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Science (New York, N.Y.) Jan 2022The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this...
The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain.
Topics: Animals; Animals, Newborn; Cell Movement; Cell Proliferation; Cerebral Cortex; GABAergic Neurons; Gene Expression Profiling; Gestational Age; Humans; Interneurons; Median Eminence; Mice; Neural Stem Cells; Neurogenesis; Prosencephalon; Transplantation, Heterologous
PubMed: 35084970
DOI: 10.1126/science.abk2346 -
Philosophical Transactions of the Royal... Feb 2022We are curious by nature, particularly when young. Evolution has endowed our brain with an inbuilt obligation to educate itself. In this perspectives article, we posit... (Review)
Review
We are curious by nature, particularly when young. Evolution has endowed our brain with an inbuilt obligation to educate itself. In this perspectives article, we posit that self-tuition is an evolved principle of vertebrate brain design that is reflected in its basic architecture and critical for its normal development. Self-tuition involves coordination between functionally distinct components of the brain, with one set of areas motivating exploration that leads to the experiences that train another set. We review key hypothalamic and telencephalic structures involved in this interplay, including their anatomical connections and placement within the segmental architecture of conserved forebrain circuits. We discuss the nature of educative behaviours motivated by the hypothalamus, innate stimulus biases, the relationship to survival in early life, and mechanisms by which telencephalic areas gradually accumulate knowledge. We argue that this aspect of brain function is of paramount importance for systems neuroscience, as it confers neural specialization and allows animals to attain far more sophisticated behaviours than would be possible through genetic mechanisms alone. Self-tuition is of particular importance in humans and other primates, whose large brains and complex social cognition rely critically on experience-based learning during a protracted childhood period. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.
Topics: Animals; Brain; Neurosciences; Primates; Prosencephalon; Telencephalon
PubMed: 34957855
DOI: 10.1098/rstb.2020.0530 -
Developmental Neuroscience 2023Human neurodevelopment is characterized by the appearance, development, and disappearance or transformation of various transient structures that underlie the...
Human neurodevelopment is characterized by the appearance, development, and disappearance or transformation of various transient structures that underlie the establishment of connectivity within and between future cortical and subcortical areas. Examples of transient structures in the forebrain (among many others) include the subpial granular layer and the subplate zone. We have previously characterized the precise spatiotemporal dynamics of microglia in the human telencephalon. Here, we describe the diversity of microglial morphologies in the subpial granular layer and the subplate zone. Where possible, we couple the predominant morphological phenotype with functional characterizations to infer tentative roles for microglia in a changing neurodevelopmental landscape. We interpret these findings within the context of relevant morphogenetic and neurogenetic events in humans. Due to the unique genetic, molecular, and anatomical features of the human brain and because many human neurological and psychiatric diseases have their origins during development, these structures deserve special attention.
Topics: Humans; Microglia; Telencephalon; Phenotype; Prosencephalon; Mental Disorders
PubMed: 36720218
DOI: 10.1159/000528911 -
Anesthesiology Apr 2021
Topics: Acetylcholine; Anesthesia; Animals; Consciousness; Isoflurane; Ketamine; Mice; Prosencephalon
PubMed: 33635939
DOI: 10.1097/ALN.0000000000003696 -
Environmental Pollution (Barking, Essex... Nov 2023The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in...
The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in pluripotent cell-derived organoid systems open up novel avenues for human development, disease and toxicity modeling. Here, we have established a forebrain organoid system and recapitulated early human cortical development spatiotemporally including neuroepithelium induction, apical-basal axis formation, neural progenitor proliferation and maintenance, neuronal differentiation and layer/region patterning. To explore whether this forebrain organoid system is suitable for neurotoxicity modeling, we subjected the organoids to bisphenol A (BPA), a common environmental toxicant of global presence and high epidemic significance. BPA exposure caused substantial abnormalities in key cortical developmental events, inhibited progenitor cell proliferation and promoted precocious neuronal differentiation, leading premature progenitor cell depletion and aberrant cortical layer patterning and structural organization. Consistent with an antagonistic mechanism between thyroid hormone and BPA, T3 supplementation attenuated BPA-mediated cortical developmental abnormalities. Altogether, our in vitro recapitulation of cortical development with forebrain organoids provides a paradigm for efficient neural development and toxicity modeling and related remedy testing/screening.
