Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior

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.

Treatment-resistant depression: are animal models of depression fit for purpose?

“…They are usually compared to mice displaying normal anxiety behaviour (NAB mice). A first study reported that chronic fluoxetine was able to alleviate the depressive-like features in HAB mice but had no effects on the anxiety behaviours and on hippocampal neurogenesis (Sah et al 2012), while a second study from the same group reported that HAB mice responded normally to chronic noradrenergic drugs such as reboxetine or desipramine but were resistant to the effects of chronic SSRIs including fluoxetine, paroxetine and citalopram (Schmuckermair et al 2013). However, HAB mice did respond to repeated DBS of the nucleus accumbens (Schmuckermair et al 2013).…”

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

“…The sucrose preference test was conducted based on the modification of a previously published study [47]. During this test, mice were given a free choice between two bottles, one with an escalating dose of 0.5%-1% sucrose and another with tap water.…”

“…We conducted the sucrose preference test, to evaluate anhedonia which is a recognised feature of human depression [47]. The animal´s preference in drinking sweet sucrose containing water compared to plain drinking water was measured over a five week-period with increasing sucrose concentrations (0.5%, 0.6%, 0.75% and 1%).…”

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

“…Owing to selective inbreeding for the high anxiety traits for ∼ 45 generations, the HAB phenotype is extremely robust and barely amenable to any kind of pharmacological manipulation (Landgraf et al, 2007). Intriguingly, HAB mice, which largely remain unresponsive to chronic treatment with conventional anxiolytics or widely used non-specific antioxidants (Sah et al, 2012), responded to MitoQ that specifically targets mitochondria. At the molecular level, MitoQ treatment resulted in altered levels of sarcosine, AMP, and ascorbic acid in the HAB hippocampus.…”