Abstract
Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety.
Highlights
Depression and anxiety are the most common psychiatric disorders in modern society and share a high degree of comorbidity
The higher depression-like behavior as well as anhedonia coincided with a lower number of BrdU þ cells in the dentate gyrus (DG) of HABs compared with normal anxiety/depression-like behavior (NAB) indicating a lower rate of surviving newly born cells (Figure 1c, Figures 2a and b)
A 3-week drug-free period (b) decreased the immobility time in HABs but not in NABs, (c) did not alter the number of BrdU þ cells in HABs but reduced it in NABs, (d) increased the number of c-Fos þ cells in HABs but not in NABs. (e) Depression-related behavior was negatively correlated with the number of c-Fos immunoreactive cells in the DG of HABs. (f) Schematic representation of the experimental design for the 7-week drug-free period
Summary
Depression and anxiety are the most common psychiatric disorders in modern society and share a high degree of comorbidity (up to 80–90%, for review, see Klenk et al.[1]). Antidepressants (ADs) are not effective in 30–40% of patients,[2,3] and only 33% of patients achieve remission in the first line of treatment with widely used selective serotonin reuptake inhibitors (SSRIs).[4] Mood-elevating effects of ADs are observed mainly in depressed patients but are almost absent in non-depressed volunteers,[5,6,7] suggesting that the neurobiological targets of ADs in pathophysiologically deranged systems might differ from those in intact systems.[8] it is important to study AD-mediated changes in the brains of animal models that are as close to the clinical situation as possible, that is, in terms of exhibiting depression and comorbid anxiety One of those animal models displaying higher trait anxiety- and depression-like behavior consists of HAB mice and HAB rats that have been selectively bred (for review, see Landgraf et al.,[9] Sartori et al.[10] and Singewald[11]). Relevant animal models in this area that has up to now been under-studied may Regeneration Center Salzburg, Paracelsus Medical University, Strubergasse, Salzburg, Austria
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