Welcome to the Bishop Lab!
Welcome to the Bishop Lab!
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What is Parkinson’s disease?
Parkinson’s disease is the most common neurodegenerative movement disorder, and the second most common neurodegenerative disorder overall, impacting more than 8.5 million people globally. Parkinson’s disease is characterized by the loss of dopamine in the brain, impairing patients’ ability to initiate, coordinate, and execute movements.
While there is currently no cure for Parkinson’s disease, most patients will be prescribed a medication called Levodopa or L-DOPA, which effectively replenishes the lost dopamine in the brain and restores the ability to move. Unfortunately, within 10 years of L-DOPA treatment, up to 90% of patients will develop abnormal involuntary movements in a syndrome called L-DOPA-induced dyskinesia, as well as a myriad of nonmotor symptoms, including pain, autonomic dysfunction, cognitive impairments, and neuropsychiatric disturbances.
What do we study?
The research in our laboratory aims to optimize existing pharmacological and non-pharmacological therapies for Parkinson’s disease by targeting various aspects of disease and treatment-related neuroplasticity. To do so, we employ various lesion and proteinopathy models in rats, combined with behavioral, neurochemical, and neuroanatomical techniques, to characterize the role of different neurotransmitter systems and neurocircuits in Parkinson’s symptoms and treatment-related side effects. The overarching goal of our research is to identify viable targets for novel therapies that would provide patients with viable treatment options through the end stages of the disease.
Techniques
Techniques
6-OHDA Lesion Model
To induce a Parkinsonian model, we can use a neurotoxin called 6-hydroxydopamine (6-OHDA), which is taken up by dopamine neurons in a part of the brain called the substantia nigra pars compacta. The toxin causes severe metabolic dysfunction and oxidative stress, leading to cell death. Lesioned rats exhibit motor deficits similar to those of the human disease, which can be reversed with pharmacological therapies.
Alpha-Synuclein Overexpression Model
Alpha-synuclein is the primary protein involved in the pathological inclusions that create Lewy bodies in Parkinson’s disease. We can employ a AAV-mediated overexpression of human alpha-synuclein to study the effects of a progressive proteinopathy in our animal model.
Abrnomal Involuntary Movements (AIMs)
The AIMs test is a behavioral test used to measure symptoms of L-DOPA-induced dyskinesia (LID). We can induce this behavioral phenotype with L-DOPA treatment, and subsequently, we can study the effects of various pharmacological, lifestyle, or chemogenetic interventions on LID.
Motor Performance Tests
We use various behavioral assays, including the forepaw-adjusting step test, rotarod, CatWalk gait analysis, and locomotor chambers, to assess motor performance in our Parkinsonian animals. We can study the effects of dopamine denervation and treatment-related benefits on motor function.
Nonmotor Tests
We use various behavioral tasks to evaluate nonmotor symptoms common in Parkinson’s disease such as cognitive impairments, psychosis-like behaviors, anxiety-like behaviors, pain, and impulse control disorders. Assays include multimodal prepulse inhibition, operant chamber learning tasks, open field, elevated plus maze, novelty-induced hypophagia, and conditioned place preference.
In Vivo Microdialysis
In vivo microdialysis allows us to collect cerebral spinal fluid samples from animals while they are awake and moving around. By surgically implanting a probe in a specific brain region, we can measure changes in the concentration of neurotransmitters over an extended period of time related to pharmacological or behavioral interventions.
High Performance Liquid Chromatography
High-performance liquid chromatography (HPLC) is a neurochemical assay that allows us to measure the concentration of neurotransmitters in tissue or cerebrospinal fluid samples.
Immunohistochemistry & Immunifluorenscence
We use immunohistochemical and immunofluorescent stains to visualize structural and molecular components of neurons involved in brain regions or circuits related to motor and nonmotor behaviors in Parkinson’s disease.
Gene and Protein Analysis
We use various molecular assays, including reverse-transcription PCR, western blots, ELISA, and RNA scope, to analyze gene and protein expression in the brain.
Chemogenetics
Chemogenetics is a strategy we use to employ designer receptors exclusively activated by designer drugs (DREADDs). We use viral vectors to express designer receptors on neurons in specific brain regions to modulate the activity of the neural circuit.
Current Projects
Serotonin Transporter Involvement in L-DOPA-Induced Dyskinesia
Serotonin Transporter Involvement in L-DOPA-Induced Dyskinesia
Using a combination of genetic and pharmacological strategies, we are investigating the role of the serotonin transporter (SERT) in the development and expression of L-DOPA-induced dyskinesia (LID) in a 6-OHDA lesion model of Parkinson’s disease. To date, we have employed a prophylactic and interventional genetic knockdown of SERT to attenuate LID development and reduce LID severity, respectively. Additionally, we have used the selective serotonin reuptake inhibitor (SSRI), citalopram, to investigate the regional effects of SERT-blockade on LID and motor performance.
