The hippocampus is a multimodal allocortical structure known for its role in learning and memory. Neuronal activity in the hippocampus displays rhythmic patterns of activity including delta, theta and gamma band activities during specific brain states. These oscillatory patterns of activity are typically thought to arise from neuronal inputs to the hippocampus. Within this thesis it is shown that theta, gamma, and delta rhythms can be self-generated by the intrinsic circuits of the intact hippocampus. Different frequencies of rhythms were generated in specific hippocampal sub-regions demonstrating that separate regions have neural circuit properties that promote different rhythmic patterns. The coordination between hippocampal regions arises through dynamic phase coupling between autonomous oscillators. Finally, a novel form of phase synchronization was found to support communication between hippocampal regions in a manner contrary to contemporary views on hippocampal circuit organization. These results suggest that a major component of activity and communication in the hippocampus arises from the self-organized synchronization that occurs between weakly coupled intrinsically generated oscillators. / L'hippocampe est une structure corticale connue pour son implication dans les processus d'apprentissage et de mémoire. Au niveau éléctrophysiologique, l'hippocampe est caractérisé par la survenue d'activités oscillatoire aux rythmes delta, thêta et gamma. Il était communément admis que ces différents types d'activités oscillatoires étaient dus à l'activité synchrone de structures extra-hippocampique. Au cours de ce travail de doctorat, nous avons pu montrer que l'hippocampe intact contient les réseaux neuronaux nécessaires et suffisants à la genèse spontanée des activités delta, thêta et gamma. De plus, ces rythmes sont générés spécifiquement dans des sous-régions de l'hippocampe indiquant que chaque aire hippocampique possède un réseau neuronal unique propice à la survenue d'activités oscillatoires spécifiques. Nous avons également démontré que la synchronisation entre les différents champs de l'hippocampe se fait grâce à un couplage de phase dynamique entre différents oscillateurs indépendants. Enfin, nous avons pu mettre en évidence que ce couplage de phase entre les différents champs de l'hippocampe permet un transfert d'information multidirectionnel, remettant ainsi en question la vision actuelle de l'organisation cytoarchitecturale de la formation hippocampique. L'ensemble de nos travaux suggèrent donc que l'hippocampe contient de multiples oscillateurs indépendants pouvant interagir entre eux, régulant non seulement l'activité global de la formation hippocampe, mais également les interactions entre les différents champs de l'hippocampe.

<p>Discovering the cellular and molecular mechanisms underlying the pathophysiology underlying the development of epilepsy is key to the creation of improved treatments. The neurotrophins and their receptors, in particular BDNF and TrkB, are likely candidates to be involved in the process by which a normal brain becomes epileptic (epileptogenesis). The work presented in the dissertation has investigated the hypothesis that TrkB is a central factor in epileptogenesis in multiple animal models of epilepsy.</p><p>Conditional deletion of TrkB in the Syn-Cre TrkB-/- mouse prevented nearly all epileptogenesis in the kindling model, despite the ability to have a tonic-clonic seizure. Reduction of TrkB de novo in mature Act-CreER TrkB-/- mice also delayed epileptogenesis in the kindling model. Additionally, Syn-Cre TrkB+/- and Act-CreER TrkB-/- mice had impaired persistence of the hyperexcitable state following kindling. It remained unclear from these findings whether reduction of TrkB during and/or following induction of kindling was responsible for the impaired persistence. The inducible Act-CreER TrkBflox/flox mice were used to reduce TrkB only after the fully kindled state had been reached and demonstrated that loss of TrkB after completion of kindling impairs persistence of the hyperexcitable state.</p><p>Status epilepticus is a medical emergency defined by prolonged continuous seizure activity. Conditional deletion of TrkB in the Syn-Cre TrkB-/- mice prevents sustained seizure activity evident in wild type mice following pilocarpine injection. Furthermore, the Syn-Cre TrkB-/- mice may also retain greater sensitivity to diazepam following status epilepticus than control mice. Together with biochemical evidence of TrkB activation during status epilepticus, these findings suggest that TrkB activation is required for persistence of status epilepticus.</p><p>In conclusion, the findings in this dissertation demonstrate TrkB to be a molecular mechanism critical for: 1) epileptogenesis in the kindling model; 2) persistence of hyperexcitability in the kindling model; 3) persistence of limbic status epilepticus in a chemoconvulsant model. These discoveries provide the basis for developing novel therapeutic approaches to three distinct and devastating aspects of the limbic epilepsy in humans. These aspects are: 1) preventing progression of limbic epilepsy to a medically refractory state; 2) reversal of medically refractory limbic epilepsy; 3) medically refractory status epilepticus.</p> / Dissertation

