Research & Publications
Dr Pieribone is developing genetically encoded fluorescent probes of membrane electrical potential. These probes allow one to use optical instruments (microscopes) to monitor the electrical activity of neurons. Such an approach is less invasive, allows study of identified cell types over large regions of the cortical surface. The laboratory has also engineered miniature imaging systems that can be head mounted on mammels and allow mobile recording of neuronal activity. These types of studies will allow a better understanding of the neuronal networks that encode information in the central nervous system.
Specialized Terms: Neurophysiology; Neurotransmission; Voltage and calcium imaging; Sensory physiology; Drug development; Coral biology; Fluorescent proteins
Extensive Research Description
My published research has spanned 37 years (beginning with a Science paper published in 1986 while I was an undergraduate), produced >115 publications in peer-reviewed journals and I co-authored a well received (Nature, Technology or Mixed Signals Blog, CBE Life Science Education, Oceanography, Development, Yale Scientific and Nature Cell Biology), original peer-reviewed lay scientific book (“Aglow in the dark: the revolutionary science of biofluorescence” Harvard Press). My research has spanned a number of scientific areas: catecholamine anatomy and physiology, neuropeptide anatomy and physiology, adrenoceptor distribution in the central nervous system, serotonergic anatomy, the physiology, ultrastructure and biochemistry of synaptic transmission, development of genetically-encoded voltage probes, identification of fluorescent proteins in marine animals, and information content in cortex using voltage imaging. My work has received some 12,000 citations (as of 2023), an average of 58 per publication and 181 per year since 1986 (h-index of 54).
As an undergraduate and graduate student I published a series of papers on the afferent control of the locus coeruleus. These publications developed a novel and still held, concept that control of the brain’s main norepinephrine system largely resided in the hind brain. This concept realigned the fields perception of what factors controlled this important brain system. The locus coeruleus/norepinephrine system is involved in the actions of a number of widely used psychopharmacological interventions for depression, mania and schizophrenia.
As a Fogarty and National Science Foundation Fellow at the Nobel Institute of Neurophysiology in Stockholm Sweden, I published a series of studies on the anatomical distribution of the newly cloned adrenoceptors. These studies were the first to accurately identify which cells in the brain (and rest of the body) expressed which adrenoceptors. Previous receptor binding studies could not identify which cells or which cellular elements produced the labeled receptors and the specificity of the labeling was always questionable. These studies remain the most complete mapping of adrenoceptor subtypes in the brain (and other organs). While in Sweden I also examined the neurophysiologic response of monoaminergic neurons to the neuropeptide galanin and nitrous oxide. These represent one of only a handful of studies examining the neurophysiologic effects of galanin.
At The Rockefeller University I developed an in situ experimental preparation of an isolated large synapse for use in biochemical studies of neurotransmitter release. My research focused on the role of synapsin and actin in neurotransmission. We established that acute removal of the synaptic vesicle protein, synapsin from an adult synapses causes little change in low frequency neurotransmitter release but highly impairs high frequency neurotransmitter release. These studies combined with corroborative electron microscopic data, strongly suggested that the role of the most prevalent synaptic vesicle protein known is to create a reserve of synaptic vesicles that can be rapidly mobilized during bouts of high activity. The loss of this control was later shown to produce seizures in adult mice and in humans. At The Pierce Laboratory/Yale University I continued my work on synaptic transmission and moved to study the role of actin and actin- binding proteins on synaptic ultrastructure and physiology. In a series of papers we identified a clear cut role for actin, synapsins and talin in the recycling and clustering of synaptic vesicles.
