Dissertation Defense Announcement:
A novel dopamine depletion paradigm: Investigation of progressive circuit dysfunction in Parkinson’s disease
Carnegie Mellon University
Department of Biological Sciences
Monday, August 20th, 2018
Mellon Institute Social Room (328)
The development of animal models of Parkinson’s disease (PD) and assessing their electrophysiological differences has played a critical role in our understanding of basal ganglia function and the underlying mechanisms of PD. The wide range of animal models available and the quest to explore new ways to recover motor function have greatly enhanced our understanding of the remarkable reorganization that occurs in the brain following dopamine neurodegeneration. However, it remains unclear how and when pathophysiological features develop during the progression of the disease; information that could be critical to advancing the development of disease-modifying therapies. In order to address this question, we developed a novel paradigm for modeling progressive dopamine loss and used this paradigm, in addition to other well-studied animal models of PD, to investigate how and when basal ganglia activity changes in PD. First, we developed a gradual dopamine depletion mouse model by injecting multiple low doses of 6-OHDA over months to better recapitulate the slow progression of dopamine loss seen in PD. Behavioral assessment revealed a differential degradation of motor symptoms, with vertical movement declining linearly while horizontal movement remained robust until late stages. Interestingly, we found that motor coordination was significantly less impaired in animals that had undergone gradual depletions as opposed to acute depletions. These results establish a gradual depletion paradigm that can be used to study changes at various stages of dopamine loss, while modeling the progressive degeneration in PD so as not to preclude any compensatory plasticity that may be missing in more acute models. Next, we demonstrated a stereotyped, hierarchical progression of pathophysiology in the output nucleus of the basal ganglia using a number of animal models of PD. Briefly, firing rate changes occurred first at early stages of dopamine loss, followed by changes in firing pattern at more intermediate stages. The progression of pathophysiology was similar between two mechanistically different models of PD and end stage pathophysiology was similar regardless of the rate or lateralization of depletion. These results provide the first quantitative analysis of the trajectory with which the basal ganglia output breaks down over the course of progressive dopamine depletion. Taken together, these results demonstrate the complex interplay between the onset and progression of various motor deficits and pathological basal ganglia activity that develop due to the progressive degeneration of dopamine.
Dr. Aryn Gittis (Advisor)
Dr. Sandra Kuhlman
Dr. Alison Barth
Dr. Robert Turner
Department of Neurobiology
Presents a Special Seminar:
“Imaging Brain Anatomy, Function and Disease in Common Marmosets”
Afonso C. Silva, Ph.D.
Senior Investigator, Intramural Research Program
Chief, Section on Cerebral Microcirculation
Laboratory of Functional and Molecular Imaging
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health (NIH)
Friday, August 24, 2018
Dissertation Defense Announcement:
In vivo imaging to characterize dynamic tissue responses after neural electrode implantation
University of Pittsburgh
Department of Bioengineering
Wednesday, August 29, 2018
Benedum Hall 102
Implantable neural electrodes are promising technologies to restore motor, sensory, and cognitive function in many neural pathologies through brain-computer interfacing (BCI). Many BCI applications require electrode implantation within neural tissue to resolve and or modulate the physiological activity of individual neurons via electrical recording and stimulation. This invasive implantation leads to acute and long-term deterioration of both the electrode device as well as the neurons surrounding the device. Ultimately, damage to the electrode and neural tissue results in electrode recording failure within the first years after implantation.
Many strategies to improve BCI longevity focus on mitigating tissue damage through improving neuronal survival or reducing inflammatory activity around implants. Despite incremental improvements, electrode failure persists as an obstacle to wide-spread clinical deployment of BCIs. This can be partly attributed to an incomplete understanding of the biological correlates of recording performance. These correlates have largely been identified through post-mortem histological staining, which cannot capture dynamic changes in cellular physiology and morphology.
In the following dissertation, we use longitudinal 2-photon in vivo imaging to quantify how neurons, microglia, and meningeal immune cells are affected by an intracortical electrode during and after implantation in mouse cortex. We go beyond conventional histological techniques to show the time-course of neuronal injury and microglial recruitment after implantation. Neuronal injury occurs instantaneously, with prolonged, high calcium levels evident in neurons within 100 µm of implants. Microglial activation occurs within minutes of implantation and subsequent microglial encapsulation of electrodes can be modulated by bioactive surface coatings. Within the first day post-implant, there is high trafficking of peripheral immune cells through venules at the surface of the brain as well as along the electrode’s shank at the surface of the brain. Over the next month, calcium activity in neurons increases while the collagenous meningeal tissues at the surface of the brain thicken. We further show that meningeal thickening can have profound implications for devices implanted in higher order pre-clinical models for neural interfaces as well. In sum, these results define new potential therapeutic targets and windows that could improve the longevity of implantable neural electrodes.