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Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host–microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain–gut–kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain–gut–kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain–gut–kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.

Folding of the cerebral cortex is a fundamental milestone of mammalian brain evolution and is associated with dramatic increases in size and complexity. New animal models, genetic tools and bioengineering materials have moved the study of cortical folding from simple phenomenological observation to sophisticated experimental testing. Here, we provide an overview of how genetics, cell biology and biomechanics shape this complex and multifaceted process and affect each other. We discuss the evolution of cortical folding and the genomic changes in the primate lineage that seem to be responsible for the advent of larger brains and cortical folding. Emerging technologies now provide unprecedented tools to analyse and manipulate cortical folding, with the promise of elucidating the mechanisms underlying the stereotyped folding of the cerebral cortex in its full complexity.

Key Points Notable heterogeneity exists in the neuropathological substrates that underlie dementia in the setting of Parkinson's disease dementia (PDD). Nevertheless, the presumptive caudal-to-rostral spread of Lewy body and neurite pathology from the lower brainstem to telencephalic regions, which culminates in a heavy burden of this α-synuclein (α-syn) pathology in limbic and neocortical structures, is the most characteristic pathological finding in most PDD cases. Up to 50% of patients with PDD can have sufficient amyloid-β (Aβ) plaque and tau neurofibrillary tangle (NFT) pathology for the diagnosis of a second neurodegenerative dementia — that is, Alzheimer's disease (AD) — and this co-morbid pathology is more common in PDD than PD. Tau NFT and Aβ plaque pathology may act synergistically with Lewy body and neurite pathology to confer a worse prognosis and a higher burden of cortical Lewy body and neurite pathology in PDD. Clinical phenotypes of PD may help to identify neuropathological subtypes of PD that exhibit differing propensities for developing dementia. For example, non-tremor-dominant or postural gait instability PD phenotypes may often be associated with greater Aβ plaque pathology and shorter times to dementia in patients with PDD than in patients with PD exhibiting less co-morbid AD neuropathology and a tremor-dominant phenotype. Genetic variations may contribute to the heterogeneity in the neuropathology and the time-of-onset of dementia in PD. For example, the apolipoprotein E ( APOE ) ε4 genotype may increase both Lewy body and neurite pathology and AD neuropathology and result in an increased risk of dementia in PD. Moreover, heterozygous mutations in β-glucocerebrosidase ( GBA ) may increase the severity of Lewy body and neurite patholgy in 'pure' synucleinopathies. Further biomarker and detailed clinicopathological correlation studies of prospective patients will help to further elucidate the inter-relationships of AD and α-syn pathology in PD and the development of dementia in patients with PD. These discoveries will be crucial in the development of meaningful disease-modifying therapies for PDD. Many cases of Parkinson's disease (PD) are characterized by not only deficits in movement but also cognitive dysfunction, which can develop into dementia. Here, Irwin et al . review the complex connections between the neuropathological aetiologies that underlie the cognitive deficits associated with PD. Dementia is increasingly being recognized in cases of Parkinson's disease (PD); such cases are termed PD dementia (PDD). The spread of fibrillar α-synuclein (α-syn) pathology from the brainstem to limbic and neocortical structures seems to be the strongest neuropathological correlate of emerging dementia in PD. In addition, up to 50% of patients with PDD also develop sufficient numbers of amyloid-β plaques and tau-containing neurofibrillary tangles for a secondary diagnosis of Alzheimer's disease, and these pathologies may act synergistically with α-syn pathology to confer a worse prognosis. An understanding of the relationships between these three distinct pathologies and their resultant clinical phenotypes is crucial for the development of effective disease-modifying treatments for PD and PDD.

The cortical patterning principle has been a long-standing question in neuroscience, yet how this translates to macroscale functional specialization in the human brain remains largely unknown. Here we examine age-dependent differences in resting-state thalamocortical connectivity to investigate its role in the emergence of large-scale functional networks during early life, using a primarily cross-sectional but also longitudinal approach. We show that thalamocortical connectivity during infancy reflects an early differentiation of sensorimotor networks and genetically influenced axonal projection. This pattern changes in childhood, when connectivity is established with the salience network, while decoupling externally and internally oriented functional systems. A developmental simulation using generative network models corroborated these findings, demonstrating that thalamic connectivity contributes to developing key features of the mature brain, such as functional segregation and the sensory-association axis, especially across 12–18 years of age. Our study suggests that the thalamus plays an important role in functional specialization during development, with potential implications for studying conditions with compromised internal and external processing. The thalamus is important for neocortical functional specialization. Here the authors show its shifting role in shaping large-scale functional organization during early life in humans, particularly in developing the internal–external cortical hierarchy.

