Abstract:Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) – the causal agent in COVID-19 – affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.

Recent reports suggest an association between COVID-19 and altered olfactory function. Here we analyze bulk and single cell RNA-Seq datasets to identify cell types in the olfactory epithelium that express molecules that mediate infection by SARS-CoV-2 (CoV-2), the causal agent in COVID-19. We find in both mouse and human datasets that olfactory sensory neurons do not express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. In contrast, olfactory epithelial support cells and stem cells express both of these genes, as do cells in the nasal respiratory epithelium. Taken together, these findings suggest possible mechanisms through which CoV-2 infection could lead to anosmia or other forms of olfactory dysfunction.

Summary Although the hippocampus is known to be important for declarative memory, how hippocampal output regulates motivated behaviors, such as social aggression, is less well understood. Here we report that hippocampal CA2 pyramidal neurons, which are important for social memory, promote social aggression. This action depends on CA2 output to the lateral septum that is selectively enhanced immediately prior to attack. Activation of lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventro-medial hypothalamus known to trigger attack. The social hormone arginine-vasopressin enhances social aggression by acting on arginine-vasopressin 1b receptors on CA2 presynaptic terminals in lateral septum to facilitate excitatory synaptic transmission. In this manner, release of vasopressin in lateral septum, driven by an animal’s internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter or proceeds to promote motivated social aggression.

The cortex organizes sensory information to enable discrimination and generalization 1 – 4 . Systematic representations of chemical odor space have not been described in olfactory cortex, and so it remains unclear how odor relationships are encoded to place chemically distinct but similar odors, like lemon and orange, into perceptual categories, like citrus 5 – 7 . Here we demonstrate that both the piriform cortex (PCx) and its sensory inputs from the olfactory bulb represent chemical odor relationships through correlated patterns of activity. However, cortical odor codes differ from those in the bulb: cortex more strongly clusters together representations for related odors, selectively rewrites pairwise odor relationships, and better matches odor perception. The bulb-to-cortex transformation depends upon the associative network originating within PCx, and can be reshaped by passive odor experience. Thus, cortex actively builds a structured representation of chemical odor space that highlights odor relationships; this representation is similar across individuals but remains plastic, suggesting a means through which the olfactory system can assign related odor cues to common and yet personalized percepts.