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1.
Cell ; 179(5): 1129-1143.e23, 2019 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-31730854

RESUMEN

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding.


Asunto(s)
Conducta Alimentaria/fisiología , Fenómenos Genéticos , Células Receptoras Sensoriales/fisiología , Nervio Vago/fisiología , Proteína Relacionada con Agouti/metabolismo , Animales , Encéfalo/fisiología , Tracto Gastrointestinal/inervación , Marcadores Genéticos , Mecanorreceptores/metabolismo , Ratones , Nervio Vago/anatomía & histología , Vísceras/inervación
2.
Nature ; 568(7750): 98-102, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30918408

RESUMEN

Satiation is the process by which eating and drinking reduce appetite. For thirst, oropharyngeal cues have a critical role in driving satiation by reporting to the brain the volume of fluid that has been ingested1-12. By contrast, the mechanisms that relay the osmolarity of ingested fluids remain poorly understood. Here we show that the water and salt content of the gastrointestinal tract are precisely measured and then rapidly communicated to the brain to control drinking behaviour in mice. We demonstrate that this osmosensory signal is necessary and sufficient for satiation during normal drinking, involves the vagus nerve and is transmitted to key forebrain neurons that control thirst and vasopressin secretion. Using microendoscopic imaging, we show that individual neurons compute homeostatic need by integrating this gastrointestinal osmosensory information with oropharyngeal and blood-borne signals. These findings reveal how the fluid homeostasis system monitors the osmolarity of ingested fluids to dynamically control drinking behaviour.


Asunto(s)
Encéfalo/fisiología , Ingestión de Líquidos/fisiología , Tracto Gastrointestinal/fisiología , Neuronas/fisiología , Saciedad/fisiología , Sed/fisiología , Animales , Encéfalo/citología , Femenino , Neuronas GABAérgicas/metabolismo , Tracto Gastrointestinal/inervación , Glutamatos/metabolismo , Masculino , Ratones , Orofaringe/inervación , Orofaringe/fisiología , Concentración Osmolar , Prosencéfalo/metabolismo , Nervio Vago/fisiología , Vasopresinas/metabolismo
3.
Proc Natl Acad Sci U S A ; 108(10): 4206-11, 2011 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-21368124

RESUMEN

Signaling through N-methyl-D-aspartate-type glutamate receptors (NMDARs) is essential for the development of behavioral sensitization to psychostimulants such as amphetamine (AMPH). However, the cell type and brain region in which NMDAR signaling is required for AMPH sensitization remain unresolved. Here we use selective inactivation of Grin1, the gene encoding the essential NR1 subunit of NMDARs, in dopamine neurons or their medium spiny neuron (MSN) targets, to address this issue. We show that NMDAR signaling in dopamine neurons is not required for behavioral sensitization to AMPH. Conversely, removing NMDARs from MSNs that express the dopamine D1 receptor (D1R) significantly attenuated AMPH sensitization, and conditional, virus-mediated restoration of NR1 in D1R neurons in the nucleus accumbens (NAc) of these animals rescued sensitization. Interestingly, sensitization could also be restored by virus-mediated inactivation of NR1 in all remaining neurons in the NAc of animals lacking NMDARs on D1R neurons, or by removing NMDARs from all MSNs. Taken together, these data indicate that unbalanced loss of NMDAR signaling in D1R MSNs alone prevents AMPH sensitization, whereas a balanced loss of NMDARs from both D1R and dopamine D2 receptor-expressing (D2R) MSNs is permissive for sensitization.


Asunto(s)
Anfetaminas/farmacología , Neuronas/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Ratones , Ratones Noqueados , Neuronas/metabolismo , Transducción de Señal
4.
bioRxiv ; 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38562891

RESUMEN

Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity in vivo. Using fiber photometry, we observed that both GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) agonism acutely inhibit AgRP neuron activity in fasted mice and reduce the response of AgRP neurons to food. Moreover, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, suggesting that AgRP neuron inhibition is necessary for the full appetite-suppressing effects of incretin-based therapeutics. Finally, we found that GIP but not GLP-1 is necessary for nutrient-mediated AgRP neuron inhibition, representing a novel physiologic role for GIP in maintaining energy balance. Taken together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies. Understanding these drugs' mechanisms of action is crucial for the development of next-generation obesity pharmacotherapies with an improved therapeutic profile.

