A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss

Yang, Fan; Yh, Liu; Chen, Shan-Ping; Dai, Zhongquan; Yang, Dazhi; Gao, Dashuang; Shao, Jie; Wang, Yuyao; Wang, Ting; Zhang, Zhijian; Lu, Zhigang; Lu, William W.; Li, Yinghui; Wang, Liping

doi:10.1172/jci136105

Cited by 45 publications

(50 citation statements)

References 63 publications

(79 reference statements)

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“…Chronic Stress-Induced Anxiety and Bone Loss Promote cfos Expression in VMH Nuclei. We previously identified a BNST-VMH-NTS neural circuit that mediates chronic stress-induced bone loss, whereby the VMH integrates "anxiety information" from the BNST and "bone regulation information" from the NTS [26]. To investigate the role of the VMH in chronic stress-induced anxiety and bone loss, we established a chronic unpredictable mild stress-induced anxiety model in mice.…”

Section: Resultsmentioning

confidence: 99%

“…The VMH plays a crucial role in energy metabolism [ 39 ], bone metabolism [ 22 , 24 ], and emotional regulation [ 15 , 16 ]. We previously identified a BNST-VMH-NTS neural circuit mediating chronic stress-induced anxiety and bone loss [ 26 ] and revealed the regulatory mechanism of anxiety-induced bone loss at the central circuit level. However, the mechanism related to chronic stress-induced anxiety and bone loss regulation by the VMH nucleus as an intermediate linker of the neural circuit remains unclarified.…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying mechanism by which chronic stress changes the function of astrocytes remains unclear. We previously showed that the concentration of VMH GABA is significantly higher in stressed mice than in control mice [ 26 ]. Whether astrocytes release glutamate under physiological conditions is controversial; however, recent studies have shown that GABA-induced upregulation of astrocyte calcium promotes the release of glutamate and ATP, and short-term high-concentration GABA stimulation induces astrocytes to release glutamate, which causes an excitatory response in neurons [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Anxiety and Bone Loss. Astrocytes are involved in the regulation of emotional disorders and metabolic functions [24][25][26][27]. Thus, we examined the role of astrocytes in the VMH nucleus in chronic stress-induced anxiety and bone loss.…”

Section: Activation Of Vmh Astrocytes In Chronic Stress-inducedmentioning

confidence: 99%

“…Thus, SF-1 neurons in the VMH are crucial for central regulation of anxiety and bone metabolism. We previously revealed a BNST SOM -VMH SF-1 -NTS Vglut2 neural circuit that regulates the activities of the peripheral sympathetic nervous system and mediates bone loss caused by chronic stress [ 26 ]. As a key link in this circuit, the VMH is responsible for integrating “anxiety information” sent by the upstream bed nucleus of the stria terminalis (BNST) and “bone regulation information” from the downstream—the nucleus of the solitary tract (NTS).…”

Section: Introductionmentioning

confidence: 99%

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

Shao

Gao

et al. 2021

Neural Plasticity

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Activation Of Vmh Astrocytes In Chronic Stress-inducedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Shao

Gao

et al. 2021

Neural Plasticity

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Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

Guo,

Zhu,

et al. 2024

Advanced Science

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Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain‐bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.

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A Novel Mouse Model for Polysynaptic Retrograde Tracing and Rabies Pathological Research

Song

et al. 2023

Cell Mol Neurobiol

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Retrograde tracing is an important method for dissecting neuronal connections and mapping neural circuits. Over the past decades, several virus-based retrograde tracers have been developed and have contributed to displaying multiple neural circuits in the brain. However, most of the previously widely used viral tools have focused on mono-transsynaptic neural tracing within the central nervous system, with very limited options for achieving polysynaptic tracing between the central and peripheral nervous systems. In this study, we generated a novel mouse line, GT mice, in which both glycoprotein (G) and ASLV-A receptor (TVA) were expressed throughout the body. Using this mouse model, in combination with the well-developed rabies virus tools (RV-EnvA-ΔG) for monosynaptic retrograde tracing, polysynaptic retrograde tracing can be achieved. This allows functional forward mapping and long-term tracing.Furthermore, since the G-deleted rabies virus can travel upstream against the nervous system as the original strain, this mouse model can also be used for rabies pathological studies.

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A GABAergic neural circuit in the ventromedial hypothalamus mediates chronic stress–induced bone loss

Cited by 45 publications

References 63 publications

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

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

Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

A Novel Mouse Model for Polysynaptic Retrograde Tracing and Rabies Pathological Research

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