Compiled by Carolan Gladden and Shelley Marquez
We gratefully acknowledge the support of the Kavli Foundation.
The Kavli Institute for Brain and Mind is now an institute with walls, since a celebration on June 9, 2010 heralded the opening of the KIBM Laboratory of Genetics and Neurobiology. Situated on the first floor of the AP&M Annex, the 1500 square foot space has been turned into a wet lab with funds from the Kavli Foundation endowment, as well as the W.M. Keck Foundation, and the Legler Benbough Foundation. The lab houses studies on the relationship between genes and behavior, as well as the network principles underlying this relationship, in drosophila, cnidarians (jellyfish), paramecium, and cyanobacteria. The focus is on these simple organisms to be able to monitor their networks as comprehensively as possible.
In January 2010, under the auspices of the Kavli Foundation, Professor of Neurobiology and KIBM Co-Director Nicholas Spitzer led a discussion on the intersection of neuroscience and nanoscience with nanoscience pioneers Kwabena Boahen of Stanford and Hongkun Park of Harvard. Prof. Spitzer has pursued groundbreaking studies into the activity and development of neurons and neuronal networks for some four decades, and in this discussion titled “Using Nanoscale Technologies to Understand and Replicate the Human Brain,” the esteemed trio ventured into such questions as how does the brain compute; can we emulate the brain to create supercomputers far beyond what currently exists; will we one day have tools small enough to manipulate individual neurons and, if so, what might be the impact of this new technology on neuroscience?
On August 13, 2010, during an Annual Cognitive Science Society meeting, themed “cognition in flux,” Jeff Elman (Cognitive Science Professor, Dean of the Division of Social Sciences and KIBM Co-Director) engaged in a wide-ranging interview with Roger Bingham on The Science Network, UCSD’s web-based video channel. The piquant exchange traces an intriguing history back to World War II, when the need to crack enemy codes first spurred brain/mind study. Soon after came early computers, and the success of the digital machine prompted such diverse disciplines as anthropology, mathematics, biology and philosophy to weigh in – especially in the nature vs nurture debate. However, as Prof. Elman describes it, “As a young institution UCSD was very free of tradition and free of disciplinary firewalls. Here in the 1980s computer scientists were talking to psychologists and psychologists were talking to biologists, and so UCSD was the site of the revolution.” (There is much more of interest in the 66-minute video, which may be viewed here: http://thesciencenetwork.org/programs/cogsci-2010/jeff-elman/)
Ralph Greenspan (Research Scientist and Associate Director of KIBM) joined UCSD full-time this year. He received a prestigious $1 million grant titled “A Universal Principle of Biological Networks.” The grant was awarded by the W.M. Keck Foundation, one of the world’s largest philanthropic organizations and one that has supported pioneering discoveries in science and other research for half a century.
Finding that there is a fundamental, unifying principle for the operation of biological networks, one that cuts across phylogeny and type of network, would revolutionize the natural sciences. This Keck project will utilize a research strategy to identify this principle. The concept is based on the idea of relational networks, in which the coordinated interactions among functional sectors of the network are more critical than the specific identities of any of the interacting components. The proposed strategy combines a program of experimental network perturbation and global monitoring in selected genetic and neuronal model systems, followed by theory development. The envisioned theory goes beyond the standard computational modeling to capture the essential, relational nature of the system at a higher level.
Dr. Greenspan has several other research projects funded by the National Science Foundation, the National Institutes of Health and the Army Research Office (see grant list on pages 18-19).
The Discovery Channel filmed Howard Poizner and Gary Lynch in Dr. Poizner’s lab on June 12, 2010, for a series called ‘Curiosity: The Questions of Our Life,’ on research of the future. The segment is on memory and will air in 2011. Dr. Poizner’s research on motion capture began with an Innovative Research Grant.
Shown in photo, on the left is series producer Kyle McCabe and on the right, series host Dr. Dan Riskin, who is wearing Dr. Poizner’s motion capture body suit, EEG cap and virtual reality head-mounted display. Dr. Riskin explored a large-scale virtual environment while his body movements and cortical EEG were simultaneously recorded and his memory monitored.
