Working Groups 2009-2010

Statistical analysis of multimodal neural data during memory related experiments – Uri Eden. The focus of this working group is to develop and apply statistical methods to understand brain activity during memory tasks. These methods will allow us to characterize common features of neural coding associated with electrophysiological and imaging data, understand and appropriately model sources of variability in this data, and make inferences about how brain areas represent memory or context dependent information. Specifically, we are working to characterize the role of theta oscillations in memory encoding and retrieval by developing descriptive statistics and parametric models both for spiking activity in rat hippocampus in relation to the phase of the theta activity in the LFP and for the theta phase in human EEG/MEG data during behavioral tasks that favor both memory encoding and retrieval. Additionally, we are developing parallel statistical models for spike train, LFP, EEG, MEG and fMRI data capable of describing stimulus/response relationships and characterizing how functional connections between neurons and between brain areas are reflected across these data modalities. Members: Howard Eichenbaum (Psychology); Michael Hasselmo (Psychology); Chantal Stern (Psychology); Kyle Lepage (Post-Doctoral Fellow, Mathematics and Statistics)

The Neural Coding of Drug Action – David H. Farb, Ph.D., PI. The central goal of this proposal is to integrate existing electrophysiological, behavioral, pharmacological, and molecular genetic technologies to create a novel systems-level platform for the discovery of more effective therapeutics for cognitive disorders, by directly assessing their impact upon fundamental hippocampal systems for pattern separation (encoding), and pattern completion (retrieval) that are believed to be essential for cognition in all mammals, including man. This research platform will fill a critical mechanistic gap between in vitro, ex vivo and behavioral models for drug discovery. Deficits in aspects of episodic memory dependent on hippocampal function are evident in a variety of mental disorders that have a huge social impact, including  schizophrenia, autism, Alzheimer’s Disease, and normal aging. Existing pharmacotherapies for many such conditions are limited and carry substantial risk of adverse effects. There remains a huge gap between target-based drug discovery and identification of high-value therapeutic agents for mental disorders as the targets may be located in different subcellular domains, on different types of neurons, and in different interconnected brain regions. As a result, identification of pharmacological agents for treatment of cognitive disorders relies upon simplified behavioral models of learning and memory, such as maze navigation or responding to a threatrelated stimulus, providing little insight into the mechanism of drug action and little guidance for improving efficacy and decreasing risk. As proof of principle, high-density electrophysiological recordings in awake behaving rats will be used to identify deficits in hippocampal function that underlie cognitive deficits exhibited by animals reared in social isolation, a model for environmental stress during development. Two smallmolecule pharmacologically active cognitive enhancers that act via different mechanisms will be used as probes: methylphenidate, a therapeutic for attention-deficit hyperactivity disorder (ADHD) that is proposed to act by inhibiting monoamine reuptake, and L-655,708, an experimental drug that may act via negative modulation of !5 subunit containing GABAARs in the hippocampus. In addition, a novel gene therapeutic strategy involving viral delivery of shRNA will be used to specifically knock-down !5 subunit mRNA in the hippocampus to test the consequences of silencing this receptor-mediated downstream pathway. This research will establish a generally useful platform for utilizing systems level measures of cognitive enhancement for the discovery of therapeutic treatments for disorders or diseases of the nervous system. Members: Howard Eichenbaum, Ph.D., Co-PI; Terrell T. Gibbs, Ph.D., Collaborator; Shelley J. Russek, Ph.D., Collaborator

Probing the relationship between neuronal cell cycle control and cognition: translational research aspects of Alzheimer’s disease, epilepsy, and depression – Ulla Hansen. The overall goal is to investigate how regulation of gene expression underlying neuronal cell cycle control is altered in disease, and how such alterations may play a direct role in processes of cognition. The long-term objective is translational research that is aimed at developing novel therapeutics to treat the cognitive disorders of multiple disease presentations. The short term goal is to merge basic knowledge regarding transcription factors that mediate and maintain cell cycle entry and exit with descriptive anatomical and biochemical changes that occur in disease and to directly test their influence over cognitive function by use of viral vectors to alter function. This proposal focuses on Alzheimer’s disease, where neurodegeneration is associated with ectopic cell cycle re-entry of post-mitotic neurons.  However, relevance to other brain disorders in which cell cycle control is believed dysregulated in distinct fashions will also be considered, including epilepsy, where hyperexcitability has been linked to the birth of new dentate granule cells; and depression, where the effectiveness of antidepressants has been hypothesized to reflect their ability to restore dentate neurogenesis.  The specific aims are to use molecular and behavioral approaches in investigations of Alzheimer’s disease, addressing two questions: 1) Is there a relationship between molecular cell cycle entry markers and the anatomical changes measured in Alzheimer’s disease models, and 2) Does this relate to changes in cognitive function as measured by behavioral assays? The initial focus will concern the role of the transcription factor LSF in pathophysiology and cognitive decline, due to prior linkages between Alzheimer’s Disease and LSF.  The long term translational outcome would be use of small molecules or genetic therapeutic approaches to target the relevant signaling pathways for treatment of multiple diseases in which neuronal cell cycle control is key. Members: Carmela R. Abraham, (Biochemistry), Ulla Hansen, Project Leader (Biology), Conan Kornetsky (Psychology and Behavioral Pharmacology) and Shelley Russek, (Pharmacology).

