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1.
Nat Commun ; 11(1): 640, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005806

RESUMO

Reduced food intake is common to many pathological conditions, such as infection and toxin exposure. However, cortical circuits that mediate feeding responses to these threats are less investigated. The anterior insular cortex (aIC) is a core region that integrates interoceptive states and emotional awareness and consequently guides behavioral responses. Here, we demonstrate that the right-side aIC CamKII+ (aICCamKII) neurons in mice are activated by aversive visceral signals. Hyperactivation of the right-side aICCamKII neurons attenuates food consumption, while inhibition of these neurons increases feeding and reverses aversive stimuli-induced anorexia and weight loss. Similar manipulation at the left-side aIC does not cause significant behavioral changes. Furthermore, virus tracing reveals that aICCamKII neurons project directly to the vGluT2+ neurons in the lateral hypothalamus (LH), and the right-side aICCamKII-to-LH pathway mediates feeding suppression. Our studies uncover a circuit from the cortex to the hypothalamus that senses aversive visceral signals and controls feeding behavior.


Assuntos
Agentes Aversivos/toxicidade , Córtex Cerebral/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Córtex Cerebral/efeitos dos fármacos , Feminino , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
2.
Epilepsia ; 61(3): 572-588, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32030748

RESUMO

OBJECTIVE: Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic-clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2 ) in low-risk and high-risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high-risk KO mice. METHODS: Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. RESULTS: Intermittent bradycardia was more prevalent in high-risk KO mice, an effect that may be the result of increased parasympathetic drive. High-risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild-type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea-apnea. Blocking orexin receptors prevented the methacholine (MCh)-induced increase in breathing frequency in KO mice and reduced MCh-induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high-risk KO mice increased longevity. SIGNIFICANCE: High-risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.


Assuntos
Apneia/genética , Bradicardia/genética , Epilepsia/genética , Hipóxia/genética , Canal de Potássio Kv1.1/genética , Morte Súbita Inesperada na Epilepsia , Animais , Apneia/fisiopatologia , Bradicardia/fisiopatologia , Epilepsia/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/patologia , Hipóxia/fisiopatologia , Cloreto de Metacolina/toxicidade , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/metabolismo , Oximetria , Oxigênio , Sistema Nervoso Parassimpático/fisiopatologia , Parassimpatomiméticos/toxicidade , Taxa Respiratória/efeitos dos fármacos , Convulsões/induzido quimicamente
3.
J Neurosci ; 40(8): 1744-1755, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31953368

RESUMO

Cognitive processes contribute to the control of feeding behavior and help organism's survival when they support physiological needs. They can become maladaptive, such as when learned food cues drive feeding in the absence of hunger. Associative learning is the basis for cue-driven food seeking and consumption, and behavioral paradigms with Pavlovian cue-food conditioning are well established. Yet, the neural mechanisms underlying circuit plasticity across cue-food learning, cue memory recall, and subsequent food motivation are unknown. Here, we demonstrated the medial prefrontal cortex (mPFC) is a site of learning-induced plasticity and signaling of the neuropeptide orexin within the mPFC mediates cue potentiated feeding (CPF). First, using a marker of neuronal activation, c-fos, we confirmed that the mPFC is activated during CPF. Next, to assess whether the same mPFC neuronal ensemble is activated during cue-food learning and later CPF, we used the Daun02 chemogenetic inactivation method in c-fos-lacZ transgenic male and female rats. Selective inactivation of the mPFC neurons that were active during the last cue-food training session abolished CPF during test, demonstrating that the mPFC is a site of plasticity. We postulated that integration of food cue memory and feeding motivation requires mPFC communications with lateral hypothalamus and showed that disconnection of that system abolished CPF. Then we showed that lateral hypothalamus orexin-producing neurons project to the mPFC. Finally, we blocked orexin receptor 1 signaling in the mPFC and showed that it is a neuromodulator necessary for the cue-driven consumption. Together, our findings identify a causal function for the mPFC in the cognitive motivation to eat.SIGNIFICANCE STATEMENT Obesity has reached epidemic proportions, and the associated health consequences are serious and costly. The causes of obesity are complex because, in addition to physiological energy and nutrient needs, environmental cues can drive feeding through hedonic and cognitive processes. Learned food cues from the environment can powerfully stimulate appetite and food consumption in the absence of hunger. Using an animal model for cue-potentiated feeding, the current study determined the mPFC neuronal plasticity and neuropeptide orexin signaling are critical circuit and neurotransmitter mechanisms involved in this form of cognitive motivation to eat. These findings identify key targets for potential treatment of excessive appetite and overeating.