"Curiosity: The Questions of Our Life" is a 60-episode, five year series that aims to answer vital questions of human existence. Beginning in January 2011, a new one-hour episode of "Curiosity" will be shown each month. Dr. Poizner's Lab was filmed for the episode that focuses on memory. A recent New York Times article reports that the channel calls “Curiosity” a landmark series, drawing comparisons to “Planet Earth,” the 11-part environmental overview that received wide acclaim when it was shown in the United States in 2007. For more information about “Curiosity,” please click here.
In February Fred Kavli visited UCSD, meeting with Our Chancellor and touring the UCSD California Institute of Technology and Telecommunications. We also hosted visitors from the Norwegian Academy of Sciences on February 18, 2010. The distinguished visitors included Nils Christian Stenseth (President), Oivind Andersen (Secretary General), and Oyvind Sorensen (Chief Executive).
On May 1, 2010, KIBM sponsored the 2010 Kavli Institute for Brain and Mind Symposium in the Trustees Room at the Salk Institute for Biological Studies. The symposium featured presentations on the spectrum of research projects in progress by recipients of KIBM Innovative Research Awards.
The UCSD Academic Senate Council reviewers were favorably impressed by our achievements during the past five years and point to our Innovative Research Grants program as one of our greatest strengths. The summary report is appended at the end of this report.
Pat Churchland (Professor of Philosophy) retired this year, and we added the following faculty to our Advisory Board:
|Pamela Reinagel (Associate Professor of Neurobiology, UCSD) is interested in the neural basis of real-world sensory perception, combining theory and experiments to study how neurons encode visual scenes for transmission from the retina to the brain.|
|Anirvan Ghosh (Professor of Biological Science, UCSD). His lab studies the mechanisms that regulate both synapse formation and synapse specificity in the developing cerebral cortex.|
|Katerina Semendeferi (Associate Professor of Anthropology, UCSD), with an interdisciplinary education in anthropology and neuroscience, her research delves into the evolution of emotional and cognitive processes in hominoids.|
|Charles Stevens (Adjunct Professor of Pharmacology, Salk Institute), The work in his Molecular Neurobiology Laboratory centers on mechanisms responsible for synaptic transmission, using a combination of molecular, biological, electrophysiological, anatomical and theoretical methods.|
We will issue a call for new proposals for the Innovative Research Grants in spring 2011. Our annual symposium will be held on May 14, 2011. We are changing the venue from the Salk Institute for Biological Studies to UCSD’s San Diego Supercomputer Auditorium. We are also co-sponsoring a session on UCSD research (with the Temporal Dynamics of Learning Center) at the International Mind, Brain, and Education Society (IMBES) meeting in San Diego on June 11, 2011 (see brochure at end of document).
Based on the recommendations of our five year review, the Office of Graduate Studies has agreed to fund a graduate student researcher at KIBM for the next three years. The graduate student researcher will work with faculty across the disciplines that bridge brain and mind, and will coordinate graduate student activities at the Institute, including talk series, web updates, and special events. We are in the process of recruitment.
The 2010 KIBM Innovative Research Grants encompass a wide range of topics – from the playfully titled “Babbling Baby Neurons in the Dentate Gyrus” to “Is Seeing Believing?” and with such far-reaching explorations as “Human – Chimpanzee Neuronal Differences Using Pluripotent Stem Cells” in between. Selected from a total of 46 submissions, the 8 projects chosen for KIBM awards indeed represent innovative research at its best. Following are titles, researchers and précis for the 2010 Awards:
Larry R. Squire, Ph.D., Research Career Scientist, San Diego VA
Healthcare System, and Distinguished Professor of Psychiatry, Neurosciences, and
Psychology, University of California, San Diego; Jacopo Annese, Radiology, UCSD; David Amaral, Psychiatry, Behavioral Sciences, M.I.N.D. Institute, UC Davis
We have the extraordinary opportunity to carry out neurohistological analysis of the brains of two patients (EP and AB), who passed away recently after we had studied them for 13 and 24 years, respectively. Having anatomical information about amnesic study patients is now more essential than ever, because many pressing questions about memory focus on the relative contributions of the medial and lateral temporal lobe and on potentially different contributions to memory function of the anatomical components of the medial temporal lobe (e.g., hippocampus and adjacent cortex along the parahippocampal gyrus). It has rarely been possible to obtain neurohistological information from memory-impaired patients who have been well studied during life.