See related publications for more information:
Development & Characterization of Combined Lesion/Alpha-Synuclein model of Parkinson's Disease
Development & Characterization of Combined Lesion/Alpha-Synuclein model of Parkinson's Disease
While lesion models and proteinopathy models each offer unique benefits to studying various aspects of Parkinson’s disease, each has inherent limitations. Lesion models allow us to study a severely dopamine-depleted state, produce an overt behavioral phenotype, and are highly responsive to dopamine replacement treatments. However, these models are static, and pathology and symptoms do not progress over a long period of time, as happens in the human disease state. Proteinopathy models do involve a progressive pathology, but they often do not produce enough dopamine cell death to yield a behavioral phenotype in the form of motor deficits and LID that can be readily studied. Therefore, our lab is pioneering a novel animal model that combines a neurotoxic 6-OHDA lesion with an alpha-synuclein overexpression model. This will allow us to study a progressive pathological process under a level of dopamine denervation that results in motor deficit and responsiveness to L-DOPA treatment.
See related publications for more information:
Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo
Characterisation of functional deficits induced by AAV overexpression of alpha-synuclein in rats
Investigating the Role of Serotonin and Glutamate in L-DOPA-Induced Dyskinesia
Investigating the Role of Serotonin and Glutamate in L-DOPA-Induced Dyskinesia
Recent evidence has supported a role for convergent serotonin and glutamate neuroplasticity in the development and expression of LID. Unfortunately, the mechanisms by which dysregulation in these neurotransmitter systems drives LID are poorly understood. To further study this, we employ a novel genetic knockdown of the synaptic vesicular protein, vesicular glutamate transporter 3 (VGLUT3) in serotonin projections in the striatum of 6-OHDA lesioned rats. We can study the behavioral effects of the intervention as well as the structural and neurochemical characteristics of this model.
See related publications for more information:
Maladaptive Serotonin Neuroplasticity in the Development of Cognitive Impairments and Psychosis in Parkinson's Disease
Maladaptive Serotonin Neuroplasticity in the Development of Cognitive Impairments and Psychosis in Parkinson's Disease
Nearly all PD patients experience disease or treatment-related nonmotor symptoms. Two of the most common and most troublesome symptoms are cognitive impairments and neuropsychiatric disturbances. Importantly, these symptoms are often unresponsive to or exacerbated by common dopamine replacement therapies like L-DOPA. Evidence from humans and animal models has suggested a key role of maladaptive neuroplasticity within serotonin circuits in the prefrontal cortex in these nonmotor symptoms, though the underlying mechanisms are not yet known. To further study this, we use a chemogenetic strategy in 6-OHDA lesioned rats whereby designer receptors exclusively activated by designer drugs (DREADDs) are expressed on serotonin cells in the prefrontal cortex. This allows us to modulate the activity of specific neural circuits to investigate the effects on cognitive impairments and psychosis-like behaviors, as well as neuroanatomical and neurochemical changes.
See related publications for more information:
Non-Motor Symptoms Burden in Early Stages of Parkinson's Disease
Psychotic complications of long term levodopa treatment of Parkinson's disease
Pharmacological Targeting of the Serotonin System to Reduce L-DOPA-Induced Dyskinesia
Pharmacological Targeting of the Serotonin System to Reduce L-DOPA-Induced Dyskinesia
It is well-established that as dopamine neurons degenerate in Parkinson’s disease, serotonin neurons can uptake exogenously administered L-DOPA, releasing it as dopamine. Although this is beneficial early on, allowing patients’ motor ability to be restored, because serotonin neurons do not have dopamine-specific autoregulatory properties, the serotonin system can become hyper-innervated, resulting in an over-release of dopamine. This is believed to be a primary mechanism underlying the development of LID. Therefore, our lab tests various known and experimental pharmacological agents that target specific components of serotonin circuits to assess their antidyskinetic properties. The goal of these studies is to identify druggable targets for adjunctive treatments to L-DOPA that will reduce LID severity without compromising effects on motor performance.
See related publications for additional information:
Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats
The effects of Vilazodone, YL-0919 and Vortioxetine in hemiparkinsonian rats
Investigating the Reinforcing Properties od Dopaminergic Drugs in a Parkinson's Disease Model
Investigating the Reinforcing Properties od Dopaminergic Drugs in a Parkinson's Disease Model
Dopamine dysregulation syndrome (DDS) is a neuropsychiatric behavioral syndrome characterized by issues with impulse control associated with substance misuse and behavioral disturbances. Incidence of DDS in Parkinson’s disease is thought to be attributed to dopamine replacement with L-DOPA. We study DDS-related behaviors and neurochemical changes in 6-OHDA-lesioned rats by studying the effects of various dopaminergic drugs under conditions of dopamine loss and treatment with L-DOPA.
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