Although the ability to genetically modify the mouse genome has revolutionized biomedical research, its impact on our understanding of brain disorders is limited due to the inherent differences in the structure and physiology of the brain between rodents and humans. Lack of appropriate animal models is considered one of the key bottlenecks in developing and testing effective treatments for many neurological and neuropsychiatric disorders. We propose the development of marmosets as a model system for studying complex behaviors and their neural circuit substrates. Considerable evidence supports the notion that there is a large overlap in both the perceptual and motor domains between humans and nonhuman primates. This includes similarities in temporal dynamics, as well as the interactions between primary cortical and higher-order brain areas. These similarities, combined with well-developed frontal cortical circuits, make nonhuman primates highly effective experimental models for studying the neurobiology of social behavior and cognition. We propose to take advantage of the unique strengths of the MIT community in primate research, multielectrode and multiphoton recordings, optogenetic technologies, fMRI, and behavioral and computational approaches, to create a collaborative research program focused on dissecting neural circuit mechanisms of ASD-relevant behaviors in marmosets.
Neural circuits for social attention and social reward (Robert Desimone)
Impaired social interaction is a hallmark of ASD. In this project, we will study the neural circuitry of social attention and cognition in wild type marmosets in order to develop circuit-based hypotheses for the social impairments in autism and to lay the groundwork for future genetic studies of autism in marmosets. In particular, we will establish the connectivity of the prefrontal cortex with other cortical areas, including ones important for social cognition, as well as neural systems for processing social cues and the learning of social cues.
Aim 1: fMRI mapping of circuits of social gaze and reward. To identify brain areas involved in social gaze versus reward, we will localize areas with correlations between the BOLD signal and manipulations of social versus non-social stimuli and amount of liquid reward.
Aim 2: Neuronal mechanisms for social gaze and reward. To further characterize neuronal activity at the moment the animal makes a choice to seek social stimuli, we will perform multi-electrode recordings during a forced choice between juice reward and exposure to social stimuli.
Aim 3: Reward pathways during social decision making. We will manipulate activity in the raphe nucleus to affect choice behavior in the forced choice task as well as behavior in the home cage.
Investigation of striatal circuits in marmoset brain underlying repetitive, perseverative behaviors (Ann M. Graybiel)
There is an enormous potential for use of the marmoset as a tractable primate model with which to study basic mechanisms that could contribute to ASD and to apply molecular editing methods. Yet still lacking is a focused effort to understand the brain systems in the marmoset that could be most specifically affected in relation to ASD symptoms. These symptoms include not only abnormal social behaviors, but also perseverative, overly focused behaviors and stereotypies. In our laboratory, we have concentrated on these neural systems in mice, rats and macaques, and we propose to capitalize on this knowledge base to define these circuits in the marmoset. The goal of our project is to provide specific, computational-model based predictions of the role of inhibition in cortical circuits employing two tasks that have high relevance for ASD, and examine the model predictions in wild-type marmosets using a range of techniques.
Aim 1: Anatomical characterization of the striosomal system and striosome-based circuits.
Aim 1.1. A critical first step will be to apply advanced immunohistochemical techniques using immunoreagents such as Kv1 potassium channel interacting protein (KChIP1), mu-opioid receptor 1 (MOR1), enkephalin, calbindin and tyrosine hydroxlase (TH) antibodies for a detailed reconstruction of striosomal system in the marmoset.
Aim 1.2. In the second part of the anatomical work, we will focus on input from the pACC and cOFC to striosomes. We will determine the degree of overlap, and non-overlap, of the virus and striosomes, bilaterally; we have noted a strong and highly selective crossed projection in macaques. Such studies would open up the marmoset to future manipulations to block or reverse symptoms in a marmoset ASD model when they become available.
Aim 2: Characterization of perseverative behaviors and stereotypies and their neural origins in the marmoset.
Aim 2.1. We propose to determine whether striosome:matrix ratios of activation of striatal neurons are critical for stereotypic behaviors in marmosets, as is the case in squirrel monkeys, mice and rats. As an initial proxy, we propose to use dopamine agonist treatments in the marmoset to elicit these behaviors, as we have previously done in the rodents and new world monkeys.
Mechanisms of switching and prediction in marmoset cortex (Mriganka Sur)
A major challenge in ASD research is to bridge levels of analysis – between genes that underlie ASD, synapses and circuits that mediate function, and the behavioral and cognitive manifestations of the disorder. We propose that circuit mechanisms are fundamental for bridging genes and phenotypes, especially when phenotypes are well-posed and relevant to humans. Disruption in the balance of excitatory-inhibitory (E-I) neurotransmission has been postulated as a key circuit mechanism in ASD. Mutations in several ASD genes have been shown to affect this balance.
Aim 1: Examine the role of inhibition in binocular rivalry in primary visual cortex (V1).
Aim 1a. Establish a stimulus protocol to elicit physiological binocular rivalry in marmoset V1.
Aim 1b. Manipulate eye-specific inhibition optogenetically in marmoset V1.
Aim 1c. Examine the role or inhibition in perceptual rivalry in behaving marmosets.
Aim 2. Examine the role of inhibition in a temporal prediction task.
Aim 2a. Establish a change detection task with temporal expectation and uncertainty, and analyze V1 responses under predictable and unpredictable task conditions.
Aim 2b. Examine the role of inhibition in modulating behavioral and neural responses to temporal expectation and uncertainty.
Molecular measurement and perturbation of marmoset brain networks (Alan Jasanoff)
Autism spectrum disorders (ASDs) are marked by both social and non-social abnormalities that imply the involvement of multiple brain networks in autism-associated neural function. For instance, hypersensitivity or hyposensitivity to sensory stimuli is often reported for ASD subjects, but the relationship between this phenomenon and the better known social deficits is not understood. By combining noninvasive imaging with cellular level neural measurement and modulation methods, we can discern the interactions among disparate brain networks in complex ASD-related phenotypes. Our laboratory has applied such techniques in a rat genetic model of the ASD-related fragile X syndrome, but such studies are limited both by the nonspecificity of the imaging readout (hemodynamic functional magnetic resonance imaging, fMRI) and by the non-equivalence of rodents to primates, which differ both neuroanatomically and behaviorally in many respects. In this project we therefore propose to adapt and extend molecular tools we have used for studying ASD-related phenotypes in rodents, so that we can map network-level function of interacting brain systems in wild-type marmosets, with the longer term agenda of applying these tools in primate genetic models once they become available.
Aim 1: Image-guided activity manipulation and functional connectivity mapping. Human ASD phenotypes are increasingly associated with differences in the patterns of long-range correlated activity observed by fMRI in the absence of stimulation—the phenomenon of resting-state functional connectivity (RSFC). In this Aim, we propose to establish RSFC methods in awake marmosets using fMRI at 9.4 T, and to apply these techniques in conjunction with novel MRI-detectable pharmacological agents that enable us to perform image-guided activity manipulations. The manipulations will allow us to probe the contribution of spatially and molecularly-defined neural processing components to RSFC networks relevant to social cognition and ASDs, with a degree of control that is difficult to achieve using other methods.
Aim 2: Molecular imaging of dopaminergic function in marmosets. Dopaminergic circuitry is critical to social reward and learning-related processes that can be altered in ASDs. Here we will adapt a dopamine-selective molecular-level fMRI technology for use in marmosets, where we will have the ability to relate striatal dopamine maps for the first time to activity in primate brain areas such as prefrontal cortex and superior temporal sulcus (STS), as well as striatal compartments like striosomes, which are too small in rodents to be resolved with confidence. We expect strong synergies with the Desimone, Graybiel and Sur components of this multi-PI project.