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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Optogenetic dissection of septohippocampal neural circuitry for the treatment of epilepsy

Laxpati, Nealen G. 27 May 2016 (has links)
Over 50 million people worldwide suffer from epilepsy. Of these, nearly a third will be refractory to medical therapy, and many will be poor candidates for surgical resection. Thus there is a need for novel targets and therapies, the former of which will require a greater understanding of neural networks involved in epilepsy, and the latter of which demands the development of novel therapeutic techniques. Seizures are less frequent during periods where theta – a 3-12Hz oscillatory rhythm in the hippocampal local field potential – is present. Theta is thought to originate in the medial septum, a basal forebrain structure that projects to the site of origin for the most common form of intractable epilepsy, the hippocampus. As has been demonstrated with pharmacologic and electrical stimulation, theta generation via the medial septum is consequently an ideal target for intervention. However, of the three neuron populations within the medial septum – cholinergic, GABAergic, and glutamatergic – it is unclear which is responsible for theta, or indeed if a single population is driving the oscillation. Optogenetics, a novel technique that enables activation and inhibition of genetically-defined neurons on a millisecond time-scale, provides the means to functionally dissect this septohippocampal axis and leverage the results for seizure therapy. In this thesis, I detail the current state of deep brain stimulation for epilepsy, and describe our motivation for targeting the medial septum and the importance of the hippocampal theta rhythm. I describe new technologies, software, and adaptations to our electrophysiology platform, NeuroRighter, to enable concurrent optogenetic neuromodulation and electrophysiology in awake and behaving animals, and demonstrate how these technologies and techniques can be used in several experimental approaches. I next use this system to show that both the GABAergic and glutamatergic neurons of the medial septum can drive and pace hippocampal oscillatory rhythms, but only the glutamatergic neurons are necessary to maintain phase relationships between successive theta cycles. I also demonstrate that activating and inhibiting the cholinergic neurons of the medial septum does not alter hippocampal local field potential activity, but does alter single-unit firing rates. These results shed light on the function of the medial septum in generating and modulating theta, and provide clear targets for optogenetic modulation of epilepsy.
2

Nanoscale probing of single synapse function and BDNF Cell-to-Cell transfer

Stahlberg, Markus Andreas 13 May 2016 (has links)
No description available.
3

Spatiotemporal Control of Human Cardiac Tissue Through Optogenetics

Ma, Stephen January 2018 (has links)
Cardiac arrhythmias are caused by disordered propagation of electrical activity. Progress in understanding and controlling arrhythmias requires novel methods to characterize and control the spatiotemporal propagation of electrical activity. We used patterned illumination of cardiomyocytes derived from optogenetic human induced pluripotent stem cells to create dynamic conduction blocks, and to test spatially extended control schemes. Using this model, we demonstrated the ability to initiate, circumscribe, relocate, and terminate pathologic spiral waves that drive many arrhythmias. When cells were derived from patients with long QT syndrome, longer action potential durations made spiral waves more resistant to termination. This work lays the foundation for personalized models of cardiac injury and disease, and the development of tailored approaches to the management of arrhythmias.
4

