Matthew A. Wilson - US grants

DESCRIPTION: (Adapted from Application) This project contributes to the Center's overall objectives by addressin g three fundamental concepts in the study of memory formation. The first concept is that memory traces are represented at the level of neuronal ensembles. In order to study memory formation at the neural level, the manner in which memory traces are represented in the activity of neuronal ensembles must be identified. This is essential when using molecular or behavioral approaches to manipulate memory formation in order to provide an observable neuronal correlate which reveals the effects of these manipulations. The neuronal ensemble level forms the interface between behavior and cellular mechanisms. Specific Aims #1, #2, and #3 attempt to identify the basic network properties of memory trace formation in neocortical circuits by systematically examining the contributions of stimuli, experience, and behavior to alterations in ensemble activity. The impact of development will also be addressed by comparing the characteristics of neural memory formation in young and old animals. This work will be coordinated with related efforts by Mark Bear in Individual Project #6 to study mechanisms of neocortical synaptic plasticity. A second concept that is addressed by this project is that of distributed mnemonic function. Memory is a property of multiple brain structures that can be altered by experience. Therefore, to study the process of memory formation requires that the contributions of multiple brain areas are identified. By monitoring regions that have involvement in different types and aspects of memory formation we will begin to identify how multiple brain regions are coordinated in the larger process of memory formation. A specific hypothesis regarding a mnemonic process which involves coordination of multiple brain regions is that of hippocampal-neocortical memory consolidation. Specific Aim #3 examines this particular interaction by simultaneously monitoring ensemble activity in the hippocampus and visual ncocortical areas during a behavioral memory task that requires the participation of both regions over the course of training. A specific focus of this investigation is the formation of memory representations for visual landmarks used during spatial navigation. This is contrasted with a visual memory task which does not require hippocampal involvement to allow separation of mnemonic effects from general task dependencies. The third concept is that of molecular and physiological mechanisms operating at both the cellular and network levels. By identifying the effects of altering plasticity within restricted regions of the brain on both behavior and ensemble activity, we can use these probes to determine the larger role of these cellular and molecular mechanisms in regulating the structure and process of memory information at the circuit and network level. This will be addressed in Specific Aim #4 in collaboration with Susumu Tonegawa.

This proposal seeks to carry out experiments that will relate long-term memory formation in the hippocampus with working memory in the prefrontal cortex (PFC) by simultaneously monitoring ensemble activity in these regions during spatial and non-spatial memory tasks. By relating this activity to neural patterns observed during REM and NREM sleep we seek to find evidence of mnemonic reactivation encompassing multiple brain regions. The first set of experiments will establish this structure by recording from ensembles of individual neurons in rodent PFC during acquisition and performance of working memory tasks. Working memory can be thought of as the active maintenance and use of selective long-term memory representations. Interactions between the hippocampus and prefrontal cortex may serve as the basis for this process. Anatomical and physiological evidence indicates that ventral hippocampus and PFC are directly interconnected and receive related dopaminergic innervation thus providing a substrate for these mnemonic interactions. Having identified potential neural representations of working memory in hippocampal and prefrontal regions through multiple neuronal recording we will examine the role of key cellular and molecular mechanisms in this process as well as determining the nature of processing of mnemonic information that occurs during different stages of sleep. This work is motivated by recent observations of reactivation of experience-related neural patterns in the hippocampus during both NREM and REM sleep that will be extended into the PFC. These studies will contribute to our understanding of the relationship between the hippocampus and prefrontal cortex during memory formation, the role of sleep in processing of mnemonic information, and the contribution of specific receptors in these functions. These results will provide insight in the nature of memory and memory disorders as well as disorders that have been related to prefrontal function such as schizophrenia.

This project will study of memory formation at three levels - behavioral, network, and cellular, with a specific focus on the evaluation of the transformation of event-specific (episodic) memory to context-independent (semantic) memory. A basic working hypothesis in the study of memory consolidation is that the process of establishing longer-term memory in the neocortex involves a transformation of event-specific information that is maintained within the hippocampus, into more generalized, context-independent forms. We will be specifically studying cross-contextual generalization in entorhinal cortical representations, evaluating both the structure of these representations and their dynamics as a function of time, pattern of behavioral exposure (training), behavioral performance, and neural activity and memory reactivation during offline states such as sleep. The study of memory representations at the network level using behavioral electrophysiological techniques will be complemented by the study of cellular and network mechanisms for regulating plasticity and function using molecular genetic manipulations. In particular, collaborative efforts with the Tonegawa laboratory using EC and DG specific knockouts will be carried out to study the contributions of activity and plasticity within these regions to the formation of specific and generalized memory representations. A hypothesis [regarding the essential involvement of specific properties of synaptic plasticity, such as the timing and/or coincidence detection abilities of NMDAR-dependent synaptic modification, in the formation of hippocampal memory traces will be examined through collaboration with the Heinemann, Sheng laboratories and the study of GluR2 mutants. Together these approaches will provide insight into the mechanisms of memory consolidation and the functional role of brain systems that are affected by neurological disorders of memory such as schizophrenia and Alzheimer' s disease.

