Implications of the Functional Integration of Adult-Born Hippocampal Neurons in Anxiety-Depression Disorders

Abstract

Adult neurogenesis in the dentate gyrus of the hippocampus has gained considerable attention as a cellular substrate for both the pathophysiology and treatment of depression. Overall, the studies of adult hippocampal neurogenesis are still in their infancy because most of them explore only one stage of this process. Importantly, given the built-in homeostatic mechanisms that act at each stage during the progression from stem cells to mature neurons (proliferation, differentiation, maturation, survival), it is very difficult to extrapolate the efficiency of a drug on adult neurogenesis from analysis of one stage alone. Here, we review the most significant data on hippocampal neurogenesis, focusing on the importance of studying each stage of adult hippocampal neurogenesis and also on the importance of choosing the appropriate mouse strain to perform the experiment. Specifically, strains with a high number of basal proliferating cells in the dentate gyrus of the hippocampus should be used only under stressed conditions to detect the effects of antidepressants on adult neurogenesis. We also discuss how adult hippocampal neurogenesis could be involved in affective state disorders such as depression and anxiety. Finally, we reveal that the behavioral effects of fluoxetine are mediated through both neurogenesis-dependent and -independent actions.

Adult Neurogenesis and Psychiatric Disorders

“…In a pioneering study, Rene Hen and colleagues reported that inhibition of hippocampal neurogenesis by X-irradiation resulted in the striking finding that the effects of fluoxetine on anxiety-like behavior were abolished (Santarelli et al 2003). Given these provocative results, many studies attempted to replicate these findings, and the cumulative evidence now suggests that this effect depends on the strain of mice, as well as the type of antidepressant (Surget et al 2008;David et al 2009David et al , 2010. For example, behavioral effects of chronic fluoxetine in BALB/ cJ mice do not require adult hippocampal neurogenesis or the 5-HT1A receptor, suggesting that antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can lead to antidepressant-like effects via distinct mechanisms in different mouse strains (Holick et al 2008).…”

“…The effects of antidepressants on specific stages of neurogenesis have been investigated in detail and revealed several potential mechanisms of action ( Fig. 1) (David et al 2010). For example, fluoxetine increases the rate of symmetric divisions of amplifying neural progenitors (Encinas et al 2006).…”

“…For example, fluoxetine increases the rate of symmetric divisions of amplifying neural progenitors (Encinas et al 2006). In addition, it accelerates maturation of immature neurons after chronic treatment, as shown by enhanced dendritic arborization and complexity (David et al 2010). On the other hand, tianeptine decreases apoptotic cell death in the dentate gyrus (Lucassen et al 2004).…”

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

“…Standard models of depression that rely on environmental stress manipulations such as learned helplessness or the chronic mild stress are hampered by protocol variability and reported difficulties in replication, thus highlighted the need for a reliable, easily replicable depression model (Nestler et al, 2002). The corticosterone model is a chronic exposure method optimized for use in modeling the persistent anxiety/depressionlike state in rodents, allowing for multiple behavioral tests in the same animals using an etiologically relevant model of depression that is easily replicable between and within laboratories (David et al, 2009;David et al, 2010;Gould, 2011;Mendez-David et al, 2013).…”

Neurogenic hypothesis and psychiatric disorders

“…Furthermore, the anxiolytic effect of a melaninconcentrating hormone receptor antagonist was found to be neurogenesis-independent while a recent study shows that pregabalin, an 2 ligand used for the treatment of neuropathic pain and generalized anxiety disorders, prevented stress-induced depression-like behaviors and promotes the generation of neural precursor cells [57]. The discrepancy in the findings depends on the choice of behavior tests and method to abolish neurogenesis [51], in which forced swimming test and open field test are neurogenesis independent while NSF and coat state are neurogenesis-dependent. As great differences between choice of stress model, method of blocking neurogenesis, behavioral testing and type of drugs used for treatment are commonplace, significance of neurogenesis in anxiety and treatment effect requires further investigations.…”