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.
Highlights
Chronic stress can lead to different mental disorders, manifesting as anxiety, depression, panic, and other symptoms [1,2,3]
We previously revealed a BNSTSOM-VMHSF-1-NTSVglut2 neural circuit that regulates the activities of the peripheral sympathetic nervous system and mediates bone loss caused by chronic stress [26]
Expression of c-fos in the ventromedial hypothalamus (VMH) brain area of the stressed group was significantly higher than that in the control group (Figures 1(h) and 1(i)), suggesting that neural activity in the VMH nucleus is involved in the maintenance of the anxiety state and decrease in bone mineral density (BMD)
Summary
Chronic stress can lead to different mental disorders, manifesting as anxiety, depression, panic, and other symptoms [1,2,3]. Clinical studies have shown that the probability of osteoporosis and fractures in patients with anxiety and depression is significantly higher than that in normal controls [12,13,14], suggesting that an individual’s anxiety state is closely related to bone metabolism. The VMH is closely related to mood disorders such as anxiety and depression. Studies have shown that VMH brain activity is significantly increased in cats with anxiety-like symptoms [15, 16], while blocking VMH glutamate signals can effectively reduce anxiety in animals [17], suggesting that the VMH is involved in the regulation of mood disorders. Subsequent studies have demonstrated that leptin and serotonin act on SF-1 neurons to regulate bone metabolism by regulating sympathetic nerve
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