Dysfunctions of cellular context-sensitivity in neurodevelopmental learning disabilities.

Pyramidal neurons have a pivotal role in the cognitive capabilities of neocortex. Though they have been predominantly modeled as integrate-and-fire point processors, many of them have another point of input integration in their apical dendrites that is central to mechanisms endowing them with the sensitivity to context that underlies basic cognitive capabilities. Here we review evidence implicating impairments of those mechanisms in three major neurodevelopmental disabilities, fragile X, Down syndrome, and fetal alcohol spectrum disorders. Multiple dysfunctions of the mechanisms by which pyramidal cells are sensitive to context are found to be implicated in all three syndromes. Further deciphering of these cellular mechanisms would lead to the understanding of and therapies for learning disabilities beyond any that are currently available.

Influence of chest wall conformation on reproducibility of main echocardiographic indices of left ventricular systolic function.

BACKGROUND: The possible influence of chest wall conformation, as noninvasively assessed by Modified Haller Index (MHI, the ratio of chest transverse diameter over the distance between sternum and spine), on reproducibility of both left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) has never been previously investigated. METHODS: Two equal groups of healthy individuals, matched by age, sex, and cardiovascular risk factors and categorized according to MHI in those with concave-shaped chest wall (MHI>2.5) and those with normal chest shape (MHI≤2.5), who underwent transthoracic echocardiography implemented with echocardiographic deformation imaging between June 2018 and May 2019, were retrospectively analyzed. LVEF and GLS were measured twice by the two echocardiographers in a double blinded manner. Intra-class correlation coefficients (ICCs), bias and limits of agreement determined with Bland-Altman analysis were calculated for repeated measurements of both LVEF and GLS. RESULTS: Thirty-four healthy individuals with MHI>2.5 (54.9±6.4 years, 58.8% females) and 34 matched controls with MHI≤2.5 (52.5±8.1 years, 50% females) were separately analyzed. In comparison to MHI≤2.5 group, the MHI>2.5 group was found with significantly smaller cardiac chambers and significantly lower GLS magnitude (-15.8±2.5 vs. -22.2±1.3%, P<0.001), despite similar LVEF (61.3±6.4 vs. 61.1±3.6%, P=0.87). In the MHI>2.5 group, intra-rater and inter-rater ICCs were ≤0.5 for both LVEF and LV-GLS, whereas in the MHI≤2.5 group intra-rater and inter-rater ICCs values indicated good reliability for LVEF and excellent reliability for GLS. The greatest bias and largest limits of agreement were detected for LVEF assessment (bias ranging from -1.09 to 2.94%, with the 95% limits of agreement ranging from -13.9 to 21.3%) in individuals with MHI>2.5. On the other hand, the smallest bias and narrowest limits of agreement were obtained for GLS measurement (bias ranging from -0.26 to 0.09%, with the 95% limits of agreement ranging from -1.4 to 1.4%) in participants with normal chest wall conformation (MHI≤2.5). CONCLUSIONS: The test reliability of LVEF and GLS is strongly influenced by the chest wall conformation. MHI might represent an innovative approach for selecting the best echocardiographic method for LV systolic function estimation in the individual case.

Prognostic role of CHA2DS2-VASc score for mortality risk assessment in non-advanced idiopathic pulmonary fibrosis: a preliminary observation.

During the last decade, the CHA2DS2-VASc score has been used for stratifying the mortality risk in both atrial fibrillation (AF) and non-AF patients. However, no previous study considered this score as a prognostic indicator in non-AF patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). All consecutive non-AF patients with mild-to-moderate IPF, diagnosed between January 2016 and December 2018 at our Institution, entered this study. All patients underwent physical examination, blood tests, spirometry, high-resolution computed tomography and transthoracic echocardiography. CHA2DS2-VASc score, Gender-Age-Physiology (GAP) index and Charlson Comorbidity Index (CCI) were determined in all patients. Primary endpoint was all-cause mortality, while the secondary endpoint was the composite of all-cause mortality and rehospitalizations for all causes over mid-term follow-up. 103 consecutive IPF patients (70.7 ± 7.3 yrs, 79.6% males) were retrospectively analyzed. At the basal evaluation, CHA2DS2-VASc score, GAP index and CCI were 3.7 ± 1.6, 3.6 ± 1.2 and 5.5 ± 2.3, respectively. Mean follow-up was 3.5 ± 1.3 yrs. During the follow-up period, 29 patients died and 43 were re-hospitalized (44.2% due to cardiopulmonary causes). On multivariate Cox regression analysis, CHA2DS2-VASc score (HR 2.15, 95% CI 1.59-2.91) and left ventricular ejection fraction (LVEF) (HR 0.91, 95% CI 0.86-0.97) were independently associated with all-cause mortality in IPF patients. CHA2DS2-VASc score (HR 1.66, 95% CI 1.39-1.99) and LVEF (HR 0.94, 95% CI 0.90-0.98) also predicted the secondary endpoint in the same study group. CHA2DS2-VASc score > 4 was the optimal cut-off for predicting both outcomes. At mid-term follow-up, a CHA2DS2-VASc score > 4 predicts an increased risk of all-cause mortality and rehospitalizations for all causes in non-AF patients with mild-to-moderate IPF.