I am aware of 12 published cases, and our laboratory is responsible for 7 of them. EP is of enormous interest because his large medial temporal lobe lesion (as seen by MRI) was caused by viral encephalitis and yet is strikingly similar to the surgical lesion of the famous patient HM, who also passed away recently. EP’s brain will be prepared at UCSD in the same laboratory as HM’s brain and in the same time frame (in the laboratory of our collaborator, Jacopo Annese, Ph.D.). Accordingly, we will be able to compare the two brains and determine what specific aspect of EP’s lesion made his memory impairment more severe than HM’s impairment. Our patient AB is also of enormous interest because he wore a pacemaker and was ineligible for MRI. Accordingly, despite a circumscribed, moderately severe amnesia (caused by cardiac arrest) and suspected hippocampal damage, we have no information about the anatomical basis of his memory impairment. Both patients were studied extensively and quantitatively during life. EP’s data contributed to 31 publications, and AB’s data contributed to 71 publications. Anatomical information about these patients will be invaluable and will contribute substantially to the understanding of memory and memory impairment.
Michael Pitts, Department of Neurosciences, UCSD
Steve Hillyard, Department of Neurosciences, UCSD
Eric Halgren, Department of Radiology, UCSD
With the advent of modern neuroimaging, much excitement and optimism has surrounded the possibility of answering a fundamental question in cognitive neuroscience, namely, “what is the neural basis of consciousness?” Our current understanding of conscious and non-conscious neural processing, however, remains inadequate. Progress in this area requires not only the techniques of modern functional brain imaging, but also innovative experimental designs that isolate neural correlates of conscious experience. The current proposal introduces a novel experimental paradigm that, when used in conjunction with anatomically and temporally precise non-invasive neurophysiological measures, promises to provide fresh insights into the brain processes responsible for conscious perception.
The general idea behind the proposed research stems from the dramatic demonstration of “inattentional blindness” by Simons & Chabris (1999). In their experiments, observers viewed a movie and performed an attentionally demanding task, e.g. count the number of passes made by some basketball players while ignoring passes made by others. During this task, more than half of all observers failed to notice a confederate dressed in a gorilla costume who slowly walks across the court, stops in the center to thump his chest, and exits the other side. What observers find most striking is that a salient object (man in gorilla suit) directly passes through their center of gaze for such a long time while completely escaping their conscious awareness. Other studies have demonstrated inattentional blindness behaviorally, yet few attempts have been made to modify and simplify these experiments for use in brain imaging studies. In this proposal we introduce an experimental design in which salient but irrelevant visual stimuli, when attention is directed elsewhere, go completely unnoticed even after more than 400 appearances. These same stimuli are easily detectable when expected and attended. The goal of the proposed research is to use this new paradigm along with anatomically-constrained (structural MRI) magnetoencephalography (MEG) and electroencephalography (EEG) to track the timing, locations, and interactions between brain events associated with conscious and nonconscious processing.
