Elucidation of prefrontal-amygdala neural circuitry with optogenetic techniques

描述（由申请人提供）：本提案涉及广泛的挑战领域（15）转化科学，以及特定的挑战主题15-MH-109前额皮质对高级脑功能和复杂行为的调节。几乎所有的精神疾病，从精神分裂症到抑郁症再到成瘾，都会扰乱情绪处理。这些精神疾病背后的病理生理学的一个关键方面被认为在于前额叶皮层的功能障碍，特别是前额叶皮层调节情绪的方式。我们的建议集中在前额叶皮层和杏仁核之间的相互作用，杏仁核是情绪行为的关键协调器。这种回路被强调为控制情绪反应的关键。我们的实验室最近发现，灵长类动物杏仁核中的神经元会根据线索预测的是奖励还是厌恶刺激而做出不同的反应，不同的神经元群体分别倾向于奖励和厌恶关联。最近的初步数据表明，这种灵活的表示强化突发事件可以“门控”-或即时更新-这取决于一个主题的学习和应用规则解释线索准确。在这个建议中，我们将测试的假设，这种门控的神经信号在杏仁核的关键取决于输入从眶额皮层（OFC），一个组成部分的前额叶皮层与杏仁核的强连接。我们的方法是适应遗传和解剖学靶向表达通道视紫红质（ChR 2）和盐视紫红质（NpHr）（光激活通道，可用于光激活或光激活神经元）的方法。这些光遗传学技术将与神经生理学和复杂行为实验结合使用。我们将确定杏仁核中灵活的生理特性是否需要前额叶输入，通过选择性地用盐视紫红质使前额叶输入失活，我们将进一步确定破坏从OFC到杏仁核的信息传输是否会影响复杂的行为。总的来说，这些技术的发展有望通过阐明前额叶输入如何调节杏仁核的反应性来改变前额叶/杏仁核相互作用的研究，杏仁核是维持正常适应性情绪反应的关键机制，在许多精神疾病中可能会变得功能失调。 公共卫生相关性：该提案涉及光遗传学技术的开发，用于研究前额叶皮质如何调节杏仁核以控制情绪行为。由于大多数精神疾病，包括情绪和焦虑症，精神分裂症和抑郁症都涉及这些神经回路的功能障碍，因此该项目有望为开发新的治疗方法奠定基础。

DESCRIPTION (provided by applicant): This proposal addresses broad Challenge Area (15) Translational Science, and specific challenge topic 15-MH-109 Prefrontal cortex regulation of higher brain function and complex behaviors. Nearly all psychiatric disorders, from schizophrenia to depression to addiction, disrupt emotional processing. A key aspect of the pathophysiology underlying these psychiatric disorders is thought to lie in the dysfunction of the pre-frontal cortex, especially with respect to the manner by which the pre-frontal cortex regulates emotions. We focus in this proposal on the interactions between the pre-frontal cortex and the amygdala, a key coordinator of emotional behavior. This circuitry has been highlighted as being critical for controlling emotional responses. Our lab has recently shown that neurons in the primate amygdala respond differentially depending upon whether a cue predicts a reward or an aversive stimulus, with different populations of neurons preferring reward and aversive associations, respectively. More recent preliminary data indicates that this flexible representation of reinforcement contingencies can be "gated" - or updated instantly - depending upon a subject's learning and applying a rule for interpreting cues accurately. In this proposal, we will test the hypothesis that this gating of neural signals in the amygdala depends critically on input from the orbitofrontal cortex (OFC), a component of the pre-frontal cortex with strong connections to the amygdala. Our approach is to adapt methods for genetically and anatomically targeted expression of channelrhodopsin (ChR2) and halorhodopsin (NpHr) (light-activated channels that can be used to photo-activate or photo-inactivate neurons). These optogenetic techniques will be used in combination with neurophysiological and complex behavioral experiments. We will determine if the flexible physiological properties in the amygdala require pre-frontal input by selectively inactivating pre-frontal input with halorhodopsin, and we will further determine if disrupting information transmission from OFC to the amygdala impacts complex behavior. Overall, the development of these techniques promises to transform the study of pre-frontal/amygdala interactions by elucidating how pre-frontal input can regulate the responsivity of the amygdala, a key mechanism in maintaining normal adaptive emotional responses that likely becomes dysfunctional in many psychiatric disorders. PUBLIC HEALTH RELEVANCE: This proposal involves the development of optogenetic techniques for investigating how the prefrontal cortex regulates the amygdala in order to control emotional behavior. Since most psychiatric disorders, including mood and anxiety disorders, schizophrenia, and depression involve dysfunction in these neural circuits, this project promises to lay the groundwork for developing new treatments.