Assuntos
Comportamento Alimentar/fisiologia , Região Hipotalâmica Lateral/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de Orexina/metabolismo , Córtex Pré-Frontal/fisiologia , Transdução de Sinais/fisiologia , Animais , Sinais (Psicologia) , Feminino , Região Hipotalâmica Lateral/metabolismo , Aprendizagem/fisiologia , Masculino , Vias Neurais/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos
4.
Sleep ; 43(1)2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31556946

RESUMO

Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease.


Assuntos
Cataplexia/genética , Metilação de DNA/genética , Região Hipotalâmica Lateral/metabolismo , Esclerose Múltipla/genética , Narcolepsia/genética , Lobo Temporal/metabolismo , Cataplexia/fisiopatologia , DNA/metabolismo , Epigenoma , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Narcolepsia/fisiopatologia , Neurônios/metabolismo , Orexinas/genética , Orexinas/metabolismo
5.
Neuropsychopharmacol Rep ; 39(4): 289-296, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31618533

RESUMO

AIM: The lateral hypothalamus (LH) is known as the hunger center, but the mechanisms through which the LH regulates food intake are unclear. Since GABA neurons are reported to project to the LH, the present study investigated the role of GABAergic function in the LH in the regulation of feeding behavior. METHODS: GABA levels in the LH were measured by in vivo microdialysis. Food intake after drug injection into the LH was measured every 1 hour for 4 hours. The mRNA levels were measured using RT-PCR. RESULTS: Food intake significantly increased GABA levels in the LH, suggesting that food intake stimulates GABAergic function in the LH. Injection of the GABAA receptor agonist muscimol into the LH significantly inhibited food intake, whereas injection of the GABAA receptor antagonist bicuculline into the LH did not significantly affect food intake. The inhibitory effect of muscimol injected into the LH was blocked by co-administration of bicuculline. These results indicate that the stimulation of GABAA receptors in the LH inhibits food intake. We next examined whether the stimulation of GABAA receptors affects hypothalamic neuropeptides that are known to regulate feeding behavior. The injection of muscimol significantly decreased preproorexin mRNA in the hypothalamus. CONCLUSION: These results indicate that food intake activates GABAergic function in the LH, which terminates feeding behavior by stimulating GABAA receptors. Moreover, it is suggested that the stimulation of GABAA receptors in the LH reduces food intake through inhibition of orexin neurons.


Assuntos
Ingestão de Alimentos/fisiologia , Região Hipotalâmica Lateral/metabolismo , Orexinas/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Bicuculina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Microdiálise , Muscimol/farmacologia
6.
Nat Commun ; 10(1): 4923, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664021

RESUMO

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.


Assuntos
Hipocampo/metabolismo , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/metabolismo , Comportamento Impulsivo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Animais , Hormônios Hipotalâmicos/genética , Masculino , Melaninas/genética , Vias Neurais , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Hormônios Hipofisários/genética , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo
7.
Biochem Biophys Res Commun ; 519(3): 547-552, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31537386

