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Background Although cerebellar morphological involvement has been increasingly recognized in autism spectrum disorder (ASD) and schizophrenia (SZ), the extent to which there are morphological differences between them has not been definitively quantified. Furthermore, although previous studies have demonstrated increased anatomical cerebellocerebral correlations in both conditions, differences between their associations have not been well characterized. Methods We compared cerebellar volume between males with ASD (n = 31), males with SZ (n = 28), and typically developing males (n = 49). A total of 31 cerebellar subregions were investigated with the cerebellum segmented into their constituent lobules, in gray matter (GM) and white matter (WM) separately. Additionally, structural correlations with the contralateral cerebrum were analyzed for each cerebellar lobule. Results We found significantly larger WM volume in the bilateral lobules VI and Crus I in the ASD group than in other groups. While WM or GM volumes of these right lobules had positive associations with ASD symptoms, there was a negative association between GM volume of the right Crus I and SZ symptoms. We further observed, in the ASD group specifically, significant correlations between WM of the right lobule VI and WM of the left frontal pole (r = 0.67) and between GM of the right lobule VI and the left caudate (r = 0.60). Conclusions Our findings support evidence that cerebellar morphology is involved in ASD and SZ with different mechanisms. Furthermore, this study showed that these biological differences require consideration when determining diagnostic criteria and treatment for these disorders.

Summary Angelman syndrome is a complex neurodevelopmental disorder characterized by delayed development, intellectual disability, speech impairment, and ataxia. It results from the loss of UBE3A protein, an E3 ubiquitin ligase, in neurons of the brain. Despite the dynamic spatiotemporal expression of UBE3A observed in rodents and the potential clinical importance of when and where it is expressed, its expression pattern in humans remains unknown. This reflects a common challenge of studying human neurodevelopment: prenatal periods are hard to access experimentally. In this work, human cerebral organoids reveal a change from weak to strong UBE3A in neuronal nuclei within 3 weeks of culture. Angelman syndrome human induced pluripotent stem cell-derived organoids also exhibit early silencing of paternal UBE3A, with topoisomerase inhibitors partially rescuing UBE3A levels and calcium transient phenotypes. This work establishes human cerebral organoids as an important model for studying UBE3A and motivates their broader use in understanding complex neurodevelopmental disorders., Graphical Abstract, Highlights • UBE3A signals in neuronal nuclei in hCOs correlate to early stages of development • UBE3A exhibits a change from weakly to strongly nuclear in cortical layers • UBE3A is imprinted and aberrantly localized in Angelman syndrome hCOs • Topoisomerase inhibitors partially rescue UBE3A and neuronal function in AS hCOs, In this article Keung and colleagues use human cerebral organoids to show that important spatiotemporal dynamics of the imprinted gene UBE3A occur early in human neurodevelopment. Organoids exhibit stronger UBE3A in the neuronal nuclei within 3 weeks and imprinting of paternal UBE3A within 6 weeks of culture, with topoisomerase inhibitors partially rescuing UBE3A and neuronal function in Angelman syndrome organoids.

During domestication, many different chicken breeds have been developed that show many alterations compared with their wild ancestors and large variability in parameters such as body size, coloring, behavior, and even brain morphology. Among the breeds, one can differentiate between commercial and noncommercial strains, and commercial strains do not usually show variability as high as noncommercial breeds but exhibit a high production rate of eggs (or meat). The breeding of high-performing laying hens, including the housing conditions of hens, is often a focus of concern for animal welfare, and to date, little is known about the correlation between housing conditions and artificial selection on brain structure. Based on an allometric approach, we compared the relative brain sizes of 2 inbred strains of laying hens (WLA and R11) with those of 7 other noncommercial chicken breeds. In addition, we examined the brain composition of laying hens and analyzed the relative sizes of the telencephalon, hippocampus, tectum opticum, and cerebellum. Half of WLA and R11 lines were kept in floor-housing systems, and the other half were kept in a single cage-housing system. Both strains of laying hens showed significantly smaller brains than the other chicken breeds. In addition, there was a significant difference between WLA and R11 hens, with R11 hens having larger brains. There was no difference in the relative brain sizes of floor-housed and cage-housed hens. WLA and R11 hens did not differ in their brain composition, but floor-housed hens showed a significantly larger cerebellum than cage-housed hens. Apparently, pure breeding over a long time and strong artificial selection for a high production of eggs is accompanied by (unintentional) selection for smaller brains. Further studies may also reveal differences in brain composition and the influence of housing conditions on brain composition.

Ischemic stroke is associated with several neurodegenerative factors, which are exacerbated further during reperfusion. Increased iron storage in the brain also contributes to stroke progression and worsens the outcome with the induction of oxidative stress and inflammation. Further, several clinical studies have demonstrated that disease susceptibility, response to infection and inflammation, worsen with increased iron levels. So, in the present study, the iron levels were assessed using atomic absorption spectroscopy and Prussian blue staining in the brain and retina of the rats post ischemic insult. The retinal alterations were also assessed as retina is a projection of the CNS. The expressions of the regulatory genes of iron homeostasis were estimated in the cerebrum. In addition to it, the BBB disruption due to iron overload and oxidative stress, were measured. The iron levels were found to be significantly higher in the cortical and hippocampal regions leading to the appearance of iron deposits and cellular damage in retina post ischemic injury. In the current study the protective role of apocynin, a NADPH oxidase assembly inhibitor, was assessed against the alterations induced by disturbed iron homeostasis post cerebral ischemia. Apocynin supplementation was able to maintain the iron homeostasis in the brains of ischemic rats through the normalization of the gene expressions of regulatory genes and restoration of the BBB integrity. The decline in the iron levels in the brain after apocynin supplementation also prevented the appearance of iron deposits and cellular damage in the retina during the states of cerebral ischemia.

