ALPHA-2 ADRENERGIC RECEPTORS IN BNST REGULATE ANXIETY-LIKE BEHAVIOR VIA HPA AIXS IN MICE
Authors: Gao *Teng , Lu Tang Sheng , Han Ying , Lu Lin 
Published: February 2025

Abstract

Background
Anxiety disorders constitute the most widespread category of psychiatric conditions which can result from adverse life events and involve stress response generalization. The pursuit of innovative pharmaceutical interventions for these disorders is motivated by the escalating demand. The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. α2A adrenergic receptors (α2A-ARs) are both expressed on pre- and post-synaptic, which could regulate calcium-dependent transmitter release as well as the firing rate of the neuron. Research with animal models has shed light on potential anti-anxiety effects by intervening α2A-AR. Mice with α2A-AR knockout exhibited anxiety-like behavior, and inhibiting α2A-AR on the bed nucleus of the stria terminalis (BNST) elicits anxiety-like behavior in the elevated plus maze. However, the neuron basis of α2A-AR populations and their contributions to behavior remain unknown. As we all know, the hypothalamic-pituitary-adrenal (HPA)axis is the main way an organism responds to stress. A recent study demonstrated that the BNST→ hypothalamic paraventricular nucleus(PVN) project may be a crucial circuit regulating a variety of stressful conditions. Therefore, we speculate that α2A-AR acts on the BNST and ultimately controls the HPA axis through specific projections, thereby modulating mice behavior.

Aims
Elaborate further on the pivotal regulatory role of α2A-AR in anxiety behavior induced by chronic stress, elucidating the underlying neural circuitry that ultimately impacts the HPA axis.

Method
We adopted a 7-day restraint stress model to induce anxiety-like behavior in mice, with the α 2A-AR agonist-dexmedetomidine (DEX) or saline (SAL) injected at the last 3 days of restraint. Then open field test (OFT), new object recognition (NOC), light-dark box(LDB) and elevated plus maze(EPM) were assessed after the restraint procedure. Mice were placed back in their home cage for an additional 60 minutes before being sacrificed for cFos expression. Blood glucocorticoids were tested as well. We will further co-label α2A-AR, cFos, and subtype of neurons, manipulating α2A-AR expressed by virus injection at specific ensembles at BNST. Then neural circuits will be explored by electrophysiology in vitro, optogenetics, and fiber photometry.

Results
Mice after chronic restraint stress exhibited anxiety-like behavior which can be improved by DEX (Figure 1). Mice administrated with DEX had less neuron activation at the PVN area but an independent ensemble of activation at BNST (Figure 2), fiber photometry during EPM similarly demonstrates a corresponding trend.

Discussion
The α2A-AR agonist effectively alleviates anxiety-like behavior induced by chronic stress in mice, while its neural circuit mechanism requires further clarification. This groundwork will pave the way for the identification of potential targets in the development of anti-anxiety medications.

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