Pattern separation: a common function for new neurons in hippocampus and olfactory bulb

Abstract

While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, "Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron.

Figure 1. Neurogenesis and pattern separation in the dentate gyrus and olfactory bulb

The dentate gyrus and the olfactory bulb (blue boxes) are required for discrimination between similar contexts and similar odors (A and B), respectively. This process is termed pattern separation and is modulated by adult neurogenesis which is the generation of new neurons throughout life (yellow box). When adult neurogenesis is blocked either by irradiation (X-ray) or by genetic ablation, discrimination is impaired leading to generalization and an inability to distinguish A from B. In contrast when neurogenesis is stimulated by genetic manipulations (iBax) or exercise, discrimination is enhanced.

Figure 2. Neural circuits underlying pattern separation in the dentate gyrus and olfactory bulb

Contextual information arrives in the dentate gyrus from the entorhinal cortex (EC) via the perforant path. In the dentate gyrus, the granule cell layer (space between the dotted lines) is composed of mature granule cells (black neuron) born during development and new granule cells born in adulthood (blue neuron). Both mature and new granule cells activate a variety of interneurons which include inhibitory neurons such as the basket cells (red triangular-shaped neuron) and excitatory neurons such as the mossy cells (grey diamond-shaped neuron). Mossy cells send axons to the molecular layer where they activate both inhibitory interneurons and excitatory granule cells. Inhibitory interneurons, in turn, inhibit mature granule cells but not new granule cells (at least when they are less than 4 weeks old). Activation of new granule cells may therefore result in a preferential inhibition of mature granule cells and consequently, increase sparseness of activity in the dentate gyrus which may improve pattern separation. Sensory information arrives in the olfactory bulb through axons of olfactory sensory neurons, which synapse onto dendrites of principal cells (mitral or tufted cells) in a structure called a glomerulus (dotted circle). A variety of inhibitory interneurons (red triangles) inhibit the mitral or tufted cell either at the level of the glomeruli (mature juxtaglomerular neuron) or at dendrodendritic synapses (mature granule cell). Adult neurogenesis generates new granule cells and new juxtaglomerular neurons (blue triangles), which also inhibit mitral/tufted cells. In addition, adult-born granule cells contact other granule and juxtaglomerular cells (not shown here). Like in the dentate gyrus, the addition of new neurons in the olfactory bulb may therefore result in increased inhibition and possibly as a result, increased pattern separation. Pattern completion has been proposed to take place in the projection zone of the dentate gyrus and olfactory bulb, which are the hippocampal CA3 field for contextual information and the piriform cortex for olfactory information. Symbols in Dentate Gyrus; Black oval-shaped cell: mature granule cell; Blue oval- shaped cell: young adult-born granule cell; both young and mature granule cells excite CA3 pyramidal neurons well as hilar inhibitory interneurons such as basket cells (red triangular-shaped cell), and hilar mossy cells (grey diamond-shaped cell) ; +: excitatory projections; −: inhibitory projections. Symbols in Olfactory Bulb; Black round-shaped cell: mitral cells and tufted cells which send excitatory projections to the piriform cortex; red triangular-shaped cell: mature granule cells and mature juxtaglomerular cells (periglomerular cells and short axon cells) which are all inhibitory; blue triangular-shaped cell: young adult-born granule cells and young adult-born juxtaglomerular cells (periglomerular cells and short-axon cells) which are all inhibitory.

Figure 3. Environmental influences on neurogenesis and pattern separation

Environments rich in odors or contexts stimulate neurogenesis in the olfactory bulb (OB) and dentate gyrus (DG), respectively. Similarly, learning stimulates neurogenesis in the OB and DG depending on whether the modalities are olfactory or contextual and spatial. Other manipulations such as exercise or antidepressants stimulate neurogenesis primarily in the DG. Stress, aging and sensory deprivation result in a decrease in neurogenesis in both the DG and OB. We propose that an increase in neurogenesis favors pattern separation, which alters the balance that normally exists between pattern separation (taking place in DG or OB) and pattern completion (taking place in CA3 or PC). Conversely, a decrease in neurogenesis impairs pattern separation, which shifts the balance in favor of pattern completion and results in generalization. These shifts may be a part of the normal adaptive response to changing environments. In an enriched environment, discrimination and cognitive flexibility (which result from increased pattern separation) are advantageous because they favor exploration and learning; in contrast, in a dangerous environment, generalization (which results from decreased pattern separation) may be advantageous because it favors avoidance of new and potentially dangerous situations. However, these normal adaptive responses when exaggerated may lead to pathologies: excessive generalization may for example lead to anxiety disorders such as Post Traumatic Stress Disorder (PTSD) or to the impairments that often accompany aging such as Mild Cognitive Impairment (MCI). Similarly, excessive pattern separation may lead to an excessive attention to details such as seen in some psychiatric disorders such as autism and obsessive-compulsive personality disorder (OCPD).