Heightened lateral habenula activity during stress produces brainwide and behavioral substrates of susceptibility.

Some individuals are susceptible to chronic stress, and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After (but not before) chronic social defeat stress, the LHb is active when susceptible mice are in proximity of the aggressor strain. During stress, activity is higher in susceptible mice during aggressor interactions, and activation biases mice toward susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical vs. cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.

A small population of stress-responsive neurons in the hypothalamus-habenula circuit mediates development of depression-like behavior in mice.

Accumulating evidence has shown that various brain functions are associated with experience-activated neuronal ensembles. However, whether such neuronal ensembles are engaged in the pathogenesis of stress-induced depression remains elusive. Utilizing activity-dependent viral strategies in mice, we identified a small population of stress-responsive neurons, primarily located in the middle part of the lateral hypothalamus (mLH) and the medial part of the lateral habenula (LHbM). These neurons serve as "starter cells" to transmit stress-related information and mediate the development of depression-like behaviors during chronic stress. Starter cells in the mLH and LHbM form dominant connections, which are selectively potentiated by chronic stress. Silencing these connections during chronic stress prevents the development of depression-like behaviors, whereas activating these connections directly elicits depression-like behaviors without stress experience. Collectively, our findings dissect a core functional unit within the LH-LHb circuit that mediates the development of depression-like behaviors in mice.

Distinct populations of lateral preoptic nucleus neurons jointly contribute to depressive-like behaviors through divergent projections in male mice.

The lateral preoptic area (LPO) is a component of the hypothalamus involved in various physiological functions including sleep-wakefulness transition, thermoregulation, and water-salt balance. In this study, we discovered that distinct LPO excitatory neurons project separately to the aversive processing center lateral habenula (LHb) and the reward processing hub ventral tegmental area (VTA). Following chronic restraint stress (CRS), the LHb-projecting and VTA-projecting LPO neurons exhibited increased and decreased neuronal activities, respectively. Optogenetic activation of LHb-projecting LPO excitatory neurons and LPO excitatory neuronal terminals within LHb evoked aversion and avoidance behaviors, while activation of VTA-projecting LPO excitatory neurons and LPO excitatory neuronal terminals within VTA produced preference and exploratory behaviors in mice. Furthermore, either optogenetic inhibition of LHb-projecting LPO excitatory neurons or activation of VTA-projecting LPO excitatory neurons during CRS effectively prevented the development of depressive-like behaviors. Our study unveils, for the first-time, divergent pathways originating from LPO that regulate opposite affective states in mice and implicates that an imbalance of their activities could lead to depressive-like behaviors. These circuitries represent promising therapeutic targets to relieve emotional dysfunctions in neuropsychiatric disorders.

Chronic Social Defeat Stress Induces Pathway-Specific Adaptations at Lateral Habenula Neuronal Outputs.

The lateral habenula (LHb) has emerged as a pivotal brain region implicated in depression, displaying hyperactivity in human and animal models of depression. While the role of LHb efferents in depressive disorders has been acknowledged, the specific synaptic alterations remain elusive. Here, employing optogenetics, retrograde tracing, and ex vivo whole-cell patch-clamp techniques, we investigated synaptic transmission in male mice subjected to chronic social defeat stress (CSDS) at three major LHb neuronal outputs: the dorsal raphe nucleus (DRN), the ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). Our findings uncovered distinct synaptic adaptations in LHb efferent circuits in response to CSDS. Specifically, CSDS induced in susceptible mice postsynaptic potentiation and postsynaptic depression at the DRN and VTA neurons, respectively, receiving excitatory inputs from the LHb, while CSDS altered presynaptic transmission at the LHb terminals in RMTg in both susceptible and resilient mice. Moreover, whole-cell recordings at projection-defined LHb neurons indicate decreased spontaneous activity in VTA-projecting LHb neurons, accompanied by an imbalance in excitatory-inhibitory inputs at the RMTg-projecting LHb neurons. Collectively, these novel findings underscore the circuit-specific alterations in LHb efferents following chronic social stress, shedding light on potential synaptic adaptations underlying stress-induced depressive-like states.

Lateral habenula IL-10 controls GABAA receptor trafficking and modulates depression susceptibility after maternal separation.

Maternal separation (MS), a form of early life adversity, increases the risk of psychiatric disorders in adulthood by intricately linking cytokines and mood-regulating brain circuits. The Lateral Habenula (LHb) encodes aversive experiences, contributes to negative moods, and is pivotal in depression development. However, the precise impact of MS on LHb cytokine signaling and synaptic plasticity remains unclear. We reported that adolescent MS offspring mice displayed susceptibility to depression behavioral phylotypes, with neuronal hyperactivity and an imbalance in pro-inflammatory and anti-inflammatory cytokines in the LHb. Moreover, the decreased IL-10 level negatively correlated with depressive-like behaviors in susceptible mice. Functionally, LHb IL-10 overexpression restored decreased levels of PI3K, phosphorylated AKT (pAKT), gephyrin, and membrane GABAA receptor proteins while reducing abnormally elevated GSK3ß and Fos expression, rescuing the MS-induced depression. Conversely, LHb neuronal IL-10 receptor knockdown in naive mice increased Fos expression and elicited depression-like symptoms, potentially through impaired membrane GABAA receptor trafficking by suppressing the PI3K/pAKT/gephyrin cascades. Hence, this work establishes a mechanism by which MS promotes susceptibility to adolescent depression by impeding the critical role of IL-10 signaling on neuronal GABAA receptor function.