RESUMO

This study investigated dopaminergic function in the lateral hypothalamus (LH) in the regulation of feeding behavior. Refeeding increased dopamine levels in the LH. Glucose injection also increased dopamine levels in the LH. When the retrograde tracer Fluoro-Gold (FG) was injected into the LH, FG-positive cells were found in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC), which were mostly tyrosine hydroxylase-positive. Injection of the dopamine D1 receptor agonist SKF 38393, but not the antagonist SCH 23390, into the LH increased food intake. Similarly, injection of the dopamine D2 receptor agonist quinpirole, but not the antagonist l-sulpiride, into the LH increased food intake. The effect of each agonist was blocked by its respective antagonist. Furthermore, injection of quinpirole, but not SKF 38393, decreased the mRNA level of preproorexin. In addition, injection of SKF 38393 decreased the mRNA levels of neuropeptide Y and agouti-related peptide, whereas the injection of quinpirole increased the mRNA level of proopiomelanocortin. These results indicate that food intake activates dopamine neurons projecting from the VTA/SNC to the LH through an increase in blood glucose levels, which terminates food intake by stimulation of dopamine D1 and D2 receptors. It is also possible that stimulation of dopamine D1 and D2 receptors in the LH inhibits feeding behavior through different neuropeptides.


Assuntos
Dopaminérgicos/farmacologia , Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Neuropeptídeos/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Agonistas de Dopamina/farmacologia , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Quimpirol/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo
8.
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
9.
Biomed Res Int ; 2019: 2389485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346513

RESUMO

Acute alcohol exposure induces unconscious condition such as coma whose main physical manifestation is the loss of righting reflex (LORR). Xingnaojing Injection (XNJI), which came from Chinese classic formula An Gong Niu Huang Pill, is widely used for consciousness disorders in China, such as coma. Although XNJI efficiently shortened the duration of LORR induced by acute ethanol, it remains unknown how XNJI acts on ethanol-induced coma (EIC). We performed experiments to examine the effects of XNJI on orexin and adenosine (AD) signaling in the lateral hypothalamic area (LHA) in EIC rats. Results showed that XNJI reduced the duration of LORR, which implied that XNJI promotes recovery form coma. Microdialysis data indicated that acute ethanol significantly increased AD release in the LHA but had no effect on orexin A levels. The qPCR results displayed a significant reduction in the Orexin-1 receptors (OX1R) expression with a concomitant increase in the A1 receptor (A1R) and equilibrative nucleoside transporter type 1 (ENT1) expression in EIC rats. In contrast, XNJI reduced the extracellular AD levels but orexin A levels remained unaffected. XNJI also counteracted the downregulation of the OX1R expression and upregulation of A1R and ENT1 expression caused by EIC. As for ADK expression, XNJI but not ethanol, displayed an upregulation in the LHA in EIC rats. Based on these results, we suggest that XNJI promotes arousal by inhibiting adenosine neurotransmission via reducing AD level and the expression of A1R and ENT1.


Assuntos
Proteínas de Transporte/genética , Coma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Receptor A1 de Adenosina/genética , Adenosina/genética , Adenosina/metabolismo , Animais , Coma/induzido quimicamente , Coma/genética , Coma/patologia , Transportador Equilibrativo 1 de Nucleosídeo , Etanol/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Receptores de Orexina/genética , Orexinas/genética , Orexinas/metabolismo , Ratos , Reflexo de Endireitamento/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Vigília/efeitos dos fármacos
10.
Endocrine ; 65(3): 675-682, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31325084

RESUMO

PURPOSE: The aim of this study is to evaluate the effects of adrenalectomy (ADX) and glucocorticoid in the changes induced by intracerebroventricular (ICV) administration of vasoactive intestinal peptide (VIP) on food intake and plasma parameters, as well as VIP receptor subtype 2 (VPAC2) mRNA expression in different hypothalamic nuclei of male rats. METHODS: Male Wistar rats (260-280 g) were subjected to ADX or sham surgery, 7 days before the experiments. Half of ADX animals received corticosterone (ADX + CORT) in the drinking water. Animals with 16 h of fasting received ICV microinjection of VIP or saline (0.9% NaCl). After 15 min: (1) animals were fed, and the amount of food ingested was quantified for 120 min; or (2) animals were euthanized and blood was collected for biochemical measurements. Determination of VPAC2 mRNA levels in LHA, ARC, and PVN was performed from animals with microinjection of saline. RESULTS: VIP treatment promoted the anorexigenic effect, which was not observed in ADX animals. Microinjection of VIP also induced an increase in blood plasma glucose and corticosterone levels, and a reduction in free fatty acid plasma levels, but adrenalectomy abolished these effects. In addition, adrenalectomy reduced mRNA expression of VPAC2 in the lateral hypothalamic area and arcuate nucleus, but not in the paraventricular nucleus. CONCLUSIONS: These results suggest that adrenal glands are required for VIP-induced changes in food intake and plasma parameters, and these responses are associated with reduction in the expression of VPAC2 in the hypothalamus after adrenalectomy.


