Serotonin release in the habenula during emotional contagion promotes resilience.

Negative emotional contagion-witnessing others in distress-affects an individual's emotional responsivity. However, whether it shapes coping strategies when facing future threats remains unknown. We found that mice that briefly observe a conspecific being harmed become resilient, withstanding behavioral despair after an adverse experience. Photometric recordings during negative emotional contagion revealed increased serotonin (5-HT) release in the lateral habenula. Whereas 5-HT and emotional contagion reduced habenular burst firing, limiting 5-HT synthesis prevented burst plasticity. Enhancing raphe-to-habenula 5-HT was sufficient to recapitulate resilience. In contrast, reducing 5-HT release in the habenula made witnessing a conspecific in distress ineffective to promote the resilient phenotype after adversity. These findings reveal that 5-HT supports vicarious emotions and leads to resilience by tuning definite patterns of habenular neuronal activity.

Mental health: The REM sleep paradox in depression.

The relationship between mental disorders and sleep remains unclear. Two new studies show that the lateral habenula, a brain region associated with value-guided behavior, controls REM sleep and promotes emotional stability but also contributes to REM sleep disinhibition in depression.

Brain region-specific action of ketamine as a rapid antidepressant.

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.

The lateral habenula integrates age and experience to promote social transitions in developing rats.

Early caregiving adversity (ECA) is associated with social behavior deficits and later development of psychopathology. However, the infant neural substrates of ECA are poorly understood. The lateral habenula (LHb), a highly conserved brain region with consistent links to adult psychopathology, is understudied in development, when the brain is most vulnerable to environmental impacts. Here, we describe the structural and functional ontogeny of the LHb and its behavioral role in infant and juvenile rat pups. We show that the LHb promotes a developmental transition in social approach behavior under threat as typically reared infants mature. By contrast, we show that ECA disrupts habenular ontogeny, including volume, protein expression, firing properties, and corticohabenular connectivity. Furthermore, inhibiting a specific corticohabenular projection rescues infant social approach deficits following ECA. Together, these results identify immediate biomarkers of ECA in the LHb and highlight this region as a site of early social processing and behavior control.

Psychological resilience is positively correlated with Habenula volume.

BACKGROUND: Psychological resilience is defined as the process and outcome of individuals' successful adaptation to challenging life experiences. The Habenula (Hb) is known to be involved in the stress response; however, the relationship between Hb volume and resilience in humans remains unclear. This study investigated the correlation among resilience, Hb volume, and depressive tendencies in adults. METHODS: Hb volumes were assessed using deep learning techniques applied to 110 healthy participants. Resilience and depression were evaluated using the Connor-Davidson Resilience Scale and Beck Depression Inventory-II, respectively. We examined the relationship between Hb volume and resilience and assessed the mediating effects of resilience on the relationship between Hb volume and depressive tendencies. RESULTS: Correlation analysis revealed a positive correlation between resilience and Hb volume (partial r = 0.176, p = 0.001), which was more pronounced in women (partial r = 0.353, p = 0.003). Hb volumes on the left and right sides exhibited significant lateralization (LI = 0.031, 95 % CI = [0.016, 0.046]). Despite Hb asymmetry, lateralization was not significantly associated with resilience. The mediation analysis shows significant indirect effect of resilience on the relationship between Hb volume and depressive tendencies (ß = -0.093, 95%CI = [-0.189, -0.019]). CONCLUSION: This study found that populations with lower resilience have smaller Hb volume. Previous research has shown that Hb volume decreased with the increasing severity of depression symptoms in patients. Our findings support this view and extend it to a population that has not been clinically diagnosed with depression. Additionally, we found that psychological resilience can be predicted by Hb volume and may serve as a mediating factor indirectly affecting depressive tendencies, even in healthy individuals. LIMITATIONS: Due to its cross-sectional design, this study was unable to analyze dynamic changes in Hb volume during the process of resilience adaptation.

The putative role of the habenula in animal migration.

