Prefrontal cortex projections to the mediodorsal thalamus are uniquely vulnerable to the effects of early adolescent alcohol consumption

: A bevy of clinical and preclinical evidence has established that the prefrontal cortex (PFC) is negatively affected by heavy alcohol consumption during adolescence, yet the specific neuroadaptations to the PFC associated with adolescent alcohol are not well understood. Using a retrograde viral approach and ex vivo whole-cell patch-clamp electrophysiology, we examined the impact of adolescent alcohol consumption on neuronal excitability in specific projections from the prelimbic PFC to the contralateral PFC (PFC cPFC ), nucleus accumbens (PFC NAc ), or mediodorsal thalamus (PFC MdT ). Following adolescent alcohol consumptions, we observed several electrophysiological effects specifically to PFC Mdt pyramidal neurons (PNs) including increased intrinsic excitability due to a reduction in the hyperpolarization-activated, nonselective cation current (I h ) and decreased excitatory synaptic neurotransmission. Many of these effects were persistent in male mice as they were observed after 10 days of abstinence in PFC MdT PNs and were not seen when IA EtOH was initiated in adulthood or even in late adolescence. To further characterize the consequences of adolescent alcohol consumption on PFC dependent behaviors, we performed touchscreen-based operant tasks aimed at more directly assessing PFC-dependent cognition. We found that cognitive flexibility and working memory performance were not largely affected by adolescent alcohol, however, additional analyses revealed blunted task shifting and delayed response latencies. The PFC MdT circuit has previously been implicated in response timing and attentional processes and therefore exposure to alcohol during the early adolescent window may disrupt executive function through adaptations to PFC MdT circuitry.