Differential roles of specific sub-regions of the longitudinal axis of the hippocampus in the behavioural and neurogenesis responses to stress and antidepressant drugs

Abstract

Accumulating evidence suggests that the hippocampus is functionally segregated along its longitudinal axis into a dorsal (dHi) and a ventral sub-region (vHi). Indeed, recent gene expression studies suggest that the hippocampus has a gradient of gene expression and that the area between the dHi and vHi, the intermediate hippocampus (iHi), may also be functionally independent, but it remains understudied. The hippocampus is also one of few brain regions where neurogenesis, the birth of new neurons, occurs throughout life and this process has been shown to play roles in learning and memory as well as in responses to stress and antidepressants. These diverse roles may be related to the functional segregation of the hippocampus along its longitudinal axis. Indeed, the dorsal hippocampus (dHi) plays a predominant role in spatial learning and memory, while the ventral hippocampus (vHi) is predominantly involved in the regulation of anxiety, a behaviour impacted by stress and chronic treatment with some antidepressants. In vivo studies have shown that chronic stress and chronic antidepressant treatment change neurogenesis preferentially in the vHi rather than the dHi. However, whether these findings are due to differential intrinsic sensitivities of neural progenitor cells (NPCs) resident in the dHi, iHi or vHi in response to the stress hormone corticosterone or in response to antidepressants is unknown. Moreover, the roles of the dHi, iHi and vHi in the behavioural responses to chronic stress, a risk factor for depression and anxiety disorders, and in the behavioural responses to acute and chronic antidepressant treatment have not yet been investigated. Thus, the aims of this thesis were to determine whether NPCs isolated from the dHi, iHi and vHi have differential intrinsic sensitivities in response to the stress hormone corticosterone, the glucocorticoid receptor agonist dexamethasone, and the antidepressant, fluoxetine. To this end, we isolated NPCs from the three hippocampal sub-regions and cultured them for 4 h or 4 days in vitro with either corticosterone, fluoxetine, or corticosterone with fluoxetine or for 7 days in vitro with either corticosterone or dexamethasone. Cell proliferation, neuronal differentiation and maturation, nuclear GR expression and cell viability were then assessed. Moreover, we also aimed to determine the roles of each hippocampal sub-region on emotional behaviours and neuroendocrine response under baseline conditions, chronic psychosocial stress conditions and under chronic antidepressant treatment conditions. To this end, we performed stereotaxic surgeries in C57BL/6 mice to lesion the dHi, iHi or vHi with ibotenic acid. After recovery, animals were submitted to emotional behaviour and neuroendocrine tests under baseline conditions, or after chronic psychosocial stress, or after acute and chronic fluoxetine treatment. As result, we determined for the first time that NPCs isolated from the iHi and especially vHi are more sensitive to the effects of long-term exposure (7 DIV) to corticosterone and dexamethasone. Long-term (7 DIV) corticosterone and dexamethasone exposure also reduced nuclear GR expression preferentially in cells from the vHi. Fluoxetine alone did not have any effect on cell proliferation or neuronal differentiation or maturation. However, fluoxetine prevented corticosterone-induced reductions in neuronal differentiation after 4 DIV treatment and these effects were observed predominantly in the iHi and vHi cell cultures. In vivo experiments showed that vHi lesions reduced anxiety under baseline conditions. Under chronic psychosocial stress conditions, iHi lesions increased stress-induced social avoidance and the lesion of all sub-regions prevented chronic stress-induced anxiety; dHi and vHi lesions prevented stress-induced anhedonia and only vHi lesions caused antidepressant-like behaviour in the forced swim test and promoted active coping behaviour. In the antidepressant experiment, vHi lesions prevented the antidepressant effects of acute fluoxetine treatment while iHi lesions prevented the antidepressant effects of chronic fluoxetine treatment, and both iHi and vHi lesions prevented the anxiolytic effects of chronic fluoxetine treatment. Taken together, these findings show for the first time that iHi and vHi NPCs have increased intrinsic sensitivity to longer term exposure to the stress hormone corticosterone, and that the vHi seems to be an important sub-region for antidepressant-like effects under chronic stress. Also, both the iHi and vHi but not the dHi seem to modulate the antidepressant and anxiolytic effects of fluoxetine.