Katerina Semendeferi; Anthropology, UCSD, Alysson Muotri, School of Medicine, UCSD; Fred Gage, Salk Institute
Accumulating evidence suggests that the evolution of the human brain, after the split from the common ancestor with the chimpanzees, was accompanied by discrete modifications in local circuitry and interconnectivity of selected parts of the brain. These selective changes may have occurred in specific parts of the cortex and/or selected subcortical structures. Here we propose to identify and characterize a neuronal subpopulation that we believe will be proven to differ between humans and chimpanzees. Morphologically distinct cortical neurons from humans and chimpanzees will be isolated from brain tissue using laser-capture procedures after Golgi staining. The expression profile of small RNAs from both human and chimpanzee neurons will be compared using deep sequencing and bioinformatics analysis. Unique candidates will be used to model genetic reporter systems to allow the identification of the putative human specific neuronal population. Modeling neuronal differentiation will be achieved from induced pluripotent stem cells, generated from human and chimpanzee somatic cells. It is our expectation that this proposal will lead to novel knowledge regarding the developmental and evolutionary aspects of human-specific neuronal populations.
Stefan Leutgeb and Yimin Zuo, Neurobiology, UCSD
It is a mystery how spatial information of our environment is represented in the brain and how our mind knows where we are. Place cells in the hippocampus and grid cells in the entorhinal cortex are at the heart of such brain circuitry, which integrates external sensory information to construct an internal sense of space. Place cells fire at a specific location in the environment. They receive their input from entorhinal cortex, which contains a number of cell types that are spatially tuned. The most strikingly organized spatial firing is seen in the dorsomedial subdivision of entorhinal cortex, where the firing pattern of each grid cell forms an exact matrix of repeating equidistant triangles that cover the entire environment available to the animal. We propose to study how the grid cells in the entorhinal cortex and the place cells in the hippocampus are connected during development to ensure proper function and whether lesions to this area of the brain can change the organization of connectivity to the extent that disrupts spatial orientation and spatial memory. We will also examine whether the reinstatement of developmentally regulated genes can result in restoring sufficient organization of the connectivity along the dorsoventral axis to result in partial recovery of spatial cognition/perception of the animal. These studies will not only shed light on how this spatial cognition circuitry is assembled to give rise to a sense of space but also provide tools to help regenerate the circuits following injury or degeneration such as in Alzheimer’s Disease.
Ian Nauhaus; Ed Callaway, Salk Institute
Kristina Nielsen; Tatyana Sharpee, Salk Institute
Primary visual cortex (V1) is the first cortical stage to receive visual input and has provided a model system for understanding sensory processing as a whole. There has been some success in building models that characterize V1 function at the level of individual neurons using artificial stimuli. However, to ultimately converge on an understanding of how the neural code represents the outside world, we must measure the activity of large populations under more natural conditions. A paradigm that satisfies the latter constraints is more demanding from both an experimental and computational standpoint. The collaboration in the proposed research is designed to satisfy these demands.
Here, we propose the use of two-photon imaging of bulk loaded AM esters to measure the activity of multiple neurons in V1 that are stimulated with natural movies. Traditional methods for capturing the response properties of each neuron can’t be used with natural stimuli. For this, we will employ a novel computational technique that maximizes the amount of mutual information between the visual stimulus and the neural activity. Once we have the receptive fields, we will examine how the neurons act in concert to encode the natural stimuli. This study will incorporate powerful experimental and theoretical tools to help decode the language by which the cortex represents sensory input.
Hendrikje Nienborg, Ed Callaway, John Reynolds; Salk Institute
Ali Cetin, John Curtis; Salk Institute
How activity in neurons gives rise to conscious perception is one of neuroscience’s most fundamental puzzles. We strive to understand the neural mechanisms underlying visual perception of the world at the network level and with single neuron resolution. In the past half-century since the classical work by Hubel and Wiesel, visual neurophysiologists have enormously advanced our knowledge of the feed-forward receptive field properties in the visual cortex. However, although we know from anatomical studies that the majority of afferents in cortex constitute feedback projections, their functions and significance are still largely unknown and controversial. In light of their proportion, cortico-cortical feedback projections are likely to play a key role in perception. In humans and monkeys detection of a visual stimulus depends on expectation, context and selective attention. Moreover, as demonstrated by many illusions, visual perception depends on the context such as prior experience and memory, preceding stimuli, surrounding stimuli and it is subject to Gestalt influences. Each of these perceptual phenomenon is hypothesized to be mediated by feedback projections, and many of these have been found to be altered in schizophrenic patients. This points to a possible involvement of cortico-cortical feedback connections in the pathophysiology of schizophrenia.
