Region‐specific response of the hippocampus to chronic unpredictable stress

Abstract

The objective of the present study was to determine whether chronic unpredictable stress (CUS) would induce hippocampal neuroplasticity in a region-specific manner. Recent evidence suggests that the hippocampus has two functionally distinct subsections. The dorsal (septal) portion appears to be primarily associated with spatial navigation, while the ventral (temporal) region has been linked to affect-related functions, such as anxiety. Chronic stress has previously been shown to negatively affect the hippocampus by decreasing survival of progenitor cells, although it has also been shown to increase adaptive responses, such as increased expression of neuropeptide Y (NPY) and ΔFosB. Whether such events occur in a region-specific manner has not been investigated. We hypothesized that CUS would selectively impact cell survival, NPY, and ΔFosB expression in the more affect-related ventral subregion. Individually housed Long-Evans rats (n = 31) were divided into two groups: stressed and control. Stressed animals were exposed daily to an unpredictable schedule of ethologically relevant stressors, such as predator odors, forced swim, and open field exposure. All rats were injected with bromodeoxyuridine (BrdU) daily during the first 5 days of CUS in order to label dividing progenitor cells. Unbiased stereology was used to quantify BrdU+, NPY+, and ΔFosB+ cells in dorsal and ventral hippocampal subregions. In support of our hypothesis, we found that CUS selectively decreased cell survival in the ventral subregion. However, both NPY and ΔFosB were significantly increased only in the dorsal hippocampus. These results suggest that stress-induced adaptive neuroplasticity occurs primarily in the dorsal subregion, which may coincide with behavioral aspects of the stress response, such as avoidance or amelioration of the stressor.

Ventral hippocampus, Stress and Psychopathology: Translational implications

“…Nev ertheless, a significant increase in BDNF mRNA lev els in the DG of the DH correlated with chronic anti depressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity. The data reported by Hawley et al [11,34] support a dual role for the hippocampus in stressful experiences, with the more resilient dorsal portion undergoing adaptive plasticity (perhaps to facilitate escape from or neutralization of the stressor), and the ventral portion involved in affective responses. CUS in rodents, a widely used animal model of depression, selectively enhanced cellular plasticity in the DH while it nega tively impacted the VH.…”

“…In animal models of depression, effects to the VH are reported more frequently than DH specific effects. For exam ple, CUS [11,34,42,43] or learned helplessness behavior (after inescapable shocks) [44] most nega tively affected neurogenesis in the VH as compared to the DH. However, stage specificity exists, and effects concerning neurogenesis in general may differ from effects on cell proliferation or survival.…”

“…The morphological analysis performed by Pinto et al [10] demonstrated that chronic unpredictable stress (CUS) had opposite outcomes in the structure of the DH and VH of rats: whereas in the DH, stress triggered a volumetric reduction as a result of atrophy of CA3 and CA1 apical dendrites, in the VH an increase in hippocampal vol ume concurrent with the increase of CA3 apical den drites took place. Hawley and Leasure [11] have stud ied whether CUS affects hippocampal neuroplasticity in a region specific manner. They hypothesized that CUS selectively impacts cell survival, NPY, and ΔFosB expression in the more affect related VH.…”

Effects of Isx-9 and stress on adult hippocampal neurogenesis: Experimental considerations and future perspectives

“…26,27 Here we attempted to use unpredictable stressors to reduce any potential habituation of the stress response to repeated restraint, 28 using a protocol that produced deficits in hippocampal neurogenesis. 20,29 This protocol failed to induce significant deficits in our hands, which may indicate that either the period of exposure to each of the stressors was too short or that procedural stress (due to repeated injections and daily manipulations) was confounding our results. Other studies have increased the exposure period to similar stressors for longer periods of time (i.e., more than 3 weeks).…”

“…20,29 Briefly, 2 distinct stressors were used in a variable sequence at random times of the day. The following stressors were used: vinegar water (drinking bottle replaced with a solution of water containing 10% vinegar for 6 h), tail clip (an hair clip was placed at the base of the animal's tail for 10 min), strobe light (for 2 h), predator odor (cotton ball containing 2.5 ml of fox urine was placed in front of each cage for 6 h), tilted cage (cages were tilted on a 45-degree angle for 6 h), damp bedding (400 ml of tap water was placed in the bottom of the cage for 4 h), predator sounds (a record of predator sounds was played for 1 h), altered light cycle (lights off for 6 h during light phase), open field (for 5 min), novel stimulus (a toy was placed in the home cage for 5 min), and white noise (for 4 h).…”