Synaptic Integration in Neurons of the Thalamic Reticular Nucleus

描述(由申请人提供)：丘脑网状核(TRN)的GABA能神经元在控制感觉加工、在丘脑皮质网络中产生同步振荡以及在调节注意力方面发挥关键作用。TRN神经元被起源于皮质和丘脑的谷氨酸能输入迅速激活。反过来，它们与丘脑背侧核中的几个中继细胞形成强大的抑制性联系。TRN神经元的输出受局部GABA能突触网络以及起源于脑干和基底前脑的胆碱能传入系统的调节。这项建议的长期目标是更好地了解TRN在调节丘脑活动中所扮演的复杂角色。主要目的是确定不同类型的GABA能和胆碱能突触输入如何控制TRN神经元的输出。中心假说认为GABA能和胆碱能都能强烈地兴奋TRN神经元，并且特定类型的树突表达的电压和钙门控电导参与了这些输入的整合。这项拟议研究的基本原理是，了解TRN中GABA能和胆碱能信号转导的机制将有助于揭示TRN中潜在的网络活动的原理，最终转化为更好地理解导致TRN功能障碍的特定过程，这些过程与许多神经系统疾病相关。在强大的初步数据的指导下，中心假说将受到三个具体目标的检验：1)确定TRN中GABA能突触传递的功能特性。在这一目标下，将研究GABA激活TRN神经元的潜在机制及其对中继细胞活动的功能影响。2)确定树突电压和钙激活电导的功能作用。在这一目标下，将测试T型钙电导和SK钾电导对GABA能突触输入加工的贡献。3)确定TRN的胆碱能输入的性质。在这一目标下，我们将研究TRN内源性乙酰胆碱释放激活突触后烟碱受体和毒碱受体的动力学。这一方法将导致对丘脑突触传递的新见解。这项拟议的研究意义重大，因为它有望促进和扩大对不同突触输入如何塑造TRN网络活动的理解。 与公共健康相关：丘脑网状核是大脑中处理感觉输入和调节注意力的关键区域。这一提议将确定局部GABA能突触和传入胆碱能突触如何调节TRN神经元的活动。这些研究的结果将有助于确定新的治疗靶点，以治疗与TRN功能障碍相关的神经系统疾病，如失神癫痫或精神分裂症。

DESCRIPTION (provided by applicant): GABAergic neurons of the thalamic reticular nucleus (TRN) have critical roles in controlling sensory processing, in generating synchronous oscillations in thalamocortical networks, and in modulating attention. TRN neurons are rapidly activated by glutamatergic inputs that originate in both cortex and thalamus. In turn, they form powerful inhibitory connections with relay cells in several dorsal thalamic nuclei. TRN neuronal output is regulated by networks of local GABAergic synapses as well as by a system of cholinergic afferents that originate in the brainstem and basal forebrain. The long-term goal of this proposal is to better understand the complex roles TRN plays in regulating thalamic activity. The primary objective is to determine how distinct types of GABAergic and cholinergic synaptic inputs control the output of TRN neurons. The central hypothesis states that both GABAergic and cholinergic inputs can powerfully excite TRN neurons and that specific types of dendritically expressed voltage- and calcium gated conductances are involved in the integration of these inputs. The rationale for the proposed research is that understanding the mechanisms that underlie GABAergic and cholinergic signaling in the TRN will aid in revealing the principles underlying network activity in the TRN, ultimately translating into a better understanding of the specific processes leading to TRN dysfunction associated with a number of neurological diseases. Guided by strong preliminary data, the central hypothesis will be tested by three specific aims: 1) Determine the functional properties of GABAergic synaptic transmission in the TRN. Under this aim, both the mechanisms underlying GABA-evoked activation of TRN neurons as well as its functional consequences on relay cell activity will be examined. 2) Determine the functional role of dendritic voltage- and calcium activated conductances. Under this aim, the contribution of T-type calcium and SK potassium conductances for the processing of GABAergic synaptic inputs will be tested. 3) Determine the properties of cholinergic inputs to TRN. Under this aim, the dynamics underlying activation of postsynaptic nicotinic and muscarinic receptors by the release of endogenous acetylcholine in the TRN will be examined. This approach will lead to novel insights concerning synaptic transmission in the thalamus. The proposed research is significant, because it is expected to advance and expand understanding of how distinct synaptic inputs shape network activity in TRN. PUBLIC HEALTH RELEVANCE: The thalamic reticular nucleus is a brain area critical for the processing of sensory inputs and for the regulation of attention. This proposal will determine how local GABAergic synapses and afferent cholinergic synaptic inputs regulate activity in TRN neurons. Results from these studies will help to identify novel therapeutic targets to treat neurological diseases associated with TRN dysfunction, such as absence seizures or schizophrenia.