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Zhihua Gao' s group published in Current Biology

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On May 10, the research team led by Prof. GAO Zhihua at the Zhejiang University School of Brain Science and Brain Medicine published an open-access article titled “Microglia modulate general anesthesia through P2Y12 receptor” in the journal Current Biology. It is the first time that scientists have uncovered the function of microglia in regulating general anesthesia via the P2Y12 receptor.General anesthesia, which can induce reversible unconsciousness, is extensively used in modern surgeries and related medical checkups. Although it has been in use for 170 years, its neurobiological mechanisms are still not fully understood. It is known that anesthetic drugs act on neurons to induce the overall suppression of neuronal activity in brain, such as GABAA, NMDA, and β2A receptors. Therefore, studies on the mechanisms related to anesthesia have been primarily focused on neurons.Microglia are the main immune and homeostatic regulatory cells in the brain, which play crucial neuro-modulatory roles in addition to immune response functions. Recent studies have revealed that general anesthesia also substantially enhances the dynamics of microglia, with increased process motility and territory surveillance. However, whether microglia are actively involved in general anesthesia modulation remains obscure.Prof. GAO Zhihua et al. administered an inhibitor of the colony stimulating factor-1 receptor (CSF1R) to remove microglia from the brain and found that mice deprived of microglia awakened earlier from anesthesia (Fig. 1). EEG recordings and righting reflex analysis revealed that mice deprived of microglia were less sensitive to general anesthetics, as evidenced by the reduced depth of anesthesia and earlier awakening (Fig 1).Fig. 1: Microglial depletion accelerated emergence from pentobarbital-induced general anesthesiaIn addition to unconsciousness, general anesthesia also triggers analgesia and hypothermia. The researchers conducted analgesic experiments using low-dose ketamine and found that microglia depletion significantly attenuated the analgesic effect of low-dose ketamine and alleviated hypothermia induced by general anesthesia (Fig 2).Fig. 2: Microglial depletion weakened anesthetic-induced analgesia and hypothermiaThrough pharmacological blockade and gene knockdown, the researchers found that the P2Y12 receptor specifically expressed by microglia was a key target of microglia in regulating anesthesia, and that blocking or knocking down the P2Y12 receptor also significantly reduced the sensitivity of mice to anesthesia and its duration.Fig. 3: Graphical abstractThis study presents the first line of evidence that microglia participate actively in the multiple processes of general anesthesia through P2Y12 receptor-mediated signaling and expands the non-immune role of microglia in the brain, thus having important clinical implications (Fig. 3).More information: Prof. GAO Zhihua and Duan Shumin，CAS fellow, from the School of Brain Science and Brain Medicine, are the corresponding authors of this paper. Dr. CAO Kelei and Dr. QIU Liyao from the MOE Frontier Science Center for Brain Science and Brain-Machine Integration, Zhejiang University, are the co-first authors.

Aimin Bao's group published in Alzheimer’s and Dementia

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Alzheimer's disease (AD) is the most common type of dementia in the elderly and poses a heavy health burden to the patients and the society. Women have a higher prevalence of AD than men, and a faster decline and deterioration of cognitive functions. The entorhinal cortex (EC) is one of the earliest structures affected in AD. In recent postmortem human brain research, the team led by Prof Ai-Min Bao, from the School of Brain Science and BrainMedicine of Zhejiang University in close collaboration with Prof. Dick Swaab in Amsterdam observed in donorswith intact cognition higher levels of hyperphosphorylated Tau (pTau) in the EC of elderly women than well-matched men (Hu et al. Hu et al., Neuropathol Appl Neurobiol. 2021;47:958-966.). This implied that the EC was an excellent structure to further study the mechanisms underlying the remarkable susceptibility of the EC for AD in women.Fig 1: Distribution of the neuropathological Braak and Amyloid staging of AD over the brain and the accumulation of AD neuropathological proteins in relation to these neuropathological staging in the EC of cognitively intact elderly.On March 24, 2023. Prof Ai-Min Bao’s team subsequently published an article titled “Sexually dimorphic age-related molecular differences in the entorhinal cortex of cognitively intact elderly: Relation to early Alzheimer's changes” in the Journal Alzheimer’s & Dementia.Researchers measured the changes in 12 characteristic molecules in relation to age by quantitative immunohistochemistry or in situ hybridization in the postmortem EC of cognitively intact elderly women and well-matched men (46-93 years of age). The molecules were arbitrarily grouped into sex steroid-related molecules, markers of neuronal activity, neurotransmitter-related molecules, and cholinergic activity-related molecules. Impressively, the molecular changes in relation to age indicated increasing local estrogenic and neuronal activity, accompanied by a higher and faster hyperphosphorylated Tau accumulation in women’s EC, versus a mainly stable local estrogenic/androgenic and neuronal activity in men’s EC. This indicated that EC employs a different neurobiological strategy in women and men to maintain cognitive function, which seems to be accompanied by an earlier start of AD in women. In other words, the activation in the elderly women’s EC may not only be a compensatory response to the altered brain functions related to age but also be ‘the beginning of the end’ in terms of the start of AD.Fig 2. Sex differences in the alterations of sex steroid-related molecules and neuronal activity-related molecules in relation to age in the EC of cognitively intact elderly.‘Dead brains can tell the truths’, said Prof Ai-Min Bao, ‘These findings from human postmortem brains are novel and inspiring, especially in relation to the sex difference in vulnerability for AD.’

