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Hailan Hu's group published in Neuron on neural mechanism underlying social hierarchy

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The research team led by Prof. Hailan Hu has recently published an article titled Deconstructing the neural circuit underlying social hierarchy in mice on Neuron online on Dec 10th, 2024. This research revealed the antagonistic interplay between win-related and lose-related dmPFC downstream pathways in mediating social competition.Social competition determines hierarchical social status, which profoundly influences animals’ behavior and health. The dorsomedial prefrontal cortex (dmPFC) plays a fundamental role in regulating social competitions, but it was unclear how the dmPFC orchestrates win- and lose-related behaviors through its downstream neural circuits. Here, we dissected the individual contribution and reciprocal interaction of dmPFC downstream circuits in modulating dominance behavior. Brain-wide c-Fos mapping experiment revealed that winner mice in the tube test competition exhibited a significantly higher number of c-Fos-positive neurons in the dmPFC downstream targets, including the DRN and PAG, whereas loser mice exhibited more c-Fos-positive neurons in the aBLA. Consistently, pathway-specific manipulations outlined a dmPFC-centric social dominance neural network, in which the dmPFC-DRN and dmPFC-PAG circuits act as win-related pathways, whereas the dmPFC-aBLA circuit acts as a lose-related pathway. Moreover, the activation or inhibition of the aBLA itself yielded similar effects as manipulation of the dmPFC-aBLA pathway. Accordingly, these win- and lose-related dmPFC circuits showed opposing calcium activities when mice initiated ‘‘effortful’’ push behaviors in the tube test competition. Retrograde tracing study revealed that these functionally divergent pathways are anatomically segregated, with the lose-related aBLA-projecting neurons located in the layer 2/3 and the win-related DRN- and PAG- projecting neurons located in the layer 5 of the dmPFC. Finally, using in vivo and in vitro electrophysiological recordings, we found an inhibition from the lose-related neurons to the win-related neurons through local PV and SST interneurons in the dmPFC. One interesting speculation of the function of this unidirectional interaction is that losing mentality may dominate over winning during competitions: once animals initiate the idea of quitting or withdrawing from the rivalry, the inhibition on the win pathway from the lose pathway would help them execute the idea and end the fight quickly. Such antagonistic interplay may represent a central principle in how the mPFC orchestrates complex behaviors through top-down control.dmPFC-centric social dominance neural networkhttps://www.cell.com/neuron/abstract/S0896-6273(24)00807-9HAILAN HU'S RESEARCH GROUP: For social animals, emotions and health are regulated by various social behaviors. Hailan Hu's group is dedicated to studying the neural basis and plasticity mechanisms of emotion and social behavior. They use cutting-edge techniques including imaging, electrophysiology (both in vitro and in vivo), molecular genetics, and optogenetics to conduct deep analysis of emotion- and social behaviors- and their related neural circuits.

Shumin Duan and Yan-qin Yu 's group published in Advanced Science on astrocytes and arousal

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The research team led by Prof. Shumin Duan and Yan-qin Yu has recently published a study in Advanced Science titled Adenosine‐Dependent Arousal Induced by Astrocytes in a Brainstem Circuit on October 16, 2024 This study provides the first evidence that astrocytes in the brainstem parafacial zone (PZ) play a unique role in promoting and sustaining wakefulness through extracellular adenosine and elucidates the underlying circuit-level mechanisms.Astrocytes play a crucial role in regulating sleep-wake behavior. However, how astrocytes govern a specific sleep-arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep-wake cycles with state-differential Ca2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they found that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes, while impeding transitions from wakefulness to non-rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZGABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal-promoting effect of astrocytes within the PZ through extracellular adenosine, and elucidates the underlying mechanism at the neural circuit level. Summary of the molecular and neural circuit mechanisms underlying PZ astrocyte activation in sleep-wake regulation.Website: https://onlinelibrary.wiley.com/doi/10.1002/advs.202407706SHUMIN DUAN AND YAN-QIN YU'S RESEARCH GROUP: Shumin Duan and Yan-qin Yu's group is dedicated to studying the roles of glial cells in synaptic plasticity and the mechanisms of neuron-glia interactions in health and disease. They use cutting-edge techniques including imaging, fiber photometry, electrophysiology (both in vitro and in vivo), molecular genetics, and optogenetics to conduct deep analysis of higher brain functions such as sensory processing, sleep-wake modulation, and emotion-related diseases such as anxiety and depression, learning and memory.