Topics: Humans; Neurogenesis; Prosencephalon; Stem Cells; Organoids
PubMed: 37757934
DOI: 10.1016/j.envpol.2023.122624 -
Handbook of Clinical Neurology 2021The arcuate nucleus (ARC) is located in the mediobasal hypothalamus and forms a morphological and functional entity with the median eminence (ME), the ARC-ME. The ARC... (Review)
Review
The arcuate nucleus (ARC) is located in the mediobasal hypothalamus and forms a morphological and functional entity with the median eminence (ME), the ARC-ME. The ARC comprises several distinct types of neurons controlling prolactin release, food intake, and metabolism as well as reproduction and onset of puberty. The ME lacks a blood-brain barrier and provides an entry for peripheral signals (nutrients, leptin, ghrelin). ARC neurons are adjacent to the wall of the third ventricle. This facilitates the exchange of signals from and to the cerebrospinal fluid. The ventricular wall is composed of tanycytes that serve different functions. Axons of ARC neurons contribute to the tuberoinfundibular tract terminating in the ME on the hypophysial portal vessels (HPV) and establish one of the neurohumoral links between the hypothalamus and the pituitary. ARC neurons are reciprocally connected with several other hypothalamic nuclei, the brainstem, and reward pathways. The hypophysial pars tuberalis (PT) is attached to the ME and the HPV. The PT, an important interface of the neuroendocrine system, is mandatory for the control of seasonal functions. This contribution provides an update of our knowledge about the ARC-ME complex and the PT which, inter alia, is needed to understand the pathophysiology of metabolic diseases and reproduction.
Topics: Arcuate Nucleus of Hypothalamus; Humans; Hypothalamus; Median Eminence; Neurons; Pituitary Gland
PubMed: 34225932
DOI: 10.1016/B978-0-12-820107-7.00015-X -
Interventional Neuroradiology : Journal... Dec 2020
Topics: Humans; Intracranial Arteriovenous Malformations; Prosencephalon; Vein of Galen Malformations
PubMed: 33283591
DOI: 10.1177/1591019920935316 -
Neuropharmacology Jul 2021Glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) form the delta family of ionotropic glutamate receptors; these proteins plays widespread roles in synaptic... (Review)
Review
Glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) form the delta family of ionotropic glutamate receptors; these proteins plays widespread roles in synaptic architecture, motor behavior, and cognitive function. Though the role of GluD2 at cerebellar parallel fiber-Purkinje cell synapses is well established, attention now turns to the function of GluD receptors in the forebrain. GluD1 regulates synaptic assembly and modulation in multiple higher brain regions, acting as a postsynaptic cell adhesion molecule with effects on both excitatory and inhibitory transmission. Furthermore, variations and mutations in the GRID1 gene, which codes for GluD1, and in genes which code for proteins functionally linked to GluD1, are associated with mental disorders including autism, schizophrenia, bipolar disorder, and major depression. Cerebellin (Cbln) family proteins, the primary binding partners of delta receptors, are secreted C1q-like proteins which also bind presynaptic neurexins (NRXNs), forming a tripartite synaptic bridge. Published research explores this bridge's function in regions including the striatum, hippocampus, cortex, and cerebellum. In this review, we summarize region- and circuit-specific functions and expression patterns for GluD1 and its related proteins, and their implications for behavior and disease.
Topics: Animals; Brain Mapping; Humans; Mental Disorders; Prosencephalon; Receptors, Glutamate; Synapses
PubMed: 33992669
DOI: 10.1016/j.neuropharm.2021.108587 -
Journal of Alzheimer's Disease : JAD 2021Memory and cognitive impairment as sequelae of neurodegeneration in Alzheimer's disease and age-related dementia are major health issues with increasing social and... (Review)
Review
Memory and cognitive impairment as sequelae of neurodegeneration in Alzheimer's disease and age-related dementia are major health issues with increasing social and economic burden. Deep brain stimulation (DBS) has emerged as a potential treatment to slow or halt progression of the disease state. The selection of stimulation target is critical, and structures that have been targeted for memory and cognitive enhancement include the Papez circuit, structures projecting to the frontal lobe such as the ventral internal capsule, and the cholinergic forebrain. Recent human clinical and animal model results imply that DBS of the nucleus basalis of Meynert can induce a therapeutic modulation of neuronal activity. Benefits include enhanced activity across the cortical mantle, and potential for amelioration of neuropathological mechanisms associated with Alzheimer's disease. The choice of stimulation parameters is also critical. High-frequency, continuous stimulation is used for movement disorders as a way of inhibiting their output; however, no overexcitation has been hypothesized in Alzheimer's disease and lower stimulation frequency or intermittent patterns of stimulation (periods of stimulation interleaved with periods of no stimulation) are likely to be more effective for stimulation of the cholinergic forebrain. Efficacy and long-term tolerance in human patients remain open questions, though the cumulative experience gained by DBS for movement disorders provides assurance for the safety of the procedure.
Topics: Alzheimer Disease; Animals; Basal Nucleus of Meynert; Cholinergic Agents; Cognition Disorders; Deep Brain Stimulation; Humans; Prosencephalon
PubMed: 34334401
DOI: 10.3233/JAD-210425 -
Proceedings of the National Academy of... Jun 2023Mental health disorders often arise as a combination of environmental and genetic factors. The gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key...
Mental health disorders often arise as a combination of environmental and genetic factors. The gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic () and GABAergic () neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.
Topics: Male; Female; Humans; Mental Disorders; GABAergic Neurons; Prosencephalon; Tacrolimus Binding Proteins
PubMed: 37252963
DOI: 10.1073/pnas.2300722120