Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.

SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.

血压受内分泌、自主神经和行为反应的控制，这些反应将血容量和灌注压维持在最适合生存的水平。尽管中枢血管紧张素 1a 型受体（AT1aR；由Agtr1a基因编码）影响这些过程是显而易见的，但对调节这些作用的神经元回路尚不完全了解。目前的研究表征了终板中 AT1aR 神经元的结构和功能（包含终板的正中视前核和器官血管），从而评估它们在血压控制中的作用。使用雄性Agtr1a-Cre 小鼠，神经解剖学研究表明，该区域的 AT1aR 神经元主要是谷氨酸能神经元，并将投射物发送到下丘脑 (PVN) 的室旁核，这些神经元似乎突触到合成加压素的神经元上。为了评估这些终末层 AT1aR 神经元的功能，我们通过病毒传递光敏视蛋白，然后在评估心血管参数或液体摄入量的同时光遗传学激发或抑制神经元。光遗传学激发强烈提高血压、水摄入量和钠摄入量，而光遗传学抑制产生相反的效果。有趣的是，这些终板 AT1aR 神经元的光遗传学激发也导致 PVN 和视上核内加压素神经元的 Fos 诱导。此外，在 PVN 内，对源自这些终末层 AT1aR 神经元的传入神经的选择性光遗传学刺激可诱导谷氨酸盐释放到大细胞神经元上，并足以增加血压。这些心血管作用通过血管加压素-1a-受体拮抗剂的全身预处理减弱。总的来说，这些数据表明终板 AT1aR 神经元的兴奋诱导神经内分泌和行为反应，从而增加血压。

意义声明高血压是一个普遍存在的健康问题，也是心血管疾病的危险因素。尽管存在治疗方法，但相当大比例的患者患有“抗药性”高血压，这是一种与脑血管紧张素受体激活增加、交感神经系统活动增强和血管加压素水平升高相关的病症。本研究强调了位于终末层内表达血管紧张素 1a 型受体的神经元在调节参与维持心血管稳态的内分泌和行为反应中的作用。更具体地说，这里提供的数据揭示了椎板末端血管紧张素敏感神经元和下丘脑室旁核血管加压素神经元之间的功能性兴奋连接，并进一步表明该回路的激活会导致血压升高。这些神经元可能是抗高血压治疗的有希望的靶点。