Alcohol and GABA in the Thalamus

描述(申请人提供)：本研究项目的目的是研究酒精对小鼠丘脑抑制的调节。众所周知，丘脑是将感觉信息传递到大脑皮层的中继器，在调节睡眠方面发挥着重要作用。丘脑皮质中继神经元在腹基底部(VB)复合体中表现出双稳态的兴奋性模式。在“紧张性放电”模式下(神经元去极化时)，神经元持续放电，而在“爆发放电”模式下(神经元超极化时)，VB神经元发射叠加在大约3-5赫兹的慢(增量)节律上的短暂、快速的动作电位爆发，这是慢波睡眠和失神癫痫的特征。VB神经元接受外周网状核(RTN)内GABA能神经元的抑制性输入，从而激活突触GABA受体(GABAA-R)，并在VB神经元中产生快速的IPSP。除了这些“相”抑制事件，VB神经元也表现出“紧张性”抑制，这是由于突触外GABAA-R的持续激活所致。这种紧张性抑制对VB神经元产生持续的超极化影响。有人假设，突触抑制和紧张性抑制都可以对中继神经元的“爆发放电”的时间和同步性产生强烈的影响。我们建议对酒精和GABA在丘脑中的相互作用进行全面的研究。虽然丘脑中存在多种GABA亚型，但突触抑制涉及VB中的α和y2亚基，以及RTN中的CC3、f33和Y2亚基。VB中的紧张性抑制是由含有CT4和5亚基的受体产生的，这是一组被认为对酒精调节高度敏感的GABAA-R。这项修订提案的具体目的是：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。众所周知，急性和长期饮酒会扰乱睡眠，因此，对酒精对丘脑影响的详细研究应该会提供一些见解，可能会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。

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.