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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).

Fang Guo's Group Published in Nature Communications on Temperature and Sleep

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On April 2, Fang Guo's research group at the School of Brain Science and Brain Medicine at Zhejiang University published a research paper titled "Dynamic Encoding of Temperature in the Central Circadian Circuit Coordinates Physiological Activities" in the prestigious journal "Nature Communications". Employing advanced experimental techniques, the study unveiled the pivotal temperature-sensing circadian neuron DN1a in Drosophila, capable of rhythmically responding to environmental temperature fluctuations. DN1a neurons modulate Drosophila sleep activity at varying temperatures by targeting distinct downstream circadian neurons, namely LNd and DN3. This groundbreaking discovery lays a critical experimental foundation for elucidating the mechanisms through which circadian neurons regulate animal physiological activities across different thermal environments. Across species, including humans, circadian activity patterns typically entail activity during daylight hours and rest during the night. As seasons transition, these rhythms adapt accordingly. For instance, colder autumn and winter months often prompt earlier daytime activities due to earlier nightfall. Conversely, in hot summers, high temperatures can impede sleep onset. Moreover, the escalating greenhouse effect and global warming amplify the impact of temperature fluctuations on human sleep patterns. Consequently, comprehending the intricate interplay between temperature and the circadian mechanism of animal sleep has emerged as an imperative research focus.Drosophila has emerged as an exemplary model organism for dissecting circadian mechanisms owing to its distinctive physiological traits. Notably, research on the Drosophila circadian clock, which elucidated fundamental insights, was honored with the 2017 Nobel Prize in Physiology and Medicine, with Michael Rosbash among the laureates. Within the fruit fly's brain lies a neural circuit comprising approximately 75 pairs of circadian neurons, orchestrating various behaviors such as feeding, locomotion, sleep, and wakefulness at distinct times of the day. Previous investigations have underscored the role of DN1a neurons in responding to low temperatures[1, 2], while DN1p neurons are implicated in Drosophila's physiological responses to temperature fluctuations[1, 2]. Nonetheless, the identity of the pivotal regulator governing temperature regulation within the central circadian neural circuit remains an unresolved enigma. In this study, researchers employed in-vivo two-photon calcium imaging technology coupled with a new-developed precision temperature control system. They discovered that DN1a neurons exhibit a nuanced response to temperature variations: being inhibited by low temperatures and excited by high temperatures, with a diurnal pattern of response characterized by weak and strong rhythmic changes during nighttime. Molecular mechanism investigations revealed that the temperature-dependent rhythmicity of DN1a is governed by the intrinsic circadian clock. Notably, RNAi screening unveiled the role of the circadian clock, specifically circadian proteins, in regulating calcium signal oscillations in circadian neurons via the SERCA calcium pump protein on the endoplasmic reticulum, shedding light on the circadian regulation of neuronal calcium levels. Furthermore, the study elucidated that DN1a neurons, after integrating environmental temperature cues, target distinct downstream circadian neurons—LNd and DN3—thus regulating early initiation of evening activity (DN1a-LNd) in Drosophila at low temperatures and increased nighttime activity (DN1a-DN3) at high temperatures.The Circuit Mechanism of Circadian Neuron DN1a in Regulating Temperature-Dependent Changes in Sleep Activity This study offers significant insights into the influence of temperature on sleep activity, particularly amidst global warming and escalating greenhouse effects, which are altering the physiological dynamics of animals. Elevated temperatures have been associated with increased prevalence of issues such as sleep disorders and anorexia in animals, suggesting a potentially enduring impact of climate warming on the physiological activities and disease occurrence in both humans and diverse animal species [3, 4]. While the precise mechanisms underlying the effects of temperature on animal physiology remain incompletely elucidated, Drosophila, renowned as a classic model organism for circadian biology, offers a rich array of genetic tools that can aid in uncovering the physiological responses to varying temperature environments. Leveraging conserved signaling pathways and neural mechanisms underlying activity changes, in-depth exploration of circadian mechanisms in model organisms like Drosophila promises valuable insights into understanding how humans and other animals respond to environmental changes at a physiological level.Schematic illustrating the regulation of sleep/wake patterns in Drosophila by DN1a under different temperature conditions. Hailiang Li, a PhD student at the School of Brain Science and Brain Medicine, Zhejiang University, served as the first author of the paper, with PhD student Zhiyi Li also contributing significantly. Researcher Fang Guo acted as the corresponding author. The School of Brain Science and Brain Medicine of Zhejiang University is listed as the first author organization. The research received support from Prof. Xiaoming Li and Prof. Wei Gong from Zhejiang University, as well as Prof. Junhai Han from Southeast University. Funding for the research was provided by the Key Research and Development Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the National High-level Young Talents Program, and the Science and Technology Innovation Team 2.0 Support Program of Zhejiang University. Dr. Fang Guo, a researcher and doctoral supervisor at Zhejiang University School of Medicine, was selected for the National High-level Young Talents Program. He returned to ZJU to establish his lab in early 2018 after completing his postdoctoral fellowship in Michael Rosbash's lab. Dr. Fang has made significant contributions to the fields of circadian rhythms and sleep regulation, publishing several impactful academic papers in journals such as Nature, Neuron (2018, 2022), Nature Communications, PNAS, and Elife. Currently, the group is seeking postdoctoral candidates, and individuals interested in the field of neurology are encouraged to contact researcher Guo Fang via email at gfang@zju.edu.cn. 1.Yadlapalli, S., et al., Circadian clock neurons constantly monitor environmental temperature to set sleep timing. Nature, 2018. 555(7694): p. 98-102. 2.Jin, X., et al., A subset of DN1p neurons integrates thermosensory inputs to promote wakefulness via CNMa signaling. Curr Biol, 2021. 31(10): p. 2075-2087.e6. 3.Siegel, J.M., Sleep function: an evolutionary perspective. Lancet Neurol, 2022. 21(10): p. 937-946. 4.Gutiérrez, E., R. Vázquez, and R.A. Boakes, Activity-based anorexia: ambient temperature has been a neglected factor. Psychon Bull Rev, 2002. 9(2): p. 239-49.