Xiao-Ming Li and Jiadong Chen 's group published in Advanced Science on the neural mechanism of amygdala in regulating temporal lobe epilepsy

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The research team led by Prof. Xiao-Ming Li and Jiadong Chen has recently published an article titled Posterior Basolateral Amygdala is a Critical Amygdaloid Area for Temporal Lobe Epilepsy in Advanced Science on October 30, 2024. This research revealed the pBLA as a pivotal nucleus in the amygdaloid complex for regulating epileptic seizures in TLE.The amygdaloid complex consists of multiple nuclei and is a key node in controlling temporal lobe epilepsy (TLE) in both human and animal model studies. However, the specific nucleus in the amygdaloid complex and the neural circuitry governing seizures remain unknown. Here, it is discovered that activation of glutamatergic neurons in the posterior basolateral amygdala (pBLA) induces severe seizures and even mortality. The pBLA glutamatergic neurons project collateral connections to multiple brain regions, including the insular cortex (IC), bed nucleus of the stria terminalis (BNST), and central amygdala (CeA). Stimulation of pBLA-targeted IC neurons triggers seizures, whereas ablation of IC neurons suppresses seizures induced by activating pBLA glutamatergic neurons. GABAergic neurons in the BNST and CeA establish feedback inhibition on pBLA glutamatergic neurons. Deleting GABAergic neurons in the BNST or CeA leads to sporadic seizures, highlighting their role in balancing pBLA activity. Furthermore, pBLA neurons receive glutamatergic inputs from the ventral hippocampal CA1 (vCA1). Ablation of pBLA glutamatergic neurons mitigates both acute and chronic seizures in the intrahippocampal kainic acid-induced mouse model of TLE. Together, these findings identify the pBLA as a pivotal nucleus in the amygdaloid complex and offer novel circuit mechanisms of pBLA in regulating epileptic seizures in TLE. This insight holds promise for advancing more precise, circuit-targeted therapies for TLE. Model diagram showing the role of pBLA glutamatergic neurons and their collateral projections in epileptic seizures in TLE Website: https://doi.org/10.1002/advs.202407525 Xiao-Ming Li's RESEARCH GROUP: Dr Xiao-Ming Li's group is focusing on the research of different synapses and neural circuits, seeking treatment for mental illnesses such as anxiety, depression and schizophrenia by revealing approachable molecular targets and designing corresponding treatment strategies. The main research content is:1) Research on the neural circuit of emotional and affective disorders2) Pathogenesis study of neuropsychiatric diseases such as anxiety, depression and schizophrenia3) Basic and clinical research on neuropsychiatric diseases such as anxiety, depression and schizophrenia (Clinical)

Hailan Hu's group published in Science on ketamine

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The research team led by Prof. Hailan Hu has recently published an article titled Brain region–specific action of ketamine as a rapid antidepressant on Science online on Aug 9th, 2024. This research revealed ketamine blocks NMDARs in vivo in a brain region– and depression state–specific manner.The use-dependent nature of ketamine as an NMDAR blocker converges with local brain region properties to distinguish the LHbas a primary brain target of ketamine action.Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-D-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine’s antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine’s antidepressant effects and blocked the systemic ketamine–induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.Brain region–specific action of ketamine as a rapid antidepressantWebsite: https://science.org/doi/10.1126/science.ado7010HAILAN HU'S RESEARCH GROUP: For social animals, emotions and health are regulated by various social behaviors. Hailan Hu's group is dedicated to studying the neural basis and plasticity mechanisms of emotion and social behavior. They use cutting-edge techniques including imaging, electrophysiology (both in vitro and in vivo), molecular genetics, and optogenetics to conduct deep analysis of emotion- and social behaviors- and their related neural circuits.

