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1.
Neuron ; 107(2): 368-382.e8, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32442399

RESUMO

The ventral tegmental area (VTA) has dopamine, GABA, and glutamate neurons, which have been implicated in reward and aversion. Here, we determined whether VTA-glutamate or -GABA neurons play a role in innate defensive behavior. By VTA cell-type-specific genetic ablation, we found that ablation of glutamate, but not GABA, neurons abolishes escape behavior in response to threatening stimuli. We found that escape behavior is also decreased by chemogenetic inhibition of VTA-glutamate neurons and detected increases in activity in VTA-glutamate neurons in response to the threatening stimuli. By ultrastructural and electrophysiological analysis, we established that VTA-glutamate neurons receive a major monosynaptic glutamatergic input from the lateral hypothalamic area (LHA) and found that photoinhibition of this input decreases escape responses to threatening stimuli. These findings indicate that VTA-glutamate neurons are activated by and required for innate defensive responses and that information on threatening stimuli to VTA-glutamate neurons is relayed by LHA-glutamate neurons.


Assuntos
Agressão/fisiologia , Ácido Glutâmico/fisiologia , Neurônios/fisiologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/fisiologia , Animais , Reação de Fuga , Humanos , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/fisiologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Camundongos , Neurônios/ultraestrutura , Optogenética , Estimulação Luminosa , Reflexo Monosináptico/fisiologia , Área Tegmentar Ventral/ultraestrutura , Ácido gama-Aminobutírico/fisiologia
2.
Proc Natl Acad Sci U S A ; 117(15): 8611-8615, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32229573

RESUMO

Electrical or optogenetic stimulation of lateral hypothalamic (LH) GABA neurons induces rapid vigorous eating in sated animals. The dopamine system has been implicated in the regulation of feeding. Previous work has suggested that a subset of LH GABA neurons projects to the ventral tegmental area (VTA) and targets GABA neurons, inhibiting them and thereby disinhibiting dopaminergic activity and release. Furthermore, stimulation-induced eating is attenuated by dopamine lesions or receptor antagonists. Here we explored the involvement of dopamine in LH stimulation-induced eating. LH stimulation caused sated mice to pick up pellets of standard chow with latencies that varied based on stimulation intensity; once food was picked up, animals ate for the remainder of the 60-s stimulation period. However, lesion of VTA GABA neurons failed to disrupt this effect. Moreover, direct stimulation of VTA or substantia nigra dopamine cell bodies failed to induce food approach or eating. Looking further, we found that some LH GABA fibers pass through the VTA to more caudal sites, where they synapse onto neurons near the locus coeruleus (LC). Similar eating was induced by stimulation of LH GABA terminals or GABA cell bodies in this peri-LC region. Lesion of peri-LC GABA neurons blocked LH stimulation-induced eating, establishing them as a critical downstream circuit element for LH neurons. Surprisingly, lesions did not alter body weight, suggesting that this system is not involved in the hunger or satiety mechanisms that govern normal feeding. Thus, we present a characterization of brain circuitry that may promote overeating and contribute to obesity.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Neurônios GABAérgicos/metabolismo , Região Hipotalâmica Lateral/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Animal , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Feminino , Neurônios GABAérgicos/citologia , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Vias Neurais , Receptores de GABA-A/metabolismo , Recompensa , Área Tegmentar Ventral/citologia , Ácido gama-Aminobutírico/metabolismo
3.
Nat Commun ; 10(1): 4560, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594935

RESUMO

The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting.


Assuntos
Habenula/fisiologia , Fome/fisiologia , Região Hipotalâmica Lateral/fisiologia , Núcleos Septais/fisiologia , Paladar/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Comportamento Apetitivo/fisiologia , Neurônios GABAérgicos/metabolismo , Habenula/citologia , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Modelos Animais , Vias Neurais/fisiologia , Optogenética , Técnicas de Patch-Clamp , Núcleos Septais/citologia , Técnicas Estereotáxicas
4.
Pharmacol Biochem Behav ; 187: 172794, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31654653

