Authors: Zhengxiao Fan, Jiarui Chang, Yilan Liang...

Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism remains elusive. Here, by forcing mice to lose against their subordinates in a non-violent social contest, we lower their social ranks stably and induce depressive-like behaviors. These rank-decline-associated depressive-like behaviors can be reversed by regaining social status. In vivo fiber photometry and single-unit electrophysiological recording show that forced loss, but not natural loss, generates negative reward prediction error (RPE). Through the lateral hypothalamus, the RPE strongly activates the brain's anti-reward center, the lateral habenula (LHb). LHb activation inhibits the medial prefrontal cortex (mPFC) that controls social competitiveness and reinforces retreats in contests. These results reveal the core neural mechanisms mutually promoting social status loss and depressive behaviors. The intertwined neuronal signaling controlling mPFC and LHb activities provides a mechanistic foundation for the crosstalk between social mobility and psychological disorder, unveiling a promising target for intervention.

Topics: Mice; Animals; Social Status; Reward; Social Behavior; Habenula; Depression

PubMed: 36693374
DOI: 10.1016/j.cell.2022.12.033

Review

Authors: Yan Yang, Hao Wang, Ji Hu...

Depression is a devastating disorder with a combination of diverse symptoms such as low self-esteem, lack of motivation, anhedonia, loss of appetite, low energy, and discomfort without a clear cause. Depression has been suggested to be the result of maladaptive changes in specific brain circuits. Recently, the lateral habenula (LHb) has emerged as a key brain region in the pathophysiology of depression. Increasing evidence from rodent, non-human primate and human studies indicates that the aberrant activity of the LHb is associated with depressive symptoms such as helplessness, anhedonia, and excessive negative focus. Revealing the molecular, cellular and circuit properties of the LHb will help explain how abnormalities in LHb activity are linked to depressive disorders, and shed light on developing novel strategies for depression treatment.

Topics: Animals; Depressive Disorder; Disease Models, Animal; Habenula; Humans; Nerve Net; Neurons

PubMed: 29175713
DOI: 10.1016/j.conb.2017.10.024

Authors: Daniela Calvigioni, Janos Fuzik, Pierre Le Merre...

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used patch-sequencing (Patch-seq) guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles and projection patterns. We found that genetically defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors, such as estrogen receptor 1-expressing (Esr1) LHA-LHb neurons induce aversion, whereas neuropeptide Y-expressing (Npy) LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1 LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive signals in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1 LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types and provide evidence for the role of Esr1 neurons in aversion and sexually dimorphic stress sensitivity.

Topics: Female; Mice; Animals; Habenula; Hypothalamus; Hypothalamic Area, Lateral; Neurons; Affect; Neural Pathways

PubMed: 37349481
DOI: 10.1038/s41593-023-01367-8

Review

Authors: Dun Xian Tan, Bing Xu, Xinjia Zhou...

The pineal gland is a unique organ that synthesizes melatonin as the signaling molecule of natural photoperiodic environment and as a potent neuronal protective antioxidant. An intact and functional pineal gland is necessary for preserving optimal human health. Unfortunately, this gland has the highest calcification rate among all organs and tissues of the human body. Pineal calcification jeopardizes melatonin's synthetic capacity and is associated with a variety of neuronal diseases. In the current review, we summarized the potential mechanisms of how this process may occur under pathological conditions or during aging. We hypothesized that pineal calcification is an active process and resembles in some respects of bone formation. The mesenchymal stem cells and melatonin participate in this process. Finally, we suggest that preservation of pineal health can be achieved by retarding its premature calcification or even rejuvenating the calcified gland.

Topics: Aging; Animals; Calcinosis; Humans; Melatonin; Pineal Gland; Rejuvenation

PubMed: 29385085
DOI: 10.3390/molecules23020301

Authors: Zhiwei Zheng, Chen Guo, Min Li...

Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.

Topics: Animals; Depression; Habenula; Hypothalamic Area, Lateral; Hypothalamus; Mice; Synapses

PubMed: 35114101
DOI: 10.1016/j.neuron.2022.01.011

Authors: Xin-Yue Wang, Xiang Xu, Rui Chen...

Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

Topics: Mice; Animals; Depression; Neurons; Habenula; Chronic Pain; Thalamic Nuclei

PubMed: 37738124
DOI: 10.1016/j.celrep.2023.113170

Authors: Chi Kin Ip, Jemma Rezitis, Yue Qi...

Chronic stress fuels the consumption of palatable food and can enhance obesity development. While stress- and feeding-controlling pathways have been identified, how stress-induced feeding is orchestrated remains unknown. Here, we identify lateral habenula (LHb) Npy1r-expressing neurons as the critical node for promoting hedonic feeding under stress, since lack of Npy1r in these neurons alleviates the obesifying effects caused by combined stress and high fat feeding (HFDS) in mice. Mechanistically, this is due to a circuit originating from central amygdala NPY neurons, with the upregulation of NPY induced by HFDS initiating a dual inhibitory effect via Npy1r signaling onto LHb and lateral hypothalamus neurons, thereby reducing the homeostatic satiety effect through action on the downstream ventral tegmental area. Together, these results identify LHb-Npy1r neurons as a critical node to adapt the response to chronic stress by driving palatable food intake in an attempt to overcome the negative valence of stress.

Topics: Mice; Animals; Neural Pathways; Habenula; Hypothalamic Area, Lateral; Ventral Tegmental Area; Neurons

PubMed: 37295418
DOI: 10.1016/j.neuron.2023.05.010

Authors: Liang Yang, Chen Guo, Zhiwei Zheng...

Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders. As a key modulator of brain homeostasis, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.

Topics: Autophagy; Animals; Mice; Neurons; Stress, Psychological; Antidepressive Agents; Male; Depression; Habenula; Synaptic Transmission; Neuronal Plasticity; Homeostasis; Chronic Disease; Mice, Inbred C57BL

PubMed: 40205038
DOI: 10.1038/s41586-025-08807-4

Authors: Emily L Sylwestrak, YoungJu Jo, Sam Vesuna...

Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential for full insight into cellular-level mechanisms underlying brain function and dysfunction. Applying this approach to the habenula (a structure with diverse, intermingled molecular, anatomical, and computational features), we identified encoding of reward-predictive cues and reward outcomes in distinct genetically defined neural populations, including TH cells and Tac1 cells. Data from genetically targeted recordings were used to train an optimized nonlinear dynamical systems model and revealed activity dynamics consistent with a line attractor. High-density, cell-type-specific electrophysiological recordings and optogenetic perturbation provided supporting evidence for this model. Reverse-engineering predicted how Tac1 cells might integrate reward history, which was complemented by in vivo experimentation. This integrated approach describes a process by which data-driven computational models of population activity can generate and frame actionable hypotheses for cell-type-specific investigation in biological systems.

Topics: Habenula; Population Dynamics; Reward

PubMed: 36113428
DOI: 10.1016/j.cell.2022.08.019

Review

Authors: Onur Güntürkün, Sebastian Ocklenburg

The brains of humans and other animals are asymmetrically organized, but we still know little about the ontogenetic and neural fundaments of lateralizations. Here, we review the current state of understanding about the role of genetic and non-genetic factors for the development of neural and behavioral asymmetries in vertebrates. At the genetic level, the Nodal signaling cascade is of central importance, but several other genetic pathways have been discovered to also shape the lateralized embryonic brain. Studies in humans identified several relevant genes with mostly small effect sizes but also highlight the extreme importance of non-genetic factors for asymmetry development. This is also visible in visual asymmetry in birds, in which genes only affect embryonic body position, while the resulting left-right difference of visual stimulation shapes visual pathways in a lateralized way. These and further studies in zebrafish and humans highlight that the many routes from genes to asymmetries of function run through left-right differences of neural pathways. They constitute the lateralized blueprints of our perception, cognition, and action.

Topics: Animals; Functional Laterality; Habenula; Humans; Neural Pathways; Photic Stimulation; Visual Pathways; Visual Perception

PubMed: 28426959
DOI: 10.1016/j.neuron.2017.02.045