DESCRIPTION (provided by applicant): Our previous study successfully identified the relationship between activity in the hippocampus and the medial prefrontal cortex during active choice behavior in a spatial working memory task in which prefrontal neurons became phase-locked to the hippocampal theta rhythm and tightly correlated with hippocampal place cells prior to accurate choice responses. Our studies also identified a novel form of hippocampal activity during quiet wakefulness in which sequential place cell activity reflecting past behavior was reactivated during stopping at goal locations. Preliminary results have provided further evidence of reactivation of forward sequences reflecting future trajectories during stopping at non-goal locations. Together these findings suggest that interactions between the hippocampus and prefrontal cortex during both active behavior and periods of awake inactivity may contribute to learning of behavioral contingencies in choice tasks through both prospective evaluation of future states, and retrospective evaluation of past states, and that these interactions may serve as a general biological substrate for unsupervised reinforcement learning. The possible contribution of these events to reinforcement learning would further suggest the involvement of reinforcement related activity in areas known to express correlates of reward and expectation of reward such as the ventral tegmental area (VTA). The present proposal seeks to further elaborate the relationship between the structure of neuronal activity, and behavioral events involved in learning of simple reinforced spatial working memory tasks by conducting simultaneous multielectrode recording of neuronal ensembles at multiple sites within the medial prefrontal cortex area (RFC), the ventral tegmental area (VTA), and the CA1 region of the hippocampus during active behavior, awake inactivity, and during sleep. These aims will extend the basic relationship between behavioral correlates of PFC activity established in previous work to the newly discovered phenomena of forward and reverse hippocampal sequence memory reactivation during quiet wakefulness, and will identify novel correlates of reinforcement-related activity in the VTA and their relationship to activity in both the hippocampus and PFC as they may relate to the general process of reinforcement learning. Given the known involvement of these brain areas in a broad spectrum of cognitive functions and behavioral and neuropsychiatric disorders, including spatial navigation, memory encoding and retrieval, addiction, schizophrenia, autism, and attention deficit disorders, this study will provide important insights into basic mechanisms that may contribute to learning, memory, and cognition, and establish novel biological substrates for computational models of neural function.

DESCRIPTION (provided by applicant): General anesthesia is a reversible, drug-induced behavioral state comprised of unconsciousness, amnesia, analgesia and immobility with stability and control of vital physiological systems. This fundamental tool of modern medicine is crucial for allowing thousands of patients daily to safely undergo most surgical and many non-surgical procedures. Today this state is induced and maintained by administering multiple drugs that act at multiple sites in the brain and central nervous system. Emergence from general anesthesia is a passive process whereby anesthetic drugs are merely discontinued at the end of surgery and no drugs are administered to actively reverse their effects. Allowing multiple drugs to act at multiple sites without specific mechanisms to terminate their effects most likely explains a significant component of anesthesia-related morbidity; drug side effects (nausea, hypotension, respiratory depression, hypothermia) are due to actions at sites other than their intended targets whereas persistent effects (delirium, cognitive dysfunction) are due to actions at intended targets for periods longer than desired. Hence, general anesthesia, as presently produced, is highly non-specific and inefficient. Despite the central role of anesthesiology in modern healthcare, research in this field is overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with little to no attention being paid to developing new approaches. The paradigm-shifting question whose answer will revolutionize anesthesiology is not, how do current anesthetics work?, but rather, how should the state of general anesthesia be designed? We hypothesize that the answer is by developing strategies to control directly the brain's natural inhibitory pathways and arousal centers. We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral state through precisely timed control of the brain's natural inhibitory pathways and its arousal centers. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: neurophysiologically-designed approaches to creating general anesthesia; reduction in morbidity; improved brain function monitoring; safer anesthesia care by non-anesthesiologists; and possibly novel therapies for arousal disorders such as depression, insomnia, pain and coma. PUBLIC HEALTH RELEVANCE: In the United States, more than 100,000 patients receive general anesthesia daily to safely undergo most surgical and many non-surgical procedures Use of anesthetic drugs by non-anesthesiologists in intensive care units and outpatient settings continues to grow. At the same time, anesthesia-related morbidity, including intra-operative awareness, altered neurological development and delirium in children and cognitive dysfunction in the elderly remains a significant problem. Despite the central role of anesthesiology in modern healthcare, research in this field is stagnant; overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with no attention to developing new approaches. We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral state through precisely timed control of the brain's natural inhibitory pathways and its arousal centers. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: neurophysiologically-designed approaches to creating general anesthesia; reduction in morbidity; improved brain function monitoring; safer anesthesia care by non- anesthesiologists; and possibly novel therapies for arousal disorders such as depression, insomnia, pain and coma.

