Neurobiology and Behavior Eric R. Kandel, M.D., Director; Research
Scientist VIII OVERVIEW The guiding philosophy of the Center for Neurobiology and Behavior maintains
that an integrated approach, ranging from cell and molecular biology to
systems and behavioral analysis, is required to understand the basis of
normal and abnormal human behavior. In line with this approach, the main
focus of the research and education in the Center is primarily on basic
science aspects of neural development and the functions of the nervous
system that underlie normal and abnormal behavior. Approaches range from
the cell and molecular level to the systems level. A wide range of experimental
techniques are used, including molecular genetics, neurochemistry, cell
biology, biophysics, behavior, electrophysiology, computational biology,
and psychophysics. The subjects investigated in these studies range from
simple invertebrates to humans. Many of the studies carried out in the
Center focus on processes such as learning and memory, attention, perception,
and affective behavioral traits that can be affected by mental illness.
Several ongoing projects may someday contribute to our understanding of
the etiology of, and new therapeutic approaches to, autism, ADHD, anxiety,
addiction, benign-age-related memory loss, impulsivity, aggressivity,
fragile-X syndrome, cerebral palsy, spinal cord trauma, depression, and
schizophrenia. The faculty of the Center is actively involved in training
medical, dental and predoctoral students and postdoctoral fellows. CURRENT RESEARCH Eric Kandel’s laboratory has focused on developing reductionist approaches to learning in both Aplysia and in genetically modified mice designed to explore the molecular mechanisms of memory storage and to uncover new aspects of neuronal signaling. Persistence of Synaptic Facilitation. Dr. Kandel has found that in both Aplysia and mice, long-term synapse-specific plasticity can occur and that it requires a local marking signal. In Aplysia he found that one component of the synapse-specific marking signals requires local protein synthesis at the activated synapse. This synthesis serves two functions: (1) it marks the activated synapse that confers synapse specificity, and (2) it stabilizes the synaptic growth associated with long-term facilitation. He has found that a neuron-specific isoform of cytoplasmic polyadenylation element binding protein (CPEB) regulates this synaptic protein synthesis in an activity-dependent manner. Aplysia CPEB protein is upregulated locally in activated synapses and it is needed not for the initiation, but for the stable maintenance of long-term facilitation. Recent work suggests that Aplysia CPEB is the stabilizing component of the synaptic mark. Dr. Kandel has further found that CPEB may serve as a stabilizer because it has prion-like properties. Prion proteins have the unusual capacity to fold into functionally distinct conformations, one of which is self-perpetuating. When prion proteins convert to the self-perpetuating state they can cause disease (in mammals) or a non-functioning protein (in yeast). Compared to other CPEBs, the neuronal form has an N-terminal extension that shares characteristics of yeast prion-determinants: a high glutamine content and predicted conformational flexibility. When fused to a reporter protein in yeast, this region is sufficient to confer upon it the prototypical epigenetic changes in state that characterize yeast prions. Full-length CPEB undergoes similar changes but, surprisingly, it is the dominant, self-perpetuating prion-like form that has the greatest capacity to stimulate translation of CPEB-regulated mRNA. Preliminary studies suggest that conversion of CPEB to a prion-like state in stimulated synapses helps to maintain long-term synaptic changes associated with memory storage. A Reductionist Approach to Attention. The hippocampal formation plays a critical role in the acquisition and consolidation of memories. When recorded in freely moving animals, hippocampal pyramidal neurons fire in a location-specific manner: These "place" cells are thought to generate an internal representation of space. To explore the relationship between place cells and spatial memory, Dr. Kandel recorded from the hippocampal pyramidal cells of mice under various degrees of task demands. He found that long-term stability of place cells correlates with the degree of task demands, and that successful performance of a spatial task was associated with stable place fields. This suggests that the storage and retrieval of place cells is modulated by a top-down cognitive process resembling attention. Consistent with the idea of an attention-like process, conditions that maximize place field stability greatly increase orientation to novel cues. These results suggest that place cells are neural correlates of spatial memory, and that the rodent analog of selective attention modulates place field stability. His results have implicated dopamine in this process, and suggest a learning model whereby attention recruits a neuromodulatory input that switches short-term homosynaptic plasticity to long-term heterosynaptic plasticity. Voltage-Gated Ion Channels and Learning. Relatively little is known about how a neuron’s complement of voltage-gated ion channels interact with plastic changes in synaptic strength to generate an appropriate output signal to influence behavior. Dr. Kandel has addressed this problem using