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

Abstract

The central nervous system has evolved to coordinate the regulation of both the behavior response to the external environment and homeostasis of energy expenditure. Recent studies have indicated the dorsomedial ventromedial hypothalamus (dmVMH) as an important hub that regulates both innate behavior and energy homeostasis for coping stress. However, how dmVMH neurons control neuronal firing pattern to regulate chronic stress-induced anxiety and energy expenditure remains poorly understood. Here, we found enhanced neuronal activity in VMH after chronic stress, which is mainly induced by increased proportion of burst firing neurons. This enhancement of VMH burst firing is predominantly mediated by Cav3.1 expression. Optogenetically evoked burst firing of dmVMH neurons induced anxiety-like behavior, shifted the respiratory exchange ratio toward fat oxidation, and decreased food intake, while knockdown of Cav3.1 in the dmVMH had the opposite effects, suggested that Cav 3.1 as a crucial regulator. Interestingly, we found that fluoxetine (anxiolytics) could block the increase of Cav3.1 expression to inhibit the burst firing, and then rescued the anxiety-like behaviors and energy expenditure changes. Collectively, our study first revealed an important role of Cav3.1-driven bursting firing of dmVMH neurons in the control of anxiety-like behavior and energy expenditure, and provided potential therapeutic targets for treating the chronic stress-induced emotional malfunction and metabolism disorders.

Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice

“…Acute or chronic stress is associated with a higher risk of many psychological disorders, including anxiety and depressive disorders 41 , 42 . As the CeA is the main information output nucleus in the amygdala, many studies have reported that CeA hyperactivity following exposure to stress or stressor events contributes to the pathogenesis of anxiety 23 , 43 , 44 ; these findings are consistent with our results.…”

Mediodorsal thalamic nucleus mediates resistance to ethanol through Cav3.1 T-type Ca2+regulation of neural activity

“…4), could increase ethanol resistance in WT mice. Reducing MD firing using phasic inhibition under ethanol, potentially leading to inhibition and rebound burst 52 , could also increase the duration of the fLOM in WT mice injected with a lower dose of ethanol (Figure S12; 2.0 g/kg). We propose that the relative change in firing rate in MD RS neurons might be an important driver and indicator of the change of transition in and out of consciousness as demonstrated for other nuclei of the dMT 8,9,32,33 .…”

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

“…The VMH serves as a critical hub for transmitting and processing stress-related information inputs, thereby playing a regulatory role in the homeostasis of peripheral tissues, such as bone (Yang et al, 2020) and adipose (Viskaitis et al, 2017;Shao et al, 2022). However, the synaptic mechanism responsible for VMH activation following chronic stress remains unclear.…”

“…The VMH also serves as a vital hub linking emotional states and peripheral physiological homeostasis (Fioramonti et al, 2009;Kuperman et al, 2010;Anderson, 2016;Viskaitis et al, 2017). Recent studies from our research group revealed profound electrophysiological and molecular changes within the VMH following chronic stress, precipitating anxietylike emotional states and disruptions in peripheral metabolic equilibrium (Yang et al, 2020;Shao et al, 2022). For example, chronic stress over a 4-week period has been shown to enhance projections from the bed nucleus of the stria terminalis (BNST) to the VMH, thereby provoking anxiety-like behavior and specifically affecting bone loss (Yang et al, 2020).…”

“…The CNS stress-response circuitry, comprising integral components such as the ventromedial hypothalamus (VMH) and paraventricular hypothalamus (PVN) (Anthony et al, 2014;Henckens et al, 2016;Yuan et al, 2019;Shao et al, 2022) perform an essential role in transmitting and processing stress-related information, as well as modulating peripheral SNS activity and regulating hormonal secretion via the hypothalamic-pituitaryadrenal (HPA) axis (Shenton and Pyner, 2016;Iigaya et al, 2017;Yang et al, 2020;Liu et al, 2023). Despite these critical functions, the definitive neuroanatomical locus mediating chronic stress-induced SNS hyperactivity, along with the corresponding neurobiological mechanisms, remains poorly understood.…”