Wendy Suzuki - US grants

How do medial temporal lobe structures contribute to memory? Finding the answer to this question is a long-term goal of neuroscience research. Recent findings from neuroanatomical, behavioral and functional imaging studies have provided new insight into the potential functions of two of these medial temporal lobe structures, the perirhinal and parahippocampal cortices. These findings suggest that like the hippocampal formation, these cortical medial temporal lobe areas may also contribute importantly to spatial functions. To address this possibility, proposed research combines the use of sensitive neuroanatomical tracing techniques and single-unit neurophysiological techniques to explore the role of the perirhinal and parahippocampal cortices in two aspects of spatial function: spatial representation and spatial memory. Anterograde tracing techniques will be used to define the regional and laminar topography of parahippocampal inputs arising from "dorsal stream" structures involved in processing stimulus location. Single unit physiological techniques will be used to define the kinds of spatial and mnemonic information carried by neurons in the perirhinal and parahippocampal cortices as animals perform a delayed match to place task. These experiments will also define the spatial frame of reference of the place-selective neurons in these areas. A separate task will be used to examine the role of perirhinal and parahippocampal neurons in the formation of new long-term memories for spatial information. Neural activity will be recorded as monkeys learn the spatial locations of particular rewarded targets in the context of a set of complex visual "scenes". Analyses will be directed at identifying any "tuning" of neural activity associated with learning these new, long-term location-scene associations. Because memory for spatial information plays such a prominent role in human episodic (i.e. event) memory, findings from these studies may also serve to establish links between experimental work in monkeys and current work on the brain basis of memory in humans.

[unreadable] DESCRIPTION (provided by applicant): While it is clear that the structures of the medial temporal lobe (MTL) are essential for our ability to learn and retrain new information for facts, events and relationships, the specific contributions of individual MTL structures to learning and memory remain poorly understood. The goal of this proposal is to take advantage of the precise spatial and temporal resolution of behavioral neurophysiology in the non-human primate to characterize the specific contributions of individual MTL areas and their interactions to various MTL-dependent tasks. In Aim 1, we will use a conditional motor association learning task known to be sensitive to MTL damage, to characterize the task-related and learning related signals in both the entorhinal and parahippocampal cortices using single and multiple tetrode recordings. We will interpret our findings in the context of our previous studies describing the associative learning signals in both in the hippocampus and perirhinal cortex during performance of the same associative learning task. Using variants of the conditional motor association task that emphasize either encoding, requiring pattern separation or recall, requiring pattern completion, we will test the hypothesis that area CA3 of the hippocampus may be most strongly or most quickly engaged in both encoding and recall versions of the task compared to area CA1 or the entorhinal cortex. Single and multi-tetrode recordings done throughout these experiments will allow us for the first time to characterize the correlated activity both within individual areas as well as across areas during new associative learning. In Aim 2 we will also use the computations of pattern completion and pattern separation to differentiate the functions of individual MTL areas using an incidental looking task analogous to incidental spatial/contextual encoding tasks used in rats. Understanding the functions and functional interactions of individual MTL structures has important implications for the development of treatments for the wide variety of disease states that affect memory including Alzheimer's disease, schizophrenia, attention deficit disorder as well as the memory impairments present in aging. Alzheimer's disease, schizophrenia, developmental disorders and aging all involve impairments in learning and memory associated with damage to the medial temporal lobe. Here we propose to use neurophysiological recording techniques to characterize the individual contributions and interactions of the key medial temporal lobe areas important for memory. This information will serve as an important foundation for the development of treatments for disorders of memory that affect the medial temporal lobe. [unreadable] [unreadable] [unreadable]

