One of the goals of our lab is to use the olfactory system as a model to study the disruption and repair neural circuits within the central nervous system. To achieve this goal we first determined that the olfactory system maintains the capacity to re-establish its proper wiring following broad disruption (Cheng et al, J Neurosci. 2011). Using this knowledge we have established the mouse olfactory system as a model to study Traumatic Brain Injury (TBI). Studies have shown that loss of the sense of smell is commonly associated with head trauma but its functional and molecular basis is unclear. We find that olfactory nerve injury can produce a similar loss of function along with with clear molecular TBI markers. This system will likely prove useful in understanding and possibly diagnosing some early/mild forms of TBI. In related injury experiments we are also studying the process of circuit disruption associated with neurodegeneration. In collaboration with Dr. Huaibin Cai at NIA we established an olfactory based model of disease related neurodegeneration. By expressing a mutant form of the Amyloid Precursor Protein (APP), linked to Alzheimers disease, in OSNs, we present three main findings;1) we show that neurodegeneration can be initiated very rapidly in the olfactory system (by 3 weeks of age), 2) we reveal that APP induces neural loss in a cell-autonomous manner suggesting that Amyloid plaques may not be the fundamental cause of neural loss, and 3) that blocking APP over-expression can rescue OSNs and reduce neural loss (Cheng et al., J Neurosci., 2011). We are currently in the process of examining the olfactory bulb circuitry in this mouse model to assess any organizational or functional disruption as well as determine the capacity for repair. Another goal of this project is to determine the role of the regenerating olfactory bulb interneurons on circuit plasticity and repair. For these experiments we are collaborating with the laboratory of Dr. Heather Cameron at NIMH by utilizing a transgenic approach to selectively eliminate neuroblasts that originate in from the subventricular zone (SVZ) and migrate to the bulb via the rostral migratory stream (RMS). Since these regenerating interneurons are the post-synaptic targets of intrabulbar projections that give rise to the intrabulbar map, they have direct bearing on map plasticity and restoration. Currently, we are assessing the circuitry of the olfactory bulb for deficits associated with eliminating these interneurons. Together these studies will help us understand the mechanisms that regulate circuit plasticity and repair in the olfactory bulb and possibly throughout the brain as well.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
$985,749
Indirect Cost
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State
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Cheng, Ning; Jiao, Song; Gumaste, Ankita et al. (2016) APP Overexpression Causes Aβ-Independent Neuronal Death through Intrinsic Apoptosis Pathway. eNeuro 3:
Xydakis, Michael S; Mulligan, Lisa P; Smith, Alice B et al. (2015) Olfactory impairment and traumatic brain injury in blast-injured combat troops: a cohort study. Neurology 84:1559-67
Saar, Galit; Cheng, Ning; Belluscio, Leonardo et al. (2015) Laminar specific detection of APP induced neurodegeneration and recovery using MEMRI in an olfactory based Alzheimer's disease mouse model. Neuroimage 118:183-92
Steuer, Elizabeth; Schaefer, Michele L; Belluscio, Leonardo (2014) Using the olfactory system as an in vivo model to study traumatic brain injury and repair. J Neurotrauma 31:1277-91
Cheng, Ning; Bai, Li; Steuer, Elizabeth et al. (2013) Olfactory functions scale with circuit restoration in a rapidly reversible Alzheimer's disease model. J Neurosci 33:12208-17
Cheng, Ning; Cai, Huaibin; Belluscio, Leonardo (2011) In vivo olfactory model of APP-induced neurodegeneration reveals a reversible cell-autonomous function. J Neurosci 31:13699-704
Cheng, Kai; Bai, Li; Belluscio, Leonardo (2011) Fas-associated factor 1 as a regulator of olfactory axon guidance. J Neurosci 31:11905-13
Bagley, J A; Belluscio, L (2010) Dynamic imaging reveals that brain-derived neurotrophic factor can independently regulate motility and direction of neuroblasts within the rostral migratory stream. Neuroscience 169:1449-61