LIGHT-ACTIVATION OF CHANNELRHODOPSIN-2 EXPRESSED IN HINDLIMB MUSCLE OF LIVING CHICK EMBRYOS

Whitaker, Jessica Rae 01 August 2016 (has links)
The importance of activity during the development of central components of the nervous system such as the visual system has long been recognized (Wiesel & Hubel 1963) and it is beginning to be understood that sensory experience and motor behavior are equally important for neuromuscular development (Brumley et al. 2015; Sharp & Bekoff 2015). The chick embryo model has proven to be especially useful in studying the relationships among motor behavior, sensory experience, and neuromuscular development (Oppenheim et al. 1978; Sharp & Bekoff 2001) due to its accessibility and early onset of movement behavior. Traditionally, neuromuscular blockers have been used to broadly study the role of neural activity and muscle activity during development (Oppenheim et al. 1978; Ding et al. 1983). In order to noninvasively alter neural activity in specific populations of cells, the Sharp lab has developed an optogenetic approach that allows the expression of ChIEF, a variant of channelrhodopsin-2, in the spinal cord of living chick embryos (Sharp & Fromherz 2011). In order to better understand the unique role that muscle activity plays in neuromuscular development, it would be advantageous to directly and noninvasively control muscle activity through light-activation of ChIEF expressed in muscle fibers. Therefore, the primary objective of this thesis research was to achieve ChIEF expression in the plasma membrane of myotubes in living chick embryos. Initial attempts to express ChIEF in chick muscle resulted in low success rates. The CAG promoter in pPB-ChIEF-Tom, the plasmid vector that encodes ChIEF, was likely hindering expression of ChIEF in muscle tissue. Therefore, standard molecular cloning techniques were used to replace the CAG promoter with the myosin light chain promoter which was known to drive transgene expression in chick muscle (Wang et al. 2011). The new DNA construct that resulted from modifying pPB-ChIEF-Tom was identified as pPB-MLC-ChIEF-Tom (mChIEF). ChIEF was successfully expressed in hindlimb muscles of chick embryos via somite electroporation of mChIEF and observed between E7 and E18. Expression patterns corresponded with the current understanding of muscle progenitor contributions of somites to hindlimb muscles (Rees et al. 2003). ChIEF was located in the outer membrane of muscle fibers on E9, E14, and E18 when tissue was histologically examined in conjunction with myosin heavy chain immunofluorescence. Importantly, light-activation of ChIEF in the hindlimb muscle of living chick embryos resulted in muscle contraction and light-evoked hindlimb movements. In addition to demonstrating the functionality of ChIEF expression, an effort was made to characterize the effects of altered parameters of light stimuli on light-evoked movement and determine whether light-evoked muscle contraction could be used to imitate normal, neuronal muscle control. Light intensity was directly related to amplitude and rate of light-evoked movement. Light duration was directly related to amplitude and latency of peak movement. Unfused and fused tetanus were observed when bursts of short duration light pulses with varying interpulse intervals were used to activate ChIEF. This thesis research strongly suggests that light-activation of ChIEF expressed in living, chick embryo hindlimb muscle results in muscle contractions in manner similar to normal, neurally-driven muscle contraction.
5

EFFECTS OF OPTOGENETICALLY STIMULATING THE REUNIENS NUCLEUS DURING SLEEP IN A NOVEL ATTENTIONAL SET-SHIFTING TASK

Unknown Date (has links)
Sparse thalamocortical cell population synchronicity during sleep spindle oscillations has been hypothesized to promote the integration of hippocampal memory information into associated neocortical representations 1. We asked the question of whether sparse or rhythmic activity in thalamocortical cells of the reuniens nucleus influence memory consolidation and cognitive flexibility during learning after sleep. For this study, I designed a novel attentional set-shifting task and incorporated optogenetics with closed-loop stimulation in sleeping rats to investigate the effects of sparse (nonrhythmic) or rhythmic spindle-like (~10Hz) activity in thalamic cells of the reuniens nucleus on learning and cognitive flexibility. We show that, as predicted, post-sleep setshifting performance improved after sleep with non-rhythmic optogenetic stimulation in the thalamic nucleus reuniens relative to rhythmic optogenetic stimulation. While both non-rhythmic and rhythmic optogenetic stimulation led to an increase in perseverative errors, only non-rhythmic optogenetic stimulation showed effects of learning from errors, which correlated with sleep, and which ultimately had a net benefit in set-shifting performance compared to rhythmic optogenetic stimulation and the control group. / Includes bibliography. / Thesis (M.A.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection
6

