Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders

Abstract

The autism spectrum disorders (ASDs) arise from a diverse array of genetic and environmental origins that disrupt the typical developmental trajectory of neural connectivity and synaptogenesis. ASDs are marked by dysfunctional social behavior and cognition, among other deficits. Greater understanding of the biological substrates of typical social behavior in animal models will further our understanding of the etiology of ASDs. Despite the precision and tractability of molecular genetics models of ASDs in rodents, these organisms lack the complexity of human social behavior, thus limiting their impact on understanding ASDs to basic mechanisms. Non-human primates (NHPs) provide an attractive, complementary model for ASDs, due in part to the complexity and dynamics of social structures, reliance on vision for social signaling, and deep homology in brain circuitry mediating social behavior and reward. This knowledge is based on a rich literature, compiled over 50 years of observing primate behavior in the wild, which, in the case of rhesus macaques, is complemented by a large body of research characterizing neuronal activity during cognitive behavior. Several recent developments in this field are directly relevant to ASDs, including how the brain represents the perceptual features of social stimuli, how social information influences attention processes in the brain, and how the value of social interaction is computed. Because the symptoms of ASDs may represent extreme manifestations of traits that vary in intensity within the general population, we will additionally discuss ways in which nonhuman primates also show variation in social behavior and reward sensitivity. In cases where variation in species-typical behavior is analogous to similar variations in human behavior, we believe that study of the neural circuitry underlying this variation will provide important insights into the systems-level mechanisms contributing to ASD pathology.

Figure 1

A three-pronged approach to understanding and treating ASD. Progress in any individual research domain (human, mouse, or primate-based studies) can be used to inform research directions in the other two domains. All images downloaded from Wikimedia Commons.

Figure 2

Integration of visual and auditory information is commonplace in both humans and rhesus macaques, and is deficient in individuals with ASD. (A) Behavioral and fMRI studies reveal differences in multisensory integration in ASD. Left, ASD and TD individuals perform similarly when discriminating speech sounds using auditory information alone, but ASD individuals are significantly impaired relative to TD individuals when visual information is added to the task. Speech information consisted of short sentences read aloud overlaid on a background of auditory noise. Y-axis, speech reception threshold, the speech-to-noise ratio at which individuals accurately report the speech signal. More negative values indicate better performance. Right, activity in the STS during audiovisual integration of speech is absent in ASD subjects. Images modified from [46,47]. (B) Single neurons of rhesus macaques represent audio-visual integration while perceiving meaningful vocalizations. Left, image and corresponding spectrogram of rhesus macaque performing a coo vocalization. Black dot on gray background is a visual control stimulus. Right, firing of a single STS neuron in response to hearing a coo (green), observing a coo (blue), or simultaneously hearing and observing a coo (red). Y-axis indicates the firing frequency of the neuron (spikes/second); X-axis indicates time, with coo stimulus presented at time zero. Note that higher neuronal firing is elicited when auditory and visual information is presented simultaneously. Images reproduced from [44].

Figure 3

Both humans and monkeys follow others’ gazes, a tendency that is reduced in autism.A. Gaze-following, which occurs as early as 3 months of age in humans, promotes the phenomenon of joint visual attention. Image from [59]B. Social gaze enhances neural firing in lateral intraparietal cortex (LIP) during a visual target selection task. Left, LIP neurons in rhesus macaques are sensitive to particular locations in space. Here, the location of one of these so-called “response fields” is depicted for a single LIP neuron. Firing frequencies (hotter colors = higher firing rates, cooler colors = lower firing rates, in spikes per second) are overlaid in the form of a colorimetric map onto the visual scene. This particular neuron fires most when the monkey makes an eye movement to the right part of the monitor. Right, peri-stimulus time histogram of the same neuron firing when the eye movement is preceded by a picture of a monkey looking towards the response field (thick red line) or away from the response field (thick blue line). X-axis denotes time during a single trial, aligned at zero to cue, target, or saccade (eye movement) onset. Y-axis is spikes per second, i.e., the mean firing rate for this neuron. Note the increase in neuronal firing in response to an image of a familiar monkey looking towards the response field. Similar to humans, rhesus macaques exhibit gaze-following tendencies, as evidenced by decreased response times when monkeys saccade towards a target accompanied by a congruent social gaze stimulus. Image reproduced from [51].