Regional-specific effect of fluoxetine on rapidly dividing progenitors along the dorsoventral axis of the hippocampus

Abstract

Hippocampus-dependent cognitive and emotional function appears to be regionally dissociated along the dorsoventral (DV) axis of the hippocampus. Recent observations that adult hippocampal neurogenesis plays a critical role in both cognition and emotion raised an interesting question whether adult neurogenesis within specific subregions of the hippocampus contributes to these distinct functions. We examined the regional-specific and cell type-specific effects of fluoxetine, which requires adult hippocampal neurogenesis to function as an antidepressant, on the proliferation of hippocampal neural stem cells (NSCs). Fluoxetine specifically increased proliferation of NSCs located in the ventral region of the hippocampus while the mitotic index of NSCs in the dorsal portion of the hippocampus remained unaltered. Moreover, within the ventral hippocampus, type II NSC and neuroblast populations specifically responded to fluoxetine, showing increased proliferation; however, proliferation of type I NSCs was unchanged in response to fluoxetine. Activation or inhibition of serotonin receptor 1A (5-HTR1A) recapitulated or abolished the effect of fluoxetine on proliferation of type II NSCs and neuroblast populations in the ventral hippocampus. Our study showed that the effect of fluoxetine on proliferation is dependent upon the type and the position of the NSCs along the DV axis of the hippocampus.

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

“…However, long term regulation of gene expression and epigenetic mechanisms are likely to occur after chronic administration. In this regard, it is important to mention that different classes of antidepressant drugs have been demonstrated to have a plethora of effects in CNS disorders and are also known to have a role in neurogenesis ( Wang et al, 2011 ; Masuda et al, 2012 ; Meneghini et al, 2014 ; Zhou et al, 2016 ; King et al, 2017 ). Many of these effects are sex-dependent ( Gray and Hughes, 2015 ; Kokras and Dalla, 2017 ) and fluoxetine itself is known to induce sex specific effects on neurogenesis ( Hodes et al, 2010 ).…”

Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice

“…FLX effect in increasing neurogenesis is well grounded in the literature [87][88][89] . Interestingly, one study that measured neurogenesis based on specific cell types showed that FLX effects depend on the dorsoventral axis of the hippocampus 27 . However, in the present study we used a general neurogenesis marker and found a similar effect of FLX in dHIP and vHIP neurogenesis.…”

“…Unmedicated depressed adults presented less granule neurons in the anterior dentate gyrus (DG) when compared to healthy controls 24 , which agrees with reduced hippocampal volume findings observed in patients with major depression 25 . Accordingly, neurogenesis has been proposed by several independent researchers as one of the mechanisms for the antidepressant effect of fluoxetine 26,27 .…”

Dentate nNOS accounts for stress‐induced 5‐HT1A receptor deficiency: Implication in anxiety behaviors

“…The hippocampal CA1 and DG densely expresses 5‐HT 1A receptor . In the DG, 5‐HT 1A receptor majorly expresses on dentate granular cells . Both transgenic and pharmacological evidences showed that 5‐HT1A receptor on dentate granular cells is engaged for depression and anxiety pathology, and antidepressant response .…”

“…35 In the DG, 5-HT 1A receptor majorly expresses on dentate granular cells. 35,36 Both transgenic and pharmacological evidences showed that 5-HT1A receptor on dentate granular cells is engaged for depression and anxiety pathology, and antidepressant response. 29,33,37 However, the molecular mechanism responsible for the key pathophysiological process, the dysfunction of 5-HT 1A receptor on dentate granular cells, remains obscure.…”