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Akaysha C. Tang Research Statement 1
My work falls within the broad area of systems neuroscience and cognitive neuroscienc...
Akaysha C. Tang Research Statement 2
As cross-species investigation is critical for valid generalization of basic research...
Akaysha C. Tang Research Statement 3
suggesting a membrane mediated effect among the neonatal novelty exposed rats (in add...
Akaysha C. Tang Research Statement 4
theoretical model of stress modulation of learning and memory and (2) testing the val...
Akaysha C. Tang Research Statement 5
2003, abs). This basic paradigm potentially provides a framework for studying the str...
Akaysha C. Tang Research Statement 5
2003, abs). This basic paradigm potentially provides a framework for studying the str...
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My work falls within the broad area of systems neuroscience ...

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Transcript of "My work falls within the broad area of systems neuroscience ..."

  1. 1. Akaysha C. Tang Research Statement 1 My work falls within the broad area of systems neuroscience and cognitive neuroscience. In the past fifteen years, I have examined the relationship between learning and memory and their neural substrates using behavioral, physiological, neuroanatomical, in vitro electrophysiological (brain slice), in vivo electrophysiological (EEG and MEG), and computational techniques. I have worked across species from invertebrates, rodents, to humans. The research focus is on the understanding of sources of variations in learning and memory, the mediating mechanisms at multiple levels of analysis, and the development of new techniques that improve the capacity of observing and interpreting changes associated with learning and memory. The results of my work are likely to improve our ability in diagnose dysfunctions of neural systems in mental disorders and possibly provide remediation for those who suffer from these mental disorders. 1. Pre- and Post- Doctoral Work GABAergic modulation of recognition memory. The key source of variations in learning and memory I have examined is the neuromodulatory system. As part of my PhD thesis work in Dr. Michael Hasselmo's lab at Harvard University, I investigated the modulatory role played by the inhibitory neurotransmitter GABA. Using brain slice electrophysiological technique, we found that GABAb agonist selectively modulates those synapses made by the intrinsic fibers of the olfactory cortex leaving the afferent fiber synapses little affected (Tang & Hasselmo 1994.). Using computational modeling techniques, we found that this selective modulation is critical for the network's ability to detect novelty/familiarity of a patterned input (Tang & Hasselmo 1996b). We tested and confirmed the model's predictions for recognition memory performance in rats whose GABAb receptor system was perturbed with systemic injection of the GABAb agonist baclofen (Tang & Hasselmo 1996a.). Learning and memory in invertebrates. I broadened my training by spending one year in Dr. Lawrence Cohen's lab at the Department of Cellular and Molecular Physiology, Yale University. I applied multivariate analysis techniques to optical imaging data to reveal multiple expressions in firing patterns across hundreds of neurons underlying non-associative learning (habituation) in the invertebrate aplysia (Falk et al 1993; Wu et al 1994). In addition, I spent one and a half summers in Dr. Daniel Alkon's lab in the Marine Biological laboratory (MBL) designing and implementing a new learning experiment and provided the first demonstration that operant conditioning can be obtained in hermissenda (another invertebrate model system for learning and memory). These experiences exposed me to multiple animals and multiple levels of analysis and gave me a broad background in the neurobiology of learning and memory. Neuromodulation of spike timing. To gain deeper understanding of how neuromodulators can affect learning and memory in the mammalian brain, I studied the effects of neuromodulation on spike timing with Dr. Terrence Sejnowski in his Computational Neurobiology Lab, at the Salk Institute. Using both whole cell patch clamp and single-neuron compartmental modeling techniques, I found that the spike timing changes as a result of increasing concentration of the several classical modulators were relatively small (a few milliseconds) despite large increases in neuronal excitability (Tang et al 1997). Thus, neuromodulatory effects on memory related mechanisms are likely to be primarily mediated through changes in neuronal excitability and in network properties (such as the selective modulation of different fiber pathways shown in both my and my PhD advisor's work). 2. Research at University of New Mexico
