CRF & 5HT & Mood

• Stress pathway dysregulation is the most pervasive symptom in neuropsychiatric disease. Patients with schizophrenia and autism show heightened stress sensitivity and exacerbated symptoms during stress experience.
• It has long been postulated that a hyperactive stress system links stress dysregulation to neuropsychiatric disease, which has promoted the pharmaceutical pursuit of therapeutic targets including antagonists of the CRF receptor-1 (CRFR1) that would blunt this response.
• Utilizing CRF receptor-2 (CRFR2) deficient mice in which disruption of normal stress neurocircuitry prevents the recruitment and promotion of homeostatic mechanisms during stress, we have demonstrated that an inability to adapt to stress has severe consequences, including cell death within the 5-HT producing raphe nucleus, maladaptive physiological and behavioral stress responses, and increased perseverative behaviors.
• CRFR2-deficient mice showed elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and a 20-fold increased level of the CRF binding protein (CRF-BP).
• These alterations likely contribute to the increased cell death and stress-sensitivity phenotype in these mice.
• Therefore, we hypothesize that cytokine-induced increases in CRF-BP prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response in the raphe and an inhibition of the normal stress-induced 5-HTergic neurotransmission necessary to promote arousal and coping behaviors.

Early Pregnancy Stress Programming of Offspring Emotionality

• Sex-biased neurodevelopmental disorders, including schizophrenia, have been associated with maternal stress experienced during pregnancy.
• We have recently identified a specific period of early pregnancy where male offspring were sensitive to the effects of maternal stress, displaying as adults behaviors and stress physiology suggestive of brain feminization.
• Our hypothesis to be examined in these proposed studies is that prenatal stress exerts programming effects on the developing male brain via changes in methylation patterns affecting testis development and testosterone production during the organizational period of sexually dimorphic brain development. Organizational and activational testosterone has been shown to be important in programming of male stress neurocircuitry.
• Stress pathway dysregulation and sensitivity is a hallmark of most neuropsychiatric disorders. Therefore, these studies are designed:

1. To determine the contribution of SRY gene methylation and expression in the programming of a feminized stress-sensitive phenotype of early prenatal stress male mice.
2. To examine the heritability of early prenatal stress effects in second generation offspring to identify possible gene targets of PNS that may be epigenetically modified in the germline.
3. To utilize prenatal testosterone treatment or DNMT1 inhibition to ameliorate the effects of early prenatal stress on male offspring stress sensitivity.

• Determination of the fetal antecedents and mechanisms by which alterations in brain development of these circuits occur, and identification of potential heritable aspects of this phenotype may provide insight into novel therapeutic targets and disease prevention.

Early Gestation as a Sensitive Period to Stress in Sex-Dependent Neurodevelopment

• The mechanism through which fetal antecedents contribute to disease development is not understood, though likely involves a complex interaction between maternal environment, placental changes, embryo sex and epigenetic programming. As most neurodevelopmental disorders exhibit a sex bias in presentation, elucidation of the mechanisms by which sex-specific susceptibility arises is likely to provide critical insight into disease etiology.
• We have recently identified a sensitive period of early gestation where stress has sex-specific long- term programming effects on offspring stress pathway neurodevelopment.
• Mechanistically, we have detected sex-specific effects of maternal stress on placental inflammatory cytokines, growth factors and epigenetic machinery. From these studies, we hypothesize that early pregnancy is a highly sensitive period for the long- term sex-specific consequences of maternal stress through effects on placental inflammation, epigenetic machinery and nutrient transport altering programming of the developing embryo.
• Therefore, our studies will examine:

1. How early prenatal stress (EPS) alters the long-term programming of stress pathway neurodevelopment through sex-specific placental and embryonic inflammation, nutrient transport and changes in epigenetic machinery during a highly sensitive period of early gestation
2. The possible rescue of the sex- specific programming effects of EPS by maternal treatment with an anti-inflammatory or a specific inhibitor of NFkB activation, NBD
3. Genomic and proteomic technology including ChIP-Sequencing and pathway focused PCR Arrays to analyze placental and embryonic brain tissues and proteomic analysis of amniotic fluid across gestation to identify potential translatable biomarkers and genes important in the programming of stress dysregulation predictive of neurodevelopmental disorders in EPS offspring.