The lateral habenula (LHb) neurons and astrocytes have been strongly implicated in depression etiology, but it was not clear how the two dynamically interact during depression onset. Here, using multi-brain-region calcium photometry recording in freely moving mice, we discover that stress induces a most rapid astrocytic calcium rise and a bimodal neuronal response in the LHb. LHb astrocytic calcium requires the α1A-adrenergic receptor and depends on a recurrent neural network between the LHb and locus coeruleus (LC). Through the gliotransmitter glutamate and ATP/adenosine, LHb astrocytes mediate the second-wave LHb neuronal activation and norepinephrine (NE) release. Activation or inhibition of LHb astrocytic calcium signaling facilitates or prevents stress-induced depressive-like behaviors, respectively. These results identify a stress-induced positive feedback loop in the LHb-LC axis, with astrocytes being a critical signaling relay. The identification of this prominent neuron-glia interaction may shed light on stress management and depression prevention.

The "winner effect," where prior victories increase the likelihood of future wins, profoundly shapes social hierarchy dynamics and competitive motivation. Although human literature suggests a less pronounced winner effect in females, the neural mechanisms underlying these sex differences remain unclear. Here, we show that, compared with male mice, female mice take longer to form social hierarchies and exhibit a weaker winner effect. The dorsomedial prefrontal cortex (dmPFC), crucial for social dominance in males, plays a similar role in female mice. However, female mice exhibit reduced long-term potentiation (LTP) at the mediodorsal thalamus (MDT)-to-dmPFC synapses. In vitro recordings revealed that female mice have heightened excitability of dmPFC parvalbumin interneurons (PV-INs). Modulation of dmPFC PV-IN activity regulates LTP and the winner effect in a sexually dimorphic manner. This work identifies dmPFC PV-INs as a target for enhancing the winner effect, establishing a circuit-level framework for sex differences in competitive behaviors.

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems 1 . However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a ‘single-cell HCL analysis’ pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

Heat defense is crucial for survival and fitness. Transmission of thermosensory signals into hypothalamic thermoregulation centers represents a key layer of regulation in heat defense. Yet, how these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that lateral parabrachial nucleus (LPB) glutamatergic prodynorphin and cholecystokinin neuron populations are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuits with downstream preoptic hypothalamic neurons to inhibit the thermogenesis of brown adipose tissues (BATs) and activate tail vasodilation, respectively. Both circuits are activated by warmth and can limit fever development. The prodynorphin circuit is further required for regulating energy expenditure and body weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, inhibition of BAT thermogenesis and activation of vasodilation.

氯胺酮的快速抗抑郁功效被认为是“整个精神疾病领域近半个世纪最重要的发现”.氯胺酮快速抗抑郁的机制尚不明确.胡海岚团队的研究揭示了“反奖赏中心”外侧缰核的簇状放电是抑郁发生的充分条件.抑郁状态下,外侧缰核胶质细胞Kir4.1通道表达上调,引发簇状放电神经元比例上升,增强对下游奖赏中心的抑制作用.而氯胺酮则可通过阻断外侧缰核的NMDA受体减少簇状放电,释放对奖赏中心的抑制,产生快速抗抑郁效果.这一研究为抑郁症的治疗和诊断提供了全新的分子靶点.

The neural substrates for predatory hunting, an evolutionarily conserved appetitive behavior, remain largely undefined. Photoactivation of zona incerta (ZI) GABAergic neurons strongly promotes hunting of both live and artificial prey. Conversely, photoinhibition of these neurons or deletion of their GABA function severely impairs hunting. Here electrophysiological recordings reveal that ZI neurons integrate prey-related multisensory signals and discriminate prey from non-prey targets. Visual or whisker sensory deprivation reduces calcium responses induced by prey introduction and attack and impair hunting. ZI photoactivation largely corrects the hunting impairment caused by sensory deprivations. Motivational and reinforcing assays reveal that ZI photoactivation is associated with a strong appetitive drive, causing repetitive self-stimulatory behaviors. These ZI neurons project to the periaqueductal gray matter to induce hunting and motivation. Thus, we have delineated the function of ZI GABAergic neurons in hunting, which integrates prey-related sensory signals into prey detection and attack and induces a strong appetitive motivational drive.