Modified Haller index validation and correlation with left ventricular strain in a cohort of subjects with obesity and without overt heart disease.

The present study was primarily designed to validate the modified Haller index (MHI), the ratio of chest transverse diameter over the distance between sternum and spine, measured by a ruler and transthoracic echocardiography (TTE), respectively, in a cohort of subjects with obesity, but otherwise healthy, by comparing the results to the conventional Haller index (HI) measured on chest X-ray (CXR). 100 consecutive subjects with body mass index (BMI) ≥ 30 kg/m2 and 60 matched controls with BMI < 30 kg/m2, who underwent a two-plane CXR for any clinical indication, were prospectively examined over a 6-month period. All participants underwent MHI assessment, TTE and speckle-tracking analysis of left ventricular (LV) global longitudinal strain (GLS). Bland-Altman analysis was used to compare the radiological and nonradiological techniques. Second, independent predictors of subclinical myocardial dysfunction, defined as LV-GLS less negative than - 20%, were evaluated. Bland-Altman analysis revealed a bias of - 4.91 cm for latero-lateral thoracic diameter, of - 0.74 cm for antero-posterior (A-P) thoracic diameter and of - 0.22 for HI assessment, suggesting a systematic overestimation of the nonradiological methodology in comparison to that radiological. Despite normal LV systolic function on TTE, LV-GLS resulted impaired in 76% of subjects with obesity. Waist circumference (OR 1.13, 95%CI 1.04-1.22) and nonradiological A-P thoracic diameter (OR 0.51, 95%CI 0.28-0.93) were the main independent predictors of subclinical myocardial dysfunction in subjects with obesity. The impairment in LV myocardial strain detected in subjects with obesity appears to be primarily related to extrinsic abdominal and thoracic compressive phenomena, rather than intrinsic myocardial dysfunction.

Dendrites of Neocortical Pyramidal Neurons: The Key to Understand Intellectual Disability.

Pyramidal neurons (PNs) are the most abundant cells of the neocortex and display a vast dendritic tree, divided into basal and apical compartments. Morphological and functional anomalies of PN dendrites are at the basis of virtually all neurological and mental disorders, including intellectual disability. Here, we provide evidence that the cognitive deficits observed in different types of intellectual disability might be sustained by different parts of the PN dendritic tree, or by a dysregulation of their interaction.

The Phosphorylated Form of the Histone H2AX (γH2AX) in the Brain from Embryonic Life to Old Age.

The γ phosphorylated form of the histone H2AX (γH2AX) was described more than 40 years ago and it was demonstrated that phosphorylation of H2AX was one of the first cellular responses to DNA damage. Since then, γH2AX has been implicated in diverse cellular functions in normal and pathological cells. In the first part of this review, we will briefly describe the intervention of H2AX in the DNA damage response (DDR) and its role in some pivotal cellular events, such as regulation of cell cycle checkpoints, genomic instability, cell growth, mitosis, embryogenesis, and apoptosis. Then, in the main part of this contribution, we will discuss the involvement of γH2AX in the normal and pathological central nervous system, with particular attention to the differences in the DDR between immature and mature neurons, and to the significance of H2AX phosphorylation in neurogenesis and neuronal cell death. The emerging picture is that H2AX is a pleiotropic molecule with an array of yet not fully understood functions in the brain, from embryonic life to old age.

Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice.

