RESUMO
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.
Assuntos
Habenula , Status Social , Camundongos , Animais , Recompensa , Comportamento Social , Habenula/fisiologia , DepressãoRESUMO
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.
Assuntos
Habenula , Recompensa , Dinâmica PopulacionalRESUMO
GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles (SVs) at the presynaptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca2+-dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV-associated distribution similar to the vesicular transmembrane protein SPO, and they were colocalized in the same terminals. We developed the "Flash and Freeze-fracture" method, and revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals.
Assuntos
Habenula , Receptores de GABA-B , Animais , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Habenula/metabolismo , Astacoidea/metabolismo , Terminações Pré-Sinápticas/metabolismo , Cafeína , Neurotransmissores/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
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.
Assuntos
Habenula , Camundongos Endogâmicos C57BL , Neurônios , Derrota Social , Estresse Psicológico , Animais , Habenula/fisiologia , Masculino , Estresse Psicológico/fisiopatologia , Camundongos , Neurônios/fisiologia , Vias Neurais/fisiologia , Vias Neurais/fisiopatologia , Área Tegmentar Ventral/fisiologia , Optogenética , Adaptação Fisiológica/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
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.
RESUMO
Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.
Assuntos
Habenula , Pneumopatias , Receptores Nicotínicos , Camundongos , Animais , Nicotina/farmacologia , Nicotina/metabolismo , Habenula/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Receptores Nicotínicos/metabolismo , Neurônios Colinérgicos/metabolismo , Pneumopatias/metabolismoRESUMO
As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.
Assuntos
Habenula , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias , Humanos , Ratos , Animais , Habenula/fisiologia , Estudos Longitudinais , Comportamento Compulsivo , Lobo Frontal/diagnóstico por imagemRESUMO
The recent increase in the use of nicotine products by teenagers has revealed an urgent need to better understand the impact of nicotine on the adolescent brain. Here, we sought to examine the actions of extracellular ATP as a neurotransmitter and to investigate whether ATP and nicotinic signaling interact during adolescence. With the GRABATP (G-protein-coupled receptor activation-based ATP sensor), we first demonstrated that nicotine induces extracellular ATP release in the medial habenula, a brain region involved in nicotine aversion and withdrawal. Using patch-clamp electrophysiology, we then demonstrated that activation of the ATP receptors P2X or P2Y1 increases the neuronal firing of cholinergic neurons. Surprisingly, contrasting interactive effects were observed with nicotine exposure. For the P2X receptor, activation had no observable effect on acute nicotine-mediated activity, but during abstinence after 10 d of nicotine exposure, coexposure to nicotine and the P2X agonist potentiated neuronal activity in female, but not male, neurons. For P2Y1 signaling, a potentiated effect of the agonist and nicotine was observed with acute exposure, but not following extended nicotine exposure. These data reveal a complex interactive effect between nicotinic and ATP signaling in the adolescent brain and provide mechanistic insights into extracellular ATP signaling with sex-specific alterations of neuronal responses based on prior drug exposure.SIGNIFICANCE STATEMENT In these studies, it was discovered that nicotine induces extracellular ATP release in the medial habenula and subsequent activation of the ATP purinergic receptors increases habenular cholinergic neuronal firing in the adolescent brain. Interestingly, following extended nicotine exposure, nicotine was found to alter the interplay between purinergic and nicotinic signaling in a sex-specific manner. Together, these studies provide a novel understanding for the role of extracellular ATP in mediating habenular activity and reveal how nicotine exposure during adolescence alters these signaling mechanisms, which has important implications given the high incidence of e-cigarette/vape use by youth.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Habenula , Receptores Purinérgicos P2 , Masculino , Adolescente , Feminino , Humanos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Transmissão Sináptica , Neurônios Colinérgicos , Receptores Purinérgicos P2/fisiologia , Trifosfato de Adenosina/farmacologiaRESUMO
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.
Assuntos
Depressão , Habenula , Desamparo Aprendido , Receptores Opioides mu , Transmissão Sináptica , Animais , Habenula/metabolismo , Masculino , Receptores Opioides mu/metabolismo , Transmissão Sináptica/fisiologia , Ratos , Depressão/metabolismo , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Modelos Animais de DoençasRESUMO
Having experienced stress during sensitive periods of brain development strongly influences how individuals cope with later stress. Some are prone to develop anxiety or depression, while others appear resilient. The as-yet-unknown mechanisms underlying these differences may lie in how genes and environmental stress interact to shape the circuits that control emotions. Here, we investigated the role of the habenulo-interpeduncular system (HIPS), a critical node in reward circuits, in early stress-induced anxiety in mice. We found that habenular and IPN components characterized by the expression of Otx2 are synaptically connected and particularly sensitive to chronic stress (CS) during the peripubertal period. Stress-induced peripubertal activation of this HIPS subcircuit elicits both HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We also show that HIPS silencing through conditional Otx2 knockout counteracts these effects of stress. Together, these results demonstrate that a genetic factor, Otx2, and stress interact during the peripubertal period to shape the stress sensitivity of the HIPS, which is shown to be a key modulator of susceptibility or resilience to develop anxiety.