Ke Jia's group published in Science Advances on human brain plasticity

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The research team led by Dr. Ke Jia published an article titled “Recurrent inhibition refines mental templates to optimize perceptual decisions” in Science Advances on July 31, 2024. This study capitalises onstate-of-the-art ultra-high-field (7T) multimodal brain imaging approach and reveals a recurrent inhibitory plasticity mechanism for optimized perceptual decisions.The idea that the brain solves complex tasks by forming mental templates—that is, internal representations of key information relevant for behaviour—has attracted the attention of psychologists and neuroscientist since William James. Training has been suggested to support the brain’s ability to refine these templates and optimize perceptual decisions. Yet, exactly how the brain achieves this remains debated; we still lack a comprehensive account of the experience-dependent plasticity mechanisms that support adaptive decision making.Here, we propose recurrent inhibition: an integrative brain plasticity mechanism for improving perceptual decisions. Combining fMRI at submillimeter resolution with magnetic resonance spectroscopy, we investigate interactions between functional and neurochemical plasticity mechanisms. Our results demonstrate that training on a challenging visual discrimination task alters GABAergic inhibition in visual cortex and enhances the discriminability of feature (i.e., orientation) representations in superficial V1 layers. Importantly, learning-dependent changes in GABAergic inhibition drive plasticity in superficial—rather than middle or deeper—layers in visual cortex, that are linked to recurrent—rather than input—processing. Taken together, our results propose that GABAergic inhibition drives improved perceptual decisions by strengthening task-relevant representations through recurrent processing in visual cortex. Our findings provide a mechanistic account of how GABAergic and functional plasticity mechanisms interact in the human brain at unprecedent resolution, bridging the gap in understanding animal and human brain inhibitory circuits that support adaptive behavior.

Han Xu’s group published in Brain on social fear

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The research team led by Professors Han Xu and Yuzheng Hu published an article titled “A Prefrontal-Habenular Circuitry Regulates Social Fear Behavior” in Brain on July 4, 2024. This study elucidates the critical role of the prefrontal-habenular circuitry in modulating social fear.Social behaviors are vital for survival and reproduction across species, evolving dynamically based on social experiences. Clinically, intense social fear is a prevalent symptom in various mental disorders, highlighting the urgency of understanding how negative social experiences alter brain structure and function, leading to social fear behaviors. Research has demonstrated that the medial prefrontal cortex (mPFC) plays a key role in social behaviors, and its dysfunction is linked to social deficits. A prior study by this team emphasized the prefrontal cortex’s involvement in social fear behavior. However, the exact subcortical partners involved remained unclear. Among the downstream brain regions of the mPFC, the lateral habenula, recognized as an “anti-reward” center, directly influences negative emotions. Nonetheless, the precise role of the prefrontal-habenular pathway in regulating social fear behavior was yet unknown.To investigate this, the researchers used social fear conditioning and social defeat paradigms to induce social fear behaviors in mice. Initially, they recorded neural activity in the prefrontal cortex-lateral habenula pathway using fiber photometry. They observed a significant increase in neural activity in prefrontal cortex neurons projecting to the lateral habenula, which synchronized with the activity of lateral habenula neurons during social fear expression. Furthermore, they demonstrated that optogenetic inhibition of abnormal activity in this pathway significantly reduced social fear behaviors in mice. Extending their research to humans, they employed resting-state functional magnetic resonance imaging (fMRI) and identified a significant positive correlation between social anxiety scale scores and the strength of functional connectivity between the prefrontal cortex and the habenula. These results suggest that, consistent with findings in mouse models, structural and functional abnormalities in this pathway may also be present in patients with social anxiety.This study is the first to demonstrate the crucial role of the prefrontal cortex-lateral habenula pathway in regulating social anxiety behavior through cross-species research. It offers significant insights into the mechanisms underlying social fear and supports the development of targeted interventions for patients with social anxiety.

