NMARC P50 Preclinical Research Components

Photo of a ToddlerP50 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.

P50 Pilot Project 8B (PI: Weick) will employ human embryonic stem cells to examine whether ethanol exposure during critical periods of early neural development can alter the differentiation of GABAergic and glutamatergic neurons, as well as the signaling mechanisms underlying this putative shift in transmitter specification.

P50 Pilot Project 8C (PI: Milligan) will examine whether a prenatal ethanol-induced elevation in allodynia (i.e., pain due to a stimulus which does not normally provoke pain) involves increased spinal cord expression of glial-reactivity, cytokine markers, and leukocyte enrichment into CNS regions critical for pain signaling, as monitored by whole animal SPECT/CT imaging.  These proposed studies are inspired by preliminary data which show that after induction of a localized peripheral neuropathy, greater allodynia is observed in rodents with prenatal ethanol exposure compared to non-exposed controls.  A separate pilot, using SPECT/CT to image live healthy intact rats, has revealed discrete leukocyte enrichment occurring in the lumbar spinal cord region that is significantly greater in neuropathic subjects compared to non-neuropathic controls.  While most of the center’s focus to date has been on the impact of prenatal ethanol exposure on different forms of learning, this study will be the center’s first examination of other behavioral alterations that are emerging in the field and being recognized as so-called “secondary medical disabilities” that arise as a consequence of prenatal ethanol exposure.