Assuntos
Habenula , Resiliência Psicológica , Camundongos , Animais , Transtornos de Ansiedade/metabolismo , Emoções , Habenula/metabolismo , AnsiedadeRESUMO
BACKGROUND: Previous studies have suggested that the habenula (Hb) may be involved in the mechanism of obsessive-compulsive disorder (OCD). However, the specific role of Hb in OCD remains unclear. This study aimed to explore the structural and functional abnormalities of Hb in OCD and their relationship with the clinical symptoms. METHODS: Eighty patients with OCD and 85 healthy controls (HCs) were recruited as the primary dataset. The grey matter volume, resting-state functional connectivity (FC), and effective connectivity (EC) of the Hb were calculated and compared between OCD group and HCs. An independent replication dataset was used to verify the stability and robustness of the results. RESULTS: Patients with OCD exhibited smaller Hb volume and increased FC of right Hb-left hippocampus than HCs. Dynamic causal model revealed an increased EC from left hippocampus to right Hb and a less inhibitory causal influence from the right Hb to left hippocampus in the OCD group compared to HCs. Similar results were found in the replication dataset. CONCLUSIONS: This study suggested that abnormal structure of Hb and hippocampus-Hb connectivity may contribute to the pathological basis of OCD.
Assuntos
Habenula , Hipocampo , Imageamento por Ressonância Magnética , Transtorno Obsessivo-Compulsivo , Humanos , Habenula/fisiopatologia , Habenula/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Masculino , Feminino , Adulto , Hipocampo/fisiopatologia , Hipocampo/diagnóstico por imagem , Adulto Jovem , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Estudos de Casos e ControlesRESUMO
The habenula (Hb) is involved in many natural human behaviors, and the relevance of its alterations in size and neural activity to several psychiatric disorders and addictive behaviors has been presumed and investigated in recent years using magnetic resonance imaging (MRI). Although the Hb is small, an increasing number of studies have overcome the difficulties in MRI. Conventional structural-based imaging also has great defects in observing the Hb contrast with adjacent structures. In addition, more and more attention should be paid to the Hb's functional, structural, and quantitative imaging studies. Several advanced MRI methods have recently been employed in clinical studies to explore the Hb and its involvement in psychiatric diseases. This review summarizes the anatomy and function of the human Hb; moreover, it focuses on exploring the human Hb with noninvasive MRI approaches, highlighting strategies to overcome the poor contrast with adjacent structures and the need for multiparametric MRI to develop imaging markers for diagnosis and treatment follow-up. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.
Assuntos
Habenula , Transtornos Mentais , Imageamento por Ressonância Magnética Multiparamétrica , Humanos , Habenula/anatomia & histologia , Imageamento por Ressonância Magnética/métodosRESUMO
Rheumatoid arthritis (RA) patients have a high prevalence for depression. On the other hand, comorbid with depression is associated with worse prognosis for RA. However, little is known about the underlying mechanisms for the comorbidity between RA and depression. It remains to be elucidated which brain region is critically involved in the development of depression in RA, and whether alterations in the brain may affect pathological development of RA symptoms. Here, by combining clinical and animal model studies, we show that in RA patients, the level of depression is significantly correlated with the severity of RA disease activity and affects patients' quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA also develops depression-like behaviors, accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region critical for processing negative valence. Importantly, inhibition of the LHb not only alleviates depression-like behaviors, but also results in rapid remission of RA symptoms and amelioration of RA-related pathological changes. Together, our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.
Assuntos
Artrite Experimental , Artrite Reumatoide , Habenula , Animais , Camundongos , Humanos , Depressão/epidemiologia , Qualidade de Vida , Artrite Reumatoide/complicações , ComorbidadeRESUMO
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.