mice with general and forebrain-restricted deletion of the HCN1 gene, which encodes a voltage-gated nonselective CA ion channel thought to be important for neural integration. Deletion of HCN1 causes profound learning and memory deficits in visible platform and rotarod tasks, which require complex and repeated coordination of motor output. Cerebellar Purkinje cells are a key component of the cerebellar circuit required for learning of correctly timed movements. In these cells HCN1 mediates a large inward current that opposes hyperpolarization below the spike threshold. This ionic mechanism ensures that the integrative properties of Purkinje cells are stable and independent of the neuron’s history of activity. Based on these findings, he has proposed and is now testing a model according to which this non-synaptic integrative function of HCN1 is required for accurate decoding of input patterns. Such an effect may enable synaptic plasticity within the cerebellar cortex to influence, appropriately, the performance of motor activity. James Schwartz has characterized second-messenger cascades that underlie simple forms of learning, using biochemical, pharmacological, immunocytochemical, electrophysiological and recombinant DNA techniques. The most interesting components of these cascades are secondary effector enzymes, usually protein kinases. There are two basic forms of synaptic plasticity—facilitation and depression. A common feature of synapses that can be modulated is the bidirectional nature of modulation. In the past Dr. Schwartz has studied the molecular pathway for long-term facilitatory processes that are thought to underlie memory. This pathway primarily is governed by the cyclic-AMP-dependent protein-kinase and involves the synthesis of new protein in the neuron. This synthesis is produced by activity-dependent gene expression. Recently he has begun to examine the molecular basis of synaptic depression, which involves p38 MAP kinase. He has found that the inhibitory neurotransmitter blocks gene expression by altering the structure of the neuron’s chromatin. Samuel Schacher studies the long-term changes in the strength of synapses that are a key form of cellular plasticity that contributes to learning and memory. The synapses between sensory and motor neurons in Aplysia are altered for varying durations by experience that produces changes in behavior for varying durations. In the past year he has focused on several aspects of long-term facilitation of sensorimotor synapses produced by serotonin. He found that local protein synthesis at isolated sensory neuron synapses is regulated by serotonin and contributes directly to long-term facilitation. Serotonin activation of a specific isoform of protein kinase A (PKA) that is expressed selectively at synapses may regulate this local synthesis. Moreover, serotonin and its activation of PKA regulate the secretion and autocrine actions of a neuropeptide that is secreted by sensory neurons that leads to sequential activation of additional kinases that are required for long-term facilitation. These studies suggest that the cellular changes that accompany long-term behavioral changes may be initiated when stimuli are sufficient to recruit secretion of a neuropeptide that plays an important role in synapse development. Craig Bailey studies the molecular basis and functional consequences of the synaptic growth that accompanies long-term facilitation of synaptic connections in Aplysia. Over the past year he has focused on the time course and functional significance of the structural plasticity associated with long-term facilitation of the identified sensory to motor neuron synaptic connections. Using time-lapse confocal imaging of individual sensory neuron varicosities labeled with three different fluorescent markers, he has found that the storage of long-term facilitation is associated with two temporally, morphologically and molecularly distinct presynaptic changes. First, there is a rapid activation of silent presynaptic terminals by filling of preexisting empty varicosities with synaptic vesicles that is completed within 3-6 hr and requires new protein but not new RNA-synthesis. Second, there is a slower generation of new functional varicosities that occurs between 12-18 hr and requires both protein and RNA synthesis. These results demonstrate that changes in both the number and structure of synaptic connections induced by learning are functionally effective and capable of contributing to memory storage. Robert Hawkins investigates the neural mechanisms of learning and memory. During the past year he has continued his studies in Aplysia and in the mammalian hippocampus. In experiments on Aplysia he has begun to study the contributions of postsynaptic as well as presynaptic mechanisms to short-term facilitation at sensory-motor neuron synapses in isolated cell culture and to behavioral dishabituation and sensitization of siphon withdrawal in a semi-intact preparation. These studies have demonstrated that protein kinase A, protein kinase C, cytoplasmic calcium and calmodulin-kinase II all contribute to these forms of synaptic plasticity. Their roles vary depending on location (pre- or post-synaptic) and time course of the modulatory stimulus. In parallel studies Dr. Hawkins has investigated the contributions of pre- and postsynaptic mechanisms to long-term potentiation of synaptic transmission (LTP) in hippocampus. He found that LTP