Key Points Corticostriatal (CStr) projections are formed by two distinct classes of cortical pyramidal neurons: intratelencephalic (IT) and pyramidal tract (PT) neurons. IT and PT neurons are highly differentiated at multiple levels, including long-range axonal projections, local cortical circuits, intrinsic electrical properties, neuromodulatory mechanisms and molecular profiles. Many neurological and neuropsychiatric diseases involve dysfunction in the CStr system. In several of these, evidence is accumulating for specific changes in the functional properties of IT and PT neurons and their circuits. Autism appears to involve changes especially in IT neurons and networks. Amyotrophic lateral sclerosis involves degeneration of corticospinal neurons, a major subtype of PT neurons. In Parkinson's disease, a hypokinetic movement disorder, PT neurons are particularly implicated in the disease process. The therapeutic efficacy of deep brain stimulation in the subthalamic nucleus has been ascribed to antidromic activation of PT neurons in the cortex. In Huntington's disease, a hyperkinetic movement disorder, CStr changes suggest both IT and PT involvement. CStr changes are prominent in neuropsychiatric disorders such as schizophrenia and obsessive-compulsive disorder. In major depression, animal studies point to IT specificity. Collectively the evidence suggests that 'IT/PT imbalance' may be a useful concept for guiding further research into diseases involving CStr dysfunction. The distinct properties of IT and PT neurons present abundant opportunities for developing cell type-specific interventions in these disorders. Corticostriatal pathways consist of two distinct classes of cortical pyramidal cells: intratelencephalic and pyramidal tract neurons. In this Review, Shepherd explains how changes in the functional properties of these neurons result in an imbalance in activity that contributes to a wide variety of neurological disorders. Corticostriatal projections are essential components of forebrain circuits and are widely involved in motivated behaviour. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) neurons. Convergent evidence points to IT versus PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signalling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an aetiological factor in neurodevelopmental, neuropsychiatric and movement disorders — autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington's and Parkinson's diseases and major depression are highlighted here.

Key Points Recent neurobiological insights into this gut–brain crosstalk have revealed a complex, bidirectional communication system that not only assures proper maintenance of gastrointestinal homeostasis and digestion but is likely to have multiple effects on affect, motivation and higher cognitive functions. Sympathetic and parasympathetic innervations modulate intestinal function and are likely to mediate the reported emotion-related patterns of regional changes in motor, secretory and possibly immune activity in the gastrointestinal tract. There are three basic mechanisms by which sensory information is encoded in the gut: by primary afferent neurons, by immune cells and by enteroendocrine cells. Both extrinsic and intrinsic primary afferents provide input to multiple reflex loops that are aimed at optimizing gut function and maintaining gastrointestinal homeostasis during internal perturbations. The output of enteroendocrine cells is involved both in the regulation of digestive functions through enteric nervous system circuits, as well as in the regulation of CNS processes through endocrine and paracrine signalling to vagal afferents. Immune cells in the gut remain immunologically hyporesponsive to commensal bacteria, while maintaining their responsiveness to pathogenic organisms, and their products indirectly influence the functional properties of enteroendocrine cells. Recent evidence suggests that various forms of subliminal interoceptive inputs from the gut, including those generated by intestinal microbes, may influence memory formation, emotional arousal and affective behaviours. The human insula, and related brain networks (including the anterior cingulate cortex, orbitofrontal cortex and amygdala), has emerged as the most plausible brain region to support this integration. It remains to be determined whether intuitive decision making is based on an interoceptive map of gut responses that enables the brain to make rapid gut-based decisions based on interoceptive memories of such responses. There is extensive evidence of alterations in brain–gut signalling systems during perturbation to gut homeostasis, in several chronic gastrointestinal disorders and in eating disorders. Further understanding of the bidirectional crosstalk between the brain and the digestive system may aid the development of effective therapies for these conditions. The importance of interactions between the brain and the digestive system in health and disease has been recognized for centuries. Mayer reviews the neuroanatomy and signalling mechanisms that underlie this bidirectional communication system in health and disease, as well as possible consequences for higher-level executive functions and emotional states. The concept that the gut and the brain are closely connected, and that this interaction plays an important part not only in gastrointestinal function but also in certain feeling states and in intuitive decision making, is deeply rooted in our language. Recent neurobiological insights into this gut–brain crosstalk have revealed a complex, bidirectional communication system that not only ensures the proper maintenance of gastrointestinal homeostasis and digestion but is likely to have multiple effects on affect, motivation and higher cognitive functions, including intuitive decision making. Moreover, disturbances of this system have been implicated in a wide range of disorders, including functional and inflammatory gastrointestinal disorders, obesity and eating disorders.