Summary Thalidomide is a teratogen that causes multiple malformations in the developing baby through its interaction with cereblon (CRBN), a substrate receptor subunit of the CRL4 E3 ubiquitin ligase complex. CRBN was originally reported as a gene associated with autosomal recessive non-syndromic mild mental retardation. However, the function of CRBN during brain development remains largely unknown. Here we demonstrate that CRBN promotes brain development by facilitating the proliferation of neural stem cells (NSCs). Knockdown of CRBN in zebrafish embryos impaired brain development and led to small brains, as did treatment with thalidomide. By contrast, overexpression of CRBN resulted in enlarged brains, leading to the expansion of NSC regions and increased cell proliferation in the early brain field and an expanded expression of brain region-specific genes and neural and glial marker genes. These results demonstrate that CRBN functions in the determination of brain size by regulating the proliferation of NSCs during development., Graphical Abstract, Highlights • CRBN is a determinant of head and brain size during zebrafish development • Thalidomide causes a reduction in head and brain size by binding to CRBN • CRBN prevents apoptosis and promotes NSC proliferation during brain development • crbn overexpression results in a concomitant increase in neurons and glial cells, Cellular Neuroscience; Developmental Neuroscience; Molecular Neuroscience

Holoprosencephaly (HPE) is a birth defect that occurs during the first weeks of pregnancy and as a result the prosencephalon does not clearly divide in diencephalon, two halves of the telencephalon and lateral ventricles in the brain of the fetus and, in general, HPE is accompanied by facial defects. There are three main types of holoprosencephaly according to severity; alobar, semi-lobar and lobar. We report here a case that could be defined as a semi-lobar form of HPE with hydrocephalus and scarce facial malformations. Keywords: Human foetus, Holoprosencephaly, Brain malformation, Facial defects

Cerebellar connectivity with the cerebrum is formed during early fetal stages, but details about its development are scarce. Most of what we know today comes from animal studies that address the relationship between early activity patterns found in the cerebellothalamocortical tract and its functional maturation. In humans, cerebellar disruption early in life has been associated with various neurodevelopmental disorders and the occurrence of epilepsy, urging the field to investigate the critical periods of cerebellothalamocortical tract development. Abnormal cerebellothalamocortical tract connectivity has been correlated with abnormal neuronal activity, such as hypersynchronicity. In various rodent models, it has been shown that the cerebellothalamocortical tract is a key player in motor and nonmotor functioning. This chapter provides an up-to-date overview of the experimental and clinical work regarding the developmental code of the cerebellothalamocortical tract and can be utilized to guide novel studies developing therapeutic strategies for neurodevelopmental disorders, epilepsy and possibly other neurological disorders.

The appearance of the first cases of microcephaly related to the Zika virus (ZIKV) and the massive dissemination of the congenital syndrome have required the investigation of the CNS function in the vertically infected population. In the congenital ZIKV syndrome, swallowing dysphagia and the thinning of the brainstem detected in MRI images were described and justified a study on the implication level of the brainstem in the syndrome. Aiming to shed light on this question, we studied the auditory function in microcephalic children by short-latency brainstem auditory evoked potentials (BAEPs), the most sensitive method for describing topographic alterations in the brainstem by measuring electrical responses of auditory pathways after an acoustic stimulus. Surprisingly, our results returned a normal function of the brainstem in these children. This finding suggests that brainstem alterations are probably secondary to the effects on telencephalon and that brainstem progenitor cells that generate brainstem nuclei may not present the same tropism for the virus or may be further from virus entry sites.

Corticotropin-Releasing Factor (CRF) is one of the main mediators of the Hypothalamic-Pituitary–Interrenal (HPI) axis to stress response. In Atlantic salmon, a comparative understanding of the crf1 paralogs role in the stress response is still incomplete. Our database searches have identified four crf1 genes in Atlantic salmon, named crf1a1, crf1a2, crf1b1 and crf1b2. Brain distribution analysis revealed that the four crf1 paralogs were widely distributed, and particularly abundant in the telencephalon, midbrain, and hypothalamus of Atlantic salmon post-smolts. To increase the knowledge on crf1-mediated response to stress, Atlantic salmon post-smolts were exposed to either repeated chasing, hypoxia or a combination of chasing and hypoxia for eight days, followed by a novel-acute stressor, confinement. Cortisol, glucose, lactate, and creatinine levels were used as markers for the stress response. The crf1 paralogs mRNA abundance showed to be dependent on the stress exposure regime. Both crf1 mRNA levels in the telencephalon and crf1a1 mRNA levels in the hypothalamus showed similar response profiles to the serum cortisol levels, i.e., increasing levels during the first 24 h after stress exposure followed by a decline during the eight-day exposure. The similar trend between crf1 and cortisol disappeared once exposed to the novel-acute stressor. There was a minor response to stress for both crf1b1 and crf1b2 in the hypothalamus, while no changes at mRNA level were observed in the hypothalamic crf1a2 under the different stress conditions. No or weak relationship was found between the crf1 paralogs mRNA expression and the other serum stress-indicators analysed. In summary, our data provide novel insights on the dynamic of the HPI axis activation in Atlantic salmon, and thus underline the involvement of the crf1 paralogs as additional factors in the regulation of the stress response in this species. Likewise, the data highlight the importance of analysing all crf1 paralogues response to a stress-condition, in particular in this premature knowledge stage of their functionality. Further analysis and a more detailed time-point series will help to elucidate the response of the HPI axis and the link of crf1 paralogs in the stress response mechanism. publishedVersion

Vocal communication is important for reproductive success in birds. Conspecific vocalization of birds is processed in the auditory system from ear to higher-order auditory regions in the telencephalon, including the caudomedial nidopallium (NCM). Higher-order auditory regions are involved in the perception of vocal communication in songbirds and nonsongbirds. In a nonsongbird parrot, the NCM of females is involved in the perception of song complexity, which has been considered an intersexually selected trait. Social information is thought to converge on the hypothalamus and is then transduced into a reproductive endocrine response. In another nonsongbird dove, the information from the courtship call is relayed to the hypothalamic neuroendocrine cells through the auditory thalamic nucleus. Together, the existing studies suggest that auditory inputs to higher-order auditory regions and the hypothalamic-pituitary-gonadal (HPG) axis are important for nonsongbird reproduction. It remains unclear whether the HPG axis receives auditory information from higher-order auditory regions.