A prefrontal-habenular circuitry regulates social fear behaviour.

The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified. Employing a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are synchronously activated during social fear expression. Moreover, optogenetic inhibition of the mPFC-LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal-habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear. These results unravel a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptom often observed in many psychiatric disorders.

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.

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.

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.

The neuronal and synaptic dynamics underlying post-inhibitory rebound burst related to major depressive disorder in the lateral habenula neuron model.

A burst behavior observed in the lateral habenula (LHb) neuron related to major depressive disorder has attracted much attention. The burst is induced from silence by the excitatory N-methyl-D-aspartate (NMDA) synapse or by the inhibitory stimulation, i.e., a post-inhibitory rebound (PIR) burst, which has not been explained clearly. In the present paper, the neuronal and synaptic dynamics for the PIR burst are acquired in a theoretical neuron model. At first, dynamic cooperations between the fast rise of inhibitory γ-aminobutyric acid (GABA) synapse, slow rise of NMDA synapse, and T-type calcium current to evoke the PIR burst are obtained. Similar to the inhibitory pulse stimulation, fast rising GABA current can reduce the membrane potential to a level low enough to de-inactivate the low threshold T-type calcium current to evoke a PIR spike, which can enhance the slow rising NMDA current activated at a time before or after the PIR spike. The NMDA current following the PIR spike exhibits slow decay to induce multiple spikes to form the PIR burst. Such results present a theoretical explanation and a candidate for the PIR burst in real LHb neurons. Then, the dynamical mechanism for the PIR spike mediated by the T-type calcium channel is obtained. At large conductance of T-type calcium channel, the resting state corresponds to a stable focus near Hopf bifurcation and exhibits an "uncommon" threshold curve with membrane potential much lower than the resting membrane potential. Inhibitory modulation induces membrane potential decreased to run across the threshold curve to evoke the PIR spike. At small conductance of the T-type calcium channel, a stable node appears and manifests a common threshold curve with higher membrane potential, resulting in non-PIR phenomenon. The results present the dynamic cooperations between neuronal dynamics and fast/slow dynamics of different synapses for the PIR burst observed in the LHb neuron, which is helpful for the modulations to major depressive disorder.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice, as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Because persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we tested whether the LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors toward more passive action locking rather than escape behaviors in response to an aerial threat in both male and female mice, as well as prolonging the latency to escape responses in female mice. While this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI during late adolescence.

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.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI injury during late adolescence (at ~8 weeks old). Here we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior, and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Since persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we then tested whether LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb normalizes mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors towards more passive action-locking rather than escape behaviors in response to an aerial threat in both male and female mice as well as prolonging the latency to escape responses in female mice. While, this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this preclinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI injury during late adolescence.

Mu-opioid receptor activation in the habenula modulates synaptic transmission and depression-like behaviors.

Opioid system dysregulation in response to stress is known to lead to psychiatric disorders including major depression. Among three different types of opioid receptors, the mu-type receptors (mORs) are highly expressed in the habenula complex, however, the action of mORs in this area and its interaction with stress exposure is largely unknown. Therefore, we investigated the roles of mORs in the habenula using male rats of an acute learned helplessness (aLH) model. First, we found that mOR activation decreased both excitatory and inhibitory synaptic transmission onto the lateral habenula (LHb). Intriguingly, this mOR-induced synaptic depression was reduced in an animal model of depression compared to that of controls. In naïve animals, we found an unexpected interaction between mORs and the endocannabinoid (eCB) signaling occurring in the LHb, which mediates presynaptic alteration occurring with mOR activation. However, we did not observe presynaptic alteration by mOR activation after stress exposure. Moreover, selective mOR activation in the habenula before, but not after, stress exposure effectively reduced helpless behaviors compared to aLH animals. Our observations are consistent with clinical reports suggesting the involvement of mOR signaling in depression, and additionally reveal a critical time window of mOR action in the habenula for ameliorating helplessness symptoms.

Lateral habenula 5-HT1B receptors are involved in regulation of anxiety-like behaviors in parkinsonian rats.

