Functional Connectivity and Metabolic Alterations in Medial Prefrontal Cortex in a Rat Model of Fetal Alcohol Spectrum Disorder: A Resting-State Functional Magnetic Resonance Imaging and in vivo Proton Magnetic Resonance Spectroscopy Study

Abstract

Prenatal ethanol exposure alters brain structure, functional connectivity, and behavior in humans and rats. Behavioral changes include deficits in executive function, which requires cooperative activity between the frontal cortices and other brain regions. In this study, we analyzed the functional connectivity and neurochemical levels of the prefrontal cortex (PFC) using resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) in ethanol-exposed (Eth) and control (Ctr) rats. Pregnant Long-Evans rats were fed a liquid diet containing ethanol (2.1–6.46% v/v ethanol) from gestational days 6 to 21 (Eth). Ctr animals received an isocaloric, isonutritive liquid diet. In young adulthood, male and female offspring underwent in vivo MRI using a 7.0-Tesla system. 1H-MRS from the PFC and whole brain rsfMRI were obtained on the animals. Seed-based functional connectivity analysis was performed with seeds placed in the PFC, matching the voxel of MRS. Male, but not female, Eth rats showed less functional connectivity between PFC and dorsal striatum than Ctr animals. In Eth males glucose levels were significantly lower, and in Eth females lower levels of phosphorylcholine but an increased gamma-aminobutyric acid/glutamate ratio were observed in the PFC compared with Ctr animals. Prenatal ethanol alters brain metabolism and functional connectivity of the PFC in a sex-dependent manner.

Choline Plus Working Memory Training Improves Prenatal Alcohol-Induced Deficits in Cognitive Flexibility and Functional Connectivity in Adulthood in Rats

“…We then analyzed males and females separately to determine differences between treatment groups within sex. Previous work from our group found sex differences in both behavioral and rs-fMRI measures in our models of FASD [20,21]. Trials to criterion of each of the 6 phases was the dependent variable, and experimental group was the between-group variable.…”

“…One of the most consistent findings across rodent models with various means of delivery, concentrations, and timing of prenatal alcohol exposure is poor executive function and cognitive flexibility. The neurological underpinnings of cognitive deficits point to poor prefrontal cortex organization, and dysregulated functional cooperation between the frontal cortices and striatum (e.g., [17,19,20]). This sensitivity to ethanol exposure persists from the prenatal phase to adolescence [19,63].…”

“…In children with FASD, however, a less-selective, general pattern of activation is evident [17]. Poor frontal lobe organization and connectivity is emerging as a paramount feature of FASD [19,20]. In rodents, this loss of adaptive frontal lobe modulation of learned responses can manifest as poor reversal learning and use of inefficient problem-solving strategies [21].…”

“…Efficient performance in specific phases of the ASST-R task requires discrete regions of the prefrontal cortex and the striatum [25]. Interestingly, in an escalating model of prenatal EtOH exposure that typically results in blood alcohol concentrations of 120 mg/dL-150 mg/dL [26,27], in a separate cohort of animals [20] we observed reduced functional connectivity between the prefrontal cortex and dorsolateral striatum in adult males, while females exhibited changes in small-world organization and network integration that suggest reductions in long-range regional communication.…”

Detection of Prenatal Alcohol Exposure Using Machine Learning Classification of Resting-State Functional Network Connectivity Data

“…Other resting state fMRI research conducted with rats exposed to prenatal alcohol has also revealed sex-dependent alterations in connectivity. Using a seed-based approach, Tang and colleagues showed baseline sex-dependent differences in functional connectivity among controls and a sex-by-alcohol interaction in cortico-striatal connectivity (Tang et al, 2019). In a subsequent investigation relying on a graph theory approach, the same research group found altered network organization in females, but not males, following PAE (Tang, Xu, Zhu, Gullapalli, & Mooney, 2020).…”