SummaryNon-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.
Under the influence of genes and a varying environment, human brain structure changes throughout the lifespan. Even in adulthood, when the brain seems relatively stable, individuals differ in the profile and rate of brain changes 1 . Longitudinal studies are crucial to identify genetic and environmental factors that influence the rate of these brain changes throughout development 2 and aging 3 . Inter-individual differences in brain development are associated with general cognitive function 4,5 and risk for psychiatric disorders 6,7 and neurological diseases 8,9 . Genetic factors involved in brain development and aging overlap with those for cognition 10 and risk for neuropsychiatric disorders 11 . A recent cross-sectional study showed brain age to be advanced in several brain disorders. Brain age is an estimate of biological age based on brain structure, which can deviate from chronological age. Several shared loci were found between the genome-wide association study (GWAS) summary statistics for advanced brain age and psychiatric disorders 12 . However, information is still lacking on which genetic variants influence an individual's brain changes throughout life, because this requires longitudinal data. Discovering genetic factors that explain variation between individuals in brain structural changes may reveal key biological pathways that drive normal development and aging and may contribute to identifying disease risk and resilience-a crucial goal given the urgent need for new treatments for aberrant brain development and aging worldwide.As part of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium 13 , the ENIGMA Plasticity Working Group quantified the overall genetic contribution to longitudinal brain changes by combining evidence from multiple twin cohorts across the world 14 . Most global and subcortical brain measures showed genetic influences on change over time, with a higher genetic contribution in the elderly (heritability, 16-42%). Genetic factors that influence longitudinal changes were partially independent of those that influence baseline volumes of brain structures, suggesting that there might be genetic variants that specifically affect the rate of development or aging. However, the genes involved in these processes are still not known, with only a single, small-scale GWAS performed for longitudinal volume change in gray and white matter of the cerebrum, basal ganglia and cerebellum 15 . In this study, we set out to find genetic variants that may influence rates of brain changes over time, using genome-wide analysis in individuals scanned with magnetic resonance imaging (MRI) on more than one occasion. We also aimed to identify references
We used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male rhesus monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine--oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hSyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD-transduced cells using stereological analysis of mCherry-immunolabeled neurons. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared with monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory. Cognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (designer receptor exclusively activated by designer drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine--oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.
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