Phosphorylation of H2AX is a response to DNA damage, but γH2AX also associates with mitosis and/or apoptosis. We examined the effects of X-rays on DNA integrity to shed more light on the significance of H2AX phosphorylation and its relationship with activation of caspase 3 (CASP3), the main apoptotic effector. After administration of the S phase marker BrdU, brains were collected from untreated and irradiated (10 Gray) 24-month-old mice surviving 15 or 30 min after irradiation. After paraffin embedding, brain sections were single- or double-stained with antibodies against γH2AX, p53-binding protein 1 (53BP1) (which is recruited during the DNA damage response (DDR)), active CASP3 (cCASP3), 5-Bromo-2-deoxyuridine (BrdU), and phosphorylated histone H3 (pHH3) (which labels proliferating cells). After statistical analysis, we demonstrated that irradiation not only induced a robust DDR with the appearance of γH2AX and upregulation of 53BP1 but also that cells with damaged DNA attempted to synthesize new genetic material from the rise in BrdU immunostaining, with increased expression of cCASP3. Association of γH2AX, 53BP1, and cCASP3 was also evident in normal nonirradiated mice, where DNA synthesis appeared to be linked to disturbances in DNA repair mechanisms rather than true mitotic activity.

Reduced Myocardial Strain Parameters in Subjects With Pectus Excavatum: Impaired Myocardial Function or Methodological Limitations Due to Chest Deformity?

Pectus excavatum (PE) may cause symptoms and alter cardiopulmonary function. Left ventricular (LV) and right ventricular (RV) function have been reported to be impaired in PE subjects. However, this issue has not been systematically investigated with respect to the degree of chest wall abnormality. We aimed to evaluate the influence of severity of chest shape abnormality on myocardial strain parameters in PE subjects. We studied 30 healthy subjects (55.8 ± 14.0 year/old, 18 males) with PE, assessed by the ratio of chest transverse diameter over the distance between sternum and spine (modified Haller index, MHI, >2.5), and 30 controls (MHI ≤2.5) matched by age, sex, and cardiovascular risk factors. Participants underwent 2-dimensional (2D) transthoracic echocardiography implemented with 2D-speckle tracking echocardiography. Right-heart and left-heart chamber dimensions, and stroke volume, were significantly reduced in PE subjects (all P< 0.0001). While LV ejection fraction, E/A, and E/e', did not significantly differ between the 2 groups, all LV and RV strain and strain rate parameters were severely reduced in subjects with PE (P < 0.0001). Importantly, in PE subjects, but not in controls, LV global longitudinal strain, LV global circumferential strain, LV global radial strain, and RV free wall systolic strain, were all linearly correlated to MHI (all P < 0.0001). In healthy subjects with PE, abnormal chest anatomy progressively impairs myocardial strain. However, this impairment is not due to subclinical myocardial dysfunction; it might reflect intraventricular dyssynchrony due to compressive phenomena, or technical limitations of strain methodology, due to chest wall abnormality.

Asymmetry in the Cytoarchitecture of the Area 44 Homolog of the Brain of the Chimpanzee Pan troglodytes.

The evolution of the brain in apes and man followed a joint pathway stemming from common ancestors 5-10 million years ago. However, although apparently sharing similar organization and neurochemical properties, association areas of the isocortex remain one of the cornerstones of what sets humans aside from other primates. Brodmann's area 44, the area of Broca, is known for its implication in speech, and thus indirectly is a key mark of human uniqueness. This latero-caudal part of the frontal lobe shows a marked functional asymmetry in humans, and takes part in other complex functions, including learning and imitation, tool use, music and contains the mirror neuron system (MNS). Since the main features in the cytoarchitecture of Broca's area remains relatively constant in hominids, including in our closest relative, the chimpanzee Pan troglodytes, investigations on the finer structure, cellular organization, connectivity and eventual asymmetry of area 44 have a direct bearing on the understanding of the neural mechanisms at the base of our language. The semi-automated image analysis technology that we employed in the current study showed that the structure of the cortical layers of the chimpanzee contains elements of asymmetry that are discussed in relation to the corresponding human areas and the putative resulting disparity of function.

The Reeler Mouse: A Translational Model of Human Neurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment?

