The organization of connectivity in neuronal networks is fundamental to understanding the activity and function of neural networks and information processing in the brain. Recent studies show that the neocortex is not only organized in columns and layers but also, within these, into synaptically connected clusters of neurons (Ko et al., 2011; Perin et al., 2011). The recently discovered common neighbor rule, according to which the probability of any two neurons being synaptically connected grows with the number of their common neighbors, is an organizing principle for this local clustering. Here we investigated the theoretical constraints for how the spatial extent of neuronal axonal and dendritic arborization, heretofore described by morphological reach, the density of neurons and the size of the network determine cluster size and numbers within neural networks constructed according to the common neighbor rule. In the formulation we developed, morphological reach, cell density, and network size are sufficient to estimate how many neurons, on average, occur in a cluster and how many clusters exist in a given network. We find that cluster sizes do not grow indefinitely as network parameters increase, but tend to characteristic limiting values.
data driven modeling; neuronal assemblies; layer 5 pyramidal cell; layer 2 pyramidal cell; clustering
Embryonic development in mammals has evolved a platform for genomic conflict between mothers and embryos and, by extension, between maternal and paternal genomes. The evolutionary interests of the mother and embryo may be maximized through the promotion of sex-chromosome genes and imprinted alleles, resulting in the rapid evolution of postzygotic phenotypes preferential to either the maternal or paternal genome. In eutherian mammals, extraordinary in utero maternal investment in the brain, and neocortex especially, suggests that convergent evolution of an expanded mammalian neocortex along divergent lineages may be explained, in part, by parent-of-origin-linked gene expression arising from parent-offspring conflict. The influence of this conflict on neocortical development and evolution, however, has not been investigated at the genomic level. In this hypothesis and theory article, we provide preliminary evidence for positive selection in humans in the regions of two platforms of intragenomic conflict—chromosomes 15q11-q13 and X—and explore the potential relevance of cis-regulated imprinted domains to neocortical expansion in mammalian evolution. We present the hypothesis that maternal- and paternal-specific pressures on the developing neocortex compete intragenomically to influence neocortical expansion in mammalian evolution.
parent-offspring conflict; evolution; neocortex; genomic imprinting; X-chromosome; development; mammals
Expansion of the cortical gray matter in evolution has been accompanied by an even faster expansion of the subcortical white matter volume and by folding of the gray matter surface, events traditionally considered to occur homogeneously across mammalian species. Here we investigate how white matter expansion and cortical folding scale across species of rodents and primates as the gray matter gains neurons. We find very different scaling rules of white matter expansion across the two orders, favoring volume conservation and smaller propagation times in primates. For a similar number of cortical neurons, primates have a smaller connectivity fraction and less white matter volume than rodents; moreover, as the cortex gains neurons, there is a much faster increase in white matter volume and in its ratio to gray matter volume in rodents than in primates. Order-specific scaling of the white matter can be attributed to different scaling of average fiber caliber and neuronal connectivity in rodents and primates. Finally, cortical folding increases as different functions of the number of cortical neurons in rodents and primates, scaling faster in the latter than in the former. While the neuronal rules that govern gray and white matter scaling are different across rodents and primates, we find that they can be explained by the same unifying model, with order-specific exponents. The different scaling of the white matter has implications for the scaling of propagation time and computational capacity in evolution, and calls for a reappraisal of developmental models of cortical expansion in evolution.
