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Greenberg_Anastasia_201608_PhD.pdf
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Electrical manipulation of cortical and hippocampal dynamics during slow-wave states

  • Author / Creator
    Greenberg, Anastasia
  • Oscillations are a fundamental principle of neural operation, organized into a hierarchy of frequency bands with the dominant rhythm alternating within and across behavioral states. During states of sleep and anesthesia, brain activity in forebrain regions displays two major distinct activity patterns: activated states of low voltage fast activity in the neocortex along with theta activity in the hippocampus, and deactivated states of synchronized slow-wave activity in both structures. The signature event during such slow-wave states is the large amplitude slow oscillation (~1 Hz, SO) which is cortically generated through transitions between highly active depolarized (UP, ON) states and hyperpolarized (DOWN, OFF) states of complete quiescence. The SO dynamically propagates across the cortex and reaches the hippocampus, making this rhythm attractive for mediating cortico-hippocampal interactions. It has been demonstrated that such interactions during the SO support the consolidation of declarative (hippocampal-mediated) memories in humans, and that directly manipulating the SO using rhythmic electrical stimulation at a similar frequency to the SO can affect both properties of the SO as well as subsequent memory. However, such evidence is currently lacking a mechanistic explanation for how rhythmic stimulation alters the dynamic properties of the SO, such as its propagation patterns, and how it supports cortico-hippocampal communication that would ultimately lead to the behavioral memory effects. The aim of my thesis was to address these issues using a urethane-anesthetized rat and mouse model and applying slowly alternating rhythmic electrical fields to the frontal portions of the cortex. In Chapter 2 I examine the influence of sinusoidal electrical stimulation on spontaneous SO propagation dynamics using a simple three-channel linear electrode array across the anterior-posterior axis of the rat motor cortex. We show that during the spontaneous SO, two major propagation patterns traveling in both directions along the anterior-posterior plane appeared to compete for expression with alternations between these patterns occurring specifically during the OFF state. Applying rhythmic stimulation successfully entrained the local-field potential (LFP) at all recording sites along with gamma and multi-unit activity. The stimulation also biased the SO propagation in favour of the anterior-to-posterior direction in an intensity dependent fashion. Within local networks, cortico-cortical gamma synchrony was enhanced during the stimulation. In Chapter 3, I extend these findings to a more encompassing cortical network using voltage-sensitive dye (VSD) imaging in a large bilateral window of the mouse cortex. In accordance with findings from Chapter 2, spontaneous SO propagation showed several distinct propagation patterns with two major patterns emerging: anterior-to-posterior and posterior-to-anterior directions; with these patterns traveling along a slightly angled medio-lateral plane. The application of sinusoidal field stimulation entrained the VSD signal at multiple widespread cortical sites and biased SO propagation. Propagation during stimulation showed multiple initiation zones, mainly around anteriorly located regions, with a very specific termination zone in the somatosensory cortex. Importantly, there was no SO propagation detected during the application of neural activity blockers. Surprisingly, following the cessation of stimulation, hemisphere-specific activity was suppressed for a period of time with recovery thereafter. In Chapter 4 I introduce cortical and hippocampal (linear probe) recordings using rats in an attempt to address the effects of sinusoidal electrical stimulation on cortico-hippocampal interplay. As with the cortex, stimulation successfully entrained hippocampal LFP activity, likely by way of a specific pathway from the entorhinal cortex to the hippocampus. Stimulation also boosted the occurrence of hippocampal ripples which are implicated in memory replay as well as cortical spindles which are likewise associated with cortical plasticity and learning. Following the cessation of stimulation, cortico-hippocampal coordination at the SO band was enhanced and the flow of information, as assessed using Granger causality, was biased in the hippocampo-cortical direction. Gamma activity between the cortex and hippocampus showed enhanced synchrony following stimulation, with the effect being restricted to the hippocampal pyramidal cell layer, the output layer of the hippocampus, suggesting further that information flow was occurring in the hippocampal-cortical direction. These results show that rhythmic electrical field stimulation alters forebrain-wide SO dynamics. Changes in cortico-cortical, cortico-hippocampal and hippocampo-cortical interplay as a result of stimulation may all play important roles during sleep. Understanding the mechanisms that are at play during and following the administration of such stimulation can promote the development of targeted protocols for the enhancement and disruption of memory consolidation for use in experimental settings and eventually to affect clinical outcomes.

  • Subjects / Keywords
  • Graduation date
    2016-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R30Z7125W
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Centre for Neuroscience
  • Supervisor / co-supervisor and their department(s)
    • Dickson, Clayton (Psychology, Centre for Neuroscience, Physiology)
  • Examining committee members and their departments
    • Caplan, Jeremy (Psychology, Centre for Neuroscience)
    • Timofeev, Igor (University of Laval, external examiner)
    • Funk, Greg (Physiology, Centre for Neuroscience)
    • Smith, Peter (Pharmacology, Centre for Neuroscience)
    • Jones, Kelvin (Physical Education and Recreation, Centre for Neuroscience)