5.
Cell Rep ; 43(2): 113675, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38224492

RESUMEN

Rapid gut-brain communication is critical to maintain energy balance and is disrupted in diet-induced obesity. In particular, the role of carbohydrate overconsumption in the regulation of interoceptive circuits in vivo requires further investigation. Here, we report that an obesogenic high-sucrose diet (HSD) selectively blunts silencing of hunger-promoting agouti-related protein (AgRP) neurons following intragastric delivery of glucose, whereas we previously showed that overconsumption of a high-fat diet (HFD) selectively attenuates lipid-induced neural silencing. By contrast, both HSD and HFD reversibly dampen rapid AgRP neuron inhibition following chow presentation and promote intake of more palatable foods. Our findings reveal that excess sugar and fat pathologically modulate feeding circuit activity in both macronutrient-dependent and -independent ways and thus may additively exacerbate obesity.


Asunto(s)
Neuronas , Sacarosa , Humanos , Proteína Relacionada con Agouti/genética , Obesidad , Ingestión de Alimentos
6.
Neuropsychopharmacology ; 48(4): 690-699, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36380221

RESUMEN

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.


Asunto(s)
Antipsicóticos , Esquizofrenia , Ratones , Animales , Esquizofrenia/tratamiento farmacológico , Dopamina , Haloperidol/farmacología , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Anfetamina/farmacología , Anfetamina/uso terapéutico , Ratones Noqueados , Cognición , Neuronas Dopaminérgicas
7.
J Neurosci ; 31(31): 11362-9, 2011 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-21813695

RESUMEN

NMDA receptors (NMDARs) contribute to phasic transmission and synaptic plasticity and are thought to be important for learning. To better understand where NMDAR signaling is necessary for learning, we combined viral genetic strategies with genetic mouse models to investigate the contribution of NMDARs in the dopamine system to appetitive Pavlovian conditioning. NMDAR signaling in dopamine neurons was not required for Pavlovian conditioning; however, NMDARs in D(1) dopamine receptor (D(1)R)-expressing medium spiny neurons (MSNs), which receive input from dopamine neurons, were critical for this type of learning. NMDAR signaling was also required in brain regions that project to dopamine neurons, because removing NMDARs from afferent neurons to the ventral tegmental area (VTA) also prevented learning. This effect was likely attributable to loss of NMDAR signaling in the neurons of the prefrontal cortex (PFC), because learning could be restored in these animals by rescuing NMDAR expression in the PFC. Moreover, removing NMDARs exclusively from the PFC also prevented learning. Our findings suggest that NMDARs in neurons that project to and receive projections from the VTA are necessary for Pavlovian conditioning and specifically implicate the PFC and D(1)R-expressing MSNs in associative learning.


Asunto(s)
Conducta Apetitiva/fisiología , Ganglios Basales/metabolismo , Condicionamiento Clásico/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Recompensa , Transducción de Señal/fisiología , Análisis de Varianza , Animales , Corteza Cerebral/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/deficiencia , Femenino , Proteínas Fluorescentes Verdes/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vías Nerviosas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/deficiencia , Área Tegmental Ventral/citología
8.
Elife ; 92020 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-32720646

RESUMEN

Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.


Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Peso Corporal/fisiología , Grasas de la Dieta/metabolismo , Ingestión de Alimentos/fisiología , Homeostasis/fisiología , Hambre/fisiología , Obesidad/fisiopatología , Animales , Dieta Alta en Grasa , Humanos , Ratones , Modelos Animales
9.
Genesis ; 46(7): 357-67, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18615733

RESUMEN

The medium spiny neurons (MSNs), which comprise the direct and indirect output pathways from the striatum, use gamma-aminobutyric acid (GABA) as their major fact-acting neurotransmitter. We generated mice carrying a conditional allele of the Gad1 gene, which encodes GAD67, one of the two enzymes responsible for GABA biosynthesis, and bred them to mice expressing Cre recombinase at the dopamine D1 receptor locus (Drd1a) to selectively reduce GABA synthesis in the direct output pathway from the striatum. We show that these mice are deficient in some types of motor skills, but normal for others, suggesting a differential role for GABA release from D1 receptor-containing neurons.


