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1.
Nat Neurosci ; 22(10): 1649-1658, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451801

RESUMO

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.


Assuntos
Dor Crônica/patologia , Depressão/patologia , Vias Neurais/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Dor Crônica/complicações , Dor Crônica/diagnóstico por imagem , Depressão/complicações , Depressão/diagnóstico por imagem , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/patologia , Feminino , Habenula/diagnóstico por imagem , Habenula/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Optogenética , Serotonina/metabolismo , Somatostatina/metabolismo
3.
Mol Brain ; 11(1): 5, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29394901

RESUMO

The epithalamus, which is dorsal to the thalamus, consists of the habenula, pineal gland and third ventricle choroid plexus and plays important roles in the stress response and sleep-wake cycle in vertebrates. During development, the epithalamus arises from the most dorsal part of prosomere 2. However, the mechanism underlying epithalamic development remains largely unknown. Foxg1 is critical for the development of the telencephalon, but its role in diencephalic development has been under-investigated. Patients suffering from FOXG1-related disorders exhibit severe anxiety, sleep disturbance and choroid plexus cysts, indicating that Foxg1 likely plays a role in epithalamic development. In this study, we identified the specific expression of Foxg1 in the developing epithalamus. Using a "self-deletion" approach, we found that the habenula significantly expanded and included an increased number of habenular subtype neurons. The innervations, particularly the habenular commissure, were severely impaired. Meanwhile, the Foxg1 mutants exhibited a reduced pineal gland and more branched choroid plexus. After ablation of Foxg1 no obvious changes in Shh and Fgf signalling were observed, suggesting that Foxg1 regulates the development of the epithalamus without the involvement of Shh and Fgfs. Our findings provide new insights into the regulation of the development of the epithalamus.


Assuntos
Epitálamo/crescimento & desenvolvimento , Epitálamo/metabolismo , Fatores de Transcrição Forkhead/deficiência , Deleção de Genes , Proteínas do Tecido Nervoso/deficiência , Animais , Contagem de Células , Diencéfalo/metabolismo , Epitálamo/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Habenula/patologia , Proteínas Hedgehog/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Glândula Pineal/patologia , Transdução de Sinais
4.
Nature ; 554(7692): 323-327, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29446379

RESUMO

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.


Assuntos
Astrócitos/metabolismo , Depressão/metabolismo , Habenula/metabolismo , Neurônios/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/patologia , Habenula/efeitos dos fármacos , Habenula/patologia , Masculino , Terapia de Alvo Molecular , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Recompensa
5.
Nature ; 554(7692): 317-322, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29446381

RESUMO

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Habenula/efeitos dos fármacos , Habenula/metabolismo , Ketamina/farmacologia , Ketamina/uso terapêutico , Afeto/efeitos dos fármacos , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Habenula/patologia , Habenula/efeitos da radiação , Ketamina/administração & dosagem , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Recompensa , Ritmo Teta/efeitos dos fármacos
6.
Curr Opin Neurobiol ; 48: 90-96, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29175713

RESUMO

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


Assuntos
Transtorno Depressivo/patologia , Habenula/patologia , Habenula/fisiopatologia , Rede Nervosa/patologia , Animais , Modelos Animais de Doenças , Humanos , Neurônios/fisiologia
7.
Proc Natl Acad Sci U S A ; 114(49): 13012-13017, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29158387

RESUMO

Repeated exposure to drugs of abuse can produce adaptive changes that lead to the establishment of dependence. It has been shown that allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk of tobacco dependence. In the brain, α5-containing nAChRs are expressed at very high levels in the interpeduncular nucleus (IPN). Here we identified two nonoverlapping α5 + cell populations (α5- Amigo1 and α5- Epyc ) in mouse IPN that respond differentially to nicotine. Chronic nicotine treatment altered the translational profile of more than 1,000 genes in α5- Amigo1 neurons, including neuronal nitric oxide synthase (Nos1) and somatostatin (Sst). In contrast, expression of few genes was altered in the α5- Epyc population. We show that both nitric oxide and SST suppress optically evoked neurotransmitter release from the terminals of habenular (Hb) neurons in IPN. Moreover, in vivo silencing of neurotransmitter release from the α5- Amigo1 but not from the α5- Epyc population eliminates nicotine reward, measured using place preference. This loss of nicotine reward was mimicked by shRNA-mediated knockdown of Nos1 in the IPN. These findings reveal a proaddiction adaptive response to chronic nicotine in which nitric oxide and SST are released by a specific α5+ neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine.


