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habenulaの検索結果　from Pubmed

Delcourte S, Bouloufa A, Rovera R, Brunet E, Le HD

Front Pharmacol. 2025

PMID:40337515

Abstract

Beside image vision, light plays a pivotal role in regulating diverse non-visual functions, including affective behaviors. Recently, bright light stimulation (BLS) was revealed to be beneficial for treating non-seasonal depression, although its mechanism of action is not fully understood.

Kung PH, Greaves MD, Guerrero-Hreins E, Harrison BJ, Davey CG

Nat Commun. 2025 May 7

PMID:40335503

Abstract

Self-related cognitions are integral to personal identity and psychological wellbeing. Persistent engagement with negative self-cognitions can precipitate mental ill health; whereas the ability to restructure them is protective. Here, we leverage ultra-high field 7T fMRI and dynamic causal modelling to characterise a negative self-cognition network centred on the habenula - a small midbrain region linked to the encoding of punishment and negative outcomes. We model habenula effective connectivity in a discovery sample of healthy young adults (n = 45) and in a replication cohort (n = 56) using a cognitive restructuring task during which participants repeated or restructured negative self-cognitions. The restructuring of negative self-cognitions elicits an excitatory effect from the habenula to the posterior orbitofrontal cortex that is reliably observed across both samples. Furthermore, we identify an excitatory effect of the habenula on the posterior cingulate cortex during both the repeating and restructuring of self-cognitions. Our study provides evidence demonstrating the habenula's contribution to processing self-cognitions. These findings yield unique insights into habenula's function beyond processing external reward/punishment to include abstract internal experiences.

Sun Y, Cao J, Xu C, Sun J, Liu X

J Headache Pain. 2025 May 6

PMID:40329200

Abstract

The monoamine system, particularly the serotonergic neurons in the dorsal raphe nucleus (DRN), associated with the synthesis and release of 5-hydroxytryptamine, is crucial for regulating pain. The lateral habenula (LHb) modulates DRN neurons by acting through GABAergic neurons located in the rostromedial tegmental nucleus (RMTg). However, the role of RMTg in mediating the LHb and regulating pain remains unclear. Thus, we aimed to assess the role of the LHb-RMTg pathway in inflammatory pain.

Liu S, Qi Y, Hu S, Wei N, Zhang J

IEEE J Biomed Health Inform. 2025 May 1

PMID:40310745

Abstract

Deep brain stimulation (DBS) targeting the lateral habenula (LHb) is a promising therapy for treatment-resistant depression (TRD) but its clinical effect has been variable, which can be improved by adaptive DBS (aDBS) guided by a neural biomarker of depression symptoms. Existing neural biomarkers, however, cannot simultaneously track slow and fast symptom dynamics, do not sufficiently respond to stimulation parameters, and lack neurobiological interpretability, which hinder their use in developing aDBS.

DePasquale O, O'Brien C, Gordon B, Barker DJ

ACS Chem Neurosci. 2025 May 7

PMID:40295925

Abstract

G protein-coupled receptors (GPCRs) are among the most prominent druggable targets in the human genome, accounting for approximately 40% of marketed drugs. Despite this, current GPCR-targeted therapies address only about 10% of the GPCRs encoded in the genome. Expanding our knowledge of the remaining "orphan" GPCRs represents a critical frontier in drug discovery. GPR151 emerges as a compelling target due to its distinct expression in the habenula complex, spinal cord neurons, and dorsal root ganglia. This receptor is highly conserved across mammals and possesses orthologs in species such as zebrafish and chickens, underscoring its evolutionarily conserved role in fundamental mammalian processes. Although the precise function of GPR151 remains unknown, it has been strongly implicated in pain modulation and reward-seeking behavior. These attributes position GPR151 as a promising candidate for the development of targeted and specialized pharmacological therapies. This review summarizes the current literature on GPR151, including its discovery, structure, mechanisms, anatomical distribution, and functional roles, while also exploring potential directions for future research.

