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

Fan Yang; Yunhui Liu; Shanping Chen; Zhongquan Dai; Dazhi Yang; Dashuang Gao; Jie Shao; Yuyao Wang; Ting Wang; Zhijian Zhang; Lu Zhang; William W. Lu; Yinghui Li; Liping Wang

doi:10.1172/jci136105

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

Neural Plasticity ◽

10.1155/2021/7806370 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Yunhui Liu ◽

Jie Shao ◽

Dashuang Gao ◽

Lu Zhang ◽

Fan Yang

Keyword(s):

Bone Loss ◽

Chronic Stress ◽

Neural Circuits ◽

Cell Function ◽

Ventromedial Hypothalamus ◽

Brain Regions ◽

Receptor Blocker ◽

Steroidogenic Factor 1 ◽

Regulation Of Metabolism ◽

Nmda Receptor Blocker

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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Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss

10.1101/812875 ◽

2019 ◽

Author(s):

Fan Yang ◽

Yunhui Liu ◽

Shanping Chen ◽

Zhongquan Dai ◽

Dazhi Yang ◽

...

Keyword(s):

Bone Loss ◽

Bone Metabolism ◽

Neural Circuit ◽

Neural Mechanism ◽

Neural Circuitry ◽

Ventromedial Hypothalamus ◽

Bed Nucleus ◽

The Central Nervous System ◽

Somatostatin Neurons ◽

Human Participants

AbstractThe homeostasis of bone metabolism is finely regulated by the central nervous system and recent studies have suggested that mood disorders, such as anxiety, are closely related to bone metabolic abnormalities; however, our understanding of central neural circuits regulating bone metabolism is still largely limited. In this study, we first demonstrate that confined isolation of human participants under normal gravity resulted in decreased bone density and elevated anxiety levels. We then used an established mouse model to dissect the neural circuitry regulating anxiety-induced bone loss. Combining electrophysiological, optogenetic and chemogenetic approaches, we demonstrate that GABAergic neural circuitry in ventromedial hypothalamus (VMH) modulates anxiety-induced bone loss; importantly, the GABAergic input in VMHdm arose from a specific group of somatostatin neurons in the bed nucleus of the stria terminalis (BNST), which is both indispensable for anxiety-induced bone loss and able to trigger bone loss in the absence of stressors. VGLUT2 neurons in Nucleus tractus solitaries (NTS) and peripheral sympathetic system were employed by this BNST-VMH neural circuit to regulate anxiety-induced bone loss. Overall, we uncovered new GABAergic neural circuitry from the forebrain to hypothalamus, used in the regulation of anxiety-induced bone loss, and revealed a population of somatostatin neurons in BNST not previously implicated in bone mass regulation. These findings thus identify the underlying central neural mechanism of psychiatric disorders, such as anxiety, that influences bone metabolism at the circuit level.One Sentence SummaryIdentification of a new GABAergic neural circuit from forebrain to hypothalamus used for regulation of anxiety-induced bone loss.

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Testosterone Programs Adult Social Behavior before and during, But Not after, Adolescence

Endocrinology ◽

10.1210/en.2008-1708 ◽

2009 ◽

Vol 150 (8) ◽

pp. 3690-3698 ◽

Cited By ~ 67

Author(s):

Kalynn M. Schulz ◽

Julia L. Zehr ◽

Kaliris Y. Salas-Ramirez ◽

Cheryl L. Sisk

Keyword(s):

Social Behavior ◽

Mating Behavior ◽

Reproductive Behavior ◽

Neural Circuit ◽

Pubertal Development ◽

Ventromedial Hypothalamus ◽

Gonadal Hormones ◽

Medial Amygdala ◽

Steroid Dependent ◽

Juvenile Males

Whereas the adolescent brain is a major target for gonadal hormones, our understanding of hormonal influences on adolescent neural and behavioral development remains limited. These experiments investigated how variations in the timing of testosterone (T) exposure, relative to adolescence, alters the strength of steroid-sensitive neural circuits underlying social behavior in male Syrian hamsters. Experiment 1 simulated early, on-time, and late pubertal development by gonadectomizing males on postnatal d 10 and treating with SILASTIC brand T implants for 19 d before, during, or after adolescence. T treatment before or during, but not after, adolescence facilitated mating behavior in adulthood. In addition, preadolescent T treatments most effectively increased mating behavior overall, indicating that the timing of exposure to pubertal hormones contributes to individual differences in adult behavior. Experiment 2 examined the effects of preadolescent T treatment on behavior and brain regional volumes within the mating neural circuit of juvenile males (i.e. still preadolescent). Although preadolescent T treatment did not induce reproductive behavior in juvenile males, it did increase volumes of the bed nucleus of the stria terminalis, sexually dimorphic nucleus, posterodorsal medial amygdala, and posteroventral medial amygdala to adult-typical size. In contrast, juvenile anterodorsal medial amygdala and ventromedial hypothalamus volumes were not changed by preadolescent T treatment yet differed significantly in volume from adult controls, suggesting that further maturation of these brain regions during adolescence is required for the expression of male reproductive behavior. Thus, adolescent maturation of social behavior may involve both steroid-independent and -dependent processes, and adolescence marks the end of a postnatal period of sensitivity to steroid-dependent organization of the brain.

