Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive-like behavior

Abstract

Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all-trans retinoic acid (RA) potently activated the hypothalamus-pituitary-adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive-like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor-α (RAR-α) protein expression in the hippocampus, suggesting an activation of RA-induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders. © 2016 Wiley Periodicals, Inc.

Adult Neurogenesis in Mammals: Variations and Confusions

“…Future studies must address this issue, but at present it fits well to theories assuming that variations in levels of AHN predispose individuals of a given species to different levels of exploring and adapting to new environments within the natural lifespan. The strong correlations between propensity for sucrose preference in the home cage and AHN in rats [Hu et al, 2016] points in the same direction, as they were observed in both treated and control rats. Obviously, ethological observational approaches are not superior per se, but they avoid the notorious confounds in behavioral testing of mice, thus increasing the chance for observing reproducible correlations.…”

“…Such inspection does not require large sample sizes. In a recent study, the number of BrdUpositive neurons was reduced by retinoic acid, followed by assessment of water maze learning and sucrose preference [Hu et al, 2016]. The data revealed that the proliferation rate appeared to be strongly correlated with individual sucrose preference within both control and treated rats, even though it included 6 rats per condition only.…”

Evolutionary Shaping of Adult Hippocampal Neurogenesis in Mammals–Cognitive Gain or Developmental Priming of Personality Traits?

“…Genetic suppression of AHN resulted in impairments of species-typical behaviors and sucrose preference in mice (Jedynak et al, 2012) and rats (Snyder et al, 2016). Studies of individual correlations showed positive correlations of AHN levels with sucrose preference (Hu et al, 2016), and with roaming in large enclosures (Freund et al, 2013). Conversely, reactions to novelty correlated negatively with the number of proliferating neurons (van Dijk et al, 2016).…”

“…For example, sucrose preference shows strong genetic variability in mice and humans (Reed et al, 1997). Yet testing inbred mice for sucrose preference shows often a minority of individuals with initial taste neophobia, indicating that this long-lasting trait can develop purely epigenetically, remaining correlated in rats with individual levels of AHN (Hu et al, 2016). Sweet preference is an adaptive trait that seemingly deserves to be naturally selected, fixing it rapidly genetically.…”

Enhancement of Local Retionic Acid Signaling: A Pivotal Mechanism in Fluoxetine's Pleiotropic Actions

“…This pathway might explain fluoxetine's capability to potently modulate neuronal plasticity 37,38 as well as its neuroprotectant properties 39,40 . Conversely, chronic RA treatment, which likely results in dysbalance of the homeostatically controlled endogenous RA signaling, has been shown to suppress hippocampal neurogenesis in adult rats, being associated with increased hippocampal RARα expression and occurrence of depressive-like symptoms 41 .…”