Robert Desimone, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): When people are confronted by a typical, crowded visual scene, attentional mechanisms are needed to limit visual processing to objects that are currently relevant to behavior. An understanding of these attentional mechanisms will ultimately help in developing a visual prosthesis for people with severe visual impairments, and will also help in developing treatments for people with brain disorders affecting attention, including ADHD. The long term goal of this proposal is to not only uncover attentional influences on visual processing in the brain but also to understand the neuronal mechanisms by which these effects occur. Our focus is on visual areas V1, V2, and V4, which are among the earliest processing stages in the cortical pathway important for object recognition. New results suggest that the attentional bias in favor of behaviorally relevant stimuli may involve not only changes in the average firing rate of neurons but also the timing of neural activity in different cortical layers. The first specific aim is to identify the effects of spatially-directed attention on the timing of spikes in populations of cells in V4, and relate these effects to specific visually- guided behaviors. The next aim is to differentiate the effects of spatially directed attention on cells in the superficial versus deep lamina of areas V1, V2, and V4. The third aim is to establish the sequence of the effects of spatially directed attention on the visual pathway extending from V1 through area V4. The central hypotheses of the research program are that top-down attentional mechanisms induce changes in not only the firing rate but also the temporal synchrony of responses in extrastriate cortex, that these attentional effects on neural activity have functional correlates, and that these changes are relayed in a "backward" direction from higher order areas to lower order ones. These hypotheses test novel ideas, but they are well supported by preliminary data, and we are well-positioned to test them since we have had many years of experience with the techniques. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): A typical visual scene will contain many different objects, few of which will be relevant to the task at hand. Thus, attentional mechanisms are needed to find relevant objects and suppress distracters. An understanding of these attentional mechanisms will ultimately help in developing a visual prosthesis for people with severe visual impairments, and will also help in developing treatments for people with brain disorders affecting attention, including ADHD. The long term goal of this proposal is to not only uncover attentional influences on visual processing in the brain, but also to understand the neuronal mechanisms by which these effects occur. It is particularly important to understand how the attentional mechanism operates under naturalistic conditions, such as when we freely move our gaze to find objects based on their features (e.g. visual search, or finding a "face in a crowd"). Our focus is on visual area V4, which is an intermediate processing stage in the cortical pathway important for object recognition. New results suggest that the attentional bias in favor of behaviorally relevant stimuli may involve not only changes in the average firing rate of V4 neurons, but also the synchronous timing of V4 activity. The first specific aim is to test hypotheses about the different functional contributions of the upper and lower layers in area V4 to feature-based attention in visual search. The next aim is to establish the specific contributions of firing rates and neural synchrony to the behavioral performance of animals engaged in visual search. The third aim is to determine the contribution of prefrontal cortex to the attentional effects on V4 neuronal responses and synchrony during visual search. These aims will give us a better understanding of the functional anatomy of attention in the visual cortex, the contributions of specific biological mechanisms of attention to behavior, and the nature of top-down feedback to the visual cortex. The central hypothesis of the research program is that neurons in prefrontal cortex induce changes in both firing rates and neural synchrony in ventral stream visual areas such as area V4, and that these changes mediate the selection of relevant objects under naturalistic conditions of visual search. These hypotheses test novel ideas, but they are well supported by preliminary data, and we are well-positioned to test them since we have had many years of experience with the techniques.

This award provides funds which permit Drs John Gabrieli and Robert Desimone to purchase an Elekta Neuromag system for human brain imaging. The instrument will be integrated into the Martinos Imaging Center at MIT and will complement the Center's existing neuroimaging capabilities currently based on magnetic resonance imaging. The Neuromag has 306 MEG channels plus up to 124 channels for simultaneous EEG. Magnetoencephalography (MEG) is a powerful technology for noninvasive imaging of human brain activity. It measures magnetic signals given off by active brain cells and it combines good spatial with very high temporal resolution. In particular, MEG makes it possible to study the flow of information through the brain during cognitive tasks and can reveal the high-frequency oscillations which are fundamental to the physiological mechanism by which different brain areas communicate with each other. The technique therefore is extremely well suited to answering a wide range of basic questions about human brain function. For example it has made important contributions in areas such as somatosensory and auditory processing, and particularly in the study of language, a distinctively human capability for which the rapid neural processes involved are not well resolved by fMRI. It is also possible to use this technique on children, including newborns, and this approach has the potential to transform understanding of early brain development including development of perceptual abilities, language and many other aspects of brain function.

