Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

突触传递：调节、可塑性和滥用药物的影响

• 批准号: 8344686
• 负责人: David M Lovinger
• 金额: $ 156.58万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344686
• 关键词: Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; Animal Model; Animals; Axon; Behavior; Behavior Control; Behavioral; Blood alcohol level measurement; Brain; Brain region; CNR1 gene; Calcium Channel; Cell Nucleus; Chronic; Cognition; Corpus striatum structure; Decision Making; Dendrites; Dendritic Spines; Dependence; Development; Dorsal; Drug Exposure; Elements; Endocannabinoids; Ethanol; Excitatory Synapse; Exposure to; Fetal Alcohol Spectrum Disorder; Frequencies; G-Protein-Coupled Receptors; Glutamates; Goals; Habits; Human; Individual; Intake; Interneurons; Intoxication; Investigation; Knowledge; L-Type Calcium Channels; Laboratories; Learning; Life; Light; Lobular Neoplasia; Long-Term Depression; Macaca; Mediating; Membrane Potentials; Membrane Proteins; Monkeys; Mus; Neurons; Neurosciences; Output; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Pregnancy; Process; Production; Prosencephalon; Receptor Activation; Reporting; Research; Research Personnel; Rhodopsin; Risk Factors; Role; Shapes; Signal Transduction; Site; Sorting - Cell Movement; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Work; addiction; alcohol behavior; alcohol effect; alcohol seeking behavior; alcohol use disorder; base; caudate nucleus; chronic alcohol ingestion; drinking; drug of abuse; early onset; fetal; habit learning; in vivo; interest; neural circuit; neuroadaptation; neuronal cell body; neuronal excitability; neuroregulation; postnatal; postsynaptic; presynaptic; putamen; relating to nervous system; research study; response; synaptic depression; transmission process; vapor; voltage

Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning. Long-term depression at striatal GABAergic synapses We have continued our studies of long-term synaptic depression (LTD) at synapses in striatum. Previous work in the laboratory indicated that LTD occurs at GABAergic synapses intrinsic to the striatum. This LTD can be induced by afferent activation at low-moderate frequencies, and requires endocannabinoid signaling. The two predominant GABAergic inputs to striatal projection neurons (medium spiny neurons or MSNs) come from axon collaterals of other MSNs that synapse mainly on the MSN dendrites, and from the fast-spiking interneurons that synapse mainly near the MSN soma. We have used optogenetic techniques to activate the two GABAergic inputs independently, by expressing channel rhodopsin 2 selectively in the two neuronal subtypes and activating this channel with light. This approach has revealed two types of LTD at these GABAergic synapses. When the membrane potential of the postsynaptic MSN is near the normal resting potential called the "down-state", LTD occurs at both sets of inputs, and does not require activation of voltage-gated calcium channels. However, when the MSN membrane potential is depolarized to values near the "up-states" seen in vivo, LTD occurs exclusively at MSN-MSN synapses, and appears to involve L-type calcium channel activation. Under all conditions, LTD is mediated by endocannabinoids acting at CB1 receptors. Current experiments are exploring the different mechanisms involved in up-state versus down-state GABAergic LTD. These studies have revealed that endocannabinoids can produce differential patterns of synaptic plasticity depending on the afferent input and the state of the postsynaptic neuron. These mechanisms have the potential to shape striatal output in multiple ways by differentially affecting inhibition near excitatory synapses on the MSN dendrites, or neuronal activation controlled by GABAergic synapses near the soma. Ethanol actions at striatal GABAergic synapses We are also continuing our studies of ethanol (EtOH) effects on GABAergic synaptic transmission in dorosolateral (DLS) and dorsomedial striatum (DMS). Our observation that