Neural and Behavioural Mechanisms of Olfactory Matching

Abstract

Matching sensory stimuli involves different decision processes such as detection and discrimination, along with holding the perceived information. Therefore, it provides a combined readout of sensory and cognitive fitness. In the context of increasing reports of brain disorders where olfactory system’s functions are hampered, establishing precise methods for quantifying olfactory fitness has become an emerging need. We have developed a novel olfactory matching paradigm to probe sensory and cognitive functions involving olfactory system, using an automated custom-built olfactory-action meter. In over 300 healthy subjects, with a mean detection accuracy of around 90%, we observed significantly better olfactory matching performance for simple odors, in comparison to complex odor mixtures. Olfactory matching accuracy remained unaltered across varying inter-stimulus intervals. However, the olfactory matching time shown by the subjects for correct responses was significantly lower than the incorrect responses. We further studied symptomatic COVID-19 patients’ behavioural readouts, and found olfactory and cognitive deficits. These deficits were shown to be persistent in certain subjects even after the recovery. To investigate the neural mechanisms of olfactory matching, we performed a delayed odor matching task in freely-moving mice. We gradually increased the stimulus delay from 2s up to 52s by training the same batch of animals for many weeks. With the gradual increase in delay period, mice successfully performed odor matching tasks with high accuracy even for long stimulus delays, on extensive training. As after-odor representation in the olfactory bulb (OB) controls olfactory memory (unpublished data from the lab), we studied the role of OB circuits in modulating olfactory working memory. The inhibitory interneurons of OB directly modulate the activity of projection neurons, mitral and tufted cells, and refine the output from OB. Using conditional knockout mouse lines of GluA2 (AMPA receptor subunit), and NR1 (NMDA receptor subunit), we generated granule cell layer-specific (inhibitory interneurons) knockouts (KOs) by delivering Cre through the viral vectors. Knocking out the GluA2 subunit of AMPA receptors on inhibitory interneurons can enhance the inhibition on projection neurons. Conversely, the deletion of NR1 subunit renders NMDA receptors non-functional, resulting in reduced inhibition on the projection neurons. As these two groups were trained for three different stimulus delays with their respective control groups, GluA2 KO mice showed significantly improved performance in comparison to control mice, whereas the NR1 KO group exhibited a slower learning pace compared to control animals. These results indicate the potential role of OB inhibitory circuits in modulating olfactory matching readouts, where working memory is involved.