Chronic Isolation Stress Affects Subsequent Crowding Stress-Induced Brain Nitric Oxide Synthase (NOS) Isoforms and Hypothalamic-Pituitary-Adrenal (HPA) Axis Responses

Abstract

The nitric oxide (NO) pathway in the brain is involved in response to psychosocial stressors. The aim of this study was to elucidate the role of nNOS and iNOS in the prefrontal cortex (PFC), hippocampus (HIP), and hypothalamus (HYPO) during social isolation stress (IS), social crowding stress (CS), and a combined IS + CS. In the PFC, 3 days of CS increased iNOS but not nNOS protein level. In the HIP and HYPO, the levels of nNOS and iNOS significantly increased after 3 days of CS. In the PFC, IS alone (11 days) enhanced iNOS protein level following 3 days of CS and increased nNOS level in the HIP and HYPO after 14 days of CS. By contrast, in the HIP, IS abolished the subsequent CS-induced increase in nNOS in the HIP and strongly elevated iNOS level after 7 days of CS. In the HYPO, prior IS inhibited nNOS protein level induced by subsequent CS for 3 days, but increased nNOS protein level after longer exposure times to CS. Isolation stress strongly upregulated plasma interleukin-1β (IL-1β) and adrenocorticotropic hormone (ACTH) levels while corticosterone (CORT) level declined. We show that the modulatory action of the NO pathway and ACTH/CORT adaptation to chronic social isolation stress is dependent on the brain structure and nature and duration of the stressor. Our results indicate that isolation is a robust natural stressor in social animals; it enhances the NO pathway in the PFC and abolishes subsequent social CS-induced NOS responses in the HIP and HYPO.

PDTC Alleviates Depressive Symptoms and Colon Tissue Injury via Inhibiting NO Overproduction in CUMS Rats

“…A previous study demonstrated that stress could increase iNOS levels in the cerebral cortex through the NF-κB pathway (Zlatkovic and Filipovic, 2013). Furthermore, stress caused the overproduction of iNOS-derived NO, which further led to behavioral changes and HPA axis dysfunction (Gadek-Michalska et al, 2019). Based on these findings, it is suggested that PDTC could influence behavioral changes induced by CUMS.…”

“…On the other hand, NO is a kind of gas molecule that has been reported to play a major role in the pathogenesis of stress-related disorders (Gulati et al, 2015). Evidence is accumulating that chronic stress exposure can cause overproduction of NO, resulting in disruption of hypothalamic-pituitary-adrenal (HPA) axis activity (Gadek-Michalska et al, 2019). The activation of the HPA axis is one of the central physiological mechanisms involved in the stress response (McEwen et al, 2015).…”

“…The dysfunction of the HPA axis plays an important etiological role in the development of depression (Dantzer, 2006;Zhou et al, 2011). Furthermore, a recent study also found chronic or acute stress-induced iNOS-derived NO overproduction in both the hippocampus and prefrontal cortex of rats (Gadek-Michalska et al, 2019). Accordingly, it has been suggested that NOS inhibition be developed as a novel antidepressant strategy (Montezuma et al, 2012).…”

Animal Models for Functional Gastrointestinal Disorders

“…Overactivation of the insular cortex related with colonic hypersensitivity (19) (Continued) Increased mast cells density (145) In WKY rat activated mast cells, MPO level & transient hyperpermeability, alteration of mitochondrial activity (146) Anxiety-like and depression-like symptoms Early transient changes (Day 3) in the nitrergic expression in the PFC, hippocampus, hypothalamus (147) Social isolation Alterations in the IL-18 pathway and MUC2/TFF3 expression (149) Anxiety-like and depression-like symptoms Reduced BDNF levels & increased reactivity of the HPA axis (148) Changes in the nitrergic expression in the PFC, hippocampus, hypothalamus (147) Abdominal surgery Impaired gastric emptying Low ghrelin concentration (249,251,252) Impaired motility through the activation of the inhibitory reflex pathway increased cytokines expression (TNFa, IL1α, IL6, IL1β, CCL2) (241) infiltration resident macrophages (245) Impaired motility, delayed transit increased cytokines expression in muscular layers (240) 241Increased permeability non-related to TLR2/4 (244) Activation of nuclei (supraoptic nucleus, locus coeruleus, paraventricular nucleus of the hypothalamus & rostral raphe pallidus) expressing nucleobindin2/nefastin complex involved in the decrease of food intake and GI transit (253) 5HT, serotonin; 5HT1A/1B/2A/2B, serotonin receptor type 1A, 1B, 2A, 2B; ACTH, adreno cortico trophic hormone; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; CCL2, chemokine ligand 2; CRH, corticotropin-releasing hormone; CRHR1 corticotropin-releasing hormone receptor type 1; D1/2/3/4/8/10, day 1/2/3/4/8/10; Eo, eosinophils; GC-C/cGMP, guanylate cyclase C/cyclic guanylin monophosphate; GI, Gastrointestinal; GR, Glucocorticoid receptor; HPA, hypothalamus-pituitaryadrenal; IL, interleukin; MC, mast cell; MPO, myeloperoxidase activity; MUC2, Mucin 2; NMDA, N-methyl-D-aspartate; PFC, prefrontal cortex; SC, spinal cord; SERT, serotonin transporter; TFF3, rail fold factor 3; WKY, wistar kyoto. (29), etc.…”

“…Conversely, in the social isolation stress (SIS) model, the animal is isolated from the rest of the cage. Often applied just after the weaning, SIS modifies the development of the brain and influences the nitrergic system in several brain areas such as the hippocampus, the frontal cortex by increasing the nNOS expression in the hippocampus and hypothalamus and iNOS in the prefrontal cortex (147). A decrease production of BDNF, and an activation of the HPA axis which produce more corticosterone.. Mice exposed to SIS, have an impaired reactivity to stress with an overreaction to another stressor together with increased anxiety-and depression-like symptoms (148).…”