The protracted nature of development makes the cerebellum vulnerable to a broad spectrum of pathologic conditions, especially during the early fetal period. This study aims to characterize normal cerebellar growth in human fetuses during the early second trimester. We manually segmented the fetal cerebellum using 7.0-T high-resolution MR images obtained in 35 specimens with gestational ages ranging from 15 to 22 weeks. Volume measurements and shape analysis were performed to quantitatively evaluate global and regional cerebellar growth. The absolute volume of the fetal cerebellum showed a quadratic growth with increasing gestational age, while the pattern of relative volume changes revealed that the cerebellum grew at a greater pace than the cerebrum after 17 gestational weeks. Shape analysis was used to examine the distinctive development of subregions of the cerebellum. The extreme lateral portions of both cerebellar hemispheres showed the lowest rate of growth. The anterior lobe grew faster than most of the posterior lobe. These findings expand our understanding of the early growth pattern of the human cerebellum and could be further used to assess the developmental conditions of the fetal brain.

Previous in-vivo magnetic resonance imaging (MRI)-based studies of age-related differences in the human brainstem have focused on volumetric morphometry. These investigations have provided pivotal insights into regional brainstem atrophy but have not addressed microstructural age differences. However, growing evidence indicates the sensitivity of quantitative MRI to microstructural tissue changes in the brain. These studies have largely focused on the cerebrum, with very few MR investigations addressing age-dependent differences in the brainstem, in spite of its central role in the regulation of vital functions. Several studies indicate early brainstem alterations in a myriad of neurodegenerative diseases and dementias. The paucity of MR-focused investigations is likely due in part to the challenges imposed by the small structural scale of the brainstem itself as well as of substructures within, requiring accurate high spatial resolution imaging studies. In this work, we applied our recently developed approach to high-resolution myelin water fraction (MWF) mapping, a proxy for myelin content, to investigate myelin differences with normal aging within the brainstem. In this cross-sectional investigation, we studied a large cohort (n = 125) of cognitively unimpaired participants spanning a wide age range (21–94 years) and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. We believe that this study is the first investigation of MWF differences with normative aging in the adult brainstem. Further, our results provide reference MWF values.

Tissue patterning by gradients of form-generating substances, or ‘morphogens,’ is a fundamental paradigm of developmental biology. Nonetheless, it has been unclear whether classic morphogen gradients pattern the mammalian telencephalon and neocortex, or whether these highly specialized and evolved tissues use entirely unique mechanisms. Recent studies indicate that, like most other tissues, the telencephalon is indeed patterned by classic morphogen gradients. This chapter reviews the history and general principles of morphogen gradients in development, the known sources of morphogens in the developing telencephalon, and the evidence that bone morphogenetic proteins and fibroblast growth factors act as graded morphogens to pattern the dorsal telencephalon and neocortex. It then highlights the unique and complex interactions among morphogens within the dorsal telencephalon, and the roles of morphogen gradients and their interactions in human developmental anomalies, particularly holoprosencephaly.

Neglect after stroke is most accurately diagnosed by a systematic, ecological observation during everyday behaviour using the Catherine Bergego Scale (CBS). However, the CBS is time-consuming and often omitted in clinical settings, especially stroke units. In this study, we aimed to explore if video-oculography during free visual exploration (FVE), which can be performed in few minutes, is sensitive in mirroring neglect in everyday behaviour and whether it is more sensitive than conventional neuropsychological paper-pencil tests. In this retrospective, observational, multicentre study, we identified 78 patients in our database with subacute right-hemispheric stroke, with and without neglect in everyday behaviour, diagnosed by the CBS, who also performed FVE. 40 age-matched healthy participants served as controls. The sensitivity to detect neglect was compared between FVE (i.e., mean gaze position on the horizontal axis) and conventional neuropsychological paper-pencil tests, i.e., Random Shape Cancellation, Line Bisection, Two-Part Picture, Bells, Star Cancellation, Letter Cancellation, Sensitive Neglect, and Five-Point. FVE correctly identified neglect in 85%of patients, with an AUC-value of .922 in ROC-analysis. Conventional neuropsychological paper-pencil tests, considered alone or in combination, showed heterogeneous results, and identified neglect significantly less often (21.74%–68.75%). Moreover, there was a significant correlation between mean gaze position and CBS scores, providing evidence for the relationship between FVE and neglect in everyday behaviour. Furthermore, VLSM analyses suggested that the absence of a pathological rightward bias in FVE might depend on the integrity of the second branch of the right Superior Longitudinal Fascicle (SLF II), a white-matter tract connecting cortical areas critical for visual attention. Video-oculography during FVE has a high sensitivity and specificity to diagnose neglect after stroke and it is more sensitive than conventional neuropsychological paper-pencil tests. It can be performed in short time and has the potential to be used as a fast and accurate screening tool that allows the initiation of comprehensive neuropsychological diagnostics and therapy from early on.