Several theories on the role of feedback projections exist, but until now methodological limitations have made it nearly impossible to test these empirically. Novel innovative approaches put us in the unique position to address the role of cortico-cortical feedback in visual perception in the awake monkey animal model. This interdisciplinary project will capitalize on novel genetic techniques to target specific cortico-cortical projections in vivo, and stimulate these projection neurons with light. We will combine this technique with state-of-the art electrophysiological techniques, animal behavior and computational analyses. We will first quantify the effect of activating cortico-cortical feedback from extrastriate visual cortex V2 and V4 on neurons in the primary visual cortex and next examine its effect on the animal’s visual perception. If successful, this approach opens the possibility to examine the full richness of perceptual experience by targeting feed-back projections from a wide range of structures
Thomas D. Albright and Sergei Gepshtein, Salk Institute, Vision Center Laboratory
Modern sensory biology rests on two tenets. First, activity of sensory neurons underlies perception. Second, sensory systems adapt to environmental change. To make these premises concrete and precise, we developed a normative‐economic framework for investigating how sensory neurons (a limited resource) should be allocated to stimulation. According to our analysis, the understanding of how activity of single neurons relates to perception requires a study of sensitivity across neurons tuned to the entire range of perceptible stimuli. We demonstrate that this approach promises to resolve some of the longstanding contradictions that have plagued previous attempts to understand the relationship of perceptual and neuronal sensitivity.
We predict that the effect of prevailing environment on visual sensitivity should depend on how a particular stimulus, or a neuron exposed to the stimulus, relates to the distribution of sensitivity across all visible stimuli. Proposed studies will test these predictions using speed adaptation as the experimental paradigm. The proposed research constitutes a richly interwoven collection of theoretical, psychophysical, and neurophysiological approaches to the topics of neuronal mechanisms of perception and visual adaptation. Experiments have been designed to yield an unprecedented body of comprehensive data bearing on the spatiotemporal sensitivity of the primate visual system and the effects of environmental change.
Andrea A. Chiba, UCSD, Cognitive Science; Rusty Gage, Salk Institute; Janet Wiles, University of Queensland; Laleh Quinn, UCSD Cognitive Science; Lara Rangel, UCSD, Graduate Program in Neuroscience
A unique property of the dentate gyrus of the hippocampus is its ability to continually generate new neurons in the adult brain. A theoretical framework regarding the functional properties of these new neurons was recently set forth in a computational model by Aimone, Wiles, and Gage (2009). Yet, there are few studies performed in behaving animals that describe the properties of neurons in the dentate gyrus and none that can determine the properties of newborn neurons in the dentate gyrus. As newborn neurons in the dentate gyrus region of the hippocampus mature and integrate into the existing hippocampal circuits the dynamics of their activity may mature as well. The activity of adult-born neurons during their immature state as they transition into mature granule cells has yet to be characterized in vivo. Preliminary in vivo electrophysiological recordings in the dentate gyrus of the awake, behaving rat reveal a small subset of granule cells that exhibit initially indiscriminate firing to a spatial environment which becomes more specific over the course of days, thus dramatically increasing the information content of their activity over a very short timescale. This plasticity occurs even in the presence of other granule cells that can maintain stable place field activity over the course of months.
The proposed study aims to examine whether this plasticity is a property of mature granule cells in the dentate gyrus or if it is instead a mechanism by which immature adult-born neurons “babble,” or test a spatial environment, before becoming dedicated to encoding specific information as mature granule cells. In this experiment, the information content of granule cell activity over time will be examined during behavioral manipulations designed to examine their coding while implementing tools for temporarily reducing levels of neurogenesis in the rat dentate gyrus. The proposed interdisciplinary experiments will be the first to investigate the physiological role of adult-born neurons in the in vivo hippocampal circuit, and will provide valuable insight regarding the possibility that theoretical principals in information theory may generalize across multiple scales of learning and development.
