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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.

Lijun Kang's Group Published in Neuron on Glial GABA Signaling

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Glial cells play a crucial role in the development, function, and health of the nervous system and brain. From Caenorhabditis elegans, Drosophila to zebrafish, mice, and humans, the origin, structure, and function of glial cells have been highly conserved [1].On March 6, 2024, Professor Lijun Kang and his team published a research article titled "Phasic/Tonic-like Glial GABA Differentially Transduce for Olfactory Adaptation and Neuronal Aging" in the journal Neuron. In their study, they discovered that AMsh glial cells regulate real-time olfactory adaptation and long-term neuronal aging through two distinct GABA signaling pathways (Figure 1) [2].Figure 1: Differential regulation of olfactory adaptation and neuronal aging by phasic/tonic-like glial GABA signaling.Adaptability is one of the fundamental characteristics of the nervous system. In their previous research, Professor Lijun Kang's team revealed that sheath-like glial cells called AMsh glia sense odorant stimuli via G-protein coupled receptors (GPCRs) in the chemosensory organ of C. elegans. These glial cells release GABA, which acts on the GABAA receptor LGC-38 in ASH sensory neurons, leading to the inhibition of their activity and promoting olfactory adaptation. This work proposed a dual receptor model involving glial cells and neurons for olfactory sensation, emphasizing the essential role of glial cells as driving forces behind neuronal adaptation (Neuron 2020) [3].In their recent publication in Neuron, Professor Lijun Kang's team demonstrated that AMsh glial cells elevate cytoplasmic calcium levels upon sensing odorant stimuli. This elevation triggers the secretion of GABA from vesicles, a process dependent on the vesicular GABA transporter UNC-47/VGAT. The released GABA acts on ASH sensory neurons to facilitate olfactory adaptation. Additionally, at resting calcium levels, AMsh glial cells can gradually release GABA through bestrophin ion channels (Best-9/-13/-14), which activates the GABAB receptor GBB-1 on ASH sensory neurons, and regulates the activity of the transcription factor HSF-1 via the PLCβ signaling pathway, thus slowing down the aging process of ASH neurons.This research has revealed two distinct GABA signaling pathways within the local circuitry involving AMsh glial cells and ASH sensory neurons. Each pathway plays crucial physiological roles: (1) UNC-47/VGAT--LGC-38/GABAA fast signaling pathway. The key gene UNC-47 is predominantly expressed in the soma and proximal processes of AMsh glial cells, while LGC-38 is localized to the soma and axons of ASH neurons. (2) Bestrophin channels--GBB-1/GABAB slow signaling pathway. The critical genes, the bestrophin channels and GBB-1, are extensively expressed in AMsh glial cells and ASH neurons, respectively. Notably, UNC-47/VGAT-dependent GABA release is triggered by high calcium levels, whereas bestrophin channels can release GABA under low calcium conditions. Furthermore, GBB-1/GABAB receptors exhibit higher affinity for GABA compared to LGC-38/GABAA receptors. These findings provide novel insights into the significant role of glial cells in sensory encoding and neuronal aging.References:(1) Nagai et al., Behaviorally consequential astrocytic regulation of neural circuits. Neuron (2021) 109, 576-596.(2) Cheng et al., Phasic/Tonic-like Glial GABA Differentially Transduce for Olfactory Adaptation and Neuronal Aging. Neuron. 2024 Mar 1:S0896-6273(24)00090-4. doi: 10.1016/j.neuron.2024.02.006.(3) Duan et al. Sensory glia detect repulsive odorant and drive olfactory adaptation. Neuron (2020) 108,707-721.

Yanqin Yu’s group published in National Science Review on neuromechanism of defensive behavior

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The research team led by Prof. Yan-qin Yu has recently published an article titled Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons in National Science Review on Mar 5th, Beijing time. This research identifies a previously unrecognized role for the lPAGglu-NDGABA-GiVglu pathway in controlling defensive behaviors.Threatening situations, such as the presence of a predator or exposure to stimuli predicting imminent or perceived danger, evoke an evolutionarily conserved brain state, fear, which triggers defensive behaviors to avoid or reduce potential harm.The defensive behaviors to threats play a fundamental role in survival. Several brain areas have been implicated in defensive behaviors, including periaqueductal gray, amygdala, hypothalamus. But many nuclei which play important roles in defensive behaviors remain to be discovered.The nucleus of Darkschewitsch (ND), mainly composed of GABAergic neurons, is recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons (NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot-shock. Optogenetic and chemogenetic manipulations revealed that NDGABA neurons mediate freezing behavior. Moreover, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal grey (lPAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part (GiV). Together, these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from lPAG to GiV, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain. Our results advance the current understanding of how threats selectively trigger freezing, a specific defensive response, via the lPAGGlu-NDGABA-GiVGlu circuitry and provide precise anatomical and functional information that is important for the discovery and development of new therapeutic interventions for mood disorders.Prof. Yan-qin Yu from Zhejiang University School of Medicine is the main corresponding author. Prof. Hongbin Yang from Zhejiang University MOE Frontier Science Center for Brain Science & Brain-Machine Integration is co-corresponding author. This research was strongly supported by Prof. Shumin Duan from Zhejiang University School of Medicine. Dr. Huiying Zhao, Jinrong Liu and Yujin Shao are the first authors. This work was mainly supported by STI2030-Major Projects and the National Natural Science Foundation of China.

