Causally connecting neural activity to behavior with caged compounds

 描述（由申请人提供）：清醒动物的电生理记录允许神经科学家测量与感觉或运动事件相关的神经回路活动。从这种方法中获得的信息对于分析神经回路如何产生与药物成瘾相关的行为至关重要，包括寻求药物和奖励。然而，使用传统的电生理学方法，以这种方式获得的数据是纯粹相关的。此外，仅仅记录神经活动不足以确定回路一部分中神经元编码的信息如何影响“下游”节点中神经元的信息表示--这是神经回路分析的一个重要目标。在这里，我们提出了一种方法来操纵神经传输的时间和时间特异性的方式，允许实验者建立上游神经元如何有助于记录的神经活动和活动如何导致一个特定的行为事件。所提出的方法将允许我们将“笼”神经递质激动剂和拮抗剂应用于我们在清醒的行为动物中记录其活动的神经元。笼状化合物是通过共价连接的发色团而变得无效的生物活性分子。适当波长的光的应用导致键断裂，释放活性化合物。这种方法被广泛用于体外电生理研究，但迄今为止还没有研究报道其在清醒行为哺乳动物体内的应用。为了在清醒的大鼠中应用这种方法，我们将利用我们的专业知识，将药物应用于清醒动物中记录的神经元。我们将修改这种方法，通过光纤将光传递到大脑中，使我们能够通过局部灌注将化合物释放到组织中。拟议的实验将开发和测试能够进行此类实验的设备，并通过确定谷氨酸受体激动剂如何影响丘脑核中与行为相关的放电来证明该技术的有效性。

 DESCRIPTION (provided by applicant): Electrophysiological recording in awake animals allows neuroscientists to measure the neural circuit activity related to sensory or motor events. The information obtained from this approach is essential for analyzing how neural circuits produce behaviors related to drug addiction, including drug- and reward-seeking. However, with conventional electrophysiological methods, the data obtained in this way is purely correlative. In addition, merely recording neural activity is insufficient to determine how information encoded by neurons in one part of the circuit influences the representation of information by neurons in a "downstream" node - an important goal of neural circuit analysis. Here, we propose a method for manipulating neural transmission in a temporally and pharmacologically specific fashion, allowing the experimenter to establish both how upstream neurons contribute to recorded neural activity and how the activity causes a particular behavioral event. The proposed method will allow us to apply "caged" neurotransmitter agonists and antagonists to neurons whose activity we record in awake, behaving animals. Caged compounds are biologically active molecules that are rendered ineffective by a covalently attached chromophore. Application of light of the appropriate wavelength causes the bond to be broken, releasing the active compound. This method is widely used in electrophysiological studies in vitro, but no study to date has reported its application in vivo in awake behaving mammals. To apply this method in awake rats, we will take advantage of our expertise with application of drugs to neurons being recorded in awake animals. We will modify this approach by including light delivery into the brain via fiber optics, allowing us to uncage compounds introduced to the tissue via local perfusion. The proposed experiments will develop and test apparatus capable of such experiments, and demonstrate the effectiveness of the technique by determining how a glutamate receptor agonist influences behaviorally- relevant firing in the nucleus accumbens.