Elizabeth Buffalo, Ph.D., Professor, Dept. of Physiology & Biophysics, University of Washington School of Medicine; and Chief, Neuroscience Division, Washington National Primate Research Center
Neural Dynamics of Memory and Cognition in the Primate Hippocampal Formation
Dr. Buffalo and her team investigate the mechanisms that drive memory and cognition by studying how changes in the neuronal activity of non-human primates correlate with their ability to learn and remember. In this project, researchers at the Buffalo Lab have trained macaque monkeys to use joysticks as they navigate through an immersive virtual game environment, while brain activity deep in the medial temporal lobe is recorded and analyzed. The goal is to gain a greater understanding of how ensembles of neurons in the primate hippocampal formation support memory formation, and whether theories of network organization fostered in rodents are applicable to the primate. Her findings could shed new light on why damage to these structures can compromise the brain’s ability to store and retrieve information, leading the way toward new therapies for individuals challenged by temporal lobe Epilepsy, Depression, Schizophrenia, and Alzheimer’s disease.
Mauricio R. Delgado, Ph.D., Associate Professor, Dept. of Psychology, Rutgers University
The Regulation of Negative Autobiographical Memories via Positive Emotion-focused Strategies
The Delgado Lab for Social and Affective Neuroscience explores the interaction of emotion and cognition in the human brain during the learning and decision-making processes. Leveraging Dr. Delgado’s previous research revealing that the recall of positive memories can recruit neural reward systems and dampen cortisol response, he and his team will now investigate whether focusing on a positive aspect of a negative memory can alter how that memory is remembered, and even change the feeling it induces the next time that memory is retrieved. To do so, researchers will ask study participants to recollect a negative memory over time, using behavioral and fMRI analysis to characterize the neural mechanisms involved in the regulation of negative autobiographical memories. Such findings could lead to new tools and therapeutic strategies for improving the quality of life for people with mental health and mood disorders.
Bruce E. Herring, Ph.D., Assistant Professor, Section of Neurobiology, Dept. of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California
Understanding Synaptic Dysfunction in Autism Spectrum Disorder
Dr. Herring and his team recently zeroed in on a potential “hot spot” for the development of Autism Spectrum Disorders, discovering eight different autism-related mutations clustered on the TRIO gene responsible for a protein that drives the strength or weakness of connections between brain cells. Now, Herring Lab researchers will deploy engineered mice as the animal model for determining whether the disruption of TRIO function during a critical early period in brain development stunts the connection between brain cells contributing to development of ASD. By learning more about this promising convergence point for ASD-risk genes, Dr. Herring’s research may aid the development of new theories regarding the molecular mechanisms underlying Autism, shedding new light on how synaptic dysfunction contributes to cognitive disease.
Steve Ramirez, Ph.D., Assistant Professor, Dept. of Psychological and Brain Sciences, Boston University, Center for Integrated Life Sciences and Engineering
Artificially Modulating Positive and Negative Memories to Alleviate Maladaptive Fear Responses
Dr. Ramirez is focused on revealing the neural circuit mechanisms of memory storage and retrieval, and finding ways to artificially modulate memories to combat maladaptive states seen in such cognitive diseases as Post-traumatic Stress Disorder. Researchers with the Ramirez Group have recently developed a genetic tagging system in which cells that are active specifically during positive or negative memory formation are labeled with light-sensitive effects, a new technology that gives researchers optical control over memory bearing cells in mice. Using this novel approach, Ramirez and his team will now explore whether artificially modulating or strengthening positive memories can diminish the fear response tied to negative memories, research that may lay the groundwork for future treatment paths and drug targets for humans affected by PTSD and other psychiatric disorders.
Donna J. Calu, Ph.D., Assistant Professor in the Department of Anatomy and Neurobiology, University of Maryland, School of Medicine
Individual Differences in Attention Signaling in Amygdala Circuits
Dr. Calu’s research is driven by her desire to understand individual vulnerability to addiction, which is manifest in the addicts’ compulsion to seek and take drugs even in the face of known negative consequences of drug abuse. Generally, humans modify their behavior when outcome values suddenly get better or worse than expected, but the ability to modify behavior when situations get worse is compromised in addicted individuals. To better understand the addiction vulnerable phenotype it is critical to understand how individuals differ prior to any exposure to drugs of abuse. Dr. Calu’s lab uses animal models to study the brain mechanisms underlying sign-tracking and goal-tracking individual differences in rats. Sign-trackers show heightened motivational drive triggered by food and drug-associated cues, while goal-trackers use cues to guide flexible responding based on the current value of the outcome. Dr. Calu is recording real-time activity of individual amygdala neurons to examine how they fire when sign- and goal-trackers perform tasks that violate their expectations for reward. She is also selectively inhibiting neurons to examine the role of amygdala pathways in driving attention towards cues in the face of negative consequences. Dr. Calu will consider her team’s findings as they relate to understanding individual vulnerability to and prevention of addiction.