Xin Q, Wang J, Zheng J, Tan Y, Jia X

Cell. 2025 Apr 23

PMID:40280131

Abstract

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

Oubraim S, Hausknecht K, Micov V, Shen RY, Haj-Dahmane S

Sci Rep. 2025 Apr 24

PMID:40275074

Abstract

Prenatal ethanol exposure (PE) causes Fetal Alcohol Spectrum Disorders (FASD), characterized by cognitive, behavioral, and emotional deficits, including anxiety and depression. PE-induced alteration in the function of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons is thought to be major contributing factor for increased anxiety. However, the precise neuronal circuits involved are unknown. Using electrophysiology, optogenetics, chemogenetics, and behavioral approaches, we find that PE preferentially potentiates medial prefrontal cortex (mPFC) glutamatergic inputs, but not lateral habenula (LHb), to DRN 5-HT neurons projecting to mPFC. Additionally, PE also increases the strength of LHb but not mPFC excitatory inputs to DRN 5-HT neurons projecting to central amygdala (Ce). This input and target selective effect of PE was mediated by a circuit-specific increase in nitric oxide (NO) signaling. Importantly, chemogenetic inhibition of mPFC-DRN neuronal circuit blunted anxiety-like behaviors in PE rats. As such, our results unraveled the DRN neuronal circuitries affected by PE, which gate FASD-induced anxiety-like behaviors.

de Klerk-Sluis JM, Geugies H, Mocking RJT, Figueroa CA, Groot PFC

Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Apr 22

PMID:40274233

Abstract

Hypersensitivity to punishment is one of the core features of major depressive disorder. Hypersensitivity to punishment has been proposed to originate from aberrant aversive learning. One of the key areas in aversive learning is the habenula. Although evidence for dysfunctional aversive learning in depressed patients is well established, it remains largely unexplored whether this dysfunction and its neural correlates persists during symptomatic remission of depression.

Boateng KO, Hadford LD, Stauch KL, Kincaid AE, Thoreson WB

IBRO Neurosci Rep. 2025 Jun

PMID:40271494

Abstract

The principal Ca sensors that control fusion of synaptic vesicles are synaptotagmins 1, 2 and 9. Synaptotagmin 9 (Syt9) has received the least attention. We applied RNAscope techniques to coronal sections of adult mouse brain to study the distribution of Syt9 mRNA. Our results showed weak Syt9 mRNA expression in many brain regions but elevated levels in a handful. Regions of strong expression were largely in limbic and sensory areas and included both excitatory and inhibitory neurons. Strongest expression in the brain was in the medial habenula. The interpeduncular nucleus that provides input to medial habenula and amygdala that receives medial habenula output also showed elevated Syt9 mRNA. Sensory regions with strong Syt9 mRNA expression included mitral and periglomerular cells in the olfactory bulb, thalamus, and sensory layers of the superior colliculus. A few putative layer 5 pyramidal cells in somatosensory, auditory and visual cortex were also strongly labeled. Neurons in motor regions including cortex did not generally show elevated expression with the exception of strong labeling of granular and molecular (but not Purkinje) cells in the cerebellum. Hippocampal neurons also showed only weak labeling.

Prévost ED, Root DH

Neuropsychopharmacology. 2025 Apr 22

PMID:40263415

Abstract

Jehl J, Ciscato M, Vicq E, Guyon N, Dejean de la Batie G

Neuron. 2025 Apr 16

PMID:40262615

Abstract

Nicotine stimulates ventral tegmental area (VTA) dopaminergic neurons, producing a rewarding effect that drives tobacco consumption. The interpeduncular nucleus (IPN) is thought to become engaged at high nicotine doses to limit drug intake, but its response dynamics are unknown. We developed a chemogenetic approach using a "suicide" antagonist that selectively attaches to designer β4 nicotinic acetylcholine receptors (nAChRs) in genetically modified mice, enabling sustained and pharmacologically specific antagonism. Local infusion in the IPN revealed that nicotine, even at low doses, simultaneously activates and inhibits two distinct populations of IPN neurons, with β4-containing nAChRs mediating only the activation response. Blocking nicotine-induced IPN activation enhanced VTA responses and increased the drug's rewarding effect in a conditioned place preference paradigm. Moreover, optogenetic inhibition of IPN projections to the laterodorsal tegmental nucleus (LDTg) replicated these behavioral effects. Our findings indicate that the IPN acts as a regulatory brake on the nicotine reward circuit via the LDTg.

