Both Basal and Acute Restraint Stress-Induced c-Fos Expression Is Influenced by Age in the Extended Amygdala and Brainstem Stress Centers in Male Rats

Abstract

The hypothalamus-pituitary-adrenal axis (HPA) is the main regulator of the stress response. The key of the HPA is the parvocellular paraventricular nucleus of the hypothalamus (pPVN) controlled by higher-order limbic stress centers. The reactivity of the HPA axis is considered to be a function of age, but to date, little is known about the background of this age-dependency. Sporadic literature data suggest that the stress sensitivity as assessed by semi-quantitation of the neuronal activity marker c-Fos may also be influenced by age. Here, we aimed at investigating the HPA activity and c-Fos immunoreactivity 2 h after the beginning of a single 60 min acute restraint stress in eight age groups of male Wistar rats. We hypothesized that the function of the HPA axis (i.e., pPVN c-Fos and blood corticosterone (CORT) level), the neuronal activity of nine stress-related limbic areas (i.e., magnocellular PVN (mPVN), medial (MeA), central (CeA), basolateral nuclei of the amygdala, the oval (ovBNST), dorsolateral (dlBNST), dorsomedial (dmBNST), ventral and fusiform (fuBNST) divisions of the bed nucleus of the stria terminalis (BNST)), and two brainstem stress centers such as the centrally projecting Edinger-Westphal nucleus (cpEW) and dorsal raphe nucleus (DR) show age dependency in their c-Fos response. The somatosensory barrel cortex area (S1) was evaluated to test whether the age dependency is specific for stress-centers. Our results indicate that the stress-induced rise in blood CORT titer was lower in young age reflecting relatively low HPA activity. All 12 stress-related brain areas showed c-Fos response that peaked at 2 months of age. The magnitude of c-Fos immunoreactivity correlated negatively with age in seven regions (MeA, CeA, ovBNST, dlBNST, dmBNST, fuBNST and pPVN). Unexpectedly, the CeA, ovBNST and cpEW showed a considerable basal c-Fos expression in 1-month-old rats which decreased with age. The S1 showed a U-shaped age-related dynamics in contrast to the decline observed in stress centers. We conclude that the age- and brain area dependent dynamics in stress-induced neuronal activity pattern may contribute to the age dependance of the stress reactivity. Further studies are in progress to determine the neurochemical identity of neurons showing age-dependent basal and/or stress-induced c-Fos expression.

Stress-Related Neuronal Clusters in Sublenticular Extended Amygdala of Basal Forebrain Show Individual Differences of Positions

“…We found novel neuronal clusters in SLEA, SLEA-zNCs, responding to stress stimuli. The RS induced Zif268 expression in SLEA-zNCs, and its induction was suppressed by antistress treatment with diazepam (Figures 3, 4; Umemoto et al, 1997;Sztainberg et al, 2011;Kovács et al, 2018), indicating that SLEA-zNCs participate in stress processing. Sublenticular extended amygdalar Zif268/Egr1-expressing neuronal clusters were not distinguishable by their cytoarchitecture but by expression of Zif268 (Figures 2A-C).…”

Destruction of the Dorsal Motor Nucleus of the Vagus Aggravates Inflammation and Injury from Acid-Induced Acute Esophagitis in a Rat Model

“…The borders of the nucleus were determined according to the stereotaxic atlas by Paxinos and Watson [16, 17]. To avoid the error caused by the slight difference in cut planes of the same nucleus, each nucleus was calculated based on five consecutive sections [17]. Data were expressed as number of c-fos-positive neurons [18].…”

Corticotropin-Releasing Factor-Producing Cells in the Paraventricular Nucleus of the Hypothalamus and Extended Amygdala Show Age-Dependent FOS and FOSB/DeltaFOSB Immunoreactivity in Acute and Chronic Stress Models in the Rat

“…Sporadic literature data suggested that stress sensitivity in terms of FOS immunoreactivity (ir) might be affected by age (Kellogg et al, 1998; Viau et al, 2005; Romeo et al, 2006; Meyza et al, 2007). In our previous study (Kovács et al, 2018), we assessed the FOS sensitivity of numerous stress centers in the rat brain throughout the whole lifespan systematically. We showed that the magnitude of FOS rise elicited by acute stress exposure was also a function of age in stress adaptation centers of the rat.…”

“…Indeed, PVN Crf expression increases upon stress exposure at mRNA level (Imaki et al, 1995; Choi et al, 2008; Sterrenburg et al, 2012) in the rat. It is well-documented that acute (Gaszner et al, 2012; Sterrenburg et al, 2012; Kovács et al, 2018) and chronic stress exposure (Sterrenburg et al, 2011) results in the rise of FOS and FOSB immunoreactivities in rodent PVN neurons, respectively (for reviews see Kovács, 1998, 2008). Importantly, the Crf gene promoter contains AP-1 binding sites which control the expression of Crf mRNA in interaction with glucocorticoids (Malkoski and Dorin, 1999).…”

“…The existence of IEG products was also shown in the CeA both in acute (Romeo et al, 2006; Sterrenburg et al, 2012) and chronic stress models (Sterrenburg et al, 2011) in the rat. In our previous study we found that the magnitude of FOS response to acute restraint stress (ARS) was age dependent in the rat CeA (Kovács et al, 2018). The question, if the age-related decrease of FOS ir is characteristic for the CRF-producing cells in the CeA remained to be answered.…”