white matter; number of neurons; allometry; brain size; cortical expansion; gyrification
Three-dimensional (3D) reconstruction of synaptic arrangement on a particular dendrite provides essential information regarding neuronal properties and neural microcircuits. Unconventional synapses are particularly good candidates for such steric attribution. In main and accessory olfactory bulbs (MOBs and AOBs), there are dendrodendritic reciprocal synapses (RSs) between excitatory projection neurons and inhibitory interneurons. Although the fine structure and configuration of these synapses have been investigated in MOB, their characteristics in AOB were unknown. In this study, we performed 3D AOB reconstruction using serial section transmission electron microscopy. We found numerous RSs on primary dendrites from glomeruli to mitral/tufted (MT) cell somas. These synapses formed between dendritic shafts of MT cells and large dendritic spines, or so-called gemmules, of granule (Gr) cells. This indicates that chemical signals received by a glomerulus are regulated in the primary dendrite of an MT cell before reaching its soma. In MOB, RSs are located on secondary dendrites and act as lateral and self-inhibiting following mitral cell depolarization. Our results indicate that AOB intrabulbar microcircuitry is quite different from that in the MOB.
dendrodendritic reciprocal synapses; dendritic spines; gemmules; self-inhibition; electron microscopy
The cerebellum plays a key role in the acquisition and execution of motor tasks whose physiological foundations were postulated on Purkinje cells' long-term depression (LTD). Numerous research efforts have been focused on understanding the cerebellum as a site of learning and/or memory storage. However, the controversy on which part of the cerebellum participates in motor learning, and how the process takes place, remains unsolved. In fact, it has been suggested that cerebellar cortex, deep cerebellar nuclei, and/or their combination with some brain structures other than the cerebellum are responsible for motor learning. Different experimental approaches have been used to tackle this question (cerebellar lesions, pharmacological agonist and/or antagonist of cerebellar neurotransmitters, virus tract tracings, etc.). One of these approaches is the study of spontaneous mutations affecting the cerebellar cortex and depriving it of its main input–output organizer (i.e., the Purkinje cell). In this review, we discuss the results obtained in our laboratory in motor learning of both Lurcher (Lc/+) and tambaleante (tbl/tbl) mice as models of Purkinje-cell-devoid cerebellum.
cerebellum; motor learning; Lurcher; tambaleante; Purkinje cells
The cerebellum is organized into parasagittal zones that control sensory-motor behavior. Although the architecture of adult zones is well understood, very little is known about how zones emerge during development. Understanding the process of zone formation is an essential step toward unraveling how circuits are constructed to support specific behaviors. Therefore, we focused this study on postnatal development to determine the spatial and temporal changes that establish zonal patterns during circuit formation. We used a combination of wholemount and tissue section immunohistochemistry in mice to show that the cytoskeletal protein neurofilament heavy chain (NFH) is a robust marker for postnatal cerebellar zonal patterning. The patterned expression of NFH is initiated shortly after birth, and compared to the domains of several known zonal markers such as zebrin II, HSP25, neurogranin, and phospholipase Cβ4 (PLCβ4), NFH does not exhibit transient expression patterns that are typically remodeled between stages, and the adult zones do not emerge after a period of uniform expression in all lobules. Instead, we found that throughout postnatal development NFH gradually reveals distinct zones in each cerebellar lobule. The boundaries of individual NFH zones sharpen over time, as zones are refined during the second and third weeks after birth. Double labeling with neurogranin and PLCβ4 further revealed that although the postnatal expression of NFH is spatially and temporally unique, its pattern of zones respects a fundamental and well-known molecular topography in the cerebellum. The dynamics of NFH expression support the hypothesis that adult circuits are derived from an embryonic map that is refined into zones during the first 3-weeks of life.
purkinje cells; patterning; topography; circuit; development
In the recent decades structural connectivity between Broca's area and the basal ganglia has been postulated in the literature, though no direct evidence of this connectivity has yet been presented. The current study investigates this connectivity using a novel diffusion-weighted imaging (DWI) fiber tracking method in humans in vivo. Our findings suggest direct connections between sub-regions of Broca's area and the anterior one-third of the putamen, as well as the ventral anterior nucleus of the thalamus. Thus, we are the first to provide a detailed account of inferred circuitry involving basal ganglia, thalamus, and Broca's area, which would be a prerequisite to substantiate their support of language processing.