Shumin Duan and Yanqin Yu’s group published in Neuron on sexually dimorphic aggressive behavior

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In July 16, 2024, Neuron published the latest research by Professor Shumin Duan and Yanqin Yu's team from the School of Brain Science and Brain Medicine at Zhejiang University. The article, entitled “A Hypothalamic-Amygdala Circuit Underlying Sexually Dimorphic Aggression,” identifies a hypothalamic-amygdala circuit that mediates male-biased aggression in mice.Mammals have evolved sexual reproduction to achieve higher evolutionary potential and adapt to environmental changes, resulting in an efficient division of labor. Many instinctive behaviors are sexually dimorphic to enhance survival and reproductive capabilities. Aggressive behavior, an innate behavior, is a powerful tool for guarding territories, competing for critical resources, and defending oneself and family. It is more prevalent in males due to selective pressures associated with limited mating opportunities, with males typically exhibiting higher levels of aggression. Sexually dimorphic aggression is a stereotypical innate behavior with evolutionary conservation, genetically hardwired to be displayed without training. While brain areas are known to elicit sexually dimorphic or monomorphic aggression in rodents, how these circuits are interconnected and gate sexually dimorphic attacks remain unclear.Decades of studies have identified the ventrolateral part of the ventromedial hypothalamus (VMHvl) as a key region associated with male-biased aggression. In this study, the team screened cFos expression in downstream brain regions when chemogenetic activation of estrogen receptor-α (Esr1) positive VMHvl neurons in male and female mice, identifying a potential downstream target in the posterior substantia innominata (pSI). The pSI, an area in the extended amygdala, promotes similar levels of attack in both sexes of mice.Anterograde and retrograde tracing revealed that the VMHvl sends projection terminals to the pSI. Optogenetic inhibition of pSI neurons during chemogenetic activation of VMHvlEsr1 neurons confirmed that the VMHvl functionally innervates the pSI unidirectionally. The study showed that while excitatory neurons in the VMHvl promote sexually dimorphic aggression, the role of inhibitory VMHvl neurons in regulating male and female aggression is less understood. The team found that the VMHvl innervates the pSI through both excitatory and inhibitory connections. In males, strengthened excitatory VMHvl-pSI projections promote aggression, whereas stronger inhibitory connections in females reduce aggressive behavior. Overall, the convergent hypothalamic input onto the pSI leads to heightened pSI activity in males, resulting in male-biased aggression when VMHvlEsr1-pSI projections are opto-activated.In conclusion, these studies suggest that a convergent, sexually distinct circuit from the VMHvl to the pSI mediates male-biased aggression. The sexually distinct excitation-inhibition balance of the hypothalamic-amygdala circuit underlies sexually dimorphic aggression.Drs. Zhenggang Zhu and Lu Miao from the School of Brain Science and Brain Medicine of Zhejiang University are co-first authors. Professors Shumin Duan and Yan-Qin Yu from the School of Brain Science and Brain Medicine of Zhejiang University are the corresponding authors. This work was supported by grants from the National Natural Science Foundation (NSFC) of China (82288101, 82090033, U20A6005; T2293733, T2293730; 32171007; 32241004); STI2030-Major Projects (2021ZD0203400); Key R&D Program of Zhejiang Province (2024SSYS0017,2020C03009; 2022C03034); CAMS Innovation Fund for Medical Sciences (2019-I2M-5-057); the Natural Science Foundation of Zhejiang Province (LZ22H090001); the Non-profit Central Research Institute Fund of Chinese Academy 451 of Medical Sciences (2023-PT310-01).

