Carlos D. Aizenman - US grants

The scientific goal of this project is to understand the mechanisms by which the external environment shapes the way the nervous system is wired. The brains of developing organisms face an immense challenge since they must allow the organisms to function within their environment even while the nervous system is not yet fully developed. It is not fully known how the brain achieves the balance between early function and the need to remain flexible. One strategy employed by the brain to achieve this is through a process called neural plasticity, which allows brain circuits to adapt to patterns of sensory input received from the external environment. This project uses the developing visual system of frog tadpoles as a model for early brain development. Experiments will study the correlation between the developmental emergence of visually-guided swimming behavior to the properties of tiny electrical signals generated in the tadpole brain in response to visual stimuli. This will allow investigators to first map neural circuits involved in processing visual stimuli and then to understand the role of the visual environment in building this circuitry through neural plasticity. For example, if visual input is required for proper wiring of visual circuits, then tadpoles raised in a dark environment or under conditions in which communication between the eye and brain is disrupted, are expected to develop abnormally. This study will also focus on mechanisms by which the brain can adapt to deficits in sensory input to achieve normal function. Together, these experiments will provide important insight into the mechanisms by which the brain's complex circuitry emerges during development and which allow it to adapt to a changing environment. A second goal of this project is to develop an educational program which will allow high-school students from underrepresented minority groups to engage first-hand in this research. This program will allow for two students each year to come to Brown and participate in a basic Neuroscience course and work in Dr. Aizenman's laboratory over the summer. The ultimate goal is to encourage these students to pursue a career in the life sciences by providing first-hand laboratory experience and mentoring. In addition, the program will also provide training opportunities to undergraduate and graduate students in the laboratory.

DESCRIPTION (provided by applicant): The process by which organisms use incoming sensory information to adjust their motor output in meaningful ways is fundamental to a successful interaction with their environment. Correct wiring during early development of neural circuits mediating this sensorimotor integration is essential for organism survival. In developing neural circuits both circuit architecture and the signaling properties of individual neurons within the circuit undergo profound changes. However, organisms can begin to interact meaningfully with their environment even before these circuits are fully mature. This suggests that neural circuits underlying sensory processing and behavior can employ different strategies to carry out their function, based on the circuit's developmental state. The process by which this occurs remains obscure. Since several human neurodevelopmental disorders are believed to result from inappropriate neural circuit formation during early development, it is important to understand the basic mechanisms by which these circuits develop. Our proposal focuses on the developing optic tectum of the Xenopus laevis tadpole as a model system to address these issues. The tectum, and its mammalian homologue the superior colliculus, receive direct input from the retina as well as from other sensory modalities. It functions to integrate visual and other sensory information, and transform this into orienting behavior. Tadpoles are known to rapidly swim away from approaching objects, and this avoidance behavior requires processing by local circuits within the tectum. It is not known how these local circuits develop, nor how developmental changes in the organization and response properties of this circuit relate to visually guided motor behavior. We propose to use a combination of behavioral analyses, in vivo and in vitro electrophysiology and in vivo Ca++ imaging of neuronal populations, to address how the tectum integrates visual information and transforms it into visual avoidance behavior. In the first aim we characterize the types of stimuli which trigger visual avoidance and address specific hypotheses about how these stimuli are encoded in the tectum. In the second aim, we address the mechanisms by which neurons in the tectum encode behaviorally relevant stimuli, by focusing specifically on the role of tectal neuron intrinsic excitability, the properties of retinotectal synapses, and the role of local inhibition. These experiments will elucidate how multiple developmental processes known to occur at the single cell and network levels in the tectum, can work together to optimize its ability to transform visual input into motor behavior. Understanding the basic mechanisms by which neural circuits adjust multiple properties to achieve stable function will provide important insight into the ability of the CNS to compensate for developmental deficits, opening several therapeutic avenues for the early treatment of neurodevelopmental and vision disorders. PUBLIC HEALTH RELEVANCE: Many neurological and psychiatric disorders including autism, schizophrenia, epilepsy and amblyopia are not always clearly associated with a well defined neuropathological profile. Rather, they are believed to result from abnormal functioning at the level of microcircuits within different brain regions, and many of these abnormalities are thought to arise during development when these circuits are first formed. Understanding the basic mechanisms by which the microcircuitry of the brain becomes established during development, and how and when functional properties of these microcircuits emerge, is therefore a crucial step towards understanding why neural circuits develop abnormally during some neurological disorders, and is important for developing novel therapeutic strategies.

The only way to truly understand how the human brain works is to understand how it is first put together during early development. To do this, we need to first grasp, at a basic level, the fundamental principles by which developing brain circuits are initially formed and how early experience can shape these connections. This project addresses these questions by studying the development of the visual system of tadpoles from the African clawed frog, Xenopus laevis. This relatively simple brain circuit allows investigators to ask highly tractable questions about early brain development and answer them by designing experiments that investigate development at the level of single brain cells to the more complex behavior of brain circuits, and ultimately, to complex behaviors. Thus, these studies will provide an understanding of the mechanisms underlying visually guided behavior from initial perception in the eye all the way to behavioral output. An in-depth, integrated, view of this developing brain circuit can be used to derive fundamental principles of brain development. Remarkably, these principles have been shown to be applicable to all vertebrates including humans. This proposal continues a program established by the investigator to run a Neuroscience Summer Fellowship at Brown University for underrepresented minority high-school students, with the goal of increasing the participation of these students in careers related to Science, Technology, Engineering, and Mathematics (STEM).

