Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking
强迫性饮酒发展过程中内侧前额叶皮层的突触变化
基本信息
- 批准号:10573176
- 负责人:
- 金额:$ 35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-15 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholsAmygdaloid structureAnimal ModelAnimalsAutomobile DrivingBackBehaviorC57BL/6 MouseCREB1 geneCellsChloride ChannelsChronicCognitiveCognitive deficitsCuesDataDendritesDependenceDevelopmentElectrophysiology (science)Genetic RecombinationGlutamate ReceptorGlutamatesGoalsImmunohistochemistryImpaired cognitionImpulsive BehaviorInterneuronsLabelLightLithium ChlorideMedialModelingMorphologyMotivationMusN-Methyl-D-Aspartate ReceptorsNeuronsNucleus AccumbensOutputPathway interactionsPharmaceutical PreparationsPlayPopulationPrefrontal CortexPyramidal CellsReceptor Up-RegulationRelapseReporterResistanceResolutionRodentRoleSelf AdministrationSelf DirectionSynapsesSynaptic plasticityTaste aversionTestingTimeVertebral columnVisualizationWithdrawalWorkactivity markeralcohol availabilityalcohol exposurealcohol seeking behaviorcognitive changecognitive functioncombinatorialdrinkingdrug of abusedrug seeking behaviorexecutive functionexperimental studyflexibilityhippocampal pyramidal neuronimprovedincentive saliencelearning extinctionneuroadaptationnoveloptogeneticspatch clamppostsynapticpresynapticproblem drinkerreceptor expressionreceptor functionreceptor upregulationrelapse predictionresponsesynaptic functionvaporvoltage clamp
项目摘要
SUMMARY:
The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-
associated cues. Repeated alcohol exposure induces neuroadaptations that persist beyond acute withdrawal, and which
increase alcohol’s incentive salience, leading to escalation of alcohol intake and aversion-resistant alcohol seeking. Alcohol
use also causes deficits in cognitive functions associated with the medial prefrontal cortex (mPFC), which further fuel
compulsive drinking and relapse. In rodents, alcohol seeking activates specialized networks within the ventral (infralimbic,
IL) and prelimbic (PL) regions of the mPFC, which play largely opposite roles in the control of relapse behavior. While
activation of the PL drives reinstatement, neurons in the IL facilitate extinction learning and inhibit drug-seeking through
their projections to the Nucleus Accumbens shell, as well as the basolateral amygdala (BLA). However, the synaptic
mechanisms that drive maladaptive plasticity in these circuits during the transition from controlled to compulsive alcohol-
seeking remain largely unclear. The experiments in this application will provide a better understanding of network-specific
mechanisms through which chronic alcohol exposure and withdrawal affect executive cognitive functions of the mPFC and
diminish inhibitory control over goal-directed behavior.
In Aim 1 we use patch-clamp electrophysiology and optogenetic stimulation to determine changes in long-range
glutamatergic inputs from the BLA onto identified projection neurons in the IL and PL following extended access to alcohol,
as well as under postdependent conditions. We will use Targeted Recombination in Active Populations (TRAP2) with Fos2A-
iCreER mice to express channelrhodopsin selectively in those BLA afferents to the mPFC that are activated during withdrawal,
and we will determine how alterations in these inputs develop over time (from goal-directed to compulsive alcohol-
seeking). We will perform voltage-clamp recordings from retrogradely-labeled neurons that project back to the BLA, and
we will determine alcohol-induced changes in postsynaptic glutamate receptor function and presynaptic release following
reinstatement. Experiments in Aim 2 will use combinational retrograde Cre delivery and a Cre-dependent reporter to label
the same IL and PL projection neurons for high-resolution morphometric analyses of spines and glutamate receptor
expression in order to compare changes specifically in those neurons that contribute to relapse behavior (visualized via
co-labeling for the activity marker phospho-CREB) and those that do not (pCREB-negative cells). In Aim 3 we will again
use TRAP2 mice to test whether optogenetic manipulations of specific ensembles in the mPFC, or of inputs from the BLA
to the mPFC (each again TRAPed during withdrawal) can reverse alcohol-induced cognitive deficits and reduce drug-
seeking.
Taken together, these studies will provide important novel information about alcohol-induced synaptic changes in
networks of the IL that contribute to cognitive flexibility and cue-induced reinstatement.
