Adult neurogenesis and the olfactory system

Abstract

Though initially described in the early 1960s, it is only within the past decade that the concept of continuing adult neurogenesis has gained widespread acceptance. Neuroblasts from the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) into the olfactory bulb, where they differentiate into interneurons. Neuroblasts from the subgranular zone (SGZ) of the hippocampal formation show relatively little migratory behavior, and differentiate into dentate gyrus granule cells. In sharp contrast to embryonic and perinatal development, these newly differentiated neurons must integrate into a fully functional circuit, without disrupting ongoing performance. Here, after a brief historical overview and introduction to olfactory circuitry, we review recent advances in the biology of neural stem cells, mechanisms of migration in the RMS and olfactory bulb, differentiation and survival of new neurons, and finally mechanisms of synaptic integration. Our primary focus is on the olfactory system, but we also contrast the events occurring there with those in the hippocampal formation. Although both SVZ and SGZ neurogenesis are involved in some types of learning, their full functional significance remains unclear. Since both systems offer models of integration of new neuroblasts, there is immense interest in using neural stem cells to replace neurons lost in injury or disease. Though many questions remain unanswered, new insights appear daily about adult neurogenesis, regulatory mechanisms, and the fates of the progeny. We discuss here some of the central features of these advances, as well as speculate on future research directions.

Figure 1. Cellular Organization of the Olfactory Bulb

Schematic of the primary cellular organization of the olfactory bulb. Subpopulations of olfactory sensory neuron axons, shown in red, blue, and purple, innervate specific glomeruli based on odor receptor expression. The projection neurons, mitral and tufted cells, extend a single apical dendrite which arborizes within one glomerulus, and several lateral dendrites in the external plexiform layer. In the glomerulus, OSN axons make excitatory synapses onto the apical dendrites of mitral/tufted cells, as well as onto the periglomerular cell dendrites. Intraglomerular circuits also include reciprocal dendrodendritic synapses between the mitral/tufted cell dendrites and the periglomerular cell dendrites. The other primary population of interneurons, granule cells, have their somata located in the granule cell layer and an apical spiny dendrite that arborizes in the external plexiform layer, where they establish reciprocal dendrodendritic synapses with the secondary or lateral dendrites of mitral/tufted cells. Centrifugal axons distribute across the olfactory bulb laminae. The rostral migratory stream provides a continuous addition of new neuroblasts, which differentiate into granule and periglomerular cells. ONL, olfactory nerve layer; GL, glomerular layer; EPL, external plexiform layer; MCL, mitral cell layer; IPL, internal plexiform layer; GCL, granule cell layer; RMS, rostral migratory stream; OSN, olfactory sensory neuron; PG, periglomerular cell, M, mitral cell; Gr, granule cell MNB, migrating neuroblast.

Figure 2. Adult Neurogenesis

Schematic of neurogenic regions of the mouse brain and developmental stages of new interneurons in the olfactory bulb. In the dentate gyrus, neuroblasts are born in the subgranular zone and migrate into the overlying granule cell layer, where they differentiate into dentate granule cells. Neuroblasts born in the SVZ migrate through the RMS using a unique form of migration, tangential chain migration. In the olfactory bulb, neuroblasts migrate radially into the granule cell layer and glomerular layer and differentiate into granule cells and periglomerular cells. Granule cells first receive synapses on their basal dendrites, as their apical dendrites grow into the external plexiform layer. They then elaborate an extensive apical dendritic arbor and form spines and reciprocal synapses with the dendrites of mitral and tufted cells. DG, dentate gyrus; CC, corpus callosum; Ctx, cortex; SVZ, subventricular zone; RMS, rostral migratory stream; OB, olfactory bulb.

Figure 3

Stem cells in different areas of SVZ give rise to specific types of neurons. Stem cells within the RMS and in anterior medial areas of SVZ form most new PG cells and calretinin-expressing PG and granule cells. Dorsal regions adjacent to cortex give rise to TH+ (dopaminergic) PG cells and superficial granule cells. Deep granule cells and calbindin-expressing PG cells come from ventral SVZ. CC, corpus callosum; Ctx, cortex; SVZ, subventricular zone; RMS, rostral migratory stream; OB, olfactory bulb; TH, tyrosine-hydroxylase; CR, calretinin; CB, calbindin.

Figure 4. Migration in the RMS

A: Overview of the path of the RMS from the lateral ventricle to the olfactory bulb. DCX⁺ neuroblasts are labeled. B: Magnification of the RMS, showing the chains of DCX⁺ neuroblasts (green), GFAP⁺ astrocytes (red), and nuclei (stained with DRAQ5, a nuclear marker) (blue). Scale bar in A equals 1mm and in B equals 50μm. LV: lateral ventricle; Ctx: Cortex; RMS: rostral miratory stream; OB: olfactory bulb; D: dorsal; V: ventral; C: caudal; R: rostral.

Figure 5. Hippocampal Neurogenesis

Schematic diagram of dentate granule cell maturation. Cells proliferate in the subgranular zone (SGZ) and migrate into the overlying granule cell layer within 3 days. By 10 days they extend dendrites into the molecular layer and an axon to CA3. Dendritic spine formation begins at 16 days, and increases in density to 56 days, when it plateaus. ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone. Modeled after: (Schmidt and Duman, 2007).