Research at the Khoshbouei Lab
The Khoshbouei Lab investigates the intricate role of dopamine transmission in neurological and neuropsychiatric diseases, with a particular focus on how midbrain dopamine neuron activity influences both central and peripheral functions. A major research theme is deciphering the interplay between dopamine transporter (DAT) activity, dopamine neurotransmission, and immune regulation through brain-body circuits.
Clinical Research at the Khoshbouei Lab:
A key breakthrough from the lab is the development of a biomarker that reliably detects Parkinson’s disease (PD), tracks disease progression, and evaluates therapeutic efficacy. This discovery has significant implications for early diagnosis, personalized treatment strategies, and monitoring the effectiveness of interventions in PD patients.
Dopamine Transporter (DAT) as a Peripheral Biomarker for PD: One of the lab’s most innovative findings is the connection between dopamine neuronal loss in the brain and increased DAT expression in peripheral immune cells. While the exact mechanisms driving this relationship is being studied at the lab (see below), this biomarker provides a non-invasive approach to understanding disease progression. Unlike traditional diagnostic methods that focus solely on central nervous system (CNS) dysfunction, our research highlights the peripheral immune system as a critical biomarker in PD pathology. Dopamine signaling dysfunction has long been associated with various neurological and psychiatric conditions, but emerging evidence indicates that altered CNS dopamine transmission is not confined to the CNS, it also affects peripheral immunity. DAT, a key regulator of dopamine homeostasis in the brain, is now recognized as an important link between inflammation and dopamine dysregulation in PD.
The Role of Peripheral DAT in Neuroimmune Communication: The dopamine transporter (DAT) is an essential protein responsible for clearing extracellular dopamine by transporting it back into neurons for storage and reuse. While DAT has traditionally been studied in the CNS, recent research from the Khoshbouei Lab has shown that peripheral immune cells, such as monocytes and macrophages, also express DAT. This bidirectional communication between the CNS and the peripheral immune system suggests that changes in dopamine levels in the brain may directly influence immune function. Our studies have demonstrated that in drug-naïve PD patients, there is a paradoxical increase in DAT expression in peripheral blood mononuclear cells (PBMCs), while DAT levels in the CNS decrease due to dopamine neuronal loss. This suggests a compensatory mechanism where the peripheral immune system responds to dopamine neuron degeneration, potentially exacerbating inflammation and disease progression. By unraveling the mechanisms that drive DAT dysregulation in peripheral immune cells, the Khoshbouei Lab is developing novel methodologies and tools to:
Enhance early detection of PD through peripheral biomarkers.
Monitor disease progression using non-invasive blood tests.
Evaluate therapeutic efficacy by tracking changes in immune cell DAT expression.
Develop alternative treatment strategies that target peripheral DAT-expressing immune cells to modulate peripheral inflammation.
Understanding the DAT-driven feedback loop between the CNS and peripheral immune system opens new possibilities for intervening in PD at earlier stages. These insights may pave the way for targeted immunotherapies that prevent or slow disease progression by regulating dopamine transmission in both the brain and the immune system.
Basic science research at the Khoshbouei lab
Methamphetamine, Dopamine, and the Reward-Immune Connection: A Window into Brain-Body Dynamics: One major research area in the lab investigates how methamphetamine alters DAT-dependent midbrain dopamine neuronal activity, dopamine transmission and disrupts the natural reward pathway. By dissecting the effects of psychostimulants on dopamine neurotransmission, the lab is uncovering how methamphetamine-induced changes in the brain extend far beyond the CNS, directly impacting the body’s immune system. These findings reveal a dynamic, two-way communication between the brain and the periphery, offering new insights into addiction’s profound immunological consequences and potential therapeutic interventions.
Midbrain Dopamine Neurons as the Command Center for Peripheral Immunity: Imagine midbrain dopamine neurons as a master conductor, orchestrating not only motivation and reward but also immune responses. The Khoshbouei Lab has made groundbreaking discoveries in mapping the precise neural circuits through which dopamine neurons in the midbrain communicate with the immune system, particularly the spleen, a critical immune organ. Using Cre-dependent viral tracers and chemogenetic approaches, the lab has traced a brain-to-body pathway. Our research shows that dopamine neurons project to the dorsal vagal complex (DVC), a key brainstem region that acts as a relay station for neural signals to peripheral organs, such as lung, gut, heart and spleen. Signals from the DVC are then transmitted through the celiac ganglion to the spleen, influencing immune cell populations and overall immune function. This pioneering work sheds new light on conditions where both the nervous and immune systems are dysregulated, such as Parkinson’s disease (PD), methamphetamine addiction, and neuroimmune disorders. While dopamine’s role in CNS function is well known, these findings provide critical insights into its underexplored influence on immune regulation.
Parkinson’s Disease and the Gut-Brain Connection: Another major project in the Khoshbouei Lab examines the role of enteric nervous system (ENS)-resident macrophages in Parkinson’s-like gut pathology. Misfolded alpha-synuclein (αSyn) aggregates in the ENS are a hallmark of PD, but their precise role in disease progression remains unclear. The lab has demonstrated that ENS macrophages initially attempt to clear αSyn aggregates through complement C1q-dependent engulfment. However, prolonged exposure to these toxic protein deposits leads to macrophage exhaustion, exacerbating enteric neuropathology and gut dysfunction. This research highlights a crucial link between peripheral immune responses and neurodegeneration, emphasizing the gut’s potential role as a therapeutic target in PD. By modulating complement signaling and macrophage activity, the lab aims to develop new strategies to mitigate PD-related gastrointestinal symptoms and better understand how peripheral immune dysfunction contributes to neurodegeneration.
Exploring the Frontiers of Neuroscience and Immunology: Through these innovative clinical and preclinical research projects, the Khoshbouei Lab is uncovering the complex neural circuits that connect the brain and immune system, revealing novel mechanisms underlying neuroimmune interactions. These discoveries hold transformative implications for understanding and treating neurological disorders such as Parkinson’s disease, addiction, and immune-related conditions. By pushing the boundaries of scientific knowledge, the lab is working toward developing novel therapies that improve the lives of individuals affected by neuropsychiatric and immune-related diseases. Stay tuned as we continue to explore the fascinating interplay between the brain, body, and immune system, one discovery at a time!