Corticostriatal networks and NMDAR mediation of habitual and flexible action in the mouse. The objective of the proposed research is to investigate the neurocircuitry modulating the balance of habitual and flexible action that is thought to be dysfunctionally altered in alcohol dependence. Although studies in other species have provided strong evidence that these behaviors are mediated by networks connecting cortical and striatal subregions, this has not been well established in the mouse. In order for alcohol research to take full advantage of the molecular and genetic techniques that mouse models permit it is essential to first establish the role of these circuits in that species. I propose to elucidate the networks and molecular mechanism underlying habitual and flexible action in the mouse by using an integrative approach that combines traditional techniques (lesion and microinfusion) with emerging genetic and electrophysiological techniques. In order to do this, I propose three specific aims 1) Determine the involvement of corticostriatal networks and NMDAR mediation of well-learned and flexible behavior in the mouse. To accomplish this aim I propose to map endogenous activation patterns and examine the effects of subregion specific lesions in mice performing a task that requires both habitual and flexible action: visual discrimination and reversal. Further, the effects of NMDAR subunit loss in corticostriatal subregions on habitual and flexible performance will be tested using a conditional GluN2B mutant mouse model. 2. Examine in vivo electrophysiological activity of corticostriatal networks and the role of NMDAR during well- learned and flexible behavior. To accomplish this aim I propose to perform in vivo recording of neuronal activity in cortical and striatal subregions during performance of the discrimination-reversal task in both non-mutant mice and the GluN2B conditional mutant model. 3. Examine in vivo electrophysiological activity of corticostriatal networks during higher-order measures of executive control. In order to complete this aim I propose to perform electrophysiological recording in non-mutant and GluN2B mutant mice performing an operant task directly adapted from those used to measure executive control in clinical populations: visual set-shifting. Taken together, the completion of these specific aims will provide strong evidence for the role of corticostriatal networks and NMDAR in the mediation of flexible and habitual actions and provide a strong foundation for future studies investigating how these systems are dysregulated in alcohol abuse and dependence. During my graduate training and fellowship I developed the knowledge of scientific design and conduct necessary to complete the mentored training and development necessary to succeed in the proposed experiments. As a graduate student in the laboratory of Dr. Lawrence Rothblat I was trained in the fundamentals of design and conduct of neuroscience research using operant behavioral tasks with transgenic and mutant mouse models and gained experience in stereotaxic surgical procedures and histological techniques. During my fellowship at NIAAA under the mentorship of Dr. Andrew Holmes I have received extensive hands-on training in a broad range of behavioral measures and a variety of techniques for acute and chronic systemic drug administration as well as tissue micro-dissection for western blotting and high pressure liquid chromatography. In addition I have expanded his surgical techniques to include implantation of indwelling guide cannulae and micro-infusion of bioactive drugs in awake behaving animals. The mentored phase of the proposal will be conducted in the Division of Intramural Clinical and Biological Research at NIAAA under the mentorship of Dr. Andrew Holmes and the co-mentorship of Dr. David Lovinger. Dr. Holmes has extensive expertise in behavioral neuroscience techniques and a well-established research program using behavioral paradigms to investigate genetic and environmental factors underlying addiction and neuropathology using mouse models. Dr. Lovinger is a leader in studying the targets of alcohol and drugs of abuse using in vivo and ex vivo electrophysiology. This environment will provide all the necessary resources necessary to complete the research goals including, but not limited to behavioral apparatus, surgical equipment and animal care, histological resources and multi-channel acquisition systems for in vivo recording. The training and career development resources in the intramural program such as weekly laboratory meetings, seminar series conducted by leading scientists in the field, career development workshops, and training in the responsible conduct of research, make NIAAA an excellent scientific environment for conducting the mentored phase of the proposal.
Alcohol disorders represent a major health issue in the United States as 17.6 million people (H 1 in every 12 adults) abuse alcohol or are alcohol dependent. Current theories of dependence suggest that increases in habitual drug and alcohol seeking during the cycle of dependence may be caused by dysfunction in circuits connecting cortical and striatal brain areas. This project seeks to understand how these systems mediate behavior in the mouse, in order to provide a unique model for investigating the genetic and environmental factors underlying alcohol abuse and dependence.
|Marquardt, K; Saha, M; Mishina, M et al. (2014) Loss of GluN2A-containing NMDA receptors impairs extra-dimensional set-shifting. Genes Brain Behav 13:611-7|
|Brigman, Jonathan L; Powell, Elizabeth M; Mittleman, Guy et al. (2012) Examining the genetic and neural components of cognitive flexibility using mice. Physiol Behav 107:666-9|