Periodic Reporting for period 5 - FeedHypNet (Dynamic regulation of feeding behaviors in health and disease by top-down control of hypothalamic networks)
Período documentado: 2023-04-01 hasta 2024-03-31
Feeding behaviors represent a complex set of crucial for survival abilities required to meet upcoming nutritional demands. Eating disorders, such as anorexia nervosa, are widespread, difficult to treat and extremely dangerous, displaying the highest mortality rate of all psychiatric disorders and a very high relapse rate. Mechanisms of onset, progression and relapse of eating disorders are unknown. Feeding behaviors are regulated by hypothalamus, an evolutionary conservative brain region. While a role of neurochemically defined hypothalamic neurons in feeding has been recently studied, little is known about an adaptive regulation of hypothalamus by extrahypothalamic inputs. Further, it is not known how dynamic signaling in hypothalamus upon changing metabolic and environmental demands is organized to generate consistent adaptive behavior. The overarching goal of the action is to provide insight into neural mechanisms of healthy and pathological feeding behaviors. To do so we performed recordings of neuronal activity using electrophysiology and calcium imaging, as well as selectively manipulated neuronal activity using optogenetics.We identified neuronal circuits mediating feeding behavior in health and pathology, and thus gained insights into neuronal mechanisms of eating disorders and obesity.
We investigated a role of neural circuitries that translate cognitive-related information to the lateral hypothalamus during adaptive feeding behaviors. We found that inputs from the prefrontal cortex regulate activity of hypothalamic neurons and affect feeding-related behavior. Further, we investigated how metabolic demands changes upon reduction of food intake, or an exposure to a high-fat diet, affect the signaling from the top-down brain regions to the hypothalamus. We investigated these changes and the behavioral output at various time scales - from subsecond timing of neuronal network oscillations to changes of activity of the same, genetically defined neurons in the lateral hypothalamus across weeks. Further, we investigated how signaling in hypothalamus changes during development of anorexia nervosa symptoms and study consequences of optogenetically restored physiological signaling. We found that neuronal populations in the lateral hypothalamus signal alternative future behaviors, encode the one most likely to be selected and enable rapid coordination with cognitive and reward-processing circuitries, commanding adaptive eating behaviors and social contact. Further, we showed that two neuronal populations of the lateral hypothalamus balance nutritional and social needs: one of them limited feeding or drinking and promoted social interaction despite hunger or thirst whereas another one preferentially encoded water despite hunger pressure and promoted water seeking, while relegating social needs. Thus, lateral hypothalamic neuronal populations act in a complementary manner to enable the flexible fulfillment of multiple essential needs.We published the results of this project in top journals and distributed press releases. Both papers sparked considerable media interest. We also presented results of this project on major conferences.
This innovative and interdisciplinary approach enables identification of neuronal circuits mediating feeding behavior in health and pathology, and thus gain insights into neuronal mechanisms of eating disorders.