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Browsing by Subject "Electrophysiology"

Now showing 1 - 17 of 17
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    Astrocyte-neuron signaling in the nucleus accumbens: implications for brain reward signaling
    (2019-05) Corkrum, Michelle
    Dopamine is one of the major reward signaling molecules in the brain. Dopaminergic transmission contributes to physiological states such as learning, memory encoding, movement and motivated behaviors; and, the disruption of dopamine signaling can contribute to neuropsychiatric diseases such as substance use disorders. The majority of research on reward signaling has focused on neurons; however, astrocytes are emerging as key components of brain information processing. Astrocytes are a subset of glial cell, one of the most abundant cell types in the brain. Although astrocytes are not electrically excitable, in response to brain activity, they demonstrate increases in intracellular calcium and the subsequent release of neuroactive substances, termed gliotransmitters. Therefore, my dissertation aimed to investigate the hypothesis that astrocytes respond to brain reward signaling with elevations in cytoplasmic calcium, and subsequently modulate neuronal activity in the nucleus accumbens, one of the major reward centers of the brain. Utilizing fiber photometry, I found that astrocytes in the nucleus accumbens respond to dopamine and amphetamine with cytoplasmic calcium elevations in vivo. To elucidate the cellular mechanisms of this phenomenon and the consequences of astrocyte calcium signals on neuronal activity, we conducted experiments applying multiphoton calcium imaging and whole-cell patch clamp electrophysiology in acute brain slices containing the nucleus accumbens core. We found that astrocytes respond to dopamine, amphetamine and opioids with intracellular calcium elevations and subsequently modulate neuronal activity, either through adenosine signaling in the case of dopamine and amphetamine or glutamatergic signaling in the case of opioid exposure. Furthermore, we demonstrate that astrocytes contribute to the acute psychomotor behavioral effects of amphetamine, illustrating astrocyte modulation of drug-related behaviors. Overall, the current body of work provides evidence that astrocytes actively contribute to brain reward processing via responding to dopamine and drugs of abuse with intracellular calcium increases and modulating neuronal and synaptic activity in the nucleus accumbens, one of the major nodes of the reward system.
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    Development Of Multi-Modal Techniques For The Investigation Of Brain Energetics
    (2015-10) Taylor, Jennifer
    The study of spontaneous and highly variable brain activity, or task-evoked activity and its quantitative relationship with neuroimaging signals, is severely restricted by the lack of techniques to investigate multiple measures of brain activity simultaneously. In order to study the coupling and interactions between metabolic, hemodynamic, and neuronal activity, we here develop the technology to acquire in vivo magnetic resonance (MR) spectroscopy (MRS) simultaneously from two or more nuclei, as well as develop MR-compatible electrodes for neuronal recording in the MR scanner with minimal susceptibility artifacts. We apply these techniques to investigate metabolic trends resulting from a whole brain occlusion in the rat and to study neuronal, hemodynamic, and network responses to changes in anesthesia depth. Lastly, we show the first steps in developing an MR-compatible optrode to allow simultaneous MR imaging (MRI), neuronal recording, and optogenetic stimulation. With these new techniques, a wide field of studies becomes feasible to investigate direct neuronal, metabolic, and hemodynamic correlations under resting and working conditions to advance our understanding of brain function and dysfunction.
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    Does cerebellar cortex function as a forward internal model for motor control?
    (2013-06) Hewitt, Angela L.