Although the justification for purchase of this instrument rests on the basic research which will be performed and the insights into normal brain functioning which will result, MEG also has clinical applications. It is a potentially powerful tool for translational research, for example for identifying patterns of brain activity that might serve as biomarkers for brain disorders. The instrumentation can also be used to study the neural effects of educational interventions in such areas as reading or musical training and as a basis for developing human brain-machine interfaces.

DESCRIPTION (provided by applicant): Recovery Act Limited Competition: NIH Challenge Grants in Health and Science Research (RC1) RFA-OD-09-003 Broad Challenge Area: 15, Translational Science Research Area: 15-MH-109 Prefrontal cortex regulation of higher brain function and complex behaviors. Summary/Abstract The prefrontal cortex (PFC) plays an important role in executive function, including the control of attention. Lesions of PFC impair the ability to focus attention, ignore distracters, and switch attention in a flexible manner. The cognitive dysfunctions found in schizophrenia and other mental disorders likely involve some dysfunction of the PFC, and thus, understanding the functional circuitry that mediates cognitive function in PFC is consistent with the NIMH strategic plan. In spite of all the evidence that top-down feedback from PFC to the sensory association cortex is important for the control of attention and other cognitive functions, the nature of the PFC feedback is still unclear. We recently found that one key component of this mechanism may be phase-coupled gamma-frequency synchrony between PFC and the association cortex. Synchrony between the frontal eye field (FEF, within PFC) and area V4 (within association cortex) is strongly modulated by attention. Most importantly, the cross area synchrony is shifted in time by 8-12 ms, which appears to be just the right amount of time to allow for conduction and synaptic delays between the two areas. Thus, spikes from one area will begin to affect cells in the coupled area when they are maximally depolarized and prepared to receive new input. Such phase- coupled synchrony during attention may generally allow PFC to communicate effectively with other cortical areas. However, neurophysiological data such as these necessarily reveal only correlations between neural activity and behavior, not causality. The proposed studies will directly test whether the phase coupled oscillations between FEF and V4 cause firing rate changes and mimic the effects of attention on behavior. For these tests, we will use novel new optogenetic technology, which we have recently demonstrated can be used for stimulating primate neurons with millisecond precision. Using optogenetic tools, we will simultaneously stimulate FEF and record from area V4. We will stimulate FEF cells at gamma frequencies (~ 40 Hz), and we will dynamically adjust the phase of stimulation to maintain a time/phase delay of approximately 8-12 ms relative to the phase of local field potentials in V4. Stimulation with this time delay should maximize the response of V4 cells to a stimulus in the RF, thereby mimicking the effects of attention on V4 responses and the animal's behavior. Conversely, we will stimulate in V4 and test the effects of stimulation phase on the ability of bottom-up signals from V4 to drive cells in FEF. Positive evidence that phase-coupled synchrony between PFC and other cortical areas plays an important role in the regulation of attention would have a major impact on our understanding of PFC's role in cognition. More specifically, a dysfunction of neural synchrony in PFC may contribute to the cognitive dysfunctions in schizophrenia, and positive results from the present application would potentially provide an important lead in understanding the role of impaired cross-area communication. . PUBLIC HEALTH RELEVANCE: The proposed research seeks to understand the fundamental biological mechanisms of attention in prefrontal cortex. This research addresses a critical public health need, as disorders of attention are common in many mental disorders, including schizophrenia, depression, and ADHD. These disorders affect millions of Americans and current treatments remain inadequate for many people.

