Olfactory neurogenesis and its role in fear memory modulation

Abstract

Olfaction is a critical sense that allows animals to navigate and understand their environment. In mammals, the critical brain structure to receive and process olfactory information is the olfactory bulb, a structure characterized by a laminated pattern with different types of neurons, some of which project to distant telencephalic structures, like the piriform cortex, the amygdala, and the hippocampal formation. Therefore, the olfactory bulb is the first structure of a complex cognitive network that relates olfaction to different types of memory, including episodic memories. The olfactory bulb continuously adds inhibitory newborn neurons throughout life; these cells locate both in the granule and glomerular layers and integrate into the olfactory circuits, inhibiting projection neurons. However, the roles of these cells modulating olfactory memories are unclear, particularly their role in fear memories. We consider that olfactory neurogenesis might modulate olfactory fear memories by a plastic process occurring in the olfactory bulb.

Keywords: Proust effect; fear memory; neurogenesis; odor-evoked memory; olfactory bulb; piriform cortex.

Figure 1

Organization, connectivity, and post-natal neurogenesis in the olfactory bulb. (A) The olfactory bulb (OB) has five layers: The glomerular layer (GL), where glomeruli, periglomerular cells (PGN), and newborn periglomerular cells (nPGN) are confined. The external plexiform layer (EPL) is formed by the soma of tufted cells (TC) (dark green cells), which form reciprocal connections with granule cells dendrites. The mitral cell layer (MCL) possesses the soma of mitral cells (MC) (light blue cells), which form reciprocal connections with granule cells (GC) and newborn granule cells (nGC) dendrites. MCs/TCs have axon collaterals within the internal plexiform layer (IPL). (B) The OB receives odorant information coming from the olfactive epithelium, then the information is processed by the internal circuity of the OB. The MCs/TCs send their outputs to the piriform cortex (PC), anterior olfactory nucleus (AON), and olfactory tubercle (OT). TC projections are specific and scarcer, while projections of MC are extensive to several areas. The MC also connects to the entorhinal cortex (EC) and the amygdala (Amy), which stores information regarding emotions such as fear and aversion. The EC communicates with the hippocampus (HPC), which encodes and processes episodic-like memories. HPC and Amy send their axons to the prefrontal cortex (PFC), which process and store Odor-episodic memories. (C) The OB undergoes a constant turnover of GC and PGC. The process of neurogenesis starts in the walls of the subventricular zone (SVZ). The neuronal stem cells (NSC) replicate several times and generate transient-amplifying neuronal progenitor cells (NPC), which in turn produce neuronal progenitor cells (NPC). The NPCs migrate to the OB through the rostral migratory stream (RMS). The newborn neurons integrate into the GCL or GL preexisting circuits and become nGCs or nPGCs.

Figure 2

Odor fear conditioning resembles the Proust effect. (A) The writer Marcel Proust coined the term “involuntary memory,” referring to remembering his mother as a result of smelling a tilia tea. As a result, we name the “Proust effect,” the phenomenon in which an odorant stimulus can trigger remote episodic memories. (B) In the odor fear conditioning test, a conditioned odorant is paired with an aversive stimulus; the animal then expresses fear-related behavior in any place with the same odorant. However, after a month of increasing olfactory bulb neurogenesis, animals with the conditioned odorant should not show high fear responses. In contrast, animals with low neurogenesis should show normal fear responses in the presence of the conditioned odorant.