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1.
Semin Cell Dev Biol ; 156: 210-218, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-37507330

RESUMO

The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.


Assuntos
Neurônios Eferentes , Nervo Vago , Nervo Vago/metabolismo , Neurônios/fisiologia
2.
J Neurosci ; 44(31)2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-38918066

RESUMO

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control, serving as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the molecular and cellular organization of the VLM has remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing in male and female mice. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and five subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in seven subtypes of neurons, which were validated through in situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with premotor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified nine and six subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in two subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLM's role in vital functions and motor control.


Assuntos
Bulbo , Neurônios , Medula Espinal , Animais , Bulbo/citologia , Bulbo/fisiologia , Camundongos , Masculino , Feminino , Neurônios/fisiologia , Medula Espinal/citologia , Medula Espinal/fisiologia , Camundongos Endogâmicos C57BL , Sistema Nervoso Autônomo/fisiologia , Sistema Nervoso Autônomo/citologia
3.
Am J Physiol Regul Integr Comp Physiol ; 323(4): R512-R531, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35993562

RESUMO

In mammals, the pontine noradrenergic system influences nearly every aspect of central nervous system function. A subpopulation of pontine noradrenergic neurons, called A5, are thought to be important in the cardiovascular response to physical stressors, yet their function is poorly defined. We hypothesized that activation of A5 neurons drives a sympathetically mediated increase in blood pressure (BP). To test this hypothesis, we conducted a comprehensive assessment of the cardiovascular effects of chemogenetic stimulation of A5 neurons in male and female adult rats using intersectional genetic and anatomical targeting approaches. Chemogenetic stimulation of A5 neurons in freely behaving rats elevated BP by 15 mmHg and increased cardiac baroreflex sensitivity with a negligible effect on resting HR. Importantly, A5 stimulation had no detectable effect on locomotor activity, metabolic rate, or respiration. Under anesthesia, stimulation of A5 neurons produced a marked elevation in visceral sympathetic nerve activity (SNA) and no change in skeletal muscle SNA, showing that A5 neurons preferentially stimulate visceral SNA. Interestingly, projection mapping indicates that A5 neurons target sympathetic preganglionic neurons throughout the spinal cord and parasympathetic preganglionic neurons throughout in the brainstem, as well as the nucleus of the solitary tract, and ventrolateral medulla. Moreover, in situ hybridization and immunohistochemistry indicate that a subpopulation of A5 neurons coreleases glutamate and monoamines. Collectively, this study suggests A5 neurons are a central modulator of autonomic function with a potentially important role in sympathetically driven redistribution of blood flow from the visceral circulation to critical organs and skeletal muscle.


Assuntos
Neurônios Adrenérgicos , Neurônios Adrenérgicos/fisiologia , Animais , Pressão Sanguínea/fisiologia , Feminino , Glutamatos/farmacologia , Masculino , Mamíferos , Ponte/fisiologia , Ratos , Sistema Nervoso Simpático/fisiologia
4.
Am J Physiol Endocrinol Metab ; 320(2): E379-E389, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356995

RESUMO

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1loxP/loxP or AgRP-Cre; LRP1loxP/loxP). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.


Assuntos
Ingestão de Alimentos , Metabolismo Energético , Neurônios GABAérgicos/patologia , Leptina/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Obesidade/patologia , Receptores para Leptina/metabolismo , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Feminino , Neurônios GABAérgicos/metabolismo , Glucose/metabolismo , Homeostase , Resistência à Insulina , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Receptores para Leptina/genética
5.
iScience ; 27(3): 109137, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38420585

RESUMO

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole-cell patch-clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs and is capable of cardioinhibition and robust anxiolysis.

6.
Neuron ; 111(12): 1876-1886.e5, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37086721

RESUMO

The superficial superior colliculus (sSC) carries out diverse roles in visual processing and behaviors, but how these functions are delegated among collicular neurons remains unclear. Here, using single-cell transcriptomics, we identified 28 neuron subtypes and subtype-enriched marker genes from tens of thousands of adult mouse sSC neurons. We then asked whether the sSC's molecular subtypes are tuned to different visual stimuli. Specifically, we imaged calcium dynamics in single sSC neurons in vivo during visual stimulation and then mapped marker gene transcripts onto the same neurons ex vivo. Our results identify a molecular subtype of inhibitory neuron accounting for ∼50% of the sSC's direction-selective cells, suggesting a genetic logic for the functional organization of the sSC. In addition, our studies provide a comprehensive molecular atlas of sSC neuron subtypes and a multimodal mapping method that will facilitate investigation of their respective functions, connectivity, and development.