Broca's area; basal ganglia; thalamus; diffusion-weighted imaging; connectivity
The medullary reticular formation contains large populations of inadequately described, excitatory interneurons that have been implicated in multiple homeostatic behaviors including breathing, viserosensory processing, vascular tone, and pain. Many hindbrain nuclei show a highly stereotyped pattern of localization across vertebrates suggesting a strong underlying genetic organization. Whether this is true for neurons within the reticular regions of hindbrain is unknown. Hindbrain neurons are derived from distinct developmental progenitor domains each of which expresses distinct patterns of transcription factors (TFs). These neuronal populations have distinct characteristics such as transmitter identity, migration, and connectivity suggesting developmentally expressed TFs might identify unique subpopulations of neurons within the reticular formation. A fate-mapping strategy using perinatal expression of reporter genes within Atoh1, Dbx1, Lmx1b, and Ptf1a transgenic mice coupled with immunohistochemistry (IHC) and in situ hybridization (ISH) were used to address the developmental organization of a large subset of reticular formation glutamatergic neurons. All hindbrain lineages have relatively large populations that extend the entire length of the hindbrain. Importantly, the location of neurons within each lineage was highly constrained. Lmx1b- and Dbx1- derived populations were both present in partially overlapping stripes within the reticular formation extending from dorsal to ventral brain. Within each lineage, distinct patterns of gene expression and organization were localized to specific hindbrain regions. Rostro-caudally sub-populations differ sequentially corresponding to proposed pseudo-rhombomereic boundaries. Dorsal-ventrally, sub-populations correspond to specific migratory positions. Together these data suggests the reticular formation is organized by a highly stereotyped developmental logic.
brainstem; transcription factors; reticular formation; fate-mapping; development; rhombomeres; hindbrain
Spinal inhibition is required to generate coordinated outputs between antagonistic muscles during locomotion. It relies on low neuronal chloride concentration set by two cation-chloride cotransporters, NKCC1 and KCC2 which, respectively, pumps Cl− in or out of neurons. It is generally accepted that NKCC1 is gradually inactivated during development, while KCC2 is upregulated and activated, resulting in low intracellular [Cl−]. Newborn opossums are very immature but perform rhythmic and alternate movements of the forelimbs to crawl on the mother's belly and attach to a teat. Their hindlimbs are immobile. The alternation of the forelimbs suggests that mechanisms allowing spinal inhibition are present at birth. We studied the anatomical basis of inhibition in the spinal enlargements of postnatal opossums by immunolocalizing NKCC1 and KCC2. In some specimens, motoneurons and sensory afferents were labeled with TRDA prior to immunolabeling. At birth, both NKCC1 and KCC2 are detected in the presumptive gray and white matter of the ventral and the intermediolateral cord of both enlargements, but are sparse in the dorsal horn, where KCC2 is mostly seen on a small bundle of dendrites along primary afferents. KCC2 labeling is bright and has a mesh-like appearance in the gray matter and a radial appearance in the white matter, whereas NKCC1 is pale and diffuse. The subsequent expression of the cotransporters follows general ventrodorsal and mediolateral gradients, with the lumbar segments slightly lagging the cervical segments, until the mature pattern is observed around the 5th week. At all ages studied, KCC2 labeling is strong in the periphery of neurons. NKCC1 labeling decreases and becomes more uniformly distributed in the cells with age. Despite the significant anatomical and motor differences between the forelimbs and the hindlimbs of neonatal opossums, the maturation of KCC2 and NKCC1 is quite similar in both enlargements.
