Changes in Representation of Thalamic Projection Neurons within Prefrontal-Thalamic-Hippocampal Circuitry in a Rat Model of Third Trimester Binge Drinking

Abstract

Alcohol exposure (AE) during the third trimester of pregnancy—a period known as the brain growth spurt (BGS)—could result in a diagnosis of a fetal alcohol spectrum disorder (FASD), a hallmark of which is impaired executive functioning (EF). Coordinated activity between prefrontal cortex and hippocampus is necessary for EF and thalamic nucleus reuniens (Re), which is required for prefrontal-hippocampal coordination, is damaged following high-dose AE during the BGS. The current experiment utilized high-dose AE (5.25 g/kg/day) during the BGS (i.e., postnatal days 4–9) of Long-Evans rat pups. AE reduces the number of neurons in Re into adulthood and selectively alters the proportion of Re neurons that simultaneously innervate both medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC). The AE-induced change unique to Re→(mPFC + vHPC) projection neurons (neuron populations that innervate either mPFC or vHPC individually were unchanged) is not mediated by reduction in neuron number. These data are the first to examine mPFC-Re-HPC circuit connectivity in a rodent model of FASD, and suggest that both short-term AE-induced neuron loss and long-term changes in thalamic connectivity may be two distinct (but synergistic) mechanisms by which developmental AE can alter mPFC-Re-vHPC circuitry and impair EF throughout the lifespan.

Representation of prefrontal axonal efferents in the thalamic nucleus reuniens in a rodent model of fetal alcohol exposure during third trimester

“…There was no significant main effect of sex on Re volume, as well as no significant interaction between postnatal treatment and sex. Upon investigation of group means, AE reduced Re volume, which is similar to previous findings from our lab ( Gursky et al, 2019 ; Gursky and Klintsova, 2021 , 2022 ). These data are represented in Figure 2A .…”

“…Previous work from our lab has established that AE brings on immediate death of neurons in Re that lasts long into adulthood ( Gursky et al, 2020b ). However, we have also demonstrated that AE leads to an increase in proportion of Re neurons that collaterally project to both mPFC and HPC without altering the number of neurons that project to only one of these two structures ( Gursky and Klintsova, 2021 ). Thus, AE may be creating an imbalance of excitatory neurons in the Re that could ultimately affect the anatomical substrates of the mPFC-Re-HPC circuit (i.e., mPFC axonal projections).…”

“…Previous studies on the effects of AE on Re volume and its projections to mPFC and HPC revealed no difference between SI and suckle control animals, and thus the latter group was not included in the present study ( Gursky and Klintsova, 2021 ). However, human literature exists demonstrating that females may be more resilient to prenatal and early life stress ( Hodes and Epperson, 2019 ).…”

“…While AE reduced the total number of Re neurons, the proportion of remaining neurons that innervate both mPFC and HPC was larger in AE rats than in normal or procedural controls. However, AE had no significant effect on the proportion of remaining Re neurons that innervate only one of the two structures ( Gursky and Klintsova, 2021 ).…”

“…Despite this evidence, mPFC-Re-HPC circuitry is understudied in regard to early life alcohol exposure. In fact, only four papers to date have addressed the effects of AE on this specific circuitry ( Gursky et al, 2019 , 2020b ; Gursky and Klintsova, 2021 , 2022 ). Indeed, work from our lab has shown that Re, but not neighboring thalamic nuclei such as the rhomboid nucleus, is specifically damaged in a rodent model of third-trimester binge drinking targeting the brain growth spurt (BGS).…”