2003 Grand Prize Winner

Dr. Michael Ehlers grew up in Grand Island, Nebraska, and earned his bachelor's degree in chemistry from the California Institute of Technology in 1991. He holds MD and PhD degrees since 1998 from the Johns Hopkins University School of Medicine in Maryland, where he also conducted postdoctoral research. Currently Dr. Ehlers is an Assistant Professor of Neurobiology and the Director of the Neuroproteomics Laboratory at Duke University in North Carolina. He is the recipient of numerous awards in neuroscience and a Scholar of the Ruth K. Broad Foundation. His research focuses on the interface between neuronal cell biology and the plasticity of neural circuits, with emphasis on protein trafficking and turnover mechanisms in dendrites.

Ubiquitin and the deconstruction of synapses.
The remodeling of synapses is a fundamental mechanism for information storage and processing in the brain. Much of this remodeling occurs at the postsynaptic density (PSD) a specialized biochemical apparatus, containing neurotransmitter receptors and associated scaffolding proteins, that organizes signal transduction pathways at the postsynaptic membrane (Figure).Far from being an immutable structure, the PSD undergoes long-lasting global changes in ist molecular composition, which are dictated by neuronal activity. These changes are bidirectional, reversible, and involve networks of PSD proteins that rise and fall in abundance as coordinated ensembles.Activity-dependent remodeling of the PSD is accompanied by altered protein turnover, which is remarkably rapid and robust. In turn, this remodeling occurs with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and requires proteasome-mediated degradation. Functionally, these modifications alter synaptic signaling to major downstream effectors.Thus, richly dynamic in its internal life, the postsynaptic density contains hidden dimensions of interconnected protein networks within which reside the molecular trace of experience. By demonstrating that activity controls the global composition of the synapse through ubiquitin-dependent turnover, our research provides a new conceptual framework for understanding and ultimately predicting functional changes in neural circuits.

See 2003 Grand Prize Winner receiving his prize!
See 2003 Grand Prize Winner visiting Eppendorf AG, Hamburg!
Find out more about Dr. Ehlers and his work at ehlerslab.org

2003 Finalists

Dr. Karel Svoboda grew up in the Czech Republic and Germany, and he received his bachelor's degree in physics in 1988 from Cornell University in New York. As a graduate student in biophysics at Harvard University in Massachusetts, he measured the tiny steps and forces produced by individual kinesin molecules. After being awarded his PhD in 1994 he pursued postdoctoral work at Bell Laboratories, where his interests shifted to synaptic and dendritic function and plasticity. In 1997 Dr. Svoboda started his own laboratory at Cold Spring Harbor Laboratory in New York. Work in his laboratory focuses on experience- and activity-dependent plasticity in the cortex, probed with imaging, physiological, and molecular tools.

Imaging experience-dependent synaptic plasticity in the adult neocortex in vivo.
Cortical neural circuits support our stable view of the sensory world. However, the cortex also subserves learning and memory, which indicates that it is continuously fine-tuned by experience, even in adult animals. What is stable and what is plastic in cortical circuits? Our approach is to directly image the mechanisms of experience-dependent plasticity at the level of single synapses in vivo. We find that in the adult mouse barrel cortex the large-scale structure of dendrites and axons is stable over months. Similarly, a large fraction (> 50%) of dendritic spines, tiny postsynaptic specializations, are stable. However, a striking finding was that a subset of dendritic spines (~ 20%) disappeared within a day, to be replaced by other spines. What is the implication of spine addition and subtraction for the plasticity of cortical circuits? Ultrastructural analysis revealed that new spines make synapses; therefore, spine formation and retraction is associated with synapse formation and elimination, respectively. Induction of experience-dependent plasticity increased the turnover of synapses, coincident with a change in receptive field structure. Thus synapse formation and elimination contribute to the experience-dependent rewiring of adult cortical circuits in vivo.

For Dr. Svoboda’s full essay, see Science Online at sciencemag.org.

Dr. Rudolf Cardinal was born in Norwich, UK, and grew up in Folkestone, UK. He studied medical sciences and neuroscience at the University of Cambridge, where he received his bachelor's degree in 1996 and then pursued courses in clinical medicine and surgery, earning his PhD in behavioral neuroscience under the supervision of Prof. Barry Everitt. He was awarded his MB Bchir PhD in 2001. His PhD thesis examined the neuropsychology of reinforcement processes, including the contribution of the anterior cingulate cortex to Pavlovian conditioning and the neuroanatomy of impulsive choice. After qualifying, he worked as a house physician and surgeon in East Anglian hospitals, and he is now a neuroscience lecturer at Cambridge.

Succumbing to instant gratification without the nucleus accumbens.
When animals act to obtain rewards, their actions are sometimes rewarded or reinforced immediately, but often this is not the case; to be successful, animals must learn to act on the basis of delayed reinforcement. They may also profit by choosing delayed reinforcers over immediate reinforcers if the delayed reinforcers are sufficiently large. Individuals differ in their ability to do this: self-controlled individuals are better able to choose delayed rewards than impulsive individuals. Impulsive choice contributes to psychiatric disorders, including drug addiction and attention-deficit/hyperactivity disorder.Damage to the nucleus accumbens core (AcbC) caused rats to become impulsive in their choices, preferring small, immediate rewards to larger, delayed rewards; damage to two of its afferents (the anterior cingulate and medial prefrontal cortex) did not. AcbC damage also impaired the rats ability to learn to act when the consequences of their actions were delayed. Impairment of AcbC function may therefore underlie some symptoms of impulse-control disorders.

For Dr. Cardinals’s full essay, see Science Online at sciencemag.org.

Dr. Satchin Panda was born and raised in India, where he earned his bachelor's degree in plant biology from Orissa University of Agriculture and Technology. He joined the graduate program at the Scripps Research Institute in California, where he studied the circadian oscillator mechanism in plants in the laboratory of Dr. Steve Kay. Since receiving his PhD in 2001, he has pursued postdoctoral research in Dr. John Hogenesch's lab at the Genomics Institute of the Novartis Research Foundation, San Diego. Here he uses genetic and genomic approaches to gain an understanding of the light input pathway, as well as circadian regulation of behavior and physiology in mammals. His work has demonstrated tissue-specific circadian regulation of transcription, and it has elucidated a complex mechanism by which mammals recruit multiple photoreceptors to adapt to their natural environment.

Shedding light on non-image-forming photo perception in mammals.
Although mice lacking rod and cone photoreceptors are blind, they retain many eye-mediated responses to light, possibly through photosensitive retinal ganglion cells (RGC). These cells express melanopsin (Opn4), a photopigment that confers this photosensitivity. Mice lacking melanopsin (Opn4-/-) still retain nonvisual photoreception, suggesting that rods and cones could operate in this capacity. We observed that mice with both outer retinal degeneration and a deficiency in melanopsin exhibited: complete loss of photoentrainment of the circadian oscillator and pupillary light responses; photic suppression of arylalkylamine-N-acetyltransferase (AA-NAT) transcript; and acute suppression of locomotor activity by light. This indicates the importance of both nonvisual and classical visual photoreceptor systems for nonvisual photic responses in mammals.

For Dr. Panda’s full essay, see Science Online at sciencemag.org.