The first description of the Reeler mutation in mouse dates to more than fifty years ago, and later, its causative gene (reln) was discovered in mouse, and its human orthologue (RELN) was demonstrated to be causative of lissencephaly 2 (LIS2) and about 20% of the cases of autosomal-dominant lateral temporal epilepsy (ADLTE). In both human and mice, the gene encodes for a glycoprotein referred to as reelin (Reln) that plays a primary function in neuronal migration during development and synaptic stabilization in adulthood. Besides LIS2 and ADLTE, RELN and/or other genes coding for the proteins of the Reln intracellular cascade have been associated substantially to other conditions such as spinocerebellar ataxia type 7 and 37, VLDLR-associated cerebellar hypoplasia, PAFAH1B1-associated lissencephaly, autism, and schizophrenia. According to their modalities of inheritances and with significant differences among each other, these neuropsychiatric disorders can be modeled in the homozygous (reln-/-) or heterozygous (reln+/-) Reeler mouse. The worth of these mice as translational models is discussed, with focus on their construct and face validity. Description of face validity, i.e., the resemblance of phenotypes between the two species, centers onto the histological, neurochemical, and functional observations in the cerebral cortex, hippocampus, and cerebellum of Reeler mice and their human counterparts.

The Claustrum of the Pig: An Immunohistochemical and a Quantitative Golgi Study.

Despite increasing interest in the claustrum (Cl) over the last decades, its function is still a puzzling problem. Among the experimental species of potential use in Cl research, the pig is considered an interesting model, because of the similarities of its brain with the corresponding cortical and subcortical human structures. The swine Cl presents a peculiar morphology, characterized by a wide posterior enlargement, ideal for physiological investigations. There is a wealth of data on general anatomy, cytoarchitecture, and chemo architecture of the Cl, but much less is known about the dendritic morphometry of its neurons. Dendritic length and branching pattern are key features to understand the organization of the microcircuitry, and thus the delineation of the structure-function relationships of the Cl. To this effect, we undertook (a) a quantitative study of the dendrites of the spiny neurons of the swine Cl, employing the Golgi staining; and (b) an immunohistochemical analysis to describe the distribution of the parvalbumin (PV)-immunoreactive interneurons throughout the same nucleus. Taken together, the results that we report here show that the dendritic architecture and the distribution of the PV expressing interneurons change when the Cl of this species changes its shape along the rostro-caudal axis, thus suggesting a potentially specific function for the large posterior puddle. Anat Rec, 302:1638-1646, 2019. © 2019 American Association for Anatomy.

Alcohol and the Developing Brain: Why Neurons Die and How Survivors Change.

The consequences of alcohol drinking during pregnancy are dramatic and usually referred to as fetal alcohol spectrum disorders (FASD). This condition is one of the main causes of intellectual disability in Western countries. The immature fetal brain exposed to ethanol undergoes massive neuron death. However, the same mechanisms leading to cell death can also be responsible for changes of developmental plasticity. As a consequence of such a maladaptive plasticity, the functional damage to central nervous system structures is amplified and leads to permanent sequelae. Here we review the literature dealing with experimental FASD, focusing on the alterations of the cerebral cortex. We propose that the reciprocal interaction between cell death and maladaptive plasticity represents the main pathogenetic mechanism of the alcohol-induced damage to the developing brain.

Effects of Acute Alcohol Exposure on Layer 5 Pyramidal Neurons of Juvenile Mice.

Early-onset drinking during childhood or preadolescence is a serious social problem. Yet, most of the basic neurobiological research on the acute effects of ethanol has been carried out on adult or early postnatal animals. We studied the effect of alcohol exposure on the basic electrophysiological properties and cell viability of layer 5 pyramidal neurons from the somatosensory cortex of juvenile (P21-P23) C57BL/6N mice. After bath application of 50 mM ethanol to acute slices of the somatosensory cortex, no adverse effects were detected on cells survival, whereas the input resistance and firing rate of layer 5 neurons were significantly reduced. While the effect on the input resistance was reversible, the depressing effect on cell firing remained stable after 6 min of alcohol exposure. Ethanol application did not result in any significant change of mIPSC frequency, amplitude, and rise time. A slight increase of mIPSC decay time was observed after 6 min of ethanol exposure. The molecular mechanisms leading to these alterations and their significance for the physiology of the cerebral cortex are briefly discussed.

The laminar organization of the motor cortex in monodactylous mammals: a comparative assessment based on horse, chimpanzee, and macaque.