Today's AI technologies, such as Watson, Siri and MobilEye, are impressive yet still confined to a single domain or task. Imagine how truly intelligent systems --- systems that actually understand their world --- could change our world. The work of scientists and engineers could be amplified to help solve the world's most pressing technical problems. Education, healthcare and manufacturing could be transformed. Mental health could be understood on a deeper level, leading in turn to more effective treatments of brain disorders. These accomplishments will take decades. The proposed Center for Brains, Minds, and Machines (CBMM) will enable the kind of research needed to ultimately achieve such ambitious goals. The vision of the Center is of a world where intelligence, and how it emerges from brain activity, is truly understood. A successful research plan for realizing this vision requires four main areas of inquiry and integrated work across all four guided by a unifying theoretical foundation. First, understanding intelligence requires discovering how it develops from the interplay of learning and innate structure. Second, understanding the physical machinery of intelligence requires analyzing brains across multiple levels of analysis, from neural circuits to large-scale brain architecture. Third, intelligence goes beyond the narrow expertise of chess or Jeopardy-playing computers, bridging several domains including vision, planning, action, social interactions, and language. Finally, intelligence emerges from the interactions among individuals ? it is the product of social interactions. Therefore, the research of the Center engages four major research thrusts (Reverse Engineering the Infant Mind, Neuronal Circuits Underlying Intelligence, Integrating Intelligence, and Social Intelligence) with interlocking teams and working groups, and a common theoretical, mathematical, and computational platform (Enabling Theory).

The intellectual merit of the Center is its focus on elucidating the mechanisms and architecture of intelligence in the most intelligent system known: the human brain. Success in this project will ultimately enable us to understand ourselves better, to produce smarter machines, and perhaps even to make ourselves smarter. The Center's potential legacy of a deep understanding of intelligence, and the ability to engineer it, is tantalizing and timeless. It includes the creation of a community of researchers by programs such as an intensive summer school, technical workshops and online courses that will train the next generation of scientists and engineers in an emerging new field -- the Science and Engineering of Intelligence. This new field will catalyze continuing progress in and cross-fertilization between computer science, math and statistics, robotics, neuroscience, and cognitive science. Sitting between science and engineering, it will attract growing interest from the best students at all levels. The broader impact of the Center program could be to revolutionize K-12, and also 0-K, and 12-life with a deeper understanding of the process of learning. The ability to build more human-like intelligence in machines will transform our productivity, enabling robots to care for the aged, drive our cars, and help with small-business manufacturing. The Center team is composed of over 23 investigators, many having already made significant accomplishments in multiple research areas relevant to the science and the technology of intelligence. The Center team has a mix of junior and senior researchers, bringing expertise in Computer Science, Neuroscience, Cognitive Science and Mathematics. The institutional partners include nine institutions (MIT, Harvard, Cornell, Rockefeller, UCLA, Stanford, The Allen Institute, Wellesley, Howard, Hunter and the University of Puerto Rico), three of which have significant underrepresented student populations. The academic institutions are complemented by the Center's industrial partners (Microsoft, IBM, Google, DeepMind, Orcam, MobilEye, Willow Garage, RethinkRobotics, Boston Dynamics) and by world-renowned researchers at international institutions (Max Planck Institute, The Weizmann Institute, Italian Institute of Technology, The Hebrew University).