The thalamus is the largest structure of the diencephalon, the central region of the brain between the midbrain and telencephalon. In the mature thalamus, neurons sharing similar structural and functional properties are spatially aggregated in cellular clusters called nuclei, unlike cortical areas where neurons are organized in horizontal layers. While neurons within nuclei share many properties, a varied collection of features arises when comparing neurons among nuclei, including different patterns of connectivity, molecular signatures, cell morphology, electrophysiological profile, and many other properties. Even more functional and cellular diversity is found if other diencephalic territories are taken in account. Remarkably, this congregation of heterogeneous cell types and connectivity patterns emerges from a rather homogeneous territory early in development. A progressive sequence of specification and differentiation programs patterns the initial diencephalon to craft dozens of heterogeneous nuclei, including the thalamic complex. In this chapter, we summarize the current knowledge on the patterning of diencephalic structures with a special focus on the thalamus.

Transient anatomical entities play a role in the maturation of brain regions and early functional fetal networks. At the postmenstrual age of 7 weeks, major subdivisions of the brain are visible. At the end of the embryonic period, the cortical plate covers the neopallium. The choroid plexus develops in concert with it, and the dorsal thalamus covers about half the diencephalic third ventricle surface. In addition to the fourth ventricle neuroepithelium the rhombic lips are an active neuroepithelial production site. Early reciprocal connections between the thalamus and cortex are present. The corticospinal tract has reached the pyramidal decussation, and the arteries forming the mature circle of Willis are seen. Moreover, the superior sagittal sinus has formed, and at the rostral neuropore the massa commissuralis is growing. At the viable preterm age of around 24 weeks PMA, white matter tracts are in full development. Asymmetric progenitor division permits production of neurons, subventricular zone precursors, and glial cells. Myelin is present in the ventral spinal quadrant, cuneate fascicle, and spinal motor fibers. The neopallial mantle has been separated into transient layers (stratified transitional fields) between the neuroepithelium and the cortical plate. The subplate plays an important role in organizing the structuring of the cortical plate. Commissural tracts have shaped the corpus callosum, early primary gyri are present, and opercularization has started caudally, forming the lateral fissure. Thalamic and striatal nuclei have formed, although GABAergic neurons continue to migrate into the thalamus from the corpus gangliothalamicum. Near-term PMA cerebral sublobulation is active. Between 24 and 32 weeks, primary sulci develop. Myelin is present in the superior cerebellar peduncle, rubrospinal tract, and inferior olive. Germinal matrix disappears from the telencephalon, except for the GABAergic frontal cortical subventricular neuroepithelium.

Volumetric structural magnetic resonance imaging (MRI) is commonly used to determine the extent of neuronal loss in aging, indicated by cerebral atrophy. The brain, however, exhibits other biophysical characteristics such as mechanical properties, which can be quantified with magnetic resonance elastography (MRE). MRE is an emerging noninvasive imaging technique for measuring viscoelastic tissue properties, proven to be sensitive metrics of neural tissue integrity, as described by shear stiffness, μ and damping ratio, ξ parameters. The study objective was to evaluate global and regional MRE parameter differences between young (19-30 years, n = 12) and healthy older adults (66-73 years, n = 12) and to assess whether MRE measures provide additive value over volumetric magnetic resonance imaging measurements. We investigated the viscoelasticity of the global cerebrum and 6 regions of interest (ROIs) including the amygdala, hippocampus, caudate, pallidum, putamen, and thalamus. In older adults, we found a decrease in μ in all ROIs, except for the hippocampus, indicating widespread brain softening; an effect that remained significant after controlling for ROI volume. In contrast, the relative viscous-to-elastic behavior of the brain ξ did not differ between age groups, suggesting a preservation of the organization of the tissue microstructure. These data support the use of MRE as a novel imaging biomarker for characterizing age-related differences to neural tissue not captured by volumetric imaging alone.

This data article contains complementary tables related to the research article entitled, âEffects of repetitive transcranial magnetic stimulation on ER stress-related genes and glutamate, γ-aminobutyric acid, and glycine transporter genes in mouse brainâ (Ikeda et al. (2017) [1]), which showed that rTMS modulates glutamate, GABA and glycine transporters and regulates ER stress-related genes. Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in mouse cerebrum treated with rTMS for 30 days (Tables 1â10).

Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10 µg/50 µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1 mg/50 µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7 T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72 mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5 g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats., Highlights • Imaging of animal models of pain often focuses on evoked rather than on-going pain. • We tested whether such on-going pain could be detected with manganese-enhanced MRI. • Robust behavioural measures of pain were found in our rat models of knee-joint pain. • Behavioural measures were correlated with MR intensity in several key brain regions. • Manganese-enhanced MRI could be useful in studying neural bases of spontaneous pain.

Understanding how humans code for and respond to environmental uncertainty/regularity is a question shared by current computational and neurobiological approaches to human cognition. To date, studies investigating neurobiological systems that track input uncertainty have examined responses to uni-sensory streams. It is not known, however, whether there exist brain systems that combine information about the regularity of input streams presented to different senses. We report an fMRI study that aimed to identify brain systems that relate statistical information across sensory modalities. We constructed temporally extended auditory and visual streams, each of which could be random or highly regular, and presented them concurrently. We found strong signatures of “regularity matching” in visual cortex bilaterally; responses were higher when the level of regularity in the auditory and visual streams mismatched than when it matched, [(AudHigh/VisLow and AudLow/VisHigh) >(AudLow/VisLow and AudHigh/VisHigh)]. In addition, several frontal and parietal regions tracked regularity of the auditory or visual stream independently of the other stream's regularity. An individual-differences analysis suggested that signatures of single-modality-focused regularity tracking in these fronto-parietal regions are inversely related to signatures of regularity-matching in visual cortex. Our findings suggest that i) visual cortex is a junction for integration of temporally-extended auditory and visual inputs and that ii) multisensory regularity-matching depends on balanced processing of both input modalities. We discuss the implications of these findings for neurobiological models of uncertainty and for understanding computations that underlie multisensory interactions in occipital cortex.

