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| Poster #256 Optogenetic stimulation of the olfactory sensory neuron input to the olfactory bulb elicits gamma entrainment of dorsal hippocampus in a mouse model of Alzheimer’s disease |
| Joseph A. Villanueva1,2, Maray Valle3, Ming Ma1, Emily A. Gibson4, Maria A. Nagel5,6, Diego Restrepo1,6 1Department of Cell & Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States 2Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States 3Bioengineering Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States 4Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, United States 5Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States 6Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States |
Entrainment of the hippocampus in low gamma (40 Hz) oscillation through activation of visual or auditory cortex elicits both neuronal and glial responses that attenuate AD pathologies (Martorell et al. 2019, PMC6774262). Theta frequency-coupled gamma oscillations of the olfactory bulb (OB) are known to entrain gamma oscillation in the hippocampus and are robust in non-disease states. Therefore, it is plausible that the reintroduction of directionally coupled low gamma entrainment of the hippocampus by the OB will also attenuate AD pathologies and will slow the cognitive decline in 5xFAD mice. We are in the process of testing whether 40 Hz optogenetic activation of the input to the OB in OMP-ChR2 mice will attenuate AD pathologies and slow the cognitive decline in 5xFAD mice. Mice were stimulated by 473 nm laser light pulses targeting the olfactory epithelium continuously for 1 hr in at 40Hz. Stimulation was performed in a full cohort of control and 5xFAD mice and C57Bl/6 mice (with or without cross to OMP-ChR2 mice). The local field potential was recorded in both OBs and in both dorsal hippocampi. We find reliable activation of the OB at 40Hz that entrains CA1 in the hippocampus. However, the effect of the entrainment is smaller in the 5xFAD mice compared to C57BL/6. In addition, we are performing two-photon imaging of the calcium indicator GCaMP6f in pyramidal cells in dorsal CA1 in 5xFAD mice. Surprisingly, we find waves of increased calcium crossing the field of view. These waves have not been observed in any of the control mice. We are currently performing experiments to determine whether entrainment along the OB-hippocampus circuit can induce transcription level changes in immune glial cells that result in amelioration of AD pathology. |