Defining the Effects of A-Synuclein Pathology on the Amygdala Circuitry: Relevance to Neuropsychiatric Dysfunction in Parkinson s Disease
Abstract
Parkinson s disease (PD) is a complex disorder in which our movement, emotion, and cognitive capacity are affected. The progressive loss of function in these three domains reflects the development of pathological changes that affect the function of the brain regions responsible for controlling them. One of the featured neuropathologies in Parkinson s brain is the abnormal accumulation of alpha-synuclein in neurons. Though the pathologic factors that promote alpha-synuclein aggregation remain unknown, once formed these aggregates spread between neurons in the brain and thus are thought to be critical in disease progression. This study aims to define what happens at the molecular and cellular level when alpha-synuclein aggregation accumulates in a key brain region, the amygdala. The amygdala is the brain area that controls emotion and that has been shown to be particularly vulnerable to alpha-synuclein accumulation. We believe that alterations in the cellular and network function of the amygdala are caused by alpha-synuclein accumulation resulting in changes in emotion. To test this idea, we propose to study alterations in the amygdala function and its behavioral consequence as the alpha-synuclein pathology develops over time in the brain. To achieve these goals, we will inject small fragments of abnormally aggregated alpha-synuclein into the mouse brain, where these fragments work as seeds, causing the accumulation of the alpha-synuclein that is naturally found in the amygdala in a time-dependent manner. We will then establish how the alpha-synuclein aggregates alter the function of the neurons in the amygdala and their effects on the behavior of the mice at a series of time points that mimic different stages of PD. Our preliminary studies using this approach show an increased activity of amygdala neurons associated with alpha-synuclein pathology. This observation strongly supports our idea and warranting the proposed research. We expect to demonstrate that the development of alpha-synuclein pathology, as it occurs in PD, alters the activity of neurons in the amygdala, leading to emotion dysregulation. We also expect to show that alpha-synuclein pathology significantly decreases cognitive control of the activity of amygdala neurons through a reduced connection between the prefrontal cortex and the amygdala, an observation that has been reported in clinical studies in PD patients. Our proposed research will provide deeper insights into how the amygdala is affected by alpha-synuclein pathology as PD progresses. This information could guide the application of noninvasive therapies (e.g., transcranial magnetic stimulation) or the repurposing of already-approved medicines (e.g., anti-epileptic drugs) to modulate the amygdala activity and prevent or alleviate neuropsychiatric symptoms in PD patients. Altogether, our study shall not only improve our understanding of the basic biology of non-motor symptoms in PD (a FY20 Neurotoxin Exposure Treatment Parkinson s Focus Area), but also provide insight into the type of cellular changes associated with psychiatric deficits in general. It is worth mentioning that Veterans who suffer from posttraumatic stress disorder (a pathological condition caused by an increased amygdala activity) are prone to develop PD later in life. Although it remains unclear if a shared biology between posttraumatic stress disorder and PD exists, defining biological changes leading to the dysfunction of the amygdala will be of relevance to these two devastating disorders. Altogether, our research is relevant to all individuals affected by PD, including their families, as cognitive and emotion deficits are common and represent an increasing burden as the disease worsens.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110943
Entities
People
- Hong-yuan Chu
Organizations
- United States Army
- Van Andel Institute