Effects of early adolescent environmental enrichment on cognitive dysfunction, prefrontal cortex development, and inflammatory cytokines after early life stress

Abstract

Early postnatal stress such as maternal separation causes cognitive dysfunction later in life, including working memory deficits that are largely mediated by the prefrontal cortex. Maternal separation in male rats also yields a loss of parvalbumin-containing prefrontal cortex interneurons in adolescence, which may occur via inflammatory or oxidative stress mechanisms. Environmental enrichment can prevent several effects of maternal separation; however, effects of enrichment on prefrontal cortex development are not well understood. Here, we report that enrichment prevented cognitive dysfunction in maternally separated males and females, and prevented elevated circulating pro-inflammatory cytokines that was evident in maternally separated males, but not females. However, enrichment did not prevent parvalbumin loss or adolescent measures of oxidative stress. Significant correlations indicated that adolescents with higher oxidative damage and less prefrontal cortex parvalbumin in adolescence committed more errors on the win-shift task; therefore, maternal separation may affect cognitive dysfunction via aberrant interneuron development. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 482-491, 2016.

Adolescent environmental enrichment prevents behavioral and physiological sequelae of adolescent chronic stress in female (but not male) rats

“…In combating the effects of stress applied early in the postnatal period, later adolescent exposure to environmental enrichment is largely successful in restoring behavioral and hormonal function (do Prado et al, 2016; Francis, Diorio, Plotsky, & Meaney, 2002; Hui et al, 2011;Morley-Fletcher, Rea, Maccari, & Laviola, 2003). As environmental enrichment in adolescence can ameliorate the effects of prior stress in early postnatal life, we predicted that it may also prevent the enduring effects of stress occurring in late adolescence.…”

Immunoadolescence: Neuroimmune development and adolescent behavior

“…While this idea is generally accepted, the mechanisms that underpin healthy-state BBB dynamics throughout development are not clear. Recent work supports the idea that circulating immune molecules play critical roles in adolescent brain function (do Prado et al, 2015; Wieck et al, 2013), therefore one might hypothesize that the BBB has evolved to allow differential access to specific immune actors throughout adolescence to influence proper neural development at this time.…”

“…Therefore, here we will limit our discussion to potential mechanistic underpinnings of adolescence as a discrete period of vulnerability. Specifically, we recently showed that early life stress exposure in rats led to adolescent increases in circulating levels of the pro-inflammatory cytokine IL-6 (do Prado et al, 2015), which has been reported in depressed patients (Miller and Cole, 2012). Importantly, this increase in IL-6 is positively correlated with prefrontal cortex parvalbumin-positive interneuron loss as well as NMDA receptor subunit changes (do Prado et al, 2015).…”

“…Specifically, we recently showed that early life stress exposure in rats led to adolescent increases in circulating levels of the pro-inflammatory cytokine IL-6 (do Prado et al, 2015), which has been reported in depressed patients (Miller and Cole, 2012). Importantly, this increase in IL-6 is positively correlated with prefrontal cortex parvalbumin-positive interneuron loss as well as NMDA receptor subunit changes (do Prado et al, 2015). Central administration of the anti-inflammatory cytokine IL-10 during early adolescence prevented the NMDA changes and prevented parvalbumin loss (Wieck et al, 2013), suggesting that central inflammatory activity was a consequence of peripheral pro-inflammatory activity.…”

Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder

“…These results suggested that NOX2-mediated phenotype loss of PV interneurons and consequent PTSD symptoms might be causally linked. By exposing neonatal rats to early life stress, however, EE did not prevent PV interneuron loss or adolescent measures of oxidative stress [36]. Reasons for the discrepancy might be attributed to the different animal models used.…”