Using Deep In Vivo Two-Photon Ca2+ Imaging to Study Temporal Pattern Separation
Drs. Gage and Shtrahman are exploring how the hippocampus distinguishes similar experiences to form discrete memories, a process termed pattern separation. Specifically, they are investigating how the hippocampus processes dynamic sensory information that varies with time during memory formation. They will focus their studies on the dentate gyrus, a region within the hippocampus thought to be critical for pattern separation and one of only two regions within the mammalian brain that generates new neurons throughout life. Gage and Shtrahman will use two-photon calcium imaging to probe the activity of newborn neurons in this deep brain region to better understand this important brain function. Understanding these mechanisms will provide crucial insights into why our ability to learn and remember declines with age and how hippocampal disease leads to significant memory impairment in disorders such as Alzheimer’s disease and schizophrenia.
Gabriel Kreiman, Ph.D., Associate Professor of Ophthalmology and Neurology, Children’s Hospital Boston, Harvard Medical School
Behavioral, Physiological and Computational Mechanisms Underlying Episodic Memory Formation in the Human Brain
By showing movie clips to individuals and determining what they are able to remember from the viewing, Dr. Kreiman and his team endeavor to understand how episodic memories are made. Episodic memories “constitute the essential fabric of our lives,” he says, encompassing everything that happens to an individual and ultimately forming the basis of who we are. Since episodic memory formation is too complex to be tracked in real life, Kreiman uses movies as a proxy, since people develop emotional associations with characters as they do in the real world. Kreiman and his team are quantitatively studying the behavioral filtering mechanisms that lead to remembering versus forgetting and building a computational model predicting what movie content will and will not be memorable to subjects. Kreiman is collaborating with Dr. Itzhak Fried at UCLA, whose work with epilepsy patients provides an opportunity to study neuronal spiking activity in the hippocampus during episodic memory formation. Their work is significant given that cognitive disorders affecting memory formation have devastating consequences that to date cannot be treated with drugs, behavioral therapies, or other approaches.
Prefrontal Dysfunction in Fragile X Syndrome
Austin Center for Learning and Memory researchers Daniel Johnston and Boris Zemelman have teamed up to study the role of the prefrontal cortex (PFC) in Fragile X Syndrome (FXS). FXS results from a mutation in a gene called fmr1 and a loss of a protein called FMRP, disrupting neuronal function. FXS is the most common inherited form of intellectual disability and most common monogenic cause of autism. Using a mouse model in which the fmr1 gene has been deleted, the Johnston lab has been studying a simple working memory-like behavior called trace eye-blink conditioning, in which pairing a visual cue with a non-contiguous air puff leads to anticipatory eyelid closure. Interestingly, mice lacking the fmr1 gene and the protein FMRP are unable to learn this task. In this project, the investigators will use viruses designed by Zemelman to remove or replace FMRP in specific neurons of the PFC, and then examine animal behavior, the complement of neuronal proteins and the firing patterns of selected PFC cells. Long-term, their research holds promise for clinical approaches to FXS and autism by determining optimal cell targets for therapeutic interventions.
David J. Foster, Ph.D., Associate Professor of Neuroscience, Johns Hopkins University School of Medicine
The dual role of hippocampal place-cell sequences in learning and memory
David Foster and his team are exploring fundamental questions about memory and how the hippocampus functions as we plan future actions that are dependent on what we did in the past. While it is known that the same neurons in the hippocampus fire signals when we encounter a physical place we have been before, this does not yet explain what hippocampal cells have to do with memory. Foster’s team is interested in the sequence of firing patterns emitted when rats and mice anticipate moving through a physical space, in effect mapping the mental time travel or episodic memory of the hippocampus. Foster and his team will determine what happens when they disrupt the brain sequences and attempt to alter expected behavior. Hippocampal dysfunction and memory impairments are a central feature in many brain diseases and even normal aging, underscoring the need to expand our understanding of the neural basis of episodic memory.
