Causally connecting neural activity to behavior with caged compounds

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 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.