Assuntos
Adrenalectomia/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Glicemia/análise , Corticosterona/sangue , Corticosterona/farmacologia , Ácidos Graxos não Esterificados/sangue , Região Hipotalâmica Lateral/metabolismo , Masculino , Microinjeções , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Wistar , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo
11.
J Psychopharmacol ; 33(12): 1475-1490, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31282233

RESUMO

BACKGROUND: Since the discovery of rewarding intracranial self-stimulation by Olds and Milner, extensive data have been published on the biological basis of reward. Although participation of the mesolimbic dopaminergic system is well documented, its precise role has not been fully elucidated, and some authors have proposed the involvement of other neural systems in processing specific aspects of reinforced behaviour. AIMS AND METHODS: We reviewed published data, including our own findings, on the rewarding effects induced by electrical stimulation of the lateral hypothalamus (LH) and of the external lateral parabrachial area (LPBe) - a brainstem region involved in processing the rewarding properties of natural and artificial substances - and compared its functional characteristics as observed in operant and non-operant behavioural procedures. RESULTS: Brain circuits involved in the induction of preferences for stimuli associated with electrical stimulation of the LBPe appear to functionally and neurochemically differ from those activated by electrical stimulation of the LH. INTERPRETATION: We discuss the possible involvement of the LPBe in processing emotional-affective aspects of the brain reward system.


Assuntos
Analgésicos Opioides/farmacologia , Dopamina/metabolismo , Recompensa , Animais , Condicionamento Operante/fisiologia , Estimulação Elétrica , Humanos , Região Hipotalâmica Lateral/metabolismo , Núcleos Parabraquiais/metabolismo
12.
Life Sci ; 232: 116575, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211999

RESUMO

AIMS: Maternal smoking is considered a risk factor for childhood obesity. In a rat model of tobacco exposure during breastfeeding, we previously reported hyperphagia, overweight, increased visceral fat and hyperleptinemia in adult female offspring. Obesity and eating disorders are associated with impairment in the endocannabinoid (EC) and dopaminergic (DA) systems. Considering that women are prone to eating disorders, we hypothesize that adult female Wistar rats that were exposed to cigarette smoke (CS) during the suckling period would develop EC and DA systems deregulation, possibly explaining the eating disorder in this model. MATERIAL AND METHODS: To mimic maternal smoking, from postnatal day 3 to 21, dams and offspring were exposed to a smoking machine, 4×/day/1 h (CS group). Control animals were exposed to ambient air. Offspring were evaluated at 26 weeks of age. KEY FINDINGS: Concerning the EC system, the CS group had increased expression of diacylglycerol lipase (DAGL) in the lateral hypothalamus (LH) and decreased in the liver. In the visceral adipose tissue, the EC receptor (CB1r) was decreased. Regarding the DA system, the CS group showed higher dopamine transporter (DAT) protein expression in the prefrontal cortex (PFC) and lower DA receptor (D2r) in the arcuate nucleus (ARC). We also assessed the hypothalamic leptin signaling, which was shown to be unchanged. CS offspring showed decreased plasma 17ß-estradiol. SIGNIFICANCE: Neonatal CS exposure induces changes in some biomarkers of the EC and DA systems, which can partially explain the hyperphagia observed in female rats.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Endocanabinoides/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Animais Recém-Nascidos , Fumar Cigarros , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Endocanabinoides/fisiologia , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/metabolismo , Lactação/efeitos dos fármacos , Leptina/metabolismo , Lipase Lipoproteica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Obesidade/etiologia , Obesidade/metabolismo , Ratos , Ratos Wistar , Receptores de Canabinoides/efeitos dos fármacos , Fumar , Tabaco
13.
Neuroscience ; 413: 86-98, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31202706

RESUMO

Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep-wake patterns by sending widespread projections into many brain areas implicated in sleep-wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep-wake profile remains unknown. We found that glutamate, NMDA, AMPA or dihydrokainate, a glutamate-uptake inhibitor, dose-dependently increased wakefulness when microinjected into the rat TMN. Glutamate, NMDA, and AMPA also increased the firing rate of action potentials in TMN histaminergic neurons. The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H1 receptors.


