Elucidation of prefrontal-amygdala neural circuitry with optogenetic techniques

用光遗传学技术阐明前额杏仁核神经回路

• 批准号: 7822726
• 负责人: C. DANIEL SALZMAN
• 金额: $ 50万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822726
• 关键词: Achievement; Adaptive Behaviors; Address; Amygdaloid structure; Animal Model; Anxiety Disorders; Area; Aversive Stimulus; Behavior; Behavioral; Brain; Cognitive; Complex; Cues; Data; Deltastab; Development; Disease; Emotional; Emotions; Functional disorder; Funding; Goals; Halorhodopsins; Histology; Human; Individual; Learning; Macaca mulatta; Mental disorders; Methods; Microelectrodes; Modeling; Monkeys; Moods; Mus; Nerve; Neurons; Operative Surgical Procedures; Pathway interactions; Performance; Physiological; Population; Prefrontal Cortex; Primates; Process; Property; Psychological reinforcement; Regulation; Rewards; Rodent; Rodent Model; Role; Schizophrenia; Signal Transduction; Stimulus; Structure; Techniques; Technology; Testing; Time; Transfection; Translational Research; Update; Viral; Virus; Work; addiction; brain behavior; depression; emotion regulation; flexibility; frontal lobe; neural circuit; neuromechanism; neurophysiology; neuropsychiatry; public health relevance; relating to nervous system; research study; response; technique development; tool; transmission process

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.

描述（由申请人提供）：该提案涉及广泛的挑战领域 (15) 转化科学，以及具体的挑战主题 15-MH-109 前额皮质对高级大脑功能和复杂行为的调节。几乎所有精神疾病，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，特别是在前额叶皮层调节情绪的方式方面。我们在这个提案中重点关注前额叶皮层和杏仁核（情绪行为的关键协调者）之间的相互作用。该电路被认为对于控制情绪反应至关重要。我们的实验室最近表明，灵长类杏仁核中的神经元根据提示是否预测奖励或厌恶刺激而做出不同的反应，不同的神经元群体分别更喜欢奖励和厌恶关联。最近的初步数据表明，这种强化意外事件的灵活表示可以“门控”或立即更新，具体取决于受试者的学习和应用准确解释线索的规则。在本提案中，我们将测试这样的假设：杏仁核中神经信号的门控关键取决于来自眶额皮层（OFC）的输入，OFC是前额叶皮层的一个组成部分，与杏仁核有很强的联系。我们的方法是调整视紫红质通道 (ChR2) 和盐视紫红质 (NpHr)（光激活通道，可用于光激活或光失活神经元）的遗传和解剖学靶向表达的方法。这些光遗传学技术将与神经生理学和复杂的行为实验结合使用。我们将通过用盐视紫红质选择性地灭活前额叶输入来确定杏仁核中灵活的生理特性是否需要前额叶输入，并且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，而这种反应可能在许多精神病患者中变得功能失调。失调。 公共健康相关性：该提案涉及光遗传学技术的开发，用于研究前额叶皮层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疗法奠定基础。