at synapses between individual CA3 neurons in organotypic slice culture involves pre- as well as postsynaptic calmodulin-kinase II, and that LTP at synapses between hippocampal neurons in dissociated cell culture involves both pre- and postsynaptic actin and RhoA. In addition, he has found that Rho GTPases and another protein that regulates the actin cytoskeleton, VASP, are involved in the rapid aggregation of pre- as well as postsynaptic proteins at the onset of LTP. These results support an emerging view that coordinated pre- and postsynaptic mechanisms and structural alterations contribute to the early as well as later stages of learning-related synaptic plasticity. Steven Siegelbaum and his colleagues study the mechanisms by which both synaptic transmission and neuronal excitability are modulated during learning. During the past year this laboratory has extended its studies of how neuronal activity can lead to a long-lasting enhancement in synaptic transmission between neurons in the hippocampus. This long-term potentiation (LTP) of synaptic transmission is of great interest as it is thought to provide the cellular mechanism underlying learning and memory. Defects in LTP moreover are thought to underlie diseases of learning and memory, including Alzheimer’s disease. One key question is the extent to which LTP is due to an enhancement of transmitter release from the presynaptic neuron versus an enhancement in the sensitivity of the postsynaptic neuron to a fixed amount of transmitter release. They have approached this question by using a fluorescent dye that provides a marker of presynaptic function. By imaging dye uptake and release from presynaptic neurons before and after LTP, they can directly assay presynaptic function. Their surprising result was that LTP is not a unitary phenomenon. Rather distinct patterns of synaptic activity recruit distinct forms of LTP. One form appears to be solely due to a change in postsynaptic function. A second form recruits a presynaptic component. By studying mice with a genetic deletion of the neurotrophic factor BDNF, whose mutation has been implicated in human memory impairment, they have found that the two forms of LTP have distinct molecular requirements. Thus, BDNF deletion does not alter the postsynaptic form of LTP but it completely abolishes the presynaptic form. These results provide new insights into understanding how synaptic strength is regulated by activity and how impairments in this regulation can lead to memory impairment. Daniel Salzman studies signals related to emotional learning and behavior. In his experiments, monkeys perform a variety of tasks involving learning the value (positive or negative) of novel, neutral abstract visual images. He employs behavioral and psychophysiological quantitative measures of emotion to describe the emotional learning and behavior while simultaneously recording neural activity. The goal is to understand 1) how the neural signals could contribute to emotional learning, and 2) how such signals are correlated with quantitative measures of emotional learning and behavior. His initial target for study is the amygdala, a limbic brain structure implicated in emotional processing. To learn the value of an image, a number of computational processes must be executed: (1) The brain must form a neural representation of a visual image. (2) The representation of the image must be associated with a value in order to form a prediction about the outcome of a trial. (3) The value must be stored in memory prior to an operant response. (4) The value of the actual outcome of a trial (positive or negative) must be encoded in the brain. (5) The value of the prediction must be compared to the value of the actual outcome in order to drive adaptive changes in behavior on subsequent trials that reflect emotional learning. His initial recordings in the amygdala have found signals that could be implementing some of the computational processes identified above as important for driving emotional learning. These results have begun to reveal the neural processing within the amygdala that underlies fundamental aspects of emotional learning and behavior. Behavior and Cognition Michael Goldberg studies the neurophysiology of cognitive processes, correlating the psychophysical performance of a monkey with the activity of neurons in the monkey’s brain recorded while the monkey is performing a task. His particular interests are in the neural events underlying visual search, visual attention, spatial perception, and decision-making. During the past year he has had three major projects: (1) He has provided evidence for parallel processing of visual information in the lateral intraparietal area during ‘serial visual search.’ 