Assuntos
Ácido Glutâmico/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Receptores Histamínicos/metabolismo , Promotores da Vigília/farmacologia , Vigília/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antagonistas dos Receptores Histamínicos H1/farmacologia , Região Hipotalâmica Lateral/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sono/efeitos dos fármacos , Sono/fisiologia , Técnicas de Cultura de Tecidos , Vigília/fisiologia
14.
Science ; 364(6447): 1271-1274, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31249056

RESUMO

The current obesity epidemic is a major worldwide health concern. Despite the consensus that the brain regulates energy homeostasis, the neural adaptations governing obesity are unknown. Using a combination of high-throughput single-cell RNA sequencing and longitudinal in vivo two-photon calcium imaging, we surveyed functional alterations of the lateral hypothalamic area (LHA)-a highly conserved brain region that orchestrates feeding-in a mouse model of obesity. The transcriptional profile of LHA glutamatergic neurons was affected by obesity, exhibiting changes indicative of altered neuronal activity. Encoding properties of individual LHA glutamatergic neurons were then tracked throughout obesity, revealing greatly attenuated reward responses. These data demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.


Assuntos
Região Hipotalâmica Lateral/metabolismo , Região Hipotalâmica Lateral/fisiopatologia , Obesidade/genética , Obesidade/fisiopatologia , Transcriptoma , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Camundongos , Neurônios , Obesidade/psicologia , Recompensa , Proteína Vesicular 2 de Transporte de Glutamato/genética
15.
Obesity (Silver Spring) ; 27(7): 1123-1132, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087767

RESUMO

OBJECTIVE: The lateral hypothalamus (LH) is known for its role in feeding, and it also regulates other aspects of energy homeostasis. How genetically defined LH neuronal subpopulations mediate LH effects on energy homeostasis remains poorly understood. The behavioral effects of chemogenetically activating LH gamma-aminobutyric acid (GABA) and the more selective population of LH GABA neurons that coexpress the leptin receptor (LepR) were compared. METHODS: LepR-cre and VGAT-cre mice were injected with AAV5-hSyn-DIO-hM3DGq-mCherry in the LH. The behavioral effects of LH GABA or LH LepR neuronal activation on feeding, locomotion, thermogenesis, and body weight were assessed. RESULTS: The activation of LH GABA neurons increased body temperature (P ≤ 0.008) and decreased body weight (P ≤ 0.01) despite decreased locomotor activity (P = 0.03) and transiently increased chow intake (P ≤ 0.009). Also, similar to other studies, this study found that activation of LH GABA neurons induced gnawing on both food and nonfood (P = 0.001) items. Activation of LH LepR neurons decreased body weight (P ≤ 0.01) and chow intake when presented on the cage floor (P ≤ 0.04) but not when presented in the cage top and increased locomotor activity (P = 0.002) and body temperature (P = 0.03). CONCLUSIONS: LH LepR neurons are a subset of LH GABA neurons, and LH LepR activation more specifically regulates energy homeostasis to promote a negative energy balance.


Assuntos
Metabolismo Energético/genética , Homeostase/genética , Região Hipotalâmica Lateral/metabolismo , Leptina/metabolismo , Locomoção/genética , Neurônios/metabolismo , Termogênese/genética , Ácido gama-Aminobutírico/metabolismo , Animais , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Receptores para Leptina/metabolismo
16.
Sci Rep ; 9(1): 7132, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073137

