Biology subjects

Bauer, A. Q.

Publications and source records attributed to Bauer, A. Q..

7 recordsLinked to original sources

bioRxiv2026

Normal Aging Limits Cortical Network Reorganization and Behavioral Recovery after Experimental Stroke

Stroke is the leading cause of chronic disability in the United States, and advancing age is associated with worse recovery. Despite this, relatively little is known about how aging influences the repair and reorganization of neural circuits and large-scale cortical networks after stroke. To address this question, we compared cortical network dynamics and behavioral recovery after focal photothrombotic stroke in forepaw somatosensory cortex in young (3-month-old) and aged (18-month-old) Thy1-GCaMP6f mice. Both young and aged mice developed significant somatomotor deficits after stroke; however, only young mice exhibited substantial behavioral recovery despite similar infarct volumes across groups. Two age-dependent effects on cortical network function emerged. First, somatosensory-evoked activity and somatosensory functional connectivity were disrupted in both cohorts early after stroke, but their trajectories diverged over time. Forepaw-evoked GCaMP responses in the affected cortex were similarly reduced in both groups early after stroke; yet by 7 weeks, responses recovered in young mice but remained persistently depressed in aged animals. Likewise, bihemispheric somatosensory functional connectivity was initially disrupted in both groups but improved between 1 and 7 weeks only in young mice. Second, global temporal measures of network function evolved differently after stroke. At baseline, stimulus-locked fidelity and interhemispheric coherence were higher in young than aged mice, but after stroke, these measures declined in young animals to levels comparable to aged mice and did not recover by 7 weeks. Stroke also altered large-scale cortical entrainment dynamics, and reductions in cortical entrainment area between baseline and 1-week post-stroke predicted long-term behavioral recovery across animals. Together, these findings indicate that impaired behavioral recovery in aged mice reflects a failure of damaged somatosensory networks to reorganize, whereas recovery in young mice occurs despite persistent degradation of global network fidelity and coherence. These results highlight age-dependent mechanisms of circuit repair after stroke and suggest a potential network-level basis for chronic deficits in stroke survivors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/720447v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1f23999org.highwire.dtl.DTLVardef@1a3a433org.highwire.dtl.DTLVardef@712dd5org.highwire.dtl.DTLVardef@780eaa_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Concurrent optogenetic motor mapping of multiple limbs in awake mice reveals cortical organization of coordinated movements

BackgroundMotor mapping allows for determining the macroscopic organization of motor circuits and corresponding motor movement representations on the cortex. Techniques such as intracortical microstimulation (ICMS) are robust, but can be time consuming and invasive, making them non-ideal for cortex-wide mapping or longitudinal studies. In contrast, optogenetic motor mapping offers a rapid and minimally invasive technique, enabling mapping with high spatiotemporal resolution. However, motor mapping has seen limited use in tracking 3-dimensonal, multi-limb movements in awake animals. This gap has left open questions regarding the underlying organizational principles of motor control of coordinated, ethologically relevant movements involving multiple limbs. ObjectiveOur first objective was to develop Multi-limb Optogenetic Motor Mapping (MOMM) to concurrently map motor movement representations of multiple limbs with high fidelity in awake mice. Having established MOMM, our next objective was determine whether maps of coordinated and ethologically relevant motor output were topographically organized on the cortex. MethodsWe combine optogenetic stimulation with a deep learning driven pose-estimation toolbox, DeepLabCut (DLC), and 3-dimentional triangulation to concurrently map motor movements of multiple limbs in awake mice. ResultsMOMM consistently revealed cortical topographies for all mapped features within and across mice. Many motor maps overlapped and were topographically similar. Several motor movement representations extended beyond cytoarchitecturally defined somatomotor cortex. Finer articulations of the forepaw resided within gross motor movement representations of the forelimb. Moreover, many cortical sites exhibited concurrent limb coactivation when photostimulated, prompting the identification of several cortical regions harboring coordinated and ethologically relevant movements. ConclusionsThe cortex appears to be topographically organized by motor programs, which are responsible for coordinated, multi-limbed, and behavioral-like movements.