cation-chloride cotransporters; development; inhibition; locomotion; marsupial; motoneurons; spinal cord
Projections from auditory cortex (AC) can alter the responses of cells in the inferior colliculus (IC) to sounds. Most IC cells show excitation and inhibition after stimulation of the AC. AC axons release glutamate and excite their targets, so inhibition is presumed to result from cortical activation of GABAergic IC cells that inhibit other IC cells via local projections. However, it is not known whether cortical axons contact GABAergic IC cells directly. We labeled corticocollicular axons by injecting fluorescent dextrans into the AC in guinea pigs. We visualized the tracer with diaminobenzidine and processed the tissue for electron microscopy. We identified presumptive GABAergic profiles with post-embedding anti-GABA immunogold histochemistry on ultrathin sections. We identified dextran-labeled cortical boutons in the IC and identified their postsynaptic targets according to morphology (e.g., spine, dendrite) and GABA-reactivity. Cortical synapses were observed in all IC subdivisions, but were comparatively rare in the central nucleus. Cortical boutons contain round vesicles and few mitochondria. They form asymmetric synapses with spines (most frequently), dendritic shafts and, least often, with cell bodies. Excitatory boutons in the IC can be classified as large, medium or small; most cortical boutons belong to the small excitatory class, while a minority (~14%) belong to the medium excitatory class. Approximately 4% of the cortical targets were GABA-positive; these included dendritic shafts, spines, and cell bodies. We conclude that the majority of cortical boutons contact non-GABAergic (i.e., excitatory) IC cells and a small proportion (4%) contact GABAergic cells. Given that most IC cells show inhibition (as well as excitation) after cortical stimulation, it is likely that the majority of cortically-driven inhibition in the IC results from cortical activation of a relatively small number of IC GABAergic cells that have extensive local axons.
corticofugal pathways; inferior colliculi; auditory cortex; bouton classification; ultrastructural variations; synaptic targets
Trigeminal primary afferent fibers have small receptive fields and discrete submodalities, but second order trigeminal neurons often display larger receptive fields with complex, multimodal responses. Moreover, while most large caliber afferents terminate exclusively in the principal trigeminal nucleus, and pars caudalis (sVc) of the spinal trigeminal nucleus receives almost exclusively small caliber afferents, the characteristics of second order neurons do not always reflect this dichotomy. These surprising characteristics may be due to a network of intratrigeminal connections modifying primary afferent contributions. This study characterizes the distribution and morphology of intratrigeminal cells and axons in a macaque monkeys. Tracer injections centered in the principal nucleus (pV) and adjacent pars oralis retrogradely labeled neurons bilaterally in pars interpolaris (sVi), but only ipsilaterally, in sVc. Labeled axons terminated contralaterally within sVi and caudalis. Features of the intratrigeminal cells in ipsilateral sVc suggest that both nociceptive and non-nociceptive neurons project to principalis. A commissural projection to contralateral principalis was also revealed. Injections into sVc labeled cells and terminals in pV and pars oralis on both sides, indicating the presence of bilateral reciprocal connections. Labeled terminals and cells were also present bilaterally in sVi and in contralateral sVc. Interpolaris injections produced labeling patterns similar to those of sVc. Thus, the rostral and caudal poles of the macaque trigeminal complex are richly interconnected by ipsilateral ascending and descending connections providing an anatomical substrate for complex analysis of oro-facial stimuli. Sparser reciprocal crossed intratrigeminal connections may be important for conjugate reflex movements, such as the corneal blink reflex.
trigeminal; somatosensory; face; oro-facial reflexes; blink
This study presents a tool, Neuronize, for building realistic three-dimensional models of neuronal cells from the morphological information extracted through computer-aided tracing applications. Neuronize consists of a set of methods designed to build 3D neural meshes that approximate the cell membrane at different resolution levels, allowing a balance to be reached between the complexity and the quality of the final model. The main contribution of the present study is the proposal of a novel approach to build a realistic and accurate 3D shape of the soma from the incomplete information stored in the digitally traced neuron, which usually consists of a 2D cell body contour. This technique is based on the deformation of an initial shape driven by the position and thickness of the first order dendrites. The addition of a set of spines along the dendrites completes the model, building a final 3D neuronal cell suitable for its visualization in a wide range of 3D environments.
