Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders

Summary

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone’s effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.

Graphical abstract

Highlights

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  Acute western diet impairs memory performance, which is reversed by pregnenolone

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  Pregnenolone synthesis interference in POMC neurons causes cognitive dysfunction

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  POMC pregnenolone mediates memory function via hippocampal mechanisms

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  Pregnenolone in the CSF of individuals with unhealthy obesity correlates with cognitive score

Abstract

Ramírez et al. show that reduced hypothalamic pregnenolone levels, in the context of metabolic diseases, are associated with cognitive deterioration. POMC neuron-derived pregnenolone is a key mediator of cognition, but not metabolism, acting via hippocampal mechanisms. These results identify an unsuspected role for POMC neuron-derived pregnenolone in memory performance.