The architecture of the neocortex classically consists of six layers, based on cytological criteria and on the layout of intra/interlaminar connections. Yet, the comparison of cortical cytoarchitectonic features across different species proves overwhelmingly difficult, due to the lack of a reliable model to analyze the connection patterns of neuronal ensembles forming the different layers. We first defined a set of suitable morphometric cell features, obtained in digitized Nissl-stained sections of the motor cortex of the horse, chimpanzee, and crab-eating macaque. We then modeled them using a quite general non-parametric data representation model, showing that the assessment of neuronal cell complexity (i.e., how a given cell differs from its neighbors) can be performed using a suitable measure of statistical dispersion such as the mean absolute deviation-mean absolute deviation (MAD). Along with the non-parametric combination and permutation methodology, application of MAD allowed not only to estimate, but also to compare and rank the motor cortical complexity across different species. As to the instances presented in this paper, we show that the pyramidal layers of the motor cortex of the horse are far more irregular than those of primates. This feature could be related to the different organizations of the motor system in monodactylous mammals.

Neural plasticity and network remodeling: From concepts to pathology.

Neuroplasticity has been subject to a great deal of research in the last century. Recently, significant emphasis has been placed on the global effect of localized plastic changes throughout the central nervous system, and on how these changes integrate in a pathological context. Specifically, alterations of network functionality have been described in various pathological contexts to which corresponding structural alterations have been proposed. However, considering the amount of literature and the different pathological contexts, an integration of this information is still lacking. In this paper we will review the concepts of neural plasticity as well as their repercussions on network remodeling and provide a possible explanation to how these two concepts relate to each other. We will further examine how alterations in different pathological contexts may relate to each other and will discuss the concept of plasticity diseases, its models and implications.

Erratum to: Long-term alterations of striatal parvalbumin interneurons in a rat model of early exposure to alcohol.

[This corrects the article DOI: 10.1186/1866-1955-4-18.].

The Brain of the Domestic Bos taurus: Weight, Encephalization and Cerebellar Quotients, and Comparison with Other Domestic and Wild Cetartiodactyla.

The domestic bovine Bos taurus is raised worldwide for meat and milk production, or even for field work. However the functional anatomy of its central nervous system has received limited attention and most of the reported data in textbooks and reviews are derived from single specimens or relatively old literature. Here we report information on the brain of Bos taurus obtained by sampling 158 individuals, 150 of which at local abattoirs and 8 in the dissecting room, these latter subsequently formalin-fixed. Using body weight and fresh brain weight we calculated the Encephalization Quotient (EQ), and Cerebellar Quotient (CQ). Formalin-fixed brains sampled in the necropsy room were used to calculate the absolute and relative weight of the major components of the brain. The data that we obtained indicate that the domestic bovine Bos taurus possesses a large, convoluted brain, with a slightly lower weight than expected for an animal of its mass. Comparisons with other terrestrial and marine members of the order Cetartiodactyla suggested close similarity with other species with the same feeding adaptations, and with representative baleen whales. On the other hand differences with fish-hunting toothed whales suggest separate evolutionary pathways in brain evolution. Comparison with the other large domestic herbivore Equus caballus (belonging to the order Perissodactyla) indicates that Bos taurus underwent heavier selection of bodily traits, which is also possibly reflected in a comparatively lower EQ than in the horse. The data analyzed suggest that the brain of domestic bovine is potentially interesting for comparative neuroscience studies and may represents an alternative model to investigate neurodegeneration processes.

Reduced density of dendritic spines in pyramidal neurons of rats exposed to alcohol during early postnatal life.

Dendritic spines are the main postsynaptic sites of excitatory connections of neocortical pyramidal neurons. Alterations of spine shape, number, and density can be observed in different mental diseases, including those caused by developmental alcohol exposure. Pyramidal neurons of layer 2/3 are the most abundant cells of the neocortex and represent the main source of associative cortico-cortical connections. These neurons are essential for higher functions mediated by the cortex such as feature selection and perceptual grouping. Furthermore, their connections have been shown to be altered in experimental models of fetal alcohol spectrum disorders. Here, we used a Golgi-like tracing method to study the spine density of layer 2/3 associative pyramidal neurons in the somatosensory cortex of adult rats exposed to alcohol during the first postnatal week. The main result of the present study is represented by the decreased spine density in the apical dendrite of alcohol-treated rats, as compared to controls. As to the basal dendritic tree, there were no significant differences between the experimental and the control group. A decreased density of dendritic spines in the apical dendrite may impair the excitatory input onto pyramidal neurons, thus resulting in a widespread alteration of the cortical information flow.