Jianhong Luo's Group Published in Molecular Psychiatry on cognitive inflexibility in ASD mice model

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Jianhong Luo lab from the School of Brain Science and Brain Medicine at Zhejiang University published a paper in Molecular Psychiatry, revealing the mechanisms of frontal-striatal circuit dysfunction that lead to cognitive inflexibility in the autism mouse model NL3R451C. Cognitive flexibility is an important component of executive function, enabling animals to respond appropriately to constantly changing environment. Autism Spectrum Disorder (ASD) is characterized by social deficit, repetitive, stereotyped behaviors and limited interests, the underlying mechanisms of which may involve deficits in cognitive/behavioral flexibility.Neuroligin-3 (NL3) is significant in synapse formation and function, and its R451C missense mutation is associated with ASD. The knock-in mouse model NL3R451C exhibits autistic-like characteristics. Using two alternative forced choice task, the authors found that NL3R451C mice exhibited behavioral inflexibility in dynamic learning tasks.To investigate the neural mechanism of decision-making flexibility in reward-based learning tasks, the authors conducted single-neuron firing rate analyses and discovered that medium spiny neurons (pMSN) in the nucleus accumbens (NAc) of knock-in (KI) mice showed enhanced response to cue stimuli, and the modulation of their firing rate changes by previous task outcomes was reduced, indicating impaired experience-dependent neural plasticity. Role of midbrain-limbic dopamine (DA) signaling in the cognitive rigidity of KI mice was then studied, it was observed that DA dynamics and reward prediction error (RPE) signals, which are used for motivation and guiding goal-directed learning, were significantly disrupted in KI mice, hindering the acquisition of new strategies in set-shifting tasks. Subsequently, authors found that the medial prefrontal cortex (mPFC)-NAc circuit in KI mice was impaired using fiber photometry recording. Re-expression of NL3 in the mPFC could effectively rescue the cognitive inflexibility phenotype of KI mice, while simultaneously reconstructing the output of the mPFC-NAc, NAc MSN encoding, and DA signal dynamics, establishing the crucial role of mPFC in the cognitive flexibility deficits of NL3R451C mice.In summary, this study reveals the association between frontal-striatal circuit functional and DA modulation dysfunction and cognitive inflexibility in ASD mice, providing new insights into the neural mechanisms of cognitive/behavioral flexibility deficits and offering potential new strategies for intervention.

The 2024 Frontiers in Neuroscience Forum was Held in Hangzhou

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On March 15-16, the 2024 Frontiers in Neuroscience Forum jointly organized by the Frontier Science Center for Brain and Brain-Computer Integration of the Ministry of Education, the School of Brain Science and Brain Medicine, the Department of Psychological and Behavioral Sciences, and the Affiliated Mental Health Center of Zhejiang University, and Liangzhu Laboratory was held in Hangzhou, Zhejiang. The theme of this year's Forum, “Cutting-edge Issues in Brain Science: from Basic Research to Clinical Applications, reflects the rapid pace of discoveries and innovations in neuroscience field. The Forum gathered a stellar line-up of renowned experts and scholars from MIT, UCL, as well as the local neuroscience community. The Forum participants shared their insights and expertise on the latest advancements in neuroscience. Twenty-four speakers delivered keynote speeches in 6 sessions in the Forum, focusing on the latest breakthroughs of cellular and molecular neurobiology, cognitive neuroscience, and neurobiological mechanisms underlying neurodevelopmental and psychiatric diseases. More than 300 participants attended this Forum. The Forum also celebrates the 5th anniversary of the establishment of the School of Brain Science and Brain medicine, Zhejiang University.

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SEMINARS

Speaker：Luyang Wang

Institution：University of Toronto

Time：September 13, 2024 14:30

Locatiom：Liangzhu Laboratory

Targeting nonselective cation channels to mitigate ischemic brain...

Speaker：Sung-Yon Kim

Institution：Seoul National University

Time：August 15, 2024, 3:00pm

Locatiom：Meeting Room 205

How does drinking rapidly quench thirst?

Speaker：Chao Wei

Institution：Beijing Institute for Brain Research

Time：July 17, 2024, 10:00

Locatiom：Meeting Room 705

Brain endothelial GSDMD activation mediates inflammatory BBB break...

Speaker：Robert C. Froemke

Institution：Skirball Foundation Professor of Genetics Departm

Time：June 25, 2024, 9:00

Locatiom：Liangzhu Laboratory

Love, death, and oxytocin: the challenges of mouse maternal care

Speaker：Yun Li

Institution：Department of Zoology and Physiology，University of

Time：May 15, 2024 15:00

Locatiom：Meeting Room 705

Function and Dysfunction of the Prefrontal Cortex

Speaker：Jing Wang

Institution：Department of Neurobiology, School of Biological S

Time：May 13, 2024 10:30

Locatiom：Meeting Room 705

The Hierarchical Organization of Needs and The Gut’s Influence

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FACULTY

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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