Biology subjects

Grudny, M. M.

Publications and source records attributed to Grudny, M. M..

5 recordsLinked to original sources

bioRxiv2026

Dissociable species-specific impact of Aβ on static and dynamic functional connectomes

Temporal dynamics in functional connectomes offer a physiologically grounded signature of hidden pathologies during preclinical stages of Alzheimers disease (AD). We evaluated the effect of beta-amyloid (A{beta}) on dynamic functional connectomes in transgenic mice and human subjects. Functional magnetic resonance images (fMRI) were collected in two strains of A{beta} mice. fMRI-derived connectomes were segmented into discrete states using a hidden Markov model and network strength, efficiency, and transitivity were analyzed per state. Human fMRI-derived connectome measures were analyzed across 3 states. Static network measures were significantly different between A{beta} mice and controls, the former having high values for strength, efficiency and clustering coefficient in anterior cingulate, hippocampus and retrosplenium. Dynamic network measures were stable within-states in A{beta} mice. Similarly, human subjects with high A{beta} had high node strength in precuneus and temporoparietal areas compared to low A{beta}. In contrast, however, high A{beta} was associated with high state switch rates, high fractional occupancy and state dwell times. Also, global strength, efficiency, and transitivity were less stable within states in the high A{beta} group. Our results indicate that static, but not dynamic, connectome strength, efficiency and network integration are increased in A{beta} mice, while dynamic network states appear less stable in human functional connectomes. This data supports a dissociable, species-specific impact of A{beta}, with dynamic network alterations present in humans but not in A{beta} mouse models, suggesting additional non-A{beta}-driven influences on dynamic functional connectivity in preclinical AD. SIGNIFICANT STATEMENTDetecting Alzheimers disease before symptoms appear remains a critical challenge. This study reveals that beta-amyloid -- a hallmark Alzheimers protein -- disrupts brain network dynamics differently across species. While both transgenic mice and humans with elevated amyloid show stronger static brain connectivity, only humans exhibit unstable, rapidly shifting brain network states. This dissociation suggests that the dynamic network disruptions seen in preclinical Alzheimers patients are not solely driven by amyloid accumulation, but likely reflect additional biological factors absent in mouse models. These findings highlight an important translational gap between animal models and human disease, with implications for how we design and interpret preclinical Alzheimers research and develop early diagnostic biomarkers.

neuroscience↗

bioRxiv2023

Maturational Differences in Affective Behaviors Involves Changes in Frontal Cortical-Hippocampal Functional Connectivity and Metabolomic Profiles

The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation. We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics. Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and with re-testing with a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. The results support differential expression of emotionality across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.

neuroscience↗

bioRxiv2022

Brain mapping and spatial protein profiling reveal functional connectivity deficits and molecular changes following repetitive mild traumatic brain injury in wild-type mice.

Repetitive mild traumatic brain injury (rmTBI) is a leading and severe threat to cognition that often goes undiagnosed. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps that explain how rmTBI promotes brain dysfunction. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. In this study, we sought to define the extent of altered brain functional connectivity (FC) and expression of neuropathological markers after rmTBI. We performed two rmTBI (2x 0.6{square}J impacts 24{square}h apart) in male and female C57BL/6J wild-type (WT) (~2.5-3mo) mice using closed head injury model of engineered rotational acceleration (CHIMERA) or sham procedures. At 5-6 days post-injury (dpi), we measured changes in brain volume and FC using T2-weighted images, resting-state functional MRI (rsfMRI), and graph theory analyses. We used diffusion tensor imaging (DTI) to assess microstructural changes in white matter tracts. In addition, at 7dpi, we measured changes in Iba1 and GFAP to determine the extent of gliosis. The expression of disease-associated protein markers in grey and white matter regions were evaluated using the NanoString-GeoMx digital spatial protein profiling (DSP) platform. The rsfMRI data revealed aberrant changes in connectivity such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in thalamus and other key brain regions that process visual, auditory, and somatosensory information. In addition, DTI revealed significantly decreased fractional anisotropy (FA) and axial diffusivity in the optic tract. Also, mean, radial, and axial diffusivity (L1) were significantly increased in the hippocampus. DSP revealed that phospho-serine 199 tau (pS199) as well as glial markers such as GFAP, cathepsin-D, and Iba1 were significantly increased in the optic tract. In thalamic nuclei, the neuroinflammatory marker GPNMB was increased significantly, and the cell proliferation marker Ki-67 was decreased in the rmTBI group. Our data suggest that rmTBI significantly alters brain functional connectivity and causes a profound inflammatory response in gray matter regions, beyond chronic white matter damage.

neuroscience↗

bioRxiv2021

Compensatory changes in contralesional node strength, brain wide modularity and cross-modular functional interactions in a rat model of traumatic brain injury

Penetrating cortical impact injuries alter neuronal communication beyond the injury epicenter, across regions involved in affective, sensorimotor, and cognitive processing. Understanding how traumatic brain injury (TBI) reorganizes local and brain wide nodal functional interactions may provide valuable quantitative parameters for monitoring pathological progression and functional recovery. To this end, we investigated spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal obtained at 11.1 Tesla in rats sustaining controlled cortical impact (CCI) and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12,879 pairwise correlations between fMRI signals from 162 regions. Our data indicate that on days 2 and 30 post-CCI there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic, and basal forebrain areas. Rats imaged on day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality, and participation coefficient track early and late TBI effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to CCI may be unfavorable to brain wide communication in the early post-injury period.

neuroscience↗

bioRxiv2020

A FUNCTIONAL NETWORK TOPOLOGY ASSOCIATED WITH PRE-SCAN CONTEXTUAL EXPERIENCE

Stimuli presented at short temporal delays before functional magnetic resonance imaging (fMRI) can have a robust impact on the organization of synchronous activity in resting state networks. This presents an opportunity to investigate how sensory, affective and cognitive stimuli alter functional connectivity in rodent models. In the present study, we assessed the effect of a familiar contextual stimulus presented 10 minutes prior to sedation for imaging on functional connectivity. A subset of animals were co-presented with an unfamiliar social stimulus in the same environment to further investigate the effect of familiarity on network topology. Female and male rats were imaged at 11.1 Tesla and graph theory analysis was applied to matrices generated from seed-based functional connectivity data sets with 144 brain regions (nodes) and 10,152 pairwise correlations (edges). Our results show an unconventional network topology in response to the familiar (context) but not the unfamiliar (social) stimulus. The familiar stimulus strongly reduced network strength, global efficiency, and altered the location of the highest eigenvector centrality nodes from cortex to the hypothalamus. We did not observe changes in modular organization, nodal cartographic assignments, assortative mixing, rich club organization, and network resilience. The results suggest that experiential factors, perhaps involving associative or episodic memory, can exert a dramatic effect on functional network strength and efficiency when presented at a short temporal delay before imaging.

neuroscience↗