Research Projects
The Olfactory System
Our goal is to unravel how the olfactory system functions or malfunctions in response to environmental stimuli in health or neurological disorders.
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Organization
The olfactory system is the only sensory modality anatomically organized in such a way that its sensory neurons are directly exposed to environmental insults. Thus, it is excellent model for research on environmental toxicology and injury.
02
Structure
Distinct from other sensory systems, the olfactory system presents odorant signals to cortical structures and the limbic structures including the amygdala and hippocampus, two key structures for emotion/fear, stress and learning/memory, for processing before reaching the thalamus. Hence it potentially serves as the structural substrate of relevant neurological disorders including post traumatic stress disorder (PTSD).
03
Symptom Detection
Olfactory dysfunction is the earliest symptom of multiple neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease. Consistently, the olfactory system manifests relevant pathogeneses at the prodromal stage of corresponding disorders, thus provides an excellent structural substrate for mechanistic investigation of these devastating diseases.
APOE4 and Olfactory Dysfunction
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The gene encoding apolipoprotein E (APOE), which is 4 kDa with 299 amino acids, is located on chromosome 19q13.32.
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APOE proteins are produced at high levels in the liver and brain. In the brain they are synthesized by glia (astrocytes >> microglia).
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The APOE gene has three alleles encoding 3 common protein isoforms in humans (E2, E3, E4), which have the population prevalence of 7%, 78% and 15%, respectively.
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Between any two APOE proteins, there is only amino acid difference on the sites 112 or 158.
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Among the three human APOE gene alleles, the one encoding the APOE4 protein is the strongest genetic risk factor for Alzheimer's disease (AD).
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Carrying the APOE4 gene increases the risk of AD development by 3-4 to 15 fold.
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Binds to aggregated amyloid-beta and other amyloids.
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Human and animal studies demonstrate that APOE4 causes or exacerbates OD, the prodromal symptom of AD. However, the mechanisms of APOE4 actions on the olfactory processing remain unknown.
Project #1: Mechanisms underlying APOE4 effects on olfactory processing in the AON
NIH-funded project
The anterior olfactory nucleus (AON) is a pivotal structure of the olfactory system by receiving signal input from the olfactory bulb and remarkable feedback input from many cortical or subcortical regions including the anterior piriform cortex (APC) and hippocampus (HPC). It also manifests pathogenesis in prodromal AD thus is a potential structural substrate underlying olfactory deficit. Cutting edge technologies will be applied.
This project is meant to to address the following three fundamental questions: 1. Does APOE-4 impact olfaction-dependent behaviors?
2. Are AON neuronal excitability and network operation altered by APOE-4? 3. What are APOE-4 actions on synaptic processing in the AON?
Project #2: Astrocyte-neuron interaction in the olfactory bulb glomerulus and APOE4 effects
NIH-funded project
Glomerular astrocytes are uniquely organized with their cell bodies located on the boundary of each glomerulus and processes projecting to the glomerular center, where they enwrap the pre- and postsynaptic neuronal elements thus constitute tripartite synapses. Thus, glomerular astrocytes are well positioned to modulate olfactory signal processing at the initial synaptic site of the whole olfactory system.
However, the functional roles of these glial cells in OB remain elusive. Additionally, although APOE4 is predominantly synthesized by astrocytes and alters neuronal excitability and network operation in the OB, the underlying mechanisms is unclear. We are trying to address these open questions by focusing on astrocyte-neuron interaction in this project.
Anatomical & Functional Principles of Olfactory Processing
There are multiple anatomical features distinguishing the olfactory system from other sensory modalities, especially the organization of sensory neurons in the nasal cavity and their projections to olfactory bulb (OB) as well as pathways from the OB to downstream centers. Furthermore, olfactory signal processing is subject to robust top-down neuromodulation from many cortical and subcortical brain regions at different levels. Although there are still numerous open questions on the organizational details, the functional significance of many anatomical arrangements, especially at the cellular and microcircuit levels, remains elusive. By leverage the cutting edge technologies in the lab, we propose and design elegant experiments to elucidate the mechanisms underlying olfactory processing at the cellular to behavioral levels.
Traumatic Brain Injury & Olfactory Deficit
Traumatic brain injury (TBI) causes major posttraumatic neurological disorders including olfactory (OD) and cognitive deficits thus is considered as a risk factor for both Alzheimer’s disease (AD) and non-AD forms of dementia, highlighting the importance of identifying early biomarkers to early diagnosis of AD-related dementia after TBI. Mounting evidence points the potential of OD as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Thus, TBI survivors with OD may be an early sign heralding its progression to dementia. However, neither the cause nor the underlying mechanisms are understood. This NIH-funded project is proposed to address this open question by focusing on the TBI-induced neuroinflammation in the OB.