The ASD Living Biology: from cell proliferation to clinical phenotype.

Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child's development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD

Comprehensive in vivo Mapping of the Human Basal Ganglia and Thalamic Connectome in Individuals Using 7T MRI

Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects

The iPSC perspective on schizophrenia

Over a decade of schizophrenia research using human induced pluripotent stem cell (iPSC)-derived neural models has provided substantial data describing neurobiological characteristics of the disorder in vitro. Simultaneously, translation of the results into general mechanistic concepts underlying schizophrenia pathophysiology has been trailing behind. Given that modeling brain function using cell cultures is challenging, the gap between the in vitro models and schizophrenia as a clinical disorder has remained wide. In this review, we highlight reproducible findings and emerging trends in recent schizophrenia-related iPSC studies. We illuminate the relevance of the results in the context of human brain development, with a focus on processes coinciding with critical developmental periods for schizophrenia.Peer reviewe

Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives

The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing parvalbumin-expressing (PV) interneurons from mouse embryonic stem cells. This method, which uses an atypical protein kinase C inhibitor to enhance intermediate neurogenesis, results in a markedly increased ratio of PV+ to somatostatin-expressing interneurons. The findings suggest that the mode of neurogenesis influences cortical interneuron fate determination. Moreover, PV+ interneurons can now be generated in large numbers to study their development, screen for factors that affect their physiology, and used in therapeutic applications. The second part of this thesis examines the function of two putative transcription factors, Zswim5 and Zswim6, in the regulation of striatal development. We show that these genes are expressed in subpallial precursors, and in the case of Zswim6, expressed in the adult striatum. Next, through the generation of Zswim5 and Zswim6 knockout mice, we provide a detailed anatomical, molecular, and behavioral characterization of the resulting phenotypes. Our findings reveal that loss of Zswim6 causes a reduction in striatal volume and morphological changes in MSN. Additionally, these structural changes are associated with alterations in motor behaviors including hyperactivity, impaired rotarod performance, and hyperresponsiveness to amphetamine. These results demonstrate that Zswim6 is indispensable for normal brain development and support findings in human genome-wide association studies that implicate Zswim6 with schizophrenia. Collectively, this dissertation provides novel insights into telencephalic development through the development of in vitro stem cell systems and in vivo disease mouse models that further our ability to test and understand neurological diseases

How microbiota composition and diversity are related to striatal volumes in early life

A primary goal of gut-brain research is to understand how human gut microbiota affects mental health such as cognition or neuropsychiatric disorders. Studies employing rodent models reported that gut microbiota had a strong influence on neurodevelopment, especially during the critical period of ‘developmental programming’, which seems to be a key window for external influences. However, knowledge of the origins of the relationship between gut-microbiota and brain functions is still limited due to the scarcity of the human gut-brain studies, particularly those focusing on infant populations. Deep brain structures, in particular subcortical structures such as the striatum, are major components to the gut-brain axis and also have been shown to have a central role in neurodevelopment. Finally, previous literature demonstrates that the first years of life are critical to neurodevelopment and gastrointestinal colonization. The aim of this thesis is to explore the relationship between the fecal microbiota composition and diversity of 2.5 months infants and the striatum volumes measured at one month. This exploratory cross-sectional study was conducted using data collected on 56 infants drawn from the FinnBrain Birth Cohort study, which focuses on the effects of environmental and genetic stimuli on child development and health. The results showed no statistically significant associations between alpha and beta-diversity, and the striatum volumes. The correlation between alpha-diversity and striatum volumes tended to present visible sex-differences, despite their statistical insignificance. This novel study encourages future longitudinal studies to provide insight into the relationship between characteristics of the gut microbiota and the development of the brain especially during the critical phases of neurodevelopment throughout life

Warranting evidence in diverse evidentiary settings

Informal logic, is faced with the problematic of persuasive arguments in contexts where evidence is rich, diverse and preferentially selected on the basis of pre-established attitudes. This requires that the standard view of challenge by presenting inconsistent evidence be rethought. In this paper, I will argue that the solution is to focus less on evidence that contradicts claims and to confront the network of warrants that support the selecting and evaluating of evidentiary moves

THE LEFT HEMISPHERE’S STRUCTURAL CONNECTIVITY FOR THE INFERIOR FRONTAL GYRUS, STRIATUM, AND THALAMUS, AND INTRA-THALAMIC TOPOGRAPHY

The neuroanatomy of language cognition has an extensive history of scientific interest and inquiry. Over a century of behavioral lesion studies and decades of functional neuroimaging research have established the left hemisphere’s inferior frontal gyrus (IFG) as a critical region for speech and language processing. This region’s subcortical projections are thought to be instrumental for supporting and integrating the cognitive functions of the language network. However, only a subset of these projections have been shown to exist in humans, and structural evidence of pars orbitalis’ subcortical circuitry has been limited to non-human primates. This thesis demonstrates direct, intra-structural connectivity of each of the left IFG’s gyral regions with the thalamus and the putamen in humans, using high-angular, deterministic tractography. Novel processing and analysis methods elucidated evidence of predominantly segregated cortical circuits within the thalamus, and suggested the presence of parallel circuits for motor/language integration along the length of the putamen