de Kloet Annette D, Wang Lei, Pitra Soledad, Hiller Helmut, Smith Justin A, Tan Yalun, Nguyen Dani, Cahill Karlena M, Sumners Colin, Stern Javier E, Krause Eric G
Department of Physiology and Functional Genomics, College of Medicine, and.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32611, and.
J Neurosci. 2017 Mar 29;37(13):3478-3490. doi: 10.1523/JNEUROSCI.3674-16.2017. Epub 2017 Feb 20.
Stress elicits neuroendocrine, autonomic, and behavioral responses that mitigate homeostatic imbalance and ensure survival. However, chronic engagement of such responses promotes psychological, cardiovascular, and metabolic impairments. In recent years, the renin-angiotensin system has emerged as a key mediator of stress responding and its related pathologies, but the neuronal circuits that orchestrate these interactions are not known. These studies combine the use of the Cre-recombinase/loxP system in mice with optogenetics to structurally and functionally characterize angiotensin type-1a receptor-containing neurons of the paraventricular nucleus of the hypothalamus, the goal being to determine the extent of their involvement in the regulation of stress responses. Initial studies use neuroanatomical techniques to reveal that angiotensin type-1a receptors are localized predominantly to the parvocellular neurosecretory neurons of the paraventricular nucleus of the hypothalamus. These neurons are almost exclusively glutamatergic and send dense projections to the exterior portion of the median eminence. Furthermore, these neurons largely express corticotrophin-releasing hormone or thyrotropin-releasing hormone and do not express arginine vasopressin or oxytocin. Functionally, optogenetic stimulation of these neurons promotes the activation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as well as a rise in systolic blood pressure. When these neurons are optogenetically inhibited, the activity of these neuroendocrine axes are suppressed and anxiety-like behavior in the elevated plus maze is dampened. Collectively, these studies implicate this neuronal population in the integration and coordination of the physiological responses to stress and may therefore serve as a potential target for therapeutic intervention for stress-related pathology. Chronic stress leads to an array of physiological responses that ultimately rouse psychological, cardiovascular, and metabolic impairments. As a consequence, there is an urgent need for the development of novel therapeutic approaches to prevent or dampen deleterious aspects of "stress." While the renin-angiotensin system has received some attention in this regard, the neural mechanisms by which this endocrine system may impact stress-related pathologies and consequently serve as targets for therapeutic intervention are not clear. The present studies provide substantial insight in this regard. That is, they reveal that a distinct population of angiotensin-sensitive neurons is integral to the coordination of stress responses. The implication is that this neuronal phenotype may serve as a target for stress-related disease.
应激会引发神经内分泌、自主神经和行为反应，这些反应可减轻体内稳态失衡并确保生存。然而，长期处于这种反应状态会导致心理、心血管和代谢方面的损害。近年来，肾素 - 血管紧张素系统已成为应激反应及其相关病理过程的关键介质，但协调这些相互作用的神经回路尚不清楚。这些研究将小鼠中Cre重组酶/loxP系统的应用与光遗传学相结合，从结构和功能上对下丘脑室旁核中含1a型血管紧张素受体的神经元进行表征，目的是确定它们在应激反应调节中的参与程度。初步研究使用神经解剖学技术揭示，1a型血管紧张素受体主要定位于下丘脑室旁核的小细胞神经分泌神经元。这些神经元几乎完全是谷氨酸能的，并向正中隆起的外部发出密集投射。此外，这些神经元大多表达促肾上腺皮质激素释放激素或促甲状腺激素释放激素，不表达精氨酸加压素或催产素。在功能上，对这些神经元进行光遗传学刺激会促进下丘脑 - 垂体 - 肾上腺轴和下丘脑 - 垂体 - 甲状腺轴的激活，以及收缩压升高。当这些神经元被光遗传学抑制时，这些神经内分泌轴的活性会受到抑制，高架十字迷宫中的焦虑样行为也会减弱。总的来说，这些研究表明这群神经元参与了对应激的生理反应的整合与协调，因此可能成为应激相关病理治疗干预的潜在靶点。慢性应激会导致一系列生理反应，最终引发心理、心血管和代谢方面的损害。因此，迫切需要开发新的治疗方法来预防或减轻“应激”的有害影响。虽然肾素 - 血管紧张素系统在这方面已受到一些关注，但该内分泌系统可能影响应激相关病理并因此成为治疗干预靶点的神经机制尚不清楚。目前的研究在这方面提供了重要见解。也就是说，它们揭示了一群对血管紧张素敏感的独特神经元对于应激反应的协调至关重要。这意味着这种神经元表型可能成为应激相关疾病的靶点。