Episodic memory is defined as detail-rich and flexibly accessible memory for individual events or episodes. A key component of episodic memory is memory for the temporal order of items within an episode. While it is clear that the structures of the medial temporal lobe (MTL) and the prefrontal cortex (PFC) both contribute to memory for temporally ordered information, the nature of that contribution and the interactions between these key brain areas during temporal order memory remains to be elucidated. Also unresolved is the relative contribution of these areas to working memory versus long-term memory tasks for temporally ordered information. The proposed experiments are based on the underlying hypothesis that the MTL and PFC contribute in complementary but differentiable ways to the performance of both working memory and long- term memory tasks for temporal order memory. To test these hypothesis, we will conduct a series of hypothesis driven experiments designed to define the specific contributions and interactions of structures in the MTL and PFC during temporal order tasks requiring either working memory or long-term memory retrieval. In Specific Aim 1, we will record activity in the MTL and PFC both individually and simultaneously as animals perform a working memory temporal order memory task with objects. In Specific Aim 2, we will record simultaneously across both areas as animals perform a task requiring long-term memory for color-cue - temporal order associations. For both Aims, cross correlation analyses as well as LFP and spike-field coherence analyses will allow us to evaluate the timing and the nature of the interactions between these areas. Specifically, we predict that a major role of the MTL, mainly through the activity of the hippocampus, is to provide strong signals for particular trial events and trial timing during both the WM and the LTM versions of the temporal order task. In addition, we predict that the surrounding entorhinal and perirhinal cortex are engaged in mnemonic encoding of object and object-temporal order conjunctions for the working memory task and the perirhinal cortex is critical for the retrieval of the long-term memory for associations between color-cues and temporal order. In contrast, we hypothesize that the PFC is primarily involved in cognitive control processes including a prominent role in maintenance of temporal order information during the working memory delay period, though we may see trial timing-related activity in the PFC as well Understanding the specific contributions and functional interactions of the MTL and PFC in temporal order memory will not only provide new insight into the fundamental cognitive function of episodic memory, but also has important implications for the development of treatments for a wide variety of disease states that affect episodic memory including Alzheimer's disease, schizophrenia, and the memory impairments present in aging.

DESCRIPTION (provided by applicant): While strong evidence suggests that the medial temporal lobe (MTL) is essential for learning and retaining new information for facts and events and the striatum is important for acquiring new skills and habits, the nature of the specific interactions between these two brain regions remains poorly understood. The goal of this dual-PI proposal is to take advantage of the precise spatial and temporal resolution of behavioral neurophysiology studies in animal model systems (Suzuki) together with the broad activation monitoring and flexible behavioral manipulation available in BOLD fMRI studies in humans (Stark) to characterize the specific contributions and interactions between the MTL and the striatum during a conditional motor associative learning task known to be dependent on both areas. In Aim 1, we will use the same task in both experimental animals and humans to assess the patterns and temporal dynamics of neural activity in the MTL and striatum during new conditional motor associative learning. Neurophysiology studies will include single unit tetrode recording, network correlation analyses and LFP analyses across both the MTL and the striatum. The BOLD fMRI studies will include characterization of functional connectivity between these areas. We will test the hypothesis that both the MTL and striatum signal learning during new conditional motor associative learning, but utilize distinct computational principles during the learning process such that the MTL associates random element together in memory while the role of the striatum includes motor- based or direction-based stimulus-response learning as well as a prominent role in signaling reward prediction error. We will also test the hypothesis that the role of the striatum in signaling reward prediction error interacts directly with the MTL defining a declarative portion of the striatum described in previous studies. In Aim 2, Stark will use various task manipulations hypothesized to make the associative learning task more dependent on either the MTL or the striatum to better characterize the unique contributions of these two different brain areas to associative learning. In Aim 3 Stark and Suzuki will conduct a detailed comparison of the pattern of single unit activity, LFP signals and spike-field coherence measured in animals to the pattern of BOLD fMRI signals and functional connectivity measured in humans to define the relationship between these different levels of analysis. Understanding the details of this relationship will be essential for ultimately translating experimental single cell findings in animals to our understanding of human brain function. Understanding the functional interactions between the MTL and striatum also has important implications for the development of treatments of a wide variety of disease states that affect these brain areas including Alzheimer's disease, attention deficit disorders, cognitive impairments present in aging, Parkinson's disease and Huntington's disease.

