We previously reported that GABAergic neurons within the ventral anterior lateral bed nucleus of the stria terminalis (alBST) express glucagon-like peptide 1 receptor (GLP1R) in rats, and that virally-mediated “knock-down” of GLP1R expression in the alBST prolongs the hypothalamic-pituitary-adrenal axis response to acute stress. Given other evidence that a GABAergic projection pathway from ventral alBST serves to limit stress-induced activation of the HPA axis, we hypothesized that GLP1 signaling promotes activation of GABAergic ventral alBST neurons that project directly to the paraventricular nucleus of the hypothalamus (PVN). After PVN microinjection of fluorescent retrograde tracer followed by preparation of ex vivo rat brain slices, whole-cell patch clamp recordings were made in identified PVN-projecting neurons within the ventral alBST. Bath application of Exendin-4 (a specific GLP1R agonist) indirectly depolarized PVN-projecting neurons in the ventral alBST and adjacent hypothalamic parastrial nucleus (PS) through a network-dependent increase in excitatory synaptic inputs, coupled with a network-independent reduction in inhibitory inputs. Additional retrograde tracing experiments combined with in situ hybridization confirmed that PVN-projecting neurons within the ventral alBST/PS are GABAergic, and do not express GLP1R mRNA. Conversely, GLP1R mRNA is expressed by a subset of neurons that project into the ventral alBST and were likely contained within coronal ex vivo slices, including GABAergic neurons within the oval subnucleus of the dorsal alBST and glutamatergic neurons within the substantia innominata. Our novel findings reveal potential GLP1R-mediated mechanisms through which the alBST exerts inhibitory control over the endocrine HPA axis.

我们之前报道过，大鼠终纹腹前外侧床核 (alBST) 内的 GABA 能神经元表达胰高血糖素样肽 1 受体 (GLP1R)，并且病毒介导的 alBST 中GLP1R表达的“敲低”延长下丘脑-垂体-肾上腺轴对急性应激的反应。鉴于其他证据表明来自腹侧 alBST 的 GABAergic 投射通路用于限制应激诱导的 HPA 轴激活，我们假设 GLP1 信号传导促进直接投射到下丘脑室旁核 (PVN) 的 GABAergic 腹侧 alBST 神经元的激活。PVN显微注射荧光逆行示踪剂后离体制备大鼠脑切片、全细胞膜片钳记录在腹侧 alBST 内已确定的 PVN 投射神经元中进行。浴应用 Exendin-4（一种特定的 GLP1R 激动剂）通过网络依赖性增加兴奋性突触输入，以及与网络无关的抑制性减少，间接去极化腹侧 alBST 和相邻下丘脑旁核 (PS) 中的 PVN 投射神经元输入。额外的逆行追踪实验与原位杂交相结合，证实腹侧 alBST/PS 内的 PVN 投射神经元是 GABAergic，并且不表达GLP1R mRNA。相反，GLP1R mRNA 由投射到腹侧 alBST 的神经元子集表达，并且可能包含在冠状离体切片，包括背侧alBST椭圆亚核内的GABA能神经元和无名质内的谷氨酸能神经元。我们的新发现揭示了潜在的 GLP1R 介导的机制，alBST 通过这些机制对内分泌 HPA 轴施加抑制性控制。