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The Intrinsic Plasticity Of Medial Vestibular Nucleus Neurons During Vestibular Compensation: A Systematic Review And Meta-Analysis

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  • Title:
    The Intrinsic Plasticity Of Medial Vestibular Nucleus Neurons During Vestibular Compensation: A Systematic Review And Meta-Analysis
  • Author: Wijesinghe, Rajiv
  • Subjects: compensation ; intrinsic ; neurons ; vestibular
  • Description: The diversity of activity displayed by neurons of the central nervous system is unmatched by any other cell in the body. Each neuron displays a characteristic, stereotypic pattern of firing which often defines its functional role (Llinas, 1988). Some neurons are spontaneously active at rest, displaying pacemaker-like properties, while others are very quiescent until stimulated by synaptic inputs. Some neurons fire rapid, regular action potential trains which show little deterioration in frequency over time. Others fire only short bursts of action potentials and reduce their rate of firing quickly, producing very little response to even large inputs (Bean, 2007). These discharge characteristics are fundamentally determined by two main features: the intrinsic membrane properties of the neuron and the nature of the synaptic inputs the neuron receives. Intrinsic properties are those relating to the architecture of the neuronal membrane, intracellular ionic buffers that regular electrolyte concentrations and the types of ion channels expressed on the membrane and their pattern of distribution (Wijesinghe & Camp, 2011). Meanwhile, synaptic properties are determined by the types of transmitters arriving at the neuronal surface, the distribution of these synapses and their density over various functionally specialised regions of the neuron (Spruston, 2008). From the various permutations of these different properties emerges the vast array of different firing characteristics observed of individual neurons from different regions of the brain (Llinas, 2014). Despite the prevalent stereotypy observed across different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum & Kandel, 2012; Sweatt, 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck & Yaari, 2008; Camp, 2012; Vitureira, Letellier & Goda, 2012; Yin & Yuan, 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Bailey, Kandel & Harris, 2015; Kandel, 2001). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously attributed to synaptic mechanisms alone (Desai, 2003; Hanse, 2008; Mozzachiodi & Byrne, 2010; Titley, Brunel & Hansel, 2017). A number of studies in the past 30 years have demonstrated important activity-dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Beraneck & Idoux, 2012; Camp & Wijesinghe, 2009). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties (for example see previous work in Camp & Wijesinghe, 2009; Wijesinghe & Camp, 2011; Wijesinghe, Solomon & Camp, 2013; Wijesinghe et al., 2015). In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains our sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg et al., 2012). It mediates basic reflexes that maintain gaze stability during head movement and stabilises dynamic posture (Bronstein, Patel & Arshad, 2015). This sensory modality also has a unique property of near immediate recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys & Halmagyi, 1995). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient model to bridge in vitro findings to clinical observations (Straka, Zwergal & Cullen, 2016). Recent studies have suggested that vestibular compensation may be behavioural correlate of a form of experience-dependent plasticity occurring within the vestibular nuclei of the brainstem (Dutia, 2010; Lacour & Tighilet, 2010; Macdougall & Curthoys, 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons in a way that is necessary for the process to occur. In the thesis that follows, I present the first comprehensive systematic review of the scientific literature searching for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during the acute phase of vestibular compensation. To determine the methodological quality of studies discovered through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 17 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is evidence in favour of the hypothesis. Then, pooling quantitative data from this evidence, I performed a meta-analysis which demonstrates a moderate, statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, their spontaneous discharge rate increases by 4 spikes/sec on average and their sensitivity (or gain) in response to current stimuli increases. Using this novel approach, I demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental studies with similar aims. I also identify a number of areas in which the reporting of experimentation in field of vestibular research can be improved to strengthen the quality and validity of future work. Despite the prevalent stereotypy observed different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum et al. 2012, Sweatt 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck and Yaari 2008, Camp 2012, Vitureira, Letellier et al. 2012, Yin and Yuan 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Kandel 2001, Bailey, Kandel et al. 2015). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously solely attributed to synaptic mechanisms (Desai 2003, Hanse 2008, Mozzachiodi and Byrne 2010, Titley, Brunel et al. 2017). A number of studies in the past 20 years have demonstrated important activity dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Camp and Wijesinghe 2009, Beraneck and Idoux 2012). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties. In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains an animal’s sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg, Wilson et al. 2012). It mediates basic reflexes that maintain gaze stability during head movement (vestibuloocular reflex) and stabilises posture (vestibulospinal reflex) (Bronstein, Patel et al. 2015). This sensory modality also has a unique property of near immediate and complete recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys and Halmagyi 1995). For example, following unilateral peripheral vestibular lesions, the acute symptom of vertigo and its behavioural effects abate spontaneously within days (Fetter 2016). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient and ide
  • Creation Date: 2017
  • Language: English
  • Source: Trove Australian Thesis (Full Text Open Access)
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