Asunto(s)
Cuerpo Estriado/metabolismo , Glutamato Descarboxilasa/deficiencia , Actividad Motora/genética , Receptores Dopaminérgicos/metabolismo , Ácido gamma-Aminobutírico/biosíntesis , Animales , Benzazepinas , Southern Blotting , Western Blotting , Inmunohistoquímica , Ratones , Ratones Transgénicos
10.
Nat Metab ; 5(9): 1452-1453, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37592009
11.
Neuron ; 97(4): 739-741, 2018 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-29470967

RESUMEN

Remarkably few hormones have been identified that stimulate appetite. The recent discovery of asprosin, a hormone that activates AgRP neurons to increase food intake and body weight, begins to fill this gap (Duerrschmid et al., 2017; Romere et al., 2016).


Asunto(s)
Regulación del Apetito , Proteínas de Microfilamentos/fisiología , Neuronas/fisiología , Fragmentos de Péptidos/fisiología , Hormonas Peptídicas/fisiología , Proteína Relacionada con Agouti/fisiología , Animales , Ingestión de Alimentos , Fibrilina-1 , Ghrelina/fisiología , Humanos , Ratones Transgénicos
13.
Neuron ; 96(2): 461-475.e5, 2017 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-29024666

RESUMEN

Communication between the gut and brain is critical for homeostasis, but how this communication is represented in the dynamics of feeding circuits is unknown. Here we describe nutritional regulation of key neurons that control hunger in vivo. We show that intragastric nutrient infusion rapidly and durably inhibits hunger-promoting AgRP neurons in awake, behaving mice. This inhibition is proportional to the number of calories infused but surprisingly independent of macronutrient identity or nutritional state. We show that three gastrointestinal signals-serotonin, CCK, and PYY-are necessary or sufficient for these effects. In contrast, the hormone leptin has no acute effect on dynamics of these circuits or their sensory regulation but instead induces a slow modulation that develops over hours and is required for inhibition of feeding. These findings reveal how layers of visceral signals operating on distinct timescales converge on hypothalamic feeding circuits to generate a central representation of energy balance.


Asunto(s)
Química Encefálica/fisiología , Encéfalo/fisiología , Conducta Alimentaria/fisiología , Tracto Gastrointestinal/fisiología , Hambre/fisiología , Red Nerviosa/fisiología , Animales , Femenino , Tracto Gastrointestinal/química , Tracto Gastrointestinal/inervación , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Obesos , Ratones Transgénicos , Red Nerviosa/química , Vías Nerviosas/química , Vías Nerviosas/fisiología , Optogenética/métodos
14.
Nat Metab ; 3(9): 1142-1143, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34552270
16.
PLoS One ; 6(11): e28168, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22132236

RESUMEN

The striatum is composed predominantly of medium spiny neurons (MSNs) that integrate excitatory, glutamatergic inputs from the cortex and thalamus, and modulatory dopaminergic inputs from the ventral midbrain to influence behavior. Glutamatergic activation of AMPA, NMDA, and metabotropic receptors on MSNs is important for striatal development and function, but the roles of each of these receptor classes remain incompletely understood. Signaling through NMDA-type glutamate receptors (NMDARs) in the striatum has been implicated in various motor and appetitive learning paradigms. In addition, signaling through NMDARs influences neuronal morphology, which could underlie their role in mediating learned behaviors. To study the role of NMDARs on MSNs in learning and in morphological development, we generated mice lacking the essential NR1 subunit, encoded by the Grin1 gene, selectively in MSNs. Although these knockout mice appear normal and display normal 24-hour locomotion, they have severe deficits in motor learning, operant conditioning and active avoidance. In addition, the MSNs from these knockout mice have smaller cell bodies and decreased dendritic length compared to littermate controls. We conclude that NMDAR signaling in MSNs is critical for normal MSN morphology and many forms of learning.


Asunto(s)
Aprendizaje , Neuronas/patología , Receptores de N-Metil-D-Aspartato/deficiencia , Animales , Reacción de Prevención , Tamaño Corporal , Condicionamiento Operante , Miedo , Locomoción , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora , Receptores de N-Metil-D-Aspartato/metabolismo , Análisis y Desempeño de Tareas
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