Ablation of adult neurogenesis in mice has revealed that young adult-born granule cells (abGCs) are required for some of the behavioral responses to antidepressants (ADs), yet the mechanism by which abGCs contribute to AD action remains unknown. During their maturation process, these immature neurons exhibit unique properties that could underlie their ability to influence behavioral output. In particular, abGCs in the DG exhibit a period of heightened plasticity 4-6 weeks after birth that is mediated by GluN2B-expressing NMDA receptors. The functional contribution of this critical window to AD responsiveness is unclear. Here, we determined the behavioral and neurogenic responses to the AD fluoxetine (FLX) in mice lacking GluN2B-containing NMDA receptors in abGCs. We found that these mice exhibited an attenuated response to FLX in a neurogenesis-dependent behavioral assay of FLX action, while neurogenesis-independent behaviors were unaffected by GluN2B deletion. In addition, deletion of GluN2B attenuated FLX-induced increases in dendritic complexity of abGCs suggesting that the blunted behavioral efficacy of FLX may be caused by impaired differentiation of young abGCs.

While the hippocampus has been classically studied for its role in learning and memory, there is significant support for a role of the HPC in regulating emotional behavior. Emerging research suggests these functions may be segregated along the dorsoventral axis of the HPC. In addition to this regional heterogeneity, within the HPC, the dentate gyrus is one of two areas in the adult brain where stem cells continuously give rise to new neurons. This process can influence and be modulated by the emotional state of the animal, suggesting that adult neurogenesis within the DG may contribute to psychiatric disorders and cognitive abilities. Yet, the exact mechanism by which these newborn neurons influence behavior remains unknown. Here, we will examine the contribution of hippocampal neurogenesis to the output of the HPC, and suggest that the role of neurogenesis may vary along the DV axis. Next, we will review literature indicating that anatomical connectivity varies along the DV axis of the HPC, and that this underlies the functional segregation along this axis. This analysis will allow us to synthesize novel hypotheses for the differential contribution of the HPC to cognition and mood.

Adult-generated granule cells (GCs) in the dentate gyrus (DG) exhibit a period of heightened plasticity 4-6 weeks postmitosis. However, the functional contribution of this critical window of plasticity to hippocampal neurogenesis and behavior remains unknown. Here, we show that deletion of NR2B-containing NMDA receptors from adult-born GCs impairs a neurogenesis-dependent form of LTP in the DG and reduces dendritic complexity of adult-born GCs, but does not impact their survival. Mice in which the NR2B-containing NMDA receptor was deleted from adult-born GCs did not differ from controls in baseline anxiety-like behavior or discrimination of very different contexts, but were impaired in discrimination of highly similar contexts. These results indicate that NR2B-dependent plasticity of adult-born GCs is necessary for fine contextual discrimination and is consistent with their proposed role in pattern separation.

The dentate gyrus (DG), in addition to its role in learning and memory, is increasingly implicated in the pathophysiology of anxiety disorders. Here, we show that, dependent on their position along the dorsoventral axis of the hippocampus, DG granule cells (GCs) control specific features of anxiety and contextual learning. Using optogenetic techniques to either elevate or decrease GC activity, we demonstrate that GCs in the dorsal DG control exploratory drive and encoding, not retrieval, of contextual fear memories. In contrast, elevating the activity of GCs in the ventral DG has no effect on contextual learning but powerfully suppresses innate anxiety. These results suggest that strategies aimed at modulating the excitability of the ventral DG may be beneficial for the treatment of anxiety disorders.