The third wave: Intermediate filaments in the maturing nervous system.

Intermediate filaments are critical for the extreme structural specialisations of neurons, providing integrity in dynamic environments and efficient communication along axons a metre or more in length. As neurons mature, an initial expression of nestin and vimentin gives way to the neurofilament triplet proteins and α-internexin, substituted by peripherin in axons outside the CNS, which physically consolidate axons as they elongate and find their targets. Once connection is established, these proteins are transported, assembled, stabilised and modified, structurally transforming axons and dendrites as they acquire their full function. The interaction between these neurons and myelinating glial cells optimises the structure of axons for peak functional efficiency, a property retained across their lifespan. This finely calibrated structural regulation allows the nervous system to maintain timing precision and efficient control across large distances throughout somatic growth and, in maturity, as a plasticity mechanism allowing functional adaptation.

Transition to shift work: Sleep patterns, activity levels, and physiological health of early-career paramedics.

The physiological impact of transitioning from full-time study to work in occupations that involve high-stress environments and shift work may plausibly impact sleep patterns and quality. There are limited studies focusing on the transition to shift work in graduate paramedics. This study aimed to assess early metabolic markers of health, activity, and sleep quality during the first 5 months of rostered shift work in a cohort of 28 graduate paramedics. Participants were tested for 4-week blocks before starting shift work (baseline), and during their first and fifth month of shift work. In each block, sleep and activity levels were monitored 24 h/day (workdays and nonworking days) using a wrist-worn actigraph. During shift work, the number of sleep episodes increased by 16.7% (p = .02) and self-reporting of poor sleep quality increased by 35.4% (p = .05); however, overall sleep quantity and sleep efficiency did not differ. Sleep metrics recorded during nonwork days were not different to baseline with exception of reduced sleep duration recorded the night before returning to work (5.99 ± 1.66 hours Month 1; 5.72 ± 1.06 hours Month 5). Sedentary behavior increased by 4.8% across the study, attributable to a significant decline in light exercise (p = .05). No changes were recorded in vigorous physical activity, average steps recorded per day, fasting blood glucose levels, systolic and diastolic blood pressure, weight, or waist circumference. These results warrant further large-scale and longitudinal studies to gauge any physiological implications for ongoing paramedic health.

Increased circulating leukocyte numbers and altered macrophage phenotype correlate with the altered immune response to brain injury in metallothionein (MT)-I/II null mutant mice.

BACKGROUND: Metallothionein-I and -II (MT-I/II) is produced by reactive astrocytes in the injured brain and has been shown to have neuroprotective effects. The neuroprotective effects of MT-I/II can be replicated in vitro which suggests that MT-I/II may act directly on injured neurons. However, MT-I/II is also known to modulate the immune system and inflammatory processes mediated by the immune system can exacerbate brain injury. The present study tests the hypothesis that MT-I/II may have an indirect neuroprotective action via modulation of the immune system. METHODS: Wild type and MT-I/II(-/-) mice were administered cryolesion brain injury and the progression of brain injury was compared by immunohistochemistry and quantitative reverse-transcriptase PCR. The levels of circulating leukocytes in the two strains were compared by flow cytometry and plasma cytokines were assayed by immunoassay. RESULTS: Comparison of MT-I/II(-/-) mice with wild type controls following cryolesion brain injury revealed that the MT-I/II(-/-) mice only showed increased rates of neuron death after 7 days post-injury (DPI). This coincided with increases in numbers of T cells in the injury site, increased IL-2 levels in plasma and increased circulating leukocyte numbers in MT-I/II(-/-) mice which were only significant at 7 DPI relative to wild type mice. Examination of mRNA for the marker of alternatively activated macrophages, Ym1, revealed a decreased expression level in circulating monocytes and brain of MT-I/II(-/-) mice that was independent of brain injury. CONCLUSIONS: These results contribute to the evidence that MT-I/II(-/-) mice have altered immune system function and provide a new hypothesis that this alteration is partly responsible for the differences observed in MT-I/II(-/-) mice after brain injury relative to wild type mice.

TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy.

Mislocalization of the TAR DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm is a common feature of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects of this mislocalization are not well understood. To investigate the impact of mislocalized TDP-43 on neuronal cell bodies, axons and axonal terminals, we utilized the mouse visual system to create a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinal ganglion cells (RGCs) were transduced with GFP-tagged human wildtype TDP-43 (hTDP-WT-GFP) and human TDP-43 with a mutation in the nuclear localization sequence (hTDP-ΔNLS-GFP), to cause TDP-43 mislocalization, with ∼60% transduction efficiency achieved. Expression of both hTDP-WT-GFP and hTDP-ΔNLS-GFP resulted in changes to neurofilament expression, with cytoplasmic TDP-43 being associated with significantly (p<0.05) increased neurofilament heavy expression in the cell soma, and both forms of altered TDP-43 leading to significantly (p<0.05) decreased numbers of neurofilament-positive axons within the optic nerve. Alterations to neurofilament proteins were associated with significantly (p<0.05) increased microglial density in the optic nerve and retina. Furthermore expression of hTDP-WT-GFP was associated with a significant (p<0.05) increase in pre-synaptic input into RGCs in the retina. The current study has developed a new model allowing detailed examination of alterations to TDP-43 and will contribute to the knowledge of TDP-43-mediated neuronal alterations and degeneration.

Coherence and cognition in the cortex: the fundamental role of parvalbumin, myelin, and the perineuronal net.

The calcium binding protein parvalbumin is expressed in interneurons of two main morphologies, the basket and chandelier cells, which target perisomatic domains on principal cells and are extensively interconnected in laminar networks by synapses and gap junctions. Beyond its utility as a convenient cellular marker, parvalbumin is an unambiguous identifier of the key role that these interneurons play in the fundamental functions of the cortex. They provide a temporal framework for principal cell activity by propagating gamma oscillation, providing coherence for cortical information processing and the basis for timing-dependent plasticity processes. As these parvalbumin networks mature, they are physically and functionally stabilised by axonal myelination and development of the extracellular matrix structure termed the perineuronal net. This maturation correlates with the emergence of high-speed, highly energetic activity and provides a coherent foundation for the unique ability of the cortex to cross-correlate activity across sensory modes and internal representations.

Focal demyelination in Alzheimer's disease and transgenic mouse models.

We have investigated alterations in myelin associated with Abeta plaques, a major pathological hallmark of Alzheimer's disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Abeta pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Abeta plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Abeta plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.

Accurate and Unbiased Quantitation of Amyloid-ß Fluorescence Images Using ImageSURF.

BACKGROUND: Images of amyloid-ß pathology characteristic of Alzheimer's disease are difficult to consistently and accurately segment, due to diffuse deposit boundaries and imaging variations. METHODS: We evaluated the performance of ImageSURF, our open-source ImageJ plugin, which considers a range of image derivatives to train image classifiers. We compared ImageSURF to standard image thresholding to assess its reproducibility, accuracy and generalizability when used on fluorescence images of amyloid pathology. RESULTS: ImageSURF segments amyloid-ß images significantly more faithfully, and with significantly greater generalizability, than optimized thresholding. CONCLUSION: In addition to its superior performance in capturing human evaluations of pathology images, ImageSURF is able to segment image sets of any size in a consistent and unbiased manner, without requiring additional blinding, and can be retrospectively applied to existing images. The training process yields a classifier file which can be shared as supplemental data, allowing fully open methods and data, and enabling more direct comparisons between different studies.

Age Moderates the Effects of Traumatic Brain Injury on Beta-Amyloid Plaque Load in APP/PS1 Mice.

