Effects of Early Life Stress on Depressive and Metabolic States in Adult Individuals at Genetic Risk
Bigio B, Lee FS, Zelli D, Lau T, De Angelis P, Ferris A, Harvey S, Lai J, Kalidindi A, Rasgon N, McEwen B, Nasca C
American College of Neuropsychopharmacology. 2017.
Background: Early life experiences play a powerful role in adulthood mental and physical health. For example, naturally occurring variations in maternal care are known to increase the individual likelihood to depressive disorders in adulthood. Arising from the postulate of insulin resistance (IR) as a pathophysiological link in diabetes, depression and dementia (“the 3 D’s”), converging literature supports a role for the epigenetic modulator of pathogenic mechanisms common to the 3D’s, acetyl-L-carnitine (LAC), as a biomarker to identify a severe phenotype of depression characterized by greater severity and earlier onset. Moreover, low LAC levels are associated with childhood abuse, specifically emotional neglect in subjects with treatment resistant depression. Reverse translational studies rodents with depressive-like phenotypes have reduced LAC levels in the plasma and mood regulatory brain regions (e.g.: hippocampus and prefrontal cortex) and that low LAC levels are associated with IR.
Methods: We implemented a novel mating model using wild-type or heterozygous BDNF val66met (hets) dams and controlling for paternal care to assess the effects of maternal care on molecular, metabolic and behavioral outcomes in male hets offspring. in individuals at genetic risk for the development of the depression, diabetes, progressing to dementia (3D's). A computerized setup was devised for recording of the behavioral observation sessions (i.e., three sessions/day between postnatal days 1 and 7, between 7:00pm and 8:00pm, 12:00am and 1:00am and 4:00am and 5:00am with red lights on and animals in their active phase). Behavioral analysis was performed on the basis of previously employed ethological parameters. Behavioral and molecular analyses in adulthood mice were performed as previously described by four observers who were blind to the sample conditions. For the RNAseq, we used a design with balancedblocks by multiplexing samples, in order to eliminate potential confounding caused by lane effects. Thus, each sample was provided with a unique adapter and all samples were put in the same pool and sequenced with Illumina Hiseq2500 to yield the desired sequencing depth. The Fastq files were evaluated for quality control using FastQC and trimmed with Trimmomatic. Alignment was performed using the Tophat2 and statistical analyses were performed with EdgeR. Genes of interest were confirmed by RT-PCR and ran in triplicates. Two-tailed t-tests and multiple regression were used as appropriate to specific analyses.
Results: We find that wild-type and hets dams differ in the amount of maternal care provided to offspring assessed by in and out of the nest caring and self-maintenance behaviors. Our data show that depressive-like states manifest only in individuals at genetic risk (hets) that receive less maternal care. Indeed, hets receiving less maternal care, as compared to hets receiving more maternal care, show depressive-like traits, including abnormal social interactions. These behavioral differences are concomitant with a peripheral metabolic dysregulation (i.e., IR) and reduced LAC levels. Molecularly, we find striking different transcriptomic profiles in the hippocampal ventral dentate gyrus (vDG), a critical brain region for antidepressant responses. Among the most significant differentially expressed genes, RNAseq, qPCR and protein analyses revealed a reduction in the known marker of stress responses mGlu2, a regulator of glutamate tone, in the vDG of less nurtured hets as compared to high nurtured hets. Finally, at the behavioral characterization, more aged hets that received low nurturing showed cognitive impairments in spatial and contextual memory at the Y-maze, suggestive of dementia-like symptoms, which were not apparent before. Such cognitive impairments were not observed in high nurtured hets at either age.
Conclusions: These findings suggest that early life experience have huge influences on adulthood depressive and metabolic states