Monoaminergic regulation of prefrontal cortex inhibition during adolescence

青春期前额皮质抑制的单胺能调节

基本信息

批准号：
7992468
负责人：
Kuei-Yuan Tseng
金额：
$ 34.65万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992468
关键词：
Acoustics Adolescence Adolescent Adult Affect Amygdaloid structure Animal Model Arts Attenuated Automobile Driving Behavioral Behavioral Paradigm Brain Brain Diseases Brain region Cells Clinical Research Cognitive Cognitive deficits Data Decision Making Development Disease Dopamine Dopamine D2 Receptor Dopamine Receptor Down-Regulation Electroencephalography Event Functional disorder Glutamates Hippocampus (Brain)Impairment In Vitro Interneuron function Interneurons Knowledge Lead Link Mediating Mental disorders Microdialysis Modeling Molecular N-Methylaspartate Neurobehavioral Manifestations Neurodevelopmental Deficit Pattern Physiological Play Prefrontal Cortex Process Puberty Publishing Pyramidal Cells Rattus Receptor Signaling Regulation Relative (related person)Reporting Role Schizophrenia Short-Term Memory Signal Transduction Site Slice Staging Stress Synapses Synaptic Transmission Testing Thalamic structure Translational Research Up-Regulation Work age related base critical period dopamine system gamma-Aminobutyric Acid in vivo information processing innovation insight interest neural circuit neurodevelopment novel patch clamp postnatal postsynaptic pre-clinical prepulse inhibition presynaptic public health relevance research study response tool transmission process

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the cellular mechanisms underlying the age-dependent modulation of prefrontal cortical (PFC) interneuronal circuits. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder. However, the link between how an early developmental dysregulation of neural circuits affects the developmental trajectory of cortical interneuron maturation remains unknown. The PFC is a good site for studying the role of cortical inhibitory circuits, since the PFC plays an important role in working memory and decision-making, functions that become impaired in schizophrenia. Our recently published work and preliminary studies indicate that PFC interneuronal activity is enhanced after puberty. This postpubertal/late adolescent facilitation is thought to be related to the delayed maturation of the mesocortical dopamine system and the enhanced facilitation of glutamatergic drive onto these GABAergic interneurons. If during development, such interneuronal activity does not become enhanced, PFC inhibitory control will be altered at maturity. Such impairment would be important for the onset of PFC cognitive deficits during the periadolescent transition as observed in schizophrenia and certain psychiatric disorders. Our central hypothesis is that normal maturation of PFC GABA interneuronal function results from two concurrent late adolescent events: (i) augmentation of glutamatergic drive onto PFC interneurons; (ii) acquisition of postsynaptic Ca2+dependent signaling mechanisms that enable the increased interneuron response to dopamine. Thus, the rationale for the proposed work is that the developmental dysregulation of glutamatergic inputs to the PFC will be sufficient to alter the normal trajectory of prefrontal interneuronal function. Aim 1 will determine the cellular mechanisms that contribute to the developmental facilitation of PFC interneuronal activity. Aim 2 will determine the impact of the developmental facilitation of PFC interneuronal function on mesocortical-induced synchronous activity. Aim 3 will determine the anatomical origin of glutamatergic inputs that contribute to the late-adolescent facilitation of PFC GABA interneuron activity. Our prediction is that presynaptic facilitation of glutamatergic drive onto PFC interneurons dictates the normal maturation of dopamine control of PFC inhibitory transmission. Our results should lead to novel physiological and molecular strategies to target the presynaptic mechanisms underlying PFC interneuronal maturation that will increase cortical inhibitory transmission. PUBLIC HEALTH RELEVANCE: This proposal is aimed to determine the cellular mechanisms underlying the age-dependent modulation of cortical activity, with focus on prefrontal cortical interneuronal circuits. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder. Thus, successful completion of the proposed application should lead to the discovery of conceptual, pharmacological and physiological tools capable of dissecting the role of inhibitory network underlying normal and abnormal periadolescent transition to adulthood, and to provide critical knowledge on how cognitive symptoms in schizophrenia emerge late in adolescence.

描述（由申请人提供）：该提案的总体目的是确定前额叶皮质（PFC）中神经元电路的年龄依赖性调节的基础机制。这种发育调控与精神分裂症的病理生理学高度相关，因为在发育过程中融合了发现中的中间神经元缺陷，这是该疾病的潜在基础。但是，神经回路的早期发育失调如何影响皮质间神经元成熟的发育轨迹之间的联系仍然未知。 PFC是研究皮质抑制回路作用的好地点，因为PFC在工作记忆和决策中起着重要作用，在精神分裂症中受到损害的功能。我们最近发表的工作和初步研究表明，青春期后PFC的神经元活动得到了增强。这种后青春期晚期的促进性被认为与中皮层多巴胺系统的延迟成熟有关，并增强了谷氨酸能驱动的促进性到这些GABA能中间神经元。如果在开发过程中，这种神经元活性不会增强，则PFC抑制性控制将在成熟度时改变。这种损害对于在精神分裂症和某些精神疾病中观察到的周长过渡过程中PFC认知缺陷的发作至关重要。我们的中心假设是，PFC GABA中神经元功能的正常成熟是由两个并发的后期青少年事件引起的：（i）将谷氨酸能驱动器扩大到PFC中间神经元；（ii）获得突触后CA2+依赖性信号传导机制，从而使中间神经元对多巴胺的反应增加。因此，提出的工作的理由是，谷氨酸能输入到PFC的发育失调足以改变前额叶间神经元功能的正常轨迹。 AIM 1将确定有助于PFC中神经元活动的发育促进的细胞机制。 AIM 2将确定PFC中神经元功能对中皮层诱导的同步活性的发育促进作用的影响。 AIM 3将确定谷氨酸能输入的解剖学起源，这些输入有助于PFC GABA Interneuron活性的晚期促进。我们的预测是，谷氨酸能驱动到PFC中间神经元的突触前促进决定了多巴胺对PFC抑制性传播的正常成熟。我们的结果应导致新型的生理和分子策略，以瞄准PFC核元间成熟的突触前机制，从而增加皮质抑制性传播。公共卫生相关性：该提案旨在确定皮质活性年龄依赖性调节的基础的细胞机制，重点是前额叶皮质间神经元电路。这种发育调控与精神分裂症的病理生理学高度相关，因为在发育过程中融合了发现中的中间神经元缺陷，这是该疾病的潜在基础。因此，成功完成拟议的应用应导致发现概念，药理和生理工具，能够解剖抑制性网络的作用，而抑制性网络是正常和异常的周围会议过渡到成年期的，并就精神分裂症的认知症状如何在青少年后期出现。