Traumatic brain injury (TBI) has been identified as a risk factor for Alzheimer's disease (AD). However, how such neural damage contributes to AD pathology remains unclear; specifically, the relationship between the timing of a TBI relative to aging and the onset of AD pathology is not known. In this study, we have examined the effect of TBI on subsequent beta-amyloid (Aß) deposition in APP/PS1 (APPSWE/PSEN1dE9) transgenic mice either before (3 months of age) or after the onset (6 months of age) of plaque pathology. Lateral fluid percussion injury (LFPI), a model of diffuse brain injury, was induced in APP/PS1 and C57Bl/6 wild-type (WT) littermates. LFPI caused a significant increase in both total (p < 0.001) and fibrillar (p < 0.001) Aß plaque load in the cortex of 3-month-old APP/PS1 mice compared to sham-treated mice at 30 days post-injury. However, in the cortex of 6-month-old mice at 30 days post-injury, LFPI caused a significant decrease in total (p < 0.01), but not fibrillar (p > 0.05), Aß plaque load compared to sham-treated mice. No Aß plaques were present in any WT mice across these conditions. Glial fibrillary acidic protein immunolabeling of astrocytes and ionized calcium-binding adapter molecule 1 immunolabeling of microglial/macrophages was not significantly different (p < 0.05) in injured animals compared to sham mice, or APP/PS1 mice compared to WT mice. The current data indicate that TBI may have differential effects on Aß plaque deposition depending on the age and the stage of amyloidosis at the time of injury.

The axon as a physical structure in health and acute trauma.

The physical structure of neurons - dendrites converging on the soma, with an axon conveying activity to distant locations - is uniquely tied to their function. To perform their role, axons need to maintain structural precision in the soft, gelatinous environment of the central nervous system and the dynamic, flexible paths of nerves in the periphery. This requires close mechanical coupling between axons and the surrounding tissue, as well as an elastic, robust axoplasm resistant to pinching and flattening, and capable of sustaining transport despite physical distortion. These mechanical properties arise primarily from the properties of the internal cytoskeleton, coupled to the axonal membrane and the extracellular matrix. In particular, the two large constituents of the internal cytoskeleton, microtubules and neurofilaments, are braced against each other and flexibly interlinked by specialised proteins. Recent evidence suggests that the primary function of neurofilament sidearms is to structure the axoplasm into a linearly organised, elastic gel. This provides support and structure to the contents of axons in peripheral nerves subject to bending, protecting the relatively brittle microtubule bundles and maintaining them as transport conduits. Furthermore, a substantial proportion of axons are myelinated, and this thick jacket of membrane wrappings alters the form, function and internal composition of the axons to which it is applied. Together these structures determine the physical properties and integrity of neural tissue, both under conditions of normal movement, and in response to physical trauma. The effects of traumatic injury are directly dependent on the physical properties of neural tissue, especially axons, and because of axons' extreme structural specialisation, post-traumatic effects are usually characterised by particular modes of axonal damage. The physical realities of axons in neural tissue are integral to both normal function and their response to injury, and require specific consideration in evaluating research models of neurotrauma.

Excitotoxicity in ALS: Overstimulation, or overreaction?

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS.

The effect of focal brain injury on beta-amyloid plaque deposition, inflammation and synapses in the APP/PS1 mouse model of Alzheimer's disease.

Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aß) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aß plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aß antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aß plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p<0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p>0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d PI (p>0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aß plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aß plaque pathology that causes synaptic degeneration.

Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse.

The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous system. However, altered phosphorylation of TDP-43 may be more highly associated with aging than the levels of TDP-43 expression.

Diffuse axonal injury in brain trauma: insights from alterations in neurofilaments.

Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury.

Altered synapses and gliotransmission in Alzheimer's disease and AD model mice.

