Biology subjects

McDonald, R. J.

Publications and source records attributed to McDonald, R. J..

7 recordsLinked to original sources

bioRxiv2024

Sparsity of population activity in the hippocampus is task-invariant across the tri-synaptic circuit and dorsal-ventral axis

Evidence from neurophysiological and genetic studies demonstrates that activity sparsity - the proportion of neurons that are active at a given time in a population - systematically varies across the canonical trisynaptic circuit of the hippocampus. Recent work has also shown that sparsity varies across the hippocampal dorsoventral (long) axis, wherein activity is sparser in ventral than dorsal regions. While the hippocampus has a critical role in long-term memory (LTM), whether sparsity across the trisynaptic circuit and hippocampal long axis is task-dependent or invariant remains unknown. Importantly, representational sparsity has significant implications for neural computation and theoretical models of learning and memory within and beyond the hippocampus. Here we used functional molecular imaging to quantify sparsity in the rat hippocampus during performance of the Morris water task (MWT) and contextual fear discrimination (CFD) - two popular and distinct assays of LTM. We found that activity sparsity is highly reliable across memory tasks, wherein activity increases sequentially across the trisynaptic circuit (DG < CA3 < CA1) and decreases across the long axis (ventral < dorsal). These results have important implications for models of hippocampal function and suggest that activity sparsity is a preserved property in the hippocampal system across cognitive settings.

neuroscience↗

bioRxiv2022

Gradual cerebral hypoperfusion in a knock-in mouse model of Alzheimer's disease triggers cortical network dysfunctions

Alzheimers disease (AD) is characterized neuropathologically by amyloid-{beta} (A{beta}) plaques and neurofibrillary tangles. Vascular pathology caused by chronic cerebral hypoperfusion (HP) is hypothesised to exacerbate AD pathology and has emerged as an increasing cause of age-related cognitive impairment. In this study we examined the effects of gradual cerebral HP on cognitive dysfunction, A{beta} pathology, microgliosis, and cortical network dynamics in C57BL/6J mice and a single App knock-in mouse model of AD (AppNL-G-F). We performed unilateral common carotid artery gradual occlusion (UCAgO) in two-month-old mice using an ameroid constrictor. At 4 months of age, animals were tested in a behavioral battery consisting of tests of spatial learning and memory (Morris water task), recognition memory (novel object recognition task), and motor coordination (balance beam). Following behavioural testing, in vivo mesoscale wide-field voltage imaging was done to assess cortical functional connectivity and sensory-evoked cortical activity, and brains were harvested for pathology characterization using immunohistochemistry. We found that UCAgO reduced cerebral blood flow (CBF) in the occluded hemisphere (OH), however, subtle behavioural deficits were observed due to HP. A dissociative effect of HP was observed in resting-state functional connectivity analysis, where HP led to hyper-connectivity in C57 mice and hypo-connectivity in App mice. Interestingly, sensory stimulation of limbs contralateral to OH revealed hyper-cortical activations in the non-occluded hemisphere of C57 HP mice, however, hypo-cortical activations were observed in App HP mice. Furthermore, we found that the UCAgO increased cortical and hippocampal microgliosis in both hemispheres of C57 and App mice, a bilateral increase in A{beta} deposition was only observed in App mice. These results suggest that gradual cerebral HP leads to cortical network alterations in AD, which is partly mediated via activation of microglia.

neuroscience↗

bioRxiv2021

Multi-Dimensional Reduction Clustering of Complex Carbohydrates Reveal Tissue Metabolism, Heterogeneity and Histopathology

Formalin-fixed paraffin-embedded (FFPE) human tissues represent the world's largest collection of accessible clinical specimens with matched, well-annotated clinical course for disease progression. Currently, FFPE sections are limited to low throughput histo- and immunological assessments. Extracting largescale molecular information remains a major technological barrier to uncover the vast potential within FFPE specimens for translation and clinical research. Two critical but understudied facets of glucose metabolism are anabolic pathways for glycogen and N-linked glycan biosynthesis. Together, these complex carbohydrates represent bioenergetics, protein-structure function, and tissue architecture in human biology. Herein, we report the high-dimensional Metabolomics-Assisted Digital pathology Imaging (Madi) workflow that combines matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) with machine learning for the comprehensive assessment of tissue heterogeneity, histopathology, and metabolism in human FFPE sections. In normal human tissue sections, Madi accurately identifies anatomical regions within liver and the brain. In human lung diseases, Madi accurately predicts major lung pathologies such as honeycomb change, late-stage fibrosis, diffuse alveolar damage (DAD), and acute fibrinous and organizing pneumonia (AFOP) from idiopathic pulmonary fibrosis (IPF) and COVID-19 pneumonia specimens with precision. In depth pathway enrichment analyses reveal unique metabolic pathways are associated with distinct pathological regions, which highlight aberrant complex carbohydrate metabolism as a previously unknown molecular event associated with disease progression that could hold key to future therapeutic interventions.