RESUMO

Orexin-producing neurons in the lateral hypothalamus are a critical regulator of sleep/wake states, and their loss is associated with narcolepsy type 1 (NT1). Orexin peptides act on two G protein-coupled receptors: orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). OX2R knockout (KO) mice, but not OX1R KO mice, showed clear narcolepsy-like phenotypes, including fragmented sleep-wake cycles. Moreover, OX2R-selective antagonists have been shown to induce sleepiness in mice, and activation of OX2R has been reported to increase wakefulness. In this study, we characterized in vitro and in vivo profiles of a novel, highly selective OX2R agonist, TAK-925 [methyl (2R,3S)-3-[(methylsulfonyl)amino]-2-{[(cis-4-phenylcyclohexyl)oxy]methyl}piperidine-1-carboxylate]. TAK-925 activated human recombinant OX2R with 50% effective concentration value of 5.5 nM, and showed >5,000-fold selectivity over OX1R in calcium mobilization assays. TAK-925 induced OX2R-downstream signals similar to those displayed by orexin peptides in Chinese hamster ovary cells stably expressing human OX2R. In an electrophysiological study, TAK-925 activated physiological OX2R on histaminergic neurons in the mouse tuberomammillary nucleus (TMN). Subcutaneous (SC) administration of TAK-925 also modulated neuronal activity in various brain regions, including TMN, as measured by an immunohistochemical analysis using an anti-c-fos antibody. TAK-925 (SC) increased wakefulness in wild-type mice, but not in OX2R KO mice, during their sleep phase, demonstrating that a highly selective OX2R agonist can increase wakefulness in mice via OX2R activation. TAK-925 may have therapeutic potential to reduce hypersomnia in multiple disorders including NT1.


Assuntos
Receptores de Orexina/agonistas , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Células CHO , Cricetulus , Humanos , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Narcolepsia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Sono/genética , Transfecção , Vigília/genética
5.
J Neurosci ; 39(45): 8929-8939, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31548232

RESUMO

The histaminergic neurons of the tuberomammillary nucleus (TMNHDC) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMNHDC neurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMNHDC neurons on sleep-wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMNHDC neurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep-wake quantities, perhaps because very few TMNHDC neurons coexpressed VGAT. Acute chemogenetic activation of TMNHDC neurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMNHDC neurons in arousal control. Further, if TMNHDC neurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMNHDC neurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.SIGNIFICANCE STATEMENT The histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMNHDC) have long been thought to promote arousal. Additionally, TMNHDC neurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMNHDC neurons does not impact sleep-wake amounts and that few TMNHDC neurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMNHDC neurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMNHDC neurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.


Assuntos
Nível de Alerta , Histamina/metabolismo , Região Hipotalâmica Lateral/fisiologia , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação , Animais , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Sono , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
6.
PLoS One ; 14(7): e0219522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291348

RESUMO

Across species, motivated states such as food-seeking and consumption are essential for survival. The lateral hypothalamus (LH) is known to play a fundamental role in regulating feeding and reward-related behaviors. However, the contributions of neuronal subpopulations in the LH have not been thoroughly identified. Here we examine how lateral hypothalamic leptin receptor-expressing (LHLEPR) neurons, a subset of GABAergic cells, regulate motivation in mice. We find that LHLEPR neuronal activation significantly increases progressive ratio (PR) performance, while inhibition decreases responding. Moreover, we mapped LHLEPR axonal projections and demonstrated that they target the ventral tegmental area (VTA), form functional inhibitory synapses with non-dopaminergic VTA neurons, and their activation promotes motivation for food. Finally, we find that LHLEPR neurons also regulate motivation to obtain water, suggesting that they may play a generalized role in motivation. Together, these results identify LHLEPR neurons as modulators within a hypothalamic-ventral tegmental circuit that gates motivation.


Assuntos
Região Hipotalâmica Lateral/fisiologia , Motivação/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Condicionamento Operante/fisiologia , Comportamento Alimentar/psicologia , Feminino , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Modelos Animais , Vias Neurais/fisiologia , Neurônios/fisiologia , Recompensa , Técnicas Estereotáxicas , Sinapses , Área Tegmentar Ventral/citologia
7.
Cell Rep ; 28(3): 616-624.e5, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315042

RESUMO

Overeating is a serious issue in modern society, causing many health problems, including obesity. Although the hypothalamus has been previously identified as the key brain structure that regulates body weight homeostasis, the downstream pathways and non-canonical neural circuitry involved in feeding behavior remain largely uncharacterized. Here, we discover that suppressing the activity of GABAergic cells in the anterior ventrolateral periaqueductal gray (vlPAG), whether directly or through long-projection GABAergic inputs from either the bed nucleus of the stria terminalis (BNST) or the lateral hypothalamus (LH), is sufficient to promptly induce feeding behavior in well-fed mice. In contrast, optogenetic activation of these cells interrupts food intake in starved mice. Long-term chemogenetic manipulation of vlPAG GABAergic cell activity elicits a corresponding change in mouse body weight. Our studies reveal distinct midbrain GABAergic pathways and highlight an important role of GABAergic cells in the anterior vlPAG in feeding behavior.


