Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Brown, Arthur

2nd Supervisor

Prado, Marco A M.

Co-Supervisor

Abstract

Mild traumatic brain injury (mTBI) increases the risk of Alzheimer’s disease. The early cholinergic decline in Alzheimer’s disease and cholinergic damage observed after TBI suggest a distinct role of this neural system in vulnerability to Alzheimer’s disease following TBI. This thesis evaluated the role of repetitive mTBI and cholinergic dysfunction in the development of cognitive deficits, specifically attentional deficits, and Alzheimer’s-related pathology in mice expressing humanized amyloid-beta and tau and a vesicular acetylcholine transporter knockdown to induce a mild cholinergic deficit. Using the rodent continuous performance test, it was shown that repetitive mTBI in the presence of an already vulnerable cholinergic system induced chronic, sex-specific attentional impairments. However, repetitive mTBI and cholinergic dysfunction alone did not induce significant deficits. Injured cholinergic deficient mice also exhibited an increase in degenerative hippocampal granules. These findings indicate the synergistic role of cholinergic dysfunction and mTBI in the development of behavioural deficits with aging.

Summary for Lay Audience

Alzheimer’s disease is a progressive age-related brain disease which is the leading cause of dementia – a disorder marked by gradual cognitive decline in memory, attention and thinking. A history of mild traumatic brain injury or concussions is known to increase the likelihood of developing Alzheimer’s disease and results in earlier disease onset. Key proteins and mechanisms dysregulated in Alzheimer’s disease, particularly amyloid-beta and tau proteins, are also abnormally accumulated following traumatic brain injury. The cholinergic system, one of the brain’s neurotransmitter systems involved in cognition, including attention, is particularly damaged in Alzheimer’s disease and following traumatic brain injury. My thesis evaluated how mild traumatic brain injury and reduced cholinergic function may interact in the later development of cognitive deficits and Alzheimer’s related pathology in mice. I used mice carrying human versions of the amyloid-beta and tau proteins to mimic key aspects of Alzheimer’s disease without artificially inducing Alzheimer’s disease. To induce a mild reduction in cholinergic signalling, mice with reduced levels of a protein crucial for cholinergic signalling were used. I specifically assessed attention which is the first non-memory domain affected in Alzheimer’s disease and critical in maintaining normal daily functioning. Attention was assessed using a rodent touchscreen behavioural system to administer an attention-based task, the continuous performance test, to the mice. Following repetitive mild traumatic brain injury mice with or without reduced cholinergic signalling were evaluated on the attention-based task at chronic timepoints to evaluate attentional performance as the mice age. Mild traumatic brain injury in the presence of reduced cholinergic signalling resulted in attentional deficits that worsened with aging, particularly in females. Repetitive mild traumatic brain injury and reduced cholinergic signalling had minimal effects on their own, suggesting that the combination of traumatic brain injury and cholinergic dysfunction is particularly detrimental to development of deficits. My thesis project shows that reduced cholinergic signalling following repetitive mild traumatic brain injury increases vulnerability to attention impairments and disease related pathology. These findings suggest that individuals with reduced cholinergic signalling, through use of anti-cholinergic drugs, for example, may be at greater risk for developing attentional deficits following repetitive traumatic brain injury.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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