The long-term goals of this component are to use rodent models of binge alcohol exposure during the 3rd trimester equivalent to screen and identify molecular agents that may be effective in preventing prenatal alcohol-induced brain damage and neurodevelopmental disorders. These studies will use two neonatal rodent models. The first is the well-studied model involving binge alcohol exposure on postnatal days (PD) 4-9 in outbred rats, which is known to produce structural and functional damage to cerebellar systems. The second is a model involving a single binge alcohol exposure on PD 7 in the C57BL/6 inbred mouse strain (the focus of Zhou's mouse component), known to induce extensive forebrain neuronal cell death. These studies will assess the effectiveness of candidate therapeutic agents by evaluating alcohol-induced damage to cerebellar (rat) and hippocampal (mouse) circuits that are known to mediate specific variants of Pavlovian eyeblink classical conditioning (ECC). In keeping with the emphasis of the Core, L-NAP, a 9-amino acid derivative of activity-dependent neuroprotective protein, will be the first candidate agent tested, because of its demonstrated effectiveness in several models of cell death and in a mouse model alcoholinduced teratogenesis. If L-NAP is found to be effective, additional studies of two structural derivatives of L-NAP for which the capacity to protect against neuronal death vs. ethanol teratogenesis has been dissociated, will also be evaluated.
Specific Aim 1 tests the hypothesis that the candidate agent will protect against alcohol-induced caspase-3 activation on PD 4 in Purkinje cells, an indicator of acute Purkinje cell death.
Specific Aim 2 tests the hypothesis that the candidate agent will protect against functional and structural damage to cerebellar systems mediating eyeblink conditioning induced by binge alcohol exposure on PD 4-9.
Specific Aim 3 tests the hypothesis that binge alcohol exposure on PD 7 in C57BL/6 mice will damage hippocampal circuits necessary for eyeblink discrimination reversal learning, and that the candidate agent will protect against this hippocampal damage. Because the neural substrates and procedures for ECC are similar across species, the outcomes from these animal modelsmincluding those of the sheep model component of this Consortiummcan be translated directly to humans to guide and inform future studies of therapeutic prevention of FASD. A key advantage of integrated approaches across the Consortium is that as promising candidate molecular agents emerge, these animal models can provide in vivo tests of their therapeutic effectiveness.