Assuntos
Núcleo Interpeduncular/efeitos dos fármacos , Nicotina/farmacologia , Óxido Nítrico Sintase Tipo I/genética , Receptores Nicotínicos/genética , Somatostatina/genética , Tabagismo/genética , Animais , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Habenula/efeitos dos fármacos , Habenula/metabolismo , Habenula/patologia , Núcleo Interpeduncular/metabolismo , Núcleo Interpeduncular/patologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Biossíntese de Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Nicotínicos/metabolismo , Recompensa , Somatostatina/metabolismo , Técnicas Estereotáxicas , Transmissão Sináptica , Tabagismo/metabolismo , Tabagismo/patologia
8.
J Biol Rhythms ; 32(5): 444-455, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28954569

RESUMO

In nocturnal rodents, voluntary wheel-running activity (WRA) represents a self-reinforcing behavior. We have previously demonstrated that WRA is markedly reduced in mice with a region-specific deletion of the transcription factor Pou4f1 (Brn3a), which leads to an ablation of the dorsal medial habenula (dMHb). The decrease in WRA in these dMHb-lesioned (dMHbCKO) mice suggests that the dMHb constitutes a critical center for conveying reinforcement by exercise. However, WRA also represents a prominent output of the circadian system, and the possibility remains that the dMHb is a source of input to the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. To test this hypothesis, we assessed the integrity of the circadian system in dMHbCKO mice. Here we show that the developmental lesion of the dMHb reduces WRA under both a light-dark cycle and constant darkness, increases the circadian period of WRA, but has no effect on the circadian amplitude or period of home cage activity or the daily amplitude of sleep stages, suggesting that the lengthening of period is a result of the decreased WRA in the mutant mice. Polysomnographic sleep recordings show that dMHbCKO mice have an overall unaltered daily amplitude of sleep stages but have fragmented sleep and an overall increase in total rapid eye movement (REM) sleep. Photoresponsiveness is intact in dMHbCKO mice, but compared with control animals, they reentrain faster to a 6-h abrupt phase delay protocol. Circadian changes in WRA of dMHbCKO mice do not appear to emerge within the central pacemaker, as circadian expression of the clock genes Per1 and Per2 within the SCN is normal. We do find some evidence for fragmented sleep and an overall increase in total REM sleep, supporting a model in which the dMHb is part of the neural circuitry encoding motivation and involved in the manifestation of some of the symptoms of depression.


Assuntos
Ritmo Circadiano , Habenula/fisiologia , Atividade Motora , Animais , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Escuridão , Depressão , Habenula/patologia , Luz , Locomoção/genética , Camundongos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fotoperíodo , Sono , Sono REM , Núcleo Supraquiasmático/fisiologia , Fator de Transcrição Brn-3A/genética , Fator de Transcrição Brn-3A/metabolismo
9.
Appetite ; 117: 263-269, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28687372

RESUMO

The suprachiasmatic nucleus (SCN) times the daily rhythms of behavioral processes including feeding. Beyond the SCN, the hypothalamic arcuate nucleus (ARC), involved in feeding regulation and metabolism, and the epithalamic lateral habenula (LHb), implicated in reward processing, show circadian rhythmic activity. These brain oscillators are functionally coupled to coordinate the daily rhythm of food intake. In rats, a free choice high-fat high-sugar (fcHFHS) diet leads to a rapid increase of calorie intake and body weight gain. Interestingly, under a fcHFHS condition, rats ingest a similar amount of sugar during day time (rest phase) as during night time (active phase), but keep the rhythmic intake of regular chow-food. The out of phase between feeding patterns of regular (chow) and highly rewarding food (sugar) may involve alterations of brain circadian oscillators regulating feeding. Here, we report that the fcHFHS diet is a successful model to induce calorie intake, body weight gain and fat tissue accumulation in mice, extending its effectiveness as previously reported in rats. Moreover, we observed that whereas in the SCN the day-night difference in the PER2 clock protein expression was similar between chow-fed and fcHFHS-fed animals, in the LHb, this day-night difference was altered in fcHFHS-exposed animals compared to control chow mice. These findings confirm previous observations in rats showing disrupted daily patterns of feeding behavior under a fcHFHS diet exposure, and extend our insights on the effects of the diet on circadian gene expression in brain clocks.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Dieta Ocidental/efeitos adversos , Comportamento Alimentar , Preferências Alimentares , Regulação da Expressão Gênica , Habenula/metabolismo , Proteínas Circadianas Period/metabolismo , Fatores de Transcrição ARNTL/genética , Adiposidade , Animais , Comportamento Animal , Comportamento de Escolha , Ritmo Circadiano , Habenula/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Especificidade de Órgãos , Proteínas Circadianas Period/genética , Distribuição Aleatória , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/patologia , Ganho de Peso
10.
Cell Rep ; 20(2): 289-296, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28700932

