Serotonergic innervation of the amygdala is increased in autism spectrum disorder and decreased in Williams syndrome.

BACKGROUND: Williams syndrome (WS) and autism spectrum disorder (ASD) are neurodevelopmental disorders that demonstrate overlapping genetic associations, dichotomous sociobehavioral phenotypes, and dichotomous pathological differences in neuronal distribution in key social brain areas, including the prefrontal cortex and the amygdala. The serotonergic system is critical to many processes underlying neurodevelopment and is additionally an important neuromodulator associated with behavioral variation. The amygdala is heavily innervated by serotonergic projections, suggesting that the serotonergic system is a significant mediator of neuronal activity. Disruptions to the serotonergic system, and atypical structure and function of the amygdala, are implicated in both WS and ASD. METHODS: We quantified the serotonergic axon density in the four major subdivisions of the amygdala in the postmortem brains of individuals diagnosed with ASD and WS and neurotypical (NT) brains. RESULTS: We found opposing directions of change in serotonergic innervation in the two disorders, with ASD displaying an increase in serotonergic axons compared to NT and WS displaying a decrease. Significant differences (p < 0.05) were observed between WS and ASD data sets across multiple amygdala nuclei. LIMITATIONS: This study is limited by the availability of human postmortem tissue. Small sample size is an unavoidable limitation of most postmortem human brain research and particularly postmortem research in rare disorders. CONCLUSIONS: Differential alterations to serotonergic innervation of the amygdala may contribute to differences in sociobehavioral phenotype in WS and ASD. These findings will inform future work identifying targets for future therapeutics in these and other disorders characterized by atypical social behavior.

Comparative analyses of the neuron numbers and volumes of the amygdaloid complex in old and new world primates.

The amygdaloid complex (AC), a key component of the limbic system, is a brain region critical for the detection and interpretation of emotionally salient information. Therefore, changes in its structure and function are likely to provide correlates of mood and emotion disorders, diseases that afflict a large portion of the human population. Previous gross comparisons of the AC in control and diseased individuals have, however, mainly failed to discover these expected correlations with diseases. We have characterized AC nuclei in different nonhuman primate species to establish a baseline for more refined comparisons between the normal and the diseased amygdala. AC nuclei volume and neuron number in 19 subdivisions are reported from 13 Old and New World primate brains, spanning five primate species, and compared with corresponding data from humans. Analysis of the four largest AC nuclei revealed that volume and neuron number of one component, the central nucleus, has a negative allometric relationship with total amygdala volume and neuron number, which is in contrast with the isometric relationship found in the other AC nuclei (for both neuron number and volume). Neuron density decreases across all four nuclei according to a single power law with an exponent of about minus one-half. Because we have included quantitative comparisons with great apes and humans, our conclusions apply to human brains, and our scaling laws can potentially be used to study the anatomical correlates of the amygdala in disorders involving pathological emotion processing.

Reduced minicolumns in the frontal cortex of patients with autism.

Cell minicolumns were shown to be narrower in frontal regions in brains of autistic patients compared with controls. This was not found in primary visual cortex. Within the frontal cortex, dorsal and orbital regions displayed the greatest differences while the mesial region showed the least change. We also found that minicolumns in the brain of a 3-year-old autistic child were indistinguishable from those of the autistic adult in two of three frontal regions, in contrast to the control brains. This may have been due to the small size of the columns in the adult autistic brain rather than to an accelerated development. The presence of narrower minicolumns supports the theory that there is an abnormal increase in the number of ontogenetic column units produced in some regions of the autistic brain during corticoneurogenesis.

Humans and great apes share a large frontal cortex.

Some of the outstanding cognitive capabilities of humans are commonly attributed to a disproportionate enlargement of the human frontal lobe during evolution. This claim is based primarily on comparisons between the brains of humans and of other primates, to the exclusion of most great apes. We compared the relative size of the frontal cortices in living specimens of several primate species, including all extant hominoids, using magnetic resonance imaging. Human frontal cortices were not disproportionately large in comparison to those of the great apes. We suggest that the special cognitive abilities attributed to a frontal advantage may be due to differences in individual cortical areas and to a richer interconnectivity, none of which required an increase in the overall relative size of the frontal lobe during hominid evolution.

Prefrontal cortex in humans and apes: a comparative study of area 10.

Area 10 is one of the cortical areas of the frontal lobe involved in higher cognitive functions such as the undertaking of initiatives and the planning of future actions. It is known to form the frontal pole of the macaque and human brain, but its presence and organization in the great and lesser apes remain unclear. It is here documented that area 10 also forms the frontal pole of chimpanzee, bonobo, orangutan, and gibbon brains. Imaging techniques and stereological tools are used to characterize this area across species and provide preliminary estimates of its absolute and relative size. Area 10 has similar cytoarchitectonic features in the hominoid brain, but aspects of its organization vary slightly across species, including the relative width of its cortical layers and the space available for connections. The cortex forming the frontal pole of the gorilla appears highly specialized, while area 10 in the gibbon occupies only the orbital sector of the frontal pole. Area 10 in the human brain is larger relative to the rest of the brain than it is in the apes, and its supragranular layers have more space available for connections with other higher-order association areas. This suggests that the neural substrates supporting cognitive functions associated with this part of the cortex enlarged and became specialized during hominid evolution.

