The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny.

Summary Contemporary research suggests that the mammalian brain is a complex system, implying that damage to even a single functional area could have widespread consequences across the system. To test this hypothesis, we pharmacogenetically inactivated the rhesus monkey amygdala, a subcortical region with distributed and well-defined cortical connectivity. We then examined the impact of that perturbation on global network organization using resting-state functional connectivity MRI. Amygdala inactivation disrupted amygdalocortical communication and distributed corticocortical coupling across multiple functional brain systems. Altered coupling was explained using a graph-based analysis of experimentally established structural connectivity to simulate disconnection of the amygdala. Communication capacity via monosynaptic and polysynaptic pathways, in aggregate, largely accounted for the correlational structure of endogenous brain activity and many of the non-local changes that resulted from amygdala inactivation. These results highlight the structural basis of distributed neural activity and suggest a strategy for linking focal neuropathology to remote neurophysiological changes.

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Autism Spectrum Disorders (ASD) are a group of heterogeneous, behaviorally defined disorders characterized by disturbances in social interaction and communication, often with repetitive and stereotyped behavior. Previous studies have described the presence of antibodies to various neural proteins in autistic individuals as well as post-mortem evidence of neuropathology in the cerebellum. We examined plasma from children with ASD, as well as age-matched typically developing controls, for antibodies directed against human cerebellar protein extracts using western blot analysis. In addition, the presence of cerebellar specific antibodies was assessed by immunohistochemical staining of sections from Macaca fascicularis monkey cerebellum. Western blot analysis revealed that 13/63 (21%) of subjects with ASD possessed antibodies that demonstrated specific reactivity to a cerebellar protein with an apparent molecular weight of approximately 52kD compared with only 1/63 (2%) of the typically developing controls (p=0.0010). Intense immunoreactivity, to what was determined morphologically to be the Golgi cell of the cerebellum, was noted for 7/34 (21%) of subjects with ASD, compared with 0/23 of the typically developing controls. Furthermore, there was a strong association between the presence of antibodies reactive to the 52 kDa protein by western blot with positive immunohistochemical staining of cerebellar Golgi cells in the ASD group (r= 0.76; p=0.001) but not controls. These studies suggest that when compared with age-matched typically developing controls, children with ASD exhibit a differential antibody response to specific cells located in the cerebellum and this response may be associated with a protein of approximately 52 kDa.

Comparative studies of the structural organization of the brain are fundamental to our understanding of human brain function. However, whereas brains of experimental animals are fixed by perfusion of a fixative through the vasculature, human or ape brains are fixed by immersion after varying postmortem intervals. Although differential treatments might affect the fundamental characteristics of the tissue, this question has not been evaluated empirically in primate brains. Monkey brains were either perfused, or acquired after varying postmortem intervals before immersion-fixation in 4% paraformaldehyde. We found that the fixation method affected the neuroanatomical characteristics of the monkey hippocampal formation. Soma size was smaller in Nissl-stained, immersion-fixed tissue, although overall brain volume was larger, as compared to perfusion-fixed tissue. Non-phosphorylated high-molecular-weight neurofilament immunoreactivity was lower in CA3 pyramidal neurons, dentate mossy cells and the entorhinal cortex, whereas it was higher in the mossy fiber pathway in immersion-fixed tissue. Serotoninimmunoreactive fibers were well-stained in perfused tissue but were undetectable in immersionfixed tissue. Although regional immunoreactivity patterns for calcium-binding proteins were not affected, intracellular staining degraded with increasing postmortem intervals. Somatostatinimmunoreactive clusters of large axonal varicosities, previously reported only in humans, were observed in immersion-fixed monkey tissue. In addition, calretinin-immunoreactive multipolar neurons, previously observed only in rodents, were found in the rostral dentate gyrus in both perfused and immersion-fixed brains. In conclusion, comparative studies of the brain must evaluate the effects of fixation on the staining pattern of each marker in every structure of interest before drawing conclusions about species differences.