Spatial navigation and episodic memory are important for daily activity and survival in rodents and primates. Episodic memory consists of collections of past experiences that occurred at a particular time and space, expressed in the form of sequences of temporal or spatial events. Spatial (topographical or topological) representation of the environment is pivotal for navigation. The hippocampus plays a significant role in both spatial representations and episodic memory. However, it remains unclear how the spikes of hippocampal neurons might be used by downstream structures in order to reconstruct the spatial environment without the a priori information of the place receptive fields. Little is known how the hippocampal neuronal representation might be affected by experimental manipulation. Furthermore, cortico-hippocampal interplay and communications are critical for memory consolidation, but many questions about their temporal coordination during sleep remains unresolved. This project proposes a collaborative proposal for studying the neural representation of population codes in rodent hippocampal-cortical circuits. The investigators and collaborators at MGH, MIT and Boston University will integrate innovative computational and experimental approaches to explore the neural codes during various spatial navigation and spatial/temporal memory tasks as well as during post-behavior sleep---as sleep is critical to hippocampal-dependent memory consolidation. Notably, due to the lack of measured behavior, it remains a great challenge to analyze or interpret sleep-associated hippocampal or cortical spike data.

The important questions central to this project are: how do hippocampal (or hippocampal-cortical) neuronal representations vary with respect to species (rat vs. mouse), animal (healthy vs. diseased), experience (novel vs. familiar), environment (one vs. two-dimensional), behavioral state (awake vs. sleep), and task (active vs. passive navigation; spatial working memory vs. temporal sequence memory). The investigators will simultaneously record ensemble spike activity from two or multiple areas of the rodent brain (hippocampus, primary visual cortex, prefrontal cortex, and retrosplenial cortex) under different experimental conditions, and will decipher the population codes using a coherent statistical framework. In light of Bayesian inference (variational Bayes or nonparametric Bayes), innovative unsupervised or semi-supervised learning approaches are developed for mining and visualizing sparse (in terms of both sample size and low firing rate) neuronal ensemble spike data.

The outcome of this investigation will improve the understanding of neural mechanisms of hippocampal (or hippocampal-cortical) population coding and its implications in learning, sleep and memory. The derived findings will shed light on the links between the variability of neural responses and the animal behavior (or other external factors), and will provide further insight into memory dysfunction (such as in Alzheimer's disease). Furthermore, this project has broader impacts in developing efficient algorithms to decipher neuronal population spike activity during behavior or sleep, as well as in discovering invariant topological representation of population codes in other cortical areas. In addition to the scientific significance, this proposal bears an educational component for training researchers on advanced quantitative skills in ensemble spike data analysis as well as for disseminating scientific resources (by sharing data and software) to a broad neuroscience community.

DESCRIPTION (provided by applicant): General anesthesia is a reversible, drug-induced behavioral state comprised of unconsciousness, amnesia, analgesia and immobility with stability and control of vital physiological systems. This fundamental tool of modern medicine is crucial for allowing thousands of patients daily to safely undergo most surgical and many non-surgical procedures. Today this state is induced and maintained by administering multiple drugs that act at multiple sites in the brain and central nervous system. Emergence from general anesthesia is a passive process whereby anesthetic drugs are merely discontinued at the end of surgery and no drugs are administered to actively reverse their effects. Allowing multiple drugs to act at multiple sites without specific mechanisms to terminate their effects most likely explains a significant component of anesthesia-related morbidity; drug side effects (nausea, hypotension, respiratory depression, hypothermia) are due to actions at sites other than their intended targets whereas persistent effects (delirium, cognitive dysfunction) are due to actions at intended targets for periods longer than desired. Hence, general anesthesia, as presently produced, is highly non-specific and inefficient. Despite the central role of anesthesiology in modern healthcare, research in this field is overly focused on deciphering the anesthetic and toxic mechanisms of current drugs with little to no attention being paid to developing new approaches. The paradigm-shifting question whose answer will revolutionize anesthesiology is not, how do current anesthetics work?, but rather, how should the state of general anesthesia be designed? We hypothesize that the answer is by developing strategies to control directly the brain's natural inhibitory pathways and arousal centers. We propose to redesign general anesthesia by combining optogenetic, electrical and pharmacological manipulations in rodent models to create this behavioral state through precisely timed control of the brain's natural inhibitory pathways and its arousal centers. If successful this research will provide a new fundamental understanding of brain arousal control, and eventually, new anesthesiology practices including: neurophysiologically-designed approaches to creating general anesthesia; reduction in morbidity; improved brain function monitoring; safer anesthesia care by non-anesthesiologists; and possibly novel therapies for arousal disorders such as depression, insomnia, pain and coma.