  2. 2. Akaysha C. Tang Research Statement 2 As cross-species investigation is critical for valid generalization of basic research from animal models to human cognitive function, I address my research questions using both rodent and human subjects. This choice reflects a fundamental belief that such coordinated effort is critical for the transfer of principles and laws discovered from animal research to the understanding of human cognitive function and dysfunction. The core part of my cognitive neuroscience program consists of two parallel lines of research: one dealing with the development of animal (rodent) models of cognitive development, focusing on the neuromodulatory role of stress hormones in learning and memory and underlying neural mechanisms, and the other addressing parallel questions in humans, with an additional emphasis on the utilization of new methodologies for obtaining non-invasive measurements in humans that are parallel and as similar as possible to those typically obtained invasively in animal models. 2.1 Animal studies: Early Environment, Memory, and the Role of Stress Response System in a rodent model This line of research focuses on the role of neuromodulation in learning and memory, specifically the modulatory role of the stress hormone corticosterone. I use an early environmental manipulation as a tool to create individual differences in learning and memory and parallel individual differences in stress responses, synaptic plasticity, and brain lateralization. During this process, we made several contributions to the literature (as detailed below) concerning the relationship among early experience, stress modulation of adult learning and memory, and their asymmetric expression within the brain. Enhancing learning and memory. We improved upon the well-known neonatal handling procedure to isolate the novelty component from maternal separation and experimenter handling. By doing so, we demonstrated that adult learning and memory can be enhanced among animals who were exposed for 3 min a day to a relatively novel environment for the first 3 weeks of life (Tang 2001, from here on referred to as neonatal novelty exposure). By using improved testing and measuring instruments for spatial memory, we demonstrated that early life stimulation not only has a positive impact on learning in the Morris Water Maze task during senescence, as previously shown by Meaney et al (Science 1988 ∗ ), but has an effect throughout the entire lifespan (from as early as 4 weeks of age) (Tang 2001). By separately measuring acquisition and retention in a novel appetitive learning task, we expanded the impact of early life stimulation from aversive and stressful learning tasks (negative reinforcement) to appetitive learning situations that do not involve explicit stress (positive reinforcement) (Tang 2001). Using a novel design for social recognition memory, we demonstrated that the memory for a previously encountered individual was prolonged during adulthood among the rats who experienced neonatal novelty exposure, from less than 2 hrs to at least 24 hrs, thus expanding the impact of this early life stimulation to the social domain (Tang et al 2003). This series of behavioral work provides an emerging picture that the impact of subtle early life events on memory does not appear to be selective but includes both positive and negative reinforcement learning and spatial and social memory. Synaptic plasticity and stress hormone. Little was known from the neonatal handling literature concerning its effects on synaptic plasticity. Through electrophysiological studies using hippocampal slices, we provided the first in vitro evidence that neonatal novelty exposure was sufficient to induce persistent enhancement in adult long-term potentiation (LTP) at 7 and 13 months of age (Tang and Zou 2002) as well as adult long-term depression (LTD) at 7 months of age (Zou et al 2002 abs, manuscript in prep). By perfusing hippocampal slices with stress concentration of corticosterone, we found that the sensitivity of hippocampal neuronal excitability and plasticity to the stress hormone was also enhanced, with slices from the novelty exposed rats showing rapid modulation (a few minutes) by corticosterone,  reference other than my own.