Assuntos
Neurônios , Colículos Superiores , Animais , Camundongos , Percepção Visual , Cálcio , Perfilação da Expressão Gênica , Vias Visuais
7.
bioRxiv ; 2023 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-38014247

RESUMO

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole cell patch clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs capable of cardioinhibition and robust anxiolysis.

8.
bioRxiv ; 2023 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-38168262

RESUMO

The nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and striated esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. These cardiovagal nAmb neurons may be molecularly and anatomically distinct, but how they differ from other nAmb neurons in the adult brain remains unclear. We therefore classified adult mouse nAmb neurons based on their genome-wide expression profiles, innervation of cardiac ganglia, and ability to control HR. Our integrated analysis of single-nucleus RNA-sequencing data predicted multiple molecular subtypes of nAmb neurons. Mapping the axon projections of one nAmb neuron subtype, Npy2r-expressing nAmb neurons, showed that they innervate cardiac ganglia. Optogenetically stimulating all nAmb vagal efferent neurons dramatically slowed HR to a similar extent as selectively stimulating Npy2r+ nAmb neurons, but not other subtypes of nAmb neurons. Finally, we trained mice to perform voluntary underwater diving, which we use to show Npy2r+ nAmb neurons are activated by the diving response, consistent with a cardiovagal function for this nAmb subtype. These results together reveal the molecular organization of nAmb neurons and its control of heart rate.

9.
J Clin Invest ; 133(24)2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-38099492

RESUMO

Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and ß cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and ß cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher ß cell numbers from decreased ß cell apoptosis drove the increase in ß cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the ß cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in ß cells, which supports decreased ß cell apoptosis and/or increased ß cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes.


Assuntos
Células Secretoras de Insulina , Ilhotas Pancreáticas , Camundongos , Animais , Glicemia/metabolismo , Grelina/genética , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos Knockout , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL
10.
bioRxiv ; 2023 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-36865258

RESUMO

Salient cues, such as the rising sun or the availability of food, play a crucial role in entraining biological clocks, allowing for effective behavioral adaptation and ultimately, survival. While the light-dependent entrainment of the central circadian pacemaker (suprachiasmatic nucleus, SCN) is relatively well defined, the molecular and neural mechanisms underlying entrainment associated with food availability remains elusive. Using single nucleus RNA sequencing during scheduled feeding (SF), we identified a leptin receptor (LepR) expressing neuron population in the dorsomedial hypothalamus (DMH) that upregulates circadian entrainment genes and exhibits rhythmic calcium activity prior to an anticipated meal. We found that disrupting DMHLepR neuron activity had a profound impact on both molecular and behavioral food entrainment. Specifically, silencing DMHLepR neurons, mis-timed exogenous leptin administration, or mis-timed chemogenetic stimulation of these neurons all interfered with the development of food entrainment. In a state of energy abundance, repetitive activation of DMHLepR neurons led to the partitioning of a secondary bout of circadian locomotor activity that was in phase with the stimulation and dependent on an intact SCN. Lastly, we discovered that a subpopulation of DMHLepR neurons project to the SCN with the capacity to influence the phase of the circadian clock. This leptin regulated circuit serves as a point of integration between the metabolic and circadian systems, facilitating the anticipation of meal times.

11.
Sci Adv ; 9(34): eadh9570, 2023 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-37624889

RESUMO

Salient cues, such as the rising sun or availability of food, entrain biological clocks for behavioral adaptation. The mechanisms underlying entrainment to food availability remain elusive. Using single-nucleus RNA sequencing during scheduled feeding, we identified a dorsomedial hypothalamus leptin receptor-expressing (DMHLepR) neuron population that up-regulates circadian entrainment genes and exhibits calcium activity before an anticipated meal. Exogenous leptin, silencing, or chemogenetic stimulation of DMHLepR neurons disrupts the development of molecular and behavioral food entrainment. Repetitive DMHLepR neuron activation leads to the partitioning of a secondary bout of circadian locomotor activity that is in phase with the stimulation and dependent on an intact suprachiasmatic nucleus (SCN). Last, we found a DMHLepR neuron subpopulation that projects to the SCN with the capacity to influence the phase of the circadian clock. This direct DMHLepR-SCN connection is well situated to integrate the metabolic and circadian systems, facilitating mealtime anticipation.