Pritz MB

Brain Struct Funct. 2025 Apr 16

PMID:40240710

Abstract

The epithalamus is present in all vertebrates where it is a central part of the dorsal diencephalic conduction system whose functions are critical for survival. The epithalamus consists of both nuclei and tracts. Studies on the development of the epithalamus in amniotes (reptiles, birds, and mammals) based on cytoarchitecture have commonly been part of a larger report on the embryogenesis of the diencephalon. Of these, observations on the epithalamus of reptiles are few with limited descriptions and figures. The present analysis fills this gap in knowledge by examining the development of the epithalamus in one group of reptiles, Alligator mississippiensis, using stains for cells and fibers. The time of origin and subsequent development of the nuclei and the tracts that course through the epithalamus were determined. These data provide a basis for future studies and for comparisons with other amniotes.

Oriol L, Chao M, Kollman GJ, Dowlat DS, Singhal SM

Elife. 2025 Apr 16

PMID:40238649

Abstract

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study, we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or Mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.

Szebik H, Miskolczi C, Bruzsik B, Balla G, Szabó S

Neurobiol Stress. 2025 May

PMID:40230625

Abstract

Aggression is a complex behavior influenced by developmental experiences, internal state, and social context, yet its neurobiological underpinnings remain insufficiently understood. The serotonergic system, particularly the serotonin transporter (SERT), plays a crucial role in aggression regulation. Here, we investigated region-specific, dynamic changes in SERT expression following aggressive interactions and in mice subjected to early-life social adversity. We found that aggressive encounters (resident-intruder test) triggered a significant, rapid increase in SERT immunoreactivity within 90 min, accompanied by neuronal activation in aggression-related brain regions, including the medial prefrontal cortex (mPFC), lateral septum (LS), medial amygdala (MeA), ventromedial hypothalamus (VMHvl), lateral habenula (LH), and dorsal raphe (DR), but not in the paraventricular thalamus (PVT). Notably, this SERT upregulation occurred across the aggression circuitry but was accompanied by a significant increase in 5-HT levels only in the mPFC, a key region in top-down regulation of social and aggressive behavior. This SERT upregulation was not observed following exposure to a non-social challenge, suggesting that it may be more specifically associated with social contexts. Using super-resolution microscopy, we identified an increased density of SERT localization points within serotonergic mPFC axons after an aggressive encounter. Social isolation during adolescence, a model of early social neglect, impaired this rapid SERT response, particularly in the ventral and medial orbitofrontal regions, and altered the relationship between SERT levels and aggression-related behaviors. These findings demonstrate that SERT expression undergoes rapid, experience-dependent plasticity in response to social aggression, and that early-life adversity disrupts this adaptive mechanism, providing new insights into the serotonergic regulation of aggression and its potential relevance for stress-related social dysfunctions.

Miller BR, Gonzaga-Jauregui C, Brigatti KW, de Jong J, Breese RS

Proc Natl Acad Sci U S A. 2025 Apr 22

PMID:40228124

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in (c.1599G>T, p.Glu533Asp) associated with a two-fold increase in the relative risk of MDD. GPR156 is an orphan G protein-coupled receptor localized in the medial habenula, a region implicated in mood regulation. Insertion of a human sequence containing c.1599G>T into the murine locus induced medial habenula hyperactivity and abnormal stress-related behaviors. This work reveals a human variant that is associated with depression, implicates GPR156 as a target for mood regulation, and introduces informative murine models for investigating the pathophysiology and treatment of affective disorders.

Luo L, Jing W, Guo Y, Liu D, He A

Nat Commun. 2025 Apr 10

PMID:40210897

Abstract

Major depression is characterized by an array of negative experiences, including hopelessness and anhedonia. We hypothesize that inhibition of negative experiences or aversion may generate antidepressant action. To directly test this hypothesis, we perform multimodal behavioral screenings in male mice and identify somatostatin (SST)-expressing neurons in the region X (HBX) between the lateral and medial habenula as a specific type of antidepressant neuron. SST neuronal activity modulation dynamically regulates antidepressant induction and relief. We also explore the circuit basis for encoding these modulations using single-unit recordings. We find that SST neurons receive inhibitory synaptic inputs directly from cholecystokinin-expressing neurons in the bed nucleus of the stria terminalis and project excitatory axon terminals onto proenkephalin-expressing neurons in the interpeduncular nucleus. This study reveals a cell-type-specific circuit of SST neurons in the HBX that encodes antidepressant action, and the control of the circuit may contribute to improving well-being.

