General Introduction, Abstract
Smell deficits are one of the most reproducible changes in patients with schizophrenia (SZ). They are tightly
correlated with specific clinical features, such as negative symptoms and some cognitive deficits (e.g., social
cognitive deficits), but rarely with positive symptoms. Many studies have also observed molecular and cellular
changes in the olfactory epithelium (OE) in living patients with SZ. Our group has accumulated evidence that
the immune/inflammatory changes associated with redox imbalance may be major pathological changes in the
OE of SZ patients. Nevertheless, whether and how the OE pathology mechanistically contributes to these
specific clinical features has been a major knowledge gap. Using an inducible animal model, we have
demonstrated that chronic local OE inflammation elicits a functional alteration in prefrontal cortex (PFC)
pyramidal neurons, likely via the olfactory-prefrontal circuits. As a result, the mice showed behavioral deficits in
the positive valence systems and social processes. Consistent with this basic science observation, we have
recently obtained promising results that specific molecular changes in the inflammatory/redox signaling in the
OE are directly correlated with negative symptoms (deficits of the positive valence systems) and smell deficits
in SZ patients at the cross-sectional and longitudinal levels. Altogether, we hypothesize that molecular and
cellular changes in the OE in SZ patients, or at least in a subset of them, significantly contribute to specific
clinical manifestations that correlate with smell deficits. We expect that the OE pathology alters the olfactory-
prefrontal circuits and PFC pyramidal neuron functionality, which in turn contributes to negative symptoms and
social cognitive deficits in SZ patients. We hypothesize that the impact of OE pathology on the olfactory-
prefrontal circuits is more robust in adolescence/young adulthood when the PFC maturation dynamically
happens. We propose three Projects and three Cores. Project 1 (P1) will define how OE perturbation (e.g.,
chronic local OE inflammation) elicits the neuronal alteration in the OE and OB, which results in behavioral
deficits; P2 will determine the circuitry mechanism(s) that links OE pathology to the PFC via the olfactory-
prefrontal circuits, and identify the critical developmental period vulnerable to the OE influences; P3 will define
OE pathology in early-stage SZ patients at the molecular/cellular levels, stratify patient groups depending on
the specific mechanisms (e.g., molecular expression levels), and elucidate how the OE pathology influences
specific clinical symptoms (e.g., negative symptoms and cognitive deficits) via the olfactory-prefrontal circuits.
This molecular/circuitry mechanism cannot solely be causal for these clinical deficits. Nevertheless, we
consider this mechanism as a significant contributory factor for them. Given that inflammation/redox-associated
pathology in the OE is potentially treatable with local, non-invasive interventions, we believe that this study will
provide new translational insights into these treatment-refractory clinical domains in SZ.