    Motor control theorists have postulated that to produce rapid, finely tuned movements, a component of the control circuitry must bypass long sensory feedback delays by providing an estimate of the consequences resulting from a motor command. This control element, termed a forward internal model, receives an efferent copy of the motor command and information about the current state in order to predict the future state (i.e. kinematic variables like position, velocity) of the limb. Previous psychophysical, imaging, and patient case studies suggest that the cerebellum is a possible location for implementation of an internal model. However, very few electrophysiological studies have investigated whether the firing discharge from cerebellar neurons is consistent with the output of a forward internal model. To specifically evaluate the simple spike firing from Purkinje cells in lobules IV-VI, we trained rhesus macaques to perform different hand movement tasks using a 2 joint robotic manipulandum. Two electrophysiology experiments tested several aspects of a forward internal model. First, we hypothesize that Purkinje cell simple spike firing predicts future hand kinematics, even when the task is highly unpredictable. Second, the encoding is invariant, so that the model output can generalize to other tasks. A third hypothesis is that the simple spike discharge will show evidence of learning when animals adapt to a predictable mechanical perturbation, as expected from a forward internal model. Experimental results found many theoretical components of a forward internal model present in the Purkinje cell simple spike discharge. Simple spikes encode both feedforward and feedback representations of movement kinematics, with position and velocity signals explaining the most firing variability. These representations supply the predictive kinematic signals used downstream and the feedback information potentially used locally to construct predictions, calculate errors, and update the model. Many Purkinje cells exhibit dual encoding for a single kinematic parameter, so that these separate feedforward and feedback mechanisms may take place within individual cells. For most cells, model coefficients generated from random tracking data accurately estimate simple spike firing in either circular tracking or center-out reach. Adaptation to a predictable perturbation initiates steady, progressive changes in the parameter sensitivity (βs) of both the feedforward and feedback signals. The timing sensitivity (τ) also demonstrates significant shifts, with time encoding in the simple spikes often changing sign during adaptation (e.g. feedback to feedforward). Population analyses suggest that large changes in parameter sensitivity first occur in the feedback signals, then transfer to the feedforward representations. This may reflect use of the simple spike feedback to update model predictions. These results conclude that kinematic encoding from the cerebellar cortex uses a forward internal model that can generalize between tasks, but is also highly plastic and adaptable.
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    Electrophysiological Investigation of Brain Stimulation Strategies to Improve Hearing Restoration via Auditory Neural Prostheses
    (2013-12) Straka, Malgorzata
    The auditory lemniscal system, the core pathway thought to be responsible for conducting high-fidelity auditory information, is yet to be well-understood, particularly at the level of the midbrain. The lack of understanding of the auditory lemniscal system resulted in limited performance of a central auditory neuroprosthesis called the auditory midbrain implant (AMI). The AMI is a linear array of 20 sites designed to stimulate the auditory lemniscal nucleus in the midbrain, the central nucleus of the inferior colliculus (ICC). In the first clinical trial, five patients were implanted with the AMI, which gave users improved lip reading abilities and environmental awareness. However, the AMI was unable to deliver sufficient temporal information, which is likely associated with suboptimal placement and stimulation strategies within the ICC. This doctoral thesis project investigated the central lemniscal system in order to improve results for future AMI patients. First, the organization of responses to auditory stimuli was investigated within the auditory lemniscal midbrain. This study found different response properties within a rostral-lateral verses caudal medial ICC region, corresponding to subregions with differential input and output projection patterns. Next, we investigated various stimulation strategies that would allow the AMI to deliver sufficient temporal information. Repeated stimulation of a single site in the ICC, which was the initial strategy of the AMI, resulted in refractory effects in the auditory cortex that could only be overcome by co-activating neurons along a lamina of the ICC. This co-activation resulted in cortical activity that was enhanced beyond the sum of individual neural activation, with the greatest enhancement occurring in supragranular cortical layers. Moreover, this enhancement was largest when stimulating the rostral-lateral rather than the caudal-medial ICC region. These ICC locations with different electrical stimulation properties matched the two subregions with different acoustic-driven response properties. Together, these studies found consistent differences in physiological properties within two subregions of the ICC, confirming the presence of dual lemniscal pathways from the midbrain to the cortex. In addition, these studies identified a potential stimulation strategy and implantation location for improving AMI performance: co-activating rostral-lateral neurons along the isofrequency laminae of the ICC.
