Focus Area: Cellular and Molecular Neurobiology
With 86 billion neurons and more than 100 trillion synapses in your brain continuously passing information up to 200 miles an hour, your brain is right to believe it’s your most important organ. The connections in the brain need to develop correctly, and damaged or improperly formed connections can lead to neurological disorders.
Scientists at the Institute study exactly how neurons form, what happens if they're damaged, and work to see if they can reform. Researchers work across disciplines to understand the mechanisms of cellular and molecular neurobiology, and innovate therapeutic interventions for disorders such as traumatic brain injury, post-traumatic stress disorder, muscular dystrophy, and spinal muscular atrophy.
Synapses are specialized sites that allow information to be passed between neurons. Their importance is highlighted by the fact that even minor synaptic abnormalities, caused by disease or neurotrauma, result in devastating neurological conditions. Understanding how central nervous system synapses are formed is essential to our understanding of neurological disorders.
Dr. Michael Fox’s laboratory is interested in understanding the cellular and molecular mechanisms that drive two aspects of synapse formation—synaptic targeting and synaptic differentiation. His efforts to uncover mechanisms that drive the initial targeting of synapses focus on the visual system.
Dr. Fox is particularly interested in understanding how synapses are formed between retinal ganglion cells (RGCs), the output neurons of the retina, and target neurons within the brain. Despite monumental advances in this field, it still remains unclear how different classes of RGCs target functionally distinct nuclei within the brain. One brain region where class-specific targeting of RGC axons is most evident is the lateral geniculate nucleus—a thalamic relay nucleus that contains three structurally and functionally distinct subnuclei. Since different classes of RGCs target these subnuclei, Fox hypothesized that regionalized guidance cues must exist to direct class-specific axonal targeting. He has identified candidate molecules that may act as targeting cues for class-specific retinal targeting and is now testing their necessity in retinogeniculate circuit formation.
Each year more than 1.5 million Americans are diagnosed with traumatic brain injury. The effects can be permanent, leading to memory loss, difficulty controlling emotions, or even death. Traumatic brain injury, in fact, is the leading cause of disability and death among children in the United States.
Dr. Michael Friedlander studies the cellular processes that underlie learning in the brain in health, during development, and after traumatic brain injury. Specifically, his research is directed at understanding the processes that regulate alterations in synaptic efficiency between neurons within the cerebral cortex—known as synaptic plasticity—and how these cellular processes are affected during brain development; after experience, including learning; and in response to brain injury.
Dr. Friedlander’s laboratory uses quantitative single-neuron patch clamp electrophysiological methods, along with cellular and sub-cellular imaging, to visualize the changes in structure and calcium signals that underlie alterations in functional synaptic connectivity within the developing neocortex under normal conditions and after alterations in early sensory experience. This approach allows for the application of quantal analysis to determine how the induction of synaptic plasticity affects a variety of components of synaptic transmission.
Dr. Friedlander’s laboratory also aims to identify specific patterns of synaptic activation that are most effective at accessing the downstream plasticity signaling pathways in the immature normal and injured brain as an approach to neurorehabilitation.
Emotional trauma can cause physical changes in the brain. These changes can, in turn, cause undesirable changes in behavior and personality. Millions of people worldwide—such as veterans affected by post-traumatic stress disorder—live with these changes every day.
The anterior cingulate cortex, the primary hub of empathy in humans, and the amygdala, the emotional center of the brain, are the two major players in the response to vicarious pain. Dr. Alexei Morozov has developed an experimental procedure for studying the neurological changes in the connections between these two regions caused by emotional trauma and their subsequent effects on behavior in an animal model. Two principal goals of his research are to identify neuronal circuits that underlie empathy and to determine how those circuits become altered in posttraumatic stress disorder, depression, psychopathy, autism, and schizophrenia.
Dr. Morozov’s laboratory uses a genetic model of psychopathy that is based on animals with hippocampal CA3-restricted knockout of brain-derived neurotropic factor to explore empathy and the effects of vicarious pain. He capitalizes on advances in optogenetics to explore and manipulate those connections in behaving animals. The ultimate goal of his research is to identify targets in the brain that can be used to treat psychiatric and neurological disorders.
Neurodevelopment proceeds through a series of events culminating into formation of a productive neuronal network. One of the key final steps in neurodevelopment is the refinement of transient connections—that is, the strengthening, weakening, and elimination of transient synapses, which depends on their individual activity. These highly plastic changes in transient synapses require activity-dependent signaling. Proteins involved in synaptic plasticity are obvious effector molecules involved in synaptic pruning or refinement.
Dr. Konark Mukherjee studies the role of MAGUK—membrane-associated guanylate kinase—proteins in neurodevelopment. MAGUKs are a class of multi-domain scaffolding proteins present in both pre- and post-synaptic compartments. They play a crucial role in various forms of synaptic plasticity. Mutations in MAGUKs like CASK and SAP102 are often linked with neurodevelopmental disorders, such as X-linked mental retardation
A principal goal of Dr. Mukherjee’s laboratory is to investigate the role of MAGUKs— especially CASK—in neurodevelopment. Another major thrust of his laboratory is to develop cell biological assays to identify the molecular function and signaling pathways of CASK and other MAGUKs.
During neonatal stages, a number of diseases—including muscular dystrophy, spinal muscular atrophy, and Lambert-Eaton Myasthenic Gravis—are known to cause significant deleterious alterations and to retard the normal development of neuromuscular junctions, the motor-neuron-to-muscle-fiber synapses. Such alterations are closely associated with early death or developmental abnormalities that persist throughout the lifespan of the individual.
The focus of Dr. Gregorio Valdez’s laboratory is to discover and manipulate molecules that promote normal development and maintenance of healthy synapses and that may promote repair of deteriorating synapses during injury and diseases. In particular, Dr. Valdez studies the neuromuscular junction. In addition to being an ideal model for discovering and studying molecules that could also play critical roles in the development of brain synapses, the neuromuscular junction is essential for the proper development and functioning of the motor system.
Dr. Valdez is especially interested in discovering potential therapeutic targets that promote the proper development and health of the neuromuscular junction in normal and disease-affected people. To this end, his laboratory uses a variety of approaches, including biochemical and molecular techniques, cell culture analysis, mouse genetics, and modern imaging techniques to visualize neuromuscular junction changes throughout the different life stages of mice. Dr. Valdez’s hope is that some of these molecules, in addition to functioning at the neuromuscular junction, will dually play key roles in the proper development and functioning of brain synapses. If successful, this work could lead to the development of therapeutics for a number of debilitating developmental and acquired muscle and brain diseases.