Zhihua Gao's group published in eLife

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The research team led by Prof. Zhihua Gao has recently published an article titled A parabrachial to hypothalamic pathway mediates defensive behavior in eLife on Mar 17th, Beijing time. This research identifies a previously unrecognized role for the LPBCCK-PVN pathway in controlling defensive behaviors.It is the nature of animals to seek profit and avoid harm. In different environments, animals may adopt different defensive behaviors when they encounter threats. Both the paraventricular nucleus of the hypothalamus (PVN) and the parabrachial nucleus (PBN) have been shown to be involved in defensive behaviors. However, whether there are direct connections between them to mediate defensive behaviors remains unclear. Here, by retrograde and anterograde tracing, we uncover that cholecystokinin (CCK)-expressing neurons in the lateral PBN (LPBCCK) directly project to the PVN. LPB is known to be an important relay station in the nociceptive pathway and may function as an alarming center. By in vivo fiber photometry recording, we found that LPBCCK neurons actively respond to various threat stimuli. Selective photoactivation of LPBCCK neurons promotes aversion and defensive behaviors. Conversely, photoinhibition of LPBCCK neurons attenuates rat or looming stimuli-induced flight responses. Optogenetic activation of LPBCCK axon terminals within the PVN or PVN glutamatergic neurons promote defensive behaviors. Whereas chemogenetic and pharmacological inhibition of local PVN neurons prevent LPBCCK-PVN pathway activation-driven flight responses. These data suggest that LPBCCK neurons recruit downstream PVN neurons to actively engage in flight responses.Prof. Zhihua Gao from Zhejiang University School of Medicine is the main corresponding author. Pro. Shumin Duan from Zhejiang University School of Medicine is co-corresponding author. Dr. Fan Wang and Yuge Chen are the first authors. This work was supported by STI2030-MajorProjects, the Leading talents in Science and Technology of Zhejiang Province, the National Natural Science Foundation of China, the NSFC-Guangdong Joint Fund, the Zhejiang Major Science and Technology Project, the Research Units for Emotion and Emotion Disorders, Chinese Acedemy of Medical Sciences, the Key Area Research and Development Program of Guangdong Povince.

Shuang Qiu's group published in Biological Psychiatry

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The research team led by Prof. Shuang Qiu has recently published an article titled NMDAR-dependent synaptic potentiation via APPL1 signaling is required for the accessibility of a prefrontal neuronal assembly in retrieving fear extinction in Biological Psychiatry onFeb24th, Beijing time. This research identifies a cellular and molecular mechanism underlying fear extinction, which provides potential therapeutic targets to treat PTSD.The ventromedial prefrontal cortex (vmPFC) has been viewed as a locus to store and recall extinction memory. However, the synaptic and cellular mechanisms underlying this process remain elusive. This research combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the vmPFC for fear extinction retrieval and found that both constitutive and conditional APPL1 knockout decreases NMDA receptor (NMDAR) function in the vmPFC and impairs fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduces NMDAR currents and disrupts extinction retrieval. This research further identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolishes NMDAR-dependent synaptic potentiation and disrupts extinction retrieval, while simultaneously chemogenetic activation of this ensemble rescues the impaired behaviors. Therefore, these results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons to retrieve extinction memory via controlling NMDAR-dependent potentiation.Prof. Shuang Qiu from Zhejiang University School of Medicine is the main corresponding author. Pro. Yihui Cui from Zhejiang University School of Medicine is co-corresponding author. Dr. Shushan Hua, Jinjun Ding, Tiancheng Sun, and Chen Guo are the first authors. This work was supported by STI2030-Major Project, National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province, Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, National Key Research and Development Program of China, and Chinese Ministry of Education Project 111 Program.