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    Functional Neuroimaging of Electrophysiological Rhythms in Pathological and Normal Brains
    (2012-07) Yang, Lin
    Imaging of electrophysiological activity in the brain plays a critical role in neuroscience research. Shown by emerging neuroimaging studies, rhythmic oscillations in electrophysiology reflect important functional changes in the brain. More importantly, the mapping of electrophysiological neural signals can serve as a diagnostic tool for neurological diseases. One typical example is the electroencephalography (EEG) technique, which has been established as a core component of pre-surgical evaluation in epilepsy treatment. However, despite the recent advances of functional neuroimaging techniques, a non-invasive, high resolution, electrophysiological imaging approach still remains challenging. In the clinical application of epilepsy, there is not an established protocol that can image, non-invasively, the electrophysiological signals during the most important epileptic event - epileptic seizures. The present dissertation research aims at developing electrophysiological imaging approaches with focus on the rhythmic activity in pathological and normal brains. Towards this goal, we have developed a spatiotemporal EEG imaging method, which is suited to image dynamic changes of ictal discharges during epileptic seizures. As evaluated in a group of epilepsy patients in clinical environment, such a non-invasive seizure imaging approach could potentially translate into a more precise and less risky pre-surgical imaging tool for epilepsy diagnosis. In addition to the direct impact of seizures, we have studied the electrophysiological changes in the widespread brain networks. The spatial and spectral features of EEG rhythms can reflect important correlation with the impact of seizures and the change of cognitive functions. The electrophysiological imaging in epilepsy, therefore, can serve as a useful tool in a pathological model to study cognition and consciousness in human brains. In order to achieve higher spatial resolution, we also improved the EEG source imaging by adding a multimodal component of functional MRI. From all the results we have obtained so far in these studies, it is suggested that the spatiotemporal EEG source imaging has the potential to improve clinical diagnosis and treatment of neurological disorders. It can also advance our understanding of basic neuroscience questions.
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    Identifying the mechanism of action of the antiepileptic drug levetiracetam in synaptic vesicle release and its implications for epilepsy.
    (2011-07) Meehan, Anna L.
    In the United States alone, over 3 million people have been diagnosed with epilepsy, a dynamic disease characterized by recurring and unpredictable seizures. Antiepileptic drugs (AEDs) and other therapies have helped to combat this widespread phenomenon, yet for one-third of epilepsy patients, there is still no effective treatment. A better understanding of the mechanisms of AEDs has been called for. Levetiracetam (LEV) is one AED on the market that does not work by the typical mechanisms of action of AEDs. LEV binds to the vesicular protein SV2A in neurons in the brain, which is thought to mediate some step in neurotransmitter release. However, the exact mechanism of action of LEV is unknown. Deducing this mechanism would be of substantial benefit for the development of new, similar drugs that also work by such a non-conventional mechanism. The experiments and results I present in this dissertation detail my investigation of the effect of LEV on neurotransmission of rat hippocampal neurons. My methods include fluorescence-staining with FM dyes to label synaptic vesicles and monitor vesicle release as well as electrophysiological techniques to observe synaptic currents. My experimental protocols have allowed me to detect differences in neurotransmitter release in LEV-treated neurons. Furthermore, manipulating exposure conditions required before LEV action have allowed me to deduce that LEV must enter active neurons to reach SV2A. I believe that LEV is dependent on endocytosis for access to vesicles, a completely unique mechanism of action for a small molecule drug.
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    Intrinsically photosensitive retinal ganglion cells: diversity of form and function.
    (2010-12) Schmidt, Tiffany M.
    A subpopulation of retinal ganglion cells (RGCs) express the photopigment melanopsin, rendering them intrinsically photosensitive (ipRGCs). These ganglion cell photoreceptors are critical for several non-image forming behaviors including circadian entrainment and the pupillary light reflex. Initially thought to be a uniform population, later studies demonstrated that there was at least some degree of morphological and physiological diversity in the ipRGC population. Technical limitations, however, had prevented the comprehensive study of ipRGCs at the single cell level. The purpose of this project was to utilize a mouse model in which ipRGCs are labeled in vivo with enhanced green fluorescent protein to identify and target single ipRGCs for morphological and physiological analyses. The central hypothesis of the research presented herein is that distinct morphological ipRGC subtypes have distinct physiological properties and synaptic inputs, resulting in unique light information sent to target nuclei in the brain by the various ipRGC subpopulations. This work has confirmed the existence and further analyzed the morphological and physiological properties of at least three ipRGC subtypes: M1 cells with dendrites stratifying in the OFF sublamina of the inner plexiform layer (IPL), M2 cells with dendrites stratifying in the ON sublamina of the IPL, and M3 cells with dendrites bistratifying in both the ON and OFF sublaminas of the IPL. We find that these cell types do indeed possess distinct intrinsic light responses and intrinsic membrane properties. Furthermore, we find that these subpopulations are differentially influenced by cone-mediated signals. Finally, we find that the cation channel involved in ipRGC signal transduction is not composed solely of the canonical transient receptor potential channel (TRPC) subunit 3, 6, or 7. However, we do find that TRPC6 is involved in mediating the melanopsin-evoked light response in both M1 and M2 cells, with both subtypes showing a reduction in the magnitude of the intrinsic light response in TRPC6-/- animals. Collectively, the differential influence of intrinsic, melanopsin-mediated phototransduction and synaptically-evoked extrinsic inputs on the integrated light-evoked response of ipRGC subtypes indicates that these subtypes may serve as conduits for distinct light information sent to the brain. We discuss the implications of these findings and propose a model for the differential influence of distinct ipRGC subtypes on various non-image forming behaviors.
