Stanford Advisors

All Publications

  • Hypothalamic neurons that mirror aggression. Cell Yang, T., Bayless, D. W., Wei, Y., Landayan, D., Marcelo, I. M., Wang, Y., DeNardo, L. A., Luo, L., Druckmann, S., Shah, N. M. 2023


    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. Neuron Berendzen, K. M., Sharma, R., Mandujano, M. A., Wei, Y., Rogers, F. D., Simmons, T. C., Seelke, A. M., Bond, J. M., Larios, R., Goodwin, N. L., Sherman, M., Parthasarthy, S., Espineda, I., Knoedler, J. R., Beery, A., Bales, K. L., Shah, N. M., Manoli, D. S. 2022


    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

  • Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior. Cell Inoue, S., Yang, R., Tantry, A., Davis, C., Yang, T., Knoedler, J. R., Wei, Y., Adams, E. L., Thombare, S., Golf, S. R., Neve, R. L., Tessier-Lavigne, M., Ding, J. B., Shah, N. M. 2019


    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

  • Medial Preoptic Area Modulates Courtship Ultrasonic Vocalization in Adult Male Mice NEUROSCIENCE BULLETIN Gao, S., Wei, Y., Wang, S., Xu, X. 2019; 35 (4): 697–708


    Adult male mice emit highly complex ultrasonic vocalizations (USVs) in response to female conspecifics. Such USVs, thought to facilitate courtship behaviors, are routinely measured as a behavioral index in mouse models of neurodevelopmental and psychiatric disorders such as autism. While the regulation of USVs by genetic factors has been extensively characterized, the neural mechanisms that control USV production remain largely unknown. Here, we report that optogenetic activation of the medial preoptic area (mPOA) elicited the production of USVs that were acoustically similar to courtship USVs in adult mice. Moreover, mPOA vesicular GABA transporter-positive (Vgat +) neurons were more effective at driving USV production than vesicular glutamate transporter 2-positive neurons. Furthermore, ablation of mPOA Vgat+ neurons resulted in altered spectral features and syllable usage of USVs in targeted males. Together, these results demonstrate that the mPOA plays a crucial role in modulating courtship USVs and this may serve as an entry point for future dissection of the neural circuitry underlying USV production.

    View details for DOI 10.1007/s12264-019-00365-w

    View details for Web of Science ID 000475707300012

    View details for PubMedID 30900143

    View details for PubMedCentralID PMC6616611

  • AGRP Neurons Project to the Medial Preoptic Area and Modulate Maternal Nest-Building JOURNAL OF NEUROSCIENCE Li, X., Han, Y., Zhang, W., Wang, S., Wei, Y., Li, S., Lin, J., Yan, J., Chen, A., Zhang, X., Zhao, Z., Shen, W. L., Xu, X. 2019; 39 (3): 456–71


    AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ∼30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP→mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP→mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.

    View details for DOI 10.1523/JNEUROSCI.0958-18.2018

    View details for Web of Science ID 000455849400007

    View details for PubMedID 30459220

    View details for PubMedCentralID PMC6335756

  • Medial preoptic area in mice is capable of mediating sexually dimorphic behaviors regardless of gender NATURE COMMUNICATIONS Wei, Y., Wang, S., Jiao, Z., Zhang, W., Lin, J., Li, X., Li, S., Zhang, X., Xu, X. 2018; 9: 279


    The medial preoptic area (mPOA) differs between males and females in nearly all species examined to date, including humans. Here, using fiber photometry recordings of Ca2+ transients in freely behaving mice, we show ramping activities in the mPOA that precede and correlate with sexually dimorphic display of male-typical mounting and female-typical pup retrieval. Strikingly, optogenetic stimulation of the mPOA elicits similar display of mounting and pup retrieval in both males and females. Furthermore, by means of recording, ablation, optogenetic activation, and inhibition, we show mPOA neurons expressing estrogen receptor alpha (Esr1) are essential for the sexually biased display of these behaviors. Together, these results underscore the shared layout of the brain that can mediate sex-specific behaviors in both male and female mice and provide an important functional frame to decode neural mechanisms governing sexually dimorphic behaviors in the future.

    View details for DOI 10.1038/s41467-017-02648-0

    View details for Web of Science ID 000422745800014

    View details for PubMedID 29348568

    View details for PubMedCentralID PMC5773506



    Despite recent progress on neural pathways underlying individual behaviors, how an animal balances and prioritizes behavioral outputs remains poorly understood. While studying the relationship between hunger-induced feeding and pup-induced maternal behaviors in virgin female mice, we made the unexpected discovery that presence of pups strongly delayed and decreased food consumption. Strikingly, presence of pups also suppressed feeding induced by optogenetic activation of Agrp neurons. Such a suppressive effect inversely correlated with the extents of maternal behaviors, but did not rely on the display of these behaviors, and was also present in virgin males. Furthermore, chemogenetic activation of Vglut2+ neurons in the medial preoptic area (mPOA), a region critical for maternal behaviors and motivation, was sufficient to suppress hunger-induced feeding. However, muscimol inhibition of the mPOA, while disrupting maternal behaviors, did not prevent pup suppression of feeding, indicating that neural pathways in other brain regions may also mediate such an effect. Together, these results provide novel insights into neural coordination of pup care and feeding in mice and organizations of animal behaviors in general.

    View details for DOI 10.1016/j.neuroscience.2017.08.047

    View details for Web of Science ID 000412382100020

    View details for PubMedID 28882425

  • Sex Differences in Brain-Derived Neurotrophic Factor Signaling: Functions and Implications JOURNAL OF NEUROSCIENCE RESEARCH Wei, Y., Wang, S., Xu, X. 2017; 95 (1-2): 336–44


    Brain-derived neurotrophic factor (BDNF) regulates diverse processes such as neuronal survival, differentiation, and plasticity. Accumulating evidence suggests that molecular events that direct sexual differentiation of the brain interact with BDNF signaling pathways. This Mini-Review first examines potential hormonal and epigenetic mechanisms through which sex influences BDNF signaling. We then examine how sex-specific regulation of BDNF signaling supports the development and function of sexually dimorphic neural circuits that underlie male-specific genital reflexes in rats and song production in birds. Finally, we discuss the implications of sex differences in BDNF signaling for gender-biased presentation of neurological and psychiatric diseases such as Alzheimer's disease. Although this Mini-Review focuses on BDNF, we try to convey the general message that sex influences brain functions in complex ways and underscore the requirement for and challenge of expanding research on sex differences in neuroscience. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/jnr.23897

    View details for Web of Science ID 000388443900034

    View details for PubMedID 27870405