BACKGROUND: When an addicted animal seeks a specific substance, it is based on the perception of internal and external cues that strongly motivate to pursue the acquisition of that compound. In essence, a similar process acts out when an animal leaves its present area to begin its circannual migration. This review article examines the existence of scientific evidence for possible relatedness of migration and addiction by influencing Dorsal Diencephalic Conduction System (DDCS) including the habenula. METHODS: For this review especially the databases of Pubmed and Embase were frequently and non-systematically searched. RESULTS: The mechanisms of bird migration have been thoroughly investigated. Especially the mechanism of the circannual biorhythm and its associated endocrine regulation has been well elucidated. A typical behavior called "Zugunruhe" marks the moment of leaving in migratory birds. The role of magnetoreception in navigation has also been clarified in recent years. However, how bird migration is regulated at the neuronal level in the forebrain is not well understood. Among mammals, marine mammals are most similar to birds. They use terrestrial magnetic field when navigating and often bridge long distances between breeding and foraging areas. Population migration is further often seen among the large hoofed mammals in different parts of the world. Importantly, learning processes and social interactions with conspecifics play a major role in these ungulates. Considering the evolutionary development of the forebrain in vertebrates, it can be postulated that the DDCS plays a central role in regulating the readiness and intensity of essential (emotional) behaviors. There is manifold evidence that this DDCS plays an important role in relapse to abuse after prolonged periods of abstinence from addictive behavior. It is also possible that the DDCS plays a role in navigation. CONCLUSIONS: The role of the DDCS in the neurobiological regulation of bird migration has hardly been investigated. The involvement of this system in relapse to addiction in mammals might suggest to change this. It is recommended that particularly during "Zugunruhe" the role of neuronal regulation via the DDCS will be further investigated.

Topographic Organization of Glutamatergic and GABAergic Parvalbumin-Positive Neurons in the Lateral Habenula.

Parvalbumin-expressing (PV) neurons, classified by their expression of the calcium-binding protein parvalbumin, play crucial roles in the function and plasticity of the lateral habenular nucleus (LHb). This study aimed to deepen our understanding of the LHb by collecting information about the heterogeneity of LHb PV neurons in mice. To achieve this, we investigated the proportions of the transmitter machinery in LHb PV neurons, including GABAergic, glutamatergic, serotonergic, cholinergic, and dopaminergic neurotransmitter markers, using transcriptome analysis, mRNA in situ hybridization chain reaction, and immunohistochemistry. LHb PV neurons comprise three subsets: glutamatergic, GABAergic, and double-positive for glutamatergic and GABAergic machinery. By comparing the percentages of the subsets, we found that the LHb was topographically organized anteroposteriorly; the GABAergic and glutamatergic PV neurons were preferentially distributed in the anterior and posterior LHb, respectively, uncovering the anteroposterior topography of the LHb. In addition, we confirmed the mediolateral topography of lateral GABAergic PV neurons. These findings suggest that PV neurons play distinct roles in different parts of the LHb along the anteroposterior and mediolateral axes, facilitating the topographic function of the LHb. It would be interesting to determine whether their topography is differentially involved in various cognitive and motivational processes associated with the LHb, particularly the involvement of posterior glutamatergic PV neurons.

Atypical Course of the Habenulo-Interpeduncular Tract in Chick Embryos.

Classical studies of the avian diencephalon hardly mention the habenulo-interpeduncular tract (a.k.a. retroflex tract), although both the habenula (HB) (its origin) and the interpeduncular nuclear complex (its target) are present. Retroflex tract fibers were described at early embryonic stages but seem absent in the adult in routine stains. However, this tract is a salient diencephalic landmark in all other vertebrate lineages. It typically emerges out of the caudal HB, courses dorsoventrally across thalamic alar and basal plates just in front of the thalamo-pretectal boundary, and then sharply bends 90° caudalwards at paramedian basal plate levels (this is the "retroflexion"), to approach longitudinally via paramedian pretectum and midbrain the rostralmost hindbrain, specifically the prepontine median interpeduncular complex across isthmus and rhombomere 1. We systematize this habenulo-interpeduncular course into four parts named subhabenular, retrothalamic, tegmental, and interpeduncular. We reexamined the chicken habenulo-interpeduncular fibers at stages HH30 and HH35 (6.5- and 9-day incubation) by mapping them specifically with immunoreaction for BEN protein, a well-known marker. We found that only a small fraction of the stained retroflex tract fibers approaches the basal plate by coursing along the standard dorsoventral pathway in front of the thalamo-pretectal boundary. Many other habenular fibers instead diverge into atypical dispersed courses across the thalamic cell mass (implying alteration of the first subhabenular part of the standard course) before reaching the basal plate; this dispersion explains their invisibility. A significant number of such transthalamic habenular fibers cross orthogonally the zona limitans (ZLI) (the rostral thalamic boundary) and invade the caudal alar prethalamus. Here, they immediately descend dorsoventrally, just rostrally to the ZLI, until reaching the prethalamic basal plate, where they bend (retroflex) caudalwards, entering the thalamic basal paramedian area. These atypical fibers gradually fasciculate with the other groups of habenular efferent fibers in their final longitudinal approach to the hindbrain interpeduncular complex. We conclude that the poor visibility of this tract in birds is due to its dispersion into a diversity of atypical alternative routes, though all components eventually reach the interpeduncular complex. This case merits further analysis of the diverse permissive versus nonpermissive guidance mechanisms called into action, which partially correlate distinctly with successive diencephalic, mesencephalic, and hindbrain neuromeric fields and their boundaries.