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Chronic Social Defeat Stress Modulates Dendritic Spines Structural Plasticity in Adult Mouse Frontal Association Cortex

Neural Plasticity ◽

10.1155/2017/6207873 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Yu Shu ◽

Tonghui Xu

Keyword(s):

Prefrontal Cortex ◽

Chronic Stress ◽

Neural Circuits ◽

Neural Circuit ◽

Structural Plasticity ◽

Social Defeat ◽

Social Defeat Stress ◽

Chronic Social Defeat Stress ◽

Stress Experience ◽

Spine Dynamics

Chronic stress is associated with occurrence of many mental disorders. Previous studies have shown that dendrites and spines of pyramidal neurons of the prefrontal cortex undergo drastic reorganization following chronic stress experience. So the prefrontal cortex is believed to play a key role in response of neural system to chronic stress. However, how stress induces dynamic structural changes in neural circuit of prefrontal cortex remains unknown. In the present study, we examined the effects of chronic social defeat stress on dendritic spine structural plasticity in the mouse frontal association (FrA) cortexin vivousing two-photon microscopy. We found that chronic stress altered spine dynamics in FrA and increased the connectivity in FrA neural circuits. We also found that the changes in spine dynamics in FrA are correlated with the deficit of sucrose preference in defeated mice. Our findings suggest that chronic stress experience leads to adaptive change in neural circuits that may be important for encoding stress experience related memory and anhedonia.

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Chronic Mild Stress Causes Bone Loss via an Osteoblast-Specific Glucocorticoid-Dependent Mechanism

Endocrinology ◽

10.1210/en.2016-1658 ◽

2017 ◽

Vol 158 (6) ◽

pp. 1939-1950 ◽

Cited By ~ 5

Author(s):

Holger Henneicke ◽

Jingbao Li ◽

Sarah Kim ◽

Sylvia J. Gasparini ◽

Markus J. Seibel ◽

...

Keyword(s):

Bone Loss ◽

Chronic Stress ◽

Structural Parameters ◽

Chronic Mild Stress ◽

Bone Resorption Marker ◽

Mild Stress ◽

Male Mice ◽

Female Mice ◽

Glucocorticoid Signaling ◽

The Impact

Abstract Chronic stress and depression are associated with alterations in the hypothalamic–pituitary–adrenal signaling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Using a transgenic (tg) mouse model in which glucocorticoid signaling is selectively disrupted in mature osteoblasts and osteocytes [11β-hydroxysteroid-dehydrogenase type 2 (HSD2)OB-tg mice], the present study examines the impact of chronic stress on skeletal metabolism and structure. Eight-week-old male and female HSD2OB-tg mice and their wild-type (WT) littermates were exposed to chronic mild stress (CMS) for the duration of 4 weeks. At the endpoint, L3 vertebrae and tibiae were analyzed by micro–computed tomography and histomorphometry, and bone turnover was measured biochemically. Compared with nonstressed controls, exposure to CMS caused an approximately threefold increase in serum corticosterone concentrations in WT and HSD2OB-tg mice of both genders. Compared with controls, CMS resulted in loss of vertebral trabecular bone mass in male WT mice but not in male HSD2OB-tg littermates. Furthermore, both tibial cortical area and area fraction were reduced in stressed WT but not in stressed HSD2OB-tg male mice. Osteoclast activity and bone resorption marker were increased in WT males following CMS, features absent in HSD2OB-tg males. Interestingly, CMS had little effect on vertebral and long-bone structural parameters in female mice. We conclude that in male mice, bone loss during CMS is mediated via enhanced glucocorticoid signaling in osteoblasts (and osteocytes) and subsequent activation of osteoclasts. Female mice appear resistant to the skeletal effects of CMS.

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Exposure to chronic stress induces bone loss via glucocorticoid signalling in osteoblasts

Bone Abstracts ◽

10.1530/boneabs.5.ni7 ◽

2016 ◽

Cited By ~ 1

Author(s):

Holger Henneicke ◽

Jing-Bao Li ◽

Sylvia J Gasparini ◽

Markus J Seibel ◽

Hong Zhou

Keyword(s):

Bone Loss ◽

Chronic Stress

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An excitatory ventromedial hypothalamus to paraventricular thalamus circuit that suppresses food intake

Nature Communications ◽

10.1038/s41467-020-20093-4 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Jia Zhang ◽

Dan Chen ◽

Patrick Sweeney ◽

Yunlei Yang

Keyword(s):

Food Intake ◽

Neural Circuit ◽

Ventromedial Hypothalamus ◽

Steroidogenic Factor 1 ◽

Chemical Genetic ◽

Optogenetic Stimulation ◽

Neural Inhibition ◽

Satiety Center ◽

Paraventricular Thalamus ◽

Stimulation Of

AbstractIt is well recognized that ventromedial hypothalamus (VMH) serves as a satiety center in the brain. However, the feeding circuit for the VMH regulation of food intake remains to be defined. Here, we combine fiber photometry, chemo/optogenetics, virus-assisted retrograde tracing, ChR2-assisted circuit mapping and behavioral assays to show that selective activation of VMH neurons expressing steroidogenic factor 1 (SF1) rapidly inhibits food intake, VMH SF1 neurons project dense fibers to the paraventricular thalamus (PVT), selective chemo/optogenetic stimulation of the PVT-projecting SF1 neurons or their projections to the PVT inhibits food intake, and chemical genetic inactivation of PVT neurons diminishes SF1 neural inhibition of feeding. We also find that activation of SF1 neurons or their projections to the PVT elicits a flavor aversive effect, and selective optogenetic stimulation of ChR2-expressing SF1 projections to the PVT elicits direct excitatory postsynaptic currents. Together, our data reveal a neural circuit from VMH to PVT that inhibits food intake.

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