Abstract
Maternal nutritional programming by caloric exposure during pregnancy and lactation results in long-term behavioral modification in the offspring. Here, we characterized the effect of maternal caloric exposure on synaptic and brain morphological organization and its effects on depression-like behavior susceptibility in rats’ offspring. Female Wistar rats were exposed to chow or cafeteria (CAF) diet for 9 weeks (pre-pregnancy, pregnancy, and lactation) and then switched to chow diet after weaning. By postnatal day 60, the male Wistar rat offspring were tested for depressive-like behavior using operational conditioning, novelty suppressed feeding, sucrose preference, and open-field test. Brain macro and microstructural morphology were analyzed using magnetic resonance imaging deformation-based morphometry (DBM) and western blot, immunohistochemistry for NMDA and AMPA receptor, synaptophysin and myelin, respectively. We found that the offspring of mothers exposed to CAF diet displayed deficient motivation showing decrease in the operant conditioning, sucrose preference, and suppressed feeding test. Macrostructural DBM analysis showed reduction in the frontomesocorticolimbic circuit volume including the nucleus accumbens (NAc), hippocampus, and prefrontal cortex. Microstructural analysis revealed reduced synaptic terminals in hippocampus and NAc, whereas increased glial fibrillary acidic protein in hippocampus and lateral hypothalamus, as well as a decrease in the hippocampal cell number and myelin reduction in the dentate gyrus and hilus, respectively. Also, offspring exhibited increase of the GluR1 and GLUR2 subunits of AMPA receptor, whereas a decrease in the mGluR2 expression in hippocampus. Our findings reveal that maternal programming might prime depression-like behavior in the offspring by modulating macro and micro brain organization of the frontomesocorticolimbic circuit.
Highlights
Depression is one of the leading causes of disability worldwide affecting >300 million people of all ages[1,2].Depressive subjects show anhedonia or low motivation for natural or social stimuli, which become resistant to brain therapy and classical pharmacology approaches[3].Major depressive disorder (MDD) is characterized by an age-dependent brain dysfunction and structural alterations in selective regions of the reward circuit[4,5,6,7,8,9]
Differences in motivation behavior in the offspring were identified during the sucrose preference test (Fig. 1C; F2,46 = 4.784 p = 0.0130), showing a significant decrease in the percentage of sucrose intake in the CAF-CTRL and CAF-CAF groups compared with their baseline (Fig. 1C, Analysis of variance (ANOVA) post hoc Tukey ****p ≤ 0.0001) and a significant decrease in the CAF-CTRL and CAF-CAF compared with the CTRL-CTRL in the test day (Fig. 1C, p = 0.0015 and p = 0.0074, respectively)
We identified that maternal programming by CAF diet exposure led to depression-like behavior in the offspring, showing lower volume in many regions, among which the thalamus, hippocampus, nucleus accumbens (NAc) core, and hypothalamus, important regions in the frontostriatomesolimbic system, were correlated with their own alterations in SYP and glial fibrillary acidic protein (GFAP) expressions
Summary
Major depressive disorder (MDD) is characterized by an age-dependent brain dysfunction and structural alterations in selective regions of the reward circuit[4,5,6,7,8,9]. The. Trujillo-Villarreal et al Translational Psychiatry (2021)11:53 reward circuit integrates dopaminergic neurons located in the ventral tegmental area (VTA) that innervate the nucleus accumbens (NAc), the prefrontal cortex (PFC), central, and basolateral amygdala (BLA) and the hippocampus and dorsal striatum[10]. Major volume brain changes in adult and adolescence in MDD subjects have been documented, including hippocampus atrophy[7,14] thinner cortical gray matter in the orbitofrontal and medial cortex (OFC), anterior and posterior cingulate, insula, and temporal lobes[9,15,16,17]. Genome-wide association studies (GWAS) of MDD and schizophrenia cohorts have identified genetic variants linked to brain volume alterations during development[18], supporting the notion that brain macrostructural changes might potentially lead to MDD
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