总结:
抑制饮酒的能力对于正在康复的酗酒者来说是一个重大挑战,特别是在酒精存在的情况下-
相关线索反复的酒精暴露会诱导神经适应,这种适应在急性戒断后仍会持续,
增加酒精的激励显著性,导致酒精摄入量和厌恶酒精寻求的升级。醇
使用也会导致与内侧前额叶皮层(mPFC)相关的认知功能缺陷,这进一步加剧了
强迫性饮酒和复发在啮齿动物中,酒精寻求激活了腹侧(边缘下,
IL)和mPFC的前边缘(PL)区域,它们在控制复发行为中起着很大程度上相反的作用。而
PL的激活驱动恢复,IL中的神经元促进消退学习并通过抑制药物寻求,
它们向伏隔核壳以及基底外侧杏仁核(BLA)的投射。然而,突触
在从控制性酒精到强迫性酒精的过渡过程中,这些回路中驱动适应不良可塑性的机制,
但寻求在很大程度上仍不明确。本应用程序中的实验将提供对特定于网络的
慢性酒精暴露和戒断影响mPFC执行认知功能的机制,
减少对目标导向行为的抑制控制。
在目的1中,我们使用膜片钳电生理学和光遗传学刺激来确定长距离的变化。
在长期接触酒精后,从BLA到IL和PL中识别的投射神经元的突触能输入,
以及在依赖性条件下。我们将使用Fos 2A在活跃人群中的靶向治疗(TRAP 2)-
iCreER小鼠选择性地在戒断期间激活的mPFC的BLA传入中表达通道视紫红质,
我们将确定这些输入的变化如何随着时间的推移而发展(从目标导向到强迫性酒精,
寻求)。我们将对投射回BLA的逆行标记神经元进行电压钳记录,
我们将确定酒精诱导的突触后谷氨酸受体功能和突触前释放的变化,
复职目标2中的实验将使用组合逆行Cre递送和Cre依赖性报告物来标记
相同IL和PL投射神经元用于棘和谷氨酸受体的高分辨率形态计量学分析
表达,以比较那些有助于复发行为的神经元中的变化(通过
共标记活性标志物磷酸-CREB)和那些不共标记的(pCREB阴性细胞)。在目标3中,我们再次
使用TRAP 2小鼠来测试mPFC中特定集合的光遗传学操作或来自BLA的输入是否
mPFC(在戒断期间再次被捕获)可以逆转酒精诱导的认知缺陷,并减少药物-
寻找
总之,这些研究将为酒精诱导的突触变化提供重要的新信息。
IL的网络,有助于认知灵活性和线索诱导的恢复。
项目成果
期刊论文数量(0)
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SVEN KROENER其他文献
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{{ truncateString('SVEN KROENER', 18)}}的其他基金
Vagus nerve stimulation modulates synaptic plasticity in the rat prefrontal cortex during the extinction of drug-seeking
迷走神经刺激调节大鼠前额皮质在寻药消退过程中的突触可塑性
- 批准号:
10594495 - 财政年份:2022
- 资助金额:
$ 35万 - 项目类别:
Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking
强迫性饮酒发展过程中内侧前额叶皮层的突触变化
- 批准号:
10732680 - 财政年份:2022
- 资助金额:
$ 35万 - 项目类别:
Vagus nerve stimulation modulates synaptic plasticity in the rat prefrontal cortex during the extinction of drug-seeking
迷走神经刺激调节大鼠前额皮质在寻药消退过程中的突触可塑性
- 批准号:
10341341 - 财政年份:2022
- 资助金额:
$ 35万 - 项目类别:
Synaptic changes in the medial prefrontal cortex in the development of compulsive alcohol drinking
强迫性饮酒发展过程中内侧前额叶皮层的突触变化
- 批准号:
10367079 - 财政年份:2022
- 资助金额:
$ 35万 - 项目类别:
Effects of Chronic Alcohol Exposure on Synaptic Plasticity in the Prefrontal Cort
长期酒精暴露对前额皮质突触可塑性的影响
- 批准号:
7923710 - 财政年份:2009
- 资助金额:
$ 35万 - 项目类别:
Dopamine modulation of network activity in the prefrontal cortex.
多巴胺调节前额皮质网络活动。
- 批准号:
7369668 - 财政年份:2007
- 资助金额:
$ 35万 - 项目类别:
Dopamine modulation of network activity in the prefrontal cortex.
多巴胺调节前额皮质网络活动。
- 批准号:
7256122 - 财政年份:2007
- 资助金额:
$ 35万 - 项目类别:
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