Assuntos
Comportamento Alimentar/psicologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Vias Neurais/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Núcleos Septais/fisiologia , Animais , Antipsicóticos/farmacologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Peso Corporal/fisiologia , Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Comportamento Alimentar/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Região Hipotalâmica Lateral/citologia , Camundongos , Muscimol/farmacologia , Optogenética , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos da radiação , Núcleos Septais/citologia
8.
Neuron ; 103(3): 423-431.e4, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31196673

RESUMO

The paraventricular thalamus (PVT) is an interface for brain reward circuits, with input signals arising from structures, such as prefrontal cortex and hypothalamus, that are broadcast to downstream limbic targets. However, the precise synaptic connectivity, activity, and function of PVT circuitry for reward processing are unclear. Here, using in vivo two-photon calcium imaging, we find that PVT neurons projecting to the nucleus accumbens (PVT-NAc) develop inhibitory responses to reward-predictive cues coding for both cue-reward associative information and behavior. The multiplexed activity in PVT-NAc neurons is directed by opposing activity patterns in prefrontal and lateral hypothalamic afferent axons. Further, we find that prefrontal cue encoding may maintain accurate cue-reward processing, as optogenetic disruption of this encoding induced long-lasting effects on downstream PVT-NAc cue responses and behavioral cue discrimination. Together, these data reveal that PVT-NAc neurons act as an interface for reward processing by integrating relevant inputs to accurately inform reward-seeking behavior.


Assuntos
Aprendizagem por Associação/fisiologia , Região Hipotalâmica Lateral/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Condicionamento Clássico , Fissura/fisiologia , Sinais (Psicologia) , Ácido Glutâmico/fisiologia , Região Hipotalâmica Lateral/citologia , Camundongos , Núcleos da Linha Média do Tálamo/citologia , Vias Neurais/fisiologia , Optogenética , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Recompensa , Ácido gama-Aminobutírico/fisiologia
9.
Am J Physiol Regul Integr Comp Physiol ; 316(5): R571-R583, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30726119

RESUMO

Aging affects numerous physiological processes, as well as behavior. A large number of these processes are regulated, at least partially, by hypothalamic orexin neurons, and orexin tone may decrease with normal aging. In this study, we hypothesized that designer receptors exclusively activated by designer drugs (DREADD) stimulation of orexin neuronal activity will ameliorate the effect of aging on behavioral and metabolic alterations in young and middle-aged mice. DREADD targeting was achieved by stereotaxic injection of AAV vectors (AAV2-hSyn-DIO-hM3D(Gq)-mCherry) into the lateral hypothalamus of 5- and 12-mo old orexin-cre female mice and was confirmed by immunohistochemistry (IHC) analysis of orexin A and mCherry expression. After recovery, animals were subjected to a behavioral test battery consisting of the elevated plus maze (EPM), open field (OFT), and novel object recognition tests (NORT) to assess effects of aging on anxiety-like behavior, general locomotion, and working memory. A comprehensive laboratory animal monitoring system (CLAMS) was used to measure spontaneous physical activity (SPA) and energy expenditure (EE). The results indicate that activation of orexin neurons mitigates aging-induced reductions in anxiety-like behavior in middle-aged mice (P < 0.005) and increases locomotion in both young and middle-aged mice (P < 0.05). Activation of orexin neurons increases SPA (P < 0.01) and EE (P < 0.005) in middle-aged mice, restoring the levels to that observed in young animals. Results from this study identify orexin neurons as potential therapeutic targets for age-related impairments in cognitive and anxiety-related behavior, and energy balance.


