Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Activation of the anterior cingulate cortex ameliorates anxiety in a preclinical model of fetal alcohol spectrum disorders.

People with fetal alcohol spectrum disorders (FASD) are suffered from a wide range of interlinked cognitive and psychological problems. However, few therapeutic options are available for those patients due to limited dissection of its underlying etiology. Here we found that prenatal alcohol exposure (PAE) increases anxiety in mice due to a dysregulated functional connectivity between the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). We also show that chemogenetic activation of excitatory neurons in the ACC reduced this anxiety behavior in the PAE mice. Interestingly, although the level of plasma corticosterone correlated with the increase in anxiety in the PAE, this level was not altered by chemogenetic activation of the ACC, suggesting that the functional connectivity between the ACC and the BLA does not alter the activity of the hypothalamic-pituitary-adrenal axis. Altogether, this study demonstrated that reduced excitation in the ACC is a cause of anxiety in the PAE mice, providing critical insights into the ACC-BLA neural circuit as a potential target for treating anxiety in FASD patients.

Time-Course Evaluation of Brain Regional Mitochondrial Bioenergetics in a Pre-Clinical Model of Severe Penetrating Traumatic Brain Injury.

Mitochondrial dysfunction is a pivotal target for neuroprotection strategies for traumatic brain injury (TBI). However, comprehensive time-course evaluations of mitochondrial dysfunction are lacking in the pre-clinical penetrating TBI (PTBI) model. The current study was designed to characterize temporal responses of mitochondrial dysfunction from 30 min to 2 weeks post-injury after PTBI. Anesthetized adult male rats were subjected to either PTBI or sham craniectomy (n = 6 animals per group × 7 time points). Animals were euthanized at 30 min, 3 h, 6 h, 24 h, 3 days, 7 days, and 14 days post-PTBI, and mitochondria were isolated from the ipsilateral hemisphere of brain regions near the injury core (i.e., frontal cortex [FC] and striatum [ST]) and a more distant region from the injury core (i.e., hippocampus [HIP]). Mitochondrial bioenergetics parameters were measured in real time using the high-throughput procedures of the Seahorse Flux Analyzer (Agilent Technologies, Santa Clara, CA). The post-injury time course of FC + ST showed a biphasic mitochondrial bioenergetics dysfunction response, indicative of reduced adenosine triphosphate synthesis rate and maximal respiratory capacity after PTBI. An initial phase of energy crisis was detected at 30 min (-42%; p < 0.05 vs. sham), which resolved to baseline levels between 3 and 6 h (non-significant vs. sham). This was followed by a second and more robust phase of bioenergetics dysregulation detected at 24 h that remained unresolved out to 14 days post-injury (-55% to -90%; p < 0.05 vs. sham). In contrast, HIP mitochondria showed a delayed onset of mitochondrial dysfunction at 7 days (-74%; p < 0.05 vs. sham) that remained evident out to 14 days (-51%; p < 0.05 vs. sham) post-PTBI. Collectively, PTBI-induced mitochondrial dysfunction responses were time and region specific, evident differentially at the injury core and distant region of PTBI. The current results provide the basis that mitochondrial dysfunction may be targeted differentially based on region specificity post-PTBI. Even more important, these results suggest that therapeutic interventions targeting mitochondrial dysfunction may require extended dosing regimens to achieve clinical efficacy after TBI.

Prenatal Environment That Affects Neuronal Migration.

Migration of neurons starts in the prenatal period and continues into infancy. This developmental process is crucial for forming a proper neuronal network, and the disturbance of this process results in dysfunction of the brain such as epilepsy. Prenatal exposure to environmental stress, including alcohol, drugs, and inflammation, disrupts neuronal migration and causes neuronal migration disorders (NMDs). In this review, we summarize recent findings on this topic and specifically focusing on two different modes of migration, radial, and tangential migration during cortical development. The shared mechanisms underlying the NMDs are discussed by comparing the molecular changes in impaired neuronal migration under exposure to different types of prenatal environmental stress.