Assuntos
Depressão , Habenula , Interleucina-10 , Privação Materna , Receptores de GABA-A , Animais , Receptores de GABA-A/metabolismo , Camundongos , Interleucina-10/metabolismo , Depressão/metabolismo , Feminino , Habenula/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Suscetibilidade a Doenças/metabolismo , Neurônios/metabolismo , Transporte Proteico/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Citocinas/metabolismoRESUMO
The aversion to cold is a fundamental motivated behavior that contributes to the body temperature homeostasis. However, the involvement of the lateral habenula (LHb) as a regulatory hub for negative emotions in this physiological process remains uninvestigated. In this study, we demonstrate an elevation in the population activity of LHb neurons following exposure to cold stimuli. Additionally, we establish the necessity of Vglut2-expressing neurons within the LHb for the encoding of cold aversion behaviors. Furthermore, we have elucidated a neural circuit from excitatory neurons of the dorsomedial hypothalamus (DMH) to LHb that plays a crucial role in this progress. Manipulation of the DMH-LHb circuit has a significant impact on cold aversion behavior in mice. It is worth noting that this circuit does not exhibit any noticeable effects on autonomic thermoregulation or depression-like behavior. The identification of these neural mechanisms involved in behavioral thermoregulation provides a promising avenue for future research.
Assuntos
Habenula , Camundongos , Animais , Habenula/fisiologia , Aprendizagem da Esquiva/fisiologia , Neurônios/fisiologiaRESUMO
Neurons in the primate lateral habenula fire in response to punishments and are inhibited by rewards. Through its modulation of midbrain monoaminergic activity, the habenula is believed to play an important role in adaptive behavioural responses to punishment and underlie depressive symptoms and their alleviation with ketamine. However, its role in value-based decision-making in humans is poorly understood due to limitations with non-invasive imaging methods which measure metabolic, not neural, activity with poor temporal resolution. Here, we overcome these limitations to more closely bridge the gap between species by recording local field potentials directly from the habenula in 12 human patients receiving deep brain stimulation treatment for bipolar disorder (n = 4), chronic pain (n = 3), depression (n = 3) and schizophrenia (n = 2). This allowed us to record neural activity during value-based decision-making tasks involving monetary rewards and losses. High-frequency gamma (60-240 Hz) activity, a proxy for population-level spiking involved in cognitive computations, increased during the receipt of loss and decreased during receipt of reward. Furthermore, habenula high gamma also encoded risk during decision-making, being larger in amplitude for high compared to low risk. For both risk and aversion, differences between conditions peaked approximately between 400 and 750 ms after stimulus onset. The findings not only demonstrate homologies with the primate habenula but also extend its role to human decision-making, showing its temporal dynamics and suggesting revisions to current models. The findings suggest that habenula high gamma could be used to optimize real-time closed-loop deep brain stimulation treatment for mood disturbances and impulsivity in psychiatric disorders.
Assuntos
Habenula , Esquizofrenia , Animais , Humanos , Habenula/fisiologia , Recompensa , Neurônios/fisiologia , PuniçãoRESUMO
A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHbD1R-VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHbD1R-VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHbD1R-VTA axons. Conversely, optogenetic inhibition of the LHbD1R-VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.
Assuntos
Depressão , Modelos Animais de Doenças , Habenula , Vias Neurais , Optogenética , Receptores de Dopamina D1 , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/fisiopatologia , Área Tegmentar Ventral/fisiologia , Habenula/fisiologia , Camundongos , Masculino , Receptores de Dopamina D1/metabolismo , Depressão/fisiopatologia , Depressão/etiologia , Vias Neurais/fisiopatologia , Camundongos Transgênicos , Estresse Psicológico/fisiopatologia , Camundongos Endogâmicos C57BL , Restrição Física , Neurônios/fisiologiaRESUMO
Glutamatergic neurons in ventral pallidum (VPGlu) were recently reported to mediate motivational and emotional behavior, but its role in opioid addiction still remains to be elucidated. In this study we investigated the function of VPGlu in the context-dependent heroin taking and seeking behavior in male rats under the ABA renewal paradigm. By use of cell-type-specific fiber photometry, we showed that the calcium activity of VPGlu were inhibited during heroin self-administration and context-induced relapse, but activated after extinction in a new context. The drug seeking behavior was accompanied by the decreased calcium signal of VPGlu. Chemogenetic manipulation of VPGlu bidirectionally regulated heroin taking and seeking behavior. Anterograde tracing showed that the lateral habenula, one of the epithalamic structures, was the major output region of VPGlu, and its neuronal activity was consistent with VPGlu in different phases of heroin addiction and contributed to the motivation for heroin. VPGlu axon terminals in LHb exhibited dynamic activity in different phases of heroin addiction. Activation of VPGlu-LHb circuit reduced heroin seeking behavior during context-induced relapse. Furthermore, the balance of excitation/inhibition from VP to LHb was shifted to enhanced glutamate transmission after extinction of heroin seeking motivation. Overall, the present study demonstrated that the activity of VPGlu was involved in the regulation of heroin addiction and identified the VPGlu-LHb pathway as a potential intervention to reduce heroin seeking motivation.
