Enriched environment alleviates adolescent visceral pain, anxiety- and depression-like behaviors induced by neonatal maternal separation

Abstract

Background Neonatal maternal separation (NMS), a major kind of early life stress, increases the risk of visceral pain, anxiety- and depression-like behaviors in adulthood. An enriched environment (EE) has been shown to successfully rescue the brain from various early life psychological stressors. Therefore, this study aimed to investigate whether NMS induces visceral pain, anxiety- and depression-like behaviors in adolescents and to evaluate the impact of EE in infancy on these symptoms. Methods Male C57BL/6 J mice that had been subjected to NMS were used in this study. The visceral pain threshold test (PTT), open field test (OFT), and sucrose preference test (SPT) were conducted to evaluate visceral pain, anxiety- and depression-like behaviors in mice, respectively. An enzyme linked immunosorbent assay (ELISA) for tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), and interleukin-10 (IL-10) was performed to assess neuroinflammatory responses. Then, the effects of EE (free-turning running wheels, pipes, stairs, and various colored ocean balls, etc.) on NMS-induced behaviors and neuroinflammatory factors were examined. Results The impacts of NMS included adolescent visceral pain, anxiety- and depression-like behaviors. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and paraventricular nucleus (PVN) were biased towards pro-inflammatory features. Further, EE alleviated adolescent visceral pain, anxiety- and depression-like behaviors. The application of EE up-regulated the expression of IL-10, and down-regulated the expression of IL-1β and TNF-α in mPFC, BLA, and PVN. Conclusions The effects of NMS include adolescent visceral pain, anxiety- and depression-like behaviors, accompanied by an imbalance of neuroinflammation. Intervention with EE in pediatric mice relieved these symptoms by reducing neuroinflammation in the central nervous system.

The influence of the enriched environment in different periods on neonatal maternal separation-induced visceral pain, anxiousness, and depressive behaviors

“…Our study showed that EE intervention during prepuberty and puberty effectively prevented/alleviated NMS-induced visceral pain, anxiety, and depressive behaviors and reversed the increase in plasma corticosterone, yet EE intervention in early adulthood had no significant effect. Clinical and basic studies have shown that early life stress may negatively affect brain development, neuroplasticity, and behavior, and increase individual vulnerability to chronic pain and psychiatric disorders, including chronic visceral pain, depression, and anxiety (2,(5)(6)(7)16). In this study, we observed that exposure to NMS resulted in a decreased pain threshold and disturbed emotional response in mice.…”

“…In contrast to the negative effects of early life stress, EE had a positive effect on brain development and behavior. We have previously shown that EE from P1 to P40 can alleviate visceral pain and mental disorders in adolescence (7). Since EE appears to ameliorate stress-induced negative responses in early life, is there an optimal time window for intervention?…”

“…In addition, EE can reduce the expression level of corticosterone (11,12). We, and others, have previously shown that EE alleviates NMS-induced visceral pain, anxiety-and depression-like behaviors (7). However, these studies have not systematically explored the optimal timing of EE intervention.…”

“…In contrast to the negative effects of early life stress, an enriched environment (EE) can promote CNS development and improve chronic pain and mental disorders, including visceral pain, anxiety, and depression (7). An EE is an environmental intervention frequently used in animal studies, defined as a combination of "complex inanimate objects and social stimuli", aiming to increase sensory, physical, and social stimuli (8).…”

Sex-dependent effects of postweaning exposure to an enriched environment on visceral pain and anxiety- and depression-like behaviors induced by neonatal maternal separation

“…Noxious stress is known to cause dysfunction of the HPA axis, which is associated with visceral pain and psychiatric symptoms. In contrast, an EE improves chronic pain and psychiatric disorders caused by early life stress, including visceral pain, anxiety, and depression (8). Several studies have shown that an EE can reduce anxiety-and depressive-like behaviors in animals (9,10).…”