Cholinergic and cortical activity is recovered by insulin-like growth factor I in aging mice brains.

Abstract

It is known that IGF-I facilitates a waking state and modulates sleep architecture through the activation of orexinergic neurons. However, IGF-I may activate other neurons that may facilitate waking states, such as the locus coeruleus and the basal forebrain, orchestrating an intricate role in brain and cortical regulation. The BF is a structure that contains cholinergic neurons that project entirely to the brain cortex and support cerebral activity and cognitive function. Besides, cholinergic dysfunction through aging has been related to AD and cognitive decline. This work aims to determine if IGF-I has a modulatory role in cortical and BF activity, facilitating waking state by activating cholinergic neurons in young and old mice. We use transgenic mice models with channel-rhodopsin specifically in cholinergic neurons, and C57 (less than 6 months and over 22 months of age). We take advantage of immunofluorescence, electrophysiology and optogenetics experiments. We demonstrate that ChAT neurons have IGF-I receptors and respond to intraparenchymal IGF-I diffusion, facilitating an increased firing rate in young but not in old mice. This facilitation of cholinergic activity by IGF-I increases the EEG activation (faster activity increases in the power spectrum). The effect depends on muscarinic receptors because their activity is blocked by atropine. Also, IGF-I facilitates theta rhythm generation that is a hallmark of the waking state in young rodents. After IGF-I chronic treatment, the waking state's effects, ChAT neuronal response, and cortical activity was recovered in old mice. Consequently with our results, IGF-I can activate wakefulness by synchronously activating structures that favor it. This finding may suggest that IGF-I or mimetic drugs of this peptide would favor cholinergic activity during aging.