Converging lines of evidence support the hypothesis that the sleep spindle deficit in schizophrenia (SZ), contributes to highly disabling and treatment-refractory cognitive deficits and to symptoms and, importantly, is treatable. In the first three-year cycle of this R01, we examined the effects of eszopiclone (Lunesta) on sleep spindles and sleep-dependent memory consolidation in SZ. Although it significantly increased spindles, and spindles correlated with memory, disappointingly, eszopiclone failed to improve memory. Recent findings from our labs and others provide an explanation for this failure and motivate the present proposal. Memory consolidation relies not only on the number of spindles, but also on their temporal coordination with other sleep oscillations. During sleep, hippocampal sharp wave ripples (SWRs), which correspond to memory reactivation, coordinate with spindles and cortical slow waves (CSWs) to transfer new memories from temporary storage in the hippocampus to more permanent representation in the cortex. In SZ we recently showed that both the number of spindles and their temporal coordination with CSWs predict memory consolidation. Our preliminary findings indicate that eszopiclone disrupts this spindle-CSW timing in humans and suppresses SWRs in rats. These effects of eszopiclone on sleep oscillations may account for its failure to improve memory. The goal of this grant cycle is to develop and validate a pipeline to efficiently identify the most promising drugs for improving sleep-dependent memory consolidation by determining their effects on all three oscillations (spindles-CSWs-SWRs), their temporal coordination and memory consolidation before moving to larger and more costly clinical trials. Because hippocampal SWRs are difficult to measure noninvasively, this pipeline requires complementary rodent and human studies. The rodent studies will use large-scale neuronal ensemble recordings to examine the effects of zolpidem and eszopiclone on the coordination of hippocampal SWRs, sleep spindles and CSWs and on memory. The parallel human study will obtain high-density spatial data from simultaneously-acquired EEG/magnetoencephalography (MEG) during a daytime nap from both healthy individuals and SZ patients to test the effects of zolpidem on spindles, CSWs, and their coordination and how these effects correlate with changes in sleep-dependent declarative memory consolidation. The choice of zolpidem is based on findings that it increases both spindle-CSW coupling and hippocampal SWRs and also improves sleep-dependent declarative memory, but has not been tested in SZ. In addition to identifying the most promising drugs for future clinical trials to ameliorate cognitive deficits in SZ and evaluating zolpidem as a potential candidate, this research program will elucidate how sleep oscillations act in concert to mediate memory consolidation. This knowledge will open new avenues for identifying and treating sleep- related cognitive deficits in a range of disorders characterized by abnormal sleep.

Sleep is critical to memory and learning. During rapid eye movement (REM) or non-REM (NREM) sleep, subgroups of cell assemblies in hippocampal and sensory cortical circuits are reactivated in a temporally coordinated manner, forming a cortical-hippocampal-cortical loop of information processing during memory consolidation. Deciphering neural codes of hippocampal-neocortical memories during sleep would reveal important circuit mechanisms of memory consolidation. To date, a complete understanding of the mechanisms of hippocampal-neocortical memory processing and the interaction of their specific spatial/non­ spatial memory representations during sleep is lacking. Furthermore, little is known about the causal impact of the hippocampal-neocortical interactions on subsequent memory reactivation or post-sleep learning. In this proposal, we will dissect representations of spatial (where) and visual (what) memory in the rodent hippocampal CA1 and primary visual cortex (V1) during sleep. We will combine electrophysiology, population-decoding methods, optogenetics and closed-loop neural interface to decipher sleep-associated CA1-V1 population codes in memory coding. In Aim 1, we will identify visual cortical representations in a spatial navigation task and determine visual cortical neuronal firing dependency on space, experiences and visual cues. In Aim 2, we will uncover where (spatial) and what (visual) representations of CA1-V1 memory reactivations during sleep. In Aim 3, we will determine the causal role of the hippocampus in the V1-CA1-V1 loop of memory consolidation during sleep. Together, these results will enable us to casually dissect circuit mechanisms of hippocampal-neocortical memory coding during sleep, and to establish a new analysis paradigm to identify the contents of hippocampal-memory reactivations during sleep. Our project will provide further insight into memory-related neurological and psychiatric disorders and potential therapeutic treatment for targeted memory reactivation or enhancement.