Differential Functional Constraints on the Evolution of Postsynaptic Density Proteins in Neocortical Laminae

The postsynaptic density (PSD) is a protein dense complex on the postsynaptic membrane of excitatory synapses that is implicated in normal nervous system functions such as synaptic plasticity, and also contains an enrichment of proteins involved in neuropsychiatric disorders. It has recently been reported that the genes encoding PSD proteins evolved more slowly than other genes in the human brain, but the underlying evolutionary advantage for this is not clear. Here, we show that cortical gene expression levels could explain most of this effect, indicating that expression level is a primary contributor to the evolution of these genes in the brain. Furthermore, we identify a positive correlation between the expression of PSD genes and cortical layers, with PSD genes being more highly expressed in deep layers, likely as a result of layer-enriched transcription factors. As the cortical layers of the mammalian brain have distinct functions and anatomical projections, our results indicate that the emergence of the unique six-layered mammalian cortex may have provided differential functional constraints on the evolution of PSD genes. More superficial cortical layers contain PSD genes with less constraint and these layers are primarily involved in intracortical projections, connections that may be particularly important for evolved cognitive functions. Therefore, the differential expression and evolutionary constraint of PSD genes in neocortical laminae may be critical not only for neocortical architecture but the cognitive functions that are dependent on this structure

Adolescent brain maturation and cortical folding: evidence for reductions in gyrification

Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development

Developmental Patterns of Doublecortin Expression and White Matter Neuron Density in the Postnatal Primate Prefrontal Cortex and Schizophrenia

Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC). Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX), a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque) and density of white matter neurons (humans) during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37) and matched controls (n = 37) and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in schizophrenia

Origins of Cortical GABAergic Neurons in the Cynomolgus Monkey

In human most cortical γ-aminobutyric acidergic (GABAergic) neurons are produced in the proliferative zones of the dorsal telencephalon in contrast to rodents. We report that in cynomolgus monkey fetuses cortical GABAergic neurons are generated in the proliferative zones of the dorsal telencephalon, in addition to the proliferative region of the ventral telencephalon, the ganglionic eminence (GE), however, with a temporal delay. GABAergic neuron progenitors labeled for Mash1 and GAD65 were present mainly in the GE at embryonic days (E) 47–55, and in the entire dorsal telencephalon at E64–75. These progenitors within the dorsal telencephalon are generated locally rather than in the GE. The ventral and dorsal lineages of cortical GABAergic neurons display different laminar distribution. Early generated GABAergic neurons from the GE mostly populate the marginal zone and subplate, whereas cortical plate GABAergic neurons originate from both ventral and dorsal telencephalon. A differential regulation of the two GABA synthesizing enzymes (GAD65 and GAD67) parallels GABAergic neuron differentiation. GAD65 is preferentially expressed in GABAergic progenitors and migrating neurons, GAD67 in morphologically differentiated neurons. Therefore, the dorsal telencephalic origin of cortical GABAergic neurons is not human-specific but appears as a former event in the ascent of evolution that could provide GABAergic neurons to an expending neocortex

Executive function and IQ predict mathematical and attention problems in very preterm children

Objective of this study was to examine the impact of executive function (EF) on mathematical and attention problems in very preterm (gestational age ≤ 30 weeks) children. Participants were 200 very preterm (mean age 8.2 ± 2.5 years) and 230 term children (mean age 8.3 ± 2.3 years) without severe disabilities, born between 1996 and 2004. EFs assessed included verbal fluency, verbal working memory, visuospatial span, planning, and impulse control. Mathematics was assessed with the Dutch Pupil Monitoring System and parents and teachers rated attention problems using standardized behavior questionnaires. The impact of EF was calculated over and above processi

Extending Epigenesis: From Phenotypic Plasticity to the Bio-Cultural Feedback

The paper aims at proposing an extended notion of epigenesis acknowledging an actual causal import to the phenotypic dimension for the evolutionary diversification of life forms. Section 1 offers introductory remarks on the issue of epigenesis contrasting it with ancient and modern preformationist views. In Section 2 we propose to intend epigenesis as a process of phenotypic formation and diversification a) dependent on environmental influences, b) independent of changes in the genomic nucleotide sequence, and c) occurring during the whole life span. Then, Section 3 focuses on phenotypic plasticity and offers an overview of basic properties (like robustness, modularity and degeneracy) that allows biological systems to be evolvable – i.e. to have the potentiality of producing phenotypic variation. Successively (Section 4), the emphasis is put on environmentally-induced modification in the regulation of gene expression giving rise to phenotypic variation and diversification. After some brief considerations on the debated issue of epigenetic inheritance (Section 5), the issue of culture (kept in the background of the preceding sections) is considered. The key point is that, in the case of humans and of the evolutionary history of the genus Homo at least, the environment is also, importantly, the cultural environment. Thus, Section 6 argues that a bio-cultural feedback should be acknowledged in the “epigenic” processes leading to phenotypic diversification and innovation in Homo evolution. Finally, Section 7 introduces the notion of “cultural neural reuse”, which refers to phenotypic/neural modifications induced by specific features of the cultural environment that are effective in human cultural evolution without involving genetic changes. Therefore, cultural neural reuse may be regarded as a key instance of the bio-cultural feedback and ultimately of the extended notion of epigenesis proposed in this work

