This K01 Mentored Research Scientist Development Award aims to provide Dr. Elif Engin with the support required to reach the following career goals: 1) to conduct high-quality, multi-level, multi-technique research to improve our understanding of the brain circuitry and mechanisms of cognitive flexibility / rigidity in health, s well as in neuro-psychiatric disease, 2) to become a leading expert in the area of cognitive flexibility / rigidity; 3) to develop an independent research career, leading a laboratory that doe cutting edge research to address the above questions. The study of complex phenomena such as cognitive flexibility requires a multi-level approach using techniques pertaining to molecular, circuit and behavioral levels of analysis. Dr. Engin has a strong background in molecular and behavioral techniques, having received training in the laboratories of Dr. Dallas Treit, a pioneer in the field of rodent behavioral pharmacology, and Dr. Uwe Rudolph, a world renowned expert in mouse genetics and behavior. Dr. Engin also has experience in histological, pharmacological and optogenetic techniques. The training objectives of the proposed project are to 1) Provide Dr. Engin with training in in vivo electrophysiology in freely moving mice, using cutting-edge multi-tetrode microdrive systems and sophisticated analyses, as well as in other widely-used techniques, such as in situ hybridization, 2) Facilitate Dr. Engin's career development through training in research communication, leadership, grant-writing and other necessary skills to successfully establish and maintain a research laboratory, 3) Establish a knowledge base to address ethical issues in scientific research through training in responsible conduct of research, 4) Extend Dr. Engin's professional network to include possible future collaborators, mentors, mentees, experts in related scientific areas, and 5) Assure the appropriate dissemination of the scientific findings through high quality publications and oral presentations. Dr. Engin's mentoring team is comprised of 3 experts in their respective areas. The primary mentor, Dr. Kerry Ressler, will provide technical training in behavioral tasks related to fear learning and memory, and in sit hybridization, research training in translational research, as well as general training in grant-writing, laboratory management, and the preparation for a job search. Dr. Michael Hasselmo is an expert in hippocampal neurophysiology and computational modeling of neural systems, and will provide training in the analysis of hippocampal spike and field potential data, the theoretica underpinnings of hippocampal encoding and retrieval processes, as well as in career development. Dr. Shantanu Jadhav is an expert in in vivo electrophysiology, especially in the field of hippocampal replay / reactivation, and will provide technical training in the collection ad analysis of electrophysiology data. All three mentors will be involved in responsible conduct of research training. The proposed research project concentrates on the hippocampal correlates of cognitive rigidity. Despite being a cognitive symptom in a large number of neuro-psychiatric diseases, which together affect more than 30 million people in the US, a systematic study of the neural mechanisms of cognitive rigidity has not been undertaken. The overall research objective of this application is to determine the hippocampal circuit level dynamics underlying cognitive rigidity by utilizing a mouse model developed by Drs. Engin and Rudolph, which has a specific cognitive rigidity phenotype. The central hypothesis is that the cognitive rigidity phenotype is associated with a deficiency in reconsolidation, specifically in the memory destabilization phase. In our first specific aim, we propose to record local field potentials, spike activity and place cel activity in freely moving mice learning to associate rewards with specific locations on a maze using multi-tetrode micro drives to 1) Determine whether cognitive rigidity is associated with deficiencies in the hippocampal novelty response, as measured by the suppression of the hippocampal theta activity, 2) Establish if cognitively rigid mice show retrieval bias in the retrieval/encoding balance, as measured by the preferred spiking phase of the CA1 pyramidal neurons within the theta cycle, and 3) Determine whether rigid behavior is reflected in rigid hippocampal replay of old trajectories, as measured by the persistence of the replay of old reward trajectories following a reversal of the reward-location contingency. Our hypothesis is that the ?5DGKO mice will have a dampened hippocampal novelty response and a bias towards retrieval, which would impair memory destabilization upon reactivation, and that this deficiency would be reflected in rigid hippocampal replay of old trajectories. In our second specific aim, we propose to use a combined pharmacological-genetic-behavioral approach to determine whether memory destabilization during reconsolidation is impaired in cognitively rigid mice. We believe the outcomes of the proposed studies will have a positive impact because the hippocampus-mediated processes constitute the foundation for the systematic study of the brain mechanisms of cognitive flexibility and the development of therapeutic strategies for neuro-psychiatric disorders. The knowledge, experience and data gained from this proposal will lead directly to the study of hippocampal outputs to downstream structures and the larger brain network mediating adaptive cognitive flexibility, which will be proposed in an R01 grant application in 3-4 years of the award.
Cognitive rigidity is a major cognitive symptom in autism spectrum disorders, schizophrenia, some anxiety disorders and mood disorders, which together affect more than 30 million people in the US alone. However, a systematic study of the brain system underlying adaptive cognitive flexibility or the disruptions in this system leading to cognitive rigidity in neuropsychiatric disorders has not been undertaken. The proposed research aims to determine some ground-level brain processes that will form the foundation for future studies of the brain circuitry of cognitive flexibility, as well as the development of therapeutic strategies to treat cognitive rigidity.
| Engin, Elif; Benham, Rebecca S; Rudolph, Uwe (2018) An Emerging Circuit Pharmacology of GABAA Receptors. Trends Pharmacol Sci 39:710-732 |
