Environmental Enrichment and Gut Inflammation Modify Stress-Induced c-Fos Expression in the Mouse Corticolimbic System

Abstract

Environmental enrichment (EE) has a beneficial effect on rodent behaviour, neuronal plasticity and brain function. Although it may also improve stress coping, it is not known whether EE influences the brain response to an external (psychological) stressor such as water avoidance stress (WAS) or an internal (systemic) stressor such as gastrointestinal inflammation. This study hence explored whether EE modifies WAS-induced activation of the mouse corticolimbic system and whether this stress response is altered by gastritis or colitis. Male C67BL/6N mice were housed under standard or enriched environment for 9 weeks, after which they were subjected to a 1-week treatment with oral iodoacetamide to induce gastritis or oral dextran sulfate sodium to induce colitis. Following exposure to WAS the expression of c-Fos, a marker of neuronal activation, was measured by immunocytochemistry. EE aggravated experimentally induced colitis, but not gastritis, as shown by an increase in the disease activity score and the colonic myeloperoxidase content. In the brain, EE enhanced the WAS-induced activation of the dentate gyrus and unmasked an inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression within this part of the hippocampus. Conversely, EE inhibited the WAS-evoked activation of the central amygdala and prevented the inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression in this region. EE, in addition, blunted the WAS-induced activation of the infralimbic cortex and attenuated the inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression in this area. These data reveal that EE has a region-specific effect on stress-induced c-Fos expression in the corticolimbic system, which is likely to improve stress resilience. The response of the prefrontal cortex – amygdala – hippocampus circuitry to psychological stress is also modified by the systemic stress of gut inflammation, and this interaction between external and internal stressors is modulated by the housing environment.

A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

“…Those with a low cortisol response to stress tasks had a higher level of Il-6 and Il-1ra at baseline, and an increased Il-1ra elevation after stress (Kunz-Ebrecht et al, 2003). Experimentally induced inflammation in mice causes an alteration in stress induced expression of c-Fos, an experimental marker of neural activation, in several regions of the brain and appeared to alter the corticosterone response (Reichmann et al, 2013). In addition, prior peripheral injection of Il-1b causes an elevated ACTH and corticosterone response to stresses such as Il-1b and electric foot shocks (Schmidt et al, 1995).…”

A novel unbiased counting method for the quantification of synapses in the mouse brain

“…The main reason to investigate the DGpl within the dentate gyrus was that preliminary results demonstrated increased neuropeptide Y (NPY) expression in this cell layer after EE ( Reichmann et al, 2012 ). A further reason was that EE also increases the activity of dentate granule cells, as measured by the expression of the immediate early gene c-Fos ( Reichmann et al, 2013 ), which may result in EE-evoked enhanced signaling because some granule cells terminate in the DGpl ( Acsady et al, 1998 ).…”

Nod-like receptors are critical for gut-brain axis signaling

“…Neuronal activation was further assessed by quantification of c-Fos-positive cells in the DG and CA3 regions of the dorsal hippocampus by confocal microscopy in mice exposed to WAS. Given that the peak of c-Fos expression occurs 1-3 h following exposure an acute stimulus (21), c-Fos positive cells were enumerated in hippocampal sections collected at 1 h post-WAS. The total number of c-Fos-positive cells, as quantified using Imaris, was significantly lower in NodDKO(+WAS) mice compared to WT(+WAS) in both the DG and CA3 region of the dorsal hippocampus (Fig 2A).…”

“…Mice exposed to 1 hour of WAS were left undisturbed in their home-cages for 1 hour followed by measurement of c-FOS expression levels in the hippocampus (21). Animals were then perfused as described above.…”