Synaptic Mechanisms of Hypothalamic Control of Vigilance and Cognitive Function

下丘脑控制警觉和认知功能的突触机制

基本信息

批准号：
8906539
负责人：
Alexander Choi Jackson
金额：
$ 23.91万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906539
关键词：
Acetylcholine Address Animals Arousal Attention Award Behavior Behavior Control Behavioral Behavioral Genetics Behavioral Model Brain Cells Circadian Rhythms Cognition Cognitive Complex Dementia Disease Dopamine Electroencephalography Electrophysiology (science)Fiber Frequencies Functional disorder Genetic Goals Health Heterogeneity Histamine Human Hypothalamic structure In Vitro Institution Investigation Laboratories Lead Learning Link Maintenance Mediating Memory Mental Health Mental disorders Mentors Methods Mus Neurologic Neurons Neurosciences Research Neurotransmitters Norepinephrine Patch-Clamp Techniques Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Play Positioning Attribute Postdoctoral Fellow Preparation Principal Investigator Probability Psyche structure Quality of life Regulation Research Research Proposals Role Schizophrenia Sleep Sleep Architecture Slice Son Specificity Synapses System Techniques Testing Therapeutic Intervention Training Transgenic Mice Wakefulness Work awake basal forebrain base career cell type cholinergic cognitive function cognitive performance gamma-Aminobutyric Acid improved in vivo innovation mammilloinfundibular nucleus structure millisecond multidisciplinary nervous system disorder neural circuit neuropsychiatry neuroregulation neurotransmission neurotransmitter release new technology novel optogenetics patch clamp research study tool transmission process vigilance

项目摘要

PROJECT SUMMARY / ABSTRACT The overall goal of this research proposal is to better understand how hypothalamic histaminergic (HA) proje c- tion neurons control behavioral state transitions and cognitive performance, using electrophysiological, genetic and behavioral methods in transgenic mice. The applicant for the K99/R00 Pathway to Independence Award, Dr. Alexander C. Jackson, is currently a postdoctoral fellow in Dr. Roger Nicoll's laboratory at UCSF. Dr. Jack- son's long-term research goal is to elucidate the cellular, synaptic and circuit-level mechanisms through which hypothalamic neural circuits regulate fundamental behavioral states, such as sleep, wakefulness, attention and cognition, in health and disease. Dr. Jackson's long-term career goal is to lead a basic neuroscience research laboratory as a tenure-track principal investigator in an academic research institution. Many of the neuro- transmitter pathways in the brain that are implicated in the pathophysiology of neuropsychiatric illnesses are inexorably linked to those known to regulate sleep, wakefulness and circadian rhythms. Multiple lines of evi- dence implicate the hypothalamic HA system in regulating wakefulness, attention and aspects of cognitive function. Moreover, novel drugs that selectively enhance the activity of HA neurons are promising in promoting wakefulness and boosting cognitive function in disorders such as schizophrenia and dementias. However, largely owing to the heterogeneity of hypothalamic circuits, our understanding of the fundamental mechanisms of HA-mediated neurotransmission and its role in behavior is gravely lacking. As part of his research proposal, Dr. Jackson will circumvent current limitations in probing hypothalamic circuits by employing a cutting-edge optogenetic strategy to manipulate the excitability of genetically targeted HA neurons with millisecond preci- sion, in both brain slices and awake/behaving animals. By building on his training in cellular and synaptic elec- trophysiology, he will pursue additional training in optogenetics, EEG/EMG recording and behavioral analysis with his co-mentor Dr. Luis de Lecea (Stanford). Using these new tools, he will interrogate the HA system in a multidisciplinary manner through three Specific Aims: 1) To use novel optogenetic techniques to specifically target HA neurons with channelrhodopsin (ChR2) and then apply whole-cell patch clamp electrophysiology in brain slices to determine the synaptic mechanisms underlying the regulation of target neuron excitability by en- dogenous HA release (mentored). 2) To elucidate the role of HA neurotransmission in general arousal, sleep- wake transitions and cognitive performance, by optogenetically activating HA neurons in vivo, and quantifying cortical activation, sleep-wake transitions and cognitive function through two behavioral models of learning and memory (mentored). 3) To determine the role of co-transmission in the HA system, by assessing the possibil- ity of HA/GABA co-release, its target cell-specificity and its functional role in sleep-wake behavior and cognition (independent). The training period afforded by the K99/R00 Award will provide Dr. Jackson with a powerful toolbox for his independent career investigating hypothalamic function in health and disease.

项目摘要 /摘要该研究建议的总体目标是更好地了解下丘脑组胺能（HA）ProJE C-如何使用电生理，遗传学的神经元控制行为状态过渡和认知表现和转基因小鼠的行为方法。 K99/R00独立奖的申请人，亚历山大·C·杰克逊（Alexander C.杰克博士儿子的长期研究目标是阐明细胞，突触和电路级机制下丘脑神经回路调节基本的行为状态，例如睡眠，清醒，注意力和认知，健康和疾病。杰克逊博士的长期职业目标是领导基本的神经科学研究实验室是学术研究机构的终身制首席研究员。许多神经 - 与神经精神疾病的病理生理有关的大脑中的发射机途径是与已知的调节睡眠，清醒和昼夜节律的人无情有关。多行 Dence暗示下丘脑HA系统在调节觉醒，注意力和认知方面功能。此外，有选择地增强HA神经元活性的新型药物有望促进精神分裂症和痴呆等疾病中的清醒和增强认知功能。然而，在很大程度上，由于下丘脑电路的异质性，我们对基本机制的理解 HA介导的神经传递及其在行为中的作用严重缺乏。作为他的研究建议的一部分杰克逊博士将通过使用尖端的探测下丘脑电路的当前限制光遗传策略以毫秒精确地操纵遗传靶向HA神经元的兴奋性 sion，在大脑切片和清醒/表现的动物中。通过在细胞和突触电子中进行培训。营养生理学，他将在光遗传学，脑电图/EMG记录和行为分析方面进行其他培训与他的同事路易斯·德·莱西（Luis de Lecea）博士（斯坦福大学）。使用这些新工具，他将在通过三个特定目的的多学科方式：1）使用新颖的光遗传技术专门靶向HA神经元与通道旋转（CHR2），然后在全细胞贴片夹电生理学中应用脑切片以确定通过EN-调节靶神经元兴奋性的突触机制 Dodenous HA释放（指导）。 2）阐明HA神经传递在一般唤醒中的作用，睡眠 - 通过在体内激活HA神经元并量化的唤醒过渡和认知性能皮质激活，睡眠效果过渡和认知功能，通过学习的两个行为模型和记忆（指导）。 3）通过评估可能的可能性来确定共汇率在HA系统中的作用 HA/GABA共同发行，其目标细胞特异性及其在睡眠效果行为和认知中的功能作用（独立的）。 K99/R00奖提供的培训期将为杰克逊博士提供强大的他独立职业的工具箱调查了健康和疾病中的下丘脑功能。