Objective We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene was expressed under the synapsin I promoter (AAV-hSLC2A1) and examined if AAV-hSLC2A1 administration can lead to functional improvement in GLUT1-deficient mice. Methods AAV-hSLC2A1 was injected into heterozygous knock-out murine Glut1 (GLUT1+/−) mice intraperitoneally (systemic; 1.85 × 1011 vg/mouse) or intra-cerebroventricularly (local; 1.85 × 1010 vg/mouse). We analyzed GLUT1 mRNA and protein expression, motor function using rota-rod and footprint tests, and blood and cerebrospinal fluid (CSF) glucose levels. Results Vector-derived RNA was detected in the cerebrum for both injection routes. In the intra-cerebroventricular injection group, exogenous GLUT1 protein was strongly expressed in the cerebral cortex and hippocampus near the injection site. In the intraperitoneal injection group, exogenous GLUT1 protein was mildly expressed in neural cells throughout the entire central nervous system. The motor function test and CSF/blood glucose ratio were significantly improved following intra-cerebroventricular injection. Conclusions AAV-hSLC2A1 administration produced exogenous GLUT1 in neural cells and improved CSF glucose levels and motor function of heterozygous knock-out murine Glut1 mice.

A growing literature is pointing towards the importance of white matter, tracts in understanding the neural mechanisms of language processing, and determining the nature of language deficits and recovery patterns in aphasia. Measurements extracted from diffusion-weighted (DW) images provide comprehensive in vivo measures of local micro structural properties of fiber pathways. In the current study, we compared microstructural properties of major white matter tracts implicated in language processing in each hemisphere (these included arcuate fasciculus (AF), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), inferior frontal-occipital fasciculus (IFOF), uncinate fasciculus (UF), and corpus callosum (CC), and corticospinal tract (CST) for control purposes) between individuals with aphasia and healthy controls and investigated the relationship between these neural indices and language deficits.Thirty-seven individuals with aphasia due to left hemisphere stroke and eleven age matched controls were scanned using DW imaging sequences. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) values for each major white matter tract were extracted from DW images using tract masks chosen from standardized atlases. Individuals with aphasia were also assessed with a standardized language test in Russian targeting comprehension and production at the word and sentence level.Individuals with aphasia had significantly lower FA values for left hemisphere tracts and significantly higher values of MD, RD and AD for both left and right hemisphere tracts compared to controls, all indicating profound impairment in tract integrity. Language comprehension was predominantly related to integrity of the left IFOF and left ILF, while language production was mainly related to integrity of the left AF. In addition, individual segments of these three tracts were differentially associated with language production and comprehension in aphasia. Our findings highlight the importance of fiber pathways in supporting different language functions and point to the importance of temporal tracts in language processing, in particular, comprehension. (C) 2016 Elsevier Ltd. All rights reserved.

Gonadotropin-inhibitory hormone (GnIH)is a hypothalamic neuropeptide belonging to the RFamide peptide family that was first discovered in quail by Tsutsui and co-workers in the year 2000. Since then, different GnIH orthologues have been identified in all vertebrate groups, from agnathans to mammals. These GnIH genes synthesize peptide precursors that encompass two to four C-terminal LPXRFamide peptides. Functional and behavioral studies carried out in birds and mammals have demonstrated a clear inhibitory role of GnIH on GnRH and gonadotropin synthesis and secretion as well as on aggressive and sexual behavior. However, the effects of Gnih orthologues in reproduction remain controversial in fish with both stimulatory and inhibitory actions being reported. In this paper, we will review the main findings obtained in our laboratory on the Gnih system of the European sea bass, Dicentrarchus labrax. The sea bass gnih gene encodes two putative Gnih peptides (sbGnih1 and sbGnih2), and is expressed in the olfactory bulbs/telencephalon, diencephalon, midbrain tegmentum, rostral rhombencephalon, retina and testis. The immunohistochemical study performed using specific antibodies developed in our laboratory revealed Gnih-immunoreactive (ir)perikarya in the same central areas and Gnih-ir fibers that profusely innervated the brain and pituitary of sea bass. Moreover, in vivo studies revealed the inhibitory role of centrally- and peripherally-administered Gnih in the reproductive axis of male sea bass, by acting at the brain (on gnrh and kisspeptin expression), pituitary (on gnrh receptors and gonadotropin synthesis and release)and gonadal (on androgen secretion and gametogenesis)levels. Our results have revealed the existence of a functional Gnih system in sea bass, and have provided evidence of the differential actions of the two Gnih peptides on the reproductive axis of this species, the main inhibitory role in the brain and pituitary being exerted by the sbGnih2 peptide. Recent studies developed in our laboratory also suggest that Gnih might be involved in the transduction of photoperiod and temperature information to the reproductive axis, as well as in the modulation of daily and seasonal rhythmic processes in sea bass., The works on sea bass Gnih system reviewed in this manuscript were supported by grants from the Junta de Andalucía (grant no. P10-AGR-05916) and University of Cádiz (Plan Propio, grants no. AT2014-020, AT2016-014, AT2017-009) to JAM-C. JAP-S was a postdoctoral fellow from the Junta de Andalucía. MA-G was recipient of a predoctoral fellowship from MINECO (BES-2011-047276). MC was recipient of a Marie Curie postdoctoral contract from the European Union’s Seventh Framework Programme (FP7/2007-2013, grant no. 331964).