DESCRIPTION (provided by applicant): In crowded visual scenes, attention is needed to selectively process information from relevant stimuli and to filter out irrelevant distracters. Accordingly, studies in humans and animals have shown that neurons in several different brain structures show enhanced responses when attention is directed into their receptive fields. However, there is still little understanding of how these ubiquitous attentional effects are actually generated through the interactions among these structures, particularly when the attentional cues arise from cognitive factors and task demands. To design an effective neural prosthesis or to treat people with attentional disorders, we need a better understanding of attention at the systems level. Three key structures thought to provide feedback to visual cortex that mediates attentional effects are the prefrontal cortex, the posterior parietal cortex and the pulvinar. In the planned experiments, we will compare the roles of each of these three structures in providing feedback to area V4 in visual cortex. Area V4 plays a central role in the relay of visual information along the ventral stream that underlies object recognition, and we have previously shown that V4 neuronal responses are modulated by attention and that damage to V4 causes attentional impairments. We have also recently shown that neurons in prefrontal cortex have attentional latencies that are short enough to mediate some of the attentional effects on V4 neuronal responses, and that prefrontal neurons have coherent activity with cells in V4. This coherent activity is time-shifted across a wide range of frequencies by about 10 ms, which may be the critical time to allow for functional interactions. In Aim 1, we will add recordings from the posterior parietal cortex to the prefrontal recordings, to compare the roles of these two structures in modulating activity in V4. The pulvinar provides an alternative anatomical route for signals from prefrontal and parietal cortex to influence V4. Therefore, in Aim 2, we will record simultaneously in the pulvinar and area V4, to test whether pulvinar neuronal properties are consistent with this feedback role. However, neurophysiological recordings alone can only provide evidence for correlations in activity, not for causality. Therefore, in Aim 3, we will supplement the neural recordings with suppression of activity in prefrontal and parietal cortex and pulvinar, to test causal hypotheses about the role of feedback from each structure in modulating V4 responses. For these experiments, we will use techniques that we and our collaborators have recently developed for the optogenetic suppression of neural activity using the proton pump, Arch-T, which is delivered by lentivirus. With Arch-T we will be able to suppress activity with resolution in the tens of milliseconds, at critical time points, to gain new mechanistic insights into the feedback to V4. In total, we expect these studies to give us the best account so far of how the interactions among multiple brain structures leads to effective visual processing with attention. PUBLIC HEALTH RELEVANCE: The aims of the project are to give us mechanistic, biological insights into how attention controls our visual processing abilities. These new insights will aid in the development of a neuro-prothesis for blindness and will also help us develop new treatments for people suffering attentional disorders.

The human vision system understands and interprets complex scenes for a wide range of visual tasks in real-time while consuming less than 20 Watts of power. This Expeditions-in-Computing project explores holistic design of machine vision systems that have the potential to approach and eventually exceed the capabilities of human vision systems. This will enable the next generation of machine vision systems to not only record images but also understand visual content. Such smart machine vision systems will have a multi-faceted impact on society, including visual aids for visually impaired persons, driver assistance for reducing automotive accidents, and augmented reality for enhanced shopping, travel, and safety. The transformative nature of the research will inspire and train a new generation of students in inter-disciplinary work that spans neuroscience, computing and engineering discipline.

While several machine vision systems today can each successfully perform one or a few human tasks ? such as detecting human faces in point-and-shoot cameras ? they are still limited in their ability to perform a wide range of visual tasks, to operate in complex, cluttered environments, and to provide reasoning for their decisions. In contrast, the mammalian visual cortex excels in a broad variety of goal-oriented cognitive tasks, and is at least three orders of magnitude more energy efficient than customized state-of-the-art machine vision systems. The proposed research envisions a holistic design of a machine vision system that will approach the cognitive abilities of the human cortex, by developing a comprehensive solution consisting of vision algorithms, hardware design, human-machine interfaces, and information storage. The project aims to understand the fundamental mechanisms used in the visual cortex to enable the design of new vision algorithms and hardware fabrics that can improve power, speed, flexibility, and recognition accuracies relative to existing machine vision systems. Towards this goal, the project proposes an ambitious inter-disciplinary research agenda that will (i) understand goal-directed visual attention mechanisms in the brain to design task-driven vision algorithms; (ii) develop vision theory and algorithms that scale in performance with increasing complexity of a scene; (iii) integrate complementary approaches in biological and machine vision techniques; (iv) develop a new-genre of computing architectures inspired by advances in both the understanding of the visual cortex and the emergence of electronic devices; and (v) design human-computer interfaces that will effectively assist end-users while preserving privacy and maximizing utility. These advances will allow us to replace current-day cameras with cognitive visual systems that more intelligently analyze and understand complex scenes, and dynamically interact with users.

Machine vision systems that understand and interact with their environment in ways similar to humans will enable new transformative applications. The project will develop experimental platforms to: (1) assist visually impaired people; (2) enhance driver attention; and (3) augment reality to provide enhanced experience for retail shopping or a vacation visit, and enhanced safety for critical public infrastructure. This project will result in education and research artifacts that will be disseminated widely through a web portal and via online lecture delivery. The resulting artifacts and prototypes will enhance successful ongoing outreach programs to under-represented minorities and the general public, such as museum exhibits, science fairs, and a summer camp aimed at K-12 students. It will also spur similar new outreach efforts at other partner locations. The project will help identify and develop course material and projects directed at instilling interest in computing fields for students in four-year colleges. Partnerships with two Hispanic serving institutes, industry, national labs and international projects are also planned.

