Neurobiology and Behavior

Eric R. Kandel, M.D., Director
Michael E. Goldberg, M.D., Research Scientist VIII
James H. Schwartz, M.D., Ph.D., Research Scientist VII
John Koester, Ph.D., Research Scientist VII
Claude Ghez, M.D., Research Scientist VI
René Hen, Ph.D., Research Scientist Vi
Craig Bailey, Ph.D., Research Scientist V
Robert Hawkins, Ph.D., Research Scientist V
Samuel Schacher, Ph.D., Research Scientist V
John Martin, Ph.D., Research Scientist III
Steven Siegelbaum, Ph.D., Professor
Lorna Role, Ph.D., Professor
Ning Qian, Ph.D., Associate Professor
Aniruddha Das, Ph.D., Assistant Professor
Vincent Ferrera, Ph.D., Assistant Professor
Jacqueline Gottlieb, Ph.D., Assistant Professor
Daniel Salzman, M.D. Ph.D., Assistant Professor


The Center for Neurobiology and Behavior consists of 17 independent basic research laboratories, including two laboratories of the Howard Hughes Medical Institute. The overall research goal of the Center is to provide an analysis of neural development, behavior, learning, and diseases of the nervous system in terms of their underlying cellular and molecular mechanisms. The subjects used in these studies range from simple invertebrates to humans. A wide range of experimental techniques are used, including molecular genetics, neurochemistry, cell biology, biophysics, behavior, electrophysiology and psychophysics. Research is carried out in an interactive environment, in which interdisciplinary collaboration between faculty, fellows and graduate students in different laboratories is the norm. The Center runs an active training program for medical and graduate students and postdoctoral fellows.

The Mahoney Center for Mind and Brain, a part of the Keck Program on Cognition and Plasticity, was built this year, and will be formally opened in September 2002. New laboratories for Michael Goldberg, Ning Qian, Vincent Fererra, Jacqueline Gottlieb, Daniel Salzman, and Aniruddah Das were constructed adjacent to the rest of the Center for Neurobiology and Behavior. A series of state-of-the-art laboratories were built to allow the investigators to study the physiology and psychophysics of perception and action, using awake, behaving primates as a primary model. They will form a new and vibrant program in systems and cognitive neuroscience. Extramural research for research in the Center is provided by NIH, NSF, the Howard Hughes Medical Institute, the Keck Foundation, the Dana Foundation, the Klosk Foundation, NARSAD, and the Matheson Foundation.

Learning and Memory
A cross-species approach to understanding the mechanisms of memory and learning has been applied, using: (1) the defensive gill and siphon withdrawal reflex of the sea hare, Aplysia californica, which undergoes habituation, sensitization, and classical conditioning; (2) the mammalian hippocampus, which exhibits a pronounced type of long-lasting synaptic plasticity, long term potentiation (LTP), which is thought to underlie long term memory. James Schwartz and colleagues have characterized second-messenger cascades that mediate simple forms of synaptic plasticity underlying learning in Aplysia. There are two basic forms of synaptic plasticity — facilitation and depression. In the past, Dr. Schwartz and colleagues have studied the molecular pathway for long-term facilitatory processes that underlie memory. They found it to be governed primarily by the cAMP-dependent protein kinase. Recently they have begun to examine the molecular basis of synaptic depression, which involves p38 MAP kinase.

Craig Bailey and colleagues have examined the structural changes that accompany long-term facilitation in Aplysia as well as their specific relationship to the changes in synaptic function. They have found that the synaptic enhancement that underlies long-term facilitation consists of both an activation of preexisting silent synapses and the growth of new functional synapses.

Synapse formation and long-term synaptic plasticity accompanying simple forms of learning are believed to share some common mechanisms. Samuel Schacher and colleagues have recently found that specific changes in the intracellular distribution of the mRNA that encodes synaptic proteins contribute both to the formation of specific synapses between appropriate partners and to activity-dependent synaptic plasticity that accompanies long-term changes in behavior.

Robert Hawkins and colleagues have continued to study cellular mechanisms of learning and memory. They showed that classical conditioning in Aplysia is due in part to associative facilitation of sensory neuron–motor neuron postsynaptic potentials, and found that that facilitation in turn involves both activity-dependent presynaptic facilitation and Hebbian long-term potentiation. In hippocampus they have found that long-term potentiation of synaptic transmission in dissociated cell cultures is accompanied by a rapid and long-lasting increase in the number of clusters of presynaptic proteins such as synaptophysin, as well as clusters of postsynaptic proteins such as glutamate receptors. These studies support the emerging view that even the early stages of long-term plasticity involve microstructural changes, and that those changes occur pre- and postsynaptically in a coordinated manner.

In studies of synaptic plasticity Eric Kandel has focused on the studies of the cyclic AMP-response element binding protein (CREB) in the mouse. When present in the phosphorylated state CREB binds to the cyclic AMP response element (CRE) in certain genes, thereby enhancing their transcription. Members of the Kandel lab have interfered with CREB-family transcription factors in region CA1 of the dorsal hippocampus. This produces a behavioral deficit specific to long-term memory of spatial learning. Several forms of particularly long-lasting (late-phase) LTP (L-LTP) are normal, but dopamine-regulated potentiation is disrupted. These experiments both confirm a role for CREB in hippocampus-dependent learning, and suggest that some forms of synaptic plasticity bypass the requirement for CREB. Parallel studies suggest that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP, providing insight into the molecular mechanisms of the synaptic tagging required to produce synapse-specific potentiation.