RESUMO

Abnormal potentiation in the lateral habenula (LHb) has been suggested to mediate depression-like behaviors. However, the underlying mechanisms of the synaptic efficacy regulation of LHb synapses and the potential for their modulation are only poorly understood. Here, we report that long-term synaptic depression (LTD) occurs in the LHb upon both low-frequency stimulation (LFS) and moderate-frequency stimulation (MFS). LFS-induced LTD (LFS-LTD) is accompanied by a reduction in presynaptic release probability, which is endocannabinoid (eCB) signaling dependent. Surprisingly, exposure to an acute stressor completely masks the induction of LFS-LTD in the LHb while leaving the MFS-induced LTD intact. Pharmacological activation of cannabinoid receptor 1 (CB1R) or blockade of αCaMKII successfully restored LTD in the LHb in an animal model of depression. Thus, our findings reveal a form of synaptic strength regulation and a stress-induced shift of synaptic plasticity in the LHb.


Assuntos
Depressão/metabolismo , Depressão/patologia , Endocanabinoides/metabolismo , Habenula/metabolismo , Habenula/patologia , Depressão Sináptica de Longo Prazo/fisiologia , Animais , Western Blotting , Modelos Animais de Doenças , Eletrofisiologia , Masculino , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
11.
Sci Rep ; 7(1): 4102, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28642586

RESUMO

The lateral habenula (LHb) has an important role in the behavioural response to salient, usually aversive, events. We previously demonstrated that activation of neurons in the LHb increases brown adipose tissue (BAT) thermogenesis and constricts the cutaneous vascular bed, indicating that the LHb contributes to the central control of sympathetic outflow to thermoregulatory effector organs. We have now investigated whether the LHb mediates BAT thermogenesis elicited by emotional stress, and whether the LHb modulates thermoregulatory sympathetic outflow via the rostral medullary raphé, a key integrative lower brainstem sympathetic control centre. In conscious animals, lesioning the LHb attenuated emotional BAT thermogenesis, suggesting that the LHb is part of the central circuitry mediating emotional hyperthermia. In anesthetized animals, inhibition of neurons in the rostral medullary raphé reversed BAT thermogenesis and cutaneous vasoconstriction elicited by activation of neurons in the LHb, indicating that the LHb-induced autonomic responses are mediated through activation of the rostral medullary raphé neurons. The latency to activate BAT sympathetic discharge from electrical stimulation of the LHb was substantially greater than the corresponding latency after stimulation of the medullary raphé, suggesting that the neuronal pathway connecting those two nuclei is quite indirect.


Assuntos
Emoções , Febre/etiologia , Febre/fisiopatologia , Habenula/fisiopatologia , Estresse Psicológico/complicações , Análise de Variância , Animais , Temperatura Corporal , Modelos Animais de Doenças , Febre/patologia , Habenula/patologia , Masculino , Núcleos da Rafe/fisiopatologia , Ratos , Termogênese
12.
Neuropsychopharmacology ; 42(9): 1813-1824, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28387223

