Stimulus and post-stimulus olfactory representations in health and disease

Abstract

Sensory systems encode different stimuli features to generate optimal behavior. In mammalian olfaction, odorants of varying physicochemical properties are first represented as glomerular activity patterns in the olfactory bulb (OB). Within a glomerulus, sensory information is relayed to OB output neurons, mitral and tufted cells (MTCs). The firing activity of MTCs is modulated by the inhibitory neuronal network of OB, thereby facilitating odor perception. It is still unknown how these odor representations intersect with sniffing behavior to account for decision-making time. Using odorants belonging to different chemical classes, we started probing glomerular activity patterns and sniffing behavior during decision-making. Mice trained to discriminate between different odor pairs increased their sniffing frequency at a fixed latency after odor onset, independent of odor identity. As sniffing frequency increased, simple monomolecular odors were discriminated within 10-40 ms, while complex binary mixtures took an additional 60-70 ms. In vivo intrinsic imaging of glomerular activity patterns revealed that Euclidean distances between the activity patterns and odor discrimination times are inversely correlated. Thus, our findings suggest that the degree of neuronal processing necessary for odor discrimination is determined by the similarity and strength of glomerular activity patterns rather than sniffing behavior (1). Additionally, odor representations formed during stimulus delivery dynamically change over time and persist even after odor cessation (2). We trained mice to perform discrimination tasks with varying stimuli durations to see how these odor representations during the stimulus and post-stimulus period control olfactory learning and long-term memory formation. Reducing the stimulus duration for binary mixture discriminations led to impairments in learning and long-term memory. The calcium imaging data from anesthetized and awake animals identified stimulus duration-dependent post-odor activities in OB inhibitory interneurons. During different stimulus delivery phases, optogenetic modulation of these interneurons revealed that MTC spiking during stimulus presentation controls discrimination learning. In contrast, post-odor MTC spiking activity influenced long-term memory formation. Our results point to a novel mechanism for long-term olfactory memory formation that relies on MTCs spiking activities during the post-odor period (3). To apply our understanding of odor representations to study olfactory functional changes in humans, we developed an innovative olfactory-action meter. In humans, olfactory dysfunctions develop in many neurodegenerative disorders and a few upper respiratory tract diseases. Olfactory dysfunctions have recently been identified as an early predictor of COVID-19 infection, and identifying asymptomatic COVID-19 carriers has become a top priority during the current pandemic. To quantitatively evaluate olfactory abilities in asymptomatic COVID-19 patients, we designed an olfactory function test, combining an odor detection test to measure detectability towards different odors and an olfactory matching test that examines patients’ cognitive skills. Quantification using our method revealed that 82% of the asymptomatic COVID-19 patient population had olfactory dysfunctions compared to healthy individuals. However, only 15% of these patients had self-awareness of their olfactory deficits. Thus, our results provide a blueprint for developing a rapid and economical strategy to screen large populations efficiently (4).

References: 1. A. S. Bhattacharjee, S. Konakamchi, D. Turaev, R. Vincis, D. Nunes, A. A. Dingankar, H.Spors, A. Carleton, T. Kuner, N. M. Abraham, Similarity and Strength of Glomerular Odor Representations Define a Neural Metric of Sniff-Invariant Discrimination Time. Cell Rep. 28, 2966-2978.e5 (2019). 2. M. A. Patterson, S. Lagier, A. Carleton, Odor representations in the olfactory bulb evolve after the first breath and persist as an odor afterimage. Proc. Natl. Acad. Sci. 110, E3340–E3349 (2013). 3. A. S. Bhattacharjee, S. Mahajan, M. Pardasani, S. Priyadharshini, N. M. Abraham, Distinct encoding of odor learning and memory by olfactory bulb projection neurons. In preparation. 4. A. S. Bhattacharjee, S. V. Joshi, S. Naik, S. Sangle, N. M. Abraham, Quantitative Assessment of Olfactory Dysfunction Accurately Detects Asymptomatic COVID-19 Carriers. EClinicalMedicine. 28, 100575 (2020).