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Background Neuronal connectivity is refined throughout development by the proliferation and pruning of axons in cerebral white matter, and progressive axon myelination that enables rapid communication across brain regions. Differences in connectivity have been observed in autism spectrum disorder (ASD), including changes in white matter volume and connectivity. In the prefrontal cortex, this includes imbalances between short- and long-ranging axons, consistent with a pattern of local hyperconnectivity, and long-range hypoconnectivity. Alterations in temporal lobe white matter development—critical for social behavior—may contribute to atypical neural connectivity. Methods We used electron microscopy to analyze 54 samples of temporal lobe white matter from 27 age-matched postmortem brains from males with ASD and neurotypical (NT) controls, ages 2–44 years. Defined regions of superficial (SWM) and deep (DWM) white matter were sampled from superior temporal (STG) and fusiform (FG) gyri. Axon density and myelin thickness were quantified, with axon size classified by inner diameter, to evaluate age-related differences between ASD and neurotypical brains. Results In neurotypical control brains, total axon density significantly decreases with age in both STG and FG SWM. Although ASD cases show a similar trend, the density of small axons in STG is significantly higher than in controls. However, FG SWM in ASD shows no significant change in small-diameter axon density with age in this region. In neurotypical brains, myelin thickness of large-diameter axons increases significantly with age in STG and FG SWM. In contrast, large-diameter axons in ASD display significantly thinner myelin sheaths than controls across both STG and FG regions. Conclusions The temporal lobe exhibits atypical patterns of white matter development in ASD. In neurotypical individuals, decreased axon density in SWM with age reflects effective neural pruning and refinement of local and short-range connectivity. In contrast, individuals with ASD maintain a high density of small-diameter axons in STG SWM, suggesting reduced pruning that results in local overconnectivity. Moreover, myelin thickness in SWM does not increase with age in ASD, implying reduced efficacy of neurotransmission. These alterations in white matter ultrastructure may contribute to the atypical connectivity and neural communication observed in ASD across the lifespan.

Increasingly, functional and evolutionary research has highlighted the important contribution emotion processing makes to complex human social cognition. As such, it may be asked whether neural structures involved in emotion processing, commonly referred to as limbic structures, have been impacted in human brain evolution. To address this question, we performed an extensive evolutionary analysis of multiple limbic structures using modern phylogenetic tools. For this analysis, we combined new volumetric data for the hominoid (human and ape) amygdala and 4 amygdaloid nuclei, hippocampus, and striatum, collected using stereological methods in complete histological series, with previously published datasets on the amygdala, orbital and medial frontal cortex, and insula, as well as a non-limbic structure, the dorsal frontal cortex, for contrast. We performed a parallel analysis using large published datasets including many anthropoid species (human, ape, and monkey), but fewer hominoids, for the amygdala and 2 amygdaloid subdivisions, hippocampus, schizocortex, striatum, and septal nuclei. To address evolutionary change, we compared observed human values to values predicted from regressions run through (a) non-human hominoids and (b) non-human anthropoids, assessing phylogenetic influence using phylogenetic generalized least squares regression. Compared with other hominoids, the volumes of the hippocampus, the lateral nucleus of the amygdala, and the orbital frontal cortex were, respectively, 50, 37, and 11% greater in humans than predicted for an ape of human hemisphere volume, while the medial and dorsal frontal cortex were, respectively, 26 and 29% significantly smaller. Compared with other anthropoids, only human values for the striatum fell significantly below predicted values. Overall, the data present support for the idea that regions involved in emotion processing are not necessarily conserved or regressive, but may even be enhanced in recent human evolution.