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    An Investigation of the Cellular Mechanisms Underlying Ultrasound Neuromodulation
    (2020-08) Newhoff, Morgan
    Focused ultrasound is an emerging neuromodulation technology with the unique potential to noninvasively modulate neuronal activity in deep brain structures with high spatial specificity, offering a potential alternative to invasive neural stimulators. Decades of research have confirmed that ultrasound induces profound effects on neuronal firing rates in a wide range of animal systems, yet the direction (increase or decrease) and primary effector of these effects remain a subject of debate. Here, we describe experiments designed to assess these core questions in a tractable invertebrate model, the medicinal leech (Hirudo verbana). We examined the effects of ultrasound (960 kHz) on an identified motoneuron, a class of cells believed to lack canonical mechanosensitive ion channels, and whose response to ultrasound we predict to be reflective of effects on most neuronal cell types. We observed both neuronal excitation and inhibition, with a bias towards inhibitory effects. These effects were direct, and persisted in the presence of synaptic blockers. Importantly, these effects were only observed when applying ultrasound of sufficient duration to generate heating in excess of 2 °C. Similar durations of ultrasound in a low-heat paradigm were insufficient to induce changes in neuronal firing rate. We thus concluded that heat is the primary effector of ultrasound neuromodulation in this system, which was reinforced by our ability to elicit comparable effects through the targeted application of heat alone. Additional experiments using non-thermal short pulses of ultrasound on sensory neurons failed to produce neuronal activation at and above intensities at which others have reported excitation, with the exception of effects we deemed artifactual due to electrode resonance, and which could be reliably mimicked with micromovements of the recording electrode. We conclude that the mechanical effects of ultrasound, which are frequently described in the literature, are less reliably achieved than thermal effects, and observations ascribed to mechanical effects may be confounded by activation of synaptically-coupled sensory structures or artifact associated with electrode resonance. Nonetheless, ultrasound can generate significant modulation at temperatures < 5 °C, which are believed to be safe for moderate durations. Ultrasound should therefore be investigated as a thermal neuromodulation technology for clinical use.
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    Lateral intraparietal area activity as a temporal production signal during precise timing.
    (2011-08) Schneider, Blaine Andrew
    We often perform movements without external cues telling us when to move. However, the way our brains time self-initiated movements is still unclear. For example, while temporal modulations in neuronal activity have been observed in a variety of timing tasks, it is not clear if these modulations are strictly related to the timing of movements or instead reflect timing measurements of external events such as sensory cues and rewards. To isolate the temporal production signals of movement initiation, we devised a self-timed task that requires non-human primates to saccade between two fixed targets at regular intervals in the absence of external cueing and without an immediate expectation of reward. To examine the potential neural basis of this temporally dependent behavior, we recorded from single neurons in the lateral intraparietal area (LIP), which has been implicated in the cognitive planning and execution of eye movements. In contrast to previous studies that observed a build-up of activity associated with the passage of time, we found that LIP activity decreased at a constant rate over the inter-saccadic interval. Moreover, this falling activity was found to be significantly predictive of inter-saccadic interval duration on an interval by interval basis. Interestingly, the relationship of this falling activity to the actual duration of the timed interval depended on eye movement direction: it was negatively correlated when the upcoming saccade was toward the neuron's response field, and positively correlated when the upcoming saccade was directed away from the response field. This suggests that LIP activity encodes timed movements in a push-pull manner by signaling for both saccade initiation towards one target and prolonged fixation for the other target. Thus timed movements in this task appear to reflect the competition between local populations of task relevant neurons, rather than a global timing signal. Additionally, microstimulation was delivered during separate experiments to determine if a causal relationship existed between LIP activity and motor production. Stimulation affected the animals perception of time in a manner consistent with the correlation results, suggesting that LIP activity provides a motor timing signal that is utilized in the initiation of precisely timed behaviors.