pyramidal cells; virtual dendrites; morphology simulation; dendritic structure; 3D models; multiresolution visualization approach
Previous investigations indicate that the superior colliculus (SC) is involved in the initiation and execution of forelimb movements. In the present study we investigated the tectofugal, in particular the tecto-reticulo-spinal projections to the shoulder and arm muscles in the rat. We simultaneously retrogradely labeled the premotor neurons in the brainstem by injection of the pseudorabies virus PrV Bartha 614 into the m. rhomboideus minor and m. acromiodeltoideus, and anterogradely visualized the tectofugal projections by intracollicular injection of the tracer FITC dextrane. Our results demonstrate that the connection of the SC to the skeletal muscles of the forelimb is at least trisynaptic. This was confirmed by long survival times after virus injections into the muscles (98–101 h) after which numerous neurons in the deep layers of the SC were labeled. Transsynaptically retrogradely labeled brainstem neurons connected disynaptically to the injected muscles with adjacent tectal terminals were predominantly located in the gigantocellular nuclear complex of the reticular formation. In addition, putative relay neurons were found in the caudal part of the pontine reticular nucleus. Both tectal projections to the nucleus gigantocellularis and the pontine reticular nucleus were bilateral but ipsilaterally biased. We suggest this projection to be involved in more global functions in motivated behavior like general arousal allowing fast voluntary motor activity.
superior colliculus; m. rhomboideus; m. acromiodeltoideus; m. trapezius; pseudorabies virus; forelimb movements
Gyrencephaly (the folding of the surface of the neocortex) is a mammalian-specific trait present in almost all mammalian orders. Despite the widespread appearance of the trait, little is known about the mechanism of its genesis or its adaptive significance. Still, most of the hypotheses proposed concentrated on the pattern of connectivity of mature neurons as main components of gyri formation. Recent work on embryonic neurogenesis in several species of mammals revealed different progenitor and stem cells and their neurogenic potential as having important roles in the process of gyrification. Studies in the field of comparative neurogenesis revealed that gyrencephaly is an evolutionarily labile trait, and that some species underwent a secondary loss of a convoluted brain surface and thus reverted to a more ancient form, a less folded brain surface (lissencephaly). This phenotypic reversion provides an excellent system for understanding the phenomenon of secondary loss. In this review, we will outline the theory behind secondary loss and, as specific examples, present species that have undergone this transition with respect to neocortical folding. We will also discuss different possible pathways for obtaining (or losing) gyri. Finally, we will explore the potential adaptive consequence of gyrencephaly relative to lissencephaly and vice versa.
brain evolution; neocortex; lissencephaly; gyrencephaly; reverse evolution
Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering, and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification, and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.
rostral hindbrain; caudal mesencephalon; cerebellum; isthmus; isthmic organizer; isthmic constriction; Fgf8; morphogenesis
Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone (AZ) and the postsynaptic density (PSD), as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM), and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the AZ and the PSD are in close apposition and have a similar surface area, they can be represented by a single surface—the synaptic apposition surface (SAS). We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret's diameter.
chemical synapses; three-dimensional; electron microscopy; active zone; postsynaptic density; surface extraction; data preprocessing; data visualization
Adult neurogenesis in mammals is predominantly restricted to two brain regions, the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), suggesting that these two brain regions uniquely share functions that mediate its adaptive significance. Benefits of adult neurogenesis across these two regions appear to converge on increased neuronal and structural plasticity that subserves coding of novel, complex, and fine-grained information, usually with contextual components that include spatial positioning. By contrast, costs of adult neurogenesis appear to center on potential for dysregulation resulting in higher risk of brain cancer or psychological dysfunctions, but such costs have yet to be quantified directly. The three main hypotheses for the proximate functions and adaptive significance of adult neurogenesis, pattern separation, memory consolidation, and olfactory spatial, are not mutually exclusive and can be reconciled into a simple general model amenable to targeted experimental and comparative tests. Comparative analysis of brain region sizes across two major social-ecological groups of primates, gregarious (mainly diurnal haplorhines, visually-oriented, and in large social groups) and solitary (mainly noctural, territorial, and highly reliant on olfaction, as in most rodents) suggest that solitary species, but not gregarious species, show positive associations of population densities and home range sizes with sizes of both the hippocampus and OB, implicating their functions in social-territorial systems mediated by olfactory cues. Integrated analyses of the adaptive significance of adult neurogenesis will benefit from experimental studies motivated and structured by ecologically and socially relevant selective contexts.