Assuntos
Prosencéfalo Basal , Ácido Glutâmico , Dependência de Heroína , Neurônios , Ratos Sprague-Dawley , Animais , Masculino , Dependência de Heroína/metabolismo , Dependência de Heroína/psicologia , Prosencéfalo Basal/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Comportamento de Procura de Droga , Heroína , Ratos , Autoadministração , Habenula/metabolismoRESUMO
Habenular (Hb) processes negative emotions that may drive compulsive food-intake. Its functional changes were reported following laparoscopic-sleeve-gastrectomy (LSG). However, structural connectivity (SC) of Hb-homeostatic/hedonic circuits after LSG remains unclear. We selected regions implicated in homeostatic/hedonic regulation that have anatomical connections with Hb as regions-of-interest (ROIs), and used diffusion-tensor-imaging with probabilistic tractography to calculate SC between Hb and these ROIs in 30 obese participants before LSG (PreLSG) and at 12-month post-LSG (PostLSG12) and 30 normal-weight controls. Three-factor-eating-questionnaire (TFEQ) and Dutch-eating-behavior-questionnaire (DEBQ) were used to assess eating behaviors. LSG significantly decreased weight, negative emotion, and improved self-reported eating behavior. LSG increased SC between the Hb and homeostatic/hedonic regions including hypothalamus (Hy), bilateral superior frontal gyri (SFG), left amygdala (AMY), and orbitofrontal cortex (OFC). TFEQ-hunger negatively correlated with SC of Hb-Hy at PostLSG12; and increased SC of Hb-Hy correlated with reduced depression and DEBQ-external eating. TFEQ-disinhibition negatively correlated with SC of Hb-bilateral SFG at PreLSG. Increased SC of Hb-left AMY correlated with reduced DEBQ-emotional eating. Higher percentage of total weight-loss negatively correlated with SC of Hb-left OFC at PreLSG. Enhanced SC of Hb-homeostatic/hedonic regulatory regions post-LSG may contribute to its beneficial effects in improving eating behaviors including negative emotional eating, and long-term weight-loss.
Assuntos
Laparoscopia , Obesidade Mórbida , Humanos , Comportamento Alimentar/fisiologia , Obesidade Mórbida/psicologia , Obesidade Mórbida/cirurgia , Emoções , Gastrectomia , Redução de Peso/fisiologia , Resultado do TratamentoRESUMO
BACKGROUND: Rodents utilize chemical cues to recognize and avoid other conspecifics infected with pathogens. Infection with pathogens and acute inflammation alter the repertoire and signature of olfactory stimuli emitted by a sick individual. These cues are recognized by healthy conspecifics via the vomeronasal or accessory olfactory system, triggering an innate form of avoidance behavior. However, the molecular identity of the sensory neurons and the higher neural circuits involved in the detection of sick conspecifics remain poorly understood. RESULTS: We employed mice that are in an acute state of inflammation induced by systemic administration of lipopolysaccharide (LPS). Through conditional knockout of the G-protein Gαi2 and deletion of other key sensory transduction molecules (Trpc2 and a cluster of 16 vomeronasal type 1 receptors), in combination with behavioral testing, subcellular Ca2+ imaging, and pS6 and c-Fos neuronal activity mapping in freely behaving mice, we show that the Gαi2+ vomeronasal subsystem is required for the detection and avoidance of LPS-treated mice. The active components underlying this avoidance are contained in urine whereas feces extract and two selected bile acids, although detected in a Gαi2-dependent manner, failed to evoke avoidance behavior. Our analyses of dendritic Ca2+ responses in vomeronasal sensory neurons provide insight into the discrimination capabilities of these neurons for urine fractions from LPS-treated mice, and how this discrimination depends on Gαi2. We observed Gαi2-dependent stimulation of multiple brain areas including medial amygdala, ventromedial hypothalamus, and periaqueductal grey. We also identified the lateral habenula, a brain region implicated in negative reward prediction in aversive learning, as a previously unknown target involved in these tasks. CONCLUSIONS: Our physiological and behavioral analyses indicate that the sensing and avoidance of LPS-treated sick conspecifics depend on the Gαi2 vomeronasal subsystem. Our observations point to a central role of brain circuits downstream of the olfactory periphery and in the lateral habenula in the detection and avoidance of sick conspecifics, providing new insights into the neural substrates and circuit logic of the sensing of inflammation in mice.