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Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.
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Birdsong as a window into language origins and evolutionary neuroscience.
Humans and songbirds share the key trait of vocal learning, manifested in speech and song, respectively. Striking analogies between these behaviours include that both are acquired during developmental critical periods when the brain's ability for vocal learning peaks. Both behaviours show similarities in the overall architecture of their underlying brain areas, characterized by cortico-striato-thalamic loops and direct projections from cortical neurons onto brainstem motor neurons that control the vocal organs. These neural analogies extend to the molecular level, with certain song control regions sharing convergent transcriptional profiles with speech-related regions in the human brain. This evolutionary convergence offers an unprecedented opportunity to decipher the shared neurogenetic underpinnings of vocal learning. A key strength of the songbird model is that it allows for the delineation of activity-dependent transcriptional changes in the brain that are driven by learned vocal behaviour. To capitalize on this advantage, we used previously published datasets from our laboratory that correlate gene co-expression networks to features of learned vocalization within and after critical period closure to probe the functional relevance of genes implicated in language. We interrogate specific genes and cellular processes through converging lines of evidence: human-specific evolutionary changes, intelligence-related phenotypes and relevance to vocal learning gene co-expression in songbirds. This article is part of the theme issue 'What can animal communication teach us about human language?'
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Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation.
Structural genomic variations represent a major driving force of evolution, and a burst of large segmental gene duplications occurred in the human lineage during its separation from nonhuman primates. SRGAP2, a gene recently implicated in neocortical development, has undergone two human-specific duplications. Here, we find that both duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain. SRGAP2C is expressed in the developing and adult human brain and dimerizes with ancestral SRGAP2 to inhibit its function. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. Expression of SRGAP2C phenocopies SRGAP2 deficiency. It underlies sustained radial migration and leads to the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex and plays an important role during human brain development.
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The restless brain: how intrinsic activity organizes brain function.
Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease.
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Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development.
The human brain is distinguished by unusually prolonged developmental timing, yet the genetic mechanisms coordinating this neoteny across cell types remain incompletely understood. Here, we show that human cortical microglia undergo neotenic structural and transcriptional maturation relative to mouse microglia. We identify SRGAP2B/C, human-specific paralogs of the ancestral SRGAP2A, as the only human-specific gene duplications expressed in human microglia. Using xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that human-specific SRGAP2B/C, previously shown to reduce SRGAP2A protein abundance, are both necessary and sufficient to induce neotenic structural microglial maturation. Our results reveal that neotenic microglial maturation modifies the timing of synaptic development, linking microglial developmental programs to the timing of circuit formation. Together with previous evidence for neuronal SRGAP2A function, our results suggest that the human-specific SRGAP2B/C paralogs coordinated the emergence of neotenic synaptic development by acting in both neurons and microglia during human brain evolution.
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Olduvai domains: humanity's lucky brake.
Neoteny-a developmental slowdown that results in the retention of juvenile traits into adulthood-has long been viewed as central to human brain expansion. Olduvai domains are proposed here to function as a dosage-dependent metabolic 'brake' that slows development via mitochondrial downregulation. Their human-specific hyperamplification, paired with NOTCH2NL accelerators and new metabolic insights, may solve a century-old evolutionary puzzle.
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Exploring the singularity of human neurons: keep calm and carry on.
The human brain's increased cognitive abilities are underpinned by evolutionary adaptations at the molecular, cellular, and circuit levels of neural structures. This perspective explores how protracted neuronal development and divergent cell intrinsic neuronal properties, including neuronal excitability, contribute to human neurobiological singularity. Those cellular aspects rely on molecular evolutionary innovations, including evolution of gene regulation and gene duplications that play critical roles in prolonging synaptogenesis and reducing neuronal excitability. These molecular evolutionary innovations are shown to interact with core neurodevelopmental molecular pathways linked to neurodevelopmental disorders. Furthermore, complementary multimodal and multiscale approaches offer promising platforms to study these processes and develop species-relevant therapeutic strategies. They include ex vivo acute brain slices and organotypic cultures which offer emerging tools for understanding human species-specificities and neural disorders.
