John A. Assad - US grants

surgery; psychology; nervous system; Mammalia; Primates; behavioral /social science research tag;

The aim of our research is to understand how the primate brain processes visual stimuli; in particular, how the brain integrates visual information for the control of visually guided behaviors such as target-directed eye or hand movements. For this purpose we will use awake, behaving macaque monkeys trained to perform visual guidance tasks. Little is known about the neuronal control of visually-guided behaviors in humans, although it is clear that damage to particular brain areas, such as parietal cortex, can adversely affect these abilities. Macaque monkeys serve as an excellent model species for studying visual guidance, in that their visual abilities are quite similar to that of humans, they show similar deficits when experimental lesions are placed in homologous brain areas, and they are capable of learning demanding behavioral tasks.

[unreadable] DESCRIPTION (provided by applicant): A great deal of evidence suggests that visual perception is affected by our predictions about the visual world. Prediction allows us to exploit and adapt to the causal, non-random structure of our visual environment, and is essential for rapid and accurate control of visually guided behavior. We previously identified neuronal signals in the monkey lateral intraparietal area (LIP) that provide a predictive representation of the direction of visual motion. The overarching issues in this new proposal are the relationship of predictive signals to behavior and the mechanisms by which predictive signals develop. Predictive motion signals in LIP seem ideally suited for feedforward control of behavior, but little is known about the relationship between predictive neuronal signals and behavior. We will address this issue by looking for trial-by-trial correlation between predictive neuronal signals and reaction time. We will examine 1 both manual reactions and eye movements to test whether the activity of single neurons is specific for particular behaviors, or rather provides a general predictive signal that is useful for multiple behaviors. We will also examine whether predictive neuronal signals and behavioral advantages arise as a result of learning based on the recent trial history of visual stimulation. We specifically hypothesize that predictive neuronal signals are updated based on prediction errors, the difference between the predicted visual stimulus and the actual visual stimulus. Moreover, we hypothesize that predictive behaviors and predictive neuronal firing will be similarly affected by recent trial history. Finally, another "extraretinal" process, selective attention, has been shown to enhance sensorimotor behaviors and to modulate neuronal responses. A key question is whether the dynamics of the neuronal modulation can account for the behavioral advantage. We will simultaneously examine the time course of neuronal modulation and the time course of the performance advantage that is gained when an animal endogenously switches attention between two visual stimuli in response to a cognitive cue. The time course of attentional modulation of a neuronal response should reflect the role that a neuron plays in endogenous shifts of attention. Our experiments will provide a mechanistic perspective on how the brain uses prior information about the sensory world to facilitate perception and action. Gaining basic information on perceptual mechanisms is an essential step for understanding normal and abnormal brain processing. [unreadable] [unreadable]

The basal ganglia (BG) are a set of subcortical nuclei that play a crucial role in the control of voluntary movements. Their importance is underscored by diseases of the BG, such as Parkinson's disease, which compromise the initiation and execution of voluntary movements. While much is known about the general organization of the BG, fundamental questions remain about their role in the normal control of movement. These questions are particularly relevant given the renewed interest in restorative neurosurgical procedures, such as chronic electrical stimulation. that target the BG to relieve Parkinsonian symptoms. The main goal of this is to understand the role of the BG in the normal control of movement, using the awake behaving macaque monkey as an experimental system. The first aim addresses an intriguing paradox about the BG: while diseases affecting the BG cause problems with initiating voluntary movements, most neurophysiological studies have found that neuronal activity in the BG occurs too late to play a role in movement initiation. However, in most of these studies the movements were in response to an external sensory stimulus. There is evidence from Parkinsonian patients that stimulus-cued movements are less severely affected than self-initiated movements. We will thus examine whether the BG play a special role in self-initiated movements - self-initiated with respect to either when a movement is made or which movement is made. The second aim addresses the roles of the direct and indirect BG pathways. The output of the BG is influenced by two distinct pathways with opposing effects on movement: a direct pathway from the striatum which facilitates movement, and an indirect pathway via the subthalamic nucleus (STN) which inhibits movement. While the identification of these pathways has provided a useful framework for understanding movement disorders, many questions remain about their roles in normal movement. We will test one hypothesis, that the two pathways may act in concert to "select" a specific movement among competing possibilities of movement, by examining how neurons in the output nuclei of the BG are affected by electrical inactivation of the STN. For this purpose, it will be necessary to examine the neuronal effects of electrical stimulation in the STN. Little is known about the neuronal effects, even though STN stimulation is now being used to treat Parkinsonian symptoms in human patients. We will directly measure the neuronal effects of electrical stimulation in the STN, and examine how these effects vary with the parameters of stimulation. For this we will develop and test new multielectrode techniques for recording from and electrically stimulating multiple deep brain sites simultaneously. The combined basic studies and technical innovations will increase our understanding of the role of the BG in normal movement and movement disorders, and will hopefully provide new approaches for treating Parkinsonian conditions.