Assuntos
Relógios Circadianos , Receptores para Leptina , Receptores para Leptina/genética , Hipotálamo , Núcleo Supraquiasmático , Aclimatação
12.
bioRxiv ; 2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37961449

RESUMO

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons increases feeding and body weight and reduces liraglutide's satiating effects. Our results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.

13.
Cell Rep ; 39(11): 110962, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35705034

RESUMO

Motor control of the striated esophagus originates in the nucleus ambiguus (nAmb), a vagal motor nucleus that also contains upper airway motor neurons and parasympathetic preganglionic neurons for the heart and lungs. We disambiguate nAmb neurons based on their genome-wide expression profiles, efferent circuitry, and ability to control esophageal muscles. Our single-cell RNA sequencing analysis predicts three molecularly distinct nAmb neuron subtypes and annotates them by subtype-specific marker genes: Crhr2, Vipr2, and Adcyap1. Mapping the axon projections of the nAmb neuron subtypes reveals that Crhr2nAmb neurons innervate the esophagus, raising the possibility that they control esophageal muscle function. Accordingly, focal optogenetic stimulation of cholinergic Crhr2+ fibers in the esophagus results in contractions. Activating Crhr2nAmb neurons has no effect on heart rate, a key parasympathetic function of the nAmb, whereas activating all of the nAmb neurons robustly suppresses heart rate. Together, these results reveal a genetically defined circuit for motor control of the esophagus.


Assuntos
Bulbo , Nervo Vago , Frequência Cardíaca/fisiologia , Bulbo/fisiologia , Neurônios Motores , Músculo Liso , Nervo Vago/fisiologia
14.
Elife ; 112022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36342840

RESUMO

Axons of retinal ganglion cells (RGCs) play critical roles in the development of inhibitory circuits in visual thalamus. We previously reported that RGC axons signal astrocytes to induce the expression of fibroblast growth factor 15 (FGF15), a motogen required for GABAergic interneuron migration into visual thalamus. However, how retinal axons induce thalamic astrocytes to generate Fgf15 and influence interneuron migration remains unknown. Here, we demonstrate that impairing RGC activity had little impact on interneuron recruitment into mouse visual thalamus. Instead, our data show that retinal-derived sonic hedgehog (SHH) is essential for interneuron recruitment. Specifically, we show that thalamus-projecting RGCs express SHH and thalamic astrocytes generate downstream components of SHH signaling. Deletion of RGC-derived SHH leads to a significant decrease in Fgf15 expression, as well as in the percentage of interneurons recruited into visual thalamus. Overall, our findings identify a morphogen-dependent neuron-astrocyte signaling mechanism essential for the migration of thalamic interneurons.


Assuntos
Proteínas Hedgehog , Interneurônios , Camundongos , Animais , Proteínas Hedgehog/metabolismo , Interneurônios/fisiologia , Tálamo/metabolismo , Axônios/metabolismo , Células Ganglionares da Retina/metabolismo
15.
Cell Rep ; 41(9): 111718, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36450244

RESUMO

Obesity comorbidities such as diabetes and cardiovascular disease are pressing public health concerns. Overconsumption of calories leads to weight gain; however, neural mechanisms underlying excessive food consumption are poorly understood. Here, we demonstrate that dopamine receptor D1 (Drd1) expressed in the agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons of the arcuate hypothalamus is required for appropriate responses to a high-fat diet (HFD). Stimulation of Drd1 and AgRP/NPY co-expressing arcuate neurons is sufficient to induce voracious feeding. Delivery of a HFD after food deprivation acutely induces dopamine (DA) release in the ARC, whereas animals that lack Drd1 expression in ARCAgRP/NPY neurons (Drd1AgRP-KO) exhibit attenuated foraging and refeeding of HFD. These results define a role for the DA input to the ARC that encodes acute responses to food and position Drd1 signaling in the ARCAgRP/NPY neurons as an integrator of the hedonic and homeostatic neuronal feeding circuits.


