Please join us in congratulating Dr. Kaustuv Saha and Danielle Sambo for receiving fellowships from the McKnight Brain Institute. The MBI Fellowships were established to support students and fellows conducting neuroscience and brain-related research in MBI affiliated laboratories. Two winners were selected and will each receive $60,000 ($30,000/year for two years). Three runner-ups were also selected and will each receive $30,000 ($15,000/year for two years).
Pre-Doctoral Fellow Runner-up:
Danielle Sambo, Department of Neuroscience
Mentor: Dr. Habibeh Khoshbouei
Sigma-1 receptor modulation of methamphetamine-induced behavioral responses and neuronal adaptations of dopaminergic neurons
Methamphetamine (METH) addiction is a major public health issue, with no effective FDA approved treatment options. METH is a highly addictive drug that has been shown to disrupt dopamine neurotransmission in the brain. Current reports support the interpretation that METH-induced neuronal injury may render METH users more susceptible to neurodegenerative pathologies such as Parkinson like symptoms or schizophrenia. The goal of this project is to identify target specific pharmacotherapies to alleviate the untoward consequences of METH. Recently an intracellular target for METH called the sigma-1 receptor (σ1R) has been identified. The σ1R is a chaperone protein that is activated by different ligands in an agonist-antagonist manner. Upon activation, the σ1R has been shown to regulate a variety of cellular functions and is considered to be neuroprotective in the brain. Interestingly, several σ1R ligands have been shown to reduce the behavioral effects of METH in rodents; however, the mechanism is largely unknown. Preliminary in vitro data in our lab suggest that the activation of the σ1R attenuates METHmediated changes in dopamine neurotransmission. The focus of this current study is to investigate the role of the σ1R in METH-mediated behavioral responses and activity of dopaminergic neurons in the brain. These findings will expand on our current findings that σ1R activation decreases METH-mediated dopamine neurotransmission. Through the completion of these studies, we are poised to determine whether σ1R is a potential therapeutic target for the treatment of METH addiction, and the long-term untoward consequences of METH.
Post-Doctoral Fellow Awardee:
Kaustuv Saha, Ph.D., Department of Neuroscience
Mentor: Dr. Habibeh Khoshbouei
How does alpha-synuclein regulate the excitability of dopamine neurons?
The greatest challenges in treatment of neuropsychiatric and neurodegenerative diseases, where brain dopamine levels are dysregulated, are to determine the underlying molecular mechanisms and to develop therapies addressing such mechanisms. Current therapies for Parkinson’s disease do not change the nature of the disease; they are shortlived and provide symptomatic relief. The long-term goal of this project is to understand the process of disease progression, which is required for the identification of disease-modifying therapies. One of the hallmarks of Parkinson’s disease is increased level of a protein called alpha-synuclein (a-syn). A-syn is found in Lewy bodies containing a-syn fibrillary aggregates. Limited information is available on how pathological levels and forms of asyn affect neuronal activity in general and dopaminergic neurons in specific. Under the mentorship of Dr. Habibeh Khoshbouei, I will be using patch-clamp electrophysiology, live cell microscopy and biochemical approaches to determine how various forms of a-syn influence the activity of mouse midbrain dopamine neurons and iPSC-derived human-like dopamine neurons obtained from a patient with Parkinson’s disease and a healthy control. The results of
this work will help us to understand the process of disease progression that can lead to identification of disease modifying therapeutic targets for the treatment of Parkinson’s disease.