HCN channels in the lateral habenula regulate pain and comorbid depressive-like behaviors in mice.

AIMS: Comorbid anxiodepressive-like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain. METHODS: After chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open-field test, and elevated plus maze test to evaluate their anxiodepressive-like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms. RESULTS: Evident anxiodepressive-like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive-like behaviors. CONCLUSION: Our results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up-regulation of HCN2 isoforms.

A discrete subpopulation of PFC-LHb neurons govern cocaine place preference.

Addiction is a complex behavioral disorder characterized by compulsive drug-seeking and drug use despite harmful consequences. The prefrontal cortex (PFC) plays a crucial role in cocaine addiction, involving decision-making, impulse control, memory, and emotional regulation. The PFC interacts with the brain's reward system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc). The PFC also projects to the lateral habenula (LHb), a brain region critical for encoding negative reward and regulating the reward system. In the current study, we examined the role of PFC-LHb projections in regulating cocaine reward-related behaviors. We found that optogenetic stimulation of the PFC-LHb circuit during cocaine conditioning abolished cocaine preference without causing aversion. In addition, increased c-fos expression in LHb neurons was observed in animals that received optic stimulation during cocaine conditioning, supporting the circuit's involvement in cocaine preference regulation. Molecular analysis in animals that received optic stimulation revealed that cocaine-induced alterations in the expression of GluA1 subunit of AMPA receptor was normalized to saline levels in a region-specific manner. Moreover, GluA1 serine phosphorylation on S845 and S831 were differentially altered in LHb and VTA but not in the PFC. Together these findings highlight the critical role of the PFC-LHb circuit in controlling cocaine reward-related behaviors and shed light on the underlying mechanisms. Understanding this circuit's function may provide valuable insights into addiction and contribute to developing targeted treatments for substance use disorders.

Dysregulation of kappa opioid receptor neuromodulation of lateral habenula synaptic function following a repetitive mild traumatic brain injury.

Mild traumatic brain injury (mTBI) increases the risk of affective disorders, anxiety and substance use disorder. The lateral habenula (LHb) plays an important role in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between mTBI-induced LHb hyperactivity due to excitation/inhibition (E/I) imbalance and motivational deficits in male mice using a repetitive closed head injury mTBI model. A major neuromodulatory system that is responsive to traumatic brain injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function are unknown. Here, we first used retrograde tracing in male and female Cre mouse lines and identified several major KOR-expressing and two prominent Dyn-expressing inputs projecting to the mouse LHb, highlighting the medial prefrontal cortex (mPFC) and the ventromedial nucleus of the hypothalamus (VMH) as the main LHb-projecting Dyn inputs that regulate KOR signaling to the LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4 week post-injury. We observed sex-specific differences in spontaneous release of glutamate and GABA from presynaptic terminals onto LHb neurons with higher levels of presynaptic glutamate and GABA release in females compared to male mice. However, KOR effects on the spontaneous E/I ratios and synaptic drive ratio within the LHb did not differ between male and female sham and mTBI mice. KOR activation generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant but sex-similar reduction in net spontaneous E/I and synaptic drive ratios in LHb neurons of sham mice. Following mTBI, while responses to KOR activation at LHb glutamatergic synapses remained intact, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition where we observed a reduction in GABA release probability in response to KOR stimulation in LHb neurons of mTBI mice. Further analysis of percent change in spontaneous synaptic ratios induced by KOR activation revealed that independent of sex mTBI switches KOR-driven synaptic inhibition of LHb neurons (normally observed in sham mice) in a subset of mTBI mice toward synaptic excitation resulting in mTBI-induced divergence of KOR actions within the LHb. Overall, we uncovered the sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. We demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global KOR-driven synaptic inhibition within the mouse LHb independent of sex. The additional engagement of KOR-mediated action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons of a subset of mTBI mice.

