Section on Cellular and Cognitive Neurodevelopment

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

Have you heard of the pulvinar region of the brain? Don't worry if you have not, as even though it is the largest component of the thalamus in humans, it has been somewhat ignored. Yet, it could hold the answer to several neurodevelopmental disorders. The pulvinar nuclei consist of medial (PM), lateral (PL), and inferior (PI) nuclei, each with multiple further subdivisions. Previous seminal work has demonstrated that the exuberant/ excessive connectivity established with the pulvinar and visual cortex is dynamically refined throughout postnatal development, suggesting that it is instrumental in establishing normal visual function. Another pulvinar nucleus, the medial pulvinar (PM), is an evolutionarily recent addition to the pulvinar that occupies 40% of pulvinar volume in humans. In contrast to PL and PI, which are principally connected with the visual cortex and involved in visual processing, the PM primarily relays to frontal areas implicated in the pathology of schizophrenia and is involved in higher cognitive functions, such as attention. As noted by Prof. Ritsner, a world leader in schizophrenia, the most consistent observation in more than 10 schizophrenia patients is the presence of changes in the medial pulvinar. To fully realize the role of the PM in neurodevelopmental disorders, including schizophrenia, we will undertake a systematic research program. This will include interrogating the development and maturation of the PM networks and exploring their contribution to the development of specific regions of the neocortex and associated behaviors. We will develop and incorporate a system-wide approach encompassing molecular, cellular, connectional, and behavioral analyses and subsequently interrogate the whole gamut of molecular, anatomical, connectional, and behavioral changes. For example, we will examine how specific subclasses of neurons fail to develop following maldevelopment of the medial pulvinar, which is a common implication in schizophrenia and is thought to be responsible for the physiological and behavioral (negative symptoms) changes associated with the disease. Further, we have created novel technology to simultaneously monitor changes in cognitive behaviors and physiology, speeding up our capacity and capability to collect data. These results from the whole gamut of experiments should lead to critical insights into the developmental and molecular mechanisms that give rise to circuit dysfunction in schizophrenia and result in behavior disruptions. The inferior pulvinar (PI) and its subdivisions have long been associated with the visual system, but their function still needs clarification. There are four subdivisions, which have different connections with the brain, making it a more complex problem to solve: the medial, PIm; posterior, PIp; centrolateral, PIcl; and centromedial PIcm, each relaying retinal information to different areas of the visual cortex. Before our team developed MRI-guided tracing technology, it was impossible to isolate the specific nuclei to target with neural tracers. Our group was the first to define the extensive connectivity map of the PI, which had caused conjecture for many years. This allowed us to investigate a possible role for the PI as a 'developmental organizer' that facilitates the establishment of visual cortical networks, a critical function for visually guided behaviors, such as reaching and grasping, which most of us can do seamlessly. However, it is vital to recognize that while this may seem like a simple task when you're reaching for an object, your brain is calculating the size, shape, hazards (e.g., is it hot), and texture in a matter of milliseconds so that the process is achieved without too much conscious activity. For example, this is easily recognized when reaching for a cup of coffee on the table while conversing with another person or reading the latest news on your phone. Therefore, while we often consider the brain a collection of areas involved in specific functions, such as vision, touch, hearing, and motor, it is important to understand that this information needs to be accurately integrated through extensive connections across brain networks to achieve what we consider simple tasks accurately and quickly. Our previous studies demonstrate that the inferior pulvinar was crucial for developing reach and grasp behaviors. Another purported functional role of PI and its subdivisions at various stages of life is in supporting residual vision following damage to the primary visual cortex, which should render a person blind. In some instances, conscious or unconscious vision appears more pronounced the younger the person receives the primary visual cortex lesion. We have begun unraveling this enigma by revealing that in early life, the inputs from the eye to the brain can be diverted through the inferior pulvinar, which may underpin this capacity. This phenomenon not only illustrates the ability of the brain to react to acute changes but the extent of plasticity and rearrangement of circuits and networks that can happen, especially early in life. Our primary objective is to 1. Fully define the role of the PI circuitry in the development and modulation of the visual cortex and visuomotor behavior; and, 2. Demonstrate that the PI circuitry preserves vision following early-life lesions of V1. These projects challenge the 'textbook' opinion on how the brain is wired together and networked in early life. The simplistic serial/parallel schema often used as a model of brain wiring does not provide a realistic interpretation of how brain connections are made, their relative importance at different stages of life, and their critical importance in the development of certain behaviors. Therefore, to uncover the specific mechanisms and how maldevelopment may lead to neurological and psychiatric disorders, we will investigate the specific molecular, cellular, and circuit dynamics of the pulvinar and its connections across the lifespan and how they impact behaviors.