Diaz-Pacheco, S. | bioRxiv Science

bioRxiv2023

A Role For Astrocytic Insulin-Like Growth Factor I Receptors In The Response To Ischemic Insult

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults by deleting it using tamoxifen-regulated Cre deletion in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detetected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion, including aquaporin 4, complement 1q subunit a, early growth response protein 1, and C-C motif chemokine ligand 2, were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

neuroscience↗

bioRxiv2021

INTEROCEPTIVE INFORMATION OF PHYSICAL VIGOR: OREXIN NEURONS GAUGE CIRCULATING IGF-I FOR MOTIVATIONAL MOTOR OUTPUT

The brain relies on interoceptive feedback signals to regulate bodily functions. Mice with low serum IGF-1 levels (LID mice) exhibit reduced spontaneous running, a behavior that normalizes after sustained systemic IGF-1 treatment. This observation led us to hypothesize that circulating IGF-1--a key regulator of skeletal muscle and bone mass that crosses the blood-brain barrier during physical activity--may convey body vigor information to the brain. Since hypothalamic orexin neurons, that are involved in regulating physical activity, express IGF-1 receptors (IGF-1R) and are modulated by this growth factor, we hypothesized that these neurons might gauge circulating IGF-1 levels to modulate physical activity. Indeed, inactivation of IGF-1R in mouse orexin neurons (Firoc mice) was associated to less time spent in free running. These mice maintain physical fitness but display altered mood and are less sensitive to the rewarding actions of exercise. Further, in response to exercise, Firoc mice showed limited c-fos activation of hypothalamic orexin neurons and monoaminergic neurons of the ventro-tegmental area (VTA) in the brainstem. This area is involved in the rewarding component of exercise that seems to be modulated by IGF-1, as mice receiving systemic IGF-1 showed increased c-fos expression in VTA neurons, while mice with reduced IGF-1R expression in VTA neurons showed no improved mood after exercise. Collectively, these results suggest that circulating IGF-1 is gauged by orexin neurons to modulate physical activity, and that VTA neurons convey the rewarding properties of exercise through direct actions of IGF-1 on them. Hence, serum IGF-1 may constitute an interoceptive signal acting onto orexin/VTA neurons to modulate physical activity according to physical vigor (muscle and bone mass).

neuroscience↗