Prenatal stress increases the striatal and hippocampal expression of correlating c‐FOS and serotonin transporters in murine offspring

Abstract

Prenatal stress (PS) is a known risk factor for several psychiatric diagnoses, including schizophrenia, attention deficit hyperactivity disorder, autism, anxiety, and depression which have been associated with serotonin transporter (SERT) dysregulation. Moreover, long-term effects in animal models associate with higher levels of immediate early genes, e.g. c-FOS (up-regulated in response to neuronal activity), in the brain of PS offspring. We therefore quantified the expression of both protein related mRNAs in adolescent BALB/c mice subjected to mild auditory stress on two separate days in mid gestation. SERT and c-FOS consistently correlated in most brain regions of PS mice and controls. Moreover, two-way ANOVAs revealed concomitantly increased levels of proteins, as well as of FOSL1 and FOSL2 mRNA, especially in the striatum and hippocampus of the PS offspring. Sex affected only and less consistently mRNA expression, yet interacted with PS, demonstrating that glucocorticoid receptor mRNA expression decreased in PS males but increased in PS females compared to the respective controls. This first finding of a correlation between SERT and c-FOS protein expression affected by PS, together with related mRNAs, may be considered a new target for behavioral and treatment studies in offspring.

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…Malespecific reduction in serum testosterone and alterations in the maturation of dendritic spines in the MPFC (Markham et al 2013). Hippocampus GR reduced in males BUT increased in females (Bielas et al 2014). …”

“…Therefore there appears to be an interaction between stress steroids and sex steroids during early brain development that affect the developing brain and its response to stress in later life (See figure 1). Indeed, hippocampal mRNA expression of glucocorticoid receptor expression in adolescent BALB/c mice exposed to prenatal stress was reduced in males, but increased in females, once again suggesting that sex significantly impacts response to prenatal stress (Bielas et al 2014). …”

“…These discrepancies may be due to strain effects, indeed alterations in brain-derived neurotrophic factor (BDNF), glucocorticoid receptors and nicotinic receptor expression in the hippocampus following prenatal stress in rats are highly dependent on background strain (Neeley et al 2011). Given that both glucocorticoid receptor expression (Bielas et al 2014), BDNF expression (Hill 2012a) and 7 nicotinic receptor expression (Schulz et al 2013) are sex-dependently M a n u s c r i p t 14 regulated during brain development, strain differences in the expression of these developmental proteins would then affect the sex-specific response to stress.…”

Pre- and Perinatal Risk for Attention-Deficit Hyperactivity Disorder: Does Neuropsychological Weakness Explain the Link?

“…For example, low birth weight (LBW) robustly predicts ADHD symptoms (Langley, Holmans, van den Bree, & Thapar, 2007; Nigg & Breslau, 2007). Other relevant pre- and perinatal health risks include maternal stress during pregnancy (Bielas, Arck, Bruenahl, Walitza, & Grünblatt, 2014; Van den Bergh & Marcoen, 2004), prenatal substance use (Ernst et al, 2001; Nigg and Breslau, 2007), and perinatal complications (D’Onofrio et al, 2013). However, these risks are often correlated and, importantly, it is unclear whether critical effects on ADHD risk occur prenatally or perinatally (or both).…”

Evaluación del estrés prenatal como inductor de la conducta depresiva asociada con la liberación de Serotonina en el Hipocampo Ventral

“…Las ratas macho estresados prenatalmente y posnatalmente muestran disminución en la movilidad en la prueba de Porsolt, baja ingesta de sacarosa y disminución de la enzima triptófano hidroxilasa en el giro dentado, en CA3 y en el giro dentado del hipocampo en machos y hembras (53). El estrés prenatal en ratones causa aumento en el transportador de 5-HT en hipocampo correlacionado con la expresión del gen FOS1 en la misma área cerebral, demostrando la participación de la 5-HT en los efectos del estrés prenatal (54). Las crías de ratas estresadas prenatalmente mostraron bajo peso corporal y disminución de la ingesta de sacarosa; los fetos tuvieron disminución de peso corporal.…”