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    Molecular mechanisms of inhibitory signaling in the heart and brain
    (2014-06) Wydeven, Nicole Marie
    G protein-gated inwardly-rectifying K+ (GIRK/Kir3) channels mediate the inhibitory effect of many neurotransmitters on excitable cells of the heart and brain. Dysregulation of GIRK signaling is known to underlie a number of disorders, including arrhythmia, epilepsy, depression, anxiety, schizophrenia, and drug addiction. GIRK channels are gated by inhibitory Gi/o proteins and temporally modulated by Regulators of G protein Signaling (RGS) proteins. GIRK channels are tetramers consisting of various combinations of four mammalian Girk subunits (GIRK1-4). This dissertation focuses on neuronal and cardiac GIRK signaling cascades as targets for new pharmacotherapies in the treatment of anxiety-related disorders and cardiac arrhythmias.Both robust GIRK channel activity and modulation by a new class of GIRK-specific drugs depend on the GIRK1 subunit. The presence of GIRK1 in channel complexes is necessary for robust channel activity. We first sought to better understand the potentiating influence of GIRK1, using the GABAB receptor and GIRK1/GIRK2 heteromer as a model system. We found residues in both the distal carboxyl-terminal domain and channel core that underlie the GIRK1-dependent potentiation of receptor-dependent and receptor-independent heteromeric channel activity. Further, ML297, the prototypical member of a new family of small molecule GIRK channel modulators, selectively activates GIRK1-containing channels. We found that ML297 activates GIRK channels via a unique mechanism that requires two amino acids specific to the GIRK1 subunit. In addition, ML297 reduces anxiety-related behavior in mice, in a GIRK1-dependent manner, without triggering addiction-related behavior. Thus, ML297 is a new tool for probing the therapeutic potential of GIRK channel modulation, which may benefit individuals with anxiety-related disorders. Cardiac GIRK signaling plays a role in the parasympathetic regulation of heart rate (HR). Parasympathetic activity decreases HR by inhibiting pacemaker cells in the sino-atrial node (SAN). RGS proteins are negative modulators of the parasympathetic regulation of HR and the prototypical M2 muscarinic receptor (M2R)-dependent signaling pathway in the SAN that involves the muscarinic-gated atrial K+ channel IKACh (a GIRK1/GIRK4 tetramer). We first identified RGS6 as a temporal regulator of cardiac M2R-IKACh signaling in atrial myocytes and SAN cells. Both RGS4 and RGS6 have been implicated in the negative modulation of the parasympathetic regulation of HR and the M2R-IKACh signaling pathway. We next looked at the contribution of RGS4 and RGS6 to the modulation of M2R-IKACh signaling. Ablation of Rgs6, but not Rgs4, correlated with decreased resting HR and a significant delay of M2R-IKACh deactivation rate. Thus, RGS6, and not RGS4, is the primary RGS modulator of cardiac M2R-IKACh. Taken together, these findings suggest that RGS6 is a potential pharmacotherapeutic target as the dysregulation of parasympathetic influence has been linked to sinus node dysfunction and arrhythmia.
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    Neural Anomalies During Vigilance in Schizophrenia: Diagnostic Specificities and Genetic Associations
    (2020-10) Klein, Samuel
    Impaired vigilance is a core cognitive deficit in schizophrenia and may serve as an endophenotype (i.e., mark genetic liability). We used a continuous performance task with perceptually degraded stimuli in schizophrenia patients (N=48), bipolar disorder patients (N=26), first-degree biological relatives of schizophrenia patients (N=55) and bipolar disorder patients (N =28), as well as healthy controls (N=68) to clarify whether previously reported vigilance deficits and abnormal neural functions were indicative of genetic liability for schizophrenia as opposed to a generalized liability for severe psychopathology. We also examined variation in the Catechol-O-methyltransferase gene to evaluate whether brain responses were related to genetic variation associated with higher-order cognition. Relatives of schizophrenia patients had an increased rate of misidentification of nontarget stimuli as targets when they were perceptually similar, suggestive of difficulties with contour perception. Larger early visual responses (i.e., N1) were associated with better task performance in patients with schizophrenia consistent with enhanced N1 responses reflecting beneficial neural compensation. Additionally, reduced N2 augmentation to target stimuli was specific to schizophrenia. Both patients with schizophrenia and first-degree relatives displayed reduced late cognitive responses (P3b) that predicted worse performance. First-degree relatives of bipolar patients exhibited performance deficits, and displayed aberrant neural responses that were milder than individuals with liability for schizophrenia and dependent on sex. Variation in the Catechol-O-methyltransferase gene was differentially associated with P3b in schizophrenia and bipolar groups. Poor vigilance in schizophrenia is specifically predicted by a failure to enhance early visual responses, weak augmentation of mid-latency brain responses to targets, and limited engagement of late cognitive responses that may be tied to genetic variation associated with prefrontal dopaminergic availability. Experimental results illustrate specific neural functions that distinguish schizophrenia from bipolar disorder and provides evidence for a putative endophenotype that differentiates genetic liability for schizophrenia from severe mental illness more broadly.