The brain and its main anatomical subdivisions in living hominoids using magnetic resonance imaging.

Primary comparative data on the hominoid brain are scarce and major neuroanatomical differences between humans and apes have not yet been described satisfactorily, even at the gross level. Basic questions that involve the evolution of the human brain cannot be addressed adequately unless the brains of all extant hominoid species are analyzed. Contrary to the scarcity of original data, there is a rich literature on the topic of human brain evolution and several debates exist on the size of particular sectors of the brain, e.g., the frontal lobe. In this study we applied a non-invasive imaging technique (magnetic resonance) on living human, great ape and lesser ape subjects in order to investigate the overall size of the hominoid brain. The images were reconstructed in three dimensions and volumetric estimates were obtained for the brain and its main anatomical sectors, including the frontal and temporal lobes, the insula, the parieto-occipital sector and the cerebellum.A remarkable homogeneity is present in the relative size of many of the large sectors of the hominoid brain, but interspecific and intraspecific variation exists in certain parts of the brain. The human cerebellum is smaller than expected for an ape brain of human size. It is suggested that the cerebellum increased less than the cerebrum after the split of the human lineage from the African ancestral hominoid stock. In contrast, humans have a slightly larger temporal lobe and insula than expected, but differences are not statistically significant. Humans do not have a larger frontal lobe than expected for an ape brain of human size and gibbons have a relatively smaller frontal lobe than the rest of the hominoids. Given the fact that the frontal lobe in humans and great apes has similar relative size, it is parsimonious to suggest that the relative size of the whole of the frontal lobe has not changed significantly during hominid evolution in the Plio-Pleistocene.

Limbic frontal cortex in hominoids: a comparative study of area 13.

The limbic frontal cortex forms part of the neural substrate responsible for emotional reactions to social stimuli. Area 13 is one of the cortical areas long known to be part of the posterior orbitofrontal cortex in several monkey species, such as the macaque. Its presence nevertheless in the human brain has been unclear, and the cortex of the frontal lobe of the great and lesser apes remains largely unknown. In this study area 13 was identified in human, chimpanzee, bonobo, gorilla, orangutan, and gibbon brains, and cortical maps were generated on the basis of its cytoarchitecture. Imaging techniques were used to characterize and quantify the microstructural organization of the area, and stereological tools were applied for estimates of the volume of area 13 in all species. Area 13 is conservative in its structure, and features such as size of cortical layers, density of neurons, and space available for connections are similar across hominoids with only subtle differences present. In contrast to the homogeneity found in its organization, variation is present in the relative size of this cortical area (as a percentage of total brain volume). The human and the bonobo include a complex orbitofrontal cortex and a relatively smaller area 13. On the contrary the orangutan stands out by having a shorter orbitofrontal region and a more expanded area 13. Differences in the organization and size of individual cortical areas involved in emotional reactions and social behavior can be related to behavioral specializations of each hominoid and to the evolution of emotions in hominids.

The evolution of the frontal lobes: a volumetric analysis based on three-dimensional reconstructions of magnetic resonance scans of human and ape brains.

Scenarios regarding the evolution of cognitive function in hominids depend largely on our understanding of the organization of the frontal lobes in extant humans and apes. The frontal lobe is involved in functions such as creative thinking, planning of future actions, decision making, artistic expression, aspects of emotional behavior, as well as working memory, language and motor control. It is often claimed that the frontal lobe is disproportionately larger in humans than in other species, but conflicting reports exist on this issue. The brain of the apes in particular remains largely unknown. In this report we measure the volume of the frontal lobe as a whole and of its main sectors (including cortex and immediately underlying white matter) in living humans, and in post-mortem brains of the chimpanzee, gorilla, orang-utan, gibbon and the macaque using three-dimensional reconstructions of magnetic resonance (MR) scans of the brain. On the basis of these data we suggest that although the absolute volume of the brain and the frontal lobe is largest in humans, the relative size of the frontal lobe is similar across hominoids, and that humans do not have a larger frontal lobe than expected from a primate brain of the human size. We also report that the relative size of the sectors of the frontal lobe (dorsal, mesial, orbital) is similar across the primate species studied. Our conclusions are preliminary, because the size of our sample, although larger than in previous studies, still remains small. With this caveat we conclude that the overall volume of the frontal lobe in hominids enlarged in absolute size along with the rest of the brain, but did not become relatively larger after the split of the human line from the ancestral African hominoid stock. Aspects other than relative volume of the frontal lobe have to be responsible for the cognitive specializations of the hominids.