The use of fast scan cyclic voltammetry (FSCV) in conjunction with discrete behavioral events, such as learned lever presses, has proven to be a useful approach for studies of addiction and reward-based learning. Nevertheless, it neglects behavioral events that occur between lever presses and is limited in that the occurrence of many behaviors may not be identifiable by unaided human observation, placing a fundamental limitation on how much neurochemical information can be attributed to behaviors. Therefore, there is a critical need to develop an approach capable of correlating subtle movement with neurochemical measurements. The long-term goal is to develop methods that facilitate researchers'efforts to understand brain function. The central aim of this proposal is to advance the ability of laboratory scientists to correlate brain DA transients with ongoing behavior by combining FSCV with high-resolution behavioral methods. The rationale is that integration of FSCV with the force-plate actometer, which is capable of objectively measuring subtle rodent movements on temporally compatible timescales, will empower investigators to combine FSCV measurement with more complex, and more informative, behavioral assays. To facilitate the use of this integrated approach for complex cognitive/behavioral paradigms, a hybrid operant chamber with a force-plate actometer as its floor will be used to study the differential reinforcement of low rates behavioral paradigm while collecting FSCV data. Because the proposed methods will help bridge the gap between motor and cognitive function and neurochemistry, it will have broad applicability to many areas of research including, but not limited to: (1) fundamental neurobiological studies of dopamine signaling and behavior/cognition;(2) dopamine-related movement disorders [e.g. Huntington's disease (HD), Parkinson's disease (PD), Tourette's syndrome (TS)];(3) studies of addiction and compulsion;and (4) mechanisms of action of CNS-active pharmacological agents. Thus, the proposed research is relevant to that part of NIH's mission pertaining to the development of fundamental knowledge that will potentially help reduce the burdens of human illness and disability. The central aim will be accomplished by completion of the following two specific aims: (1) Apply a combined behavioral/voltammetric paradigm for monitoring sub-second behaviors and corresponding neurochemical changes associated with reward expectation and delivery and (2) Apply the combined behavioral/voltammetric methodology to measure dopamine transients associated with self-initiated behaviors. This combined, high time resolution approach is innovative because it is the first approach to make use of simultaneous high temporal resolution neurochemical and behavioral measurements in a complex cognitive task. The proposed research is significant because it will expand the ability of neuroscientists to correlate brain dopamine system functions with learned, motivated rodent behaviors and thereby provide new information fundamental to understanding a range of health problems in which dopamine plays a role.
The proposed studies are designed to enhance the ability of investigators to conduct in vivo experiments aimed at resolving how sub-second alterations in extracellular dopamine levels impact subtle and complex cognitive behaviors. The proposed research has relevance to public health because this approach can be applied towards unraveling the underlying mechanisms associated with dopamine-related neurological disorders.
|Ortiz, Andrea N; Osterhaus, Gregory L; Lauderdale, Kelli et al. (2012) Motor function and dopamine release measurements in transgenic Huntington's disease model rats. Brain Res 1450:148-56|