Astrocytes in the Ventromedial Hypothalamus Involve Chronic Stress-Induced Anxiety and Bone Loss in Mice

Abstract

Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional “glial-neuron microcircuit” in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.

Cav3.1-driven bursting firing in ventromedial hypothalamic neurons exerts dual control of anxiety-like behavior and energy expenditure

“…Secondly, GABAergic neural circuits and astrocytes have been found in the VMH and are implicated in regulating anxiety and metabolism, and the frequency of inhibitory postsynaptic current (IPSC) of VMH neurons increase after chronic stress [ 45 – 47 ]. Optogenetically induced inhibitory inputs caused burst firing in thalamocortical neurons [ 48 ], thus enhanced IPSC input may promote the generation of burst firing in dmVMH neurons after chronic stress.…”

Ventromedial hypothalamus relays chronic stress inputs and exerts bidirectional regulation on anxiety state and related sympathetic activity

“…For all stereotaxic surgeries, 12-16-week-old mice were anesthetized by an intraperitoneal injection of pentobarbital sodium (0.2% in saline, 1 mL/100 g). The stereotaxic surgical procedures were performed based on previous research (Liu et al, 2021). To target the VMH, injection coordinates relative to Bregma: antero-posterior −1.58 mm, mediolateral ± 0.3 mm, and dorsoventral −5.5 mm.…”