Environmental enrichment prevents chronic stress‐induced brain‐gut axis dysfunction through a GR‐mediated mechanism in the central nucleus of the amygdala

Abstract

The usefulness of psychotherapy, such as cognitive behavioral therapy (CBT) that encompasses cognitive and behavioral strategies that aim to improve the underlying thinking or behavioral patterns, extends far beyond the treatment of stress-related mood and psychological disorders such as anxiety and depression. 1-3 Nowadays, CBT is also being used to improve the quality of life in patients suffering from chronic pain, such as musculoskeletal pain, 4-6 pelvic pain, 7 and arthritic pain. 8 Clinical evidence suggests that CBT also improves in the overall symptomatology of patients with irritable bowel syndrome (IBS). 9 Irritable bowel syndrome a common gastrointestinal disorders characterized by chronic abdominal pain, due to increased visceral sensitivity, and abnormal bowel habits. These symptoms Abstract Background: Cognitive behavioral therapy (CBT) improves quality of life of patients with irritable bowel syndrome (IBS), a disorder characterized by chronic visceral pain and abnormal bowel habits. Whether CBT can actually improve visceral pain in IBS patients is still unknown. The aim of this study is to evaluate whether environment enrichment (EE), the animal analog of CBT, can prevent stress-induced viscerosomatic hypersensitivity through changes in glucocorticoid receptor (GR) signaling within the central nucleus of the amygdala (CeA).Methods: Rats were housed in either standard housing (SH) or EE for 7 days before and during daily water avoidance stress (WAS) exposure (1-h/d for 7 days). In the first cohort, visceral and somatic sensitivity were assessed via visceromotor response to colorectal distention and von Frey Anesthesiometer 24 hous and 21 days after WAS.In another cohort, the CeA was isolated for GR mRNA quantification.Key Results: Environment enrichment for 7 days before and during the 7 days of WAS persistently attenuated visceral and somatic hypersensitivity when compared to rats placed in SH. Environment enrichment exposure also prevented the WASinduced decrease in GR expression in the CeA. Conclusion & Inferences:Pre-exposure to short-term EE prevents the stress-induced downregulation of GR, and inhibits visceral and somatic hypersensitivity induced by chronic stress. These results suggest that a positive environment can ameliorate stress-induced pathology and provide a non-pharmacological therapeutic option for disorders such as IBS. K E Y W O R D Senvironmental enrichment, pain, rat, visceral hypersensitivity

Peripheral Guanylate Cyclase‐C modulation of corticolimbic activation and corticotropin‐releasing factor signaling in a rat model of stress‐induced colonic hypersensitivity

“…Long‐Evans rats were also used to investigate alterations in corticolimbic CRF signaling following stress exposure and/or linaclotide treatment based on previous studies showing adult stress induced significantly elevated HPA axis activity within this strain 31–33 . Importantly, the homotypic stressor employed during this study (water avoidance stress) induces comparable behavioral changes in Fischer 344 and Long‐Evans rats, with both strains exhibiting an increased fecal‐pellet output during the stress exposure and a subsequent increase in the visceromotor response to colorectal distension following the exposure 34–37 . Rats were double‐housed on Sani‐Chip bedding in standard individually ventilated cages at 23°C with a relative humidity of 50% on a 12‐hr light/dark cycle (7:00 a.m. to 7:00 p.m.).…”

“…[31][32][33] Importantly, the homotypic stressor employed during this study (water avoidance stress) induces comparable behavioral changes in Fischer 344 and Long-Evans rats, with both strains exhibiting an increased fecal-pellet output during the stress exposure and a subsequent increase in the visceromotor response to colorectal distension following the exposure. [34][35][36][37] Rats were double-housed on Sani-Chip bedding in standard individually ventilated cages at 23°C with a relative humidity of 50% on a 12-hr light/dark cycle (7:00 a.m. to 7:00 p.m.). Food (5053 Irradiated PicoLab Rodent Diet; LabDiet) and water were available ad libitum.…”

Importance of Non-pharmacological Approaches for Treating Irritable Bowel Syndrome: Mechanisms and Clinical Relevance

“…Adult stress and anxiety models of IBS use physical stimuli [restraint stress ( 29 , 30 ), cold exposure ( 31 ), and forced swim test ( 32 )] and psychological stimuli such as water avoidance stress (WAS) ( 27 , 33 ) to induce visceral hypersensitivity. Chronic WAS specifically has been shown to decrease GR expression and increase CRH expression in the central nucleus of the amygdala (CeA) which induces visceral hypersensitivity that persists long after the stressor has been removed ( 20 , 27 , 34 ).…”

“…Moreover, the fact that the underlying mechanisms of CBT remain poorly understood continues to hinder the use of CBT to treat visceral pain. To unravel the underlying mechanisms of CBT, we and others have employed a rodent model of environmental enrichment (EE), the animal analog of CBT ( 20 ). In this review, we discuss the clinical presentation of chronic visceral pain, focusing on IBS.…”

Adult Stress Promotes Purinergic Signaling to Induce Visceral Pain in Rats with Neonatal Maternal Deprivation

“…Our previous studies have shown that neonatal maternal deprivation (NMD) followed by adult multiple stress (AMS) advances the occurrence of visceral hypersensitivity in rats, partly due to enhanced norepinephrine (NE)-b 2 adrenergic signaling, while NMD alone does not cause visceral hyperalgesia at the age of 6 weeks [17]. The adrenergic signaling pathway plays an important role in regulating stress responses in many organs including the nervous system [18][19][20]. It has been reported that the activation of adrenergic receptors regulates the transmission of nociceptive information by inhibiting neurons and neurotransmitter release [15].…”