Biology subjects

Lacoursiere, S. G.

Publications and source records attributed to Lacoursiere, S. G..

5 recordsLinked to original sources

bioRxiv2022

Generation of a hybrid AppNL-G-F/NL-G-F xThy1-GCaMP6s+/- Alzheimer disease mouse mitigates the behavioral and hippocampal encoding deficits of APP knock-in mutations of AppNL-G-F/NL-G-F mice

In contrast to most transgenic mouse models of Alzheimer disease (AD), knock-in mice expressing familial AD-linked mutations of the amyloid precursor protein (App) gene exhibit stereotypical age-dependent amyloid beta (A{beta}) pathology and cognitive impairment without physiologically unrealistic App overexpression. This study investigated the effect of familial AD-linked App mutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity, AppNL-G-F/NL-G-F knock-in (APPki) mice were crossed with Thy1-GCaMP6s+/- (C-TG) mice to generate AppNL-G-F/NL-G-FxThy1-GCaMP6s+/- (A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited A{beta} pathology in the hippocampus. In several configurations of an air-induced running task, A-TG mice and C-TG mice were equally successful in learning to run or to stay immobile. In the Morris water place test, A-TG mice were impaired, but learned the task. Comparisons of hippocampal CA1 neuronal activity in the air-induced running task showed that A-TG mice displayed neuronal hypoactivity both during movement and immobility. A-TG mice and C-TG CA1 neuronal encoding of distance or time in the air induced running task were not different. These results suggest that knock-in of familial AD-linked mutations in A-TG mice results in A{beta} pathology, neuronal hypoactivity, and cognitive impairment without severely affecting CA1 neuronal encoding. In comparison to APPki mice, A-TG mice had less severe AD-like memory impairments at 12 months of age (Saito et al., 2014; Mehla et al., 2019), suggesting that the disease onset was delayed in A-TG mice. The effect of APP mutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.

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↗

bioRxiv2022

Hippocampal damage causes retrograde amnesia for objects' visual, but not odour, properties

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made using N-methyl-D-aspartate (NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67-97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, does not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories.

neuroscience↗

bioRxiv2022

Amyloid-β seeding effects are dependent on the presence of knock-in genes in the AppNL-G-F mice.

Alzheimers disease (AD) is characterized by the prion-like propagation of amyloid-{beta} (A{beta}). However, the role of A{beta} in cognitive impairment is still unclear. To determine the causal role of A{beta} in AD, we intracerebrally seeded the entorhinal cortex of two-month-old AppNL-G-F mouse model with an A{beta} peptide derived from patients who died from rapidly progressing AD. When the mice were three and six months of age, or one- and four-months following seeding, respectively, spatial learning and memory were tested using the Morris water task. Immunohistochemical labeling showed seeding with the A{beta} seed increased plaque size one month following seeding, but reduced plaque counts four months following injection compared to the control seeded mice. A significant increase in microgliosis was found. However, we found no correlation between pathology and spatial performance. The results of the present study show that seeding human tissue with or without A{beta} alters learning and memory ability, A{beta} plaque deposition, plaque size, and microgliosis in the AppNL-G-F knock-in model, and these effects are dependent on the presence of a humanized App gene and the presence of A{beta} in the seed. But these pathological changes were not initially causal in memory impairment.

animal behavior and cognition↗

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↗