RESUMO

Alcohol use disorders (AUDs) and anxiety disorders (ADs) are often seen concurrently, but their underlying cellular basis is unclear. For unclear reasons, the lateral habenula (LHb), a key brain region involved in the pathophysiology of ADs, becomes hyperactive after ethanol withdrawal. M-type K+ channels (M-channels), important regulators of neuronal activity, are abundant in the LHb, yet little is known about their role in AUDs and associated ADs. We report here that in rats at 24 h withdrawal from systemic ethanol administration (either by intraperitoneal injection, 2 g/kg, twice/day, for 7 days; or intermittent drinking 20% ethanol in a two-bottle free choice protocol for 8 weeks), the basal firing rate and the excitability of LHb neurons in brain slices was higher, whereas the amplitude of medium afterhyperpolarization and M-type K+ currents were smaller, when compared to ethanol naive rats. Concordantly, M-channel blocker (XE991)-induced increase in the spontaneous firing rate in LHb neurons was smaller. The protein expression of M-channel subunits, KCNQ2/3 in the LHb was also smaller. Moreover, anxiety levels (tested in open field, marble burying, and elevated plus maze) were higher, which were alleviated by LHb inhibition either chemogenetically or by local infusion of the M-channel opener, retigabine. Intra-LHb infusion of retigabine also reduced ethanol consumption and preference. These findings reveal an important role of LHb M-channels in the expression of AUDs and ADs, and suggest that the M-channels could be a potential therapeutic target for alcoholics.


Assuntos
Alcoolismo/metabolismo , Ansiedade/metabolismo , Habenula/metabolismo , Neurônios/metabolismo , Canais de Potássio/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Alcoolismo/patologia , Alcoolismo/psicologia , Animais , Ansiedade/etiologia , Ansiedade/patologia , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/efeitos adversos , Depressores do Sistema Nervoso Central/sangue , Etanol/administração & dosagem , Etanol/efeitos adversos , Etanol/sangue , Habenula/efeitos dos fármacos , Habenula/patologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Bloqueadores dos Canais de Potássio/farmacologia , Ratos Long-Evans , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/patologia , Síndrome de Abstinência a Substâncias/psicologia , Técnicas de Cultura de Tecidos
13.
Behav Brain Res ; 328: 195-208, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28432009

RESUMO

The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self-administration and blocked yohimbine-induced reinstatement of ethanol self-administration. LHb lesions also attenuated ethanol-induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol-directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol-directed behaviors. Our results show that the LH-LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Prosencéfalo Basal/fisiopatologia , Habenula/fisiopatologia , Região Hipotalâmica Lateral/fisiopatologia , Consumo de Bebidas Alcoólicas/patologia , Animais , Prosencéfalo Basal/patologia , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Habenula/patologia , Região Hipotalâmica Lateral/patologia , Masculino , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Ratos Long-Evans , Autoadministração , Volição
14.
Neurosci Biobehav Rev ; 83: 721-735, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28223096

RESUMO

The habenula is an epithalamic structure located at the center of the dorsal diencephalic conduction system, a pathway involved in linking forebrain to midbrain regions. Composed of a medial and lateral subdivisions, the habenula receives inputs from the limbic system and basal ganglia mainly through the stria medullaris (SM), and projects to midbrain regions through the fasciculus retroflexus (FR). An increasing number of studies have implicated this structure in psychiatric disorders associated with dysregulated reward circuitry function, notably mood disorders, schizophrenia, and substance use disorder. However, despite significant progress in research, the mechanisms underlying the relationship between the habenula and the pathophysiology of psychiatric disorders are far from being fully understood, and still need further investigation. This review provides a closer look at key findings from animal and human studies illustrating the role of the habenula in mood disorders, schizophrenia, and substance use disorder, and discusses the clinical potential of using this structure as a therapeutic target.


Assuntos
Habenula/fisiopatologia , Transtornos Mentais/história , Transtornos Mentais/patologia , Pesquisa Médica Translacional/métodos , Animais , Habenula/patologia , História do Século XX , História do Século XXI , Humanos , Pesquisa Médica Translacional/história
15.
Neuropharmacology ; 116: 399-411, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28109827

RESUMO

The lateral habenula (LHb) plays an important role in the regulation of depression. At present, it is not clear whether GABAA receptor-mediated inhibitory transmission in the LHb is involved in Parkinson's disease (PD)-associated depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to sham-operated rats, which attribute to depletion of dopamine, and decreased synthesis and release of GABA and increased release of glutamate in the LHb. Intra-LHb injection of GABAA receptor agonist muscimol produced antidepressant-like effects, while the injection of GABAA receptor antagonist picrotoxin induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. However, the doses producing these behavioral effects in the lesioned rats were lower than those in sham-operated rats. Intra-LHb injection of muscimol decreased the firing rate of LHb neurons and increased the medial prefrontal cortex serotonin (5-HT) release; conversely, picrotoxin increased the firing rate of the neurons and decreased 5-HT release in two groups of rats. Compared to sham-operated rats, the duration of muscimol and picrotoxin action on the firing rate of the neurons and 5-HT release was prolonged in the lesioned rats. These changes in the lesioned rats were associated with up-regulation of the expression of α1 subunit-containing GABAA receptors and reduction of GABA release in the LHb. Collectively, our findings suggest that degeneration of the nigrostriatal pathway impairs GABAA receptor-mediated inhibitory transmission in the LHb, and the transmission is important for regulating PD-associated depression.


