January 27, 2015 Foundation News

2015 SIA Winners

Congratulations to the 2015 SIA Winners

Guoping Feng, Ph.D.

Massachusetts Institute of Technology

Disruption of the Shank3 gene in a primate model for studying ASD

 

Brain disorders represent a great societal burden but are among the least understood of all diseases; for psychiatric disorders in particular, the underlying pathologies are largely unknown and treatment is mostly ineffective. Many brain disorders have a genetic component, and advances in genomic technologies have led to the identification of many risk genes. Understanding how risk genes may cause or contribute to the pathogenesis of psychiatric disorders requires studies of brain function in animal models with genetic alterations that mimic those of human patients. Current animal model studies are largely focused on mice, but mice are imperfect models for many aspects of human biology, particularly neuroscience, given the vast differences in brain and behavior between the two species. The difficulty of modeling complex brain functions and behaviors in mice is an important obstacle both to basic research and to the development of new treatments for human brain disorders. Thus, there is an urgent need to develop animal models that are more close humans in the brain structure and function. In this application, we propose to generate a marmoset (a small primate) model of autism by disrupting the Shank3 gene, which causes autism when mutated in humans. We will use this primate model to further our understanding of neurobiological basis of autism related behaviors. These studies may lead to the identification of novel disease mechanisms and neurobiological targets for drug development foe ASD. More generally, the proposed project, if successful, will establish the marmoset as a primate genetic model for the study of psychiatric disorders.

Kristen Harris, Ph.D.

University of Texas – Austin

Synaptome of a Memory

A longstanding question in neuroscience concerns the cellular mechanisms of learning and memory. Since synapses were first discovered as the sites of communication between neurons, scientists have thought that changes in their number or structure would be a likely substrate of memory. Although evidence has accumulated, proof of this hypothesis has been elusive. Addressing this question requires substantial improvement in understanding how the brain is wired, namely, the “connectome”. Ultimately, the connectome will contain a map of the location and type of every synapse in the brain. The synaptome of a memory, sensation, or behavior is quite different from the co nectome of a brain region because these experiences likely involve a subset of synapses distributed across different brain regions. Hence, to understand mechanisms, it is necessary to know which specific synapses were involved. Detecting synapses and their subcellular components requires the nanoscale resolution of serial section electron microscopy, an approach that has been pioneered in my laboratory. We propose new strategies that will for the first time, provide specific identification of the progression and ultrastructural consequences of activity-dependent synapse remodeling in a cellular mechanism of learning and memory, a crucial first step in defining the synaptome of a memory. Nothing like this has ever been done before and the findings are crucial not only to understand the basic neuroscience and development of learning and memory, but also to illuminate synaptic dysfunction in prominent disease states, such as autism and Alzheimer’s disease.

Thomas Jessel, Ph.D.

Columbia University

The Functional Logic of Inhibitory Microcircuits

Collectively, these studies will provide crucial insights into the construction and function of inhibitory microcircuits controlling movement. Importantly, they will provide an essential foundation for interpreting behavioral experiments assessing the contribution of V1 and other inhibitory interneurons to locomotor or skilled forelimb reaching tasks, where descending and sensory feedback systems are essential24. Because many of the transcription factors identified here (e.g. Sp8, Nr4a2, and Lmo3 among others) are also expressed in inhibitory interneurons in the brain25-27, characterizing spinal interneuron diversity may prove useful for dissecting inhibitory circuits in other systems. Finally, given the emerging view that neuropsychiatric and neurodevelopmental disorders result in part from dysfunction of inhibitory circuitry13, the studies outlined here should provide significant insight into the functional organization of inhibition in both development and disease.