Interoceptive Information of Physical Vigor: Orexin Neurons Gauge Circulating Igf-I for Motivational Motor Output

Abstract

Brain regulation of bodily functions requires interoceptive feedback signals carrying information about the periphery. As mice with low serum IGF-I levels (LID mice) show reduced spontaneous physical activity, we speculated that body vigor information might be conveyed by circulating IGF-I, a regulator of skeletal muscle and bone mass that enters the brain during physical activity. Since hypothalamic orexin neurons, that are involved in regulating physical activity, express IGF-I receptors (IGF-IR), we hypothesized that these neurons might gauge circulating IGF-I levels. Inactivation of IGF-IR in mouse orexin neurons (Firoc mice) reduced spontaneous activity. Firoc mice maintain normal physical fitness but show anxiety- and depressive-like behaviors that seems to interfere with the rewarding effects of exercise, as they were less sensitive to the rewarding actions of exercise. Further, in response to exercise, Firoc mice showed reduced activation of hypothalamic orexin neurons and ventro-tegmental area (VTA) monoaminergic neurons, as indicated by c-fos staining. Collectively, these results suggest that circulating IGF-I is gauged by orexin neurons to modulate physical activity in part by stimulation of the VTA to motivate motor output. Hence, serum IGF-I may constitute a feedback signal, informing orexin neurons to adapt physical activity to physical vigor.

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology

“…These mice showed normal working memory, though ( Noriega-Prieto et al ., 2021 ). Intriguingly, absence of IGF-IR in neurons alters mood and social interactions, together with cognitive disturbances ( Zegarra-Valdivia et al ., 2021 ; Fernandez de Sevilla et al ., 2022 ). Finally, combined loss of IR and IGF-IR in all brain cells within specific regions results in both mood and cognitive disturbances ( Soto et al ., 2019 ).…”