
Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure
Author(s) -
Miloš Stanojlović,
Jean Pierre Pallais Yllescas,
Vijaya Mavanji,
Catherine M. Kotz
Publication year - 2019
Publication title -
american journal of physiology. regulatory, integrative and comparative physiology/american journal of physiology. regulatory, integrative, and comparative physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.266
H-Index - 175
eISSN - 1522-1490
pISSN - 0363-6119
DOI - 10.1152/ajpregu.00383.2018
Subject(s) - orexin , elevated plus maze , lateral hypothalamus , medicine , stimulation , orexin a , endocrinology , neuroscience , anxiety , biology , receptor , neuropeptide , psychiatry
Aging affects numerous physiological processes, as well as behavior. A large number of these processes are regulated, at least partially, by hypothalamic orexin neurons, and orexin tone may decrease with normal aging. In this study, we hypothesized that designer receptors exclusively activated by designer drugs (DREADD) stimulation of orexin neuronal activity will ameliorate the effect of aging on behavioral and metabolic alterations in young and middle-aged mice. DREADD targeting was achieved by stereotaxic injection of AAV vectors (AAV2-hSyn-DIO-hM3D(G q )-mCherry) into the lateral hypothalamus of 5- and 12-mo old orexin-cre female mice and was confirmed by immunohistochemistry (IHC) analysis of orexin A and mCherry expression. After recovery, animals were subjected to a behavioral test battery consisting of the elevated plus maze (EPM), open field (OFT), and novel object recognition tests (NORT) to assess effects of aging on anxiety-like behavior, general locomotion, and working memory. A comprehensive laboratory animal monitoring system (CLAMS) was used to measure spontaneous physical activity (SPA) and energy expenditure (EE). The results indicate that activation of orexin neurons mitigates aging-induced reductions in anxiety-like behavior in middle-aged mice ( P < 0.005) and increases locomotion in both young and middle-aged mice ( P < 0.05). Activation of orexin neurons increases SPA ( P < 0.01) and EE ( P < 0.005) in middle-aged mice, restoring the levels to that observed in young animals. Results from this study identify orexin neurons as potential therapeutic targets for age-related impairments in cognitive and anxiety-related behavior, and energy balance.