Paul Miller, Ph.D. - US grants

DESCRIPTION provided by applicant): The proposal is designed to enable the candidate to become a mature, accomplished researcher in the field of theoretical and computational neuroscience, through individual mentoring, participation in courses and seminars, and particularly through intensive training to complete a high-quality research project. The candidate has produced excellent research in theoretical physics, but requires a period of development to become an independent, productive scientist in the field of neuroscience. He has chosen an institution with an established graduate program in neuroscience, and with faculty of high acclaim in order to gain the best quality of training. The research project will address the cellular mechanisms of working memory and so help elucidate a key process in cognition. The project focuses on the mechanisms of parametric working memory, whereby a quantity (such as frequency) with a continuous range of values can be encoded and memorized in the firing rates of neurons. The candidate will implement a computational model network, containing neurons with biophysical properties, which will reproduce specific sets of data in a parametric working memory task. He will test what profiles of synaptic connectivity can produce the necessary stable network states for parametric working memory, hypothesizing that the strength of synaptic connections to a neuron correlates with the excitability of the neuron. He hypothesizes that long-term plasticity is necessary to achieve the synaptic connectivity necessary for working memory, so will test which kinds of long term plasticity stabilize the network. He hypothesizes that short-term plasticity is necessary to produce time variation in the memory states, as seen in experiment. He will test which forms of short-term plasticity lead to the observed behavior, and whether they contribute to the stability of the mnemonic states.

[unreadable] DESCRIPTION (provided by applicant): The investigators will combine experimental studies with computational simulations to uncover the neural underpinnings of taste processing. In so doing, they will provide insight into more general facets of sensory processing, such as the cause and effect of trial-to-trial variability, the role of attentiveness on cortical activity and the mechanisms of conditioning whereby a previously palatable substance is rendered unpalatable following a single association with nausea. These studies will use simulations to assess how variability at one scale can either enhance or reduce variability at a larger scale during normal cortical functioning. The studies will also use models and simulations, to uncover what changes in connections or cellular properties in a network of neurons lead to the altered behavioral response to a sensory stimulus seen in taste learning. Taste is an important, though underutilized, modality for addressing issues of sensory processing, since it has a strong connection to behavior and survival and can produce strong, rapid yet long-lasting learning. Moreover, recently the investigators have uncovered correlated changes of neural activity with the state of attentiveness of an animal during taste processing. The investigators will test how these attention-dependent changes of neural activity arise and will use simulations to assess the possible functional role of such changes. A transformative role of the research will be to change the way the apparent randomness of trial-to-trial variability is viewed. Rather than being a nuisance in the observation of neural data, the authors aim to show that such variability is an aspect of neural activity that can both provide information about underlying activity and be beneficial for some aspects of neural processing. An understanding of the modulation of noise, variability and oscillations with attentiveness will be beneficial for addressing deficiencies in all areas of sensory processing. More specifically, these investigations of what brain processes are involved in making one tastant highly desirable and another noxious may have far-flung clinical implications for, for instance, the treatment of some forms of obesity and the alleviation of childhood taste disorders caused by chemotherapy. Furthermore, an improvement in our understanding of normal cortical activity and its modulation by attention (via neuromodulators or by executive areas of the brain) will help us better address problems of abnormal cortical activity such as epilepsy and disorders of executive control associated with schizophrenia. [unreadable] [unreadable]

This Integrative Graduate Education and Research Traineeship (IGERT) award supports an interdisciplinary training program for Ph.D. students at Brandeis University, carried out in partnership with the New England Center for Complex Systems (NECSI). The goal is to create a group of mathematical scientists with the computational skills, intellectual flexibility, and global perspective needed to attack pressing problems in pure science, applied science, and public policy that require a mathematically sophisticated, interdisciplinary approach.

Intellectual Merit: Fundamental problems in the theory of fundamental particles, quantum gravity, the science of materials, the emergence of cognition, disease epidemiology, and economic forecasting all draw from a set of common mathematical concepts and techniques in geometry, complex classical and quantum systems, and probability theory. Students trained in a variety of mathematical techniques, broadly educated in the applications of these techniques, and experienced in communicating their ideas across disciplines will best be able to respond to new scientific problems whose solution requires advanced mathematics, sophisticated modeling, and the management of large data sets. The IGERT program will therefore include: hands-on experience through interdisciplinary research rotations; interdisciplinary coursework; co-advisors outside of the students? discipline; intensive NECSI-led summer institutes; an IGERT seminar series; and the opportunity for internships at the International Center for the Theoretical Sciences in Bangalore, India. Broader Impacts: Students will learn to communicate their work to prospective science students and the public via public lectures, the Brandeis Science Posse program, and the Acton Discovery Center.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

PROJECT SUMMARY The investigators will combine experimental studies with computational simulations to uncover the neural circuit mechanisms underlying taste choice behavior. A fundamental question to be addressed is how the neural activity induced by a given taste is impacted by the recent sampling of another taste and/or by the expectation that another taste is forthcoming. We will analyse data produced from ensemble recordings of neural activity and make use of optogenetic techniques that alter neural activity, to further our work on how specific features of such activity impact behavior during a decision making task. These data will provide fuel to our modeling efforts, with which we will produce a framework that can generalize to other sensory modalities, whenever decisions are based on a consideration of one stimulus at a time (even if two stimuli are present) rather than on a parallel processing of two or more stimuli simultaneously?that is, this novel framework will allow us to understand the behavior of animals when faced with a choice between any two separate stimuli. Thus, a transformative aspect of the research will be the development of a new framework for the analysis of decision-making when the choice to be made is whether to stick with the current stimulus or to switch to another. In such decision making tasks, which are ubiquitous in natural settings, the stimulus itself is chosen by the subject rather than being controled by the experimenter. Our recordings of the animal's behavior simultaneously with its neural activity allow us to tightly constrain these first dynamic models of such a process. Taste is an important, albeit underused, modality for addressing issues of sensory processing, in that it has a strong connection to behavior?indeed it is well-nigh impossible for an animal to sample a taste without a behavioral response. Moreover, given that tastants can be intrinisically hedonic or aversive, animals are internally driven to make responses and will do so without the months of training?which inevitably rewires the brain?required for animal training in behavioral tasks based on other sensory modalities. Therefore taste is ideally suited to the study of naturalistic decision making.

Health Relevance Alleviating the burden of neurological and psychiatric disorders will require a cohort of investigators who can use computational and theoretical tools to understand brain function in health and disease. This program will train undergraduates and graduate students to use quantitative modeling methods and statistics to reveal features of brain function and disease not possible without these quantitative approaches.