Assuntos
Envelhecimento , Comportamento Animal , Metabolismo Energético , Região Hipotalâmica Lateral/metabolismo , Neurônios/metabolismo , Orexinas/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/psicologia , Animais , Comportamento Exploratório , Feminino , Região Hipotalâmica Lateral/citologia , Locomoção , Aprendizagem em Labirinto , Memória de Curto Prazo , Camundongos Endogâmicos C57BL , Orexinas/deficiência , Orexinas/genética
10.
Neuropeptides ; 74: 24-33, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30700376

RESUMO

OBJECTIVE: Abnormal gastric acid secretion and gastric dyskinesia are common gastroenterological ailments. Our study aims to investigate the effect of orexin-A in the paraventricular nucleus (PVN) gastric motility and gastric acid secretion. METHODS: The source of orexin-A neuronal projections to the PVN were explored by retrograde tracing and fluorescence immunohistochemistry experiments. Neuronal discharge recordings of single cells were taken within the PVN. Gastric motility was recorded using a force transducer implanted into the stomach, and gastric acid secretion measured through a pyloric catheter. RESULTS: Orexin-A-positive neuronal projections from LHA to PVN were found. Administration of orexin-A to PVN activated the firing of 63.2% NPY-excited/GD-excitatory (GD-E) neurons but suppressed the firing of 55.9% NPY-inhibited/GD-inhibitory (GD-I) neurons, promoted gastric motility and gastric acid secretion in a dose-dependent manner. Responses produced by orexin-A could be partially blocked by Y1 receptor antagonist GR-231118; Electrical stimulation to the the hypothalamic lateral area (LHA) altered NPY-sensitive/GD neuronal activity in the PVN, stimulated gastric motility and gastric acid secretion. Additionally, these effects induced by LHA electrical stimulation were blocked by administration of the OX1R antagonist SB-334867 to the PVN. CONCLUSION: Orexin-A from LHA neurons act on the PVN to enhance gastric motility and gastric acid secretion, with Y1 receptor signaling playing a critical role.


Assuntos
Ácido Gástrico/metabolismo , Motilidade Gastrointestinal , Região Hipotalâmica Lateral/metabolismo , Neurônios/metabolismo , Orexinas/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Potenciais de Ação , Animais , Região Hipotalâmica Lateral/citologia , Masculino , Vias Neurais/citologia , Vias Neurais/metabolismo , Neurônios/citologia , Núcleo Hipotalâmico Paraventricular/citologia , Ratos Sprague-Dawley , Transdução de Sinais
11.
Endocrinology ; 160(2): 343-358, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541071

RESUMO

The central melanocortin system plays a crucial role in the control of energy balance. Although the decreased energy expenditure and increased adiposity of melanocortin-3 receptor (Mc3R)-null mice suggest the importance of Mc3R-regulated neurons in energy homeostasis, the roles for specific subsets of Mc3R neurons in energy balance have yet to be determined. Because the lateral hypothalamic area (LHA) contributes to the control of energy expenditure and feeding, we generated Mc3rcre mice to determine the roles of LHA Mc3R (Mc3RLHA) neurons in energy homeostasis. We found that Mc3RLHA neurons overlap extensively with LHA neuron markers that contribute to the control of energy balance (neurotensin, galanin, and leptin receptor) and project to brain areas involved in the control of feeding, locomotion, and energy expenditure, consistent with potential roles for Mc3RLHA neurons in these processes. Indeed, selective chemogenetic activation of Mc3RLHA neurons increased locomotor activity and augmented refeeding after a fast. Although the ablation of Mc3RLHA neurons did not alter food intake, mice lacking Mc3RLHA neurons displayed decreased energy expenditure and locomotor activity, along with increased body mass and adiposity. Thus, Mc3R neurons lie within LHA neurocircuitry that modulates locomotor activity and energy expenditure and contribute to energy balance control.


Assuntos
Metabolismo Energético , Região Hipotalâmica Lateral/fisiologia , Receptor Tipo 3 de Melanocortina/metabolismo , Adiposidade , Animais , Comportamento Alimentar , Região Hipotalâmica Lateral/citologia , Locomoção , Camundongos , Camundongos Transgênicos
12.
Neuropharmacology ; 143: 327-338, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30219501