Cognitive Enhancers and Extinction of Drug Addiction – Kathleen Kantak. Several studies suggest that cues associated with drugs of abuse undergo memory consolidation such that later exposure to just the cues induces drug craving and relapse. Cognitive-behavioral therapy is used to extinguish the motivating influence of drug-related cues to deter relapse to drug use. However, new approaches are needed to significantly augment the therapeutic efficacy of cognitive-behavioral strategies for substance abuse disorders. Importantly, laboratory studies (animal and human) have documented that the cognitive-enhancing drug D-cycloserine (DCS) can augment extinction to cues that elicit fear and anxiety. Moreover, the reductions in anxiety have been shown to be long lasting in human laboratory studies. Recently, it was demonstrated that effective doses of DCS combined with extinction training deterred reacquisition of cocaine self-administration to a significantly greater extent than either extinction training without DCS or DCS without extinction training in rat and monkey models of drug relapse. These results provide a rational framework for designing conceptually similar studies in drug-addicted individuals to evaluate the efficacy of exposure therapy combined with DCS pharmacotherapy for the clinical management of relapse. A study (pilot #1) of D-cycloserine augmentation of extinction to alcohol cues in humans began last year, and we are now extending these studies to examine daily alcohol drinking patterns at 3-mo follow-up. Assessing daily alcohol drinking is an important variable for establishing treatment efficacy. We also initiated studies (pilot #2) to determine if altered expression of the GluR1 subunit of the AMPA receptor is a mechanism by which DCS augments cocaine cue extinction learning. To extend these studies, we are using a protein cross-linking assay to distinguish between surface and intracellular pools of AMPA receptor subunit proteins. Understanding the underlying signaling pathways in the brain for these therapeutic effects may lead to the discovery of new molecular targets to augment exposure therapy in substance abusing populations. By bridging the neuroscience of addiction with the neurobiology of learning and memory, the Addictions Working Group might significantly advance the treatment of substance use disorders.

Detection of somatic mutations in mental illness – Simon Kasif. We plan to test whether somatic mutation contributes to the development of schizophrenia, either directly or as a second step in someone already predisposed by germline variants to disease. The approach will focus on simple sequence repeats as these are associated with high rates of mutation. Initially we will study tri-nucleotide repeats in coding sequences as a proof of principle. We will study DNA from post-mortem brains, using tissue from a different embryonic origin as a control. Our strategy is to enrich for these repeats by capture on magnetic beads, sequence them, map them back to the genome and then identify mutations in them. Through this analysis, we will be able to discover different classes of mutation associated with disease, including those that affect the number of repeats within a region and thus affect protein function or expression, those that lead to recombination events between different chromosomal elements and those that affect copy number by loss or gain of one or two parental chromosome. We will build laboratory and bioinformatic tools to enable this approach. Members: Alan Herbert; Charles Cantor

Temporal dynamics of odor coding in the olfactory bulb – Matt Wachowiak. The olfactory system has proven to be an extremely useful model system for investigating how external information is represented and processed in the brain. This project involves a multidisciplinary collaboration between several different groups, with the goal of understanding how odor information is represented and processed both in the earliest stages of central processing and in the awake behaving animal. The approach taken by our working group is to use statistical analyses of neural activity patterns collected from awake rodents performing odor-guided tasks, to gain insight on neural coding and early olfactory processing. Concurrently, we use these experimental data as inputs to generate a comprehensive computational model of the entire olfactory bulb processing network. This collaboration allows us to address questions that are relevant for the individual members of each group, but which cannot be addressed at this level in any single lab. During the past year of seed funding for this working group, we completed our initial statistical analysis of odor representations and developed two olfactory bulb models that address different aspects of the processing network. We propose another year of seed funding to enable an expansion of this working group and to solidify our application for independent funding from the NIH/NSF Collaborative Research in Computational Neuroscience (CRCNS) program, application planned for a fall submission. The goals over the next year are to expand our research in three directions: (i) To begin testing model predictions experimentally using a combination of optical and electrophysiological recordings in anesthetized and awake rats. (ii) To continue with the development of olfactory bulb models at different scales, including individual olfactory bulb projection neurons, small numbers of coupled neurons, and a network-level model of olfactory bulb output. (iii) To apply multiple time-scale analysis of odor information coding to the experimental datasets. Reflecting these enhanced goals, we have expanded the group to include additional members of the Kopell lab, a graduate student from the Wachowiak lab who will be trained in neural modeling, and a postdoctoral associate from the Wachowiak lab with expertise in electrophysiological recordings and data analysis of dynamical activity patterns. This continued collaboration over the next year will allow us to make significant headway towards a general and robust understanding of how the early olfactory system processes sensory information in the awake animal. Members: Nancy Kopell (Principal Investigator); Kamal Sen (Principal Investigator); Post-doctoral Fellows: Remus Osan, Erik Sherwood, Jorge Brea, Tristan Cernier; Graduate Student: Ryan Carey

Effects of Environmental Mercury on Brain Integrity and White Matter in Rhesus Monkeys – Roberta F. White. This is the second year application for a proposal to evaluate the interaction between normal aging and exposure to chronic environmental levels of organic mercury through dietary intake. Such exposure is particularly of concern for individuals who have a significant intake of fish in their diet. The consumption of fish is advocated for heart healthy diets, based in part on data from the Framingham Heart Study (FHS). This consumption is also of concern as mercury has been associated with damage to  white matter and data from an ongoing study of normal aging in the rhesus monkey has demonstrated conclusively that white matter deterioration is a primary cause of age-related cognitive impairments. This raises the question of whether the chronic environmental levels of mercury that might be encountered in normal aging humans who consume a heart healthy diet rich in fish, might exacerbate age-related white matter damage and if so what the mechanism might be. These issues will be addressed in a two-part multidisciplinary pilot study that, if successful, will justify application for a full five-year NIH funded study. Members: Peter Bergethon, MD, Dept of Anatomy/Neurobiology and Biochemistry, MED; Douglas L. Rosene, Ph.D., Dept of Anatomy and Neurobiology MED; Michael McClean, Sc. D., Dept of Environmental Health, SPH