CORE ABSTRACT NOT PROVIDED

DESCRIPTION (provided by applicant): Visual perception depends on more than visual input. The brain constantly generates internal signals that modulate responses to external visual stimuli. Dynamic internal signals allow neural networks to respond differently to the same stimulus, enabling organisms to adapt to changing task demands. Internal network dynamics also support persistent neural activity related to visual working memory. In this proposal, we examine the influence of internal signals, continuing our focus on parietal cortex. An important class of internal signals are related to self-movement. We have identified a powerful suppression of the firing of parietal neurons by microsaccades - but only during a task requiring a transient motion-detection that may be mimicked by a microsaccade's visual effect. Aim 1 examines the hypothesis that the suppression may be flexibly gated by task demands. Aim 1 also investigates the potential role of the rostral superior colliculus, an area involved in microsaccade generation, in the suppression. Aim 2 tests whether two different neuronal signals that have been reported in parietal cortex -- categorization and perceptual decision -- are actually the same thing. Most perceptual decision experiments did not test whether the signals could be independent of the form of the animal's report; we propose that if perceptual decision signals were independent of the report, they would be indistinguishable from categorical signals. We will examine whether LIP neurons provide generic visual categorical signals, and we will compare perceptual decision and categorical signals head-to- head, in the same experiment, in the same neurons. Aim 3 examines the mechanisms underlying persistent firing in parietal cortex. Recurrent network models posit that persistent memory-delay period activity is a natural dynamic of recurrent circuits. A recent recurrent network model makes several robust yet surprising predictions; for example, if different levels of persistent activity can be evoked under different conditions, the amplitude of the activities across the neuronal population should be scaled versions of each other and of the spontaneous activity. In addition, there should be a common order of preference among neurons in their persistent firing, a highly unusual organization for cortex. Aim 3 uses the experimental data generated from Aims 1&2 to test and refine this model. Our experiments will provide a mechanistic perspective on how internal states of the brain facilitate and affect the perception of the external visual world. Gaining basic information on these processes is an essential step for understanding normal and abnormal brain processing.

DESCRIPTION (provided by applicant): The brains of mammals contain an extraordinarily large number of neurons whose activity and interconnections determine the function of circuits that monitor our sensory environment, dictate our motor choices, form memories, and guide all behavior. However we do not understand how the activity of these circuits governs brain activity. A fundamental limitation has been the inability to monitor and control the activity of a significan fraction of brain cells at any one time - thus typical studies of the neural underpinnings of behavior monitor at most ~100 cells simultaneously, or approximately one millionth of the total. In order to gain insight how circuit computations are carried out and subsequently control behavior, we will develop two novel technologies. The first is a radical new class of electrode with 50-100 times more recording sites than is typical and with on-board electronics, allowing unprecedented quality recordings of high number of neurons. The second is a novel way to deliver light into the brain in a controlled manner in order to be able to perturb the activity of neurons with high precision.