This chapter focuses on the development of the human olfactory system. In this system, function does not require full neuroanatomical maturity. Thus, discrimination of odorous molecules, including a number within the mother's diet, occurs in amniotic fluid after 28-30 weeks of gestation, at which time the olfactory bulbs are identifiable by MRI. Hypoplasia/aplasia of the bulbs is documented in the third trimester and postnatally. Interestingly, olfactory axons project from the nasal epithelium to the telencephalon before formation of the olfactory bulbs and lack a peripheral ganglion, but the synaptic glomeruli of the future olfactory bulb serves this function. Histologic lamination of the olfactory bulb is present by 14 weeks, but maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the normal transitory fetal ventricular recess. Myelination occurs postnatally. Although olfaction is the only sensory system without direct thalamic projections, the olfactory bulb and anterior olfactory nucleus are, in effect, thalamic surrogates. For example, many dendro-dendritic synapses occur within the bulb between GABAergic granular neurons and periglomerular neurons. Moreover, bulbar synaptic glomeruli are analogous to peripheral ganglia of other sensory cranial nerves. The olfactory tract contains much gray as well as white matter. The olfactory epithelium and bulb both incorporate progenitor cells at all ages. Diverse malformations of the olfactory bulb can be detected by clinical examination, imaging, and neuropathology; indeed, olfactory reflexes of the neonate can be reliably tested. We recommend that such testing be routine in the neonatal neurologic examination, especially in children with brain malformations, endocrinopathies, chromosomopathies, genetic/metabolic disorders, and perinatal hypoxic/ischemic encephalopathy.

The estimated annual incidence in the United States of primary brain cancer is 23,880 with an estimated 16,830 deaths in 2018. Primary brain cancer incidence peaks in childhood and again after the age of 60 and has been increasing. The major brain sites are the cerebrum, diencephalon, brainstem, and cerebellum. The brain and spinal cord together form the central nervous system (CNS). CNS tumors are locally invasive even though cerebrospinal fluid (CSF) dissemination and drop metastases can occur along the spine; they are uncommon. Extra neuraxial metastases are extremely rare.

Hepatic encephalopathy (HE) is a brain illness produced by chronic liver damage, principally in heavy drinkers with cirrhosis, which brings about subjective, mental, and motor restraints. In these patients, the quantity of utilitarian liver cells is diminished, and some blood is utilized around the liver before poisons are removed. Therefore, poisons, for example, alkali and manganese, can gather in the blood and penetrate the brain, where they can harm nerve cells and maintain cells termed astrocytes. Positron emission tomography examinations have confirmed that ammonia levels are hoisted in the brains of HE cases; ammonia gathering can change the declaration of different critical cerebrum genes. Manganese stores might be in charge of basic variations in the astrocytes that are normal for HE. Treatment of cases with HE includes measures to bring down ammonia levels in the blood and medicines to balance alkali's consequences for brain cell work.

A robust left side cradling bias (LCB) in humans is argued to reflect an evolutionarily old left visual field bias and right hemisphere dominance for processing social stimuli. A left visual field bias for face processing, invoked via the LCB, is known to reflect a human population-level right cerebral hemisphere specialization for processing social stimuli. We explored the relationship between cradling side biases, hand dominance and socio-communicative abilities. Four and five year old typically-developing children (N = 98) participated in a battery of manual motor tasks interspersed by cradling trials comprising a(n): infant human doll, infant primate doll, proto-face pillow and no-face pillow. Mean social and communication ability scores were obtained via a survey completed by each child's key teacher. We found a population-level LCB for holding an infant human doll that was not influenced by hand dominance, sex, age or experience of having a younger sibling. Children demonstrating a LCB, did however, obtain a significantly higher mean social ability score compared with their right side cradling counterparts. Like the infant human doll, the proto-face pillow's schematic face symbol was sufficient to elicit a population-level LCB. By contrast, the infant primate doll elicited a population-level right side cradling bias, influenced by both hand dominance and sex. The findings suggest that the LCB is present and visible early in development and is likely therefore, to represent evolutionarily old domain-specific organization and function of the right cerebral hemisphere. Additionally, results suggest that a LCB requires minimal triggering but can be reversed in some situations, possibly in response to species-type or levels of novelty or stress as perceived by the viewer. Patterns of behavioral biases within the context of social stimuli and their associations with cognitive ability are important for understanding how socio-communication abilities emerge in developing children.

The avian brain displays a different brain architecture compared to mammals. This has led the first pioneers of comparative neuroanatomy to wrong conclusions about bird brain evolution by assuming that the avian telencephalon is a hypertrophied striatum. Based on growing evidence from divers analysis demonstrating that most of the avian forebrain is pallial in nature, this view has substantially changed during the past decades. Further, birds show cognitive abilities comparable to or even exceeding those of some mammals, even without a "six-layered" cortex. Beside higher associative regions, most of these cognitive functions include the processing of information in the hippocampal formation (HF) that shares a homologue structure in birds and mammals. Here we show with 3D polarized light imaging (3D-PLI) that the HF of pigeons like the mammalian HF shows regional specializations along the anterior-posterior axis in connectivity. In addition, different levels of adult neurogenesis were observed in the subdivisions of the HF per se and in the most caudal regions pointing towards a functional specialization along the anterior-posterior axis. Taken together our results point to species specific morphologies but still conserved hippocampal characteristics of connectivity, cells and adult neurogenesis if compared to the mammalian situation. Here our data provides new aspects for the ongoing discussion on hippocampal evolution and mind.

The nervous system develops from specialized ectoderm structures, with the neural tube forming the central nervous system and the neural crest forming the peripheral nervous system. The neuropore openings of the neural tube close in the fourth week. This is followed by rapid growth of neural tissue in the cranial region to yield first primary brain vesicles and then secondary brain vesicles that will develop into the cerebral hemispheres and brainstem. An alar plate is established posteriorly and a basal plate anteriorly in the neural tube. These plates differentiate into the posterior and anterior horns of the spinal cord, and the sensory and motor cranial nerve nuclei of the brainstem. Both cerebellar and cerebral cortex development involve migration of immature neurons guided by radial glial cells. In the cerebellum these neurons proliferate in external and internal germinal layers and then migrate to their final positions. In the cerebrum these neurons proliferate and then follow an inside-out pattern of development that allows successive waves of neurons to take up positions progressively closer to the pial surface. Early in nervous system development there is an overproduction of neurons, which is followed by apoptosis to produce the normal complement of neurons in the mature brain. The development of a fully functional nervous system requires neurons to proliferate and migrate, undergo myelination, and form synaptic connections.