In 2001 I began a research project to develop a genetically-encoded voltage probe based on green fluorescent protein. Being able to record electrical activity in virtually any specific cell type non-invasively will revolutionize neuroscience. In 2002 we published one of three original proof-of-concept genetically-encoded voltage probes to be developed by the scientific community. Our probe was the first to show rapid on and off kinetics. This publication led to an NIH R21 grants to explore other probes. At that time we also began to look for new fluorescent proteins that would preform better in voltage probes. We have begun a program to clone fluorescent proteins from coral. Our voltage probe became a strong proof-of- concept for the production of such probes. We subsequently received a multicenter (Yale, Riken (Japan), U. Montana, U. Penn. and U.C. Berkeley) NIH U24 grant that involved analyzing a large protein space for improved probes. This grant resulted the discovery and publication from my laboratory in September 2012, of a major advance in optical recording of brain activity (Jin, Lei et al. “Single Action Potentials and Subthreshold Electrical Events Imaged in Neurons with a Fluorescent Protein Voltage Probe.” Neuron 75.5 (2012): 779–785.) This was followed by the first ever fully optical neurophysiology study (Cao G, Platisa J, Pieribone VA, Raccuglia D, Kunst M, Nitabach MN. Genetically targeted optical electrophysiology in intact neural circuits. Cell 154: 904–913, 2013.). This work has received considerable attention in relevant media (BioTechniques, Yale Medicine, Yale Daily News, Science Daily, Scientific American, National Geographic, NIH News, Reddit).
My laboratory has also developed the first head-mountable, high speed, fluorescent microscope system for monitoring electrical activity using genetically-encoded sensors of voltage and calcium. This microscope is now being used in combination with the above mentioned probe to study wide-spread motor cortical activity in an awake behaving animal with high temporal resolution. We are developing a fully optical neural prosthesis capable of informing accurate positional information in realtime. These studies are aimed at eventual human implementation in paralyzed patients.
I have been intimately involved in the development and Phase II/III clinical testing of the neurosteroid ganaxolone and allopregnanolone (I am the author of clinical grant applications, a peer-review paper and clinical protocols). I have co-developed the three clinical trials for these compounds in epilepsy ,post traumatic stress disorder and traumatic brain injury. I consider the development of neuropharmaceuticals a natural extension of my laboratory work at Yale University and the ultimate and most significant application of basic science to the betterment of human health.
I was the President and co-founder of Affinimark Technologies, Inc. which is developing a rapid point-of-care test for the presence of cerebrospinal fluid in bodily fluids leaked from the head. No such test exists and would improve patient care following traumatic head injury and sinus/ear surgery.
My scientific achievements extend beyond my laboratory science. I am a Research Scientist at both the Mystic Aquarium and Center for Exploration in Mystic Connecticut and the American Museum of Natural History in New York City. I have co-curated an exhibit at the Mystic Aquarium and one of the most popular temporary exhibit to date at the American Museum of Natural History ("Creatures of Light") For the American Museum of Natural History exhibit we received an National Science Foundation education grant. I have led several research expeditions to study and collect biofluorescent animals from coral reefs in Belize, British Virgin Islands, Malaysia, Australia, Israel, and the Solomon Islands. These have been funded by the National Institutes of Health, National Geographic Society, National Science Foundation, EarthWatch, and the American Museum of Natural History). Accounts of these trips have been documented in televised documentaries, radio interviews (Science and Society, National Public Radio, Studio 360, National Public Radio) and in web (National Geographic, Good News, Big Think, World Science Festival, Live Science) and print articles including The New York Times ( http://scientistatwork.blogs.nytimes.com/author/vincent-pieribone/). In 2010, we (along with my collaborator David Gruber) received an NSF Major Research Instrumentation grant to develop a remotely operated vehicle (ROV) to study deep sea fluorescent and bioluminescent animals.
Recently I have been the lead on a DARPA grant (https://news.yale.edu/2017/11/...) to develop implantable instruments to monitor neuronal activity in the human brain.
Anatomy; Biomedical Engineering; Bioprosthesis; Biotechnology; Brain; Central Nervous System; Cnidaria; Drug Therapy; Electrophysiology; Epilepsy; Neuropharmacology; Neurophysiology; Neurosciences; Spinal Cord; Optics and Photonics; Organisms; Diseases; Chemicals and Drugs; Analytical, Diagnostic and Therapeutic Techniques and Equipment