Project abstract Study of movement disorders suggests that dopamine (DA) and the broader nigrostriatal circuit may play a specialized role in self-timed movements, for which the drive to move must be generated internally rather than in reaction to external events. However, classic experiments suggested that DA neurons (DANs) encode reward-prediction errors (RPEs) that occur too late to facilitate movements. In project 1, our collaborators present an updated temporal difference (TD) model for which, under appropriate conditions, RPE/DA signals ?ramp-up? during ongoing behavior. These signals could be associated with, or facilitate, self-timed movements. We will address the hypothesis in three ways, using a self-timed movement task in mice. First, we will record from genetically defined DANs during self-timed movements, to assess the relationship between DAN activity and movement time. We already have strong preliminary evidence that DANs indeed ramp up their activity before self-timed movements, with the slope of ramping inversely related to the movement time. Second, we will test whether DA ramps are causal to self-timed movements, by optogenetically stimulating genetically defined DANs and examining the effect on the timing of self-timed movements. Third, the TD/RPE theory explains how DANs can evince ramping activity, but does not address how DA ramping affects downstream targets. We hypothesize that DANs facilitate self-timed movements by oppositely modulating striatal spiny projection neurons (SPNs) of the direct and indirect striatal pathways. To test this hypothesis, we will simultaneously monitor pairwise activity from genetically identified DANs, dSPNs or iSPNs to assess 1) the relationship of dSPN/iSPN balance and movement time, and 2) the cell types' influence on each other. These experiments will provide crucial information on the function of the key nigrostriatal circuit, grounded in a novel theory that makes testable hypotheses.

Project abstract Animals, including humans, interact with their environment via self-generated and continuous actions that enable them to explore and subsequently experience the positive and negative consequences of their actions. As a result of their interactions with the environment, animals alter their future behavior, typically in a manner that maximizes positive and minimizes negative outcomes. Furthermore, how an animal interacts with its environment and the actions that it chooses depend on its current environment, its past experience in that environment, as well as its internal state. Thus, the actions taken by an animal are dynamic and evolving, as necessary for behavioral adaptation. It is thought that both the execution of actions, in particular goal-oriented actions, and the modification of future behavior in response to the outcome of actions, depend on evolutionarily old parts of the brain called the basal ganglia. Within the basal ganglia, cells that produce dopamine have a profound influence on behavior, including human behavior, and their activity appears to encode for features of the environment and animal experience that are important for directing goal-oriented behavior. Here we bring together a team of experimental and computational neurobiologists to understand how these dopamine- producing cells modulate behavior and basal ganglia circuitry. We will use unifying theories and models to integrate information acquired over many classes of behavior. Completing the proposed work, including the technical advances and biological discoveries, will provide a platform for future analyses of related circuitry and behaviors in many species, including humans.

We propose to continue a Jointly Sponsored Predoctoral Training Program in Neurosciences that is the major source of support for early year students in the Ph.D. Program in Neurosciences at Harvard University. The goals of this interdepartmental Ph.D. program, established in 1981, are (1) to organize the neuroscientists at Harvard Medical School, its affiliated hospitals, and Harvard College into a single training faculty cohort; and (2) to train research scientists and teachers who are interested in mental health, diseases of the nervous system, and fundamental mechanisms of the brain. The training program is designed to provide talented trainees with a broad and thorough background in neuroscience and to mentor them in performing original and rigorous research in important areas of neuroscience. During the first year, students are provided with initial preparation in quantitative approaches to scientific endeavors. This is followed by a year long course, The Discipline of Neuroscience, which provides integrated and rigorous training in concepts central to our understanding of the development, function, and diseases of the nervous system at the levels of cellular signaling, circuit computations, and behavior generation. All students take an additional course in Statistical Approaches to Neuroscience, a neuroanatomy course and two electives. Students also rotate through three different laboratories during the first year. Following the coursework, laboratory rotations, and a preliminary examination, students begin full time, mentored dissertation research. During the program, students are also involved in other ongoing training activities including journal clubs, seminars, retreats, skill workshops, and data presentation. There are currently 102 graduate students enrolled in the Program in Neuroscience; this grant supports 14 students in the first or second year of graduate education. There are 141 faculty in the Program in Neuroscience; the 74 faculty who are currently most actively involved in graduate education are training mentors on this proposal. Considerable effort has gone into making this program a highly interactive group with extensive formal and informal contacts between students and faculty. Graduates of this program go on to distinguished careers in biomedical research and make substantial contributions to a growing understanding of neuroscience.