Depression and hippocampal neurogenesis: a road to remission?

Abstract

Adult-generated hippocampal neurons are required for mood control and antidepressant efficacy, raising hopes that someday we can harness the power of new neurons to treat mood disorders such as depression. However, conflicting findings from preclinical research--involving stress, depression, and neurogenesis--highlight the complexity of considering neurogenesis as a road to remission from depression. To reconcile differences in the literature, we introduce the "neurogenic interactome," a platform from which to consider the diverse and dynamic factors regulating neurogenesis. We propose consideration of the varying perspectives--system, region, and local regulation of neurogenesis--offered by the interactome and exchange of ideas between the fields of learning and memory and mood disorder research to clarify the role of neurogenesis in the etiology and treatment of depression.

Figure 1. Adult hippocampal neurogenesis in depression

(A) Neurogenic niches in the mouse brain (inset, red) generate neurons throughout life. (B) The hippocampus interacts with other major brain regions (e.g. Hypothalamus, Hypo; Amygdala, Amyg; dotted lines) to contribute to brain functions like memory and mood. The hippocampal dentate gyrus hosts one neurogenic niche, the subgranular zone (SGZ; red). (C) Photomicrograph of the SGZ in a transgenic mouse depicts the process of neurogenesis, beginning with an adult neural stem cell (aNSC; yellow frame) and ending with a dentate gyrus neuron (white frame) that fully integrates into the granule cell layer (GCL). Neurogenesis is a process, not a timepoint (2), a message emphasized in the “road sign” that condenses the journey from NSC to GCL neuron. (D, E) The two branches of the neurogenic hypothesis of depression. The first branch proposes ablation of adult neurogenesis does not greatly influence mood under normal, non-stressful conditions (E). The second branch proposes antidepressants may confer their effects on improving mood via upregulating adult neurogenesis. (F) The “neurogenic interactome”. Both direct and indirect anatomical connections (solid and dashed black lines, respectively) influence adult neurogenesis in a dynamic manner (doubleheaded green line). Alterations in neurogenesis reciprocally influence the connecting regions (dashed black line). For example, intact neurogenesis inhibits the hypothalamus (dashed red line) and the “stress axis”, including the HPA axis, thus contributing to mood control. In contrast, during stress, the HPA axis and limbic system are activated (solid red lines). This influences both levels of neurogenesis and the reliance of key brain functions – like cognition and mood – on adult-generated hippocampal neurons. Thus, the stress experience (length, duration, type) influences the importance of adult-generated neurons in buffering the stress response. Moreover, involvement of adult-generated neurons in pattern separation and thus cognition can protect against depression by improving recognition and coping with stressors. The two major functions of adult-generated hippocampal neurons – mood/stress control and learning/cognition – help explain the involvement of adult neurogenesis in etiology of depression-like phenotype, and in designing novel antidepressants.