BIDMC Investigators’ New Tool Tracks the Brain's Chemical Signals in Real Time
Research Opens New Opportunities for Understanding the Brain's Chemical Signals
BOSTON — Dopamine. Serotonin. Oxytocin. The brain is awash in chemical signals that help regulate everything from learning and memory to sleep to love. Yet despite these molecules’ importance, scientists still know surprisingly little about how all these signals work at the same time to determine the activity of neurons.
To begin answering this question, scientists at Beth Israel Deaconess Medical Center (BIDMC) have developed a tool to read out many of these signals simultaneously. The new approach, called Multiplexed Optical Recording of Sensors on a micro-Endoscope, or MORSE, provides what may be the most comprehensive real-time view yet of the brain's changing chemical environment, the researchers report in Neuron.
"Changes in these extracellular signals underlie fundamental processes in brain function and physiology, including learning and motivated behavior, circadian and diurnal rhythms, development, inflammation and degeneration," said co-corresponding author Mark L. Andermann, PhD, a professor of medicine and neuroscience in the Division of Endocrinology, Diabetes, and Metabolism at BIDMC. "Our approach offers a first step towards quantitative, real-time, high-dimensional tracking of brain fluid composition."
Individual neurons are bathed in a constantly shifting mixture of signaling molecules. At any given moment, a single neuron may be responding to a dozen or more chemical cues, and the precise combination of signaling molecules shapes how that neuron functions. Many drugs used to treat neurological and psychiatric disorders work by altering these chemical signals, yet scientists have lacked the tools to observe the changing concentrations of all these signals in real time in the living brain.
"Previously, one or two molecules could be recorded rapidly to associate their changes with the activity of nearby neurons, or the changes in many molecules can be tracked over slow timescales,” said lead author Peter N. Kalugin, MD, PhD, a former graduate student in the Andermann lab, now in the lab of Maria K. Lehtinen, PhD, of Boston Children’s Hospital. "We have developed MORSE to record many molecules simultaneously on a rapid timescale."
MORSE is a tiny probe containing an array of genetically engineered sensor cells, each customized to recognize the major chemical messengers in the brain, including dopamine, norepinephrine, serotonin, acetylcholine, histamine, oxytocin and vasopressin. When one of these target molecules encounters its corresponding sensor cell, the cell produces a fluorescent signal. By recording the fluorescent signals over several hours, the scientists can track the concentrations of up to 10 brain signaling molecules at speeds relevant to neural activity.
The researchers first validated MORSE in a series of laboratory calibration experiments, exposing the probe to known signaling molecules and concentrations to establish its accuracy, sensitivity and multiplexing capabilities. The team then further validated the technology in rodent models, where it successfully monitored multiple neurochemical signals in real time.
“We expect that tools like our probe will allow for the development of combinatorial brain therapeutics, which rationally combine the dynamic effects of many drugs to achieve specific changes in brain activity, said Andermann, who is a professor of medicine at Harvard Medical School. "While a complete accounting of the coordinated dynamics of many molecular signals in brain fluids is a technically challenging goal, it could yield profound mechanistic insights into the nature of brain states, as well as new therapeutic opportunities."
Co-authors included: Peter N. Kalugin, Crystian I. Massengill, Oren Amsalem, Marta Porniece, Zachary B. Stolberg, Diana C. Guarino, David Tingley, Stephen X. Zhang, Madalon F. Hammell, Charlotte D. Ausfahl, and Andrew Lutas of BIDMC; Paul A. Soden, Jordan C. Benson, David M. Tong, Tiara E. Lacey, Ya’el Courtney, Alexandra Hochstetler, and Maria K. Lehtinen of Boston Children’s Hospital; Huan Wang, Lan Geng, Guochuan Li, Bohan Li, and Yulong Li of Peking University and PKU-IDG/McGovern Institute for Brain Research.
This work was supported by the National Institutes of Health (grants NIH F30 DK131642, T32 HL007901, T32 GM007753, and T32 GM144273 (P.N.K.); NIH R01 NS129823 (J.C.B.); NIH T32 NS007473 and F32 NS134588 (A.H.); NIH F32 DK112589 and ZIA DK075169 (A.L.); NIH K99 DK134853 (S.X.Z.); NIH R01 NS088566, R01 NS129823, RF1 DA048790, NIH DP1 AT010971, R01 EY032749, R21 EY035436); an Ellen R. and Melvin J. Gordon Center for the Cure and Treatment of Paralysis Fellowship (C.I.M.); a Walter Benjamin Fellowship of the Deutsche Forschungsgemeinschaft (M.P.); a Lefler Fellowship, Charles A. King Trust Fellowship (S.X.Z.); the Bill and Melinda Gates Millennium Scholarship (T.E.L.); a Howard Hughes Medical Institute James H. Gilliam Fellowship for Advanced Study and a National Science Foundation Graduate Research Fellowship (Y.C.); a Harvard Brain Science Initiative Bipolar Seed Grant and the New York Stem Cell Foundation (M.K.L.); Simons Foundation Pilot Award ID 976096, Pew Charitable Trusts Innovation Fund, and a Charles Robert Broderick III Phytocannabinoid Research Grant (M.L.A.); and Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center NIH U54 HD090255, P50 HD105351, and S10 OD016453 to the IDDRC Cellular Imaging Core.
Disclosures: M.L.A., P.N.K., M.K.L., P.A.S., and D.T. are co-authors of US Patent Office application number 63/481,367, docket number 01948-288001 concerning this work.
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a leading academic medical center, where extraordinary care is supported by high-quality education and research. BIDMC is a teaching affiliate of Harvard Medical School, and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is the official hospital of the Boston Red Sox.
Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a healthcare system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,700 physicians and 39,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education.