2. He has defined more precisely the relationship between the effects of saccadic eye movements on the oculomotor localization of visual targets and neural activity in the visuomotor control system. (3) He has demonstrated a dissociation between the effects of visual attention on perceptual threshold and on manual reaction time. His work on spatial perception has shed light on the nature of spatial deficits in patients with parietal lesions, and his work on attention has relevance to patients with neglect, as well as those with attention-deficit disorder and schizophrenia. Vincent Ferrera studies the neurophysiological basis of working memory storage and decision-making in prefrontal cortex. The prefrontal cortex is part of a network of brain structures that are involved in sustained attention and working memory. Dr. Ferrera studies the neurophysiological basis of working memory storage and executive function (i.e. decision-making) in prefrontal cortex of monkeys and humans. In the past year he has made progress in two areas. (1) He has shown that the persistent activity of prefrontal neurons can encode attributes of moving targets even when these targets are made temporarily invisible. This is a possible neural correlate of object permanence, i.e. a mental representation of unseen objects. (2) He has begun a collaboration with Joy Hirsch (Neuroradiology) and the fMRI Research Center to study the neural basis of decision-making in monkeys and humans. The main question is whether it is possible to establish functional homology between human and non-human primate brains engaged in the same behavior. To answer this question he proposes to use fMRI in awake behaving monkeys to map brain regions that are activated during a perceptual categorization task, using a paradigm identical to one he is currently using in human subjects. The proposed experiments will open up a new avenue of research into cognitive processes that are dramatically impaired in schizophrenia, attention-deficit disorder, Parkinson’s disease, and Alzheimer’s disease. Aniruddha Das studies the functional architecture of the brain that underlies the earliest stages of visual processing, starting at primary visual cortex (V1). Even this early stage in the visual system is tuned to pick out more complex aspects of a scene—entire surfaces, long contours, and 3-D depth relations. He has been able to relate this Gestalt-like perception to specific patterns of neural activity in V1. Over the last year he worked on two projects: Psychophysics: It is known that our ability to detect even very simple stimuli improves with practice. He found that learning – and, surprisingly, unlearning – can happen very rapidly. Over just a few days of training, people improve their ability to detect lines. This improvement is quite labile and a break of just a few days from training causes the detection threshold to revert to its original value. This rapidity of learning and unlearning runs counter to our current understanding of plasticity and learning in early visual areas and Dr. Das is currently exploring the significance of these findings for models of visual cortical processing. Physiology: The basic premise underlying his work is that we have specialized neural circuits in V1 that help pick out smooth geometric shapes, textures, etc. Further, that these circuits are built up by intracortical interactions amongst neurons that detect short lines and edges. In collaboration with Charles Gibert (Rockefeller University) he has tested this premise by looking at the interactions between V1 neurons responding to short oriented line elements, using optical imaging in alert monkeys. He found that neurons responding to single short lines are indeed influenced strongly by the presence of other lines outside their receptive fields. The strength of this influence is determined by the geometric layout of lines in the surround: the influence is strongest for smoothly collinear lines and diminishes as the lines are pulled farther away, or are moved away from collinear. These results suggest that these intracortical interactions lie at the heart of our being particularly sensitive to the presence of smooth curves or object boundaries in our visual surrounds. Jacqueline Gottlieb investigates the neurophysiological mechanisms by which the posterior parietal cortex controls spatial attention. The posterior parietal cortex in humans has been implicated in the ability to direct attention, as well as in motor control. In the past year, she began investigating the neural mechanisms underlying attention and motor preparation in one portion of the parietal cortex of the monkey. The cortical area she is working on was thought to be involved in directing spatial attention and/or in the preparation of eye movements to salient locations. To see if this area may also contribute to behavior beyond eye movements, she tested the electrical activity of its neurons while monkeys engaged in a task that required attention and hand movements, but no eye movements. She found that these parietal neurons have very strong and characteristic responses, encoding the relationship between the attended stimulus and the monkey’s hand movement. These findings require us to extend and revise our view of this area’s function, and attempt to understand it not on strict terms of attention and intention, but in the broader sense of visuo-motor integration. Ning Qian performs computational and psychophysical studies of visual information processing in humans. He has constructed physiologically and behaviorally-based models for perceptual learning and adaptation in the orientation domain, for structure-from-motion perceptual phenomena, and to explain the effect of vertical disparity on depth perception and the role of stochastic resonance phenomena in visual sensory perception. Such models are needed to determine the algorithms used by the nervous system to perform perceptual tasks. During the past year, he made two fundamental contributions in this area: (1) Motion Rivalry. There is an ongoing debate as to whether binocular
rivalry involves competition among monocular cells or binocular cells.