neuroscience↗

bioRxiv2023

Arousal as a universal embedding for spatiotemporal brain dynamics

Neural activity in awake organisms shows widespread and spatiotemporally diverse correlations with behavioral and physiological measurements. We propose that this covariation reflects in part the dynamics of a unified, multidimensional arousal-related process that regulates brain-wide physiology on the timescale of seconds. By framing this interpretation within dynamical systems theory, we arrive at a surprising prediction: that a single, scalar measurement of arousal (e.g., pupil diameter) should suffice to reconstruct the continuous evolution of multidimensional, spatiotemporal measurements of large-scale brain physiology. To test this hypothesis, we perform multimodal, cortex-wide optical imaging and behavioral monitoring in awake mice. We demonstrate that spatiotemporal measurements of neuronal calcium, metabolism, and brain blood-oxygen can be accurately and parsimoniously modeled from a low-dimensional state-space reconstructed from the time history of pupil diameter. Extending this framework to behavioral and electrophysiological measurements from the Allen Brain Observatory, we demonstrate the ability to integrate diverse experimental data into a unified generative model via mappings from an intrinsic arousal manifold. Our results support the hypothesis that spontaneous, spatially structured fluctuations in brain-wide physiology--widely interpreted to reflect regionally-specific neural communication--are in large part reflections of an arousal-related process. This enriched view of arousal dynamics has broad implications for interpreting observations of brain, body, and behavior as measured across modalities, contexts, and scales.

neuroscience↗

bioRxiv2023

Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling.

Psychedelics hold therapeutic promise for mood disorders due to rapid, sustained results. Human neuroimaging studies have reported dramatic serotonin-2A receptor-(5-HT2AR)-dependent changes in functional brain reorganization that presumably reflect neuromodulation. However, the potent vasoactive effects of serotonin have been overlooked. We found psilocybin-mediated alterations to fMRI-HRFs in humans, suggesting potentially altered NVC. To assess the neuronal, hemodynamic, and neurovascular coupling (NVC) effects of the psychedelic 5-HT2AR agonist, 2,5-Dimethoxy-4-iodoamphetamine (DOI), wide-field optical imaging (WFOI) was used in awake Thy1-jRGECO1a mice during stimulus-evoked and resting-state conditions. While DOI partially altered tasked-based NVC, more pronounced NVC alterations occurred under resting-state conditions and were strongest in association regions. Further, calcium and hemodynamic activity reported different accounts of RSFC changes under DOI. Co-administration of DOI and the 5-HT2AR antagonist, MDL100907, reversed many of these effects. Dissociation between neuronal and hemodynamic signals emphasizes a need to consider neurovascular effects of psychedelics when interpreting blood-oxygenation-dependent neuroimaging measures.

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bioRxiv2021

Sulfonylureas target the neurovascular response to decrease Alzheimer's pathology

Hyperexcitability is a defining feature of Alzheimers disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATP channels, thereby stimulating insulin release. However, KATP channels are not limited to the pancreas and systemic modulation of KATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (A{beta}), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD. Graphical abstractTargeting vascular KATP channel activity for the treatment of Alzheimers disease pathology. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗

bioRxiv2021

Normal Aging in Mice is Associated with a Global Reduction in Cortical Spectral Power and a Network-Specific Decline in Functional Connectivity

Normal aging is associated with a variety of neurologic changes including declines in cognition, memory, and motor activity. These declines correlate with neuronal changes in synaptic structure and function. Degradation of brain network activity and connectivity represents a likely mediator of age-related functional deterioration resulting from these neuronal changes. Human studies have demonstrated both general decreases in spontaneous cortical activity and disruption of cortical networks with aging. Current techniques used to study cerebral network activity are hampered either by limited spatial resolution (e.g. electroencephalography, EEG) or limited temporal resolution (e.g., functional magnetic resonance imaging, fMRI). Here we utilize mesoscale imaging of neuronal activity in Thy1-GCaMP6f mice to characterize neuronal network changes in aging with high spatial resolution across a wide frequency range. We show that while evoked activity is unchanged with aging, spontaneous neuronal activity decreases across a wide frequency range (0.01-4Hz) involving all regions of the cortex. In contrast to this global reduction in cortical power, we found that aging is associated with functional connectivity (FC) deterioration of select networks including somatomotor, cingulate, and retrosplenial nodes. These changes are corroborated by reductions in homotopic FC and node degree within somatomotor and visual cortices. Finally, we found that whole cortex delta power and delta band node degree correlate with exploratory activity in young but not aged animals. Together these data suggest that aging is associated with global declines in spontaneous cortical activity and focal deterioration of network connectivity, and that these reductions may be associated with age-related behavioral declines.

neuroscience↗

bioRxiv2021

Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke

Understanding circuit-level changes that affect the brains capacity for plasticity will inform the design of targeted interventions for treating stroke recovery. We combine optogenetic photostimulation with optical neuroimaging to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice received chronic excitation of right S1FP, a maneuver mimicking the use of the unaffected limb during recovery. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of evoked activity in the unaffected limb. Contralesional stimulation prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally-distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited suppressed transcriptional changes in several genes important for recovery. These results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of several neuroplasticity-related genes after stroke.

neuroscience↗