Circuit and synaptic basis of cognitive control in monkey prefrontal cortex

 描述（由申请人提供）：本提案的目的是描述猴子前额叶皮层中认知控制的电路基础，并了解特定故障 电路动力学的变化会导致认知控制的错误，这与包括精神分裂症在内的几种人类神经精神疾病非常相似。为了评估回路中神经元之间的功能性相互作用，我们将结合联合收割机，同时在前额叶和顶叶皮层中进行大规模的单神经元记录，同时猴子执行用于测量神经精神病患者认知障碍的相同认知控制任务。这将提供多组同时记录的神经元（每组包含约40-60个神经元）。前额叶皮层和顶叶皮层在解剖学上是相连的，两者都有助于认知控制。然后，我们将分析同时记录的神经元的尖峰序列中的时间关系，以检测它们之间的功能耦合模式。我们将推断，神经元在功能上是耦合的，在这种情况下，它们的动作电位的时间，或它们编码的行为信息的波动，随着时间的推移在快速的时间尺度上在神经元之间协变。为了测量这些相互作用，我们开发和应用两种新的分析方法，量化神经元之间的功能耦合的尖峰时间和编码信息。然后，我们将神经元之间的功能耦合模式与任务所需的特定信息处理操作相关联。这提供了一个基础，将突触功能与计算在前额叶回路。接下来，我们将使用全身给药药物阻断猴子的NMDA受体（NMDAR）。这将在猴子中引起短暂的认知障碍，在此期间，它们将在任务执行中产生特定的错误模式，这与精神分裂症患者执行相同任务的错误模式几乎相同。认知障碍期间的神经记录将使我们能够将功能耦合的变化与表现错误联系起来。我们将检验以下假设：（a）用于认知控制的计算由前额叶回路中的神经元之间的信息传递介导，（B）该传递由通信神经元中的动作电位定时的精确控制介导，（c）通信神经元中的动作电位定时受到NMDA受体的强烈影响，（d）NMDAR突触功能的丧失扭曲了神经元之间的活动定时关系，（e）这导致神经元之间的信息传递丢失，（f）导致认知控制失败。通过建立从突触到回路再到认知的事件链，我们将把神经精神疾病中出现的一种非常特殊的认知障碍模式与因果性皮质回路故障联系起来。

 DESCRIPTION (provided by applicant): The objective of this proposal is to characterize the circuit basis of cognitive control in monkey prefrontal cortex, and to learn how a specific failure of circuit dynamics can lead to errors in cognitive control that are very much like those seen in several human neuropsychiatric diseases, including schizophrenia. To evaluate functional interactions between neurons in circuits, we will combine large scale, single neuron recording in prefrontal and parietal cortex simultaneously while monkeys perform the same cognitive control task used to measure cognitive impairment in neuropsychiatric patients. This will provide many sets of simultaneously recorded neurons (each containing ~40-60 neurons). Prefrontal and parietal cortex are anatomically connected and both contribute to cognitive control. We will then analyze temporal relationships in the spike trains of simultaneously recorded neurons to detect patterns of functional coupling between them. We will infer that neurons are functionally coupled in cases that the timing of their action potentials, or fluctuations in the behavioral information they encode, covary between neurons over time on a rapid time scale. To measure these interactions, we develop and apply two novel analytical approaches that quantify functional coupling between neurons both in terms of spike times and coded information. We then relate patterns of functional coupling between neurons to specific information processing operations required by the task. This provides a basis to relate synaptic function to computation in prefrontal circuits. Next we will block NMDA receptors (NMDAR) in monkeys using a systemically administered drug. This will induce a transient period of cognitive impairment in monkeys, during which time they will make a specific pattern of errors in task performance that is nearly identical to the error pattern of patients with schizophrenia performing the same task. Neural recording during the cognitive impairment will allow us to relate changes in functional coupling to errors in performance. We will test the hypotheses that: (a) computations for cognitive control are mediated by information transfer between neurons in prefrontal circuits, (b) this transmission is mediated by precise control of the timing of action potentials in communicating neurons, (c) action potential timing in communicating neurons is strongly influenced by NMDA receptors, (d) loss of NMDAR synaptic function distorts activity timing relationships between neurons, (e) this causes loss of information transfer between neurons, (f) leading to cognitive control failure. By establishing this chain of events, from synapses through circuits to cognition, we will relate a very specific pattern of cognitive failure seen in neuropsychiatric disease to a causal cortical circuit failure.