Principal Investigators:Ralph J. Greenspan and Ursula Bellugi
Towards the goal of establishing a genetic model for social cognition, the aim is to construct strains of drosophila that contain the 11 mutations of the fly genes homologous to those deleted in Williams Syndrome, a human genetic disorder with distinctively enhanced sociality.
After placing each of the mutations ELN, LIMK1, STX1A, BAZ1B, CYLN2, NCF1, RFC2, FZD9, FKBP6, TML2,BCL7B, and EIF4H onto a neutral genetic background, the researchers began testing individuals as heterozygotes in each WS gene for those behaviors in Drosophila that have been shown to have a social component (courtship, aggression, larval burrowing, and circadian entrainment). Thus far, there are indications that at least two of the genes, LIMK1 and CLIP190, are capable of significantly altering social behavior as individual heterozygotes. Further tests are under way to test for interactions among genes of the Williams Syndrome set.
Principal Investigators: Ed Callaway, John Reynolds
Co-Investigators: Stephani Otte, Andrea Hasenstaub, Takuma Mori, Emily Anderson
Isn’t it a wonder that in spite of nearly overwhelming quantities of information bombarding our sensory systems every minute of the day, we are able to reduce, condense, amalgamate it into a manageable flow and to focus on only what relates to whatever is our current task? And the big question is how do we selectively attend to one aspect of our environment and back-burner the rest?
For starters there’s mounting evidence from both primate and human studies suggesting that:
It’s true that basic mechanisms underlying gamma frequency synchronization have been found to be the same in many species. What has not been understood is the way that the synchronization of these neurons affects their targets. How do changes, such as attentional enhancement in gamma activity, interact with small circuits or single cells to control input processing? And just what is it that makes these changes happen?
Now, taking advantage of the similarities across different species, a team of Salk Institute researchers that includes electrophysiologists, engineers, systems biologists and virologists is utilizing their Kavli Foundation award to study the functional and physiological consequences of gamma frequency spike synchronization of neurons in transgenic mice.
Making use of innovative genetic, viral and computational techniques, the collaborators aim to better understand the biological underpinnings of selection and attention. Using a real-time neuron/computer hybrid system to introduce controllable conductances into neurons, as well as targeted recordings of specific neuronal types, they have determined the differing ways that different types of neurons respond to gamma frequency synchronized inputs.
These techniques have led the group to discover systematic differences in the way distinct neuron types respond to changes in gamma frequency oscillatory synchrony and how changes in this synchrony change the neurons’ processing of input. Further, they have identified specific electrical properties that account for the differences.
Interestingly, during cortical activity these properties can quickly change, suggesting that the cortex may indeed make moment-to-moment adjustments in filtering input to fit moment-to-moment changes in functional needs --- such as what input to process and what to ignore.
Currently the team is creating viral tools to change the way that cells integrate gamma frequency inputs and to affect the emergence of gamma oscillations. Through this work they hope to uncover the role of these oscillations in attentional selection, in the long term potentially leading to treatments for attentional disorders in humans.
Principal Investigator: Gene R. Stoner, Salk Institute
Co-Investigators: Hulusi Kafaligonul, Ladan Shams, Salk Institute
As we are all aware, objects and events encountered in our daily lives stimulate several of our senses at the same time. Generally, however, the processing within the brain of objects and events is segmented, with different brain areas responding to different sensory stimuli.
The temporal dynamics of different sensory modalities also differ. For example, the processing of sound within the ear is much faster than the processing of light within the eye. This means that the brain’s responses to a single auditory-visual event occur at different locations and in different timeframes. And learning just how these spatially- and temporally-distributed activities interact to create our unified multisensory experiences is one of the most fundamental problems in neuroscience.
