Integrin triplets of marine sponges in human D2 receptor heteromers

The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neural transmission. Based on our theory, we have discovered main triplets of amino acid residues in cell-adhesion receptors of marine sponges, which appear also as homologies in several dopamine D2 receptor heteromers of human brain. The obtained results probably mean a general molecular mechanism for receptor–receptor interactions in heteromers originated from the lowest animals (marine sponges).     

Integrin triplets of marine sponges in human D2 receptor heteromers

The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neural transmission. Based on our theory, we have discovered main triplets of amino acid residues in cell-adhesion receptors of marine sponges, which appear also as homologies in several dopamine D2 receptor heteromers of human brain. The obtained results probably mean a general molecular mechanism for receptor-receptor interactions in heteromers originated from the lowest animals (marine sponges).     

Social conflict models: can they inform us about human psychopathology?

Social conflict models have been proposed as a powerful way to investigate basic questions of how brain and behavior are altered by social experience. Social defeat, in particular, appears to be a major stressor for most species, and in humans, this stressor is thought to play an important role in the onset of a variety of psychiatric disorders including depression and post-traumatic stress disorder. Aggressive experience, on the other hand, may promote disorders involving inappropriate aggression and violence. Current research using animal models of social conflict involves multiple levels of analysis from genetic and molecular to systems and overt behavior. This review briefly examines a variety of these animal models of social conflict in order to assess whether they are useful for advancing our understanding of how experience can shape brain and behavior and for translating this information so that we have the potential to improve the quality of life of individuals with mental illness and behavioral disorders.     

Angeborene Hirnfehlbildungen und geistige Behinderung

Brain malformations are clinically and genetically important causes of psychomotor retardation and seizures. Their classification is based on cerebral imaging, which also provides important information for prognostic considerations as well as for further genetic workup. For a considerable number of the affected patients, a causal genetic alteration can be identified. Mutations in some of the involved genes are also associated with allelic disorders with milder phenotypes, including mild mental retardation without obvious structural brain malformations. Characterization of the underlying causal genetic alterations not only contributes to our understanding of the genetic control of brain development but also permits new insight into the pathophysiology of mental retardation and seizures. Furthermore, identification of the underlying mutations allows individual genetic counseling of the affected families regarding specific recurrence risks and prenatal diagnostic options in a subsequent pregnancy.     

Beyond the “at risk mental state” concept: transitioning to transdiagnostic psychiatry

The “at risk mental state” for psychosis approach has been a catalytic, highly productive research paradigm over the last 25 years. In this paper we review that paradigm and summarize its key lessons, which include the valence of this phenotype for future psychosis outcomes, but also for comorbid, persistent or incident non‐psychotic disorders; and the evidence that onset of psychotic disorder can at least be delayed in ultra high risk (UHR) patients, and that some full‐threshold psychotic disorder may emerge from risk states not captured by UHR criteria. The paradigm has also illuminated risk factors and mechanisms involved in psychosis onset. However, findings from this and related paradigms indicate the need to develop new identification and diagnostic strategies. These findings include the high prevalence and impact of mental disorders in young people, the limitations of current diagnostic systems and risk identification approaches, the diffuse and unstable symptom patterns in early stages, and their pluripotent, transdiagnostic trajectories. The approach we have recently adopted has been guided by the clinical staging model and adapts the original “at risk mental state” approach to encompass a broader range of inputs and output target syndromes. This approach is supported by a number of novel modelling and prediction strategies that acknowledge and reflect the dynamic nature of psychopathology, such as dynamical systems theory, network theory, and joint modelling. Importantly, a broader transdiagnostic approach and enhancing specific prediction (profiling or increasing precision) can be achieved concurrently. A holistic strategy can be developed that applies these new prediction approaches, as well as machine learning and iterative probabilistic multimodal models, to a blend of subjective psychological data, physical disturbances (e.g., EEG measures) and biomarkers (e.g., neuroinflammation, neural network abnormalities) acquired through fine‐grained sequential or longitudinal assessments. This strategy could ultimately enhance our understanding and ability to predict the onset, early course and evolution of mental ill health, further opening pathways for preventive interventions.     

Stem cells and neonatal brain injury

Recent advances in regenerative medicine and in our understanding of neurogenesis may lead to new ways of recovering neuronal function lost or damaged during the perinatal period; such injuries are not amenable to conventional therapies. We review recent experimental studies based on immature rodental models of neonatal brain injury, especially hypoxic-ischemic encephalopathy. The developing brain is revealed to have considerable potential with respect to proliferation and migration to the injured site. However, the generation of fully differentiated neurons is extremely limited after brain injuries. Aggressive efforts to adjust the environment of the damaged brain in which tissue regeneration is occurring or more cautious stem cell transplantation will be required for the successful treatment of developmental brain injury. This work was supported by a Research Grant for Cardiovascular Diseases (18C-1) from the Ministry of Health, Labour and Welfare.     