systems biology↗

bioRxiv2021

Behaviour-driven Arc expression is greater in dorsal than ventral CA1 regardless of task or sex differences.

Evidence from genetic, behavioural, anatomical, and physiological study suggests that the hippocampus functionally differs across its longitudinal (dorsoventral or septotemporal) axis. Although, how to best characterize functional and representational differences in the hippocampus across its long axis remains unclear. While some suggest that the hippocampus can be divided into dorsal and ventral subregions that support distinct cognitive functions, others posit that these regions vary in their granularity of representation, wherein spatial-temporal resolution decreases in the ventral (temporal) direction. Importantly, the cognitive and granular hypotheses make distinct predictions on cellular recruitment dynamics under conditions when animals perform tasks with qualitatively different cognitive-behavioural demands. The cognitive function account implies that dorsal and ventral cellular recruitment differs depending on relevant behavioural demands, while the granularity account suggests similar recruitment dynamics regardless of the nature of the task performed. Here, we quantified cellular recruitment with the immediate early gene (IEG) Arc across the entire longitudinal CA1 axis in female and male rats performing spatial- and fear-guided memory tasks. Our results show that recruitment is greater in dorsal than ventral CA1 regardless of task or sex. This experimentum crucis leads to the strong inference that the granularity hypothesis for functional differences across the longitudinal axis in the rodent hippocampus is correct.

neuroscience↗

bioRxiv2020

Repeated multi-domain, but not single-domain, cognitive training prevents cognitive decline and amyloid pathology found in the APPNL-G-F mouse model of Alzheimer disease

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may prevent/ or delay the progression of various neurodegenerative diseases including Alzheimers disease (AD). To investigate this protective effect, APPNL-G-F/NL-G-F mice at 3 months of age were exposed to repeated, single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, 9 & 12 months of age. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for cognitive training groups and control group. After completion of behavioral testing, mice were sacrificed, and their brains were assessed for pathology. AppNL-G-F mice given multi-domain cognitive training compared to APPNL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. There were mild reductions in microglosis in the brain of APPNL-G-F mice with singledomain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

animal behavior and cognition↗

bioRxiv2017

A variant of the Morris water task for assessing learning and memory processes in mice

The Morris water task (MWT) is commonly used to assess rodent spatial learning and memory. Our goal was to develop a 3-phase variant of the hidden goal water task to assess old and new spatial memories acquired in the same context using various measures of spatial learning in C57BL/6 mice. In the first phase, mice were pre-trained to an initially hidden location. The second phase consisted of a massed training session to a new location in the same apparatus and context. The final phase consisted of a competition test between the original and new platform locations. AppNL-G-F/NL-G-F mice, a novel transgenic mouse model for Alzheimers disease (AD), were also used as an independent variable to validate this 3-phase variant of MWT. The results of the present study showed that C57 mice acquired and retained both the old and new location representations; however, AppNL-G-F/NL-G-F mice retained a recently acquired spatial memory but did not remember the old location acquired in the same apparatus and context. The results showed that C57 mice can show precise place learning and memory with the right amount of training and acquire and retain multiple spatial memory locations in the same environment whereas this ability was impaired in AppNL-G-F/NL-G-F mice. In the visible platform test, however, all groups of mice showed normal sensorimotor ability and motivation. These findings indicate that this new version of the MWT provides a robust way for assessment of old and new memories in mice. This paradigm could also be exploited to assess manipulations of neural circuits implicated in learning and memory processes as well as for research investigating human brain diseases.

neuroscience↗

bioRxiv2017

Gradual Cerebral Hypoperfusion Impair Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer pathology.

neuroscience↗