RESUMO
The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.
Assuntos
Manutenção do Peso Corporal/genética , Manutenção do Peso Corporal/fisiologia , Cerebelo/fisiologia , Alimentos , Biossíntese de Proteínas , Genética Reversa , Resposta de Saciedade/fisiologia , Adulto , Animais , Regulação do Apetite/genética , Regulação do Apetite/fisiologia , Núcleos Cerebelares/citologia , Núcleos Cerebelares/fisiologia , Cerebelo/citologia , Sinais (Psicologia) , Dopamina/metabolismo , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Homeostase , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/metabolismo , Neurônios/fisiologia , Obesidade/genética , Filosofia , Adulto JovemRESUMO
Although dexterity relies on the constant transmission of sensory information, unchecked feedback can be disruptive. Yet how somatosensory feedback from the hands is regulated and whether this modulation influences movement remain unclear. We found that mouse tactile afferents recruit neurons in the brainstem cuneate nucleus, whose activity is modulated by distinct classes of local inhibitory neurons. Manipulation of these inhibitory circuits suppresses or enhances the transmission of tactile information, which affects manual behaviors. Top-down cortical pathways innervate cuneate in a complementary pattern, with somatosensory cortical neurons targeting the core tactile region of cuneate and a large rostral cortical population driving feed-forward inhibition of tactile transmission through an inhibitory shell. These findings identify a circuit basis for tactile feedback modulation that enables the effective execution of dexterous movement.