Amyloid-ß (Aß) plaque accumulation in Alzheimer's disease (AD) is associated with glutamatergic synapse loss, but less is known about its effect on inhibitory synapses. Here, we demonstrate that vesicular γ-aminobutyric acid (GABA) transporter (VGAT) presynaptic bouton density is unaffected in human preclinical and end-stage AD and in APP/PS1 transgenic (TG) mice. Conversely, excitatory vesicular glutamate transporter 1 (VGlut1) boutons are significantly reduced in end-stage AD cases and less reduced in preclinical AD cases and TGs. Aged TGs also show reduced protein levels of VGlut1 and synaptophysin but not VGAT or glutamate decarboxylase (GAD). These findings indicate that GABAergic synapses are preserved in human AD and mouse TGs. Synaptosomes isolated from plaque-rich TG cortex had significantly higher GAD activity than those from plaque-free cerebellum or the cortex of wild-type littermates. Using tissue fractionation, this increased activity was localized to glial synaptosomes, suggesting that Aß plaques stimulate increased astrocyte GABA synthesis.

Neurites containing the neurofilament-triplet proteins are selectively vulnerable to cytoskeletal pathology in Alzheimer's disease and transgenic mouse models.

Amyloid-ß plaque accumulation in Alzheimer's disease (AD) is associated with dystrophic neurite (DN) formation and synapse loss in principal neurons, but interneuron pathology is less clearly characterized. We compared the responses of neuronal processes immunoreactive for either neurofilament triplet (NF(+)) or calretinin (CR(+)) to fibrillar amyloid (Aß) plaques in human end-stage and preclinical AD, as well as in APP/PS1 and Tg2576 transgenic mouse AD models. Neurites traversing the Aß plaque core, edge, or periphery, defined as 50, 100, and 150% of the plaque diameter, respectively, in human AD and transgenic mouse tissue were compared to age-matched human and wild-type mouse controls. The proportion of NF(+) neurites exhibiting dystrophic morphology (DN) was significantly larger than the proportion of dystrophic CR(+) neurites in both human AD and transgenic mice (p < 0.01). Additionally, the number of NF(+), but not CR(+), DNs, correlated with Aß plaque size. We conclude that CR(+) interneurons appear to be more resistant than NF(+) neurons to AD-mediated cytoskeletal pathology.

Cytoskeletal changes during development and aging in the cortex of neurofilament light protein knockout mice.

The neurofilament light (NFL) subunit is considered as an obligate subunit polymer for neuronal intermediate filaments comprising the neurofilament (NF) triplet proteins. We examined cytoskeletal protein levels in the cerebral cortex of NFL knockout (KO) mice at postnatal day 4 (P4), 5 months, and 12 months of age compared with age-matched wild-type (WT) mice of a similar genetic background (C57BL/6). The absence of NFL protein resulted in a significant reduction of phosphorylated and dephosphorylated NFs (NF-P, NF-DP), the medium NF subunit (NFM), and the intermediate filament α-internexin (INT) at P4. At 5 months, NF-DP, NFM, and INT remained significantly lower in knockouts. At 12 months, NF-P was again significantly decreased, and INT significantly increased, in KOs compared with wild type. In addition, protein levels of class III neuron-specific ß-tubulin and microtubule-associated protein 2 were significantly increased in NFL KO mice at P4, 5 months, and 12 months, whereas ß-actin levels were significantly decreased at P4. Immunocytochemical studies demonstrated that NF-DP accumulated abnormally in the perikarya of cortical neurons by 5 months of age in NFL KO mice. Neurons that lacked NF triplet proteins, such as calretinin-immunolabeled nonpyramidal cells, showed no alterations in density or cytoarchitectural distribution in NFL KO mice at 5 months relative to WT mice, although calretinin protein levels were decreased significantly after 12 months in NFL KO mice. These findings suggest that a lack of NFL protein alters the expression of cytoskeletal proteins and disrupts other NF subunits, causing intracellular aggregation but not gross structural changes in cortical neurons or cytoarchitecture. The data also indicate that changes in expression of other cytoskeletal proteins may compensate for decreased NFs.

Metallothionein (MT) -I and MT-II expression are induced and cause zinc sequestration in the liver after brain injury.