Thesis (Ph.D.)--Lehigh University, 2009. / Adviser: Maria Bykhovskaia.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3337. Advisers: Scott C. Baraban; Julie Schnapf.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3344. Adviser: Arturo Alvarez Buylla.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3333. Adviser: Charles Whitfield. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3340. Adviser: Roger A. Nicoll.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2098. Advisers: Laurence H. Tecott; Mary Dallman.

A few studies support the idea that the theta rhythm modulates synaptic plasticity by demonstrating that the phase of the theta cycle at which the induction stimuli are delivered determines the nature of the resulting synaptic plasticity. These studies were conducted in urethane-anesthetized animals and in vitro slice preparations where the theta rhythm is artificially generated. Our goal was to find whether and how natural theta activity affects synaptic plasticity in the hippocampus of adult and old freely behaving animals. In both adult and aged, memory-impaired rats, LTP lasting at least 48 h was induced when stimuli were delivered at theta peak. No change in synaptic strength was observed when stimuli were delivered at theta trough. These observations indicate that the naturally occurring theta rhythm modulates synaptic plasticity, and suggest a mechanism by which the phase of firing could contain meaningful information. The degree of LTP, however, was significantly smaller in the old animals. To better understand the conformational changes and the dynamic interactions that govern ion-channel kinetics we developed a new approach using simultaneous single-channel patch-clamp recording and single-molecule fluorescence microscopy. Gramicidin monomers were tagged with a fluorescence dye and single-channel current was recorded from gramicidin channels in the bilayer that was formed at the tip of a patch pipette. Co-localization and fluorescence resonance energy transfer (FRET) within a single gramicidin dimer were probed. The new technique made it possible to directly capture the conformational dynamics between the two gramicidin monomers by observing the changes in the distance between the attached dye molecules. The molecular interactions of the NMDA receptor with its ligands determine the dynamic properties of activation and desensitization that in turn shape NMDA receptor mediated currents. We have monitored the occurrence and intensity changes of FRET between two fluorescence-labeled agonists at the glutamate binding site of the receptor, simultaneously with single channel current recording. These observations can be translated to dissociation/association rates and aid in our understanding of the mechanisms that underlie the transitions of the receptor between different kinetic states.

The human hand has incredible dexterity which depends, in large part, on the ability to move the fingers relatively independently. Interestingly, many of the primary finger flexor and extensor muscles possess a single belly that gives rise distally to multiple tendons that insert onto all the fingers and consequently might produce movement in all of the fingers. Therefore, the objective of this dissertation was to examine the neuromuscular organization of a multi-tendoned finger extensor muscle, the human extensor digitorum (ED). Initially, we found that ED spike-triggered average motor unit force was broadly distributed across the digits. Consequently, we hypothesized that linkages between the distal tendons of ED may cause force developed in a single compartment to be transmitted to neighboring tendons. However, force arising from intramuscular stimulation was fairly focused to a single digit suggesting that inter-tendonous connections account for little of the broad distribution of motor unit force. An alternative possibility was that our spike-triggered averages of motor unit force were contaminated by correlated activity among motor units residing in different compartments. Strong motor unit synchrony was found for motor unit pairs within compartments and a modest degree of synchrony for motor unit pairs in neighboring compartments which likely contributed to the appearance of spike-triggered average motor unit force on multiple fingers. These results suggest that last-order synaptic projections appear to supply predominantly sub-sets of motor neurons innervating specific finger compartments of ED but also branch to supply motor neurons innervating other compartments. Finally, single motor axons branch to innervate muscle fibers situated in multiple compartments of ED. Interestingly, force resulting from intraneural micro stimulation of single motor axons innervating ED was highly focused to a single digit. Therefore, it appears that the muscle fibers innervated by a motor axon are primarily confined to one of four distinct compartments of ED. Based on these experiments we believe that each finger is acted upon by ED through a discreet population of motor units. Consequently, extension of an individual finger would require the selective activation of motor neurons innervating a specific compartment of ED.