Specifically, this proposal seeks to understand the mechanisms by which neural circuits in the Xenopus tadpole optic tectum allow the organism to process incoming sensory information and transform it into meaningful motor output. This sensory-motor transformation is essential for the organism to interact with its environment. Data from many levels of analysis will be integrated, including recording from retinal ganglion cells in the eye, recording the balance of excitation and inhibition and spike output of the tectum in vivo, recording network activity of multiple tectal cells in vivo using calcium imaging, quantifying visually guided behavior with a high speed camera, and using dynamic clamp to probe the integrative properties of tectal neurons in response to behaviorally relevant stimuli. Together these data will give us an unprecedented understanding of the steps and circuitry involved.

Project Summary This proposal seeks to understand the synaptic and circuit-level mechanisms underlying multisensory integration in the developing optic tectum. In order to correctly perceive and navigate its environment, an organism must integrate multiple types of sensory information containing different spatial and tem- poral characteristics. This process requires that the neural circuits that mediate multisensory integration are wired together appropriately during early brain development. However, the cellular mechanisms underlying the function and development of brain circuits mediating multisensory integration remain poorly understood. In the vertebrate brain, one primary locus for multisensory integration is the optic tectum, or its mamma- lian homologue, the superior colliculus. It functions to integrate visual and other sensory information, and transform this into orienting behavior. We have developed a novel and powerful experimental preparation to study the development of multisensory integration in the optic tectum using Xenopus laevis tadpoles. This preparation has an advantage over other more complex preparations such as owl tectum or mammalian superior colliculus in that it allows us to take an integrative approach in which we combine multiple levels of analysis ranging from single neurons to behavior, using a variety of tech- niques such as single-cell recordings in vivo and ex vivo, high-speed Ca++ imaging of networks of tectal neurons, visually guided behavior, and genetic alteration of neural activity. In the first aim, we will test the hypothesis that the dynamics of the balance between excitation and in- hibition determine the temporal window for multisensory integration. In the second aim we test the hy- pothesis that inhibition promotes and constrains the emergence of functional subtypes of multisensory neurons over development. In the third aim we test the hypothesis that the integrative properties and input architecture of tectal dendrites shapes multisensory interactions in tectal neurons and is responsi- ble for the principle of inverse effectiveness. We also test whether this principle extends to multisenso- ry-evoked behavior. These results will enhance our general understanding of the development and merging of neural cir- cuits and systems. Since many neurodevelopmental disorders such as autism, schizophrenia, dyslexia and ADHD are accompanied by dysfunctions in sensory integration, the findings from these experi- ments will better allow us to understand how these processes may go awry in neurodevelopmental dis- orders. !

Project Summary/Abstract Assessment of current programs designed to increase diversity in STEM disciplines at Brown University has revealed the need to specifically address the critical transition from undergraduate into doctoral training programs. The goal of Brown PREP is to diversify and enrich the biomedical research endeavor by increasing the number of students enrolled in and completing doctoral training programs. Informed by best practices and lessons learned from an institutional pilot PREP program, we describe an innovative program characterized by a comprehensive and customizable set of interventions to support and advance underrepresented students' academic and career development. Each year, our program will recruit and support eight research-oriented baccalaureate graduates from underrepresented backgrounds and provide them with interdisciplinary research experiences, individualized academic planning, professional development, and skill-building activities to increase their competitiveness and readiness for high-caliber doctoral programs. Participating departments for Brown's proposed PREP reside in the Life and Medical Sciences Division and include biology, neuroscience, psychology, public health and cognitive, linguistic and psychological sciences. In addition to intensive interdisciplinary research experiences and knowledge development, multiple mentorship and community building opportunities permeate the activities of the Brown PREP. Creating a community of scholars that will help students successfully navigate program requirements is viewed as essential to helping students reach their full potential in a short period of time. The use of Individual Development Plans (IDP) will ensure that the Brown PREP research, educational and professional development activities are specifically tailored to address each student's academic and career goals. As important, the Brown PREP will provide opportunities for faculty to engage in conversations about the importance of developing a diverse workforce in the biomedical and behavioral sciences. We have developed a comprehensive evaluation plan to assess outcomes and progress toward meeting the overall goal and aims of this project and monitor quality assurance across the proposed interventions. As designed, the Brown PREP will increase the production of underrepresented students who obtain a doctoral degree in the biomedical sciences; institutionalize best practices on training and mentoring diverse scholars that can be shared among the Brown community and beyond; and diversify the biomedical research workforce.