FAAH Inhibition Restores Early Life Stress-Induced Alterations in PFC microRNAs Associated with Depressive-Like Behavior in Male and Female Rats

Abstract

Early life stress (ELS) increases predisposition to depression. We compared the effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, and the selective serotonin reuptake inhibitor paroxetine, on ELS-induced depressive-like behavior and the expression of microRNAs (miRs) associated with depression in the medial prefrontal cortex (mPFC), hippocampal CA1 area, lateral habenula and dorsal raphe in rats. We also examined the mRNA expression of serotonergic (htr1a and slc6a4) and endocannabinoid (cnr1, cnr2 and faah) targets in the mPFC following ELS and pharmacological treatment. Adult males and females exposed to the ‘Limited Bedding and Nesting’ ELS paradigm demonstrated a depressive-like phenotype and late-adolescence URB597 treatment, but not paroxetine, reversed this phenotype. In the mPFC, ELS downregulated miR-16 in males and miR-135a in females and URB597 treatment restored this effect. In ELS females, the increase in cnr2 and decrease in faah mRNAs in the mPFC were reversed by URB597 treatment. We show for the first time that URB597 reversed ELS-induced mPFC downregulation in specific miRs and stress-related behaviors, suggesting a novel mechanism for the beneficial effects of FAAH inhibition. The differential effects of ELS and URB597 on males and females highlight the importance of developing sex-specific treatment approaches.

Epigenetic (re)programming of gene expression changes of CB1R and FAAH in the medial prefrontal cortex in response to early life and adolescence stress exposure

“…Thus, it is tempting to speculate that a ELSinduced change of CB1R expression, as found in our study in the mPFC, may result in an imbalance of excitation and inhibition and impaired brain function in this brain area and as a consequence in disturbed behavioral profiles. This is supported by our findings that the ELS-exposed animals show symptoms of anxiety-and depressive-like behavior and slight disturbances of social interaction, which is in line with previous findings applying this particular ELS paradigm (Alteba et al, 2016(Alteba et al, , 2020(Alteba et al, , 2021Portugalov et al, 2022). On the other hand, a potential neuroprotective role of CB1R signaling was proposed, since stressinduced CB1R activation, specifically on glutamatergic terminals, may protect from excitotoxicity and neuronal cell death (Zoppi et al, 2011).…”

“…Applying this model it was found that aberrant patterns of maternal care influence the maturation and refinement of functional synaptic and neuronal circuits resulting in impairments of spatial and recognition memory as well as in symptoms of mental disorders. For the present study we applied a slightly modified maternal neglect paradigm that previously has been shown to induce impairments in social preference and social recognition as well as enhanced depression-like and anxiety-like behavior in adult rats (Alteba et al, 2016(Alteba et al, , 2020(Alteba et al, , 2021Portugalov et al, 2022). These studies also showed that enhancing eCB signaling by pharmacological treatment during late adolescence restored ELSinduced depressive-like behavior and alterations in eCB signaling, which were associated with the behavioral phenotype.…”

“…As ELS an established paradigm was applied that induced maternal neglect and fragmented maternal care by inappropriate housing conditions (Avishai-Eliner et al, 2001) with modifications (Alteba et al, 2016(Alteba et al, , 2020(Alteba et al, , 2021Portugalov et al, 2022). The dam and her pups were housed in a cage with limited "Sunny Chips" bedding material (1.2 cm layer) from PND7 to PND14.…”

“…This task aims to assess sociability and short-term social memory. The "partner" rat was confined to a separate section of the open field (50 cm× 50 cm× 50 cm) by a transparent perforated Plexiglas panel (corrals) (Portugalov et al, 2022). For the preference phase, the experiment rat was given 5 min exploration with a novel juvenile and a novel object.…”

Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats

“…We are aware that translation from our animal model’s results to human depression (and different types of depression) has to be examined carefully. Although FAAH is known to be involved in depression mechanisms in animal studies (the most recent examples [ 82 , 83 ]), much more investigation is needed to ensure the same mechanisms are relevant to humans. However, only a few clinical trials performed till now support the assumption that FAAH plays an important role in depression mechanisms.…”