A Combination Optical and Electrical Nerve Cuff for Rat Peripheral Nerve

McDonald, Rachel Anne January 2019 (has links)
Spinal cord injury results in life-long damage to sensory and motor functions. Recovery from these injuries is limited and often insufficient because the lack of stimulation from supraspinal systems results in further atrophy of the damaged neural pathways. Current studies have shown that repeated sensory activity obtained by applying stimulation enhances plasticity of neural circuits, and in turn increases the ability to create new pathways able to compensate for the damaged neurons. Functional electrical stimulation has been proven to show success in this form of rehabilitation, but it has its limitations. Stimulating neural pathways with electricity results in also stimulating surrounding neurons and muscle tissue. This results in attenuation of the intended effect. The use of optogenetics mitigates this issue, but comes with its own complications. Optogenetics is a growing method of neural stimulation which utilizes genetic modification to create light activated ion channels in neurons to allow for activation or suppression of neural pathways. In order to activate the neurons, light of the appropriate wavelength must be able to penetrate the nerves. Applying the light transcutaneously is insufficient, as the skin and muscle tissue attenuate the signal. The target nerve may also move relative to an external point on the body, creating further inconsistency. Specifically in the case of using a rat model, an external object will be immediately removed by the animal. This thesis seeks to address this issue for a rat model by designing a nerve cuff capable of both optical and electrical stimulation. This device will be scaled to fit the sciatic nerve of a rat and allow for both optical activation and inhibition of the neural activity. It will be wired such that each stimulus may be operated individually or in conjunction with each other. The simultaneous stimulation is required in order to validate the neural inhibition facet. The circuit itself will be validated through the use of an optical stimulation rig, using a photoreceptor in place of an EMG. The application of the cuff will be verified in a live naive rat. Aim 1: Design and build an implantable electrical stimulation nerve cuff for the sciatic nerve of rats. An electrical nerve cuff for the sciatic nerve of a rat will be designed and assembled such that it is able to reliably activate the H-reflex. For it to be used in a walking rat, the cuff must be compatible with a head mount in order to prevent the rat from being able to chew at the wiring or their exit point. The cuff will be controlled through a Matlab program that is able to output specified signals and compare these outputs directly with the resultant EMG inputs. Aim 2: Implement LEDs onto the cuff and perform validation experiments. Light delivery capability will be added to the cuff through the use of LEDs. The functionality of the cuff will be validated through tests on naive rats. If successful, only an electric stimulation will result in a muscle twitch. An optical stimulation should result in no twitches, which would then validate that no current is leaking from the nerve cuff, given that the rat does not express any light sensitive protein channels. Ultimately, with a rat expressing ChR2 opsins on the sciatic nerve, an activation of the nerve using a blue light of wavelength 470nm will result in activating an h-wave without an m-wave when optically stimulated. Similarly, using the nerve cuff with a rat expressing ArchT opsins will result in suppressing the h-wave from an electric stimulation once the sciatic nerve is illuminated with green light of a wavelength of 520 nm. / Bioengineering
7

Vibrational spectroscopy of cation and anion channelrhodopsins

Yi, Adrian 16 January 2018 (has links)
Optogenetics is a technique to control and monitor cell activity with light by expression of specific microbial rhodopsins. Cation channelrhodopsins (CCRs) and anion channelrhodopsins (ACRs) have been demonstrated to activate and silence cell activity, respectively. In this dissertation, the molecular mechanisms of two channelrhodopsins are studied: a CCR from Chlamydomonas augustae (CaChR1) and an ACR from Guillardia theta (GtACR1). The recently discovered GtACR1 is especially interesting, as it achieves neural silencing with 1/1000th of the light intensity compared to previous microbial rhodopsin silencing ion pumps. Static and time-resolved resonance Raman, FTIR difference, and UV-visible spectroscopies were utilized in addition to various biochemical and genetic techniques to explore the molecular mechanisms of these channelrhodopsins. In CaChR1, Glu169 and Asp299 residues are located nearby the Schiff base (SB) similar to the homologous residues Asp85 and Asp212, which exist in an ionized state in unphotolyzed bacteriorhodopsin (BR) and play a key role in proton pumping. We observe significant changes in the protonation states of the SB, Glu169, and Asp299 of CaChR1 leading up to the open-channel P2 state, where all three groups exist in a charge neutral state. This unusual charge neutrality along with the position of these groups in the CaChR1 ion channel suggests that charge neutrality plays an important role in cation gating and selectivity in these low efficiency CCRs. Significant differences exist in the photocycle and protonation/hydrogen bonding states of key residues in GtACR1 compared to BR and CaChR1. Resonance Raman studies reveal that in the unphotolyzed state of GtACR1, residues Glu68, Ser97 (BR Asp85 homolog), and Asp234 (BR Asp212 homolog) located near the SB exist in charge neutral states. Furthermore, upon K formation, these residues do not change their protonation states. At room temperature, a slow decay of the red-shifted K intermediate is observed, which exists in equilibrium with the L intermediate. At 80 K, a lower thermal barrier for K → L transition is observed compared to BR and CaChR1. This effect may be due to substitution of a Met residue at position 105 for the highly conserved Leu or Ile residue.
8