DESCRIPTION (provided by applicant): We must often search cluttered scenes for items of immediate behavioral relevance - e.g. our food, our car keys, our child, and so on. In each case, we use our memory of the object's features to effectively guide our search, so that we are not forced to inspect every object in a crowded scene individually. Efficient visual search is critical for efficient visually guided behavior. Although much is known about the biological mechanisms that underlie the ability to attend to locations, very little is known about the mechanisms underlying visual search guided by object features. We do not yet understand where the information about the relevant object features is stored in the nervous system, how that information is used to guide eye movements to inspect object that are good candidates for the searched-for item, or how the feature information modulates the information processed in our visual cortex. To design an effective neural prosthesis or to treat people with attentional disorders, we need a better understanding of feature attention in visual search at the systems level. A better understanding of feature attention will likely also give us insight into the mechanisms underlying visual working memory and visual imagery, as these related functions seem to involve at least partially overlapping neural circuits. Two key structures that may play a role in the guidance of feature attention during visual search are the prefrontal cortex and the pulvinar nucleus of the thalamus. In fact, the pulvinar may serve to relay critical feature information from prefrontal cortex to visual cortex. Our Aims are focused on these two structures, and we are guided by our preliminary data regarding their functions. In Aim 1, we will simultaneously record from neurons in Area 45 of the prefrontal cortex, the frontal eye fields (FEF) and area V4 of visual cortex during performance of a visual search task. These recordings will test hypotheses about how prefrontal cells influence the subsequent processing of object feature information in FEF and area V4. In Aim 2, we will use newly developed optogenetic techniques during performance of the same tests of feature attention used in Aim 1, to test causal hypotheses about how the prefrontal cortex influences both behavior during search and the responses of FEF and V4 neurons. The optogenetic techniques we have successfully implemented with our collaborators will allow us to suppress neural circuits at precise locations and for precise periods of time. In Aim 3, we will record simultaneously from the pulvinar, area V4, and the inferior temporal cortex during the same tests of feature attention. We will test hypotheses about how the pulvinar regulates cortical processing during feature attention, including its role in synchronizing and de-synchronizing activity in cortical population. We will then test our conclusions using the same optogenetic techniques used in Aim 2, to suppress pulvinar activity at critical times during the performance of the tasks. In total, we expect these studies to give us the best account so far of how the interactions among multiple brain structures leads to effective visual processing during attention to object features.

This project consists of engineering a system for producing selective expression of light-inducible molecules in targeted neuron population in non-genetically modified animals of any species. The result will be a set of reagents that will be made freely available to the scientific community through nonprofit repositories and service centers. This new set of tools will enable the study of neural circuitry with greater resolution, power, and throughput than is currently possible, allowing major advances to be made in understanding the organization of the complex neural systems underlying perception, cognition, and behavior. This increased understanding could also result in improved artificial intelligence and machine learning. Finally, the future direct application of the technology in human patients holds promise for potentially treating conditions such as Parkinson's disease and epilepsy, by allowing the selective activation or inactivation of distinct components of the compromised neural circuitry that is associated with these disorders.

Over the last decade, sophisticated genetic tools have been developed that allow control and monitoring of neuron electrical activity using light alone. "Optogenetics", as this area of technology has become known, is only useful if optogenetic molecules can be specifically expressed in functionally meaningful groups of neurons instead of broadly in all the diverse neuron types that are present in any brain region. This requirement has confined their use almost entirely to genetically modified (transgenic) mice and rats. The approach of using transgenic animals has three major disadvantages. First, the production and maintenance of transgenic rodents is very expensive. Second, even within transgenic rodents, it allows the optogenetic study and manipulation of only one or two cell types at a time, preventing powerful combinatorial experiments in which different neuron types are independently controlled within the same tissue. These combinatorial experiments will be critical for deciphering the complex interactions between cell types. Third, it restricts the experiments to rodents, preventing studies in other important taxa including primates, in which optogenetic experimentation during complex cognitive tasks would almost certainly provide major insights into the neural circuitry underlying cognition. This project aims to create engineered binding proteins that recognize selected endogenous proteins that will then act as scaffolds for assembly of transcription factors that will activate gene expression in specific neurons.

