Acute Low Alcohol Disrupts Hippocampus-Striatum Neural Correlate of Learning Strategy by Inhibition of PKA/CREB Pathway in Rats

The hippocampus and striatum guide place-strategy and response-strategy learning, respectively, and they have dissociable roles in memory systems, which could compensate in case of temporary or permanent damage. Although acute alcohol (AA) treatment had been shown to have adverse effects on hippocampal function, whether it causes the functional compensation and the underlying mechanisms is unknown. In this study, rats treated with a low dose of AA avoided a hippocampus-dependent spatial strategy, instead preferring a striatum-dependent response strategy. Consistently, the learning-induced increase in hippocampal, but not striatal, pCREB was rendered less pronounced due to diminished activity of pPKA, but not pERK or pCaMKII. As rats approached the turn-decision area, Sp-cAMP, a PKA activator, was found to mitigate the inhibitory effect of AA on intra- and cross-structure synchronized neuronal oscillations, and rescue response-strategy bias and spatial learning deficits. Our study provides strong evidence of the critical link between neural couplings and strategy selection. Moreover, the PKA/CREB-signaling pathway is involved in the suppressive effect of AA on neural correlates of place-learning strategy. The novel important evidence provided here shows the functional couplings between the hippocampus and striatum in spatial learning processing and suggests possible avenues for therapeutic intervention.