RESUMO

Histaminergic (HA) neurons located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus fire exclusively during waking and support many physiological functions. We investigated the role of the endovanilloid N-oleoyldopamine (OLDA) in TMN, where dopamine synthesis and its conjugation with oleic acid likely occur. We show that several known targets of OLDA including TRPV1 and cannabinoid receptors are expressed in HA neurons. In contrast to capsaicin, which failed to increase firing of HA neurons in TRPV1 knockout mice (TRPVI KO), OLDA was still able to induce excitation. This excitation was not sensitive to the blockade of cannabinoid receptors 1 and 2 and could result from OLDA interaction with GPR119, as the ligand of GPR119, oleoylethanolamide (OEA), also increased the firing of HA neurons. However, we ruled out this possibility as OEA- (but not OLDA-) excitation was abolished by the PPAR (peroxisome proliferator activated receptor) alpha antagonist MK886. The dopamine uptake blocker nomifensine blanked OLDA-excitation and dopamine receptor antagonists abolished the OLDA action in TRPV1 KO mice. Therefore OLDA excites HA neurons through multiple targets suggesting a central role of the histaminergic system in the behavioral stimulation seen after systemic OLDA application.


Assuntos
Dopamina/análogos & derivados , Histamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Dopamina/farmacologia , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/crescimento & desenvolvimento , Região Hipotalâmica Lateral/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Técnicas de Cultura de Tecidos
13.
Endocrinology ; 159(11): 3631-3642, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30215694

RESUMO

Our ability to modulate and observe neuronal activity in defined neurons in freely moving animals has revolutionized neuroscience research in recent years. Findings in the lateral hypothalamus (LHA) highlighted the existence of many neuronal circuits that regulate distinct phenotypes of feeding behavior, emotional valence, and locomotor activity. Several of these neuronal circuits do not fit into a common model of neuronal integration and highlight the need to improve working models for complex behaviors. This review will specifically focus on recent literature that distinguishes LHA circuits based on their molecular and anatomical characteristics and studies their role in feeding, associated behaviors (e.g., arousal and locomotion), and emotional states (e.g., emotional valences).


Assuntos
Comportamento Alimentar/fisiologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Locomoção/fisiologia , Animais , Ansiedade , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/fisiologia , Nível de Alerta/fisiologia , Emoções/fisiologia , Ácido Glutâmico/metabolismo , Região Hipotalâmica Lateral/citologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Fenótipo
14.
Endocrinology ; 159(9): 3158-3176, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010830

RESUMO

The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they modulate dopamine or local LHA orexin neurons implicated in energy balance, they may have important, unappreciated roles for coordinating behaviors necessary for proper body weight. In this study, we genetically ablated or chemogenetically inhibited LHA Nts neurons in adult mice to determine their necessity for control of motivated behaviors and body weight. Genetic ablation of LHA Nts neurons resulted in profoundly increased adiposity compared with mice with intact LHA Nts neurons, as well as diminished locomotor activity, energy expenditure, and water intake. Complete loss of LHA Nts neurons also led to downregulation of orexin, revealing important cross-talk between the LHA Nts and orexin populations in maintenance of behavior and body weight. In contrast, chemogenetic inhibition of intact LHA Nts neurons did not disrupt orexin expression, but it suppressed locomotor activity and the adaptive response to leptin. Taken together, these data reveal the necessity of LHA Nts neurons and their activation for controlling energy balance, and that LHA Nts neurons influence behavior and body weight via orexin-dependent and orexin-independent mechanisms.


Assuntos
Adiposidade/fisiologia , Peso Corporal/fisiologia , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Região Hipotalâmica Lateral/citologia , Locomoção/fisiologia , Neurônios/fisiologia , Neurotensina/metabolismo , Orexinas/metabolismo , Adaptação Fisiológica , Animais , Comportamento Animal/fisiologia , Regulação para Baixo , Comportamento de Ingestão de Líquido/fisiologia , Expressão Gênica , Leptina/metabolismo , Camundongos , Neurônios/metabolismo , Obesidade/metabolismo
15.
Nat Neurosci ; 21(8): 1084-1095, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30038273

RESUMO

Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNST→LH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNST→LH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.