? DESCRIPTION (provided by applicant): Functional MRI (fMRI), EEG, and other completely noninvasive modalities for large-scale imaging of human brain activity have pioneeringly revealed many human brain functions, but cannot reach the single-neuron, single-spike level of neural code analysis possible in animals obtained using electrodes. This is partly due to the indirect methods of observation employed (e.g., blood flow for fMRI) and due to blurring of signals over distance by the skull (e.g., for EEG). In contrast, invasive approaches such as trans-cranially implanted multi- electrode arrays can achieve single-cell, single-spike resolution, but they necessitate opening of the skull - and, for implanted arrays, damage of the brain tissue - limiting utility to a small fraction of the population, those undergoing neurosurgery for some intractable brain disorder that justifies the risk. Trans-cranially implanted arrays also degrade i performance over time due to gliosis and other brain reactions, and create vulnerabilities to infection. Vascular access offers a less-invasive, safer and more scalable means - in comparison to trans-cranial electrodes - to deliver recording devices to the vicinity of neurons buried inside the brain parenchyma. We here propose to create a vascular platform for brain imaging, stimulation, electrical recording, and molecular access, aiming for devices that will work at least in large blood vessels, and also paving the way towards capillary-resolution neural access through vasculature. Specifically, we propose to initiate a multi-institutional, collaboratie effort to design a human-applicable vascular neural interface for multiplexed neural recording and stimulation, and to carry out preliminary pilot theoretical and experimental projects to validate the basic parameters of the resulting concepts.

7: Project Summary/Abstract Marmosets are emerging as an important model species for neuroscience research, driven by the development of new technologies such as CRISPR that allow targeted genetic modifications in this species. These developments will allow primate research to take advantage of powerful genetic tools that were previously restricted largely to rodents, including optogenetics, genetic activity reporters, and targeted mutation of endogenous genes implicated in brain function and human disease. Marmosets are well suited to this approach, being small and fast-breeding compared to most primates. They are typically housed in family groups, and exhibit a variety of social behaviors in captivity including complex vocal repertoires. Marmosets thus represent a promising system for studying social behavior and other cognitive functions in a primate model, and they also hold great promise for modeling brain disorders that affect cognitive functions that are difficult to study in other species such as rodents. To take full advantage of these emerging animal models, it is necessary to develop new methods for analyzing their behavior, including naturalistic social interactions that are imperfectly captured by standardized behavioral tasks. We therefore plan to develop a system for automated analysis of marmoset behaviors in the home cage. The system will consist of an integrated array of sensors including video cameras, depth sensors, and collar-mounted wearable microphones. The resulting multimodal data will be synchronized and analyzed using methods from computer vision, speech processing, machine learning, and multimodal data analysis. Specifically we will formulate the tracking analysis as a probabilistic graphical model, which will allow video data to be integrated with audio recordings, and with other modalities that could be explored in future, including inertial motion sensors, physiological recordings and other contextual data. Based on this approach we will develop methods to classify calls, identify individual callers, track the locations and identities of each animal in three dimensions, and classify different actions, including interactions between individuals. We envisage that our system will be useful for a wide range of studies in basic and translational neuroscience, and in particular it will be useful for studying behavioral phenotypes in genetic models of human psychiatric disorders, and for relating behavioral abnormalities to their underlying genetic and neural causes.

IMAGING CORE: Project Summary The onsite Imaging Core service module serves two critical functions to the research productivity of the NEI Core Investigators and the surrounding research community. First the Imaging Core designs, builds, and repairs advanced RF coils for MR imaging, which cannot be obtained through commercial sources. Two examples of the importance of the coil lab in the prior funding period are the special RF coils for human infants and marmoset monkeys. Specialized coils for studying infant development, including the development of the visual system are designed and built by the coil lab. These coils have given us unprecedented imaging resolution and stability during infant development, which is one of our most challenging imaging needs. Second, the Imaging Core provides consultation and workshops to faculty, students, and postdocs on basic and advanced statistical analysis of functional MRI and Magnetoencephalography (MEG) imaging data. Our experts in fMRI and MEG data analyses have developed customized tools that are important to the work of our NEI Investigators, and are also made available to all other researchers in our community.

