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Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution., Author summary Humans are distinguished from other species by several aspects of cognition. While much comparative evolutionary neuroscience has focused on the neocortex, increasing recognition of the cerebellum’s role in cognition and motor processing has inspired considerable new research. Comparative molecular studies, however, generally continue to focus on the neocortex. We sought to characterize potential genetic regulatory traits distinguishing the human cerebellum by undertaking genome-wide epigenetic profiling of the lateral cerebellum, and compared this to the prefrontal cortex of humans, chimpanzees, and rhesus macaque monkeys. We found that humans showed greater differential CpG methylation–an epigenetic modification of DNA that can reflect past or present gene expression–in the cerebellum than the prefrontal cortex, highlighting the importance of this structure in human brain evolution. Humans also specifically show methylation differences at genes involved in neurodevelopment, neuroinflammation, synaptic plasticity, and lipid metabolism. These differences are relevant for understanding processes specific to humans, such as extensive plasticity, as well as pronounced and prevalent neurodegenerative conditions associated with aging.

Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans., A comparative transcriptome study draws a connection between the gene expression alterations in autism and molecular features of cortical development that are unique to humans., Author Summary Autism spectrum disorder (ASD) involves disruptions in cognitive functions related to socialization and communication, which are also among the key behavioral capacities that separate humans from other species. This suggests that ASD may involve alterations in evolutionarily novel, human-specific developmental processes. To test this, we measured developmental gene expression trajectories in the cerebral cortex of autism cases, matched controls, and non-human primates: chimpanzees and macaques. Among a large number of disrupted developmental patterns that we detected in autism, only one, mainly including synaptic genes, was enriched in autism-linked mutations. This suggests that changes in expression of these genes in ASD brains may play a causal role in disease etiology. The same gene set exhibited more developmental expression changes unique to the human brain than any other developmental pattern disrupted in autism, reflecting extension of the synaptic maturation period in humans. Taken together, we show that a recently evolved developmental expression pattern of synaptic genes altered in autism might be associated with intense social learning abilities unique to humans.

Multisynaptic boutons (MSBs) are presynaptic boutons in contact with multiple postsynaptic partners. Although MSB synapses have been studied with static imaging techniques such as electron microscopy (EM), the dynamics of individual MSB synapses have not been directly evaluated. It is known that the number of MSB synapses increases with synaptogenesis and plasticity but the formation, behavior, and fate of individual MSB synapses remains largely unknown. To address this, we developed a means of live imaging MSB synapses to observe them directly over time. With time lapse confocal microscopy of GFP-filled dendrites in contact with VAMP2-DsRed-labeled boutons, we recorded both MSBs and their contacting spines hourly over 15 or more hours. Our live microscopy showed that, compared to spines contacting single synaptic boutons (SSBs), MSB-contacting spines exhibit elevated dynamic behavior. These results are consistent with the idea that MSBs serve as intermediates in synaptic development and plasticity.

A fundamental challenge in understanding how dendritic spine morphology controls learning and memory has been quantifying three-dimensional (3D) spine shapes with sufficient precision to distinguish morphologic types, and sufficient throughput for robust statistical analysis. The necessity to analyze large volumetric data sets accurately, efficiently, and in true 3D has been a major bottleneck in deriving reliable relationships between altered neuronal function and changes in spine morphology. We introduce a novel system for automated detection, shape analysis and classification of dendritic spines from laser scanning microscopy (LSM) images that directly addresses these limitations. The system is more accurate, and at least an order of magnitude faster, than existing technologies. By operating fully in 3D the algorithm resolves spines that are undetectable with standard two-dimensional (2D) tools. Adaptive local thresholding, voxel clustering and Rayburst Sampling generate a profile of diameter estimates used to classify spines into morphologic types, while minimizing optical smear and quantization artifacts. The technique opens new horizons on the objective evaluation of spine changes with synaptic plasticity, normal development and aging, and with neurodegenerative disorders that impair cognitive function.

The brain of a sperm whale is about 60% larger in absolute mass than that of an elephant. Furthermore, the brains of toothed whales and dolphins are significantly larger than those of any nonhuman primates and are second only to human brains when measured with respect to body size. How and why did such large brains evolve in these modern cetaceans? One current view of the evolution of dolphin brains is that their large size was primarily a response to social forces—the requirements for effective functioning within a complex society characterized by communication and collaboration as well as competition among group members. In such a society, individuals can benefit from the recognition of others and knowledge of their relationships and from flexibility in adapting to or implementing new behaviors as social or ecological context shifts. Other views focus on the cognitive demands associated with the use of echolocation. Recently, Manger made the controversial claim that cetacean brains are large because they contain an unusually large number of thermogenic glial cells whose numbers increased greatly to counteract heat loss during a decrease in ocean temperatures in the Eocene-Oligocene transition. Therefore, he argues, cetacean brain size could have evolved independently of any cognitive demands and, further, that there is neither neuronal evidence nor behavioral evidence of complex cognition in cetaceans. These claims have garnered considerable attention in the popular press, because they challenge prevailing knowledge and understanding of cetacean brain evolution, cognition, and behavior. We believe that the time is ripe to present an integrated view of cetacean brains, behavior, and evolution based on the wealth of accumulated and recent data on these topics. Our conclusions support the more generally accepted view that the large brain of cetaceans evolved to support complex cognitive abilities. Publisher PDF

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR ~/= 0). Moreover, genes known to be important in neuronal function, such as brain-derived neurotrophic factor (BDNF), are included among the genes more variably expressed in childhood. We propose that the developmental period of heightened childhood neuronal plasticity is characterized by more dynamic patterns of gene expression in the cerebral cortex compared to adulthood when the brain is less plastic. That an overabundance of these genes are annotated to the immune system suggests that the functions of these genes can be thought of not only in the context of antigen processing and presentation, but also in the context of nervous system development.