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    NMDA receptors underlie stress-induced dynamic changes in prefrontal cortical networks: plasticity and function.
    (2011-01) Parent, Marc-Alexander L.T.
    The prefrontal cortex (PFC) is a region in the frontal lobe of the cerebral cortex necessary for the proper execution of cognitive behaviors such as attention, memory, and the ordering of actions to accomplish a task. In rodents, lesions of the medial prefrontal cortex (mPFC) impact visiospatial working-memory (vsWM) functions. Neurons in the cerebral cortex are typically silent in alert animals but can become persistently active when brain networks engage them to participate in computations necessary to accomplish a task. During vsWM tasks, neurons in mPFC become persistently active for the delay period of a WM task. The persistent activation of neurons in mPFC by local networks during the delay period of a working memory task in vivo has been suggested to represent a basic neural substrate for maintenance of an internal representation. Stress can alter the performance of animals attempting working memory tasks, and its effects are dynamic over the span of days following a single exposure. Immediately following stress, vsWM is negatively affected and performance on a vsWM task is hindered, while four to twenty-four hours following exposure to stress, vsWM is enhanced. It has been hypothesized that plasticity in local mPFC glutamatergic networks in vivo, driven by stress-response mediators, alters AMPA- and NMDA-mediated neurotransmission as a function of the number of stress exposures and that this plasticity affects persistent, network-driven activity. A previous study has shown that both AMPA- and NMDA-mediated neurotransmission are upregulated twenty-four hours after exposure to mild FS stress (Yuen et al., 2009). The following doctoral thesis supports this conclusion and extends this work to quantify the effects of multiple stress exposures, over several days, on mPFC plasticity and describes a correlation between enhanced glutamatergic synaptic drive and changes in persistent activity. In animals exposed to multiple days of ten-minute, forced-swim stress, NMDA-mediated glutamatergic neurotransmission was upregulated relative to unstressed, naïve animals while AMPA-mediated neurotransmission and intrinsic cellular phenomena remained unaffected. Close examination of isolated NMDA currents from neurons in three-day stressed mice revealed a decrease in the decay rate of these currents relative to naive animals. This augmentation of NMDA-ergic tone yields greater charge entry that could potentially increase the impact of synaptic drive on neuronal activity as well as enhance synaptic integration. The upregulation of NMDA-mediated neurotransmission in three-day stressed animals was found to occur via the upregulation of the NR2B subunits at synaptic NMDA receptors. Together, a decrease in NMDA current decay rate via inclusion of NR2B subunits and the lack of evidence for stress-induced AMPA current modulation resulted in an increase in NMDA-to-AMPA ratio (NAR) at synaptic mPFC networks. These observed changes in glutamatergic neurotransmission, after a single or multiple exposures to forced swim, are paralleled by changes in persistent activity. Individual PA events were recorded from naïve, one-day and three-day stressed mice. PA events recorded from both stressed groups were increased in duration relative to naïve animals. These data support the conclusion that stress regulates glutamatergic neurotransmission in the mPFC, affecting the ability of neurons to remain persistently active.
