Vulnerability of the ascending arousal network to alpha-synuclein pathology

Cognitive fluctuations –termed “the Lewy Body Roller Coaster” by some families – are a debilitating symptom of Lewy body disorders (LBD), an Alzheimer’s disease related disorder that includes Parkinson’s Disease dementia and Dementia with Lewy Bodies. These unpredictable cognitive changes often lead to the loss of

independence in patients that could otherwise function. They are characterized by dramatic changes in two key domains: attention (ability to focus/think) and arousal (ability to stay alert/awake). Presence of fluctuations are a key feature used to diagnose LBD. Despite this, a basic understanding of fluctuations is lacking.

Our long-term goal is to determine the underlying mechanisms responsible for cognitive fluctuations in LBD such that targeted, effective treatments can be developed. Animal models allow induction of pathology in restricted brain circuits, providing the opportunity to address key basic and translational questions regarding

the origin of variability in attention and arousal. In this proposal, we will use injection of the fibrillar form of alpha-synuclein, the protein associated with LBD, into one hub of the brainstem ascending arousal network which is highly affected in patients with this disease. We will use mouse models to test the overarching

hypothesis that alpha-synuclein differentially impacts large projecting neurons in the brainstem that orchestrate brain-wide networks necessary for attention and maintenance of arousal. In Aim 1 we will evaluate which cells are vulnerable to pathology. We will focus on one brainstem region, the Locus Coeruleus, which shows

pathology in almost all patients with LBD. We will count cells and use live imaging to directly track changes in axons from this arousal hub. Then, in Aim 2 and 3 we will determine how alpha-synuclein inclusions affect arousal and attention, respectively. In Aim 2 we will evaluate arousal using continuous EEG in the context of

time-of-day, as well as after exposure to novelty in the home cage. In Aim 3, we will evaluate cognitive variability using a repeatable timing-task combined with pupillometry and imaging at the single-cell level. This proposal uses a combination of translatable non-invasive techniques (EEG, pupillometry) with powerful

laboratory methods able to probe individual neuronal activity. The findings will help us better explain findings seen in human patients. Understanding the processes occurring during cognitive fluctuations is key to eventually developing treatment targets, including non-invasive neuromodulation of abnormal neuronal activity

and pharmacological modulation of identified neuronal populations.