Behavior and Cognition
The smooth pursuit eye movement system of primates is an excellent model for studying the interactions between attention and voluntary movement selection. Dr. Ferrera and colleagues study the neural basis of smooth pursuit and saccadic eye movements by recording single neuron activity in prefrontal cortex of non-human primates. Using a behavioral paradigm for measuring the eye movement response to two or more moving targets, they have characterized the process of target selection as a transition from vector-averaging to winner-take-all motor output.

Stereovision is the perception of depth using information projected onto the two retinas. There have been many physiological studies of this phenomenon, but the relation between them is often not clear. Dr. Qian and his collaborators have performed mathematical analyses and computer simulations on the data from a wide range of physiological studies. They have developed a unified computational model that fits data from a wide range of such studies and generates specific, testable hypotheses to help guide future investigations of stereovision.

Dr. Ghez’s research examines the mechanisms of trajectory control and motor learning in reaching and pointing movements. His recent studies have shown that trajectory errors, detected through visual and proprioceptive sensory channels, are decomposed and stored in multiple memory buffers used in feedback control and adaptive learning. Thus visual and proprioceptive errors are used for adapting internal models of extrinsic and intrinsic space respectively. Visual errors are partitioned into specialized buffers devoted either to discrete processing for the learning of sequences or to the calibration of visuomotor reference-axis and scaling. Brain imaging studies have revealed that these psychophysical distinctions are mirrored in distinct prefrontal, premotor parietal and subcortical networks during learning.

René Hen uses molecular genetic techniques to create animal models to examine the role of serotonin in anxiety and depression. Serotonergic drugs are used in the treatment of a number of pathological states such as depression, appetite disorders, and migraines. There are 14 known subtypes of serotonin receptors with distinct pharmacological properties, signaling systems, and tissue distributions. The study of the function of individual serotonin receptor subtypes has been hampered by the lack of specific drugs. In addition, a number of the serotonergic drugs that are active in the treatment of neuropsychiatric disorders influence the whole serotonergic system. To dissect the contributions of individual serotonin receptors to mood control, Dr, Hen and his collaborators have used genetic engineering techniques to generate mice that carry mutations in specific receptor subtypes that result in altered emotional states. Tissue-specific and inducible strategies have been used to identify neural circuits that underlie mood control and responses to antidepressant therapies.

Hyperpolarization-activated ion channels underlie spontaneous electrical activity in both the heart and certain regions of the brain. A key feature of these channels is that their activity is regulated by the direct binding of the intracellular metabolite, cyclic AMP, to a site on the internal surface of the channel. Steven Siegelbaum and colleagues have begun to elucidate the mechanism of this regulatory action. Their results show that the cyclic AMP-binding domain exerts a tonic, inhibitory influence on channel opening. The binding of cyclic AMP to its receptor on the channel promotes channel opening by relieving this inhibition. This effect underlies the ability of modulatory neurotransmitters to regulate both cardiac and neuronal electrical rhythms.

In order to understand the control of behavior, one must understand not only the synaptic connections in a circuit, but also the ways in which voltage-gated ion channels endow different neurons with their unique response properties to a given set of synaptic inputs. John Koester uses voltage-clamp techniques to study the excitability properties of Aplysia neurons that have defined roles in generating behavior. Together with the late Irving Kupfermann and collaborators, he has analyzed the functional properties of membrane ionic currents in an unusual class of non-spiking neurons that play a key role in generating rhythmic feeding behavior.

Development
Jack Martin studies postnatal development of the corticospinal system – the principal neural system for producing skilled movement. He and his collaborators have focused on the role of behavioral experiences during early postnatal life in shaping development of the corticospinal system and development of skilled motor behavior. By restricting limb use in young animals they have produced profound retardation of corticospinal development, both in the organization of the cortical motor map and in the patterns of connections with spinal cord neurons. Current studies examine which features of retarded corticospinal organization can be corrected later in development and which are permanent. In addition to providing direct evidence for the role of experience in corticospinal development, their findings suggest a possible treatment for developmental motor disorders such as cerebral palsy. Dr. Martin and colleagues have also begun to pursue surgical and immunological lines of research aimed at promoting recovery of motor function after spinal cord injury. These studies are providing insights into the control of axon growth in maturity that may lead to effective treatments for injury of the nervous system.

Central cholinergic systems, which provide important modulatory control of synaptic excitability, have been strongly implicated in neuropsychiatric diseases. Lorna Role’s laboratory studies the generation, plasticity and maintenance of cholinergic synapses in the mammalian brain. Recent work tests the hypothesis that products of the neuregulin-1 gene are important in the susceptibility to such diseases. Recent studies in the Role lab demonstrated that neuregulin-1-signaling is bi-directional and that neuregulin-1-expressing neurons require such signaling to survive. Current work further examines the signaling cascades and target genes activated by NRG-1-erb B interactions. The role of neuroregulin-1 signaling in synaptic function is also being studied in mice genetically altered to express reduced levels of functional neuregulin-1 protein. As the neuregulin-1 gene has recently been identified as a potential susceptibility locus for schizophrenia, current work may provide important insight into mechanisms that may underlie this and other neuropsychiatric disorders.