Circuit and synaptic basis of cognitive control in monkey prefrontal cortex

 描述(申请人提供)：这项提议的目的是描述猴子前额叶皮质认知控制的回路基础，并了解特定的失败是如何 电路动力学会导致认知控制错误，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。为了评估电路中神经元之间的功能交互作用，我们将结合前额叶和顶叶皮质的大规模单个神经元记录，同时猴子执行相同的认知控制任务，用于测量神经精神疾病患者的认知障碍。这将提供多组同时记录的神经元(每组包含~40-60个神经元)。前额叶和顶叶皮质在解剖学上是相连的，都有助于认知控制。然后，我们将分析同时记录的神经元的棘波序列中的时间关系，以检测它们之间的功能耦合模式。我们将推断，如果神经元之间的动作电位的时序或它们编码的行为信息的波动在快速时间尺度上随着时间的推移而变化，神经元在功能上是耦合的。为了测量这些相互作用，我们开发并应用了两种新的分析方法，分别根据尖峰时间和编码信息来量化神经元之间的功能耦合。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联系起来。这为在前额叶电路中将突触功能与计算联系起来提供了基础。接下来，我们将使用一种全身给药的药物来阻断猴子的NMDAR。这将在猴子身上诱导一段暂时性的认知障碍，在此期间，它们会在任务执行中犯下特定的错误模式，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)认知控制的计算是通过前额叶电路中神经元之间的信息传递来调节的，(B)这种传递是通过对通讯神经元中动作电位的时序进行精确控制来调节的，(C)通讯神经元中的动作电位时序受到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时序关系，(E)这导致神经元之间的信息传输的丢失，(F)导致认知控制失败。通过建立从突触到回路再到认知的这一系列事件，我们将把神经精神疾病中出现的一种非常特殊的认知衰竭模式与因果皮质回路衰竭联系起来。

 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.