The central nervous system (CNS) is composed of cellular components organized in a complex structure that is unlike other organ systems. At the macroscopic level, the parenchyma of the CNS can be categorized into two structurally and functionally unique components: gray and white matter. The CNS can be divided into a number of anatomic regions, each with specific neurologic or cognitive functions. Disease or damage to these regions produces neurologic or cognitive deficits that correlate with the anatomic location and extent of disease. There are several ways to divide these structures. The main divisions are the cerebrum, cerebellum, brainstem, and spinal cord. Developmental neuropathology encompasses a broad variety of cerebral malformations and functional impairments caused by disturbances of brain development, manifesting during ages from the embryonic period through adolescence and young adulthood. The neurologic and psychiatric manifestations of neurodevelopmental disorders range widely depending on the affected neural systems and include such diverse manifestations as epilepsy, mental retardation, cerebral palsy, breathing disorders, ataxia, autism, and schizophrenia. In terms of morbidity and mortality, the spectrum is extremely broad: the mildest neurodevelopmental disorders can be asymptomatic, whereas the worst malformations often lead to intrauterine or neonatal demise. This chapter focuses on the genetic disorders of brain development, caused by mutations of gene loci or chromosomal regions with important neurodevelopmental functions.

In the last few decades, an increasing number of studies have focused on better characterizing the cerebellar functions beyond motor control, including emotional and social domains. Anatomic and functional evidence strongly contributes to delineating the cerebellar functional subdivisions and their integration with cerebral functional networks strictly related to emotional regulation and social functioning, thus suggesting a model of cerebellar organization that resembles that of the cerebral cortex. Overcoming the traditional segregation of cerebrocerebellar networks in sensorimotor/cognitive functional modules, during emotional/social processes, the cerebellar activity reflects a domain-specific mentalizing functionality that is strongly connected with corresponding mentalizing networks in the cerebrum. Additionally, the cerebrocerebellar organization has been shown to have a specific functional and maturational trajectory that is only in part dependent on a structural maturational process and that is protracted from an early stage of life through adolescence and adulthood, when the mature control networks involve both segregation and integration of the brain regions that comprise them. Altogether, these findings underscore the importance of regional functional differences within the cerebellum in relation to emotional and social processing and raise questions about the clinical implication of cerebellar injury on emotional/social behaviors, both in the developing and the adult brain.

The question posed today is not whether the cerebellum plays a role in cognition, but instead, how the cerebellum contributes to cognitive processes, even in the developmental age. The central role of the cerebellum in many areas of human abilities, motor as well as cognitive, in childhood as well as in adulthood, is well established but cerebellar basic functioning is still not clear and is much debated. Of particular interest is the changing face of cerebellar influence on motor, higher cognitive, and behavioral functioning when adult and developmental lesions are compared. The idea that the cerebellum might play quite different roles during development and in adulthood has been proposed, and evidence from experimental and clinical literature has been provided, including for sequencing, behavioral aspects, and executive functions Still, more data are needed to fully understand the changes of cerebrocerebellar interactions within the segregated loops which connect cerebrum and cerebellum, not only between childhood and adulthood but also in health and disease.

The telencephalon, commonly called the cerebral hemispheres, is the largest portion of the central nervous system (CNS) and consists of the cerebral cortex, subcortical white matter (commissural, association, and projection fibers), and basal nuclei. The elevations on the cortical surface are gyri/gyrus, and the grooves between gyri are called sulci/sulcus. This large CNS region arises from the rostral portion of the prosencephalon; the caudal portion gives rise to the diencephalon. The cavities of the telencephalon are two lateral ventricles, one in each hemisphere, both communicating with a single third ventricle via the two interventricular foramina. The cerebral cortex is divided, by named sulci, into six lobes: frontal, parietal, limbic, temporal, occipital, and—hidden in the depths of the lateral sulcus—limbic. Most of these lobes are associated with particular functions such as somatomotor, somatosensory, vision, and auditory perception, or with more global modalities such as behavior. The subcortical white matter is composed of fibers projecting from one cortical region to another (association, commissural) or from the cortex to targets in the thalamus, brainstem, or spinal cord. The principal nuclei of the basal nuclei are the caudate nucleus (head, body, tail), lenticular nucleus (made up of the putamen and globus pallidus), and nucleus accumbens, as well as substantia innominate. The subthalamic nucleus and the substantia nigra are not components of the basal nuclei but have essential connections with the caudate and lenticular nuclei. The hippocampal formation and the amygdaloid complex are located in the temporal lobe.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link Methylphenidate (MPH) is the front-line psychostimulant medication prescribed for alleviating the symptoms associated with attention deficit hyperactivity disorder (ADHD) in children. Here, we investigated the effects of chronic MPH (2.0 mg/kg, twice daily for 15 days) exposure to young rats (20-25 days old at start of treatment) on the expression of genes and proteins associated with neuroplasticity, such as activity regulated cytoskeleton-associated protein (Arc), insulin receptor substrate protein 53 (IRSp53), cell division control protein 42 (Cdc42), and actin-related protein 2 (Arp2). Chronic MPH increased Arc expression in areas of the cerebrum including, the striatum, nucleus accumbens and hippocampus. In addition, chronic MPH also increased the expression of IRSp53 in the striatum, while Cdc42 and Arp2 were specifically increased in the nucleus accumbens. Conversely, chronic MPH decreased Arc and IRSp53 protein expression in the cerebellum, indicating differential effects of the drug in cerebral areas relative to the cerebellum. Overall, our results indicate that chronic MPH treatment increases expression of genes and proteins associated with dendritic spine formation and neuronal plasticity in target areas of the cerebrum while it decreases the expression in the cerebellum.