RESUMO

Olfaction guides goal-directed behaviours including feeding. To investigate how central olfactory neural circuits control feeding behaviour in mice, we performed retrograde tracing from the lateral hypothalamus (LH), an important feeding centre. We observed a cluster of retrogradely labelled cells distributed in the posteroventral region of the olfactory peduncle. Histochemical analyses revealed that the majority of these retrogradely labelled projection neurons expressed glutamic acid decarboxylase 65/67 (GAD65/67), but not vesicular glutamate transporter 1 (VGluT1). We named this region containing GABAergic projection neurons the ventral olfactory nucleus (VON) to differentiate it from the conventional olfactory peduncle. VON neurons were less immunoreactive for DARPP-32, a striatal neuron marker, compared to neurons in the olfactory tubercle and nucleus accumbens, which distinguished the VON from the ventral striatum. Fluorescent labelling confirmed putative synaptic contacts between VON neurons and olfactory bulb projection neurons. Rabies-virus-mediated trans-synaptic labelling revealed that VON neurons received synaptic inputs from the olfactory bulb, other olfactory cortices, horizontal limb of the diagonal band, and prefrontal cortex. Collectively, these results identify novel GABAergic projection neurons in the olfactory cortex that may integrate olfactory sensory and top-down inputs and send inhibitory output to the LH, which may modulate odour-guided LH-related behaviours.


Assuntos
Neurônios GABAérgicos/metabolismo , Região Hipotalâmica Lateral/metabolismo , Córtex Olfatório/metabolismo , Vírus da Raiva/fisiologia , Animais , Comportamento Alimentar , Neurônios GABAérgicos/virologia , Glutamato Descarboxilase/metabolismo , Região Hipotalâmica Lateral/virologia , Masculino , Camundongos , Bulbo Olfatório/metabolismo , Bulbo Olfatório/virologia , Córtex Olfatório/virologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
17.
Am J Physiol Regul Integr Comp Physiol ; 316(6): R791-R801, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30943041

RESUMO

Amylin acts in the area postrema (AP) and arcuate nucleus (ARC) to control food intake. Amylin also increases axonal fiber outgrowth from the AP→nucleus tractus solitarius and from ARC→hypothalamic paraventricular nucleus. More recently, exogenous amylin infusion for 4 wk was shown to increase neurogenesis in adult rats in the AP. Furthermore, amylin has been shown to enhance leptin signaling in the ARC and ventromedial nucleus of the hypothalamus (VMN). Thus, we hypothesized that endogenous amylin could be a critical factor in regulating cell birth in the ARC and AP and that amylin could also be involved in the birth of leptin-sensitive neurons. Amylin+/- dams were injected with BrdU at embryonic day 12 and at postnatal day 2; BrdU+ cells were quantified in wild-type (WT) and amylin knockout (KO) mice. The number of BrdU+HuC/D+ neurons was similar in ARC and AP, but the number of BrdU+Iba1+ microglia was significantly decreased in both nuclei. Five-week-old WT and KO littermates were injected with leptin to test whether amylin is involved in the birth of leptin-sensitive neurons. Although there was no difference in the number of BrdU+c-Fos+ neurons in the ARC and dorsomedial nucleus, an increase in BrdU+c-Fos+ neurons was seen in VMN and lateral hypothalamus (LH) in amylin KO mice. In conclusion, these data suggest that during fetal development, endogenous amylin favors the birth of microglial cells in the ARC and AP and that it decreases the birth of leptin-sensitive neurons in the VMN and LH.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Área Postrema/metabolismo , Linhagem da Célula , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Microglia/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/embriologia , Área Postrema/embriologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Região Hipotalâmica Lateral/embriologia , Região Hipotalâmica Lateral/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Leptina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Fenótipo , Gravidez , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleo Hipotalâmico Ventromedial/embriologia , Núcleo Hipotalâmico Ventromedial/metabolismo
18.
PLoS Biol ; 17(3): e3000172, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30893297

RESUMO

Sleep and wakefulness are greatly influenced by various physiological and psychological factors, but the neuronal elements responsible for organizing sleep-wake behavior in response to these factors are largely unknown. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing the neuropeptide neurotensin (Nts) is critical for orchestrating sleep-wake responses to acute psychological and physiological challenges or stressors. We show that selective activation of NtsLH neurons with chemogenetic or optogenetic methods elicits rapid transitions from non-rapid eye movement (NREM) sleep to wakefulness and produces sustained arousal, higher locomotor activity (LMA), and hyperthermia, which are commonly observed after acute stress exposure. On the other hand, selective chemogenetic inhibition of NtsLH neurons attenuates the arousal, LMA, and body temperature (Tb) responses to a psychological stress (a novel environment) and augments the responses to a physiological stress (fasting).