Ueli Rutishauser, Ph.D., Assistant Professor of Neurosurgery, Cedars-Sinai Medical Center; Visiting Associate (joint appointment), California Institute of Technology
Adam Mamelak, M.D., Professor of Neurosurgery, Cedars-Sinai Medical Center
Hippocampal theta rhythm-mediated coordination of neural activity in human memory
Drs. Rutishauser and Mamelak’s interdisciplinary team of clinicians and researchers decodes what human brain cells are doing when creating new memories and recalling them. They work with patients who have electrodes implanted in their brains as part of neurosurgical procedures. While the patients are undergoing treatment, the research team administers memory tests and records the activity of individual neurons in the hippocampus, a brain structure necessary for forming new memories. Using this technique, the team is investigating how neuronal activity is coordinated by brain rhythms and how such coordination allows the formation of new memories. Deficient neuronal coordination is thought to be a key cause of memory disorders. Therefore, studying how human brains form new memories and specifically analyzing how theta oscillations coordinate activity between different functional types of neurons could lead to a better understanding of how medicine and stimulation therapy may help restore memory function.
Daphna Shohamy, Ph.D., Associate Professor of Psychology and the Zuckerman Mind, Brain, Behavior Institute, Columbia University
How episodic memory guides decisions: neural mechanisms and implications for memory loss
Dr. Shohamy is researching how memories are used when we make decisions. Even the simplest of decisions, such as what to order for lunch, rely on memory for past experiences. To understand the brain processes by which memory is used to guide decisions, Dr. Shohamy’s team will combine two different approaches. They will use fMRI to scan brain activity while healthy people make a series of simple decisions and will look at the contribution of memory regions in the brain to the decision making process. They will also compare decision-making among healthy people with patients with severe memory loss. Dr. Shohamy is collaborating with neurobiologist, Dr. Michael Shadlen, who studies how neurons accumulate evidence to make simple perceptual decisions. Their research brings together two different bodies of research: how the brain recalls memories, and how it accumulates evidence to make decisions. The long-term goal of the research is to improve the quality of life for patients with memory loss by understanding how memory loss impacts everyday decisions and creating interventions that remediate this problem.
Studying global memory traces at single synapse resolution
Neurons in our brains communicate with each other through synaptic connections, which become stronger or weaker during learning. However, only a tiny fraction of the trillions of synapses in the brain participate in forming a single memory. Dr. Kimberley Tolias and her husband, Dr. Andreas Tolias, are bringing together their respective expertise in molecular and systems neuroscience to develop a way to label the specific synapses associated with single memories. They call this tool Multi-color Neuronal Inducible Memory Engram Stamping, or MNIMES (“memories” in Greek). This approach will help them better understand how memories are formed in healthy brains, and also how this process is altered in neuropsychiatric diseases such as autism or Alzheimer’s. Their research could potentially lead to new genetic or pharmaceutical treatments to restore normal synapse function and plasticity in these diseases. Key members of the Tolias laboratories driving this project include Drs. Joseph Duman and Jacob Reimer.
Jacqueline Gottlieb, Ph.D., Associate Professor of Neuroscience, Columbia University
Population dynamics encoding uncertainty and reward in the frontal and parietal cortex
Gottlieb is investigating the nature of attention, postulating that two main factors—reward and uncertainty—engage attention and are implicated in many psychiatric diseases, such as addictions, ADHD, anxiety and depression. Using the visual systems of monkeys and looking at large populations of neurons recorded together, her lab will investigate how uncertainty and reward are implicated in attention and eye movement control.
Michael Greicius, M.D., M.P.H., Associate Professor of Neurology, Stanford University
Elucidating the interaction between sex and APOE on Alzheimer’s disease risk
More than half of Alzheimer’s patients carry a gene variant called APOE4, which poses more risk for women than for men. Greicius plans to investigate APOE4 in humans, looking for variants on other genes that interact with APOE4 differently by gender, and asking whether declining estrogen in menopause might increase the risk in women. The goal is to gain new insights into how APOE4 increases Alzheimer’s disease risk, potentially help identify new treatments and perhaps lead to recommendations for hormone replacement based on APOE4 status.
Stephen Maren, Ph.D., Professor of Psychology and Institute for Neuroscience, Texas A&M University
Prefrontal-hippocampal interplay in contextual memory retrieval
Maren seeks to understand the brain systems and circuits that place memories in context—a process that defines what, when, and where events in our lives have occurred. Many disorders of memory, including Alzheimer’s disease, are associated with an inability to recollect the rich contextual details around an experience. Maren will use cutting-edge pharmacogenetic methods in rats to manipulate neurons in the thalamus that interconnect the prefrontal cortex and hippocampus to characterize how these connections contribute to memory.