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    Noninvasive imaging of three-dimensional ventricular electrical activity
    (2012-08) Han, Chengzong
    Noninvasive imaging of cardiac electrical activity is of great importance and can facilitate basic cardiovascular research and clinical diagnosis and management of various malignant cardiac arrhythmias. This dissertation research is aimed to investigate a novel physical-model-based 3-dimensional cardiac electrical imaging (3DCEI) approach. The 3DCEI approach is developed by mathematically combining high-density body surface electrocardiograms (ECGs) with the anatomical information. Computer simulation study and animal experiments were conducted to rigorously evaluate the performance of 3DCEI. The simulation results demonstrate that 3DCEI can localize the origin of activation and image the activation sequence throughout the three-dimensional ventricular myocardium. The performance of 3DCEI was also experimentally and rigorously evaluated through well-controlled animal validation studies in both the small animal model (rabbit) and large animal model (canine), with the aid of simultaneous intramural recordings from intra-cardiac mapping using plunge-needle electrodes inserted in the ventricular myocardium. The clinical relevance of 3DCEI was further demonstrated by investigating 3DCEI in cardiac arrhythmias from animal models with experimentally-induced cardiovascular diseases. The consistent agreement between the non-invasively imaged activation sequences and its directly measured counterparts in both the rabbit heart and canine heart implies that 3DCEI is feasible in reconstructing the spatial patterns of ventricular activation sequences, localizing the arrhythmogenic foci, and imaging dynamically changing arrhythmia on a beat-to-beat basis. The promising results presented in this dissertation study suggest that this cardiac electrical imaging approach may provide an important alternative for non-invasively imaging cardiac electrical activity throughout ventricular myocardium and may potentially become an important tool to facilitate clinical diagnosis and treatments of malignant ventricular arrhythmias.
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    Principles of Computer Numerical Controlled Machining Applied to Small Research Animal Microsurgical Procedures
    (2017-12) Rynes, Mathew
    The palette of tools available for systems neuroscientists to measure and manipulate the brain during behavioral experiments has exploded in the last decade. Implementing these tools, from electrical to optical sensors require the removal of bone tissue without damage to the underlying brain tissue. This is typically a delicate procedure as the skulls of commonly used inbred mouse strains are very thin (~80-500 μm above the mice dorsal cortex). However, with increasing complexity, these microsurgical procedures have become art forms. It takes many months to become skilled at performing these operations. Automating some of the tissue removal processes would potentially enable more precise procedures to be performed. Here, we introduce the ‘Craniobot’, a microsurgery platform, assembled with off-the- shelf components, that combines automated skull surface profiling with a CNC milling machine to perform a variety of microsurgical procedures in mice. The Craniobot utilizes a low force contact sensor that can accurately measure the surface of the skull across the whole dorsal skull with a precision of 2.4 ± 8.5 µm and this information can be used to perform milling operations with comparable precision. We have used the Craniobot to perform skull thinning, small to large craniotomies, as well as drilling pilot holes for anchoring cranial implants. The system is implemented using open source and customizable machining practices, this approach can be expanded in the future to larger animal models, or for more complex procedures and a more comprehensive part of the pipeline of in vivo neuroscience.
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    The Role of High-Density Lipoproteins and Related Pathways in Alzheimer’s Disease
    (2017-12) Hottman, David
    Alzheimer’s disease (AD) is the most prevalent age-related dementia and will place an increasingly demanding burden on our healthcare system as the population ages. It has been firmly established that high plasma levels of high-density lipoprotein (HDL) protect against cardiovascular disease and accumulating evidence indicates that the beneficial role of HDL extends to the central nervous system. There are several important biological mechanisms that regulate HDL generation and metabolism/function. One is through the cholesteryl ester transfer protein (CETP), which transports cholesterol esters and triglycerides between different lipoprotein particles. Loss-of-function mutations in CETP are associated with better cognition in aging. To investigate the role of CETP in AD, human CETP transgenic mice were crossed with an Alzheimer’s mouse model, followed by biochemical and behavioral analyses. The results showed that CETP-induced modest decrease in plasma HDL levels was insufficient to affect brain amyloid pathology, neuroinflammation, or memory function. Next, to explore the therapeutic potential of a cardiovascular protective, HDL-mimetic-peptide called D-apoJ[113-122], AD mice were treated with the peptide. This treatment robustly reduced brain amyloid pathology and improved memory function in AD mice. Further analyses showed that D-apoJ[113-122] exerted its beneficial effects through reduction of cerebral vascular amyloid deposition and clearance of brain amyloid to plasma. Finally, prenyltransferase-deficient mice were used to investigate the role of protein prenylation in synaptic function. Prenylation is an important posttranslational lipid modification process that attaches isoprenoids (the intermediates in the cholesterol biosynthesis pathway) to target proteins. Electrophysiological/histochemical experiments showed that systemic or forebrain-specific deficiency of one particular prenyltransferase, geranylgeranyltransferase-1, caused marked impairment in hippocampal synaptic plasticity and decrease in neuronal dendritic spine density. Further analyses indicated that reduction of prenylation of certain small GTPases, which rely on prenylation for proper cellular localization and function, underlies the detrimental effects in these mice, as observed in aged mouse brains. These results corroborate the critical role of protein prenylation in synaptic function during development and in the adult brain. Taken together, findings from this research provide novel insights into the role of HDL and related pathways in the pathogenesis of AD, and offer new avenues to develop effective therapies for AD.
