The impact of drugs of abuse on striatal circuits

滥用药物对纹状体回路的影响

• 批准号: 9068059
• 负责人: Adam G Carter
• 金额: $ 34.53万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068059
• 关键词: AMPA Receptors; Amygdaloid structure; Behavior; Biochemical; Brain region; Cell Nucleus; Cocaine; Complement; Corpus striatum structure; Data; Dendrites; Dendritic Spines; Distal; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Electrophysiology (science); Event; Globus Pallidus; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Individual; Laboratories; Learning; Location; Membrane; Microscopy; Midbrain structure; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Physiological; Population; Prefrontal Cortex; Process; Property; Rewards; Role; Signal Pathway; Signal Transduction; Subthalamic structure; Synapses; Synaptic plasticity; Thalamic structure; Ventral Striatum; Vertebral column; Whole-Cell Recordings; Work; addiction; cell type; cocaine exposure; drug of abuse; in vivo; innovation; insight; new growth; novel; optogenetics; postsynaptic; preference; relating to nervous system; research study; response; tool; transmission process; two-photon

DESCRIPTION (provided by applicant): The Nucleus Accumbens (NAc) is important for the learning and expression of reward-related behaviors, and strongly influenced by drugs of abuse. Medium spiny neurons (MSNs) are the principal cells of the NAc, and are commonly segregated into two distinct populations. MSNs expressing D1 dopamine receptors project directly to the midbrain (D1-MSNs), while MSNs expressing D2 dopamine receptors project indirectly via the ventral pallidum (D2-MSNs). D1-MSNs and D2-MSNs process long-range excitatory inputs from the prefrontal cortex, thalamus, ventral hippocampus and basolateral amygdala. Recent findings from our laboratory indicate that synaptic connectivity in the NAc is both cell-type and input-specific, with hippocampal inputs stronger at D1-MSNs, and other long-range inputs largely unbiased. Glutamatergic inputs ultimately synapse onto spines, the small membrane protrusions found throughout the dendrites of D1-MSNs and D2-MSNs. Each spine receives a single synaptic contact, and possesses the machinery for postsynaptic transmission, including both AMPA and NMDA receptors. The types and locations of targeted spines dictate postsynaptic responses, with inputs onto smaller or distal spines evoking weaker signals. Recent studies from our laboratory, using a novel combination of two-photon microscopy and optogenetics, reveal that subcellular connectivity is also cell-type and input-specific. Thus, hippocampal inputs selectively contact larger, proximal spines at D1-MSNs, whereas other long-range inputs show limited preference. Cocaine and other drugs of abuse are well known to have dramatic effects on both the morphological and physiological properties of MSNs in the NAc. Cocaine sensitization is a hyper-responsiveness to repeated cocaine exposure, and promotes the growth of new spines and formation of new synapses. These classical observations suggest a rearrangement of functional circuits, but the types of long-range excitatory inputs that are impacted remain unknown. New preliminary data from our lab indicates that repeated cocaine exposure triggers dramatic changes to cell-type and input-specific synaptic connectivity. Our proposed experiments will characterize how cocaine sensitization impacts the synaptic organization of the NAc at the levels of neurons, dendrites and spines. This work involves a powerful combination of whole-cell recordings, optogenetics, two-photon microscopy, two-photon uncaging, in vivo pharmacology and in vivo pharmacogenetics. Our long-term goal is to further our understanding of how cocaine and other drugs of abuse reorganize striatal circuits during the transition to drug addiction.

描述（由申请人提供）：伏隔核（NAc）对奖励相关行为的学习和表达很重要，并且受到滥用药物的强烈影响。中棘神经元（msn）是NAc的主要细胞，通常分为两个不同的群体。表达D1多巴胺受体的MSNs直接投射到中脑（D1-MSNs），而表达D2多巴胺受体的MSNs通过腹侧白质（D2-MSNs）间接投射。d1 - msn和d2 - msn处理来自前额皮质、丘脑、海马腹侧和杏仁核基底外侧的远程兴奋输入。我们实验室最近的研究结果表明，NAc的突触连通性具有细胞类型和输入特异性，海马输入在d1 - msn处更强，而其他远程输入在很大程度上是无偏倚的。谷氨酸能的输入最终在脊椎上突触，d1 - msn和d2 - msn的树突上发现了小的膜突起。每个脊柱接受一个单一的突触接触，并具有突触后传递机制，包括AMPA和NMDA受体。目标脊柱的类型和位置决定了突触后的反应，输入到较小或远端脊柱唤起较弱的信号。我们实验室最近的研究，利用双光子显微镜和光遗传学的新组合，揭示了亚细胞连接也是细胞类型和输入特异性的。因此，海马输入