Xiao-Ming Li’s group published in Nature Neuroscience on neuromechanism of fear and anxiety

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Excessive or repetitive fear play a significant role in the development of anxiety disorders, with the amygdala serving as the central locus for fear processing. Clinical research has demonstrated that individuals with bilateral amygdala damage are still capable of experiencing fear, indicating the amygdala may not be absolutely required for fear. To date, the neural mechanisms underlying fear that are independent of the amygdala are still poorly understood.On February 12th, Prof. LI Xiao-Ming and his team from the Zhejiang University School of Medicine published an article entitled A molecularly defined amygdala-independent tetra-synaptic forebrain-to-hindbrain pathway for odor-driven innate fear and anxiety on Nature Neuroscience. The study revealed the significant role of the main olfactory bulb → dorsal peduncular cortex → lateral parabrachial nucleus → parasubthalamic nucleus pathway in fear and anxiety (Figure 1).Figure 1 The schematic diagram of the main olfactory bulb → dorsal peduncular cortex → lateral parabrachial nucleus → parasubthalamic nucleus pathway Olfaction serves as a common sensory modality that elicits innate fear in animals. Through the use of 2,4,5-trimethyl-3-thiazoline (TMT), a compound present in fox feces, which is a stimulus with fear-eliciting properties for rodents, the research team observed a notable decrease in aversive and freezing behaviors triggered by TMT in mice, accompanied by the apoptosis of neurons in the cortical amygdala and medial amygdala. However, this kind of apoptosis did not have a significant impact on TMT-induced escape behavior. Therefore the team focused on finding the specific brain region that mediate the olfaction-evoked escape behavior.In the subsequent experiments, Dr. WANG Hao, the first author of the study, characterized neuronal activity as reflected in Fos expression in response to TMT. He observed a notable elevation in Fos expression in the dorsal peduncular cortex (DP), which receives distinct inputs from the main olfactory bulb (MOB). In addition, the MOB-DP neural circuit exhibits markedly heightened activity following TMT stimulation (Figure 2).Figure 2The MOB-DP neural circuit is involved in TMT-induced innate fear."The role of DP in olfaction-evoked innate fear was investigated by inhibiting DP neurons in mice using an apoptosis virus, which resulted in the absence of obvious escape behavior in response to TMT stimulation and a significant reduction in aversive and freezing behaviors. Conversely, activating DP neurons using optogenetics induced escape behavior in mice, along with observable fear-like reactions such as dilated pupils and decreased heart rate," explained Dr. WANG Hao.Concurrently, the team integrated optogenetic inhibition of DP neuron function with localized amygdala damage in mice. They observed that the combination of localized amygdala damage and DP inhibition resulted in a significant reduction of escape behavior induced by TMT in mice, as well as a further decrease in aversive and freezing behaviors. "Notably, the mitral/tufted cells projecting to DP and the cortical amygdala are two distinct groups of neurons. The aforementioned functional and structural observations suggest that DP is capable of autonomously mediating olfaction-evoked innate fear bypasses the amygdala,” stated Dr. WANG Qinng, co-first author of the study. Consequently, following input from the main olfactory bulb, how does the DP convey the fear response elicited by predator odor?Combining virus tracing and patch-clamp electrophysiology, the team have discovered that DP forms excitatory synaptic connections with cholecystokinin (Cck) positive neurons in the superficial lateral parabrachial nucleus (PBNsl), which then project to tachykinin 1 (Tac1) positive neurons in the parasubthalamic nucleus (PSTh). This results in the formation of a molecularly defined tetra-synaptic pathway: MOBSlc17a7+ → DPCamk2a+ → anterior PBNslCck+ → PSThTac1+.In order to investigate whether the tetra-synaptic pathway participate in olfaction-evoked innate fear, PhD candidates CUI Liuzhe and FENG Xiaoyang delved deeper into the functional properties of the neural circuit. Their investigations revealed that this neural circuit exhibits significant activation during TMT-induced escape behavior (Figure 3). Furthermore, optogenetic inhibition of this pathway markedly diminishes mouse escape behavior and ameliorates fear-related responses. Even in mice with concurrent damage to the cortex and medial amygdala, activation of this pathway remains capable of inducing mouse escape behavior and replicating autonomic nervous response of innate fear. These findings suggest that the identified forebrain-to-hindbrain neural circuit can autonomously regulate TMT-induced innate fear independent of amygdala.Figure 3: Single-cell calcium imaging results of anterior PBNslCck+ positive neurons when TMT is close to the mouse's nose.As a consequence of excessive or repetitive fear contributing to fear-related disorders, such as anxiety, the research team conducted a more in-depth examination of the pathway’s function in anxiety. Dr. WANG Hao stated, “We observed that continuous optogenetic activation of this pathway (1h per day for three days) resulted in markedly observable anxiety-like behaviors in mice. Furthermore, the inhibition of this pathway led to a significant reversal of the anxiety-like behavior after 2h of acute restrain stress.”This study revealed a tetra-synaptic neural circuit of the main olfactory bulb → dorsal peduncular cortex → lateral parabrachial nucleus → parasubthalamic nucleus, and demonstrated that this pathway can regulate olfaction-evoked innate fear and anxiety bypasses the amygdala. Prof. LI Xiao-Ming, the corresponding author of the article, believes that this research not only expands our understanding of the neural mechanisms underlying fear and anxiety but also provides new insights into the pathogenesis of mental disorders.

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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