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: 8767134
• 负责人: Adam G Carter
• 金额: $ 35.44万
• 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/8767134
• 关键词: AMPA Receptors; Amygdaloid structure; Behavior; Biochemical; Brain region; Cell Nucleus; Cocaine; Complement; Corpus striatum structure; DNA Sequence Rearrangement; Data; Dendrites; Dendritic Spines; Distal; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Electrophysiology (science); Event; Globus Pallidus; Glutamate Receptor; Glutamates; Goals; 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; public health relevance; 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）：伏核（NAc）对于奖励相关行为的学习和表达非常重要，并且受到滥用药物的强烈影响。中棘神经元（MSNs）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MSN直接投射到中脑（D1-MSN），而表达D2多巴胺受体的MSN通过腹侧苍白球（D2-MSN）间接投射。D1-MSNs和D2-MSNs处理来自前额叶皮层、丘脑、腹侧海马和基底外侧杏仁核的长距离兴奋性输入。我们实验室的最新研究结果表明，NAc中的突触连接是细胞类型和输入特异性的，D1-MSNs的海马输入更强，其他长距离输入基本上是无偏的。谷氨酸能输入最终突触到棘上，棘是在D1-MSNs和D2-MSNs的树突上发现的小膜突起。每个棘接受单个突触接触，并拥有突触后传递的机制，包括AMPA和NMDA受体。目标棘的类型和位置决定了突触后反应，对较小或远端棘的输入引起较弱的信号。我们实验室最近的研究，使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，海马的输入 选择性地接触较大的，近端的棘在D1-MSNs，而其他远程输入显示有限的偏好。众所周知，可卡因和其他滥用药物对NAc中MSN的形态和生理特性具有显着影响。可卡因致敏是对重复接触可卡因的高反应性，并促进新棘的生长和新突触的形成。这些经典的观察表明功能电路的重新排列，但受到影响的长程兴奋性输入的类型仍然未知。来自我们实验室的新的初步数据表明，反复接触可卡因会引发细胞类型和输入特异性突触连接的巨大变化。我们提出的实验将描述可卡因敏化如何影响神经元、树突和棘水平的NAc的突触组织。这项工作涉及全细胞记录，光遗传学，双光子显微镜，双光子uncaging，体内药理学和体内药物遗传学的强大组合。我们的长期目标是进一步了解可卡因和其他滥用药物在向药物成瘾过渡期间如何重组纹状体回路。