Assuntos
Febre/metabolismo , Região Hipotalâmica Lateral/metabolismo , Neurotensina/metabolismo , Animais , Temperatura Corporal , Eletroforese , Técnicas de Genotipagem , Locomoção/fisiologia , Masculino , Camundongos , Neurônios/metabolismo
19.
Eur Neuropsychopharmacol ; 29(5): 672-680, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30878320

RESUMO

The lateral hypothalamus (LH) has been described as one of the hypothalamic areas involved in the behavioral and physiological responses triggered by aversive stimuli. Previous studies indicated involvement of the LH in cardiovascular responses to stress. Despite this evidence, the local neurochemical mechanisms involved in LH control of stress responses is still poorly understood. Therefore, in the present study, we investigated the role of GABAergic neurotransmission within the LH in cardiovascular responses induced by an acute session of restraint stress in rats. For this, we evaluated the effect of bilateral microinjection of selective antagonists of either GABAA or GABAB receptors into the LH on arterial pressure increase, heart rate (HR) increase and reduction in tail skin temperature induced by restraint stress. We found that microinjection of the selective GABAA receptor antagonist SR95531 into the LH decreased the increase in HR caused by restraint stress, but without affecting the increase in arterial pressure increase or the reduction in tail skin temperature. Conversely, LH treatment with the selective GABAB receptor antagonist CGP35348 did not affect the restraint-evoked cardiovascular changes. These findings indicate that GABAergic neurotransmission in the LH, acting through activation of local GABAA receptors, plays a facilitatory role in the tachycardic response observed during aversive threats.


Assuntos
Região Hipotalâmica Lateral/metabolismo , Angústia Psicológica , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Estresse Psicológico/metabolismo , Taquicardia/metabolismo , Animais , Antagonistas GABAérgicos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Microinjeções , Ratos , Ratos Wistar , Estresse Psicológico/psicologia , Taquicardia/psicologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-30885832

RESUMO

Mesotocin (MT) decreases food intake and induces hyperthermia in chicks although hypothalamic mechanisms are unknown. The purpose of this study was thus to investigate effects of receptor antagonists and MT on feeding behavior and hypothalamic physiology. Intracerebroventricular injection of 2.5 nmol into broiler chicks was associated with decreased food intake for 180 min and water intake from 60 to 180 min. Cloacal temperatures were elevated in chicks injected with 0.156 and 0.625 nmol at 30 and 60 min, and up to 180 min in those injected with 2.5 nmol. MT also increased temperatures and decreased food and water intake in chicks from lines selected for low (LWS) or high (HWS) body weight with a higher dose threshold but longer food intake response in HWS chicks. An oxytocin receptor antagonist prevented MT-mediated changes in food intake but not water intake or temperature. Yohimbine, an α2-adrenergic receptor antagonist, did not affect food intake, temperature, or MT-mediated effects. MT increased c-Fos immunoreactivity in the paraventricular nucleus (PVN) and lateral hypothalamus (LH). Hypothalamic agouti-related peptide, corticotropin-releasing factor receptor sub-type 1, and melanocortin receptor 3 mRNAs increased in response to MT. There was increased MT mRNA in the LH and L-aromatic amino acid decarboxylase mRNA in the PVN of MT-injected chicks. In conclusion, MT induced anorexia and hyperthermia and reduced water intake. MT was associated with activation of the PVN and LH and differences in the mRNA abundance of some appetite-associated factors, thus implicating these nuclei and several signaling pathways in the effects observed.


Assuntos
Anorexia/induzido quimicamente , Galinhas/genética , Região Hipotalâmica Lateral/efeitos dos fármacos , Ocitocina/análogos & derivados , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Descarboxilases de Aminoácido-L-Aromático/genética , Região Hipotalâmica Lateral/metabolismo , Ocitocina/farmacologia , RNA Mensageiro/metabolismo
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