Prenatal stress programs behavioral pattern separation in adult mice

Stress is an unavoidable condition in human life. Stressful events experienced during development, including in utero, have been suggested as one major pathophysiological mechanism for developing vulnerability towards neuropsychiatric and neurodevelopmental disorders in adulthood. One cardinal feature of such disorders is impaired cognitive ability, which may in part rely on abnormal structure and function of the hippocampus. In the hippocampus, the dentate gyrus is a site of continuous neurogenesis, a process that has been recently implicated in spatial pattern separation, a cognitive phenomenon that serves to reduce the degree of overlap in the incoming information to facilitate its storage with minimal interference. We previously reported that adult neurogenesis is altered by prenatal stress allowing us to hypothesize that prenatal stress may possibly lead to impairment in pattern separation. To test this hypothesis, both control (C) and prenatally stressed (PS) adult mice were tested for metric and contextual discrimination abilities. We report for the first time that prenatal stress impairs pattern separation process, a deficit that may underlie their cognitive alterations and that may result in defective behaviors reminiscent of psychiatric illness such as post-traumatic stress disorder.

Prenatal Stress Selectively Impairs Neuroligin 1-Dependent Neurogenesis by Suppressing Astrocytic FGF2-Neuronal FGFR1 Axis

Exposure to maternal stress irreversibly impairs neurogenesis of offspring through inducing life-long effects on interaction between neurons and glia under raging differentiation process, culminating in cognitive and neuropsychiatric abnormalities in adulthood. We identified how prenatal exposure to the stress-hormone glucocorticoid impairs synapse formation and subsequent neurogenesis using human induced pluripotent stem cell (iPSC)-derived neural stem cell (NSC) and ICR mice. Following prenatal glucocorticoid exposure, NSC-derived astrocytes were found to be A1-like neurotoxic astrocytes. Moreover, cortisol-treated astrocyte conditioned media (ACM) then specifically downregulated AMPA receptor-mediated glutamatergic synaptic formation and transmission in differentiating neurons, by inhibiting localization of ionotropic glutamate receptor (GluR) 1/2 into synapses. We revealed that downregulated astrocytic fibroblast growth factor 2 (FGF2) and nuclear fibroblast growth factor receptor 1 (FGFR1) of neurons are key pathogenic factors for reducing glutamatergic synapse formation, according to data from RNA sequencing and antibody array. We further confirmed that cortisol-treated ACM specifically decreased the binding of neuronal FGFR1 to the synaptogenic NLGN1 promoter, but this was reversed by FGFR1 restoration. Upregulation of neuroligin 1, which is important in scaffolding GluR1/2 into the postsynaptic compartment, eventually normalized glutamatergic synaptogenesis and subsequent neurogenesis. Moreover, FGF2 pretreatment of a prenatal corticosterone-exposed mouse elevated neuroligin 1 expression and trafficking of GluR1/2 into the postsynaptic compartment, improving spatial memory and depression/anxiety-like behaviors. In conclusion, we demonstrated that neuroligin 1 restoration by astrocytic FGF2 and its downstream neuronal nuclear FGFR1 as a critical target of prenatal stress-induced glutamatergic synaptogenesis and demonstrated its function in controlling both neurogenesis and hippocampal-related behaviors.

The Relation Between Prenatal Stress, Overweight and Obesity in Children Diagnosed According to BMI and Percentage Fat Tissue.

BackgroundOverweight and obesity in children have a negative impact not only on the physical development but also on the mental health of children. That is why researchers are constantly looking for possible causes of such high frequency of this phenomenon. One of the environmental factors contributing to abnormal weight changes in children may be maternal exposure to adverse environmental factors during pregnancy, which in previous studies led to inconclusive results showing both overweight and obesity and underweight in children. The aim of the study was to examine the relationship between prenatal stress and body weight status. MethodsThe cohort study included 254 girls and 276 boys. Information on prenatal stress was collected with a questionnaire completed by a parent/guardian of a 6–12-year-old child. We assessed the body mass status on the basis of BMI according to the IOTF criterion and on the basis of body fat according to McCarthy criterion. ResultsThe results of our study show that the prenatal stress was related to increased risk of overweight (OR 2.14, 95%CI: 1.25-3.65) diagnosed on the basis of body fat cut-off points, but not when the BMI was a diagnostic criterion (OR 1.03, 95%CI:0.58-1.83). ConclusionThe method of diagnosis based on the fat content appears to be an indicator of the occurrence of abnormalities in body composition due to prenatal stress more sensitive than that based on the BMI. Level of evidence: Evidence obtained from well-designed cohort or case-control analytic studies