  3. 3. Akaysha C. Tang Research Statement 3 suggesting a membrane mediated effect among the neonatal novelty exposed rats (in addition to the much slower genomic effect) (Zou et al 2001). The increased sensitivity to corticosterone modulation was consistent with a reduction in basal corticosterone concentration during adulthood among the neonatal novelty exposed rats (Tang et al 2003). This series of brain slice electrophysiology and physiology experiments suggest that neonatal novelty exposure induces parallel persistent changes in the stress response system and increases in dynamic range of synaptic plasticity which may mediate the observed learning and memory enhancement. Brain asymmetry in rats. Because the mechanisms mediating stress responses is known to be asymmetric, We added separate left and right measurements to our behavioral, anatomical, and electrophysiological experiments. At the behavioral level, neonatal novelty exposure induced a left shift in paw preference, suggesting a right-sided shift in brain asymmetry (Tang and Verstynen 2002), and a right turn preference during cage exploration, also suggesting a right-sided shift in brain asymmetry (see Tang and Reeb 2003 in press for explanation). At the neuroanatomical level, the right hippocampal volume in adult rats showed an increase relative to the left but only among those who received neonatal novelty exposure (Verstynen et al 2001). At the level of electrophysiology, when brain slices were examined separately for the left and right sides, the neonatal novelty exposure-induced increase in LTP and LTD and in sensitivity to stress hormone modulation were observed only in the right hippocampal slices (Tang 2003; Zou et al 2002 abs). These results provides compelling evidence that early stimulation-induced changes within the brain are asymmetrically distributed and expressed with right-side dominance. The recent report of an asymmetric distribution of the NMDA receptor subunits (NR2B) in the mouse adult hippocampus (Kawakami et al, Science 2003*) may provide the molecular mechanisms of our observed LTP and LTD asymmetry. Future plan. The work described above emphasizes the importance of neonatal novelty exposure while the work of others points out the importance of early maternal influence. The theoretical positions held by major players in the field have been that either the mild stress from novelty or the stimulation induced maternal care is responsible for the cognitive differences induced by neonatal handling. The maternal mediation hypothesis, proposed by Levine four decades ago and revived by Meaney and colleagues, currently stands uncontested. It remains unknown how environmental novelty and maternal familiarity together shape the development of the stress response profile and consequently modulate cognitive development. I plan to test an alternative hypothesis that maternal behavior modulates, instead of mediates, the impact of novelty exposure on the stress response system. New experiments will be designed to allow both the maternal and novelty effects to be concurrently investigated. Furthermore, I plan to test predictions of memory performance at the level of individuals from parameters of the stress response system, such as basal corticosterone concentration and recovery time, and from the measured synaptic plasticity. I will design and conduct new experiments in which measures of stress responses, synaptic plasticity, and memory are obtained in the same animal with interaction between these measures carefully minimized or counter-balanced. Finally, I plan to construct a computational model that (1) allows the prediction of individual differences in learning and memory from individual differences in stress response system parameters, (2) addresses the respective roles of novelty and maternal behavior in cognitive development, and (3) facilitates the generalization of such a theory from rodent to human cognitive development. 2.2 Human studies: Memory, Neural Plasticity, and the Role of Stress Response System This line of research attempts to bridge the gap between findings made from animal model systems and those from humans by (1) using the animal model as a more flexible tool for developing and testing the
  4. 4. Akaysha C. Tang Research Statement 4 theoretical model of stress modulation of learning and memory and (2) testing the validity of the model in explaining human learning and memory. The main challenge is to develop and validate the technical and methodological tools for obtaining measurements of similar theoretical constructs in humans that are comparable to those used in rodents. The first part of this long-term effort is to design and test new signal processing procedures and tools that allow non-invasive measurement of single-trial event-related activation of specific brain regions with millisecond temporal resolution. The second part is to apply the new methodologies to the problem of understanding basic associative mechanisms of learning and memory, its modulation by stress, and the relationship between individual differences in the stress response system and memory function. Developing methodology for non-invasive measurement of plasticity in humans using magnetoencephalography (MEG). MEG has the temporal resolution of milliseconds and can provide reasonable localization accuracy. If one wishes to obtain measures with signal to noise ratio similar to those obtained in vitro, one must average over hundreds of trials to improve the signal to noise ratio in the MEG sensor signals. We have applied a specific independent component analysis (ICA) algorithm, Cardoso’s second order blind identification (SOBI) to MEG data to decompose and separate signals due to the activation of specific brain regions from those due to noise arising from outside of the head. Two major papers have been published demonstrating that SOBI, as a preprocessing tool, can (1) eliminate the key subjective steps in neuromagnetic source localization and improve the detection rate for sources of brain activation that are otherwise undetectable (Tang et al 2002a), and (2) improve the effective signal to noise ratio for activity of specific brain regions in all three major sensory modalities, such that response onset time in the single-trial event-related potential (ERP) of these brain regions can be detected (Tang et al 2002). This work lays the necessary foundation for performing non-invasive measurement in humans that parallel those