37 research outputs found

    Functional networks and network perturbations in rodents

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    Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed

    Influence of Focal Activity on Macroscale Brain Dynamics in Health and Disease

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    Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory cortex (S1). Using a focal ischemic stroke model, I show that bilateral activation of somatosensory cortices is required for initiating global SWs, while spontaneous SWs are generated independent of S1. 2) That regional disruption of cortical excitability induces widespread changes across cortical networks, using chemogenetic manipulation of parvalbumin interneurons to model focal epileptiform activity in S1. We further show that local imbalances in excitability propagate differentially through intra- and interhemispheric connections, and can induce plasticity in large-scale networks. These studies begin to define the mechanisms of macro-scale network disruption after focal injuries, adding to our understanding of how local cortical circuits modulate global brain networks

    The impact of bilateral ongoing activity on evoked responses in mouse cortex

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    In the absence of external stimuli or overt behavior, the activity of the left and right cortical hemispheres shows fluctuations that are largely bilateral. Here we show that these fluctuations are largely responsible for the variability observed in cortical responses to sensory stimuli. Using widefield imaging of voltage and calcium signals, we measured activity in the cortex of mice performing a visual detection task. Bilateral fluctuations invested all areas, particularly those closest to the midline. Activity was less bilateral in the monocular region of primary visual cortex and, especially during task engagement, in secondary motor cortex. Ongoing bilateral fluctuations dominated unilateral visual responses, and interacted additively with them, explaining much of the variance in trial-by-trial activity. Even though these fluctuations occurred in regions necessary for the task, they did not affect detection behavior. We conclude that bilateral ongoing activity continues during visual stimulation and has a powerful additive impact on visual responses

    Oxygen Polarography in the Awake Macaque: Bridging BOLD fMRI and Electrophysiology

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    Blood oxygen level dependent (BOLD) fMRI is the predominant method for evaluating human brain activity. This technique identifies brain activity by measuring blood oxygen changes associated with neural activity. Although clearly related, the nature of the relationship between BOLD fMRI identified brain activity and electrophysiologically measured neural activity remains unclear. Direct comparison of BOLD fMRI and electrophysiology has been severely limited by the technical challenges of combining the two techniques. Microelectrode electrophysiology in non-human primates is an excellent model for studying neural activity related to high order brain function similar to that commonly studied with BOLD fMRI in humans, i.e. attention, working memory, engagement. This thesis discusses the development of, validation of, and first results obtained using a new multi-site oxygen polarographic recording system in the awake macaques as a surrogate for BOLD fMRI. Oxygen polarography measures tissue oxygen which is coupled to blood oxygen. This tool offers higher resolution than BOLD fMRI and can be more readily combined with electrophysiology. Using this new tool we evaluated local field potential and oxygen responses to an engaging visual stimulus in two distinct brain systems. In area V3, a key region in the visual system and representative of stimulus driven sensory cortex, we show increased tissue oxygen and local field potential power in response to visual stimulus. In area 23 of the posterior cingulate cortex (PCC), a hub of the default-mode network we show decreased oxygen and local field potential in response to the same stimulus. The default-mode network is a set of brain regions identified in humans whose BOLD fMRI activity is higher at rest than during external engagement, arguing that they sub-serve a function that is engaged as the default-mode in humans. Our results provide new evidence of default-mode network activity in the macaque similar to that seen in humans, provide evidence that the BOLD identified default-mode suppression reflects neural suppression and overall support a strong relationship between neural activity and BOLD fMRI. However, we also note that the LFP responses in both regions show substantial nuances that cannot be seen in the oxygen response and suggest response complexity that is invisible with fMRI. Further the nature of the relationship between LFP and oxygen differs between regions. Our multi-site technique also allows us to evaluate inter-regional interaction of ongoing oxygen fluctuations. Inter-regional correlation of BOLD fMRI fluctuations is commonly used as an index of functional connectivity and has provided new insight into behaviorally relevant aspects of the brains organization and its disruption in disease. Here we demonstrate that we can measure the same inter-regional correlation using oxygen polarography. We utilize the increased resolution of our technique to investigate the frequency structure of the signals driving the correlation and find that inter-regional correlation of oxygen fluctuations appears to depend on a rhythmic mechanism operating at ~0.06 Hz

    Commissural white matter disconnectivity in normal ageing and Alzheimer’s disease