UNLABELLED: Experiments with transgenic over-expressing, and null mutant mice have determined that metallothionein-I and -II (MT-I/II) are protective after brain injury. MT-I/II is primarily a zinc-binding protein and it is not known how it provides neuroprotection to the injured brain or where MT-I/II acts to have its effects. MT-I/II is often expressed in the liver under stressful conditions but to date, measurement of MT-I/II expression after brain injury has focused primarily on the injured brain itself. In the present study we measured MT-I/II expression in the liver of mice after cryolesion brain injury by quantitative reverse-transcriptase PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) with the UC1MT antibody. Displacement curves constructed using MT-I/II knockout (MT-I/II(-/-)) mouse tissues were used to validate the ELISA. Hepatic MT-I and MT-II mRNA levels were significantly increased within 24 hours of brain injury but hepatic MT-I/II protein levels were not significantly increased until 3 days post injury (DPI) and were maximal at the end of the experimental period, 7 DPI. Hepatic zinc content was measured by atomic absorption spectroscopy and was found to decrease at 1 and 3 DPI but returned to normal by 7DPI. Zinc in the livers of MT-I/II(-/-) mice did not show a return to normal at 7 DPI which suggests that after brain injury, MT-I/II is responsible for sequestering elevated levels of zinc to the liver. CONCLUSION: MT-I/II is up-regulated in the liver after brain injury and modulates the amount of zinc that is sequestered to the liver.

Axonopathy and cytoskeletal disruption in degenerative diseases of the central nervous system.

There has been growing interest in the axon as the initial focus of pathological change in a number of neurodegenerative diseases of the central nervous system. This review concentrates on three major neurodegenerative conditions--amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer's disease--with emphasis on key cellular changes that may underlie early axonal dysfunction and pathology and, potentially, the degeneration of neurons. In particular, this review will address recent data that indicate that the main pathological stimuli for these conditions, though often not definitively determined, result in an initial perturbation of the axon and its cytoskeleton, which then results in slow neuronal degeneration and loss of connectivity. The identification of a degenerative process initiated in the axon may provide new therapeutic targets for early intervention to inhibit the grim outcomes related to the progression of these diseases.

When brains expand: mind and the evolution of cortex.

OBJECTIVE: To critically examine the relationship between evolutionary and developmental influences on human neocortex and the properties of the conscious mind it creates. METHODS: Using PubMed searches and the bibliographies of several monographs, we selected 50 key works, which offer empirical support for a novel understanding of the organization of the neocortex. RESULTS: The cognitive gulf between humans and our closest primate relatives has usually been taken as evidence that our brains evolved crucial new mechanisms somehow conferring advanced capacities, particularly in association areas of the neocortex. In this overview of neocortical development and comparative brain morphometry, we propose an alternative view: that an increase in neocortical size, alone, could account for novel and powerful cognitive capabilities. Other than humans' very large brain in relation to the body weight, the morphometric relations between neocortex and all other brain regions show remarkably consistent exponential ratios across the range of primate species, including humans. For an increase in neocortical size to produce new abilities, the developmental mechanisms of neocortex would need to be able to generate an interarchy of functionally diverse cortical domains in the absence of explicit specification, and in this respect, the mammalian neocortex is unique: its relationship to the rest of the nervous system is unusually plastic, allowing great changes in cortical organization to occur in relatively short periods of evolution. The fact that even advanced abilities like self-recognition have arisen in species from different mammalian orders suggests that expansion of the neocortex quite naturally generates new levels of cognitive sophistication. Our cognitive and behavioural sophistication may, therefore, be attributable to these intrinsic mechanisms' ability to generate complex interarchies when the neocortex reaches a sufficient size. CONCLUSION: Our analysis offers a parsimonious explanation for key properties of the human mind based on evolutionary influences and developmental processes. This view is perhaps surprising in its simplicity, but offers a fresh perspective on the evolutionary basis of mental complexity.