Williams syndrome (WS) is a unique neurodevelopmental disorder with a specific behavioral and cognitive profile, which includes hyperaffiliative behavior, poor social judgment, and lack of social inhibition. Here we examined the morphology of basal dendrites on pyramidal neurons in the cortex of two rare adult subjects with WS. Specifically, we examined two areas in the prefrontal cortex (PFC)-the frontal pole (Brodmann area 10) and the orbitofrontal cortex (Brodmann area 11)-and three areas in the motor, sensory, and visual cortex (BA 4, BA 3-1-2, BA 18). The findings suggest that the morphology of basal dendrites on the pyramidal neurons is altered in the cortex of WS, with differences that were layer-specific, more prominent in PFC areas, and displayed an overall pattern of dendritic organization that differentiates WS from other disorders. In particular, and unlike what was expected based on typically developing brains, basal dendrites in the two PFC areas did not display longer and more branched dendrites compared to motor, sensory and visual areas. Moreover, dendritic branching, dendritic length, and the number of dendritic spines differed little within PFC and between the central executive region (BA 10) and BA 11 that is part of the orbitofrontal region involved into emotional processing. In contrast, the relationship between the degree of neuronal branching in supra- versus infra-granular layers was spared in WS. Although this study utilized tissue held in formalin for a prolonged period of time and the number of neurons available for analysis was limited, our findings indicate that WS cortex, similar to that in other neurodevelopmental disorders such as Down syndrome, Rett syndrome, Fragile X, and idiopathic autism, has altered morphology of basal dendrites on pyramidal neurons, which appears more prominent in selected areas of the PFC. Results were examined from developmental perspectives and discussed in the context of other neurodevelopmental disorders. We have proposed hypotheses for further investigations of morphological changes on basal dendrites in WS, a syndrome of particular interest given its unique social and cognitive phenotype.

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS.

A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. An iPSC model for Williams syndrome Individuals with the neurodevelopmental disorder Williams syndrome (WS) lack a region of about 25 genes on chromosome 7. The condition is characterized by hypersociability and a range of cognitive and behavioural impairments, but how specific genes contribute to the neuroanatomical and functional alterations is not known. Alysson Muotri and colleagues have used cellular reprogramming technologies to generate induced pluripotent stem cells (iPSCs) from individuals with WS and controls. iPSC-derived neural progenitor cells from individuals with WS had increased apoptosis owing to haploinsufficiency of the gene FZD9. In addition, iPSC-derived WS cortical neurons displayed altered activity and morphological changes, some of which matched those seen in postmortem brains of individuals with WS. This human iPSC model may provide insights into the molecular and cellular mechanisms underlying the various features of the disorder. Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1 , 2 , 3 , 4 , 5 ). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome 6 , 7 , we narrowed this cellular phenotype to a single gene candidate, frizzled 9 ( FZD9 ). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells 8 fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25–28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specific social stimuli, which is likely associated with abnormalities of frontostriatal circuitry. The striatum is characterized by a diversity of interneuron subtypes, including inhibitory parvalbumin-positive interneurons (PV+) and excitatory cholinergic interneurons (Ch+). Animal model research has identified an important role for these specialized cells in regulating social approach behavior. Previous research in humans identified a depletion of interneuron subtypes associated with neuropsychiatric disorders. Here, we examined the density of PV+ and Ch+ interneurons in the striatum of 13 WS and neurotypical (NT) subjects. We found a significant reduction in the density of Ch+ interneurons in the medial caudate nucleus and nucleus accumbens, important regions receiving cortical afferents from the orbitofrontal and ventromedial prefrontal cortex, and circuitry involved in language and reward systems. No significant difference in the distribution of PV+ interneurons was found. The pattern of decreased Ch+ interneuron densities in WS differs from patterns of interneuron depletion found in other disorders.

The evolution of the human brain has been marked by a nearly 3-fold increase in size since our divergence from the last common ancestor shared with chimpanzees and bonobos. Despite increased interest in comparative neuroanatomy and phylogenetic methods, relatively little is known regarding the effects that this enlargement has had on its internal organization, and how certain areas of the brain have differentially expanded over evolutionary time. Analyses of the microstructure of several regions of the human cortex and subcortical structures have demonstrated subtle changes at the cellular and molecular level, suggesting that the human brain is more than simply a ‘scaled-up' primate brain. Ongoing research in comparative neuroanatomy has much to offer regarding our understanding of human brain evolution. Through analysis of the neuroanatomical phenotype at the level of reorganization in cytoarchitecture and cellular morphology, new data continue to highlight changes in cell density and organization associated with volumetric changes in discrete regions. An understanding of the functional significance of variation in neural circuitry can further be approached through studies of atypical human development. Many neurodevelopmental disorders cause disruption in systems associated with uniquely human features of cognition, including language and social cognition. Understanding the genetic and developmental mechanisms that underlie variation in the human cognitive phenotype can help to clarify the functional significance of interspecific variation. By uniting approaches from comparative neuroanatomy and neuropathology, insights can be gained that clarify trends in human evolution. Here, we explore these lines of evidence and their significance for understanding functional variation between species as well as within neuropathological variation in the human brain.

