Investigator:
Sammy Alhassen, PhD
Name of Institution:
The Regents of the University of California, Los Angeles
Project Title:
Circuit Mechanisms of Prefrontal Cognitive Impairments in Parkinson’s Disease Mouse Models
Investigator Bio:
Dr. Alhassen is a postdoctoral fellow in Dr. William Zeiger’s laboratory at the Department of Neurology, University of California, Los Angeles. Dr. Zeiger’s research explores the mechanisms of cortical circuit function in the healthy brain and how disruptions in these circuits contribute to the pathology and symptoms of neurological disorders. Dr. Alhassen earned his PhD in pharmacology from the University of California, Irvine, under the mentorship of Dr. Amal Alachkar. His doctoral research focused on non-dopaminergic treatments for the motor symptoms of Parkinson’s disease (PD), where he challenged traditional views of motor control.
His work suggested that even in dopamine-deprived states, motor activity could still be triggered in mouse models of PD. For his postdoctoral work, Dr. Alhassen has shifted his focus to the cognitive impairments associated with PD, a largely underexplored aspect of the disease. He is investigating how disease progression affects cortical circuit function, aiming to uncover the relationship between neuronal activity and disease pathology in vivo.
Objectives/Background:
Cognitive impairments are common in PD, affecting functions like memory, attention, and executive function. These problems are often linked to changes in the prefrontal cortex of the brain, which helps with decision-making and problem-solving. Two key features of PD are the accumulation of the protein a-synuclein and the progressive loss of dopamine-producing neurons. We still don’t fully understand how these disease-related changes cause memory and thinking problems. Gaining a better understanding of this relationship could provide critical insights into the mechanisms of the disease and potentially lead to more effective therapeutic strategies.
Methods/Design:
This study uses mouse models of PD to investigate how the loss of dopamine-making brain cells and the buildup of a harmful Parkinson’s related protein (a-synuclein) contribute to memory and thinking problems in PD. One group of mice will get a chemical (MPTP) that slowly kills dopamine-producing brain cells, while the other will receive a-synuclein pre-formed fibrils to model a-synuclein clumping in the prefrontal cortex (PFC, a particular region of the brain involved in cognitive function and memory). Cognitive performance will be assessed using a behavioral task measuring memory and thinking. During task performance, neural activity will be recorded from the PFC using miniaturized two-photon microscopy, allowing for real-time monitoring of neuronal activity across hundreds of cells. This approach will help us understand how the loss of dopamine-producing cells and irregular protein clusters of a-synuclein disrupt brain circuits and contribute to memory and thinking problems in Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
There are several gaps in our knowledge regarding how different aspects of the disease contribute to memory and thinking problems through distinct circuit mechanisms. The results from this study will explain the mechanisms by which the loss of dopamine-producing cells and a-synuclein pathology affect certain circuits in the brain that drive memory and thinking problems. This will translate into new insights into the cognitive challenges that patients face and may help design novel approaches or repurpose existing tools for brain stimulation to help relieve memory and thinking problems in patients.