Dr. Qian investigated this issue psychophysically. He found that binocular
rivalry for two specially designed test stimuli was significantly reduced
compared with the normal rivalrous control, but not completely eliminated
compared with the non-rivalrous control. Therefore, both monocular and
binocular motion signals appear to contribute to motion rivalry, suggesting
that motion rivalry must involve competition among both monocular and
binocular cells. Claude Ghez investigates the mechanisms of trajectory control and motor learning in reaching and pointing movements. His recent studies have shown that trajectory errors 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 calibration of visuomotor reference axes and scaling. Brain imaging studies have revealed that these psychophysical distinctions are mirrored in activation of distinct cortical and subcortical networks during learning. René Hen’s research is based on the theme that single gene mutations can influence complex behaviors such as aggression, impulsivity, vulnerability to drugs of abuse, fear or anxiety, and attention deficit disorder. Using gene-targeting approaches to affect various serotonin receptors, a substance P receptor, and transporters for monoamines, he has generated animals with a number of behavioral abnormalities that are reminiscent of various features of human psychiatric diseases. This research has led to greater understanding of the etiology of and rational therapeutic approaches to psychiatric diseases. Recent studies examined the mechanisms of action of antidepressant and anxiolytic drugs. (1) Anxiety. Expression of serotonin-1A receptors in the forebrain is required to mediate the behavioral effects of the serotonin-selective reuptake inhibitor fluoxetine. Rescue of the phenotype is not dependent on the presence of the receptor in the adult, but rather requires receptor expression at some earlier stage in development. (2) Depression. He showed that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin-1A receptor-null mice were found to be insensitive to the neurogenic and behavioral effects of fluoxetine. Further, X-irradiation of a restricted region of the mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus. John Koester uses electrophysiological methods to study the excitability of identified Aplysia neurons. He analyzes the functional properties of voltage-gated membrane ionic currents in neurons that play key roles in generating specific behaviors. He determines how the biophysical properties of a particular neuron arise, and how they are adaptive for that neuron’s role in generating behavior. Most recently he has collaborated with Abraham Susswein (Bar Ilan University) on an analysis of the role of voltage-gated potassium channels in determining the functional properties of plateau-generating neurons that trigger feeding movements in Aplysia. Neural Development and Regeneration John Martin uses animal models to study the development and regeneration of neuronal circuits in the spinal cord. One of the principal research programs in his laboratory is to identify the mechanisms underlying postnatal development of the corticospinal (CS) system, which is important for controlling voluntary movements. His goal is to determine the role of motor behavioral experience and neural activity in shaping early development of connections between the brain and the spinal cord and in development of motor functions. During the past year he has completed three studies: (1) He showed that preventing an animal from using one of its arms during early postnatal life has a permanent effect on development of connections between the brain and spinal cord and on motor skills. This study is the first to demonstrate an early critical period for development of motor systems connections. (2) He showed that the period during which behavior is so important is also a period of rapid development of synapses between corticospinal axons and spinal cord neurons. (3) He devised a method to promote growth of developing corticospinal axon terminals using electrical stimulation. This finding has important implications as a novel therapy for treatment of young children with impairment of the developing corticospinal tract, which typically leads to cerebral palsy. In a separate research program Dr. Martin develops methods to promote recovery after spinal cord injury. This year he completed a study that demonstrated an innovative approach for bypassing a spinal cord injury to promote recovery of motor functions. A spinal nerve that originates above the level of a spinal injury is disconnected from its target muscle and the cut end is inserted directly into the spinal cord below the injury. Motor axons in the nerve bridge retain their