EtOH inhibits GABAergic synaptic transmission in DLS MSNs via a presynaptic mechanism, while potentiating transmission in DMS, suggests differential mechanisms of EtOH action in the two striatal subregions. We are currently using pharmacological approaches, as well as the optogenetic techniques described above, to determine if these differential EtOH effects occur at different afferent inputs to MSNs. These opposing effects are surprising, and may indicate that EtOH suppresses the output of the DMS that is important for goal-directed actions, while enhancing the output of DLS which is involved in habit formation. Our continuing studies of chronic EtOH effects in mice and macaque monkeys have revealed synaptic changes that could contribute to prolonged, habitual alcohol use and abuse. In both model organisms, chronic EtOH exposure leads to a maintained decrease in GABAergic synaptic transmission in DLS and DMS (roughly equivalent to putamen and caudate nucleus, respectively, in monkeys). The findings in monkey are particularly interesting, as the alcohol drinking in this model organism is heavy and prolonged, sharing many features with human drinking. One notable feature of drinking in these monkeys is that animals develop highly regular alcohol intake with increased duration of intake bouts after 2 years of drinking, and the blood alcohol levels they achieve gradually escalate over a three year period. The decreased GABAergic transmission we have observed in putamen MSNs from these monkeys is strongly correlated with the average alcohol intake for each individual monkey. We have also observed increases in glutamatergic synaptic transmission and increased numbers of dendritic spines (the sites of glutamatergic synapses) in the putamen of the chronic EtOH-drinking monkeys. Intrinsic neuronal excitability is also increased after prolong drinking in the putamen MSNs. Recent findings have extended our knowledge by showing that GABAergic synaptic changes are greater in monkeys with earlier onset of drinking, a known risk factor for human alcohol use disorders. The synaptic changes that we have observed in these monkeys appear to render the putamen nucleus hyperexcitable, due to a combination of decreased GABAergic inhibition and increased intrinsic and glutamatergic synaptic excitability. Given the role of the putamen and associated circuitry in development and production of repetitive habitual actions, we hypothesize that the hyperexcitable putamen contributes to maintained, invariant patterns of drinking with high alcohol loading observed in the monkeys. We are also continuing to study effects of fetal/early-postnatal EtOH exposure on striatal function. This project was stimulated by reports implicating altered corticostriatal function in humans with fetal alcohol spectrum disorder (FASD). We are using vapor exposure to EtOH during gestation and the early postnatal period. Electrophysiological experiments have revealed decreased GABAergic synaptic transmission in DLS MSNs examined in adult mice following fetal/early postnatal EtOH exposure. The normal decrease in GABAergic transmission produced by acute exposure to EtOH is lost in these mice, suggesting development of some sort of tolerance to EtOH actions. Interestingly, the synaptic depression normally produced by CB1 receptor activation is also lost in the fetal/early postnatal EtOH-exposed mouse DLS MSNs. Preliminary studies indicate that this effect is selective for CB1 in comparison to to other presynaptic G protein-coupled receptors, and that an abnormal tonic activation of CB1 receptors by eCBs may occur as a consequence of this early life EtOH exposure. Our parallel behavioral studies indicate that this early-life EtOH exposure also impairs habit learning in the mice, and disrupts the associated changes in striatal neuronal activity. These experiments have revealed changes in striatal synaptic transmission that could contribute to abnormalities in the corticostriatal circuitry seen in FASD.