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.GB Rogers, DJ Keating, RL Young, M-L Wong, J Licinio, and S Wesseling

Neuronal migration and cortical migratory disorders

U ovom radu pružili smo pregled spoznaja o neurobiološkoj osnovi poremećaja migracije koja je važna za njihovu klasifikaciju. Kortikalni neuroni rađaju se u ventrikularnoj i subventrikularnoj zoni te prolaze dugačak put do svojeg konačnog odredišta, rabeći dva osnovna mehanizma i puta migracije: (1) radijalnu migraciju, put uzduž radijalne glije i (2) tangencijalnu, najvjerojatnije “neurofilnu” migraciju. Tijek migracije je složen i može biti poremećen utjecajem različitih genetskih i vanjskih čimbenika. Poremećaj proliferacije u ventrikularnoj zoni dovodi do značajnih malformacija, kao što je shizencefalija, a poremećaj samog početka migracije uslijed genetskih abnormalnosti (mutacija FILAMIN1 gena) dovodi do periventrikularne nodularne heterotopije i strukturnih promjena vidljivih na slikovnim prikazima magnetskom rezonancijom (MRI). Tipični poremećaj migracije je lizencefalija tipa 1 koja se trenutno ubraja u spektar poremećaja agirija-pahigirija-„band“ heterotopija. Ova skupina poremećaja uzrokovana je mutacijama gena LIS1 i DCX (XLIS), a povezana je s Miller-Diekerovim, Lennox-Gastaut sindromom i epilepsijom. Poremećaji kasnijih faza migracije uzrokuju lizencefaliju tipa 2 (kompleks ”cobblestone”), koja je povezana s Walker-Warburgovim sindromom, makrocefalijom, malformacijom mrežnice, poremećajem mišić-oko-mozak i Fukuyama kongenitalnom mišićnom distrofijom. Zellwegerov sindrom je karakteriziran patomorfološki polimikrogirijom i biokemijski grješkom mithondrijskih putova desaturacije. Poremećaji kasne migracije pokazuju strukturne promjene vidljive MRI-om, koje su ograničene na moždanu koru. Drugi migracijski poremećaj, fokalna kortikalna displazija, često je prisutna kod rezistentnih oblika epilepsije, a kod dijagnostike je od posebne koristi MRI visoke rezolucije (3T). Genetski testovi zajedno s MRI-om otvaraju nove mogućnosti za ranu dijagnostiku i poboljšani pristup u liječenju poremećaja migracije.In this review we outline the neurobiological basis for classification of cortical migratory disorders. Neurons of the human cortex are born in the ventricular and subventricular zone and migrate for a long distance to reach their final point of destination in the cortex, using two types of migratory routes and mechanisms: (1) radial migration along radial glia and (2) tangential, presumably “neurophilic” migration. The process of migration is complex and may be disturbed by various genetic and extrinsic factors. The disturbances of proliferation in the ventricular zone result in major malformations such as schizencephaly, while the failure of onset of migration results in periventricular nodular heterotopia with characteristic abnormalities in magnetic resonance imaging (MRI) and with genetic aberration in the background (FILAMIN1 gene mutation). The typical migratory disorder is lissencephaly type I caused by defect of ongoing migration. The lissencephaly type I is currently included in agyria-pachigyria band spectrum disorders. This group of disorders is caused by mutations of LIS1 and DCX (XLIS) gene mutations associated with Miller-Dieker syndrome, Lennox-Gastaut syndrome and epilepsy. The defects of late phases of migration cause lissencephaly type II, cobblestone complex, which is associated with Walker-Warburg syndrome, macrocephaly, retinal malformation, muscle-eye-brain disease and Fukuyama congenital muscular dystrophy. Zellweger syndrome is morphologically characterized by polymicrogyria and biochemically by defects of the mitochondrial desaturation pathway. The disorders with later migration failure show abnormal MRI restricted to the cortex. Another migratory disorder, focal cortical dysplasia, is a frequent cause of drug resistant epilepsy. An especially helpful diagnostic tool for migratory disorders is high resolution (3T) MRI. Genetic testing together with detailed MRI of migratory disorders opens new perspectives for early detection and improved treatment of migratory disorders