Biology subjects

Rahn, R. M.

Publications and source records attributed to Rahn, R. M..

5 recordsLinked to original sources

bioRxiv2023

Myeloid cell activation during Zika virus encephalitis predicts recovery of functional cortical connectivity

Neurologic complications of Zika virus (ZIKV) infection across the lifespan have been described during outbreaks in Southeast Asia, South America, and Central America since 2016. In the adult CNS ZIKV tropism for neurons is tightly linked to its effects, with neuronal loss within the hippocampus during acute infection and protracted synapse loss during recovery, which is associated with cognitive deficits. The effects of ZIKV on cortical networks have not been evaluated. Although animal behavior assays have been used previously to model cognitive impairment, in vivo brain imaging can provide orthogonal information regarding the health of brain networks in real time, providing a tool to translate findings in animal models to humans. In this study, we use widefield optical imaging to measure cortical functional connectivity (FC) in mice during acute infection with, and recovery from, intracranial infection with a mouse-adapted strain of ZIKV. Acute ZIKV infection leads to high levels of myeloid cell activation, with loss of neurons and presynaptic termini in the cerebral cortex and associated loss of FC primarily within the somatosensory cortex. During recovery, neuron numbers, synapses and FC recover to levels near those of healthy mice. However, hippocampal injury and impaired spatial cognition persist. The magnitude of activated myeloid cells during acute infection predicted both recovery of synapses and the degree of FC recovery after recovery from ZIKV infection. These findings suggest that a robust inflammatory response may contribute to the health of functional brain networks after recovery from infection. Significance StatementDetermining the long-term cognitive impact of infections is clinically challenging. We found that the degree of myeloid cell activation correlated with the degree of recovery of functional connectivity after recovery from ZIKV encephalitis. Using functional cortical connectivity, we demonstrate that interhemispheric cortical connectivity is decreased in individuals with acute ZIKV encephalitis. This correlates with decreased presynaptic terminals in the somatosensory cortex. During recovery from ZIKV infection, presynaptic terminals recover, which is associated with recovered interhemispheric connectivity. This suggests a role for activated myeloid cells in maintenance of cognition and further supports the contribution of synapses in the cortex to functional networks in the brain, which can be detected by widefield optical imaging. These findings also suggest neuroinflammation may play a neuroprotective role in addition to aiding in local virologic control.

biophysics↗

bioRxiv2023

Visual deprivation during mouse critical period reorganizes network-level functional connectivity

A classic example of experience-dependent plasticity is ocular dominance (OD) shift, in which the responsiveness of neurons in the visual cortex is profoundly altered following monocular deprivation (MD). It has been postulated that OD shifts also modify global neural networks, but such effects have never been demonstrated. Here, we used longitudinal wide-field optical calcium imaging to measure resting-state functional connectivity during acute (3-day) MD in mice. First, delta GCaMP6 power in the deprived visual cortex decreased, suggesting that excitatory activity was reduced in the region. In parallel, interhemispheric visual homotopic functional connectivity was rapidly reduced by the disruption of visual drive through MD and was sustained significantly below baseline state. This reduction of visual homotopic connectivity was accompanied by a reduction in parietal and motor homotopic connectivity. Finally, we observed enhanced internetwork connectivity between visual and parietal cortex that peaked at MD2. Together, these findings support the hypothesis that early MD induces dynamic reorganization of disparate functional networks including association cortices. Significance StatementMonocular deprivation during the visual critical period triggers several plasticity mechanisms that collaborate to shift the excitability of neurons in the visual cortex. However, little is known about the impacts of MD on cortex-wide functional networks. Here, we measured cortical functional connectivity during short-term critical period MD. We demonstrate that critical period MD has immediate effects on functional networks beyond the visual cortex, and identify regions of substantial functional connectivity reorganization in response to MD.

neuroscience↗

bioRxiv2021

Mecp2 deletion results in profound alterations of developmental and adult functional connectivity

As a regressive neurodevelopmental disorder with a well-established genetic cause, Rett Syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into Mecp2s role in functional circuit development. Thus, we applied optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex prior to symptom onset as well as during decline. We found that FC was profoundly disrupted in Mecp2 males both in juvenile development and early adulthood. Female Mecp2 mice displayed a subtle homotopic contralateral increase in motor cortex as juveniles but not in adulthood, where instead parietal regions were implicated. Additionally, conditional rescue studies indicated FC phenotypes are driven by excitatory neurons. Altogether, the female results identify subtle candidate translatable biomarkers of disease progression, while the male results indicate MeCP2 protein is needed in a circuit-specific manner for FC.

neuroscience↗

bioRxiv2021

Functional connectivity of the developing mouse cortex

Cross-sectional studies have established a variety of structural, synaptic and cell physiological changes corresponding to key critical periods in cortical development. However, the emergence of functional connectivity (FC) in development has not been fully characterized, and hemodynamic-based measures are vulnerable to any neurovascular coupling changes occurring in parallel. We therefore used optical fluorescence imaging to trace longitudinal calcium FC in the awake, resting-state mouse cortex in the same mice at 5 developmental time points beginning at postnatal day 15 (P15) and ending in early adulthood (P60), resulting in over 500 imaging epochs with both calcium and hemodynamics available as a resource for the field. Proof-of-principle analyses revealed that calcium FC displayed coherent functional maps as early as P15, and FC significantly varied in connections between many regions across development, with the developmental trajectorys shape specific to the functional region. This longitudinal developmental calcium FC dataset provides an essential resource for further algorithm development and studies of healthy development and neurodevelopmental disorders.

neuroscience↗

bioRxiv2020

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms, and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. We therefore characterized gait using the DigiGait assay in two different NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a patient-derived heterozygous germline NF1 mutation. We collected longitudinal data across five developmental time points (postnatal days 21-30) and one early adulthood time point. Compared to wild type littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across Nf1+/R681X mouse development persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in CD mice largely resolved by adulthood. These findings suggest that gait subcomponents affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models, and a platform to examining circuits or longitudinal therapeutics. Lay SummaryGait changes have been reported in Williams Syndrome and Neurofibromatosis Type 1, but how these changes develop over time has not been explored. We therefore studied gait in mouse models of these two disorders across time. We found multiple shared differences in gait as compared to healthy controls at the younger ages in both models. However, those differences were resolved in the Williams Syndrome model by adulthood, yet persisted in the Neurofibromatosis Type 1 model.

animal behavior and cognition↗