Han Xu’s group published in Nature Communications on social fear

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The research team led by Prof. Han Xu has recently published an article titled ‘The basal forebrain to lateral habenula circuitry mediates social behavioral maladaptation’ on Nature Communications online on May 13, 2024. This research discovered a novel neural circuit mechanism of glutamatergic neurons in the basal forebrain (BF) mediating social behavioral maladaptation through their projection to the lateral habenula (LHb). In our daily life, we spend around 80% of our waking time in social related activities. A good social environment is not only indispensable for our personal survival and reproduction as well as the harmony and stability of our society, but also it provides us with the positive emotional value, which is essential for maintaining our mental health. Unfortunately, social dysfunctions are common in many neuropsychiatric disorders, including autism, depression, and social phobia. Avoidance and fearful responses to social stimuli are typical behavioral symptoms of social phobia, which seriously affects patients' physical, mental health and social functions. Adverse social experiences are important factors for the development of social fear; however, it is still unclear how these negative social experiences act on brain function and eventually lead to social fear behaviors. The basal forebrain (BF), located in the rostroventral forebrain and is well-known for its enrichment with cholinergic projection neurons, while little is known about the functions of the other two main types of neurons within the BF (GABAergic and glutamatergic neurons). A prior report by the team in 2021 revealed for the first time that a subpopulation of SST-expressing GABAergic neurons in the BF could modulate pro-social behaviors [1], suggesting that the different types of neurons within the BF may be specific in the modulation of behaviors. Interestingly, a human brain imaging study showed a significant increase in BF activity in patients with PTSD while processing trauma-related words [2]. Similarly, a recent report also found that individuals with more severe levels of social anxiety showed abnormal activation of the BF, suggesting that the BF is involved in the processing of negative emotions [3]. However, whether and how the BF is directly contributed to social fear behavior remains an important but unresolved question. The research team first induced stable and intense social fear behavior in mice using conditioned social fear conditioning. In vivo multichannel electrophysiology and fiber photometry revealed that a large number of vGluT2-expressing glutamatergic neurons in the BF were activated during social fear expression, whereas cholinergic and GABAergic neurons showed no significant changes in their activity. Using neuron type-specific manipulation approaches, they found that inhibition of vGluT2 neurons dramatically attenuated social fear behavior but not cholinergic or GABAergic neurons, suggesting that BF glutamatergic neurons plays an essential role in the expression of social fear. Through what downstream targets do BF vGluT2 neurons mediate social fear? The research team first used viral tracing and brain slice patch clamp recordings to reveal that vGluT2 neurons have close anatomical connectivity and monosynaptic functional links with both the ventral tegmental area (VTA) and lateral habenula (LHb). Interestingly, BF vGluT2→LHb projections were selectively activated during social fear behaviors, and specific inhibition of the BF vGluT2→LHb projection significantly reduced social fear in mice, while inhibition of BF vGluT2→VTA projections did not alter social fear behaviors. Finally, using brain slice patch clamp techniques, they found that social fear conditioning enhanced the glutamatergic synaptic connections from BF to LHb that may serve as a potential synaptic mechanism underlying social fear modulation by this neural circuit. Schematic illustration of neural circuit mechanism underlying social fear This study proposes a novel mechanism of social fear expression that centered on the BF at circuit and cellular levels, which sheds light on our understanding of the neural basis of social anxiety disorders, and may provide new targets for the treatment of social fear related neuropsychiatric disorders in the future. References1. Wang, J., et al. Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons. Proceedings of the National Academy of Sciences of the United States of America 118 (2021). doi: 10.1073/pnas.2019295118.2. Rabellino, D., Densmore, M., Frewen, P.A., Theberge, J. & Lanius, R.A. The innate alarm circuit in post-traumatic stress disorder: Conscious and subconscious processing of fear- and trauma-related cues. Psychiatry Res Neuroimaging 248, 142-150 (2016).3. Zhu, X., et al. Functional Connectivity Between Basal Forebrain and Superficial Amygdala Negatively Correlates with Social Fearfulness. Neuroscience 510, 72-81 (2023).

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School of Brain Science and Brain Medicine Zhejiang University

The School of Brain Science and Brain Medicine, devoted to the study of neuroscience and neuromedicine, was founded in October 2019. As the first school focusing on brain science and brain medicine in Chin... 【More】

Address : Zijingang Campus of Zhejiang University

Tel : 0571-87071107

E-mail : brains@zju.edu.cn