Philip Wong, Ph.D., Professor of Pathology and Neuroscience, and Liam Chen, MD, Ph.D., Assistant Professor of Pathology, Johns Hopkins University
Characterization and validation of a new therapeutic target in TDP-43 animal models of frontotemporal dementia
Frontotemporal dementia (FTD), a group of complex disorders resulting from neurodegeneration of the frontal and temporal lobes, is a major form of dementia affecting people under age 65. Wong and Chen hope to fill a gap in the ability to treat these diseases. They hypothesize that loss of function of a particular protein, TDP-43, is involved. TDP-43 potentially could regulate a wide variety of molecular targets that are relevant in memory loss and cognitive decline in FTD. Their lab will perform drug screening in fruit flies to discover leads to potential targets for drug development.
From good habit to bad: Examining the relationship between habit learning and compulsivity
Calakos and Yin are exploring how the pattern of firing activity among distinct cell types in the basal ganglia changes with learning. Although much is known about what goes on at synaptic connections in the brain during the learning process, much less is known about how these changes are integrated to influence neuronal firing among populations of neurons in a given circuit. The researchers have developed an approach to examine learning at this level and will apply it to examine how neural activity changes in the striatum as habits are learned and whether an aberration of the normal habit learning process leads to compulsive behaviors. This work has potential to improve our understanding of how habit learning is encoded in the striatum and how the process may be disrupted in obsessive compulsive disorder (OCD) and related disorders.
Edward Chang, M.D., Associate Professor of Neurological Surgery and Physiology, University of California, San Francisco
How we learn words: the neurophysiology of verbal memory
In childhood and adulthood, we build and maintain massive vocabularies, but we don’t know exactly how. Because language is unique to humans, Chang plans to study the mechanisms of word learning in people—specifically, patients who are undergoing neurosurgical procedures and have electrodes implanted in their brains for clinical indications, such as epilepsy localization. He hopes to gain important new knowledge about how brain networks are coordinated in learning words. Because word-finding difficulties are a common symptom related to aging and many neurological conditions, such as Alzheimer’s disease, stroke and aphasia, new treatments that can preserve or enhance brain function in these conditions will depend on understanding how words are learned.
Adam Kepecs, Ph.D., Associate Professor, Cold Spring Harbor Laboratory
Cell-type specific cognitive broadcast signals from the nucleus basalis
Kepecs’ lab is studying the nucleus basalis (NB), a vitally important but poorly understood neuromodulatory system whose degeneration parallels the decline of cognitive functions in patients with Alzheimer’s disease, Parkinson’s dementia and normal age-related cognitive decline. There is evidence that NB has roles in learning and attention but it is not known what signals this system sends to the cortex. To obtain fundamental knowledge about it, Kepecs will record identified cholinergic NB neurons in behaving mice. The research, which combines behavioral electrophysiology, quantitative psychophysics and optogenetic techniques, will determine what specific neurons signal and when, and whether they have the appropriate signals to support learning and attention. Knowledge of the firing patterns in these neurons will provide critical information for the development of therapeutic treatments for cognitive diseases.
The representation of episodic and semantic memory in single neurons of the human hippocampus
The investigators are exploring whether individual neurons in different subregions of the human hippocampus encode memories. The question of how the brain stores memories has been examined using other methodologies, but all have had limitations. For this research, Wixted and Squire are collaborating with Dr. Peter Steinmetz at the Barrow Neurological Institute to ask patients to memorize a series of pictures and/or words. The scientists will measure single neuron activity in different areas of the hippocampus as the patients later remember those items. The long-term goal is to create a foundation for the development of clinical interventions designed to slow the memory impairment associated with aging and to slow the progression of neurodegenerative diseases in the hippocampus that profoundly impair the ability to remember.
Alison Barth, Ph.D., Carnegie Mellon University
Cell-specific capture of experience-dependent plasticity in the neocortex
Using a mouse model that permits targeted electrophysiological recordings of neocortical circuits, Barth will work to identify specific neurons changed by experience and look at synaptic inputs to these cells, and also to try to drive changes in a certain subset of cells in vivo. The central question is how does experience transform cells and connections between cells, and what about this process is so critical for learning and memory.
Charles Gray, Ph.D., Montana State University
Distributed processing underlying cognition
Gray’s lab has just developed an instrument that can measure neural activity in rhesus monkeys at a very high temporal and spatial resolution from many locations. During the award period, Gray plans to measure neural activity from large areas of the brain to obtain a broad perspective on how and where information is encoded when the brain is holding something in short-term memory.
