Alcohol and GABA in the Thalamus

描述（由申请人提供）：本研究项目的目的是研究小鼠丘脑中酒精抑制的调节。众所周知，丘脑是将感觉信息传递到皮层的中继站，在睡眠调节中起着重要作用。丘脑皮质中继神经元的腹侧基底（VB）复杂表现出双稳态模式的兴奋性。在“强直放电”模式（当神经元被去极化时）中，神经元连续放电，而在“突发放电”模式（当神经元被超极化时）中，VB神经元发出叠加在约3- 5 Hz的慢（δ）节律上的动作电位的短暂快速突发，这是慢波睡眠和失神癫痫的特征。VB神经元接受来自外周网状核（RTN）中GABA能神经元的抑制性输入，这导致VB神经元中突触GABAA受体（GABAA-R）的激活和快速IPSP的产生。除了这些“阶段性”抑制事件，VB神经元也表现出“紧张性”抑制，由于突触外GABAA-R的持续激活。这种紧张性抑制对VB神经元产生持续的超极化影响。已经假设突触和紧张性抑制都可以对中继神经元中的“突发放电”的定时和同步产生强烈影响。我们建议进行全面的研究，酒精与GABA在丘脑中的相互作用。虽然在丘脑中存在多种GABAA亚型，但突触抑制涉及VB中的α 1和γ 2亚基以及RTN中的α 3、α 33和γ 2亚基。VB中的紧张性抑制是由含有α 4和β 5亚基的受体产生的，α 4和β 5亚基是GABAA-R的一个群体，被认为对酒精的调节高度敏感。本研究的具体目的是：1）研究酒精对GABA介导的VB和RTN神经元抑制的影响。2)研究酒精和GABAA-R拮抗剂对VB神经元信号处理的影响。3)探讨酒精对VB和RTN神经元抑制作用的机制。急性和慢性使用酒精会扰乱睡眠，因此对丘脑中酒精影响的详细研究应该提供一些见解，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治疗方法。

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.