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Early postnatal disruptions to glutamate and GABA systems and their contribution to reward deficits

产后早期谷氨酸和 GABA 系统的破坏及其对奖赏缺陷的影响

基本信息

批准号：
9925254
负责人：
Samuel Alan Barnes
金额：
$ 40.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925254
关键词：
Address Adult Affect Alzheimer&apos s Disease Animal Testing Anterior Attenuated Behavioral Brain Brain region Cells Complex Corpus striatum structure Development Disease Dorsal Enzymes Equilibrium Excitatory Amino Acid Antagonists Exhibits Female Functional disorder Glutamate Decarboxylase Glutamates Goals Immunofluorescence Immunologic Immunohistochemistry Impairment Interneurons Lead Major Depressive Disorder Measures Mediating Mental Depression Mental disorders Motivation N-Methylaspartate National Institute of Mental Health Neonatal Neurobiology Neurologic Neurons Parkinson Disease Parvalbumins Performance Phencyclidine Positive Valence Procedures Process Protein Isoforms Rattus Regulation Research Domain Criteria Research Project Grants Reversal Learning Rewards Role Saline Sampling Schizophrenia Somatostatin System Techniques Therapeutic Vasoactive Intestinal Peptide Ventral Striatum behavior test cingulate cortex functional disability gamma-Aminobutyric Acid improved male multidisciplinary neurobiological mechanism neurochemistry neurodevelopment neuropsychiatric disorder neurotransmission optogenetics postnatal postnatal period programs response reward processing transmission process

项目摘要

7. Project Summary/Abstract Deficits in reward function, including impaired reward valuation, effort valuation and reward responsiveness, are core features of psychiatric disorders, such as schizophrenia and major depressive disorder. These reward deficits contribute significantly to the functional disability evident in these disorders. These reward processes correspond to approach/motivation constructs within the Positive Valence Domain of the NIMH Research Domain Criteria (RDoC) Program. The neurobiology underlying reward deficits is not completely understood and, as a result, there are currently no therapeutics that effectively alleviate reward deficits in psychiatric disorders. Schizophrenia and depression are both associated with abnormalities in glutamate and GABA neurotransmission. The GABAergic system is essential in regulating correct glutamatergic transmission that maintains optimal cortical balance. Importantly, postnatal glutamate transmission is critical for the normal development of the GABAergic system. The overarching goal of this R01 application is to investigate how disrupting early postnatal glutamate transmission leads to reward deficits in adulthood. To address this experimental question, we will employ translational behavioral procedures in rats, optogenetics and immunohistochemical techniques to identify the role of altered glutamate and/or GABA transmission in brain regions associated with reward processing. Specific Aim 1 will determine whether administering the N-methyl- D-aspartate (NMDA) glutamate receptor antagonist phencyclidine (PCP) during the early postnatal period to male and female rats impairs reward valuation, effort valuation and/or reward responsiveness. Specific Aim 2 will use optogenetics to either increase or decrease glutamate activity in the orbitofrontal cortex (OFC) or anterior cingulate cortex (ACC) to determine whether such changes in glutamate activity impact reward valuation, effort valuation or reward responsiveness. Specifically, we will determine whether increased or decreased glutamate transmission impairs or improves reward processing in saline- or PCP-treated rats. These findings will provide evidence as to how changes in glutamate transmission lead to the regulation of multiple aspects of reward processing mediated by distinct brain regions. Specific Aim 3 will determine whether the reward deficits resulting from neonatal PCP treatment are associated with alterations in parvalbumin (PV)-, somatostatin (SST)- and/or vasoactive intestinal polypeptide (VIP)-positive GABA interneurons, and glutamic acid decarboxylase isoform 67 (GAD67) content, in brain regions critical for reward function (i.e., OFC, prelimbic cortex, anterior cingulate cortex, dorsal striatum and/or ventral striatum). This multidisciplinary project will promote our understanding of how alterations in neurobiology resulting from neonatally disrupted glutamate transmission contribute to deficits in reward function in adulthood. The generated findings may identify mechanisms that could be targeted to attenuate reward deficits in neuropsychiatric disorders.

7.项目总结/摘要奖励功能缺陷，包括奖励评估、努力评估和奖励响应性受损，是精神疾病的核心特征，如精神分裂症和重度抑郁症。这些奖励缺陷显著地导致这些疾病中明显的功能性残疾。这些奖励过程对应于NIMH研究的正价域中的方法/动机结构域标准（RDoC）计划。奖赏缺陷背后的神经生物学还没有完全被理解因此，目前还没有有效缓解精神病患者奖励缺陷的治疗方法。紊乱精神分裂症和抑郁症都与谷氨酸和GABA的异常有关神经传递γ-氨基丁酸能系统在调节正确的多巴胺能传输中是必不可少的，维持最佳的皮质平衡重要的是，出生后谷氨酸传输对正常的 GABA能系统的开发。此R 01应用程序的首要目标是研究如何破坏出生后早期的谷氨酸传递导致成年期的奖励缺陷。为了解决这个实验问题，我们将采用大鼠的翻译行为程序，光遗传学和免疫组织化学技术，以确定改变的谷氨酸和/或GABA传递在脑中的作用与奖励处理相关的区域。具体目标1将决定是否给予N-甲基-N-乙基-N-甲基-N D-天冬氨酸（NMDA）谷氨酸受体拮抗剂苯环利定（PCP）在出生后早期，雄性和雌性大鼠损害奖赏评价、努力评价和/或奖赏反应性。具体目标2 将使用光遗传学来增加或减少眶额皮质（OFC）中的谷氨酸盐活性，前扣带皮层（ACC），以确定谷氨酸活动的这种变化是否会影响奖励评价、努力评价或奖励响应。具体而言，我们将确定是否增加或降低谷氨酸传输损害或改善生理盐水或PCP治疗大鼠的奖励处理。这些发现将为谷氨酸传输的变化如何导致对谷氨酸的调节提供证据。奖励处理的多个方面由不同的大脑区域介导。具体目标3将确定是否新生儿PCP治疗导致的奖赏缺陷与小清蛋白（PV）的改变有关，生长抑素（SST）-和/或血管活性肠多肽（VIP）-阳性GABA中间神经元，和谷氨酸酸脱羧酶同种型67（GAD 67）含量，在对奖赏功能至关重要的脑区域（即，OFC，前边缘皮层、前扣带皮层、背侧纹状体和/或腹侧纹状体）。这个多学科项目将促进我们理解脑内谷氨酸破坏如何导致神经生物学改变传播导致成年期奖励功能的缺陷。生成的发现可以识别可能有针对性地减弱神经精神疾病中的奖励缺陷的机制。