DESCRIPTION (provided by applicant): We propose to hold a conference that will highlight current directions and exciting new findings in the area of learning memory and plasticity. This conference is entitled "The Mysteries and Marvels of Memory" and will be held at the Washington Square campus of New York University, March 26-28, 2010. We will focus the conference on a set of cutting edge questions organized around individual sessions. Each of these questions will be addressed at multiple levels of analysis and in addition we will encourage the maximal amount of discussion both between speakers as well as strong audience participation with a directed discussion/debate segment led by a member of the organizing committee that will take place at the end of each session. This conference features both well established as well as the newest generation of leaders in the field of learning, memory and plasticity. This meeting will serve the greater neuroscience community in a number of different ways. First, a major goal of this conference is to identify not only the current cutting edge questions, but the discussions stemming from the presentations will help define the most relevant future directions in this field. Second, because of our emphasis on discussion and interaction together with our inclusion of highly trained undergraduate students at the conference, it will serve as a powerful educational opportunity not only for seasoned Neuroscientists, but for up and coming students of neuroscience as well. In this way we hope to highlight some of the major themes in learning, memory and plasticity, define relevant future directions of research and educate the Neuroscience community as a whole. PUBLIC HEALTH RELEVANCE: New York University proposes to hold a conference entitled "The Mysteries and Marvels of Memory" that will focus on a set of cutting edge questions in the area of learning memory and plasticity. This conference will not only highlight major themes in this dynamic area of research but it will help define and shape relevant future research directions. This conference will also serve as a valuable educational opportunity for both seasoned Neuroscientists and up-and-coming students of neuroscience alike to promote the advancement of progress in this key research area.

Abstract New York University's (NYU) Center for Neural Science, the Department of Teaching and Learning and the Center for Research on Higher Education Outcomes will partner with New York City underserved public high schools to develop, implement, evaluate, and disseminate an innovative EEG-based cognitive neuroscience curriculum. In BrainWaves, high school students (10th and 11th grades) will become brain scientists in an original study of their own creation: They will be provided with the content knowledge and practices to design and conduct a comprehensive neuroscience research study in their own classroom with the use of portable low cost brainwave measuring devices (electroencephalography (EEG) headsets). The proposed curriculum has two units. The first unit, which will be informed by previous SEPA-funded programs, consists of a broad introduction to both cognitive neuroscience content and experimental design. Students will be trained to use EEG headsets and will learn about the process of designing a neuroscience study as well as research ethics issues. The second unit of the curriculum will differ across the intervention group and the control group. Students in the intervention group will first work in small teams to propose an original research question and formulate a detailed plan to execute an EEG study. They will then evaluate the different proposals and select one that will be carried out in the classroom. Next, students will design the experiment, collect data and analyze it, and lastly share their results with their community (e.g., through a science fair). In the process, students will be mentored by their science teacher as well as a neuroscientist affiliated with NYU. The control group will involve journal club style discussions of EEG research papers. The curriculum will be accompanied by an open-science, open-source software package (OpenEXP) that will guide students through the process of designing their experiments, as well as collecting and analyzing data. Finally, we will develop a professional development course for teachers and science mentors with an explicit emphasis on mentoring students in research projects. The main educational research questions posed in this proposal can be formulated as follows: 1) Does a technology supported, inquiry-based neuroscience curriculum (BrainWaves) impact student understandings of neuroscience content and experimental design and their attitudes toward science? 2) How does engagement with the BrainWaves curriculum and program resources affect teachers' attitudes towards neuroscience teaching? The program evaluation will take place over three years in 10 schools every year. Schools will be randomly assigned to the intervention or control group every semester. The Impact of BrainWaves on students will be assessed using pre- and post-program surveys. The effectiveness of teachers' professional development and instructional implementation will be evaluated with classroom observations and teacher surveys.