Assuntos
Depressão/metabolismo , Habenula/metabolismo , Inibição Neural/fisiologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Receptores de GABA-A/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Apomorfina/farmacologia , Depressão/patologia , Agonistas de Dopamina/farmacologia , Antagonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Habenula/efeitos dos fármacos , Habenula/patologia , Masculino , Muscimol/farmacologia , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oxidopamina , Transtornos Parkinsonianos/patologia , Picrotoxina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos Sprague-Dawley , Serotonina/metabolismo
16.
Cerebellum ; 16(2): 398-410, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27435250

RESUMO

The electrical stimulation of specific brain targets has been shown to induce striking antidepressant effects. Despite that recent data have indicated that cerebellum is involved in emotional regulation, the mechanisms by which stimulation improved mood-related behaviors in the cerebellum remained largely obscure. Here, we investigated the stimulation effects of the ventromedial prefrontal cortex (vmPFC), nucleus accumbens (NAc), and lateral habenular nucleus on the c-Fos neuronal activity in various deep cerebellar and vestibular nuclei using the unpredictable chronic mild stress (CMS) animal model of depression. Our results showed that stressed animals had increased number of c-Fos cells in the cerebellar dentate and fastigial nuclei, as well as in the spinal vestibular nucleus. To examine the stimulation effects, we found that vmPFC stimulation significantly decreased the c-Fos activity within the cerebellar fastigial nucleus as compared to the CMS sham. Similarly, there was also a reduction of c-Fos expression in the magnocellular part of the medial vestibular nucleus in vmPFC- and NAc core-stimulated animals when compared to the CMS sham. Correlational analyses showed that the anxiety measure of home-cage emergence escape latency was positively correlated with the c-Fos neuronal activity of the cerebellar fastigial and magnocellular and parvicellular parts of the interposed nuclei in CMS vmPFC-stimulated animals. Interestingly, there was a strong correlation among activation in these cerebellar nuclei, indicating that the antidepressant-like behaviors were possibly mediated by the vmPFC stimulation-induced remodeling within the forebrain-cerebellar neurocircuitry.


Assuntos
Núcleos Cerebelares/metabolismo , Transtorno Depressivo/metabolismo , Transtorno Depressivo/terapia , Terapia por Estimulação Elétrica , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Núcleos Cerebelares/patologia , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Habenula/metabolismo , Habenula/patologia , Imuno-Histoquímica , Neuroestimuladores Implantáveis , Masculino , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos Sprague-Dawley , Estresse Psicológico , Incerteza , Núcleos Vestibulares/metabolismo , Núcleos Vestibulares/patologia
17.
Exp Neurol ; 289: 46-54, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27940019

RESUMO

The habenula is activated in response to stressful and aversive events, resulting in exploratory inhibition. Although possible mechanisms for habenula activation have been proposed, the effects of chronic stress on the habenular structure have never been studied. Herein, we assessed changes in volume, cell density and dendritic structure of habenular cells after chronic stress exposure using stereological and 3D morphological analysis. This study shows for the first time that there is a hemispherical asymmetry in the medial habenula (MHb) of the adult rat, with the right MHb containing more neurons than its left counterpart. Additionally, it shows that chronic stress induces a bilateral atrophy of both the MHb and the lateral habenula (LHb). This atrophy was accompanied by a reduction of the number of neurons in the right MHb and the number of glial cells in the bilateral LHb, but not by changes in the dendritic arbors of multipolar neurons. Importantly, these structural changes were correlated with elevated levels of serum corticosterone and increased anxious-like behavior in stressed animals. To further assess the role of the habenula in stress-related anxiety, bilateral lesions of the LHb were performed; interestingly, in lesioned animals the chronic stress protocol did not trigger increases in circulating corticosterone or anxious-like behavior. This study highlights the role of the habenula in the stress responses and how its sub-regions are structurally impacted by chronic stress with physiological and behavioral consequences.


