Estradiol modulation of the renin-angiotensin system and the regulation of fear extinction.

Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue exposure therapy in humans) leads to poor extinction consolidation and increased fear during extinction recall. The renin-angiotensin system (RAS) is also associated with stress-related pathologies, and RAS antagonists can enhance extinction consolidation in males. However, less is known about how estradiol and the RAS converge to alter fear extinction consolidation in females. Since estradiol downregulates the RAS, we determined the role of surgically (via ovariectomy [OVX]) and pharmacologically (via the hormonal contraceptive [HC], levonorgestrel) clamping estradiol at low levels in female rats on fear-related behavior, serum estradiol and angiotensin II (Ang II) levels, and angiotensin II type I receptor (AT1R) binding in the brain. We then tested whether the AT1R antagonist losartan would alter fear-related behavior in an estradiol-dependent manner. We found that both OVX and HC treatment produced extinction consolidation deficits relative to intact female rats in proestrus (when estradiol levels are high), and that losartan treatment mitigated these deficits and reduced freezing. OVX, but not HC, altered AT1R ligand binding, though HC reduced estradiol and increased Ang II levels in plasma. These findings have significant clinical implications, indicating that administration of an AT1R antagonist, especially if estradiol levels are low, prior to an exposure therapy session may improve treatment outcomes in females.

A Rat Model of Fetal Alcohol Syndrome: A Series of Undergraduate Laboratory Exercises for Biopsychology Courses.

Many undergraduate students are aware that consuming alcohol during pregnancy can result in many serious physical and behavioral deficits. Student interest in this clinical syndrome allows instructors to provide engaging laboratory exercises that relate topics covered in most biopsychology courses to Fetal Alcohol Syndrome (FAS). Through this series of experiments, students will use rodents to study the behavioral deficits that can be caused by developmental alcohol exposure, including impaired ultrasonic vocalizations, hyperactivity, balance, and spatial learning. Other possible exercises include analyzing blood alcohol concentrations (BACs), completing histological studies of anatomical effects, and/or discussing the societal implications of developmental alcohol exposure. The instructor has the flexibility to determine which of the exercises fit into the class schedule and budget since he or she may choose to complete all of the behavioral tests or only one of them. Students will also learn about the benefits and drawbacks of animal models for human disorders, important considerations in research design such as reliability and validity, while also gaining experience in statistical analyses and writing empirical research papers. The application of these important concepts to a human syndrome and the use of small, easy-to-handle rodent pups make these exercises an accessible, stimulating introduction to animal research for most undergraduate students.

Molecular and Genetic Characterization of Depression: Overlap with other Psychiatric Disorders and Aging.

Genome-wide expression and genotyping technologies have uncovered the genetic bases of complex diseases at unprecedented rates; However despite its heavy burden and high prevalence, the molecular characterization of major depressive disorder (MDD) has lagged behind. Transcriptome studies report multiple brain disturbances but are limited by small sample sizes. Genome-wide association studies (GWAS) report weak results but suggest overlapping genetic risk with other neuropsychiatric disorders. We performed systematic molecular characterization of altered brain function in MDD, using meta-analysis of differential expression in eight gene array studies in three corticolimbic brain regions in 101 subjects. The identified "metaA-MDD" genes suggest altered neurotrophic support, brain plasticity and neuronal signaling in MDD. Notably, metaA-MDD genes display low connectivity and hubness in coexpression networks, and uniform genomic distribution, consistent with diffuse polygenic mechanisms. We next integrated these findings with results from over 1800 published GWAS and show that genetic variations nearby metaA-MDD genes predict greater risk for neuropsychiatric disorders and notably for age-related phenotypes, but not for other medical illnesses, including those frequently co-morbid with depression, or body characteristics. Collectively, the intersection of unbiased investigations of gene function (transcriptome) and structure (GWAS) provides novel leads to investigate molecular mechanisms of MDD and suggest common biological pathways between depression, other neuropsychiatric diseases, and brain aging.