Burst firing in Output-Defined Parallel Habenula Circuit Underlies the Antidepressant Effects of Bright Light Treatment.

Research highlights the significance of increased bursting in lateral habenula (LHb) neurons in depression and as a focal point for bright light treatment (BLT). However, the precise spike patterns of LHb neurons projecting to different brain regions during depression, their roles in depression development, and BLT's therapeutic action remain elusive. Here, LHb neurons are found projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and median raphe nucleus (MnR) exhibit increased bursting following aversive stimuli exposure, correlating with distinct depressive symptoms. Enhanced bursting in DRN-projecting LHb neurons is pivotal for anhedonia and anxiety, while concurrent bursting in LHb neurons projecting to the DRN, VTA, and MnR is essential for despair. Remarkably, reducing bursting in distinct LHb neuron subpopulations underlies the therapeutic effects of BLT on specific depressive behaviors. These findings provide valuable insights into the mechanisms of depression and the antidepressant action of BLT.

Habenula volume change in Parkinson's disease: A 7T MRI study.

OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and early non-motor symptoms. The habenula is implicated in the pathophysiology of depression. This study investigates habenular volume in PD patients without clinical depression to show the changes in PD unrelated to depression. METHODS: The study used high-resolution 7 Tesla MRI data from the TRACK-PD study involving 104 PD patients and 44 healthy controls (HCs). The habenula was manually segmented, and volumes were measured, considering demographic data and depression scores via the Beck Depression Inventory (BDI). RESULTS: No significant correlation was found between habenular volume and BDI scores in PD patients or HCs. However, the PD group exhibited a significantly larger mean and right habenular volume than HCs. Although PD patients showed higher BDI scores, indicating more subthreshold depression, these did not correlate with the habenular volume. CONCLUSION: The results suggest that while the habenula may be involved in the symptoms of PD, its role in depression within this cohort is unclear. The changes might be related to the role of the habenula in motor symptoms. This study provides a new perspective on the role of the habenula in PD, but future research could lead to a greater understanding of the neuroanatomical features of the habenula in PD.

A REM-active basal ganglia circuit that regulates anxiety.

Rapid eye movement (REM) sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in mice, somatostatin (Som) neurons in the entopeduncular nucleus (EPSom)/internal globus pallidus are predominantly active during REM sleep. This unique REM activity is both necessary and sufficient for maintaining normal REM sleep. Inhibiting or exciting EPSom neurons reduced or increased REM sleep duration, respectively. Activation of the sole downstream target of EPSom neurons, Vglut2 cells in the lateral habenula (LHb), increased sleep via the ventral tegmental area (VTA). A simple chemogenetic scheme to periodically inhibit the LHb over 4 days selectively removed a significant amount of cumulative REM sleep. Chronic, but not acute, REM reduction correlated with mice becoming anxious and more sensitive to aversive stimuli. Therefore, we suggest that cumulative REM sleep, in part generated by the EP → LHb → VTA circuit identified here, could contribute to stabilizing reactions to habitual aversive stimuli.

A potentiation of REM sleep-active neurons in the lateral habenula may be responsible for the sleep disturbance in depression.