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    The network of commissural white matter fibres responsible for connecting the hemispheres of the brain is known as the corpus callosum (CC). Atrophy to the CC is evident in studies of aging and Alzheimer’s disease (AD), but patterns and functional implications of neurodegeneration are still somewhat unclear. In this thesis, neuroimaging methods were used to further examine how structural and functional CC properties are affected by normal ageing and AD. In Study 1, diffusion tensor imaging (DTI) was used to examine the posterior CC tract bundles in young and older adults. Parietal and temporal midsagittal CC segments were particularly impaired in older adults, while occipital tracts were relatively preserved. Study 2 applied this methodology to study Mild Cognitive Impairment (MCI) and AD. MCI patients exhibited reduced integrity in midsagittal parietal segments compared to controls. AD patients exhibited reductions in parietal and temporal segments, yielding high classification accuracy (95-98%) against controls. Study 3 assessed visual interhemispheric transfer in aging using electroencephalography (EEG). Transfer speed was elongated in older adults, but was driven by earlier activation of the input hemisphere rather than delayed activation of the receiving hemisphere. This was not interpreted as impairment in older age, in line with findings of preserved occipital tracts in Study 1. Study 5 examined EEG functional connectivity methodology. We showed that connectivity was strongest at the dominant EEG frequency, which experiences slowing in older age. Previous studies using conventional frequency bands may therefore be biased against older adults. Study 6 applied these findings to study interhemispheric functional connectivity in older adults, while controlling for age-related frequency slowing. Age-related disconnectivity between frontal sites was evident, reflecting typical anterior-posterior neurodegeneration in older adults (Bennett, Madden, Vaidya, Howard, & Howard, 2010). These studies provide novel spatial and methodological insight into the CC during ageing and AD

    Bihemispheric reorganization of neuronal activity during hand movements after unilateral inactivation of the primary motor cortex

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    Le cortex moteur primaire (M1) est souvent endommagé lors des lésions cérébrales telles que les accidents vasculaires cérébraux. Ceci entraîne des déficits moteurs tels qu'une perte de contrôle des membres controlatéraux. La récupération des lésions M1 s'accompagne d'une réorganisation hémodynamique dans les zones motrices intactes des deux hémisphères. Cette réorganisation est plus prononcée dans les premiers jours et semaines qui suivent la lésion. Toutefois, nous avons une compréhension limitée de la réorganisation neuronale rapide qui se produit dans ce réseau moteur cortical complexe. Ces changements neuronaux nous informent sur l’évolution possible de la plasticité subaiguë impliquée dans la récupération motrice. Par conséquent il était grand temps qu’une caractérisation de la réorganisation rapide de l'activité neuronale dans les régions motrices des deux hémisphères soit entreprise. Dans cette thèse nous avons exploré l'impact d'une lésion corticale localisée, unilatérale et réversible dans M1 sur l'activité neuronale des zones motrices des hémisphères ipsi et contralésionnel lorsque des primates non humains ont effectués des mouvements d’atteinte et de saisie. Notre modèle d'inactivation nous a permis d'enregistrer en continu des neurones isolés avant et après l'apparition des déficits moteurs. Dans une première étude, la réorganisation rapide qui se produit dans le cortex prémoteur ventral (PMv) des deux hémisphères a été étudiée (Chapitre 2). Le PMv est une zone connue pour être impliquée dans le contrôle moteur de la main et la récupération des lésions M1. Dans une seconde étude, la réorganisation rapide du M1 contralésionnel (cM1) a été étudiée et comparée à celles se produisant dans les PMv bilatérales (Chapitre 3). Le cM1 joue un rôle complexe dans la récupération des mouvements de précision de la main suite à une blessure à son homologue. Nous révélons une réorganisation neuronale importante et beaucoup plus complexe que prévu dans les deux hémisphères lors de l’apparition initiale des déficiences motrices. Nos données démontrent que les changements neuronaux survenant quelques minutes après une lésion cérébrale sont hétérogènes à la fois dans et entre les zones du réseau moteur cortical. Ils se produisent dans les deux hémisphères lors des mouvements des bras parétiques et non parétiques, et ils varient au cours des différentes phases du mouvement. Ces découvertes constituent une première étape nécessaire pour démêler les corrélats neuronaux complexes de la réorganisation au travers du réseau moteur des deux hémisphères à la suite d’une lésion cérébrale.After brain injuries such as stroke, the primary motor cortex (M1) is often damaged leading to motor deficits that include a loss of fine motor skills of the contralateral limbs. Recovery from M1 lesions is accompanied by hemodynamic reorganization in motor areas distal to the site of injury in both hemispheres that are most pronounced early after injury. However, we have limited understanding of the rapid neuronal reorganization that occurs in this complex and distributed cortical motor network. As these neural changes reflect the landscape on which subacute plasticity involved in motor recovery will take place, an exploration of the rapid reorganization in neural activity that occurs in motor regions of both hemispheres is long overdue. In the current thesis, we set out to explore the impact of a localized, unilateral and reversible cortical injury to the M1 hand area on neuronal activity in motor-related areas of both the ipsi and contralesional hemispheres as non-human primates performed a reach and grasp task. Our inactivation model allowed us to continuously record isolated neurons before and after the onset of motor deficits. In a first study, the rapid reorganization taking place in the ventral premotor cortex (PMv) of both hemispheres was investigated (Chapter 2). The PMv is an area well-known to be critically involved in hand motor control and recovery from M1 lesions. In a second study, the rapid reorganization taking place in the contralesional M1 (cM1) was studied and compared to those occurring in bilateral PMv (Chapter 3). The cM1 has a complex role in recovery of dexterous hand movements following injury to its homologue. We reveal extensive, and much more complex than expected, neuronal reorganization in both hemispheres at the very onset of motor impairments. Our data demonstrate that neuronal changes occurring within minutes after brain injury are heterogenous both within and across areas of the cortical motor network. They occur in the two hemispheres during movements of both the paretic and non-paretic arms, and they vary during different phases of movement. These findings constitute a first step in a much needed and timely effort to unravel the complex neuronal correlates of the reorganization that takes place across the distributed motor network after brain injury