The evolution of the human brain has yielded advanced cognitive capacities supporting the development of language, technologically advanced material culture, and highly complex social behavior that has allowed for the development of the rich diversity of human cultures. Comparative neuroanatomy in evolutionary perspective continues to make great strides in characterizing and defining unique elements of the human neuroanatomical phenotype at the gross and microscopic level that underlie these key behavioral adaptations. In conjunction with these studies, an understanding of the functional implications of derived anatomical traits is gained through analyses of neurodevelopmental disorders, which help to define a spectrum of variation in the diversity of human brain phenotypes. Williams syndrome (WS) is a rare neurodevelopmental disorder caused by a hemideletion of ∼1.6 Mb (25-28 genes) on human chromosome 7q11.23, a highly dynamic region associated with recent adaptive selection in hominoid lineages. Analyzing the neuroanatomical phenotype in WS provides the unique opportunity to study correlates of a distinctive cognitive and behavioral phenotype in a neurodevelopmental disorder of known genetic cause. Among the most notable behavioral phenotypes observed in WS is a generalized disinhibition of social behavior, likely rooted in the dysfunction of frontostriatal circuitry. We targeted the rostral territories of the striatum in that share important connectivity with the prefrontal cortex in reward circuitry. We provide new evidence for variation in neuroanatomy in WS underlying its unusual social and cognitive phenotype. Specifically, we found increased glial cell density in the caudate nucleus of the striatum, as well as a significant increase in the density of oligodendrocytes in the medial caudate nucleus, likely related to dysfunctional connectivity with the prefrontal cortex. We additionally found a decrease in the density of cholinergic interneurons in the medial caudate nucleus, which may serve important functions in the regulation of social interaction. These data suggest that deficits in behavioral control may be linked to dysfunction of local circuitry within the striatum in WS, mediated by imbalance between neuronal and glial cell density and interneuron function, which may underlie important differences in social behavior.

The striatum is formed by a group of subcortical nuclei in the brain with analogues shared by all vertebrates, and as such, it has frequently been described in the literature as being evolutionarily \"conserved.\" However, its extensive connections with the neocortex, and its involvement in a variety of complex cognitive and behavioral processes, particularly those associated with social cognition, indicate phylogenetic modification that bears further exploration in an evolutionary context. Here, I will explore the anatomy and cognitive functions of the striatum, highlighting its role as an integral part of the social brain. I will assert that major modifications in its connectivity with the dynamically evolving neocortex yield important functional differences across species, contributing to derived cognitive specializations in the primate lineage. Finally, I will raise questions regarding the chemical anatomy of the striatum across species, calling for further investigation of interspecific differences in chemical anatomy. These differences in connectivity and chemical anatomy likely underlie features of primate and human cognition representing uniquely evolved specializations.

Managing endangered species often involves evaluating the relative impacts of multiple anthropogenic and ecological pressures. This challenge is particularly formidable for cetaceans, which spend the majority of their time underwater. Noninvasive physiological approaches can be especially informative in this regard. We used a combination of fecal thyroid (T3) and glucocorticoid (GC) hormone measures to assess two threats influencing the endangered southern resident killer whales (SRKW; Orcinus orca) that frequent the inland waters of British Columbia, Canada and Washington, U.S.A. Glucocorticoids increase in response to nutritional and psychological stress, whereas thyroid hormone declines in response to nutritional stress but is unaffected by psychological stress. The inadequate prey hypothesis argues that the killer whales have become prey limited due to reductions of their dominant prey, Chinook salmon (Oncorhynchus tshawytscha). The vessel impact hypothesis argues that high numbers of vessels in close proximity to the whales cause disturbance via psychological stress and/or impaired foraging ability. The GC and T3 measures supported the inadequate prey hypothesis. In particular, GC concentrations were negatively correlated with short-term changes in prey availability. Whereas, T3 concentrations varied by date and year in a manner that corresponded with more long-term prey availability. Physiological correlations with prey overshadowed any impacts of vessels since GCs were lowest during the peak in vessel abundance, which also coincided with the peak in salmon availability. Our results suggest that identification and recovery of strategic salmon populations in the SRKW diet are important to effectively promote SRKW recovery.