performed invasively in animal models. Transfer from MEG to EEG Measurement. In comparison to MEG, electroencephalography (EEG) is much more readily available. However, as a tool for non-invasive brain imaging, its ability to support source localization is considered poor. I anticipated that the methodologies developed for MEG data analysis should work similarly well on EEG data. To allow our newly developed methodologies to have a wide range of impact within the cognitive neuroscience community, I built a new laboratory for high density (128 channel) EEG/ERP work with grant support from DARPA. Currently, we have data showing that the procedures for MEG data analysis generalize well to EEG (manuscript is a few weeks from submission). From 128 channel EEG data, we were able to obtain the locations of brain activation and their continuous time courses of activation (thus single-trial measures) during both simple sensory activation tasks as well as complex cognitive tasks. With this capability of measuring the time course of activation continuously from multiple active brain regions, we have obtained several promising preliminary results as detailed below. Testing Hebbian Learning Rule in Humans. The strength of synapses among the neurons in our brain is considered to encode our past experience or memory. The study of such synaptic strength is so far mainly limited to studies in animal models, in which either electrodes are implanted or brain tissues are sliced for in vitro recording. Such invasive recording is necessary because the signal to noise ratios in scalp EEG recordings are too poor and the mixture of signals contained in the scalp EEG are too difficult to decompose into their respective underlying sources. Because SOBI increases the effective signal to noise ratio, we can now measure single-trial ERPs from specific brain regions due to the stimulation of an input pathway. We have obtained preliminary results showing that by manipulating the delays between the ipsi- and contra-lateral inputs to a particular brain region (in this case, the left or the right primary somatosensory cortex), single-trial ERPs to contra-lateral stimulation can be potentiated (Sutherland et al.,
  5. 5. Akaysha C. Tang Research Statement 5 2003, abs). This basic paradigm potentially provides a framework for studying the strength of association at a given input pathway and for optimally modifying the strength of selected pathways within the brain. Cross-modal interaction and association. Memory as we know it is often multimodal, involving visual, auditory, somatosensory information. Thus, associations must be built across different modalities. Inspired by a recent finding from University College of London that vision near the hand can be improved when the hand was touched (Macaluso, et al Science 2000 *), we examined the baseline (prior to learning) association strength between the somatosensory and visual areas. Using SOBI, we were able to provide the first electrophysiological evidence for somatosensory-to-visual crossmodal synchronization of alpha band oscillation by median nerve stimulation. An increase in alpha synchronization among a large population of neurons in the visual cortex can reduce the effective threshold for neuronal activation by otherwise sub- threshold visual stimulation. Thus, our finding provides a mechanism at the level of populational neuronal responses for mediating the cross-modal visual attention enhancement by somatosensory stimulation (McKinney et al, 2003. abs). This work provides a basis for our future study of associative learning between information presented in the somatosensory and visual modalities. Cognition in the real world. Memory related processing does not typically occur under well controlled laboratory conditions. To evaluate whether the new SOBI-based methodologies would work under a wider range of experimental conditions, we have also applied SOBI to EEG data obtained from subjects performing a real world task in an electrically noisy environment. Preliminary results showed that despite the fact that subjects were allowed to make continuous free eye movement as required by the task and despite the fact that there was no discrete stimulus on/off set due to continuously changing visual scenes during the video game, we were able to obtain well defined ERPs from several brain regions during complex cognitive events that involve basic sensory processing, language processing, divided attention, and generation of motor output (Tang et al 2003 abs) We were able to show selective activation of these sources by events that are high on cognitive load. This work suggests that the new SOBI-based methodology may have a very wide range of impact for both experimental as well as applied cognitive neuroscience research. Future Plan. The above summarized work showed that our new SOBI-based methodologies developed for MEG and EEG have provided unparalleled opportunities in addressing the parallel questions in humans concerning mechanisms of associative learning, relationship between stress and memory, the electrophysiological expressions of stress effects, and individual differences in stress response and memory function. I plan to study learning and memory under different stress conditions and in individuals with different stress response profiles. I will begin with identification of rapid stress-related or learning-related changes and subsequently relate these changes to learning and memory performance. From these experiments, hypotheses concerning the relation between stress response profile, stress, learning and memory, and the underlying neural plasticity will be tested. Finally, because SOBI can isolate activities and locations of bilaterally symmetric structures, we plan to derive measures of brain asymmetry from EEG data and continue to explore the functional significance of brain asymmetry in learning and memory and in the control of stress responses. Because the new SOBI-based methodologies can be beneficial to many who work in other areas of cognitive neuroscience, I am particularly interested in collaborations with colleagues whose work is related to the relationship between brain lateralization and various psychopathology (e.g. schizophrenia and depression), the effect of stress on social cognition/behavior, and close-loop brain-computer interfaces that utilize the detected brain states for performance optimization, improvement in training, and recovery from brain damage.