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.     

Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder. It is characterized by two principal features, microcephaly present at birth and nonprogressive mental retardation. The microcephaly is the consequence of a small but architecturally normal brain, and it is the cerebral cortex that shows the greatest size reduction. There are at least seven MCPH loci, and four of the genes have been identified: MCPH1, encoding Microcephalin; MCPH3, encoding CDK5RAP2; MCPH5, encoding ASPM; and MCPH6, encoding CENPJ. These findings are starting to have an impact on the clinical management of families affected with MCPH. Present data suggest that MCPH is the consequence of deficient neurogenesis within the neurogenic epithelium. Evolutionary interest in MCPH has been sparked by the suggestion that changes in the MCPH genes might also be responsible for the increase in brain size during human evolution. Indeed, evolutionary analyses of Microcephalin and ASPM reveal evidence for positive selection during human and great ape evolution. So an understanding of this rare genetic disorder may offer us significant insights into neurogenic mitosis and the evolution of the most striking differences between us and our closest living relatives: brain size and cognitive ability.     

Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer's disease

It has been widely accepted that vascular hypoperfusion induces oxidative stress and the outcome of this misbalance is brain energy failure. This abnormality leads to neuronal death which manifests as cognitive impairment and the development of brain pathology as in Alzheimer's disease (AD). It has been demonstrated that the AD brain is characterized by impairments in energy metabolism. We theorize that hypoperfusion induced mitochondrial failure plays a key role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and in selective population of neurons with high metabolic activity in the AD brain. All of these abnormalities have been found to occur before classic AD pathology inducing neuronal degeneration and amyloid deposition during the progression of AD. Therefore, expanding investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors such as chronic hypoxia/reperfusion may open a new avenue for effective treatments of AD. Future studies examining the importance of mitochondrial pathobiology in brain cellular compartments provide insight not only into the better understanding of the neurodegenerative and/or cerebrovascular disease but also provide targets for treating these conditions.     

Sister chromatid cohesion control and aneuploidy

Apart from a personal tragedy, could Down syndrome, cancer and infertility possibly have something in common? Are there links between a syndrome with physical and mental problems, a tumor growing out of control and the incapability to reproduce? These questions can be answered if we look at the biological functions of a protein complex, named cohesin, which is the main protagonist in the regulation of sister chromatid cohesion during chromosome segregation in cell division. The establishment, maintenance and removal of sister chromatid cohesion is one of the most fascinating and dangerous processes in the life of a cell. Errors in the control of sister chromatid cohesion frequently lead to cell death or aneuploidy. Recent results showed that cohesins also have important functions in non-dividing cells, revealing new, unexplored roles for these proteins in human syndromes, currently known as cohesinopathies. In the last 10 years, we have improved our understanding of the molecular mechanisms of the cohesin and cohesin-interacting proteins regulating the different events of sister chromatid cohesion during cell division in mitosis and meiosis.     

Prospects for research on the modulation of gene activity during brain aging

This brief review is concerned with prospects of the role of modulated gene expression in the brain during aging and in two age-related neurological diseases: Parkinson's and Alzheimer's diseases. Two key mechanisms involved in the disturbance of neuronal function during aging, i. e. deafferentation syndromes (as a result of the impairment of afferent influences) and steroid-induced neuronal changes, have been studied. The author suspects that many aspects of cell aging in the brain represent the influence of the environmental factors. The conception of new therapeutic approaches to the treatment of Alzheimer's disease has been developed.     

Language development.

Recent research suggests that our ability to learn language is innate, but not necessarily domain-specific. That is, language development appears to be based on a relatively plastic mix of neural systems that also serve other cognitive and perceptual functions. Evidence in support of this conclusion includes neural network simulations of language learning, event-related brain potential studies of normal language development, and studies of language development in several clinical populations of subjects suffering focal brain injury, specific language impairment, and contrasting forms of mental retardation.     

Searching for a baseline: functional imaging and the resting human brain

Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.     

Anatomical connectivity influences both intra- and inter-brain synchronizations

Recent development in diffusion spectrum brain imaging combined to functional simulation has the potential to further our understanding of how structure and dynamics are intertwined in the human brain. At the intra-individual scale, neurocomputational models have already started to uncover how the human connectome constrains the coordination of brain activity across distributed brain regions. In parallel, at the inter-individual scale, nascent social neuroscience provides a new dynamical vista of the coupling between two embodied cognitive agents. Using EEG hyperscanning to record simultaneously the brain activities of subjects during their ongoing interaction, we have previously demonstrated that behavioral synchrony correlates with the emergence of inter-brain synchronization. However, the functional meaning of such synchronization remains to be specified. Here, we use a biophysical model to quantify to what extent inter-brain synchronizations are related to the anatomical and functional similarity of the two brains in interaction. Pairs of interacting brains were numerically simulated and compared to real data. Results show a potential dynamical property of the human connectome to facilitate inter-individual synchronizations and thus may partly account for our propensity to generate dynamical couplings with others.     