Assuntos
Ansiedade/etiologia , Ansiedade/patologia , Habenula/patologia , Neurônios/patologia , Estresse Psicológico/complicações , Animais , Ansiedade/sangue , Doença Crônica , Corticosterona/sangue , Modelos Animais de Doenças , Eletrólise/efeitos adversos , Habenula/lesões , Masculino , Aprendizagem em Labirinto/fisiologia , Neuroglia/metabolismo , Neuroglia/patologia , Neuroglia/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Coloração pela Prata , Estatísticas não Paramétricas
18.
Behav Neurol ; 2016: 7919534, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27413249

RESUMO

Sleep is governed by homeostasis and the circadian clock. Clock genes play an important role in the generation and maintenance of circadian rhythms but are also involved in regulating sleep homeostasis. The lateral habenular nucleus (LHb) has been implicated in sleep-wake regulation, since LHb gene expression demonstrates circadian oscillation characteristics. This study focuses on the participation of LHb clock genes in regulating sleep homeostasis, as the nature of their involvement is unclear. In this study, we observed changes in sleep pattern following sleep deprivation in LHb-lesioned rats using EEG recording techniques. And then the changes of clock gene expression (Per1, Per2, and Bmal1) in the LHb after 6 hours of sleep deprivation were detected by using real-time quantitative PCR (qPCR). We found that sleep deprivation increased the length of Non-Rapid Eye Movement Sleep (NREMS) and decreased wakefulness. LHb-lesioning decreased the amplitude of reduced wake time and increased NREMS following sleep deprivation in rats. qPCR results demonstrated that Per2 expression was elevated after sleep deprivation, while the other two genes were unaffected. Following sleep recovery, Per2 expression was comparable to the control group. This study provides the basis for further research on the role of LHb Per2 gene in the regulation of sleep homeostasis.


Assuntos
Ritmo Circadiano/genética , Habenula/fisiologia , Privação do Sono/genética , Fatores de Transcrição ARNTL/biossíntese , Fatores de Transcrição ARNTL/genética , Animais , Expressão Gênica , Habenula/metabolismo , Habenula/patologia , Masculino , Proteínas Circadianas Period/biossíntese , Proteínas Circadianas Period/genética , Ratos , Ratos Wistar , Sono/fisiologia , Privação do Sono/metabolismo , Vigília/fisiologia
20.
Eur Neuropsychopharmacol ; 25(11): 2015-21, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26404405

RESUMO

The habenula (Hb) can play an important role in major depressive disorder (MDD) as it is a key node between fronto-limbic areas and midbrain monoaminergic structures. In vivo neuroimaging studies have shown reductions in Hb volume in a post-mortem sample of patients with affective disorders but findings in unipolar MDD are not consistent. The current study aimed to investigate whether the Hb volume differed between patients with different stages of unipolar MDD and healthy subjects. We also explored differences in grey (GM) and white matter (WM) volumes and potential age and gender effects. High-resolution images were acquired using a 3T-scanner from 95 participants (21 with first-episode MDD; 20 with remitted-recurrent MDD; 20 with treatment-resistant/chronic MDD; and 34 healthy controls).Two researchers blinded to clinical data manually delineated habenular nuclei, with excellent inter-rater agreement. Multivariate analysis of covariance revealed a significant group-by-gender interaction (F9,258=2.22; p=0.02). Univariate effects emerged for Hb-WM volumes (F3,86=3.12; p=0.03) but not for total Hb volumes (F3,86=0.59; p=0.62) or Hb-GM volumes (F3,86=2.01; p=0.12). Women with a first-episode MDD had greater Hb-WM volumes than healthy controls and patients with treatment-resistant/chronic MDD (p<0.01). These findings remained unaltered when controlled for total intracranial volume or medication load. Our results do not support decreased total Hb volumes in unipolar MDD, in patients with first-episode or in patients with long-lasting recurrent or chronic depression. However, the increased Hb-WM volume we observed in women with a first-episode suggests involvement of Hb and its projections in early stages of the recovery process and in the course of MDD.


Assuntos
Transtorno Depressivo Maior/patologia , Habenula/patologia , Doença Aguda , Adulto , Envelhecimento/patologia , Doença Crônica , Transtorno Depressivo Resistente a Tratamento/patologia , Progressão da Doença , Feminino , Substância Cinzenta/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Reprodutibilidade dos Testes , Substância Branca/patologia
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