Understanding Neural Networks in Awake Rat by Resting-State Functional MRI: A Dissertation

Resting-state functional magnetic resonance imaging (rs-fMRI) is a non-invasive neuroimaging technique that utilizes spontaneous low-frequency fluctuations of blood-oxygenation-level dependent (BOLD) signals to examine resting-state functional connectivity in the brain. In the past two decades, this technique has been increasingly utilized to investigate properties of large-scale functional neural networks as well as their alterations in various cognitive and disease states. However, much less is known about large-scale functional neural networks of the rodent brain, particularly in the awake state. Therefore, we attempted to unveil local and global functional connectivity in awake rat through a combination of seed-based analysis, independent component analysis and graph-theory analysis. In the current studies, we revealed elementary local networks and their global organization in the awake rat brain. We further systematically compared the functional neural networks in awake and anesthetized states, revealing that the rat brain was locally reorganized while maintaining global topological properties from awake to anesthetized states. Furthermore, specific neural circuitries of the rat brain were examined using resting-state fMRI. First anticorrelated functional connectivity between infralimbic cortex and amygdala were found to be evident with different preprocessing methods (global signal regression, regression of ventricular and white matter signal and no signal regression). Secondly the thalamocortical connectivity was mapped for individual thalamic groups, revealing group-specific functional cortical connections that were generally consistent with known anatomical connections in rat. In conclusion, large-scale neural networks can be robustly and reliably studied using rs-fMRI in awake rat, and with this technique we established a baseline of local and global neural networks in the awake rat brain as well as their alterations in the anesthetized condition

Brain connectivity studied by fMRI: homologous network organization in the rat, monkey, and human

The mammalian brain is composed of functional networks operating at different spatial and temporal scales — characterized by patterns of interconnections linking sensory, motor, and cognitive systems. Assessment of brain connectivity has revealed that the structure and dynamics of large-scale network organization are altered in multiple disease states suggesting their use as diagnostic or prognostic indicators. Further investigation into the underlying mechanisms, organization, and alteration of large-scale brain networks requires homologous animal models that would allow neurophysiological recordings and experimental manipulations. My current dissertation presents a comprehensive assessment and comparison of rat, macaque, and human brain networks based on evaluation of intrinsic low-frequency fluctuations of the blood oxygen-level-dependent (BOLD) fMRI signal. The signal fluctuations, recorded in the absence of any task paradigm, have been shown to reflect anatomical connectivity and are presumed to be a hemodynamic manifestation of slow fluctuations in neuronal activity. Importantly, the technique circumvents many practical limitations of other methodologies and can be compared directly between multiple species. Networks of all species were found underlying multiple levels of sensory, motor, and cognitive processing. Remarkable homologous functional connectivity was found across all species, however network complexity was dramatically increased in primate compared to rodent species. Spontaneous temporal dynamics of the resting-state networks were also preserved across species. The results demonstrate that rats and macaques share remarkable homologous network organization with humans, thereby providing strong support for their use as an animal model in the study of normal and abnormal brain connectivity as well as aiding the interpretation of electrophysiological recordings within the context of large-scale brain networks

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Awake Reactivation of Prior Experiences Consolidates Memories and Biases Cognition.

After experiences are encoded into memory, post-encoding reactivation mechanisms have been proposed to mediate long-term memory stabilization and transformation. Spontaneous reactivation of hippocampal representations, together with hippocampal-cortical interactions, are leading candidate mechanisms for promoting systems-level memory strengthening and reorganization. While the replay of spatial representations has been extensively studied in rodents, here we review recent fMRI work that provides evidence for spontaneous reactivation of nonspatial, episodic event representations in the human hippocampus and cortex, as well as for experience-dependent alterations in systems-level hippocampal connectivity. We focus on reactivation during awake post-encoding periods, relationships between reactivation and subsequent behavior, how reactivation is modulated by factors that influence consolidation, and the implications of persistent reactivation for biasing ongoing perception and cognition

Alterations in prefrontal-limbic functional activation and connectivity in chronic stress-induced visceral hyperalgesia.

Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([(14)C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Magnetoencephalography as a tool in psychiatric research: current status and perspective

The application of neuroimaging to provide mechanistic insights into circuit dysfunctions in major psychiatric conditions and the development of biomarkers are core challenges in current psychiatric research. In this review, we propose that recent technological and analytic advances in Magnetoencephalography (MEG), a technique which allows the measurement of neuronal events directly and non-invasively with millisecond resolution, provides novel opportunities to address these fundamental questions. Because of its potential in delineating normal and abnormal brain dynamics, we propose that MEG provides a crucial tool to advance our understanding of pathophysiological mechanisms of major neuropsychiatric conditions, such as Schizophrenia, Autism Spectrum Disorders, and the dementias. In our paper, we summarize the mechanisms underlying the generation of MEG signals and the tools available to reconstruct generators and underlying networks using advanced source-reconstruction techniques. We then survey recent studies that have utilized MEG to examine aberrant rhythmic activity in neuropsychiatric disorders. This is followed by links with preclinical research, which have highlighted possible neurobiological mechanisms, such as disturbances in excitation/inhibition parameters, which could account for measured changes in neural oscillations. In the final section of the paper, challenges as well as novel methodological developments are discussed which could pave the way for a widespread application of MEG in translational research with the aim of developing biomarkers for early detection and diagnosis

Emergent Orientation Selectivity from Random Networks in Mouse Visual Cortex

The connectivity principles underlying the emergence of orientation selectivity in primary visual cortex (V1) of mammals lacking an orientation map (such as rodents and lagomorphs) are poorly understood. We present a computational model in which random connectivity gives rise to orientation selectivity that matches experimental observations. The model predicts that mouse V1 neurons should exhibit intricate receptive fields in the two-dimensional frequency domain, causing a shift in orientation preferences with spatial frequency. We find evidence for these features in mouse V1 using calcium imaging and intracellular whole-cell recordings. Pattadkal et al. show that orientation selectivity can emerge from random connectivity, and offer a distinct perspective for how computations occur in the neocortex. They propose that a random convergence of inputs can provide signals for orientation preference in contrast with the dominant model that requires a precise arrangement.Fil: Pattadkal, Jagruti J.. University of Texas at Austin; Estados UnidosFil: Mato, German. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: van Vreeswijk, Carl. Centre National de la Recherche Scientifique; FranciaFil: Priebe, Nicholas J.. University of Texas at Austin; Estados UnidosFil: Hansel, David. Centre National de la Recherche Scientifique; Franci