NMARC Current P50 Preclinical Research Components

P50 Component 3 GSK-3 as a Therapeutic Target for FASD (PI: Lee Anna Cunningham, Co-Is: Allan & Valenzuela) is focused on investigating glycogen synthase kinase-3 (GSK-3) as a potential therapeutic target for reversing behavioral deficits in FASD. Using a combination of pharmacological and genetic approaches, this proposal will test the hypothesis that the inhibition of GSK-3 activity reverses deficits in adult hippocampal neurogenesis and associated learning behaviors in the mouse model of moderate FASD.

P50 Component 4-Mitigating Prenatal Alcohol Damage: Role of the Glucocorticoid System (Co-PIs: Allan & Caldwell; Co-I: Valenzuela) will examine whether communal housing ameliorates fetal ethanol-induced deficits in neurogenesis, dentate gyrus synaptic plasticity and hippocampal-sensitive learning, and whether improving the early maternal and social environment will re-set the hippocampal glucocorticoid system to its normal feed-back inhibitory role and ameliorate the observed hippocampal deficits. Their preliminary data support the hypothesis that early prenatal and postnatal environment can mitigate the effects of moderate PAE.

P50 Component 5 P50 Component 5:Dysregulation of Cortico-Striatal Function in Prenatal Alcohol-Exposed Mice(PI: Jonathan Brigman; Co-I: Valenzuela) will integrate mouse touch screen visual discrimination-based reversal learning paradigms with in vivo and in vitro electrophysiological recording to examine how prenatal ethanol exposure alters corticostriatal circuitry during associative learning and behavioral flexibility and whether impaired orbitofrontal regulation of the dorsal striatum increases maladaptive perseveration. Their preliminary data shows both the feasibility of performing cortical in vivo recording during touch screen learning and that prenatal exposure significantly alters associative learning.

Pilot Project 8G. Entorhinal Cortical Mechanisms of Spatial Memory Deficits after Prenatal Alcohol Exposure (PI: Benjamin Clark, Assistant Professor, Department of Psychology - July 2016 - June 2018). The overall aim of this pilot project is to determine whether spatial memory deficits in moderate PAE are due to impairments in entorhinal cortical processing of place cell, grid cell, and head direction cell activity. The project involves in vivo recording of neuronal activity from the hippocampus and entorhinal cortex in spatial tasks. To date, high-density electrophysiological recordings from 6 PAE rats and 6 saccharin control rats have been collected (~1000 cells per rat). Recordings have largely focused on the hippocampus (from CA1, CA3, and the dentate gyrus) in animals navigating along a small linear track. It was found that hippocampal neurons from these sub-fields in both PAE and saccharin control animals exhibit place cell-like firing. However, neuronal activity in PAE animals are less spatially-specific (i.e., less likely to spike in specific spatial locations and in specific movement directions). The failure of place cell firing to accurately discriminate between spatial locations and directions suggests an impairment in what is often referred to as pattern separation - that is, the capacity of the hippocampus to generate unique spatial representations for different experiences. To confirm that impairments in place cell discrimination can explain the spatial memory deficits often observed after PAE, Dr. Clark has conducted a series of experiments in a behavioral procedure referred to as the object-place paired associate (OPPA) task, which requires that animal discriminate between pairs of objects on the basis of the animals spatial location and movement direction in the environment. This experiment has found that PAE rats make significantly more errors compared to saccharin control rats during acquisition of the OPPA task. These two studies have been submitted as conference abstracts at the Research Society on Alcoholism and Society for Neuroscience in 2017 and are currently in preparation as three separate manuscript submissions. The following paper is currently under review in Current Biology: Harvey RE, Rutan SA, Willey GR, Siegel JJ, Clark BJ, Yoder RM. Linear self-motion cues contribute to the spatial distribution and stable firing of hippocampal place cells. Dr. Clark is currently expanding on these findings with simultaneous electrophysiology recordings from the hippocampus and entorhinal cortex in the OPPA task, which will test the hypothesis that the loss of spatial memory can be explained by deficits in place cell discrimination and entorhinal-hippocampal functional connectivity (i.e., reductions in the coherence of hippocampal place cell and entorhinal grid and head direction cell systems). Lastly, Dr. Clark is developing this work into an R01 application, which would include in vivo electrophysiological recordings from the entorhinal cortices and hippocampus, and aims involving the rescue of function utilizing optogenetic/chemogenetic manipulation of entorhinal-hippocampal circuitry.