Adult Female Rats Exposed to Adolescent Chronic Restraint Stress (aCRS) Display Robust Depressive‐Like Behavior, Cognitive Impairment, and an Unexpected Correlation with Serum BDNF

Abstract

IntroductionDepression is a mood disorder that disproportionately affects women, and is often predicated by childhood or adolescent stress. Symptoms of depression include persistent sadness and cognitive impairment, which have been correlated with low serum brain‐derived neurotrophic factor (BDNF), and with decreased hippocampal (HIP) volume. Our lab has previously used a novel method of adolescent chronic restraint stress (aCRS) to elicit robust depressive‐like behaviors in freely cycling female Sprague‐Dawley rats. Chronic desipramine (DES), a tricyclic antidepressant, decreased depressive‐like behaviors in aCRS rats. To estimate estrus cycle at time of behavioral testing, we removed and weighed the uteri (UTI) immediately after sacrifice, and found no differences among groups.ObjectiveThe objective of this study was to evaluate behaviors and biomarkers in female rats exposed to aCRS, DES, or aCRS+DES.Methods25adolescent female Sprague‐Dawley rats (Charles River, Kingston, NY) arrived post‐natal day (PND) 26 and habituated to the colony room for 7 days prior to the experiment. Rats were randomly assigned to Not Restrained‐Saline (NRSAL, n=6), Not Restrained Desipramine (NRDES, n=6), Restrained‐Saline (RSAL, n=6), or Restrained‐Desipramine (RDES, n=7). Beginning PND 34±1RSAL and RDES rats were restrained at random times for 60 mins/day for 14consecutive days. The final restraint session was followed by 7 days of maturation. Beginning PND 55±1, NRSAL and RSAL rats received subcutaneous (SC) saline injections (0.09% NaCl; 1 mL/kg) and NRDES and RDES rats received SC desipramine in saline solution (5 mg/kg, 1 mL/kg) daily for 14consecutive days. Behavioral testing commenced PND 70±1 and included, in order, locomotor activity (LCA), novel object recognition (NOR), and a 5‐minute forced swim test(FST). Fifteen minutes following the FST, the rats were sacrificed via rapid decapitation. Serum from trunk blood was separated using serum separating tubes, and the HIP and uteri (UTI) were harvested and weighed. Serum was evaluated for BDNF with ELISA (Boster Bio, Pleasanton, CA). All measures were evaluated with two‐way ANOVA and Holm‐Sidak post hoc, and inter‐measure relationships were evaluated with Pearson correlation analysis.ResultsNo differences were observed in locomotor activity, HIP weight, or UTI weight among groups.During NOR, RSAL rats showed significantly impaired discrimination between novel and familiar objects than NRSAL rats (p=0.011). NRDES and RDES were not different from NRSAL.In FST, RSAL rats were significantly more immobile than all other groups (p=0.011). Specifically, RSAL vs NRSAL (p=0.002), RSAL vs RDES(p=<0.001), and RSAL vs NRDES (p=0.029). NRDES and RDES were not different from NRSAL.Using Pearson correlation analysis, immobility was positively correlated with serum BDNF (r=0.54; p=0.006). No other significant correlations were observed.ConclusionsThese results indicate that aCRS elicits robust depressive‐like behavior and cognitive impairment in freely cycling female rats, effects which are ameliorated by chronic DES. Additionally, the unexpected relationship observed between serum BDNF and immobility requires further investigation.Support or Funding InformationMercer University