We must often search cluttered scenes for items of immediate behavioral relevance ? e.g. our food, our car keys, our friend, and so on. In each case, we use a memory of the target object?s features to efficiently guide our search to objects that share some of its features, so that we are not forced to inspect every object in a crowded scene individually. Efficient visual search is critical for efficient visually guided behavior. Although much is known about the biological mechanisms underlying the selection of objects based on spatial location, much less is known about the mechanisms underlying the selection of objects based on features. To design an effective neural prosthesis or to treat people with sensory or attentional impairments, we need a better understanding of feature attention at the systems level. A better understanding of feature attention will also give us more insight into the mechanisms underlying visual working memory and visual memory recall, as these related functions seem to involve at least partially overlapping neural circuits. Until recently, it was unclear if there was any specific brain structure that stored the information about attended features and used it to guide visual processing in the cortex through top-down feedback. We recently obtained evidence for such a site in prefrontal cortex, in a region that we have termed VPA. Our Aims are focused on a better understanding of VPA and the mechanisms by which it interacts with other visual areas during attention to features. In Aim 1, we will use electrical stimulation paired with fMRI to densely map the projections of a wide expanse of lateral prefrontal cortex, including VPA. This prefrontal ?connectome? will show us how VPA relates to other prefrontal circuits, and it will give us the neural wiring diagram for how VPA interacts with other functional regions throughout the brain. The published connectome will also serve as valuable resource for the neuroscience community. Preliminary results from the connectome are already being used to guide our other two Aims. In Aim 2, we will use pharmacological methods to reversibly deactivate VPA, to test our hypotheses that VPA is the source of feedback that modulates processing in area V4 during attention to features such as shape and color. A positive result would be strong evidence in favor of VPAs feedback control of the ventral stream for object recognition. In Aim 3, we will test our hypotheses about the role of VPA in the dorsal stream, during attention to objects based on their direction of motion. Cells in VPA, MT, MST, FST, and LIP will be recorded simultaneously, to test whether neural activity in VPA has the temporal properties needed to support VPA?s causal role in attention to motion. We will then use new technology we have developed to optogenetically suppress VPA and test whether it impairs attention to motion and reduces or eliminates the effects of attention to motion on the responses of cells in areas MT, MST, FST, and LIP. In total, we expect these studies to give us the best account so far of how the interactions of VPA with multiple brain structures leads to effective visual processing during attention to object features.

PROJECT SUMMARY/ABSTRACT The ability to genetically modify the mouse genome has revolutionized biomedical research. However, its impact on our understanding of brain disorders is limited partially due to the inherent differences in the structure and physiology of the brain between rodents and humans. Most notably, the prefrontal cortex is one of the largest and most developed portions of the human brain and a top candidate for pathological processes in many psychiatric disorders. Yet, rodents have only a rudimentary prefrontal cortex and are thus limited in exhibiting the complex cognitive functions that are mediated by this region. The lack of predictive animal models is now considered one of the key bottlenecks in developing effective treatments for brain disorders. Non-human primates are much more closely related to humans than are rodents, and this is reflected in their brain development, structure and physiology. Hence, it is increasingly recognized that they provide an attractive model to study higher brain function and brain disorders. The recent development of highly efficient CRISPR genome-editing technology made it feasible to directly manipulate the genome in zygotes, thus expanding genetic manipulations to many species including non-human primates. In the past 4 years, we have been collaborating with a team of scientists in the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences to use CRISPR/Cas9 to generate macaque monkey models of monogenic ASD. We have now successfully generated Shank3 mutant cynomolgus macaques. Shank3 is a glutamatergic postsynaptic scaffolding protein critical for synapse development and function. Heterozygous mutations of the Shank3 gene in humans lead to Phelan-McDermid syndrome (PMS), an autism spectrum disorder. Initial characterization of the 5 founder Shank3 mutant monkeys revealed sleep disturbances, motor deficits, and increased repetitive behaviors, as well as social and learning impairments. Unbiased analysis of fMRI data showed altered local and global connectivity patterns indicative of circuit abnormalities. Together, these results parallel some aspects of the gene-circuit-behavior dysfunction in human ASD and PMS. Here we propose, in collaboration with our colleagues in SIAT, China, to generate F1 generation of Shank3 mutant monkeys to validate initial observations, to further behavioral and neurophysiological characterization and to bring mutant sperms to US for establishing a colony for sharing with autism research community.