Orexinergic projections to neocortex: potential role in arousal, stress and anxiety-related disorders.

食欲素能投射到新皮质：在唤醒、压力和焦虑相关疾病中的潜在作用。

基本信息

批准号：
MR/W029073/1
负责人：
Zoltan Molnar
金额：
$ 75.95万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW029073%2F1
关键词：
Orexinergic projections neocortex potential role

项目摘要

Stress exacerbates many psychiatric conditions, and repeated stress contributes to the pathogenesis of disorders such as Post Traumatic Stress Disorder, Panic and Major Depressive Disorder. The mammalian cerebral cortex is responsible for our higher cognitive functions such as language, episodic memory, and complex perception. It interacts with various other structures, such as the thalamus, a large group of neurons that either relay sensory input to the cortex or mediate cortico-cortical interactions through these neurons. Our brain is not always paying attention to all details, and it does not always analyse detailed contexts. Its state is regulated by neuroendocrine factors. These are small molecules, such as orexin (hypocretin). Orexin is exclusively produced in neurons of the lateral hypothalamus. The orexin system is highly reactive to stress and regulates many physiological processes that are altered in stress-related mental illness, including sleep/wake patterns, appetite, and cognition. Changes in orexin levels have been reported in major depression and anxiety disorders, and genetic defects in the sensitivity to orexin (orexin 1 receptor polymorphism) have been associated with anxiety spectrum disorders, particularly in women who are twice as likely as men to suffer from stress-related mental illness. Orexinergic neurons have wide projection targets across the entire central nervous system, including to other local (hypothalamic) neurons that are important for modulating arousal, appetite, and neuroendocrine functions. However, the role of projections to cortical circuits remains less well understood, although they may be involved in regulating cortical arousal and the cognitive responses to stress. Thus, they could represent promising targets for drug development that selectively target cortical, but not subcortical mechanisms involved in generating anxiety. Resolving the anatomical and functional connectivity between orexinergic neurons and cortical circuits, as well as the gender differences in this system, will be critical for starting to design orexinergic treatments for anxiety. Within sensory cortex, layer 6b is the only orexin-sensitive layer. These neurons can be selectively labelled using Ctgf-/Drd1a-Cre transgenic mice, and we have very considerable expertise in studying this cell population. We demonstrated that there is a direct link between lateral hypothalamic orexin neurons and these cells. We also demonstrated that some of the orexin-sensitive layer 6b neurons selectively project to thalamic nuclei that are involved in higher cognitive functions. Sensory layer 6b neurons might therefore function as an orexin-gated circuit that amplifies feedback via cortico-thalamo-cortical loops and play an important role in regulating brain state and cognition. In our preliminary experiments we genetically silenced a selected population of Drd1a-Cre neurons across the entire cerebral cortex and observed the behaviour of these Snap25 cKO mice. This manipulation did not influence circadian rhythms or locomotor activity when mice were exposed to a novel environment. However, it led to a strong reduction in anxiety-like behaviour, as measured in three different behavioural tasks. This suggests that some of the Drd1a-Cre neurons may act as a key component in the cortex for regulating emotional behaviours. We shall examine i) functional connectivity between orexin neurons and their cortical targets, ii) physiological responses of Ctgf-/Drd1a-Cre neurons to stress and arousal, and how this is modulated by orexin, and ii) involvement of these cells in anxiety and fear learning. The selective manipulation of these circuits presents unique therapeutic avenues for the intervention against anxiety, while not influencing autonomous functions. Our proposed experiments will dissect key components, cell type and gender differences of these circuits and shall test the molecular mechanisms that could be exploited in therapy.

压力加剧了许多精神病病，反复的压力有助于诸如创伤后应激障碍，恐慌和重度抑郁症等疾病的发病机理。哺乳动物的大脑皮层负责我们较高的认知功能，例如语言，情节记忆和复杂的感知。它与其他各种结构相互作用，例如Thalamus，这是一大批神经元，它们要么通过这些神经元传递到皮质的感觉输入或介导皮质皮质相互作用。我们的大脑并不总是关注所有细节，并且并不总是分析详细的上下文。它的状态受神经内分泌因素的调节。这些是小分子，例如甲脱甲蛋白（低载素）。 Orexin仅在下丘脑外侧神经元中产生。 Orexin System对压力具有很高的反应性，并调节许多与压力相关的精神疾病（包括睡眠/唤醒模式，食欲和认知）改变的生理过程。在严重抑郁症和焦虑症中，已经报道了甲状腺素水平的变化，并且对Orexin（Orexin 1受体多态性）的敏感性遗传缺陷与焦虑症障碍有关，尤其是在与压力相关的精神疾病中遭受痛苦的女性的两倍。甲肌动蛋白能神经元在整个中枢神经系统中具有广泛的投影靶标，包括其他局部（下丘脑）神经元，这些神经元对于调节唤醒，食欲和神经内分泌功能很重要。但是，尽管它们可能参与调节皮质唤醒和对压力的认知反应，但对皮质回路的投影作用仍然不太理解。因此，它们可以代表有前途的药物开发目标，这些靶标有选择性地靶向皮质，但不能靶向涉及产生焦虑的皮质下机制。解决甲虫能神经元和皮质回路之间的解剖和功能连通性，以及该系统中的性别差异，对于开始为焦虑设计Orecinegic治疗方法至关重要。在感觉皮层中，第6B层是唯一的甲层敏感层。这些神经元可以使用CTGF-/DRD1A-CRE转基因小鼠选择性标记，并且在研究该细胞群体方面我们具有非常丰富的专业知识。我们证明了下丘脑Orexin神经元与这些细胞之间存在直接联系。我们还证明了某些针对较高认知功能的丘脑核有选择地投射到丘脑核。因此，感觉层6b神经元可能起作用，可以通过皮质 - 甲状腺皮质环路来放大反馈，并在调节脑状态和认知方面发挥重要作用。在我们的初步实验中，我们在整个大脑皮层中遗传沉默了选定的DRD1A-CRE神经元群体，并观察到这些SNAP25 CKO小鼠的行为。当小鼠暴露于新的环境时，这种操纵不会影响昼夜节律或运动活性。但是，这导致了在三种不同的行为任务中衡量的焦虑样行为的大大减少。这表明某些DRD1A-CRE神经元可以作为调节情绪行为的皮层的关键组成部分。我们将检查i）Orexin神经元及其皮质靶标之间的功能连通性，ii）CTGF-/DRD1A-CRE神经元对压力和唤醒的生理反应，以及Orexin如何调节它，以及II）这些细胞参与焦虑和恐惧和恐惧学习。这些电路的选择性操纵为防御焦虑的干预提供了独特的治疗途径，同时不影响自主功能。我们提出的实验将剖析这些电路的关键成分，细胞类型和性别差异，并应测试可以在治疗中利用的分子机制。