Sex Differences in the Enduring Effects of Social Deprivation during Adolescence in Rats: Implications for Psychiatric Disorders

Abstract

The exposure to adverse environmental situations during sensitive periods of development may induce re-organizational effects on different systems and increase the vulnerability to develop psychiatric disorders later in life. The adolescent period has been demonstrated extremely susceptible to stressful events. However, most of the studies focused on the immediate effects of stress exposure and few of them investigated sex differences. This raised the question if these modulations might also be long-lasting and how the differential maturational events taking place during adolescence between males and females might have a role in the detrimental effects of stress. Given the importance of social play for the right maturation of behaviour during adolescence, we used the preclinical model of social deprivation, based on the lack of all social contacts, for four weeks after weaning, followed by re-socialization until adulthood. We found that both male and female animals reared in isolation during adolescence developed an anhedonic phenotype at adulthood, without any impairments in the cognitive domain. At molecular level, these functional changes were associated with sex-specific impairments in the expression of neuroplastic markers as well as of hypothalamic-pituitary-adrenal axis-related genes. Lastly, we also reported anatomically-selective changes associated with the enduring effects of social isolation.

Anti-stress Properties of Atypical Antipsychotics

“…Moreover, exposure of rodents to an early-life social challenge may increase the sensitivity to the effects of psychostimulant drugs, among which amphetamine, determining an exacerbation of the hyperactivity state [ 103 , 104 ]. Furthermore, social isolation may induce a persistent anhedonic-like phenotype [ 105 , 106 ], with a disruption of sensorimotor gating, a measure of the ability to integrate cognitive and sensory inputs, as well as a deficit in novel object discrimination paradigm [ 107 , 108 ], reflecting attention and memory dysfunctions. The behavioral alterations following stress in adolescence are associated with different neurochemical and molecular changes.…”

“…Challenges occurring during adolescence may also induce disruptions in neuroplasticity-related markers. Accordingly, we have recently demonstrated that adolescent social isolation in male rats determines a selective reduction of Bdnf mRNA levels within the prefrontal cortex, but not the hippocampus [ 105 ]. Moreover, isolation rearing can impair the HPA axis functionality, highlighting the strong impact on stress-related responses.…”

“…In addition, we have found that Nr3c1 (the gene encoding for GR) mRNA levels were increased in the prefrontal cortex of isolated male rats, whereas they were reduced in the ventral hippocampus of female animals. We also observed increased expression of the chaperone Fkbp5 in the ventral hippocampus of male isolated rats [ 105 ].…”

Adolescent Stress Confers Resilience to Traumatic Stress Later in Life: Role of the Prefrontal Cortex

“…Stress during development is generally thought to evoke negative behavioral effects later in life (27,28,(30)(31)(32)(33)(34)(35). However, prior studies also support the ability of adolescent stress to confer stress resilience in adulthood, using a number of stress models (reviewed in 11,36,37).…”

“…Stress modality may also play a role in the development of resilience. For instance, complete social isolation during adolescence increases anxiety-like behavior, acoustic startle and impaired extinction in adulthood (47), whereas social instability (PND [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45], that entails poor social structure but no isolation, evokes a reduction of conditioned fear expression in adulthood (48). The same protocol of social instability proved to be less effective in female rats (49), pointing to possible sex-dependent mechanisms for the programming of the long-term effects of adolescent stress, consistent with our observed sex differences.…”