abstract: Patients with Alzheimer's disease (AD) exhibit a significantly higher incidence of unprovoked seizures compared to age-matched non-AD controls, and animal models of AD (i.e., transgenic human amyloid precursor protein, hAPP mice) display neural hyper-excitation and epileptic seizures. Hyperexcitation is particularly important because it contributes to the high incidence of epilepsy in AD patients as well as AD-related synaptic deficits and neurodegeneration. Given that there is significant amyloid-β (Aβ) accumulation and deposition in AD brain, Aβ exposure ultimately may be responsible for neural hyper-excitation in both AD patients and animal models. Emerging evidence indicates that α7 nicotinic acetylcholine receptors (α7-nAChR) are involved in AD pathology, because synaptic impairment and learning and memory deficits in a hAPPα7-/- mouse model are decreased by nAChR α7 subunit gene deletion. Given that Aβ potently modulates α7-nAChR function, that α7-nAChR expression is significantly enhanced in both AD patients and animal models, and that α7-nAChR play an important role in regulating neuronal excitability, it is reasonable that α7-nAChRs may contribute to Aβ-induced neural hyperexcitation. We hypothesize that increased α7-nAChR expression and function as a consequence of Aβ exposure is important in Aβ-induced neural hyperexcitation. In this project, we found that exposure of Aβ aggregates at a nanomolar range induces neuronal hyperexcitation and toxicity via an upregulation of α7-nAChR in cultured hippocampus pyramidal neurons. Aβ up-regulates α7-nAChRs function and expression through a post translational mechanism. α7-nAChR up-regulation occurs prior to Aβ-induced neuronal hyperexcitation and toxicity. Moreover, inhibition of α7-nAChR or deletion of α7-nAChR prevented Aβ induced neuronal hyperexcitation and toxicity, which suggests that α7-nAChRs are required for Aβ induced neuronal hyperexcitation and toxicity. These results reveal a profound role for α7-nAChR in mediating Aβ-induced neuronal hyperexcitation and toxicity and predict that Aβ-induced up-regulation of α7-nAChR could be an early and critical event in AD etiopathogenesis. Drugs targeting α7-nAChR or seizure activity could be viable therapies for AD treatment. / Dissertation/Thesis / Ph.D. Neuroscience 2011

It would be of great value to have a precise and non-damaging neuromodulation technique in the field of basic neuroscience research and for clinical treatment of neurological diseases. Infrared neural modulation (INM) is a new modulation modality developed in the last decade, which uses pulsed or continues infrared (IR) light with a wavelength of 1200 to 2200 nm to directly alter neural signals. INM includes both infrared neural stimulation (INS) and infrared neural inhibition (INI). INM is widely investigated for use on peripheral nerves, cochlear nerve fibers, cardiac cells, and the central nervous system. This technique holds the advantages of contact-free and high spatiotemporal precision compared to the traditional electrical stimulation. It does not depend on genetic modification and exogenous absorbers as other optical techniques, such as the optogenetic technique and the enhanced near-infrared neural stimulation (e-NIR). These advantages make INM a viable technique for research and clinical applications. The primary mechanism of the INM is believed to be a photothermal effect, where the IR laser energy absorbed by water leads to a rapid local temperature change. However, so far the details of the mechanism of action potential (AP) generation and inhibition remain elusive. Another issueis that the cells may be endangeredbythe heat exposure, consequently triggering a physiologicalmalfunction or even permanent damage.These concernshave hindered the transfer of the INM technique to the clinical therapy.Therefore, the general aim of this study was to improve the understanding of the details of how INM affects the cells. Laser parameters for safe and efficient stimulation were investigated on the basis of being useful for clinical applications. A tailored heating model and in vitro INM experiments on cortex neurons were used to reach this goal.The first paper was a feasibility study. A 1550nm laser with a beam spot diameter of around 6 mm was used to irradiate the rat cortex neurons, which were seeded on multi-electrode arrays (MEA) and formed well-connected networks. A heating model based on an estimated laser beam (standard Gaussian distribution) was used to simulate temperaturechanges. The damage signal ratio (DSR),based on the temperature,was calculated to predict the heat damage. The average spike rate of all the working electrodes from two MEAs was used to evaluate the degree of theinhibition of the neural networks. Results IVshowed that it is possible to use the 1550 nm laser to safely inhibit the neural network activity and that the degree of the INI is dependent on the power of the laser.The second paper wasan application and mechanism study. The aim of this study was to investigate the safety, efficiency, and cellular mechanism of INI. The same laser as in paper Iwas used in this study. A 20 X objective was used to decrease the beam spot diameteraround 240 μm. The measured laser profile (high order Gaussian beam) was used in the heating model to predict the temperature. The model was verified by local temperature measurements viamicropipette. The action potential rates, measured by the MEA electrodes, were quantified for different temperatures. Bicuculline was added to the cortex neuron cultures to induce hyperexcitation of the neural network. The results showed that the INI is temperature dependent and that the temperature needs to be less than 46 °C at 30 s laser irradiation for safe inhibition. The IR laser couldalso be used to inhibit the hyperexcitedactivity. The degree of inhibition, for the assessed subpopulation of neurons, was better correlated with the action potential amplitude than the width of it and INIcan be accomplished without inhibitory synapses / <p>QC 20180920</p><p></p>