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Human-specific regulation of neural maturation identified by cross-primate transcriptomics.
Unique aspects of human behavior are often attributed to differences in the relative size and organization of the human brain: these structural aspects originate during early development. Recent studies indicate that human neurodevelopment is considerably slower than that in other nonhuman primates, a finding that is termed neoteny. One aspect of neoteny is the slow onset of action potentials. However, which molecular mechanisms play a role in this process remain unclear. To examine the evolutionary constraints on the rate of neuronal maturation, we have generated transcriptional data tracking five time points, from the neural progenitor state to 8-week-old neurons, in primates spanning the catarrhine lineage, including Macaca mulatta, Gorilla gorilla, Pan paniscus, Pan troglodytes, and Homo sapiens. Despite finding an overall similarity of many transcriptional signatures, species-specific and clade-specific distinctions were observed. Among the genes that exhibited human-specific regulation, we identified a key pioneer transcription factor, GATA3, that was uniquely upregulated in humans during the neuronal maturation process. We further examined the regulatory nature of GATA3 in human cells and observed that downregulation quickened the speed of developing spontaneous action potentials, thereby modulating the human neotenic phenotype. These results provide evidence for the divergence of gene regulation as a key molecular mechanism underlying human neoteny.
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REM sleep vs exploratory wakefulness: Alternatives within adult 'sleep debt'?
Our declining sleep duration over early human infant development is largely through REM sleep (REM), loss, not of nonREM. It coincides with the infant's increasing locomotion providing for multisensory inputs ('exploratory wakefulness' - EW), together facilitating neural restructuring and behavioural adaptations ('neuroplasticity'). EW also involves curiosity, novelty, navigation, spatial memory, associated emotions, and feeding; all having brain processes particularly active in REM. It is proposed that: 1) REM is a proxy for EW in facilitating neuroplasticity; 2) necessitating REM having a locomotor output, actively inhibited (the atonia); 3) human adults retain many (neotenous) infant characteristics including large amounts of REM towards the end of usual sleep, where REM's qualitative changes indicate reduced sleep pressure, 4) as in infancy, some of our adult REM remains replaceable by EW (without REM rebounds), mostly in this final REM episode whenever EW need prevails. Accordingly, our adult sleep duration is adaptable to habitual shortening via this REM episode substituted by purposeful EW, which could provide extra (day) light exposure for circadian synchrony. Such processes may underlie seasonally shorter (6 h) sleep, eg in hunter-gather people. This flexibility of REM questions the extent of our western 'chronic sleep debt'. Evidence is provided to counter claims that this absent REM would cause obesity and related disorders. 200w.
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Paradox of peramorphic paedomorphosis: heterochrony and human evolution.
This paper reviews Gould's clock model for heterochronic processes and uses that model to develop simple matrix representations of growth and shape change. Matrix representations of growth and development provide a common formulation for all heterochronic processes. In particular, we show how neoteny can be diagnosed using such a matrix approach. The literature is rife with contradictory representations of how neoteny affects growth allometries and the timing of developmental events, and therefore of the role of neoteny in human evolution. Through the use of multivariate models, we explore these relationships and the internal consistency of opposing views. Gould's neoteny hypothesis for human evolution has been criticized for a number of reasons. Humans do not grow slowly. The slopes of our growth allometries show no common pattern of change vis-à-vis those of our closest relatives. Humans prolong rather than reduce rates of growth and development of body parts; the brain, for example, ceases growing later in humans than in apes, but during this prolonged period of early ontogeny, it grows at a rapid pace. This paper evaluates Gould's hypothesis and its critiques by focusing on particular questions. Does neoteny imply slow growth? Does it imply a unidirectional change in the rates of growth of traits? Under neoteny, should the brain cease growing in ancestor and descendant at the same age? Does prolongation of phases of growth and development confute neoteny? On the other hand, is paedomorphosis an inevitable consequence of prolonged growth and development? We show that, for all of these questions, the answer is no.