Assuntos
Dopamina , Neurônios , Animais , Proteína Relacionada com Agouti , Alimentos , Transdução de Sinais , Neuropeptídeo Y
16.
Neuron ; 109(13): 2106-2115.e4, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34077742

RESUMO

The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.


Assuntos
Encéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Sistema Nervoso Entérico/metabolismo , Mucosa Gástrica/metabolismo , Neurônios Motores/metabolismo , Estômago/inervação , Nervo Vago/metabolismo , Animais , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/metabolismo
17.
Nat Commun ; 11(1): 4410, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879310

RESUMO

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCNVIP) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCNVIP neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCNVIP neurons may regulate LMA rhythms. In vivo photometry revealed that while SCNVIP neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCNVIP neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCNVIP neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCNVIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCNVIP subtypes.


Assuntos
Ritmo Circadiano/fisiologia , Neurônios/metabolismo , Núcleo Supraquiasmático , Animais , Mapeamento Encefálico , Relógios Circadianos/fisiologia , Locomoção/fisiologia , Camundongos , Optogenética/métodos , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/metabolismo
18.
Curr Biol ; 30(2): 196-208.e8, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31902720

RESUMO

The widespread availability of energy-dense, rewarding foods is correlated with the increased incidence of obesity across the globe. Overeating during mealtimes and unscheduled snacking disrupts timed metabolic processes, which further contribute to weight gain. The neuronal mechanism by which the consumption of energy-dense food restructures the timing of feeding is poorly understood. Here, we demonstrate that dopaminergic signaling within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, disrupts the timing of feeding, resulting in overconsumption of food. D1 dopamine receptor (Drd1)-null mice are resistant to diet-induced obesity, metabolic disease, and circadian disruption associated with energy-dense diets. Conversely, genetic rescue of Drd1 expression within the SCN restores diet-induced overconsumption, weight gain, and obesogenic symptoms. Access to rewarding food increases SCN dopamine turnover, and elevated Drd1-signaling decreases SCN neuronal activity, which we posit disinhibits downstream orexigenic responses. These findings define a connection between the reward and circadian pathways in the regulation of pathological calorie consumption.


Assuntos
Dopamina/fisiologia , Transdução de Sinais , Núcleo Supraquiasmático/fisiologia , Aumento de Peso/fisiologia , Animais , Ingestão de Alimentos , Comportamento Alimentar , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Recompensa , Aumento de Peso/genética
19.
Neuron ; 102(3): 653-667.e6, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30879785

RESUMO

SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVHSIM1 population, melanocortin-4 receptor-expressing (PVHMC4R) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVHSIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVHPDYN) neurons, which notably lack MC4Rs, function independently and additively with PVHMC4R neurons to account for the totality of PVHSIM1 neuron-mediated satiety. Moreover, PVHPDYN neurons are necessary for prevention of obesity in an independent but equipotent manner to PVHMC4R neurons. While PVHPDYN and PVHMC4R neurons both project to the parabrachial complex (PB), they synaptically engage distinct efferent nodes, the pre-locus coeruleus (pLC), and central lateral parabrachial nucleus (cLPBN), respectively. PB-projecting PVHPDYN neurons, like PVHMC4R neurons, receive input from interoceptive ARCAgRP neurons, respond to caloric state, and are sufficient and necessary to control food intake. This expands the CNS satiety circuitry to include two non-overlapping PVH to hindbrain circuits.


Assuntos
Comportamento Alimentar/fisiologia , Neurônios/citologia , Obesidade/fisiopatologia , Núcleo Hipotalâmico Paraventricular/citologia , Resposta de Saciedade/fisiologia , Proteína Relacionada com Agouti/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Metabolismo Energético , Encefalinas/metabolismo , Locus Cerúleo/citologia , Locus Cerúleo/metabolismo , Locus Cerúleo/fisiologia , Camundongos , Neurônios/metabolismo , Neurônios/fisiologia , Núcleos Parabraquiais/citologia , Núcleos Parabraquiais/metabolismo , Núcleos Parabraquiais/fisiologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiologia , Precursores de Proteínas/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Proteínas Repressoras/metabolismo
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