Assuntos
Emoções/fisiologia , Região Hipotalâmica Lateral/fisiologia , Vias Neurais/fisiologia , Núcleos Septais/fisiologia , Animais , Colecistocinina/fisiologia , Condicionamento Operante/fisiologia , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Vias Neurais/citologia , Neurônios/fisiologia , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Orexinas/fisiologia , Estimulação Luminosa , Autoestimulação , Núcleos Septais/citologia , Ácido gama-Aminobutírico/fisiologia
16.
Neuropharmacology ; 139: 238-256, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981758

RESUMO

The rat nucleus incertus (NI) contains GABA/peptide-projection neurons responsive to orexin (hypocretin)/orexin receptor-2 (OX2) signalling. Melanin-concentrating hormone (MCH) and orexin neurons often innervate and influence common target areas. Therefore, we assessed the relationship between these hypothalamic peptidergic systems and rat NI, by investigating the presence of an MCH innervation and MCH receptor-1 (MCH1) expression, and neurophysiological and behavioural effects of MCH c.f. orexin-A (OXA), within the NI. We identified lateral hypothalamus (LH), perifornical and sub-zona incerta MCH neurons that innervate NI, and characterised the rostrocaudal distribution of MCH-containing fibres in NI. Single-cell RT-PCR detected MCH1 and OX2 mRNA in NI, and multiplex, fluorescent in situ hybridisation revealed distinct co-expression patterns of MCH1 and OX2 mRNA in NI neurons expressing vesicular GABA transporter (vGAT) mRNA. Patch-clamp recordings revealed 34% of NI neurons tested were hyperpolarised by MCH (1 µM), representing a distinct population from OXA-sensitive NI neurons (35%). Intra-NI OXA infusion (600 pmol) in satiated rats during the light/inactive phase produced increased locomotor activity and food (standard chow) intake, whereas intra-NI MCH infusion (600 pmol) produced only a trend for decreased locomotor activity and no effect on food intake. Furthermore, in satiated or pre-fasted rats tested during the dark/active phase, intra-NI infusion of MCH did not alter the elevated locomotor activity or higher food intake observed. However, quantification of neuropeptide-immunostaining revealed differential diurnal fluctuations in orexin and MCH trafficking to NI. Our findings identify MCH and orexin inputs onto divergent NI populations which may differentially influence arousal and motivated behaviours.


Assuntos
Neurônios/citologia , Neurônios/metabolismo , Receptores de Orexina/metabolismo , Núcleos da Rafe/citologia , Núcleos da Rafe/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Orexinas/metabolismo , Hormônios Hipofisários/metabolismo , RNA Mensageiro/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Técnicas de Cultura de Tecidos , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
J Neurosci ; 38(28): 6366-6378, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29915137

RESUMO

The hypothalamus plays an important role in the regulation of sleep/wakefulness states. While the ventrolateral preoptic nucleus (VLPO) plays a critical role in the initiation and maintenance of sleep, the lateral posterior part of the hypothalamus contains neuronal populations implicated in maintenance of arousal, including orexin-producing neurons (orexin neurons) in the lateral hypothalamic area (LHA) and histaminergic neurons in the tuberomammillary nucleus (TMN). During a search for neurons that make direct synaptic contact with histidine decarboxylase-positive (HDC+), histaminergic neurons (HDC neurons) in the TMN and orexin neurons in the LHA of male mice, we found that these arousal-related neurons are heavily innervated by GABAergic neurons in the preoptic area including the VLPO. We further characterized GABAergic neurons electrophysiologically in the VLPO (GABAVLPO neurons) that make direct synaptic contact with these hypothalamic arousal-related neurons. These neurons (GABAVLPO→HDC or GABAVLPO→orexin neurons) were both potently inhibited by noradrenaline and serotonin, showing typical electrophysiological characteristics of sleep-promoting neurons in the VLPO. This work provides direct evidence of monosynaptic connectivity between GABAVLPO neurons and hypothalamic arousal neurons and identifies the effects of monoamines on these neuronal pathways.SIGNIFICANCE STATEMENT Rabies-virus-mediated tracing of input neurons of two hypothalamic arousal-related neuron populations, histaminergic and orexinergic neurons, showed that they receive similar distributions of input neurons in a variety of brain areas, with rich innervation by GABAergic neurons in the preoptic area, including the ventrolateral preoptic area (VLPO), a region known to play an important role in the initiation and maintenance of sleep. Electrophysiological experiments found that GABAergic neurons in the VLPO (GABAVLPO neurons) that make direct input to orexin or histaminergic neurons are potently inhibited by noradrenaline and serotonin, suggesting that these monoamines disinhibit histamine and orexin neurons. This work demonstrated functional and structural interactions between GABAVLPO neurons and hypothalamic arousal-related neurons.


