Developmental age and fatty acid amide hydrolase genetic variation converge to mediate fear regulation in female mice.

Anxiety disorders are more prevalent in females than in males, yet a majority of basic neuroscience studies are performed in males. Furthermore, anxiety disorders peak in prevalence during adolescence, yet little is known about neurodevelopmental trajectories of fear expression, particularly in females. To examine these factors, we fear conditioned juvenile, adolescent, and adult female mice and exposed them to fear extinction and a long-term recall test. For this, we used knock-in mice containing a common human mutation in the gene for fatty acid amide hydrolase (FAAH), the primary catabolic enzyme for the endocannabinoid anandamide (FAAH-IN). This mutation has been shown to impart a low-anxiety phenotype in humans, and in rodents relative to their wild-type littermates. We find an impact of the FAAH polymorphism on developmental changes in fear behavior. Specifically, the FAAH polymorphism appears to induce a state of hypervigilance (increased fear) during adolescence. We also used markerless pose estimation software to classify alternative behaviors outside of freezing. These analyses revealed age differences in vigilance to indicators of threat and in the propensity of mice to explore an aversive environment, though genotypic differences were minimal. These findings address a gap in the literature regarding developmental patterns of fear learning and memory as well as the mechanistic contributions of the endocannabinoid system in females.

Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy.

BACKGROUND: In Duchenne muscular dystrophy (DMD), the loss of the dystrophin component of the dystrophin-glycoprotein complex (DGC) compromises plasma membrane integrity in skeletal muscle, resulting in extensive muscle degeneration. In addition, many DMD patients exhibit brain deficits in which the cellular etiology remains poorly understood. We recently found that dystroglycan, a receptor component of the DGC that binds intracellularly to dystrophin, regulates the development of oligodendrocytes, the myelinating glial cells of the brain. RESULTS: We investigated whether dystrophin contributes to oligodendroglial function and brain myelination. We found that oligodendrocytes express up to three dystrophin isoforms, in conjunction with classic DGC components, which are developmentally regulated during differentiation and in response to extracellular matrix engagement. We found that mdx mice, a model of DMD lacking expression of the largest dystrophin isoform, have delayed myelination and inappropriate oligodendrocyte progenitor proliferation in the cerebral cortex. When we prevented the expression of all oligodendroglial dystrophin isoforms in cultured oligodendrocytes using RNA interference, we found that later stages of oligodendrocyte maturation were significantly delayed, similar to mdx phenotypes in the developing brain. CONCLUSIONS: We find that dystrophin is expressed in oligodendrocytes and influences developmental myelination, which provides new insight into potential cellular contributors to brain dysfunction associated with DMD.

The role of BDNF in mediating the prophylactic effects of (R,S)-ketamine on fear generalization and extinction.

Fear generalization is a conserved survival mechanism that can become maladaptive in the face of traumatic situations, a feature central to certain anxiety disorders including posttraumatic stress disorder (PTSD). However, the neural circuitry and molecular mechanisms underlying fear generalization remain unclear. Recent studies have shown that prophylactic treatment with (R,S)-ketamine confers protective effects in stress-induced depressive behaviors and enhances contextual fear discrimination, but the extent to which these effects extend to fear generalization after auditory fear conditioning remains unclear. Here, we build on this work by using a behavioral model of fear generalization in mice involving foot shocks with differential intensity levels during auditory fear conditioning. We find that prophylactic (R,S)-ketamine treatment exerts protective effects that results in enhanced fear discrimination in wild type mice. As the growth factor, brain-derived neurotrophic factor (BDNF), has been shown to mediate the rapid antidepressant actions of (R,S)-ketamine, we used a loss-of-function BDNF mouse line (BDNF Val66Met) to determine whether BDNF is involved in (R,S)-ketamine's prophylactic effects on fear generalization. We found that BDNF Val66Met mice were resistant to the protective effects of prophylactic (R,S)-ketamine administration on fear generalization and extinction. We then used fiber photometry to parse out underlying neural activity and found that in the ventral hippocampus there were significant fear generalization-dependent patterns of activity for wild type and BDNF Val66Met mice that were altered by prophylactic (R,S)-ketamine treatment. Overall, these findings indicate a role for the ventral hippocampus and BDNF signaling in modulating the mitigating effects of prophylactic (R,S)-ketamine treatment on generalized fear.