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酒精对小鼠丘脑抑制的调节。众所周知，丘脑是向大脑皮层传递感觉信息的中转站，在调节睡眠方面发挥着重要作用。腹基底复合体中的丘脑皮质中继神经元表现出双稳定的兴奋性模式。在“强直放电”模式（当神经元去极化时），神经元连续放电，而在“爆发放电”模式（当神经元超极化时），VB神经元在约3-5Hz的慢节奏（δ）上叠加短暂的快速动作电位爆发，这是慢波睡眠和缺乏性癫痫的特征。VB神经元接受外周网状核（RTN） 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神经元也表现出“强直性”抑制。这种强直性抑制对VB神经元产生持续的超极化影响。据推测，突触抑制和强直抑制都可能对中继神经元“突发放电”的时间和同步产生强烈影响。我们建议对酒精与丘脑GABA的相互作用进行全面的研究。尽管丘脑中存在多种gaba亚型，但突触抑制涉及VB中的a和y2亚基以及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，这是一群GABAA-Rs，被认为对酒精的调节高度敏感。本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，急性和慢性饮酒都会扰乱睡眠，因此，对酒精对丘脑的影响的详细调查应该会提供一些见解，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.