Assuntos
Nível de Alerta/fisiologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Área Pré-Óptica/fisiologia , Sono/fisiologia , Animais , Neurônios GABAérgicos/citologia , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/citologia , Vias Neurais/metabolismo , Norepinefrina/metabolismo , Área Pré-Óptica/citologia , Serotonina/metabolismo
18.
PLoS One ; 13(6): e0198991, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29894514

RESUMO

Cracking the cytoarchitectural organization, activity patterns, and neurotransmitter nature of genetically-distinct cell types in the lateral hypothalamus (LH) is fundamental to develop a mechanistic understanding of how activity dynamics within this brain region are generated and operate together through synaptic connections to regulate circuit function. However, the precise mechanisms through which LH circuits orchestrate such dynamics have remained elusive due to the heterogeneity of the intermingled and functionally distinct cell types in this brain region. Here we reveal that a cell type in the mouse LH identified by the expression of the calcium-binding protein parvalbumin (PVALB; LHPV) is fast-spiking, releases the excitatory neurotransmitter glutamate, and sends long range projections throughout the brain. Thus, our findings challenge long-standing concepts that define neurons with a fast-spiking phenotype as exclusively GABAergic. Furthermore, we provide for the first time a detailed characterization of the electrophysiological properties of these neurons. Our work identifies LHPV neurons as a novel functional component within the LH glutamatergic circuitry.


Assuntos
Potenciais de Ação , Fenômenos Eletrofisiológicos , Região Hipotalâmica Lateral/fisiologia , Neurônios/fisiologia , Parvalbuminas/fisiologia , Animais , Feminino , Perfilação da Expressão Gênica , Região Hipotalâmica Lateral/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Análise de Célula Única
19.
Brain Struct Funct ; 223(3): 1313-1328, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29116427

RESUMO

Paraventricular thalamic nucleus (PVT) serves as a transit node processing food and drug-associated reward information, but its afferents and efferents have not been fully defined. We test the hypothesis that the CART neurons in the lateral hypothalamus (LH) project to the PVT neurons, which in turn communicate via the glutamatergic fibers with the nucleus accumbens shell (AcbSh), the canonical site for reward. Rats conditioned to self-stimulate via an electrode in the right LH-medial forebrain bundle were used. Intra-PVT administration of CART (55-102) dose-dependently (10-50 ng/rat) lowered intracranial self-stimulation (ICSS) threshold and increased lever press activity, suggesting reward-promoting action of the peptide. However, treatment with CART antibody (intra-PVT) or MK-801 (NMDA antagonist, intra-AcbSh) produced opposite effects. A combination of sub-effective dose of MK-801 (0.01 µg/rat, intra-AcbSh) and effective dose of CART (25 ng/rat, intra-PVT) attenuated CART's rewarding action. Further, we screened the LH-PVT-AcbSh circuit for neuroadaptive changes induced by conditioning experience. A more than twofold increase was noticed in the CART mRNA expression in the LH on the side ipsilateral to the implanted electrode for ICSS. In addition, the PVT of conditioned rats showed a distinct increase in the (a) c-Fos expressing cells and CART fiber terminals, and (b) CART and vesicular glutamate transporter 2 immunostained elements. Concomitantly, the AcbSh showed a striking increase in expression of NMDA receptor subunit NR1. We suggest that CART in LH-PVT and glutamate in PVT-AcbSh circuit might support food-seeking behavior under natural conditions and also store reward memory.


Assuntos
Ácido Glutâmico/metabolismo , Região Hipotalâmica Lateral/citologia , Núcleos da Linha Média do Tálamo/citologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Núcleo Accumbens/fisiologia , Recompensa , Animais , Anticorpos/farmacologia , Condicionamento Operante/fisiologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 2/metabolismo , Região Hipotalâmica Lateral/diagnóstico por imagem , Locomoção/efeitos dos fármacos , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/farmacologia , Vias Neurais/fisiologia , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo
20.
Cell Rep ; 21(11): 3116-3128, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29241540

RESUMO

The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may, therefore, be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss and, hence, to prevent weight regain.


Assuntos
Ingestão de Alimentos/genética , Região Hipotalâmica Lateral/metabolismo , Neurônios/metabolismo , Neurotensina/genética , Receptores de Neurotensina/genética , Perda de Peso/genética , Animais , Comportamento de Ingestão de Líquido/fisiologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Genes Reporter , Região Hipotalâmica Lateral/citologia , Locomoção/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/citologia , Receptores de Neurotensina/metabolismo , Transdução de Sinais , Técnicas Estereotáxicas
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