adult neurogenesis; adaptive significance; evolution; pattern separation; olfaction
The importance of thyroid hormones during brain development has been appreciated for many decades. In humans, low levels of circulating maternal thyroid hormones, e.g., caused by maternal hypothyroidism or lack of iodine in diet, results in a wide spectrum of severe neurological defects, including neurological cretinism characterized by profound neurologic impairment and mental retardation, underlining the importance of the maternal thyroid hormone contribution. In fact, iodine intake, which is essential for thyroid hormone production in the thyroid gland, has been related to the expansion of the brain, associated with the increased cognitive capacities during human evolution. Because thyroid hormones regulate transcriptional activity of target genes via their nuclear thyroid hormone receptors (THRs), even mild and transient changes in maternal thyroid hormone levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Here we summarize how thyroid hormones may have influenced human brain evolution through the adaptation to new habitats, concomitant with changes in diet and, therefore, iodine intake. Further, we review the current picture we gained from experimental studies in rodents on the function of maternal thyroid hormones during developmental neurogenesis. We aim to evaluate the effects of maternal thyroid hormone deficiency as well as lack of THRs and transporters on brain development and function, shedding light on the cellular behavior conducted by thyroid hormones.
human brain evolution; developmental neurogenesis; cretinism; thyroid hormones; maternal hypothyroxinemia
Ketamine, a known antagonist of N-methyl-D-aspartic (NMDA) glutamate receptors, had been used as an anesthetic particularly for pediatric or for cardiac patients. Unfortunately, ketamine has become an abusive drug in many parts of the world while chronic and prolonged usage led to damages of many organs including the brain. However, no studies on possible damages in the brains induced by chronic ketamine abuse have been documented in the human via neuroimaging. This paper described for the first time via employing magnetic resonance imaging (MRI) the changes in ketamine addicts of 0.5–12 years and illustrated the possible brain regions susceptible to ketamine abuse. Twenty-one ketamine addicts were recruited and the results showed that the lesions in the brains of ketamine addicts were located in many regions which appeared 2–4 years after ketamine addiction. Cortical atrophy was usually evident in the frontal, parietal or occipital cortices of addicts. Such study confirmed that many brain regions in the human were susceptible to chronic ketamine injury and presented a diffuse effect of ketamine on the brain which might differ from other central nervous system (CNS) drugs, such as cocaine, heroin, and methamphetamine.
ketamine; addiction; brain; lesion; atrophy; magnetic resonance imaging (MRI)
The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal–fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by “non-classical” endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict.
cerebral cortex development; placenta; maternal–fetal unit; evolution; serotonin; eutherians; transcriptome
Noise overexposure may induce permanent noise-induced hearing loss (NIHL). The cochlear nucleus complex (CNC) is the entry point for sensory information in the central auditory system. Impairments in gamma-aminobutyric acid (GABA)—mediated synaptic transmission in the CNC have been implicated in the pathogenesis of auditory disorders. However, the role of protein kinase C (PKC) signaling pathway in GABAergic inhibition in the CNC in NIHL remains elusive. Thus, we investigated the alterations of glutamic acid decarboxylase 67 (GAD67, the chemical marker for GABA-containing neurons), PKC γ subunit (PKCγ) and GABAB receptor (GABABR) expression in the CNC using transgenic GAD67-green fluorescent protein (GFP) knock-in mice, BALB/c mice and C57 mice. Immunohistochemical results indicate that the GFP-labeled GABAergic neurons were distributed in the molecular layer (ML) and fusiform cell layer (FCL) of the dorsal cochlear nucleus (DCN). We found that 69.91% of the GFP-positive neurons in the DCN were immunopositive for both PKCγ and GABABR1. The GAD67-positive terminals made contacts with PKCγ/GABABR1 colocalized neurons. Then we measured the changes of auditory thresholds in mice after noise exposure for 2 weeks, and detected the GAD67, PKCγ, and GABABR expression at mRNA and protein levels in the CNC. With noise over-exposure, there was a reduction in GABABR accompanied by an increase in PKCγ expression, but no significant change in GAD67 expression. In summary, our results demonstrate that alterations in the expression of PKCγ and GABABRs may be involved in impairments in GABAergic inhibition within the CNC and the development of NIHL.
