Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation

Abstract

Over one-quarter of adult Americans are diagnosed with a mental illness like Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), schizophrenia, and Alzheimer's Disease. In addition to the exceptional personal burden these disorders exert on patients and their families, they also have enormous cost to society. Although existing pharmacological and psychosocial treatments alleviate symptoms in many patients, the comorbidity, severity, and intractable nature of mental disorders strongly underscore the need for novel strategies. As the hippocampus is a site of structural and functional pathology in most mental illnesses, a hippocampal-based treatment approach has been proposed to counteract the cognitive deficits and mood dysregulation that are hallmarks of psychiatric disorders. In particular, preclinical and clinical research suggests that hippocampal neurogenesis, the generation of new neurons in the adult dentate gyrus, may be harnessed to treat mental illness. There are obvious applications and allures of this approach; for example, perhaps stimulating hippocampal neurogenesis would reverse the overt and noncontroversial hippocampal atrophy and functional deficits observed in Alzheimer's Disease and schizophrenia, or the more controversial hippocampal deficits seen in MDD and PTSD. However, critical examination suggests that neurogenesis may only correlate with mental illness and treatment, suggesting targeting neurogenesis alone is not a sufficient treatment strategy. Here we review the classic and causative links between adult hippocampal neurogenesis and mental disorders, and provide a critical evaluation of how (and if) our basic knowledge of new neurons in the adult hippocampus might eventually help combat or even prevent mental illness.

Figure 1. Schematic of hippocamapal dentate gyrus in (A, B) human and (C, D) mouse brains

(A) Schematic of human brain, cut through the frontal/coronal plane at the level of the thalamus (TH) and corpus callosum (cc). The hippocampus is a bilateral structure nestled within the temporal lobe; the right hippocampus is shaded in blue. (B) Human hippocampus, enlarged from blue region in (A). Adult-generate neurons in the human dentate gyrus reside in the granule cell layer (GCL; blue) and the nearby hilus (Hil). For context, other human hippocampal regions are also depicted, such as the molecular layer of the dentate gyrus (Mol), regions of Ammon’s Horn (CA1, CA3), and the nearby white matter structure the fimbria (fi). (C) Small grey form in upper-left represents the mouse brain in size relation to the human brain in (A). Larger image is schematic of the adult mouse brain in the coronal plane, with the majority of the hippocampal dentate gyrus highlighted in blue. For context, regions of Ammon’s horn (CA1, CA3) and nearby gray matter (TH) and white matter structures (cc, fi) are provided. (D) Mouse dentate gyrus, enlarged from blue region in (C). Detail is shown in (D) to highlight the current view on the “stages” or phases of neurogenesis and the cellular diversity that thus exists in the neurogenic region of the subgranular zone (SGZ). Note many aspects of the neurogenic niche are not depicted, including vasculature, inhibitory interneurons, and astrocytes. Based on current understanding, the putative stem cell (green) gives rise to progenitor cells (blue), some of which survive and mature into immature neurons (purple), which eventually mature into granule cell neurons (brown) and incorporate into hippocampal circuitry by projecting to CA3 via the mossy fiber pathway. In the rodent, projections may enter the mossy fiber pathway in less than 7 days and adult-generated neurons can present indices of morphological and phenotypic maturity from 2 weeks-2 months later. In the human, the timing of adult hippocampal neurogenesis is unknown. In addition, the anatomic and morphologic features of the human hippocampal stem cell remains unknown. CA1, CA3, Cornu Ammon subregions 1, 3; cc, corpus callosum; fi, fimbria; GCL, granule cell layer; Hil, hilus; Mol, molecular layer; SGZ, subgranular zone; TH, thalamus.