Matsumata M, Hirao K, Kobayashi T, Handa T, Zhou Y

Curr Biol. 2025 May 5

PMID:40209712

Abstract

The habenula (Hb) to interpeduncular nucleus (IPN) projection is highly conserved across vertebrates and, in zebrafish, has been shown to regulate the decision between continuing to fight and surrender during social conflict. We have recently shown that, in loser zebrafish, habenular acetylcholine release acts on postsynaptic α7 nicotinic receptors to induce the expression of Ca-permeable AMPA receptors on the silent synapses of the IPN neurons that project to the median raphe (MnR). Leveraging this evolutionary conservation, we demonstrate that the disruption of cholinergic transmission from the Hb to the IPN biases mice toward winning social conflicts, whereas optogenetic activation has the opposite effect of biasing toward losing. Further circuit dissection revealed that the losing bias is likely to be mediated via inhibition of serotonin (5-hydroxytryptamine [5-HT]) neurons in the MnR by the IPN.

Yang L, Guo C, Zheng Z, Dong Y, Xie Q

Nature. 2025 May

PMID:40205038

Abstract

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

Song S, Kang M, Lee J, Yang YR, Lee H

Exp Mol Med. 2025 Apr

PMID:40204881

Abstract

Phospholipase C (PLC) enzymes play crucial roles in intracellular calcium-signaling transduction. Several brain PLC subtypes have been extensively studied, implicating them in psychiatric disorders such as depression, epilepsy and schizophrenia. However, the role of the recently identified PLCη remains largely unknown. We found that PLCη1 is prominently expressed in lateral habenula (LHb) astrocytes. Here, to investigate its physiological role, we generated astrocyte-specific PLCη1 conditional knockout (cKO) mice (Plch1; Aldh1l1-Cre). In these cKO mice, we observed a reduction in cellular morphological complexity metrics, such as total process length, as well as a decrease in the passive membrane conductance of LHb astrocytes. Additionally, neuronal function was impacted by the cKO, as the synaptic efficacy and firing rates of LHb neurons increased, while extrasynaptic long-term depression was impaired. Both tonic α-amino-3-hydroxy-5-methyl-4-isoxazolepdlropionic acid receptor/N-methyl-D-aspartate receptor (AMPAR/NMDAR) currents and extracellular glutamate levels were reduced. Interestingly, chemogenetic activation of astrocytes restored the reduced tonic AMPAR/NMDAR currents in cKO mice. Furthermore, LHb astrocyte-specific deletion of PLCη1 via AAV-GFAP-Cre injection induced depressive-like behaviors in mice, which were reversed by chemogenetic activation of LHb astrocytes. Finally, we found that restraint stress exposure decreased Plch1 mRNA expression in the LHb. These findings suggest that PLCη1 could be a potential therapeutic target for depression and highlight the critical role of astrocytes in the etiology of neuropsychiatric disorders.

Jia Y, Yang CC, Lauterborn JC, Gall CM, Wood MA

bioRxiv. 2025 Mar 24

PMID:40196688

Abstract

Descending projections from the medial habenula potently influence brainstem systems associated with reward and mood. Relatedly, the ventral, cholinergic segment of the nucleus has been linked to nicotine and cocaine addiction. Here we report that cocaine has no effect on baseline firing in the ventral medial habenula but entirely blocks the self-sustained activity initiated by endogenous acetylcholine. This effect was not altered by antagonists to dopamine receptors and thus presumably reflects a direct action on cholinergic receptors. Remarkably, cocaine had no effect on endogenous cholinergic activity in mice that had been extinguished from an induced cocaine preference. In all, the drug has potent effects, albeit through an exotic mode of action, on the medial habenula and these are eliminated by prior experience with the drug. These results describe a novel target for cocaine that is plausibly related to the psychological effects of the drug, and an unexpected consequence of earlier use.