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    Three-Dimensional Imaging of Ventricular Electrical Activity: Method, Animal Validation and Clinical Evaluation
    (2017-02) Yu, Long
    Non-invasive cardiac electrical imaging techniques aim to directly visualize the intra-cardiac electrical activities and promise to assist in clinical diagnosis and treatment of cardiac arrhythmias, a family of highly dangerous disease leading to a hundreds of thousands of deaths and disabilities in the United States alone. In this dissertation, a line of investigations is included regarding cardiac electrical sparse imaging - a novel three dimensional cardiac imaging technique – from mathematical formulation of the imaging problem to validations studies covering numerical models, animal healthy and pathological models and patients with ventricular arrhythmias both during and before cardiac ablative procedures. With its spatiotemporal sparse problem, the novel imaging method incorporate cardiac electrophysiological features into the imaging process in order to achieve improvements in spatiotemporal resolution and, consequentially, general performance of the imaging technique. Simulation studies were conducted using a cardia automaton based heart-torso numerical model to verify the performance of the technique against various disturbances resembling the clinical challenges. Based on the numerical studies, rigorous animal studies using intra-cardiac simultaneous mapping technique were conducted to further validate the technique in biological systems such as canine and swine under healthy and pathological conditions such as myocardial infarction and congestive heart failure. Moreover, to evaluate the performance and compatibility of the technique in real life clinical challenges, further in-procedural and pre-procedural clinical studies were carried out on patients with ventricular arrhythmias. High accuracy and strong robustness can be observed by comparing the imaged activations with the mapped ones. The imaging technique achieved good performance not only in numerical simulations, but also in animal models with complex pathological conditions. Strong correlation was observed from the comparisons on ventricular arrhythmias with both focal and reentrant patterns. In further clinical studies, the technique also achieved good performance in localizing the arrhythmia foci and imaging the 3D activation pattern during the arrhythmias. The promising results shown in the studies indicate that the technique has good capability in visualizing the whole heart electrical activities and in providing key information such as arrhythmia foci and reentry pathways to assist in clinical practice in various pathological conditions.
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    Which way do I go? Strategic representations in rat prefrontal cortex on spatial decision tasks
    (2014-10) Powell, Nathaniel
    The role of the Prefrontal Cortex (PFC) in animal behavior is both complex and subtle. This dissertation concerns the role of rat PFC on spatial decision- making tasks, particularly how it represents strategies or rules necessary to solve these tasks. First I review the current state of knowledge about the role of the rat PFC in regard to behavior and decision-making (Chapter 1). Then I describe the spatial decision-making tasks and electrophysiological recording techniques I used to explore the role of PFC in rats (Chapter 2). Using one of these tasks, I found overlapping populations of PFC neurons that simultaneously encoded mul- tiple relevant task parameters, including some cases in which mulitple parameters were encoded by single neurons (Chapter 3). I also describe the spatial firing properties of PFC neurons on these tasks and conclude that although these cells do not seem to directly represent space per se, there are important differences in both single-cell and population representations that corresponded to the ani- mal's location on spatial tasks (Chapter 4). Finally, using a population decoding approach that takes advantage of the spatially coded information in the cells, I identify transitions between different strategic representations in the PFC of an- imals performing these tasks. In general the transition between states occurred after animals received information that caused them to change their strategy but before the actual change in their behavior. Additionally, these transitions cannot be accounted for solely on the basis of changes to either sensory information or mo- tor output, which proves that these transitions between strategic representational states are cognitive processes (Chapter 5).