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Gradual Cerebral Hypoperfusion Impairs Fear Conditioning and Object Recognition Learning and Memory in Mice:
Jogender Mehla1, Sean Lacoursiere1, Emily Stuart1
1Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada.
Abstract:
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's disease pathology.
Insights
This study developed a mouse model of gradual cerebral hypoperfusion, revealing significant impairments in learning, memory, and motor functions. The model shows neurodegeneration and cholinergic deficits, making it useful for studying vascular dementia therapies.
Area of Science:
- Neuroscience
- Vascular Biology
- Animal Models
Background:
- Vascular dementia (VaD) poses a significant health challenge.
- Developing reliable animal models is crucial for understanding VaD pathogenesis and testing therapeutics.
- Gradual cerebral hypoperfusion is a key factor in VaD development.
Purpose of the Study:
- To establish and validate a mouse model of gradual cerebral hypoperfusion.
- To assess the impact of hypoperfusion on cognitive and motor functions.
- To investigate the underlying neuropathological changes, including neurodegeneration and cholinergic system alterations.
Main Methods:
- Male C57BL/6J mice underwent surgical procedures to induce gradual cerebral hypoperfusion via ameroid constrictor and carotid artery stenosis.
- Sham group controls received identical procedures without constrictions.
- Cognitive functions (fear conditioning, object recognition) and motor functions (balance beam test) were evaluated one month post-surgery.
- Brain tissues were analyzed using immunostaining and histology to assess neuronal health and neurotransmitter markers.
Main Results:
- Mice subjected to hypoperfusion exhibited significant impairments in learning, memory, and motor functions compared to sham controls.
- A decrease in choline acetyltransferase immunoreactivity was observed in the dorsal striatum and basal forebrain, indicating compromised cholinergic tone.
- Increased Fluoro-Jade positive neurons in the cerebral cortex, dorsal striatum, and hippocampus confirmed neurodegeneration.
Conclusions:
- The developed mouse model effectively replicates key features of vascular dementia, including cognitive and motor deficits and neuropathological changes.
- This model serves as a valuable tool for investigating therapeutic interventions for vascular dementia.
- It can also be used to explore the effects of microvascular occlusions on cognitive impairment in various pathological contexts, including Alzheimer's disease.
