An in vitro model of saccadic eye movement choice

描述(由申请者提供)：本研究计划的总体目标是了解基底节(BG)和上丘(SC)在眼球跳动选择和决策中的作用。这项应用专注于开发一个体外脑片模型，利用该模型，我们将扩展我们最近的活体结果，并研究参与选择和决策的电路的生物物理。这一建议旨在将神经元及其回路的特性与行为联系起来，以阐明SC和BG在眼动相关认知过程中的作用。我们有四个具体目标：1)绘制整个供应链的响应模式。电压成像将被用来绘制电刺激后浅SC(SSC)和中间SC(ISC)中信号传播的空间模式。这一目标将为SC内层内和层间回路的空间范围提供基本的评估；2)评估SC活动模式中的抑制和兴奋。为此，我们将测试是否存在三条特定的层间通路：一条源于SSC并延伸至ISC的兴奋通路，一条源于ISC并延伸至SSC的抑制通路，以及一条源于ISC并延伸至SSC的兴奋通路。我们将结合电压成像和膜片钳技术来研究对SSC和ISC刺激的反应，并将这些反应分解为由谷氨酸和GABA能突触介导的贡献。使用突触受体拮抗剂的实验将评估谷氨酸和GABA能传递在层内和层间回路中的作用；3)确定BG输出对SC反应模式的影响。这一目的的实验将验证这样一种假设，即在ISC中，从SSc到运动信息的翻译是由BG的黑质网状部的抑制调制的。我们将在黑质施加电刺激，以确定黑质如何调制SC对SSC和ISC刺激的反应；4)在猴SC中映射SC的反应模式。我们将开发一种使用猴子组织的干细胞的体外制备方法。将进行目标1和目标2中概述的实验。我们将检验猴子和啮齿动物SC的潜在回路是同源的这一假设。由于BG及其靶结构与许多神经和精神疾病状态有关，我们的实验结果应该有助于我们深入了解这些回路的功能，以及在健康和疾病中复杂的行为和认知过程背后的生物物理机制。 与公共健康相关：更高心理功能的一个必要条件是我们的决策能力。选择行为的极端波动可能是某些神经和精神疾病的基础，如精神分裂症、注意力缺陷障碍、抽动症和强迫症。眼球运动异常也与这些皮质-基底节疾病有关。因此，更深入地了解基底节-上丘通路和回路，并最终了解它们在高级心理功能中的作用，可能会导致更好的诊断，更好的方法来评估治疗，并应该为这些疾病状态的症状学机制提供重要的见解。

DESCRIPTION (provided by applicant): The overall goal of this research plan is to understand the role of the basal ganglia (BG) and superior colliculus (SC) in saccadic eye movement choice and decision-making. This application focuses on developing an in vitro brain slice model with which we will extend our recent in vivo results and investigate the biophysics of a circuit involved in choice and decision-making. This proposal aims to link the properties of neurons and their circuits to behavior in order to elucidate the role of the SC and the BG in eye-movement related cognitive processes. We have four specific aims; 1) Map response patterns across the SC. Voltage imaging will be used to map the spatial patterns of signal spread following electrical stimulation in the superficial SC (sSC) and intermediate SC (iSC). This aim will provide a basic assessment of the spatial extent of both intra- and inter-laminar circuitry within the SC; 2) Evaluate inhibition and excitation in SC activity patterns. In this aim we will test for the existence of three specific interlaminar pathways: an excitatory pathway arising from the sSC extending to the iSC, an inhibitory pathway arising from the iSC and extending into the sSC and an excitatory pathway arising from the iSC and extending into the sSC. We will use voltage imaging in conjunction with patch clamping to study responses to sSC and iSC stimulation, and resolve these responses into contributions mediated by glutamatergic and GABAergic synapses. Experiments with synaptic receptor antagonists will assess the role of glutamatergic and GABAergic transmission in both intra- and interlaminar circuits; 3) Determine the influence of BG output on the response pattern across the SC. The experiments of this aim will test the hypothesis that translation of visual information from sSC into motor information in iSC is modulated by inhibition from the substantia nigra pars reticulata of the BG. We will apply electrical stimulation in the nigra to determine how the nigra modulates SC responses to sSC and iSC stimulation; 4) Map response patterns across the SC in monkey SC. We will develop an in vitro preparation of the SC using monkey tissue. Experiments as outlined in aims 1 and 2 will be performed. We will test the hypothesis that the underlying circuits in monkey and rodent SC are homologous. Because the BG and its target structures are implicated in many neurological and psychiatric disease states, the results of our experiments should lead to important insights into the functioning of these circuits and the biophysical mechanisms underlying complex behavioral and cognitive processing in both health and disease. PUBLIC HEALTH RELEVANCE: A sine qua non of higher mental function is our ability to make decisions. Extreme fluctuations in choice behavior may underlie certain neurological and psychiatric diseases such as schizophrenia, attention deficit disorder, Tourette Syndrome and obsessive compulsive disorder. Eye movement abnormalities are also associated with these cortico-basal ganglia diseases. Therefore, a deeper understanding of the basal ganglia - superior colliculus pathway and circuitry and ultimately their role in higher mental function, may lead to better diagnostics, better ways to assess therapies and should provide important insights into the mechanisms of symptomology in these disease states.