Binggui Sun'group published in Cell Reports

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The team led by Prof. Binggui Sun recently published an article titled Aberrant serotonergic signaling contributes to the hyperexcitability of CA1 pyramidal neurons in a mouse model of Alzheimer’s disease on Mar. 28, 2023, Beijing time. This study identifies new pathways accounting for hyperexcitability of CA1 pyramidal neurons in AD mice.Hyperactivity of pyramidal neurons (PNs) in CA1 is an early event in Alzheimer’s disease (AD). However, factors accounting for the hyperactivity of CA1 PNs remain to be completely investigated. In the present study, the authors report that the serotonergic signaling is abnormal in the hippocampus of hAPP-J20 mice. Interestingly, chemogenetic activation of serotonin (5-hydroxytryptamine, 5-HT) neurons in the median raphe nucleus (MRN) attenuates the activity of CA1 PNs in hAPP-J20 mice by regulating the intrinsic properties or inhibitory synaptic transmission of CA1 PNs through 5-HT3aR and/or 5-HT1aR. Furthermore, activating MRN 5-HT neurons improves memory in hAPP-J20 mice and this effect is mediated by 5-HT3aR and 5-HT1aR. Direct activation of 5-HT3aR and 5-HT1aR with their selective agonists also improves memory of hAPP-J20 mice. Together, this study identifies the impaired 5-HT/5-HT3aR and/or 5-HT/5-HT1aR signaling as pathways contributing to the hyperexcitability of CA1 PNs and the impaired cognition in hAPP-J20 mice.Prof. Binggui Sun from Zhejiang University School of Medicine is the leading corresponding author. Jing Wang, Yufei Mei and Xiaoqin Zhao are the co-first authors. This work was supported by grants from National Key R&D Program of China (2021YFA1101701, 2019YFA0110103), National Natural Science Foundation of China (32071031, 32271028, 31871025, 82071182, 82201351) and Natural Science Foundation of Zhejiang Province (LZ19C090001).Abnormal serotonergic pathways from the median raphe nucleus (MRN) to the hippocampus contribute to the hyperexcitability of CA1 pyramidal neurons and then lead to cognitive dysfunction in AD mice.

Hailan Hu's group published in Cell

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Xiaoming Li's group published in Cell Discovery

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The research team led by Prof. Xiaoming Li has recently published an article titled Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profifiling in Cell Discoveryon Feb.14th, Beijing time. This research uncovered evolutionaryconservation and divergence of the amygdala across species, and laid a solid foundation for future studies of the amygdala function at the cell type level.The amygdala, or an amygdala-like structure, is found in the brains of all vertebrates and plays a critical role in survival and reproduction. Damages or functional disruptions of the amygdala have been implicated in various neurological diseases, especially neuropsychiatric disorders, such as schizophrenia, anxiety, and bipolar disorder. The amygdala is a heterogeneous complex that includes multiple subnuclei and neuronal cell types originating from cortical and subcortical territories. However, the cellular architecture of the amygdala and how it has evolved remain elusive. This work generated single-nucleus RNA-sequencing data for more than 200,000 cells in the amygdala of humans, macaques, mice, and chickens. Abundant neuronal cell types from different amygdala subnuclei were identifified. Cross-species analysis revealed that inhibitory neurons and inhibitory neuron-enriched subnuclei of the amygdala were well-conserved in cellular composition and marker gene expression, whereas excitatory neuron-enriched subnuclei were relatively divergent. Furthermore, LAMP5+ interneurons were much more abundant in primates, while DRD2+ inhibitory neurons and LAMP5+ SATB2+ excitatory neurons were dominant in the human central amygdalar nucleus (CEA) and basolateral amygdalar complex (BLA), respectively. This work also identifified CEA-like neurons and their species-specifific distribution patterns in chickens. This research highlights the extreme cell-type diversity in the amygdala and reveals the conservation and divergence of cell types and gene expression patterns across species that may contribute to species-specifific adaptations.Prof. Xiaoming Li from Zhejiang University School of Medicine is the main corresponding author. Prof. Xiaoqun Wang and Prof. Qian Wu from Beijing normal university are co-corresponding authors. Dr. Bin Yu, Qianqian Zhang and Lin Lin are co-first authors. This work was supported by Science and Technology Innovation 2030 - “Brain Science and Brain-Inspired Technology” Major Project, Major Program of the National Natural Science Foundation of China, , the Strategic Priority Research Program of the Chinese Academy of Sciences, Key-Area Research and Development Program of Guangdong Province, Key R&D Program of Zhejiang Province, Fundamental Research Funds for the Central Universities, and CAMS Innovation Fund for Medical Sciences.Fig. 1 Profiling of amygdala cell types across mammals by snRNA-seq.

Ge Bai's group published in Cell

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Neuroimmune Regulation in Physiology and Disease

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Alzheimer's Disease: Novel Mechanisms and Drug Development

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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