    Interhemispheric Communication and Lateralization in the Mouse Hippocampus

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    The hippocampus is essential for memory and spatial navigation. Many theories have been proposed to explain how the hippocampus contributes to cognition; however, none has fully explained relevant neurophysiological and behavioral data. Hemispheric lateralization of hippocampal function has been reported in humans and in rodents, and lateralization of hippocampal neural circuitry has been reported in rodents. Most theories of hippocampal function fail to consider the hippocampus as a bilateral structure with hemispheric differences. Further, proposed theories of hippocampal lateralization have their own limitations in explaining empirical data concerning left/right function. Little is known about communication between the hippocampi across hemispheres. In addition, the information that we do have about hippocampal lateralization has been acquired in examination of CA3 or CA1, while less is known about the dentate gyrus. Here, my goal is to further our understanding of the hippocampus as a bilateral structure via novel theoretical and empirical contributions. In this dissertation, I will argue for a new model of bilateral hippocampal function, demonstrate a function of interhemispheric communication across hemispheres, and show that lateralization extends to the dentate gyrus. I will: formulate a model of left/right hippocampal function in Chapter 1; characterize lateralization in hippocampus-dependent learning and memory in Chapter 2; examine activity-dependent gene expression in the dentate gyrus across hemispheres in Chapter 3; and quantify adult neurogenesis in the left and right dentate gyrus in relation to experience in Chapter 4. The data collected in Chapters 2-4 are not tests of the model presented in Chapter 1. Rather, they are examinations of interhemispheric communication and lateralization that may be used in the future to produce more robust models of the bilateral hippocampus. Collectively, these contributions suggest that the mouse hippocampus is indeed lateralized and that the sharing of information across hemispheres enables some behaviors that are hippocampus-dependent

    Novel insights into oligodendrocyte biology from developmental myelination studies in autophagy deficient mice and analysis of oligodendrocyte translatome response to contusive spinal cord injury.

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    Loss of myelin causes severe neurological disorders and functional deficits in white matter injuries (WMI) such as traumatic spinal cord injury (SCI). This dissertation is focused on autophagy in OL development and the OL translatome after SCI. Chapter I describes the history of myelin, OL development, and their involvement in neurodegenerative diseases and SCI. The proteostasis network, in particular autophagy, and its contributions to white matter pathology is discussed. It concludes examining advantages and disadvantages of unbiased omics tools, like RiboTag, to study transcriptional/translational landscapes after SCI. Chapter II focuses on autophagy in OPC/OL differentiation, survival, and proper myelination in the mouse brain during development. Conditional deletion of Atg5, an essential autophagy gene, in neonatal mice develop a tremor and is lethal. Further investigation revealed OPC apoptosis, reduced differentiation, and reduced myelination. Atg5-/- OPCs capable of differentiating failed to properly myelinate. Lastly, pharmacologically inhibiting or activating autophagy in OPC/dorsal root ganglion(DRG) co-cultures blocked and enhanced myelination, respectively. It is proposed autophagy is an important regulator in OPC survival, maturation, and myelination. Chapter III is focused on the OL translatome before and after SCI. Using RiboTag, the OL translatome was determined in the intact mouse spinal cord and 2, 10 and 42 days post contusive thoracic SCI. Biphasic upregulation of mitochondrial-respiration mRNAs at days 2 and 42 suggest OLs shift metabolism to oxidative phosphorylation. Pro-survival and cell death regulators peaked at day 2. Acute OL upregulation of the iron oxidoreductase Steap3, was confirmed at the protein level and further tested in vitro. It is proposed metabolic shift to oxidative phosphorylation may contribute to oxidative stress and exacerbated by proteins such as STEAP3. Collectively, autophagy is a critical regulator in OPC development and myelination and may facilitate myelin compaction. Such critical roles magnifies the importance of maintaining proteostasis, and its potential as a therapeutic target in white matter injuries. OL translatomic data suggests OLs response to SCI is dynamic, and metabolic shifts may indicate biphasic waves of oxidative stress. It also identifies new targets like Steap3 that have not previously been explored, proving a valuable dataset to explore OL response to SCI
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