关于综合神经科学实验室的研究，关于突触药理学的部分，继续专注于神经调节和可塑性的基础机制以及酒精和其他滥用药物对这些神经元功能的影响。我们的主要兴趣是背纹状体（DS）的功能，这是一个涉及动作控制和选择的大脑区域以及动作学习。 纹状体GABA能突触的长期抑郁症 我们继续研究纹状体突触中长期突触抑郁症（LTD）。 实验室的先前工作表明，LTD发生在Gabaergic Synaps int int in striatum。 该有限公司可以通过低压频率的传入激活来诱导，并且需要内源性大麻素信号传导。 对纹状体投影神经元（中刺神经元或MSN）的两个主要GABA能输入来自其他MSN的轴突侧支，这些MSN主要是在MSN树突上突触的，来自MSN的突触中，来自MSN Soma附近突触的快速尖刺中间神经元。 我们已经使用光遗传技术来独立地激活两种GABA能输入，通过在两个神经元亚型中选择性地表达通道Rhodopsin 2并用光激活该通道。 这种方法在这些GABA能突触中揭示了两种类型的LTD。 当突触后MSN的膜电位接近称为“下降状态”的正常静息电位时，LTD在两组输入中都发生，并且不需要激活电压门控钙通道。 但是，当将MSN膜电位去极化为在Vivo，Ltd中看到的“ UP-States”附近的值时，仅在MSN-MSN突触处发生，并且似乎涉及L型钙通道激活。 在所有情况下，LTD都是由作用于CB1受体的内源性大麻素介导的。 当前的实验正在探索与状态与镇压Gabaergic Ltd相关的不同机制。 这些研究表明，内源性大麻素可以根据传入输入和突触后神经元的状态产生突触可塑性的差异模式。 这些机制具有通过多种方式塑造纹状体输出的潜力，通过在MSN树突上的兴奋性突触差异抑制，或者由SOMA附近的GABAergic突触控制的神经元激活。 纹状体GABA能突触的乙醇作用 我们还继续研究乙醇（ETOH）对多骨外侧（DLS）和背侧纹状体（DMS）中GABA能突触传递的影响。我们的观察结果是，ETOH通过突触前机制抑制DLS MSN中的GABA能突触传播，同时增强DMS的传播，这表明在两个纹状体子区域中EtOH作用的差异机制。我们目前正在使用上述药理方法以及上述的光遗传学技术来确定这些差异ETOH效应是否出现在不同传入输入的MSN。 这些相反的效果令人惊讶，并且可能表明ETOH抑制了DMS的输出，这对于目标指导的动作很重要，同时增强了与习惯形成有关的DLS的输出。 我们对小鼠和猕猴慢性ETOH效应的持续研究表明，突触变化可能导致长时间的习惯性饮酒和滥用。在这两种模型生物体中，慢性ETOH暴露均导致DLS和DMS中GABA能突触传播的降低（分别与猴子和尾状核大致相当于猴子）。 猴子中的发现特别有趣，因为这种模型生物体中的饮酒量很大且延长，因此与人类饮酒共享许多特征。 在这些猴子中喝酒的一个值得注意的特征是，在饮酒2年后，动物会出现高度规则的酒精摄入量，并增加了摄入量的持续时间，而血液酒精含量在三年内逐渐升级。 我们在这些猴子中观察到的Putamen MSN中观察到的GABA能传播与每个猴子的平均酒精摄入密切相关。 我们还观察到谷氨酸能突触传播的增加，并且在慢性Etoh饮用的猴子的壳中增加了树突状刺的数量（谷氨酸能突触的位置）。 长期毒壳MSN饮用后，固有的神经元兴奋性也会增加。 最近的发现扩大了我们的知识，表明猴子较早发作的猴子是人类饮酒障碍的已知危险因素。我们在这些猴子中观察到的突触变化似乎使壳核核过度可变，这是由于降低的GABA能抑制作用以及内在和谷氨酸能突触兴奋性的增加。 鉴于壳核和相关电路在重复习惯作用的发展和生产中的作用，我们假设过度可见的鬼衣有助于维持，不变的饮酒模式，并在猴子中观察到高酒精负荷。 我们还继续研究胎儿/早期postnatal etoH暴露对纹状体功能的影响。该项目的刺激是由于胎儿酒精谱系障碍（FASD）的人类皮质纹状体功能改变的报道而受到刺激。我们在妊娠期间和产后早期使用蒸气暴露于EtOH。 电生理实验表明，在胎儿/早期产后ETOH暴露后，在成年小鼠中检查的DLS MSN中的GABA能突触传播降低。 在这些小鼠中，由于急性暴露于EtOH而产生的GABA能传播的正常​​降低，这表明对ETOH作用产生了某种耐受性。 有趣的是，在产后/早期暴露于ETOH暴露的小鼠DLS MSN中，通常由CB1受体激活产生的突触抑制也丢失。 初步研究表明，与其他突触前G蛋白偶联受体相比，CB1具有选择性，并且ECB可能会因这种早期寿命ETOH暴露而导致ECB对CB1受体的异常强化。 我们的平行行为研究表明，这种早期的ETOH暴露还会损害小鼠的习惯学习，并破坏纹状体神经元活性的相关变化。 这些实验揭示了纹状体突触传递的变化，这可能导致FASD中皮质纹状体电路异常。