursor.
View details for Web of Science ID A1995TL67800005
View details for PubMedID 8845150
GLIAL GROWTH-FACTOR RESTRICTS MAMMALIAN NEURAL CREST STEM-CELLS TO A GLIAL FATE
1994; 77 (3): 349-360
Growth factors and cytokines are thought to influence the development of uncommitted progenitor cell populations, but the issue of how these factors act on individual cells remains controversial. Such factors may act simply as selective mitogens or survival factors for cells that undergo lineage restrictions stochastically. Alternatively, they may instruct or bias multipotent cells to choose one lineage at the expense of others. Here we show that glial growth factor (GGF), previously defined as a Schwann cell mitogen, strongly suppresses neuronal differentiation of rat neural crest stem cells while promoting or allowing glial differentiation. Quantitative clonal analysis suggests that the action of GGF is likely to be instructive rather than selective. Taken together with the expression pattern of GGF, these data suggest a lateral signaling model for the diversification of cell types within developing peripheral ganglia.
View details for Web of Science ID A1994NK97000006
View details for PubMedID 7910115