Brain evolution by brain pathway duplication

Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel brain pathways and functions of the nervous system. Here, we review and further develop some insights to a new hypothesis on one mechanism that may contribute to nervous system evolution, in particular by brain pathway duplication. Like gene duplication, we propose that whole brain pathways can duplicate and the duplicated pathway diverge to take on new functions. We suggest that one mechanism of brain pathway duplication could be through gene duplication, although other mechanisms are possible. We focus on brain pathways for vocal learning and spoken language in song-learning birds and humans as example systems. This view presents a new framework for future research in our understanding of brain evolution and novel behavioural traits.     

Homeobox Genes in the Developing Mouse Brain

Abstract: Any list of past and recent findings on vertebrate brain prenatal development would have to include the fundamental roles of homeobox genes, the genes encoding the nuclear regulatory homeodomain proteins. The discovery of homeobox genes and their involvement as master regulatory elements in programing the development of an embryo into a complete adult organism has provided a key to our understanding of ontogenesis. Also, the correlation of mouse developmental mutants and their corresponding human syndromes with mutations in homeobox genes has provided further evidence for the fundamental role of homeobox genes during the vertebrate brain embryonic development. Here, we review the expression patterns and the phenotypes of gene mutations that implicate a large repertoire of mouse homeobox genes in the specification of neuronal functions during brain embryogenesis.     

Autophagy: renovation of cells and tissues

Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy's role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.     

Toward a cross-species neuroscientific understanding of the affective mind: do animals have emotional feelings?

Do we need to consider mental processes in our analysis of brain functions in other animals? Obviously we do, if such BrainMind functions exist in the animals we wish to understand. If so, how do we proceed, while still retaining materialistic-mechanistic perspectives? This essay outlines the historical forces that led to emotional feelings in animals being marginalized in behavioristic scientific discussions of why animals behave the way they do, and why mental constructs are generally disregarded in modern neuroscientific analyses. The roots of this problem go back to Cartesian dualism and the attempt of 19th century physician-scientists to ground a new type of medical curriculum on a completely materialistic approach to body functions. Thereby all vitalistic principles were discarded from the lexicon of science, and subjective experience in animals was put in that category and discarded as an invalid approach to animal behavior. This led to forms of rigid operationalism during the era of behaviorism and subsequently ruthless reductionism in brain research, leaving little room for mentalistic concepts such as emotional feelings in animal research. However, modern studies of the brain clearly indicate that artificially induced arousals of emotional networks, as with localized electrical and chemical brain stimulation, can serve as "rewards" and "punishments" in various learning tasks. This strongly indicates that animal brains elaborate various experienced states, with those having affective contents being easiest to study rigorously. However, in approaching emotional feelings empirically we must pay special attention to the difficulties and vagaries of human language and evolutionary levels of control in the brain. We need distinct nomenclatures from primary (unconditioned phenomenal experiences) to tertiary (reflective) levels of mind. The scientific pursuit of affective brain processes in other mammals can now reveal general BrainMind principles that also apply to human feelings, as with neurochemical predictions from preclinical animal models to self-reports of corresponding human experiences. In short, brain research has now repeatedly verified the existence of affective experience-various reward and punishment functions-during artificial arousal of emotional networks in our fellow animals. The implications for new conceptual schema for understanding human/primate affective feelings and how such knowledge can impact scientific advances in biological psychiatry are also addressed.     

Neurodegenerative mutants in Drosophila: a means to identify genes and mechanisms involved in human diseases?

There are 50 ways to leave your lover (Simon 1987) but many more to kill your brain cells. Several neurodegenerative diseases in humans, like Alzheimer’s disease, have been intensely studied but the underlying cellular and molecular mechanisms are still unknown for most of them. For those syndromes where associated gene products have been identified their biochemistry and physiological as well as pathogenic function is often still under debate. This is in part due to the inherent limitations of genetic analyses in humans and other mammals and therefore experimentally accessible invertebrate in vivo models, such as Caenorhabditis elegans and Drosophila melanogaster, have recently been introduced to investigate neurodegenerative syndromes. Several laboratories have used transgenic approaches in Drosophila to study the human genes associated with neurodegenerative diseases. This has added substantially to our understanding of the mechanisms leading to neurodegenerative diseases in humans. The isolation and characterization of Drosophila mutants, which display a variety of neurodegenerative phenotypes, also provide valuable insights into genes, pathways, and mechanisms causing neurodegeneration. So far only about two dozen such mutants have been described but already their characterization reveals an involvement of various cellular functions in neurodegeneration, ranging from preventing oxidative stress to RNA editing. Some of the isolated genes can already be associated with human neurodegenerative diseases and hopefully the isolation and characterization of more of these mutants, together with an analysis of homologous genes in vertebrate models, will provide insights into the genetic and molecular basis of human neurodegenerative diseases.