Cognitive deficits are a major determinant of the long-term disability associated with severe neuropsychiatric disorders, including schizophrenia (Sz). This warrants increased interest in the VA research community, given the higher instance of psychiatric illness among the veteran population, treatment of which accounts for some 40% of VA mental healthcare costs nationally. Current therapeutic strategies (first and second-generation antipsychotics) do not satisfactorily address Sz-related cognitive issues. Abnormalities in the patterns of cortical EEG, most notably elevated spontaneous gamma band activity (GBA) and reduced task-evoked GBA, have been observed in a number of clinical studies of severe neuropsychiatric conditions, and have been indicated to underlie both the psychosis linked impairment of sensory, cognitive, and social domains of function. Thus, it may prove advantageous to address these symptom domains with a greater consideration to the patterns of electrophysiological activity and testing whether modulation of these patterns can improve function. One crucial variable regulating such activity is the balance between excitatory and inhibitory (E/I Balance) cortical neural activity. Recent work from our lab suggests that long range GABAergic projections from basal forebrain parvalbumin neurons (BF-PV) are capable of bi-directionally modulating E/I balance. These studies serve to provide a better understanding of the role of impaired E/I balance in the emergence of cognitive and social deficits associated with Sz, and other psychiatric disorders, as well as provide a rationale for targeting restoration of E/I balance as a novel therapeutic approach. RESEARCH DESIGN: In this study, our Overall Hypothesis postulates that modulation of BF-PV output allows tuning of cortical E/I balance, via direct projections to the cortical circuitry and through projections to the thalamic reticular nucleus (TRN).
Aim 1 will characterize a powerful systems-level model to better define how abnormal patterns of cortical activity impact cognitive and social domains of function relevant to psychiatric disease.
Aim 2 seeks to provide a more complete understanding of the mechanism behind BF-PV modulation of E/I balance. Finally, Aim 3 will test manipulations of this mechanism as a novel therapeutic means to restore cortical E/I balance, and improve cognition in two translationally relevant models of Sz. METHODOLOGY: Here we will utilize an innovative combination of electrophysiological, optogenetic, and behavioral paradigms. First, to directly examine the relationship between impaired E/I balance and cognition, we will assess performance of mice on translationally relevant sensory and cognitive paradigms both with and without BF-PV mediated alteration of cortical E/I. Using, both an immunohistochemical and optogenetic approach, we will attempt to better characterize the circuit pathway involved in BF-PV modulation of E/I balance. Finally, we will utilize both pharmacological and transgenic models of Sz, to determine if inhibition of BF-PV output is capable of restoring, E/I balance, and by extension improve cognitive function. IMPACT/SIGNIFICANCE: Normal brain function relies on the ability of neural networks to maintain stable, yet flexible, levels of activity. These experiments will provide a better understanding of aspects of coordinated neural activity that are important for sensory, cognitive, and social processing. Further, it will characterize a subcortical pathway capable of modulating E/I balance and interrogate this pathway as a novel therapeutic target to rescue impairments in neuropsychiatric disorders. Millions of Americans are currently suffering from conditions that lead to abnormal E/I balance, and associated GBA impairment, beyond Sz (e.g. Alzheimer's disease, Autism, Parkinson's disease), making it likely that this approach will benefit research into the treatment of other neuropsychiatric disease states as well. This work is novel and will provide valuable insight into the pathogenesis of such disorders, and also lay groundwork for the development of therapeutic interventions for effective prevention and treatment.
Deficits in sensory, cognitive, and social function are a major determinant of the long-term disability associated with schizophrenia (Sz) and other severe neuropsychiatric diseases. Thus, an increased focus on developing novel therapeutic interventions targeting these deficits is highly warranted and important to the VA and psychiatric community. Impaired balance in cortical excitation and inhibition (E/I balance) is believed to play a critical role in abnormal neural oscillation associated with Sz, and may represent a direct clinical correlate of Sz-related cognitive impairment. The experiments outlined in this proposal combine multilevel, state of the art, approaches using optogenetics, targeted viral expression, behavioral, and in vivo electrophysiological techniques to directly examine the effects of impaired E/I balance in active and freely behaving animals during performance of translationally relevant sensory and behavioral tasks This work will provide valuable insight for the preclinical analysis of novel therapeutic interventions to restore E/I balance and improving cognition in Sz.
