TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in
Therapeutic Development
FOA type: PAR-19-289:
Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of
psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic
development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and
behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged
across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective
processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although
disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder,
schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal
coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our
knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and
screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity
Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment
by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit
engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate
behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human
Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings
to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative
series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit
manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive
biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and
non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2)
Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement
through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface
EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral
task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate
across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures
of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The
significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the
therapeutic development pipeline for treating mental illness.