  6. 6. Akaysha C. Tang Research Statement 5 2003, abs). This basic paradigm potentially provides a framework for studying the strength of association at a given input pathway and for optimally modifying the strength of selected pathways within the brain. Cross-modal interaction and association. Memory as we know it is often multimodal, involving visual, auditory, somatosensory information. Thus, associations must be built across different modalities. Inspired by a recent finding from University College of London that vision near the hand can be improved when the hand was touched (Macaluso, et al Science 2000 *), we examined the baseline (prior to learning) association strength between the somatosensory and visual areas. Using SOBI, we were able to provide the first electrophysiological evidence for somatosensory-to-visual crossmodal synchronization of alpha band oscillation by median nerve stimulation. An increase in alpha synchronization among a large population of neurons in the visual cortex can reduce the effective threshold for neuronal activation by otherwise sub- threshold visual stimulation. Thus, our finding provides a mechanism at the level of populational neuronal responses for mediating the cross-modal visual attention enhancement by somatosensory stimulation (McKinney et al, 2003. abs). This work provides a basis for our future study of associative learning between information presented in the somatosensory and visual modalities. Cognition in the real world. Memory related processing does not typically occur under well controlled laboratory conditions. To evaluate whether the new SOBI-based methodologies would work under a wider range of experimental conditions, we have also applied SOBI to EEG data obtained from subjects performing a real world task in an electrically noisy environment. Preliminary results showed that despite the fact that subjects were allowed to make continuous free eye movement as required by the task and despite the fact that there was no discrete stimulus on/off set due to continuously changing visual scenes during the video game, we were able to obtain well defined ERPs from several brain regions during complex cognitive events that involve basic sensory processing, language processing, divided attention, and generation of motor output (Tang et al 2003 abs) We were able to show selective activation of these sources by events that are high on cognitive load. This work suggests that the new SOBI-based methodology may have a very wide range of impact for both experimental as well as applied cognitive neuroscience research. Future Plan. The above summarized work showed that our new SOBI-based methodologies developed for MEG and EEG have provided unparalleled opportunities in addressing the parallel questions in humans concerning mechanisms of associative learning, relationship between stress and memory, the electrophysiological expressions of stress effects, and individual differences in stress response and memory function. I plan to study learning and memory under different stress conditions and in individuals with different stress response profiles. I will begin with identification of rapid stress-related or learning-related changes and subsequently relate these changes to learning and memory performance. From these experiments, hypotheses concerning the relation between stress response profile, stress, learning and memory, and the underlying neural plasticity will be tested. Finally, because SOBI can isolate activities and locations of bilaterally symmetric structures, we plan to derive measures of brain asymmetry from EEG data and continue to explore the functional significance of brain asymmetry in learning and memory and in the control of stress responses. Because the new SOBI-based methodologies can be beneficial to many who work in other areas of cognitive neuroscience, I am particularly interested in collaborations with colleagues whose work is related to the relationship between brain lateralization and various psychopathology (e.g. schizophrenia and depression), the effect of stress on social cognition/behavior, and close-loop brain-computer interfaces that utilize the detected brain states for performance optimization, improvement in training, and recovery from brain damage.

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