Biology subjects

Febo, M.

Publications and source records attributed to Febo, M..

23 records · Page 2Linked to original sources

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↗

bioRxiv2020

Intestine-specific deletion of metal transporter Zip14 (Slc39a14) causes brain manganese overload and locomotor defects of manganism

Impaired manganese (Mn) homeostasis can result in excess Mn accumulation in specific brain regions and neuropathology. Maintaining Mn homeostasis and detoxification is dependent on effective Mn elimination. Specific metal transporters control Mn homeostasis. Human carriers of mutations in the metal transporter ZIP14 and whole-body Zip14 KO (WB-KO) mice display similar phenotypes, including spontaneous systemic and brain Mn overload, and motor dysfunction. Initially, it was believed that Mn accumulation due to ZIP14 mutations caused by impaired hepatobiliary Mn elimination. However, liver-specific Zip14 KO mice (L-KO) did not show systemic Mn accumulation or motor deficits. ZIP14 is highly expressed in the small intestine and is localized to the basolateral surface of enterocytes. Thus we hypothesized that basolaterally-localized ZIP14 in enterocytes provides another route for elimination of Mn. Using wild type and intestine-specific ZIP14 KO (I-KO) mice, we have shown that ablation of intestinal Zip14 is sufficient to cause systemic and brain Mn accumulation. The lack of intestinal ZIP14- mediated Mn excretion was compensated for by the hepatobiliary system; however, it was not sufficient to maintain Mn homeostasis. When supplemented with extra dietary Mn, I-KO mice displayed some motor dysfunctions, brain Mn accumulation based on both MRI imaging and chemical analysis, thus demonstrating the importance of intestinal ZIP14 as a route of Mn excretion. A defect in intestinal Zip14 expresssion likely could contribute to the Parkinson-like Mn accumulation of manganism. New & NoteworthyMn-induced parkinsonism is recognized as rising in frequency due to both environmental factors and genetic vulnerability, yet currently, there is no cure. We provide evidence in an integrative animal model that basolaterally localized ZIP14 regulates Mn excretion and detoxification and that deletion of intestinal ZIP14 leads to systemic and brain Mn accumulation, providing robust evidence for the indispensable role of intestinal ZIP14 on Mn excretion.

neuroscience↗

bioRxiv2019

Mechanism of manganese dysregulation of dopamine neuronal activity

Manganese exposure produces Parkinsons-like neurological symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies suggest manganese accumulates in dopamine neurons of the ventral tegmental area and substantia nigra via nifedipine-sensitive Ca2+ channels. Manganese produces a Ca2+ channel-mediated current which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+ channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.\n\nSignificance StatementManganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurological disorders such as a Parkinsons disease-like syndrome known as manganism. We found manganese dose-dependently increased the excitability of dopamine neurons, decreased the amplitude of action potentials, and narrowed action potential width. Blockade of Ca2+ channels prevented these effects as well as manganese accumulation in the mouse midbrain in vivo. Our data provide a potential mechanism for manganese-regulation of dopaminergic neurons.

cell biology↗

bioRxiv2019

Increased Neurite Orientation-Dispersion and Density in the TgCRND8 Mouse Model of Amyloidosis: Inverse Relation with Functional Connectome Clustering and Modulation by Interleukin-6

Extracellular {beta}-amyloid (A{beta}) plaque deposits and inflammatory immune activation are thought to alter various aspects of tissue microstructure, such as extracellular free water, fractional anisotropy and diffusivity, as well as the density and geometric arrangement of axonal processes. Quantifying these microstructural changes in Alzheimers disease and related neurodegenerative dementias could serve to accurately monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to determine how A{beta} and inflammatory interleukin-6 (IL6), alone or in combination, affect in vivo tissue microstructure in the TgCRND8 mouse model of Alzheimers-type A{beta} deposition. TgCRND8 and non-transgenic (nTg) mice expressing brain-targeted IL6 or enhanced glial fibrillary protein (EGFP controls) were scanned at 8 months of age using a 2-shell, 54-gradient direction dMRI sequence at 11.1 Tesla. Images were processed using the free water elimination method and the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern consistent with reduced white matter integrity along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean diffusivity (MD), and free water (FW), and increased neurite density (NDI) and orientation dispersion (ODI). IL6 produced a protective-like effect on FA in TgCRND8 mice, although there were minimal microstructure changes in these mice compared IL6 expressing nTg mice. In addition, we found that NDI and ODI had an inverse relationship with the functional connectome clustering coefficient, which was affected by A{beta} and IL6. The relationship between NODDI and graph theory metrics suggests that increasing the density and orientation dispersion of neurites may relate to diminished functional network organization in the brain.

neuroscience↗

bioRxiv2018

Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age

The functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multi-scale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multi-task. Aged behaviorally-impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex and dorsal striatum. Moreover, the old rats had less stable rich club participation that increased with cognitive training. The altered functional connectome of aged rats was associated with a greater engagement of neurons in the dorsal striatum during cognitive multi-tasking. These findings point to aberrant large-scale functional connectivity in aged animals that is associated with altered cellular activity patterns within individual brain regions.

neuroscience↗