Cholinergic control of spatial attention: cellular and circuit mechanisms

描述（由申请人提供）：本研究的目的是探索胆碱能控制空间注意力的细胞和电路机制。包括精神分裂症和多动症在内的各种精神疾病患者通常表现为注意力和凝视控制失调，局部场电位的伽马（25-60 Hz）振荡异常调制以及胆碱能信号功能障碍。我们假设这四种症状现象的共同出现反映了它们在机制上的联系。我们将通过研究位于中脑刺激选择网络中心的胆碱能神经元的特性来验证这一假设，这四种现象在中脑刺激选择网络中汇合。我们将结合复杂的行为，体内电生理和体外切片方法。在Aim #1中，我们定量地描述了这些胆碱能神经元在训练鸡执行选择性注意任务时控制注意力和凝视中的因果作用；在Aim #2中，我们参数化并量化了它们在这些注意力要求高的任务背景下编码的信息；在Aim #3中，我们使用体外切片技术来揭示他们用来控制伽马振荡的功率和持续时间的突触机制。这种关键的胆碱能电路元件在空间上与鸟类的其他电路元件分离（唯一）。我们的实验利用鸟类的这种空间隔离，在体内和体外选择性地记录和操纵这一关键电路元件。我们假设这些神经元的活动对于中脑控制空间注意力和凝视的选择信号的产生至关重要；初步数据支持这一假设。我们的实验结果将阐明胆碱能机制在选择信号产生中的作用。发现这些机制将有助于深入了解涉及这四种现象的疾病的症状和原因，并为改进这些症状的诊断和合理治疗提供途径。

DESCRIPTION (provided by applicant): The purpose of this research is to explore the cellular and circuit mechanisms that underlie cholinergic control of spatial attention. Patients with various psychiatric disorders, including schizophrenia and ADHD, typically exhibit dysregulation of attention and gaze control, abnormal modulation of gamma (25-60 Hz) oscillations in local field potentials, and dysfunction of cholinergic signaling. We hypothesize that the co- occurrence of these four symptomatic phenomena reflects that they are mechanistically related. We will test this hypothesis by studying the properties of cholinergic neurons that lie at the heart of the midbrain stimulus selection network, where these four phenomena converge. We will use a combination of sophisticated behavioral, in vivo electrophysiological, and in vitro slice approaches. In Aim #1, we characterize quantitatively the causal role of these cholinergic neurons in the control of attention and gaze in chickens trained to perform selective attention tasks; in Aim #2, we parameterize and quantify the information they encode in the context of these attention-demanding tasks; and in Aim #3, we use in vitro slice techniques to reveal the synaptic mechanisms they employ to control the power and duration of gamma oscillations. This critical, cholinergic circuit element is spatially segregated from other circuit components in bird (uniquely). Our experiments take advantage of this spatial segregation in birds, to selectively record from and manipulate this critical circuit element in vivo and in vitro. We hypothesize that the action of these neurons is essential to the generation of selection signals that are issued by the midbrain for controlling spatial attention and gaze; preliminary data support this hypothesis. The results from our experiments will illuminate the role of cholinergic mechanisms in the generation of selection signals. Discovering these mechanisms will give insight into the symptoms and causes of diseases that involve these four phenomena, as well as suggest avenues for improved diagnosis and rational treatments of those symptoms.