Several recent studies have reported multisensory interactions within lower-level cortical areas thought to be sensory-specific. For instance, functional Magnetic Resonance Imaging (fMRI) scans suggest that activation in human cortical area MT+ -- widely accepted to underlie visual motion perception – is indeed modulated by auditory stimuli. But it is still not known what such activations reflect at the level of the single neuron.
Thus, the longterm goal of this team’s research is to understand the neuronal mechanisms underlying such cross-modal modulation. Their unusual experimental paradigm was inspired by an illusion developed just last year by U.K. scientists Elliot Freeman and Jon Driver. In
the illusion, brief sounds systematically change the perceived direction of visual motion stimuli, although the sounds themselves provide no motion cues.
The illusion is believed to rely on the ability of sound to “capture” the timing of visual stimuli, a phenomenon known as temporal ventriloquism, and with their KIBM award the research team has successfully adapted it for use in certain neurophysiological experiments.
It seems that Freeman and Driver used “long-range” visual stimuli, involving large spatial and temporal displacements, and the neuronal basis of these is believed to involve higher-order processing than is associated with the “short-range” motion stimuli that activate area MT. Although it was believed unlikely that the F&D illusion would extend to short-range stimuli, the team happily discovered that it does. This has led to the hypothesis that area MT underlies this cross-modal illusion.
The team is now testing several other hypotheses about the way that auditory stimuli shift the timing of visual stimuli. And soon to start are neuronal recording experiments from macaque monkeys. This will be the first examination of auditory-visual perceptual interactions at the cellular level in area MT. By examining this neuronal data together with the human behavioral experiments, they envision being able to identify the mechanisms that underlie the amazing unified multisensory experience of the world that we all enjoy.
Principal Investigator: Fred H. Gage, Salk Institute
Co-Investigators: Wei Deng, Michael Saxe, James B. Aimone, Mark Mayford
That our brains generate new cells throughout our lives is no longer big news, but until now it has not been known just what these newborn neurons do. Uncovering this knowledge has been a quest of Dr. Gage’s group, and their KIBM Award provided an impetus for their investigations.
We now know that within the human brain’s 100 billion neurons (a fraction of which are shown in this slide from Dr. Gage) new neurons are continuously generated. And the most active area of neurogenesis is in the hippocampus, where information is processed and distributed to appropriate storage sections in the brain, ready for efficient memory recall. “Every day, we have countless experiences that involve time, emotion, intent, olfaction and many other dimensions,” says Gage. “All the information comes from the cortex and is channeled through the hippocampus. There, they are packaged together before they are passed back out to the cortex where they are stored.”
It has been believed that one of the areas where adult neurogenesis occurs is the dentate gyrus (DG) of the hippocampus. The generation and integration of new neurons into the existing circuitry provide the DG an additional level of plasticity. However, what impact this additional plasticity might have on hippocampus-dependent memory formation was largely unknown. And the exact role of the DG in learning and memory remained elusive until this study tested whether the DG is involved in pattern separation, the process by which overlapping neural representations are separated to keep episodes independent of each other in memory.
Now in this project the researchers investigated the role of hippocampal neurogenesis in the DG’s function, with special attention to how it might influence the process of pattern separation. Using a set of focused experiments with two distinct strategies to selectively shut down neurogenesis in the DG of adult mice, the researchers found specific impairments in spatial discrimination. In the first, mice had to learn the location within a radial maze of a food reward presented in relation to the location of an earlier reward. Mice without neurogenesis had no trouble finding the new location, as long as it was far enough from the original, but they could not differentiate between the two when they were close together. Next, a touch screen experiment offered confirmation of the finding and also revealed that the mice had no problem recalling spatial information in general.
