Alcohol and GABA in the Thalamus

丘脑中的酒精和 GABA

• 批准号: 7392407
• 负责人: NEIL L. HARRISON
• 金额: $ 7.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392407
• 关键词: Absence Epilepsy; Action Potentials; Acute; Alcohols; Animal Model; Cell Nucleus; Complex; Delta Rhythm; Development; Disruption; Effectiveness; Event; Exhibits; Fire - disasters; Frequencies; Future; Generations; Human; Intoxication; Investigation; Kinetics; Measures; Mediating; Mus; Neurons; Output; Pattern; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Physiologic pulse; Play; Population; Pulse taking; Regulation; Research Personnel; Research Project Grants; Role; Sensory; Site; Sleep; Sleep Disorders; Slow-Wave Sleep; Synapses; Synaptic Transmission; Testing; Thalamic structure; Time; alcohol effect; caN protocol; chronic alcohol ingestion; computerized data processing; drinking; experience; gabazine; gamma-Aminobutyric Acid; insight; postsynaptic; presynaptic; problem drinker; programs; receptor; research study; sleep regulation; social; synaptic inhibition; young adult

DESCRIPTION (provided by applicant): The objective of this research project is to study the regulation of inhibition by alcohol in the mouse thalamus. The thalamus is well known to act as a relay of sensory information to the cortex and to play an important role in the regulation of sleep. Thalamocortical relay neurons in the ventrobasal (VB) complex exhibit a bi-stable pattern of excitability. In the "tonic firing" mode (when the neuron is depolarized), the neurons fire continuously, while in the "burst firing" mode (when the neuron is hyperpolarized), VB neurons fire brief rapid bursts of action potentials superimposed on a slow (delta) rhythm of about 3-5Hz that is a feature of slow wave sleep and absence epilepsy. VB neurons receive inhibitory inputs from GABAergic neurons in the peripheral reticular nucleus (RTN), which results in the activation of synaptic GABAA receptors (GABAA-R) and the generation of fast IPSPs in VB neurons. In addition to these 'phasic' inhibitory events, VB neurons also show 'tonic' inhibition, due to the persistent activation of extra-synaptic GABAA-R. This tonic inhibition generates a constant hyperpolarizing influence on the VB neurons. It has been hypothesized that both synaptic and tonic inhibition can have a strong influence on the timing and synchronization of "burst firing" in the relay neurons. We propose to carry out a comprehensive study of the interactions of alcohol with GABA in the thalamus. Although a variety of GABAAsubtypes exist in the thalamus, synaptic inhibition involves a, and y2 subunits in VB and cc3, f33 and Y2 subunits in RTN. Tonic inhibition in VB is generated by receptors containing ct4 and 5 subunits, a population of GABAA-Rs that is suggested to be highly sensitive to modulation by alcohol. The specific aims of this revised proposal are: 1) To study the effects of alcohol on GABA-mediated inhibition in VB and RTN neurons. 2) To study the effects of alcohol and GABAA-R antagonists on signal processing by VB neurons. 3) To investigate the mechanisms of the effects of alcohol on inhibition in VB and RTN neurons. Acute and chronic use of alcohol is known to disrupt sleep, so the detailed investigation of alcohol effects in the thalamus should provide insights that could direct future studies into sleep disorders in alcoholics and assist in the development of useful therapies.

描述（由申请人提供）：本研究项目的目的是研究酒精对小鼠丘脑的抑制作用的调节。众所周知，丘脑充当皮质感觉信息的中继，并在睡眠调节中发挥重要作用。腹基底层 (VB) 复合体中的丘脑皮质中继神经元表现出双稳态兴奋性模式。在“强直放电”模式下（当神经元去极化时），神经元连续放电，而在“突发放电”模式下（当神经元超极化时），VB神经元会放电短暂快速的动作电位，叠加在缓慢的动作电位上。 δ）约 3-5Hz 的节律，这是慢波睡眠和失神性癫痫的特征。 VB 神经元接收来自外周网状核 (RTN) 中 GABA 能神经元的抑制性输入，导致突触 GABAA 受体 (GABAA-R) 激活并在 VB 神经元中产生快速 IPSP。除了这些“阶段性”抑制事件外，由于突触外 GABAA-R 的持续激活，VB 神经元还表现出“强直性”抑制。这种强直抑制对 VB 神经元产生持续的超极化影响。据推测，突触和强直抑制都可以对中继神经元中“爆发放电”的时间和同步产生强烈影响。我们建议对丘脑中酒精与 GABA 的相互作用进行全面研究。虽然丘脑中存在多种 GABAA 亚型，但突触抑制涉及 VB 中的 a、y2 亚基和 RTN 中的 cc3、f33 和 Y2 亚基。 VB 中的强直性抑制是由含有 ct4 和 5 亚基的受体产生的，这是一组 GABAA-R，被认为对酒精的调节高度敏感。该修订提案的具体目标是： 1) 研究酒精对 VB 和 RTN 神经元中 GABA 介导的抑制的影响。 2) 研究酒精和GABAA-R拮抗剂对VB神经元信号处理的影响。 3)探讨酒精抑制VB和RTN神经元的作用机制。众所周知，急性和慢性饮酒会扰乱睡眠，因此对酒精对丘脑影响的详细研究应该提供见解，可以指导未来对酗酒者睡眠障碍的研究，并有助于开发有用的疗法。