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）：该研究项目的目的是研究小鼠丘脑中酒精抑制的调节。丘脑众所周知，可以作为感官信息传递给皮层的继电器，并在睡眠调节中发挥重要作用。腹侧（VB）复合物中的丘脑皮质中继神经元具有双稳定的兴奋性模式。 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神经元在周围网状核（RTN）中接受GABA能神经元的抑制输入，从而导致突触GABAA受体（GABAA-R）的激活和VB神经元中快速IPSP的生成。除了这些“阶段性”抑制事件外，VB神经元还由于持续激活突触外GABAA-R而显示出“补品”抑制作用。这种补品抑制作用会对VB神经元产生恒定的超极化影响。据推测，突触和补品抑制都可以对继电器神经元中“爆发”的时间和同步产生强大的影响。我们建议对丘脑中酒精与GABA的相互作用进行全面研究。尽管丘脑中存在多种gabaasubtypes，但RTN中的VB和CC3，F33和Y2亚基中的突触抑制涉及A和Y2亚基。 Vb中的滋补抑制作用是由含有CT4和5个亚基的受体产生的，这是GABAA-RS的种群，建议对酒精调节高度敏感。该修订的建议的具体目的是：1）研究酒精对VB和RTN神经元中GABA介导的抑制作用的影响。 2）研究酒精和GABAA-R拮抗剂对VB神经元信号处理的影响。 3）研究酒精对VB和RTN神经元抑制作用的影响的机制。众所周知，急性和长期使用酒精会破坏睡眠，因此丘脑中酒精效应的详细研究应提供洞察力，可以将未来的研究指导到酒精中毒中的睡眠障碍并有助于开发有用的疗法。