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Hou, Steven

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Hou

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Steven

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Hou, Steven
Author's Publications: search.filters.isAuthorOfPublication.082944f4-1435-46a3-8ebc-b45a985fdc7a

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    Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer’s Disease
    (Public Library of Science, 2017) Kastanenka, Ksenia; Hou, Steven; Shakerdge, Naomi; Logan, Robert; Feng, Danielle; Wegmann, Susanne; Chopra, Vanita; Hawkes, Jonathan M.; Chen, Xiqun; Bacskai, Brian
    Slow oscillations are important for consolidation of memory during sleep, and Alzheimer’s disease (AD) patients experience memory disturbances. Thus, we examined slow oscillation activity in an animal model of AD. APP mice exhibit aberrant slow oscillation activity. Aberrant inhibitory activity within the cortical circuit was responsible for slow oscillation dysfunction, since topical application of GABA restored slow oscillations in APP mice. In addition, light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow oscillations by synchronizing neuronal activity. Driving slow oscillation activity with ChR2 halted amyloid plaque deposition and prevented calcium overload associated with this pathology. Thus, targeting slow oscillatory activity in AD patients might prevent neurodegenerative phenotypes and slow disease progression.
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    Time-Domain Fluorescence Diffuse Optical Tomography: Algorithms and Applications
    (2014-10-21) Hou, Steven; Bacskai, Brian; Kumar, Anand T.N.; Tarokh, Vahid; Loncar, Marko
    Fluorescence diffuse optical tomography provides non-invasive, in vivo imaging of molecular targets in small animals. While standard fluorescence microscopy is limited to shallow depths and small fields of view, tomographic methods allows recovery of the distribution of fluorescent probes throughout the small animal body. In this thesis, we present novel reconstruction algorithms for the tomographic separation of optical parameters using time-domain (TD) measurements. These technique are validated using simulations and with experimental phantom and mouse imaging studies. We outline the contributions of each chapter of the thesis below. First, we explore the TD fluorescence tomography reconstruction problem for single and multiple fluorophores with discrete lifetimes. We focus on late arriving photons and compare a direct inversion approach with a two-step, asymptotic approach operating on the same TD data. We show that for lifetime multiplexing, the two methods produce fundamentally different kinds of solutions. The direct inversion is computationally inefficient and results in poor separation but has overall higher resolution while the asymptotic approach provides better separation, relative quantitation of lifetime components and localization but has overall lower resolution. We verify these results with simulation and experimental phantoms. Second, we introduce novel high resolution lifetime multiplexing algorithms which combine asymptotic methods for separation of fluorophores with the high resolving power of early photon tomography. We show the effectiveness of such methods to achieve high resolution reconstructions of multiple fluorophores in simulations with complex-shaped phantoms, a digital mouse atlas and also experimentally in fluorescent tube phantoms. Third, we compare the performance of tomographic spectral and lifetime multiplexing. We show that both of these techniques involve a two-step procedure, consisting of a diffuse propagation step and a basis-function mixing step. However, in these two techniques, the order of the two steps is switched, which leads to a fundamental difference in imaging performance. As an illustration of this difference, we show that the relative concentrations of three colocalized fluorophores in a diffuse medium can accurately be retrieved with lifetime methods but cannot be retrieved with spectral methods. Fourth, we address the long standing challenge in diffuse optical tomography (DOT) of cross-talk between absorption and scattering. We extend the ideas developed from lifetime multiplexing algorithms by using a constrained optimization approach for separation of absorption and scattering in DOT. Using custom designed phantoms, we demonstrate a novel technique allows better separation of absorption and scattering inclusions compared to existing algorithms for CW and TD diffuse optical tomography. Finally, we show experimental validation of the lifetime multiplexing algorithms developed in this thesis using three experimental models. First, we show the reconstruction of overlapping complex shapes in a dish phantom. Second, we demonstrate the localization accuracy of lifetime based methods using fluorescent pellets embedded in a sacrificed mouse. Third, we show using planar imaging and tomography, the in vivo recovery of multiple anatomically targeted near-infrared fluorophores. In summary, we have presented novel reconstruction algorithms and experimental methods that extend the capability of time-domain fluorescence diffuse optical tomography systems. The methods developed in this thesis should also have applicability for general multi-parameter image reconstruction problems.
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    Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain
    (BioMed Central, 2017) Arbel-Ornath, Michal; Hudry, Eloise; Boivin, Josiah R.; Hashimoto, Tadafumi; Takeda, Shuko; Kuchibhotla, Kishore V.; Hou, Steven; Lattarulo, Carli R.; Belcher, Arianna M.; Shakerdge, Naomi; Trujillo, Pariss B.; Muzikansky, Alona; Betensky, Rebecca; Hyman, Bradley; Bacskai, Brian
    Background: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer’s disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. Method To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging. Results: We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point. Conclusions: These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0169-9) contains supplementary material, which is available to authorized users.