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not clear the role of LHb 5-HT1B receptors in regulation of anxiety-like behaviors, particularly in Parkinson's disease-related anxiety. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, led to decreased normalized δ power and increased normalized θ power in the LHb, and decreased dopamine (DA) level in the prelimbic cortex (PrL) compared with sham rats. Down-regulation of LHb 5-HT1B receptors by RNA interference produced anxiety-like effects, decreased normalized δ power and increased normalized θ power in the LHb in both sham and lesioned rats. Further, intra-LHb injection of 5-HT1B receptor agonist CP93129 induced anxiolytic-like responses, increased normalized δ power and decreased normalized θ power in the LHb, and increased DA and serotonin (5-HT) release in the PrL; conversely, 5-HT1B receptor antagonist SB216641 produced anxiety-like effects, decreased normalized δ power and increased normalized θ power in the LHb, and decreased DA and 5-HT release in the PrL in sham and lesioned rats. Additionally, effects of CP93129 and SB216641 on the behaviors, normalized δ and θ power in the LHb, and DA and 5-HT release in the PrL were decreased in lesioned rats, which were consistent with down-regulation of LHb 5-HT1B receptors after DA depletion. Collectively, these findings suggest that 5-HT1B receptors in the LHb are involved in the regulation of anxiety-like behaviors.

Input-output specific orchestration of aversive valence in lateral habenula during stress dynamics. / åŽ‹åŠ›åŠ¨æ€è¿‡ç¨‹ä¸­è´Ÿæ€§æƒ ç»ªåœ¨å¤–ä¾§ç¼°æ ¸çš„"è¾“å ¥-输出"特异性整合.

Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.

Whole-brain connections of glutamatergic neurons in the mouse lateral habenula in both sexes.

BACKGROUND: The lateral habenula (LHb) is an epithalamus nucleus that is evolutionarily conserved and involved in various physiological functions, such as encoding value signals, integrating emotional information, and regulating related behaviors. The cells in the LHb are predominantly glutamatergic and have heterogeneous functions in response to different stimuli. The circuitry connections of the LHb glutamatergic neurons play a crucial role in integrating a wide range of events. However, the circuitry connections of LHb glutamatergic neurons in both sexes have not been thoroughly investigated. METHODS: In this study, we injected Cre-dependent retrograde trace virus and anterograde synaptophysin-labeling virus into the LHb of adult male and female Vglut2-ires-Cre mice, respectively. We then quantitatively analyzed the input and output of the LHb glutamatergic connections in both the ipsilateral and contralateral whole brain. RESULTS: Our findings showed that the inputs to LHbvGlut2 neurons come from more than 30 brain subregions, including the cortex, striatum, pallidum, thalamus, hypothalamus, midbrain, pons, medulla, and cerebellum with no significant differences between males and females. The outputs of LHbvGlut2 neurons targeted eight large brain regions, primarily focusing on the midbrain and pons nuclei, with distinct features in presynaptic bouton across different brain subregions. While correlation and cluster analysis revealed differences in input and collateral projection features, the input-output connection pattern of LHbvGlut2 neurons in both sexes was highly similar. CONCLUSIONS: This study provides a systematic and comprehensive analysis of the input and output connections of LHbvGlut2 neurons in male and female mice, shedding light on the anatomical architecture of these specific cell types in the mouse LHb. This structural understanding can help guide further investigations into the complex functions of the LHb.

Role of electrophysiological activity and interactions of lateral habenula in the development of depression-like behavior in a chronic restraint stress model.

Closed-loop deep brain stimulation (DBS) system offers a promising approach for treatment-resistant depression, but identifying universally accepted electrophysiological biomarkers for closed-loop DBS systems targeting depression is challenging. There is growing evidence suggesting a strong association between the lateral habenula (LHb) and depression. Here, we took LHb as a key target, utilizing multi-site local field potentials (LFPs) to study the acute and chronic changes in electrophysiology, functional connectivity, and brain network characteristics during the formation of a chronic restraint stress (CRS) model. Furthermore, our model combining the electrophysiological changes of LHb and interactions between LHb and other potential targets of depression can effectively distinguish depressive states, offering a new way for developing effective closed-loop DBS strategies.

Lesions of the lateral habenula excite dopamine neurons in the ventral tegmental area and serotonin neurons in the dorsal raphe nuclei in hemiparkinsonian rats.

The lateral habenula (LHb) projects to the ventral tegmental area (VTA) and dorsal raphe nuclei (DRN) that deliver dopamine (DA) and serotonin (5-HT) to cortical and limbic regions such as the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). Dysfunctions of VTA-related mesocorticolimbic dopaminergic and DRN-related serotonergic systems contribute to non-motor symptoms in Parkinson's disease (PD). However, how the LHb affects the VTA and DRN in PD remains unclear. Here, we used electrophysiological and neurochemical approaches to explore the effects of LHb lesions on the firing activity of VTA and DRN neurons, as well as the levels of DA and 5-HT in related brain regions in unilateral 6-hydroxydopamie (6-OHDA)-induced PD rats. We found that compared to sham lesions, lesions of the LHb increased the firing rate of DA neurons in the VTA and 5-HT neurons in the DRN, but decreased the firing rate of GABAergic neurons in the same nucleus. In addition, lesions of the LHb increased the levels of DA and 5-HT in the mPFC, ventral hippocampus and BLA compared to sham lesions. These findings suggest that lesions of the LHb enhance the activity of mesocorticolimbic dopaminergic and serotonergic systems in PD.