On the Mechanisms Behind Hippocampal Theta Oscillations : The role of OLMα2 interneurons

Mikulovic, Sanja January 2016 (has links)
Theta activity is one of the most prominent rhythms in the brain and appears to be conserved among mammals.  These 4-12 Hz oscillations have been predominantly studied in the dorsal hippocampus where they are correlated with a broad range of voluntary and exploratory behaviors. Theta activity has been also implicated in a number of mnemonic processes, long-term potentiation (LTP) induction and even acting as a global synchronizing mechanism. Moving along the dorso-ventral axis theta activity is reduced in power and desynchronized from the dorsal part. However, theta activity can also be generated in the ventral hippocampus itself during anxiety- and fear-related behaviors. Until now it was unknown which hippocampal cell population was capable to generate theta activity and it was controversial if its origin was local, in the hippocampus, or driven by other brain regions. In this thesis I present compelling in vitro and in vivo  evidence that   a subpopulation of OLM interneurons (defined by the Chrna2-cre line)  distinctively enriched  in the CA1 region of  the ventral hippocampus is implicated in LTP function (paper I,II), information control (paper V) and the induction of theta activity that is under cholinergic  control (paper IV). Importantly, a concomitant effect of the optogenetically induced theta activity is reduction in anxiety (Paper IV). Another innovation of this work was the development of a methodological approach to avoid artefactual signals when combining electrophysiology with light activation during optogenetic experiments (Paper III). In summary, the work presented in this thesis elucidates the role of a morphologically and electrophysiologially identified cell population, OLMα2 interneurons, first on the cellular, then on the circuit and ultimately on the behavioral level.
9

Intracortical Excitation Rules in Piriform Cortex

Russo, Marco Joseph January 2016 (has links)
The cerebral cortex continuously encodes new sensory information and organizes it within an experiential intracortical framework. The cortical integration of internal and external information forms the associations that are the basis for higher order sensory representation, and ultimately, perception. Deciphering the cellular and synaptic principles of sensory-cortical integration requires a system with a simplified interface between the internal and external worlds. The piriform cortex provides a relatively simple substrate for the study of intracortical modulation of sensory coding. Within piriform, primary sensory information from the olfactory bulb converges onto neurons in a single cortical layer, where it directly integrates with intracortical input. The major barrier to studying intracortical influences on sensory representation in piriform has been the inability to isolate single types of intracortical input. Here, we use optogenetic techniques to functionally isolate two important classes of intracortical input to piriform pyramidal neurons, and slice electrophysiology to assess their synaptic properties. We first expressed channelrhodopsin in a small subset of piriform neurons, effectively isolating the recurrent synapses formed onto piriform pyramidal neurons by their peers. Recurrent collaterals form strong excitatory connections that extend throughout piriform without spatial attenuation in strength, linking distant piriform neurons. This extensive recurrent network is constrained by powerful disynaptic inhibition, which can also reduce activation by primary sensory inputs in a timing-dependent manner. Next, we functionally isolated inputs to the piriform from the anterior olfactory nucleus (AON), an early target of olfactory bulb output whose role in olfaction is largely unknown. The AON makes weaker excitatory connections with piriform, but unlike recurrent connections, these inputs do not drive strong disynaptic inhibition. Sequential activation of AON inputs leads to pronounced summation that boosts piriform activation in an NMDA-receptor-dependent manner, and may enhance plasticity of AON-to-piriform synapses. The AON is a potentially powerful modulator of piriform cortex, whose role in odor information processing merits further study. Our results collectively illustrate critical features of intracortical input classes to piriform cortex, and how these inputs may have distinct roles in shaping odor representations and olfactory learning.
10

The Regulation of Sleep and Wakefulness by the Hypothalamic Neuropeptide Orexin/Hypocretin

YAMANAKA, AKIHIRO, INUTSUKA, AYUMU 02 1900 (has links)
No description available.

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