CNC; GABA; GABABR; PKCγ; GAD67-GFP knock-in mice
During neocortical development, excitatory neurons are produced from apical progenitors in the ventricular zone (VZ) or from dividing cells in the subventricular zone (SVZ). We previously reported that the direct progenies of VZ cells in mice slowly exit the VZ and accumulate just above the VZ (lower SVZ) as multipolar migrating neurons, whereas subsequently dividing cells in the SVZ exit the VZ earlier than the former and become widely distributed in the SVZ. These two populations are named the slowly exiting population (SEP) and the rapidly exiting population (REP), respectively. In mice, REP cells include basal progenitors as the major population and are characterized by a long ascending process; their morphology resembles that of basal radial glial cells (bRGs), which have been observed in the inner and outer SVZ in primates. The dramatic increase in the number of bRGs in primates, especially in humans, is thought to underlie the acquisition of a huge cortex during evolution. We previously reported that the REP/SEP production rate in the lateral cortical VZ is higher than that in the dorsomedial VZ in mice. To search for molecules responsible for the higher REP production in the lateral cortical VZ, we conducted microarray analyses and identified genes that were differentially expressed between the lateral and medial VZs in mice. These genes were considered to be among the candidates responsible for the regulation of the REP/SEP production rate. To investigate the selection pressures during primate evolution on these candidate genes, we estimated the synonymous vs. non-synonymous base substitution rates. As a result, the negative selection pressures on the Megf11, Dmrt3, and Cntn3 genes were found to be significantly weaker in primates than in non-primates, while those on Jag1, Ntrk2, and Pmp22 were stronger. Candidate molecules responsible for primate cortical expansion through an increase in bRGs may be included among these genes.
neural stem cells; human evolution; notch signaling; selection bias; subventricular zone (SVZ)
We investigated effects of sign language use and auditory deprivation from birth on the volumes of three cortical regions of the human brain: the visual cortex surrounding the calcarine sulcus in the occipital lobe; the language-related cortex in the inferior frontal gyrus (pars triangularis and pars opercularis); and the motor hand region in the precentral gyrus. The study included 25 congenitally deaf participants and 41 hearing participants (of which 16 were native sign language users); all were right-handed. Deaf participants exhibited a larger calcarine volume than hearing participants, which we interpret as the likely result of cross-modal compensation and/or dynamic interactions within sensory neural networks. Deaf participants also had increased volumes of the pars triangularis bilaterally compared to hearing signers and non-signers, which we interpret is related to the increased linguistic demands of speech processing and/or text reading for deaf individuals. Finally, although no statistically significant differences were found in the motor hand region for any of the groups, the deaf group was leftward asymmetric, the hearing signers essentially symmetric and the hearing non-signers were rightward asymmetric – results we interpret as the possible result of activity-dependent change due to life-long signing. The brain differences we observed in visual, motor, and language-related areas in adult deaf native signers provide evidence for the plasticity available for cognitive adaptation to varied environments during development.
deaf; sign language; inferior frontal gyrus; motor hand region; calcarine; morphometry