Thus, the DG has been shown to be important for pattern separation, and these results show that adult neurogenesis appears to be important for the ability of the DG to optimally perform that function. In short, the researchers believe that new brain cells help us to distinguish between memories that are closely related in space.
|Dr. Gage is the recipient of multiple prestigious awards including, most recently, the Kelo Medical Science Prize for “His discovery of the physiological role of adult neurogenesis in mammalian brains.”|
Principal Investigator: Tim Brown, UCSD Neuroscience
Co-Investigators: Eric Halgren, UCSD Radiology Anders Dale and Doris Trauner, UCSD Neuroscience
In human psychological development, “words” assume a role of prime importance as the fundamental units for organizing language and much of higher cognition as well. Recent studies, using functional Magnetic Resonance Imaging (fMRI), reveal that school-age children and young adults use a strikingly different set of brain regions to perform lexical tasks that require access to a word’s meaning. In fact, it has been argued that maturation of receptive and expressive word use is the very essence of the development of human cognition.
Indeed, the performance on many single word processing and production tasks by children from elementary school age well through their teens shows a slow progression toward becoming adult-like. This protracted maturational timecourse is thought to reflect developmental changes in the way the brain represents and accesses words and their associated codes (sounds, meanings, spellings).
To test this new theoretical developmental framework, UC San Diego researchers Tim Brown, Project Scientist in the Department of Neurosciences; Eric Halgren, Professor of Radiology and Adjunct Professor of Neurosciences and Psychiatry; Doris Trauner, Professor of Neurosciences and Pediatrics; and Anders Dale, Professor of Neurosciences and Radiology and Adjunct Professor of Cognitive Science, employed their KIBM Innovative Research award to conduct a unique study of school-age children. Theirs is the very first study using multimodal, anatomically constrained magnetoencephalography (aMEG) methods with children. This innovative new tool integrates neurophysiological data with information about the individual’s brain anatomy.
The ability to measure and localize brain activity with millisecond timing gives important leverage for making inferences about which specific cognitive processing operations are occurring and specifically where they are occurring that are impossible with fMRI. Thus, results of the children’s semantic processing of both words and pictures showed repetition effects in visual perceptual locations that adults did not show. Conversely, adults showed word and picture repetition effects in higher order locations that children did not show. And, perhaps most importantly, the semantic repetition effects in children’s visual perceptual areas were shown to occur during what are typically later-stage semantic latencies (~400 ms), providing strong evidence that these regions support semantic processing at this younger age.
|Fig. 1. Dynamic statistical parametric map (dSPM) of brain activity at 400 ms in a child during performance of the shoebox task (“Is the object small enough to fit into a shoebox?”) to word and pictures.|
|Fig. 2. dSPM of averaged brain activity at several latencies in six children aged 9 to 11 years during performance of the shoebox task to words and pictures.|
This work addressed several important questions about human functional brain development not previously tested. And, although data collection and analysis are not yet complete, the group’s findings to date support a new theoretical framework for the mind-brain relationship in developing lexical semantics. This suggests a shift from concrete, perceptually based word and object representations in school age children (“anchored in seeing”) to more abstract, conceptually based representations in young adulthood (“anchored in thinking”).It has now been indisputably demonstrated that aMEG can be used successfully in children to obtain individual and group maps of cortical functional organization for comparison with other ages or with clinical populations. The KIBM Award has also laid the groundwork for a comprehensive, systematic examination of the cortical development of lexical semantics, as well as providing the scientific basis for a K08 Career Development Award proposal submitted by Dr. Brown to the National Institute of Child Health and Human Development. Future studies will apply these new technologies and results to children with developmental brain disorders such as those with perinatal stroke.
Our expenditures increased over the past year with the addition of Dr. Greenspan’s research program and his laboratory renovations. We reduced our IRG awards temporarily in 2009-10 because the endowment income was temporarily reduced in 2008-09 and 2009-10 due to the economic climate. UCSD permanent contributions were cut slightly in 2009-10 as a result of permanent budget cuts to the campus; but we also received a commitment from the Office of Graduate Studies for a graduate student research position, which is effective for 3 years and may be renewed.
These awards have been reported in the past year as having been funded partly as a result of Kavli Innovative Research Grant seed funding.
In addition, Dr. Greenspan has been awarded the following grants to his lab in the past year.
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