Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal
(HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild
stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes,
including downregulation of hippocampal neurogenesis, can be reversed by antidepressant
(AD) treatment. We investigated causality between changes in hippocampal neurogenesis
and the effects of both chronic stress and chronic ADs.
Mice were treated with either a sham procedure or focal hippocampal irradiation to
disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the
third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the
corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin
1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments,
and irradiation were assessed by physical measures (coat state, weight), behavioral
testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal
BrdU labeling.
Our results show that elimination of hippocampal neurogenesis has no effect on animals'
sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis
is not a cause of stress-related behavioral deficits. Second, we present evidence
for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced
behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects
of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of
the CRF(1) and the V(1b) antagonists.
Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract
the effects of stress, whereas similar effects could be achieved by directly targeting
the HPA axis and related neuropeptides.