The tail suspension test (TST) has been widely used as a screening assay for antidepressant drugs. However, the neural substrates underlying the stress response and antidepressant-like effect during the TST remain largely unknown despite the prevalence of this test. In the present study, we used immunohistochemistry to examine alterations in c-Fos expression as a measure of neuronal activity in the mouse brain after acute administration of the antidepressant drugs nortriptyline or escitalopram (or saline as a control) with or without a subsequent TST session. We found that without the TST session, nortriptyline administration enhanced the density of c-Fos-immunoreactive cells in regions of the central extended amygdala, paraventricular hypothalamic nucleus, and relevant regions of the brain stem, whereas escitalopram did not change c-Fos expression in any region. Following the TST in the absence of antidepressant drugs, we observed a significant increase in c-Fos-positive cell density in a number of brain regions within the limbic telencephalon, hypothalamus, and brain stem. We detected a statistically significant interaction using an analysis of variance between the main effects of the drug and stress response in four regions: the infralimbic cortex, lateral septal nucleus (intermediate part), ventrolateral preoptic nucleus, and solitary nucleus. Following the TST, escitalopram but not nortriptyline increased c-Fos-positive cell density in the infralimbic cortex and ventrolateral preoptic nucleus, whereas nortriptyline but not escitalopram increased c-Fos expression in the solitary nucleus. Both antidepressants significantly increased c-Fos expression in the lateral septal nucleus (intermediate part). The present results indicate that neuronal activity increases in septo-hypothalamic regions and related structures, especially the lateral septal nucleus, following administration of drugs producing an antidepressant-like effect in mice subjected to the TST.

Sensory input from and motor output to the two sides of the body needs to be continuously integrated between the two cerebral hemispheres. This integration can be measured through its cost in terms of processing speed. In simple detection tasks, reaction times (RTs) are faster when stimuli are presented to the side of the body ipsilateral to the body part used to respond. This advantage – the contralateral-ipsilateral difference (also known as the crossed-uncrossed difference: CUD) – is thought to reflect inter-hemispheric interactions needed for sensorimotor information to be integrated between the two hemispheres. Several studies have shown that non-informative vision of the body enhances performance in tactile tasks. However, it is unknown whether the CUD can be similarly affected by vision. Here, we investigated whether the CUD is modulated by vision of the body (i.e., the stimulated hand) by presenting tactile stimuli unpredictably on the middle fingers when one hand was visible (i.e., either the right or left hand). Participants detected the stimulus and responded as fast as possible using either their left or right foot. Consistent with previous results, a clear CUD (5.8 ms) was apparent on the unseen hand. Critically, however, no such effect was found on the hand that was visible (-2.2 ms). Thus, when touch is delivered to a seen hand, the usual cost in processing speed of responding with a contralateral effector is eliminated. This result suggests that vision of the body improves the interhemispheric integration of tactile-motor responses.

arber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1P361R/P361R mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma–like accumulations of storage-laden CD68+ microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1P361R/P361R mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder. © 2017 American Society for Investigative Pathology, Supported by National Institute of Neurological Diseases and Stroke Award 1F05 NS074790, Charles University Research Development Schemes (PRVOUK) grant P24/LF1/3, and OPPK grant CZ.2.16/3.1.00/24509 (J.S.); the Canadian Institutes of Health Research Biological Therapeutics Traineeship (S.D.); NIH grants 1R21NS078191-01A1 (J.A.M.), R01 HD045561 (S.U.W.), and P30 HD071593 (S.U.W.); Spanish Ministries of Science and Technology grant SAF2011-22444 and Economy and Competitiveness grant CTQ2014-54743-R (J.C. and G.F.); INSERM (T.L.); Vaincre les Maladies Lysosomales (T.L. and J.A.M.); and the South Carolina SmartState Endowed Research program, National Cancer Institute grant P30 CA138313 and South Carolina Clinical and Translational Research Institute grants UL1 RR029882 and UL1 TR000062 (R.R.D.).

Located in the dorsomedial forebrain of amphibians, reptiles, and birds is a structure recognized as homologous to the mammalian hippocampus. Comparing the hippocampus among nonmammalian tetrapods enables a hypothetical evolutionary reconstruction, according to which the hippocampus transitions from a small and relatively unorganized amphibian-like hippocampus, which receives direct sensory inputs from the thalamus and olfactory bulbs, to a laminated (reptiles) or partially laminated (birds) hippocampus that receives sensory inputs after some processing has already taken place in the telencephalon. Further, a hippocampal homologue is identifiable also in teleost fish. Functionally, what binds all the variation in hippocampal organization together is a shared role in the maplike representation of space.

Publisher Summary This chapter characterizes the processes of neuroinflammation and related oxidative injury and discusses alterations associated with developmental neurotoxicity. Neuroinflammation is characterized by a host of cellular and molecular changes within the brain. It investigates the effectiveness of drugs currently proposed to inhibit COX, and to suppress innate immune response and/or oxidative damage. The data furnished here imply that α-tocopherol offers broad protection in the cerebrum from oxidative damage. The increased state of neuroinflammation makes the aged brain more vulnerable to the disruptive effects of both intrinsic and extrinsic factors such as disease, infection, toxicants or stress. The exact pattern of cellular and molecular changes depends largely on the type and duration of the inflammatory challenge experienced by the organism. Neuroinflammation can result from classical injuries such as direct insult to the brain that occurs with trauma, encephalitis or ischemia, or from insults such as toxins or infection that follow exposure to bacteria. It is becoming increasingly evident that neuroinflammation and associated oxidative damage play a crucial role in the development and progression of brain diseases. Glia, and in particular microglia, are central to mediating the effects of neuroinflammation.