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.

Key Points NMDA receptor isoforms respond to glutamate with distinct kinetics and have dynamic, complex and incompletely delineated expression profiles; precise mechanistic information for specific receptor isoforms is derived from recombinant preparations. Functional attributes of recombinant receptor current match well to those of the NMDA receptor-mediated response recorded from synaptic and non-synaptic native receptors. Kinetic models derived from one-channel recordings reproduce all known features of the macroscopic response and reveal novel biophysical properties that underlie physiologically salient features of the synaptic current. The NMDA receptor response amplitude and ionic charge transfer, which initiate synaptic plasticity, depend on stimulation frequency as predicted by the kinetic model. The biphasic decay time of the NMDA receptor synaptic response, which sets the window for coincident depolarization, reflects the proportion of receptors gating in distinct kinetic modes. This insight was afforded by statistical evaluation of single-channel behaviour. Assigning molecular structures to the kinetic states postulated by statistically derived models of NMDA receptor activation is an active area of research. Kinetic models of NMDA receptor activation derived from single-molecule observations explain the biologically salient features of the excitatory current as a dynamic sequence of quasi-stable receptor states. In this Review, Iacobucci and Popescu discuss how these models will help to match emerging atomic structures with biologically important functional states. NMDA receptors are preeminent neurotransmitter-gated channels in the CNS, which respond to glutamate in a manner that integrates multiple external and internal cues. They belong to the ionotropic glutamate receptor family and fulfil unique and crucial roles in neuronal development and function. These roles depend on characteristic response kinetics, which reflect the operation of the receptors. Here, we review biologically salient features of the NMDA receptor signal and its mechanistic origins. Knowledge of distinctive NMDA receptor biophysical properties, their structural determinants and physiological roles is necessary to understand the physiological and neurotoxic actions of glutamate and to design effective therapeutics.

Key Points Glioblastoma is the paradigm of tumour-associated immunosuppression Several glioma-specific peptide vaccines, with or without dendritic cell support, are in late clinical development Vaccines can be combined with agents that nonspecifically boost immune responses, such as immune checkpoint inhibitors or TGFβ pathway inhibitors Standardization of clinical trial conduct might facilitate progress in this challenging field of oncology This Review presents an overview of vaccine-based immunotherapies for human glioma. Although efficacy remains unproven for the vaccines in clinical development, Weller and colleagues highlight promising strategies for antagonizing glioma-associated immunosuppression and boosting immune responses in vaccinated patients. Ultimately, such approaches might help to control the growth of human gliomas. Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.

Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment. Gene expression in the human brain Gene expression controls and dictates everything from development and plasticity to ongoing neurogenesis in the brain, yet the temporal dynamics of transcription throughout the brain's lifetime have been mostly unknown. Here, two groups present a large gene-expression database from a variety of human brain samples ranging from before birth to over 80 years in age. Colantuoni et al . focus on the prefrontal cortex. Although they note significant expression pattern dynamics throughout development, they identify a consistent molecular architecture of transcription across subjects from different races despite the large number of genetic polymorphisms among them. Kang et al . produce a more comprehensive time course, exploring expression in 16 different brain areas, determining that the largest spatiotemporal variability occurs before birth, with transcriptomes in brain regions converging as we age.