Link between serotonin neuron specific tau pathology and emotional dysregulation

Abstract

At present, half a million Canadians are suffering from dementia and dementia related disorders costing approximately $11 billion annually and putting additional strain on a struggling health care system. According to the World Health Organization, 70% of dementia diagnoses can be attributed to Alzheimer's Disease (AD) which is a progressive neurodegenerative disease. AD is detectable in elderly people, mainly over the age of 60, with two-thirds of diagnosed patients being women. Cognitive and memory dysfunctions are the most commonly recognized symptoms of AD, however, neuropsychiatric symptoms such as social withdrawal, anxiety and depression are observed decades prior to cognitive impairment. These behavioural changes are associated with increased conversion from mild cognitive impairment to AD. Evidence from post-mortem AD tissue indicates that the dorsal raphe nucleus (DRN), which contains the majority of serotonin neurons, is one of the initial sites to display tau pathology in the AD brain. Serotonin neurons are critical for emotional regulation and are degenerated in the AD brain. Here, using a viral approach, we developed a mouse model that expresses a tau isoform that is prone to hyperphosphorylation (hTauP301L) specifically in serotonin neurons. We performed a comprehensive behavioural analysis to determine the effects of pathological tau expression in serotonin neurons on anxiety-like, anhedonia-like behaviours, sociability, stress coping strategies and cognition. We found that about fifty percent of serotonin neurons in DRN expressed hTauP301L without changing serotonin density. The hTauP301L group mice showed increased anxiety-like behaviour, hyperactivity, sociability changes, and active stress coping strategy. Lastly, female hTauP301L mice showed slight impairment in contextual information processing and spatial working memory. Understanding the mechanisms underlying neuropsychiatric symptoms and teasing out any causal relationship has the potential to significantly facilitate our understanding of AD symptomatology and pathology.