Psychiatric disorders with dysfunction of the lateral habenula (LHb) show sleep disturbance, especially a disinhibition of rapid eye movement (REM) sleep in major depression. However, the role of LHb in physiological sleep control and how LHb contributes to sleep disturbance in major depression remain elusive. Here, we found that functional manipulations of LHb glutamatergic neurons bidirectionally modulated both non-REM (NREM) sleep and REM sleep. Activity recording revealed heterogeneous activity patterns of LHb neurons across sleep/wakefulness cycles, but LHb neurons were preferentially active during REM sleep. Using an activity-dependent tagging method, we selectively labeled a population of REM sleep-active LHb neurons and demonstrated that these neurons specifically promoted REM sleep. Neural circuit studies showed that LHb neurons regulated REM sleep via projections to the ventral tegmental area but not to the rostromedial tegmental nucleus. Furthermore, we found that the increased REM sleep in a depression mouse model was associated with a potentiation of REM sleep-active LHb neurons, including an increased proportion, elevated spike firing, and altered activity mode. Importantly, inhibition of REM sleep-active LHb neurons not only attenuated the increased REM sleep but also alleviated depressive-like behaviors in a depression mouse model. Thus, our results demonstrated that REM sleep-active LHb neurons selectively promoted REM sleep, and a potentiation of these neurons contributed to depression-associated sleep disturbance.

Habenular volume changes after venlafaxine treatment in patients with major depression.

BACKGROUND: Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement. METHODS: Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant-free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment. RESULTS: A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness. CONCLUSION: Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.

Midbrain glutamatergic circuit mechanism of resilience to socially transferred allodynia in male mice.

The potential brain mechanism underlying resilience to socially transferred allodynia remains unknown. Here, we utilize a well-established socially transferred allodynia paradigm to segregate male mice into pain-susceptible and pain-resilient subgroups. Brain screening results show that ventral tegmental area glutamatergic neurons are selectively activated in pain-resilient mice as compared to control and pain-susceptible mice. Chemogenetic manipulations demonstrate that activation and inhibition of ventral tegmental area glutamatergic neurons bi-directionally regulate resilience to socially transferred allodynia. Moreover, ventral tegmental area glutamatergic neurons that project specifically to the nucleus accumbens shell and lateral habenula regulate the development and maintenance of the pain-resilient phenotype, respectively. Together, we establish an approach to explore individual variations in pain response and identify ventral tegmental area glutamatergic neurons and related downstream circuits as critical targets for resilience to socially transferred allodynia and the development of conceptually innovative analgesics.

Modulation of habenular and nucleus accumbens functional connectivity by ketamine in major depression.

INTRODUCTION: Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks. METHODS: MDD participants (n = 58, mean age = 40.7 years, female = 28) received four ketamine infusions (0.5 mg/kg) 2-3 times weekly. Resting-state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24 h post-SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre-to-post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n = 55, mean age = 32.6, female = 31), and between HC assessed twice (n = 16) were conducted as follow-up analyses. RESULTS: Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time. CONCLUSION: Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.

Abundant extrasynaptic expression of α3ß4-containing nicotinic acetylcholine receptors in the medial habenula-interpeduncular nucleus pathway in mice.

Nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb)-interpeduncular nucleus (IPN) pathway play critical roles in nicotine-related behaviors. This pathway is particularly enriched in nAChR α3 and ß4 subunits, both of which are genetically linked to nicotine dependence. However, the cellular and subcellular expression of endogenous α3ß4-containing nAChRs remains largely unknown because specific antibodies and appropriate detection methods were unavailable. Here, we successfully uncovered the expression of endogenous nAChRs containing α3 and ß4 subunits in the MHb-IPN pathway using novel specific antibodies and a fixative glyoxal that enables simultaneous detection of synaptic and extrasynaptic molecules. Immunofluorescence and immunoelectron microscopy revealed that both subunits were predominantly localized to the extrasynaptic cell surface of somatodendritic and axonal compartments of MHb neurons but not at their synaptic junctions. Immunolabeling for α3 and ß4 subunits disappeared in α5ß4-knockout brains, which we used as negative controls. The enriched and diffuse extrasynaptic expression along the MHb-IPN pathway suggests that α3ß4-containing nAChRs may enhance the excitability of MHb neurons and neurotransmitter release from their presynaptic terminals in the IPN. The revealed distribution pattern provides a molecular and anatomical basis for understanding the functional role of α3ß4-containing nAChRs in the crucial pathway of nicotine dependence.

A Light-Responsive Neural Circuit Suppresses Feeding.

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb→5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.