Hippocampal structure and function in cognitive impairment
Kerchner plans to use two high-resolution magnetic resonance imaging (MRI) technologies to study the interlinked subregions of the hippocampus to see how they are affected in Alzheimer’s disease. He will study the physical structure of the hippocampus with one technology and, in collaboration with Wagner, will use the other technology to study how groups of hippocampal nerve cells fire during memory exercises.
Attila Losonczy, M.D., Ph.D., Columbia University
Dissecting hippocampal microcircuit dysfunctions underlying cognitive memory deficits in schizophrenia
Losonczy aims to advance understanding of memory processes in healthy and diseased brains to identify key targets for preventing and treating these memory deficits. Using mouse models, he plans to use state-of-the-art in vivo functional imaging to observe and manipulate neural circuits in the rodent hippocampus during memory behaviors, tracking how these neurons function in normal learning and how they are altered in schizophrenia.
Ben Barres, M.D., Ph.D., Professor of Neurobiology, Stanford University School of Medicine
Do Astrocytes Control Synaptic Turnover? A New Model for What Causes Alzheimer’s Disease and How to Prevent It
As our bodies age, it’s likely that some mechanism is needed to remove aging synapses in the brain so they can be replaced with new ones. Barres is investigating whether astrocytes play this role and, if so, what happens if their work is impaired. The work has potential to improve understanding and treatment of Alzheimer’s disease.
Wen-Biao Gan, Ph.D., Associate Professor of Physiology and Neuroscience, New York University School of Medicine
Microglial Function in Learning and Memory Disorders
Gan is investigating whether microglia play an important role in learning and memory formation. Using a new transgenic mouse line he developed, he will examine how eliminating microglia or making them dysfunctional affects neural circuits. The studies will provide insights for the understanding and treatment of brain disorders such as autism, mental retardation and Alzheimer’s disease.
Elizabeth Kensinger, Ph.D., Associate Professor of Psychology, Boston College
Changes in the Temporal Dynamics and Connectivity of Emotional Memory Networks Across the Adult Lifespan
Kensinger is studying the impact of emotions on memory. Her research takes a lifespan perspective, assessing memory and neural activity of adults ages 18-80. She will examine how emotional information is retrieved, including both the spatial and temporal dimensions of memory retrieval. The research has potential to advance understanding of the memory changes associated with age, as well as such disorders as depression and post-traumatic stress syndrome.
Brian Wiltgen, Ph.D., Assistant Professor of Psychology, University of Virginia
Reactivation of Neocortical Memory Networks During Consolidation
New memories are encoded by the hippocampus and over time are permanently stored in regions of the neocortex. Wiltgen is exploring the biological mechanisms that underlie this storage process, using new techniques to control the activity of memory circuits in the hippocampus and neocortex. The work has implications for the treatment of Alzheimer’s and other diseases that affect memory.
Cristina Alberini, Ph.D., Professor of Neuroscience, Mount Sinai School of Medicine
The Role of Astrocytes in Memory and Cognitive Disorders
Alberini is focusing on the interaction between neurons and astrocytes in memory formation. She will explore the hypothesis that defects in this interaction may cause cognitive impairments and look at potential new treatments for the cognitive decay related to aging and neurodegeneration.
Anis Contractor, Ph.D., Assistant Professor of Physiology, Northwestern University School of Medicine
Activating Group I mGluRs to Repress Fear Memory
Mice lacking the glutamate receptors called mGluR5 cannot extinguish fearful memories. Contractor plans to study the role of these receptors, mapping the brain circuits involved in learning to fear appropriate situations and to suppress inappropriate fear. He will also see if new drugs can accelerate the process of learning not to be excessively afraid. Similar drugs may be useful in treating human anxiety disorders.
A Circuit Level Approach to Understanding & Treating Stress-Related Memory Disorders
Frank and Dallman are examining whether small alterations in brain activity could help minimize the long-lasting effects of stress on learning and memory. If their hypothesis that stress amplifies the replay of memories proves to be the case, therapies could be designed to reduce the long-lasting effect of stressful events. The research has particular implications for post-traumatic stress disorder.
Cortical Persistent Activity Mechanisms of Working Memory
Mauk and Johnston will use both systems and cellular approaches to study working memory both in living animals and in brain slice experiments using powerful neuron recording methods. Because working memory contributes to so many cognitive processes, understanding its mechanisms could improve diagnosis and treatment of many disorders, including Alzheimer’s disease and ADHD.