connections with the brain at their origin and regenerate novel connections with spinal neural circuits at the insertion site below the injury. As novel synaptic connections develop between the regenerating motor axons and spinal networks, supraspinal motor control signals can be routed via the axons in the inserted nerve to bypass the injury. This approach is feasible for humans with spinal injury because the procedures are minimally invasive and have no untoward consequences. Moreover, because scaring at the injury site is not a factor, this approach is especially well suited for patients with chronic spinal injury. This study has great potential for promoting motor function after spinal injury. Lorna Role, in collaboration with David Talmage (Institute of Human Nutrition), conducts experiments probing the mechanisms that underlie the making and breaking of CNS synapses. Their particular focus has been in two areas: (1) identifying the molecular signals underlying the formation and maintenance of central cholinergic circuits (specifically those implicated in Alzheimers’ disease) and (2) determining the role of neuregulin-1 (Nrg1) in the establishment and plasticity of circuits whose functions go awry in certain neuropsychiatric disorders (e.g. schizophrenia). During the past year several of their efforts on defining the functions
of Nrg 1 have come to fruition. (1) One study outlined a novel signaling
mechanism employed by (at least) the type III Nrg1s that supports communication
between pre and postsynaptic cells. (2) The Nrg 2 gene has been assessed
and compared with Nrg 1 in detail. (3) Investigations of signaling mechanisms
between Type III Nrg1 and its erbB partners are revealing that this “bi-directional”
signaling capability may contribute to fundamental aspects of myelination,
the survival of pre and post synaptic partners, the establishment of specific
synapses and the maintenance of key CNS circuits. EDUCATIONAL PROGRAMS Graduate Education. The faculty of the Center for Neurobiology and Behavior has joined with faculty members from various departments uptown and from the Departments of Biological Sciences and Psychology downtown to form an interdepartmental Doctoral Subcommittee in Neurobiology and Behavior. Darcy Kelley (Biological Sciences) and John Koester are the co-directors. This program has 62 faculty members distributed across both campuses of the university. Their expertise covers virtually all aspects of neural science. The program helps to catalyze interactions between faculty and students in departments as diverse as Biology, Psychology, Biomedical Engineering, the basic science departments at the medical school, and the Departments of Neurology and Psychiatry. Students in the program have a strong interest in clinically relevant research. There are 55 students in the program, three of whom have HHMI fellowships, four have NSF Fellowships, and eight have NIH NRSA fellowships. Postgraduate Education. The Center’s postdoctoral training activities are partially supported by an NIMH-sponsored training grant in Neurobehavioral Sciences headed by John Koester. Our graduate courses are also open to post-doctoral fellows in the Center on an optional basis and all fellows on the training grant take the course Neuroscience of Neurological and Psychiatric Disorders, co-directed by René Hen and Steve Rayport. John Martin is a co-director of a Continuing Education Course course in the Basic and Clinical Neurosciences, which involves participation of several faculty members from the Center. Other. John Koester, together with Tim Pedley (Chairman of Neurology) and Dan Goldberg organized a five-day course on basic and clinical neuroscience under the auspices of the New York Times Company Foundation Immersion Institutes. Twelve science writers from across the country attended lectures at NYSPI by various clinical and basic science faculty on newsworthy neuroscience topics. The Center organizes an annual Neuroscience Poster Show, an open event at which faculty, students and postdocs from the basic and clinical departments from both campuses present their posters from recent scientific meetings. Every other year the faculty and trainees attend a two-day Retreat at Arden House Conference Center. All faculty and trainees in the doctoral program, as well as postdoctoral fellows, are invited to either give a talk or present a poster, and to participate in social activities. The Center sponsors a weekly series that features distinguished neurobiologists from throughout the country, as well as presentations of their current research by students, post-doctoral fellows and faculty members from the Columbia neuroscience community. 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