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Neuroscience and Biobehavioral Reviews Jan 2022Although classically known as an endocrine signal produced by the ovary, 17β-estradiol (E) is also a neurosteroid produced in neurons and astrocytes in the brain of... (Review)
Review
Although classically known as an endocrine signal produced by the ovary, 17β-estradiol (E) is also a neurosteroid produced in neurons and astrocytes in the brain of many different species. In this review, we provide a comprehensive overview of the localization, regulation, sex differences, and physiological/pathological roles of brain-derived E (BDE). Much of what we know regarding the functional roles of BDE has come from studies using specific inhibitors of the E synthesis enzyme, aromatase, as well as the recent development of conditional forebrain neuron-specific and astrocyte-specific aromatase knockout mouse models. The evidence from these studies support a critical role for neuron-derived E (NDE) in the regulation of synaptic plasticity, memory, socio-sexual behavior, sexual differentiation, reproduction, injury-induced reactive gliosis, and neuroprotection. Furthermore, we review evidence that astrocyte-derived E (ADE) is induced following brain injury/ischemia, and plays a key role in reactive gliosis, neuroprotection, and cognitive preservation. Finally, we conclude by discussing the key controversies and challenges in this area, as well as potential future directions for the field.
Topics: Animals; Astrocytes; Estradiol; Estrogens; Female; Male; Mice; Neuronal Plasticity; Prosencephalon
PubMed: 34823913
DOI: 10.1016/j.neubiorev.2021.11.014 -
Cell Feb 2024Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding...
Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding organoids can be grown directly from multiple somatic tissues, yet to date, brain organoids can solely be established from pluripotent stem cells. Here, we show that healthy human fetal brain in vitro self-organizes into organoids (FeBOs), phenocopying aspects of in vivo cellular heterogeneity and complex organization. FeBOs can be expanded over long time periods. FeBO growth requires maintenance of tissue integrity, which ensures production of a tissue-like extracellular matrix (ECM) niche, ultimately endowing FeBO expansion. FeBO lines derived from different areas of the central nervous system (CNS), including dorsal and ventral forebrain, preserve their regional identity and allow to probe aspects of positional identity. Using CRISPR-Cas9, we showcase the generation of syngeneic mutant FeBO lines for the study of brain cancer. Taken together, FeBOs constitute a complementary CNS organoid platform.
Topics: Humans; Brain; Central Nervous System; Extracellular Matrix; Organoids; Pluripotent Stem Cells; Prosencephalon; Tissue Culture Techniques; Stem Cells; Morphogenesis
PubMed: 38194967
DOI: 10.1016/j.cell.2023.12.012 -
Neuron Nov 2022Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory...
Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory processing, memory, and attention. Most studies to date have treated cholinergic neurons as a single population; as such, the organizational principles underling their functional diversity remain unknown. Here, we identified two subsets (D28K versus D28K) of cholinergic neurons that are topographically segregated in mice, Macaca fascicularis, and humans. These cholinergic subpopulations possess unique electrophysiological signatures, express mutually exclusive marker genes (kcnh1 and aifm3 versus cacna1h and gga3), and make differential connections with physiologically distinct neuronal classes in the hippocampus to form two structurally defined and functionally distinct circuits. Gain- and loss-of-function studies on these circuits revealed their differential roles in modulation of anxiety-like behavior and spatial memory. These results provide a molecular and circuitry-based theory for how cholinergic neurons contribute to their diverse behavioral functions.
Topics: Humans; Mice; Animals; Cholinergic Neurons; Cholinergic Agents; Prosencephalon; Hippocampus
PubMed: 36130594
DOI: 10.1016/j.neuron.2022.08.025 -
Brain Topography May 2023The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex,... (Review)
Review
The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity of the limbic circuits based on the published literature as an update to the original Papez circuit.
Topics: Humans; Limbic System; Gyrus Cinguli; Amygdala; Thalamus; Hippocampus; Neural Pathways
PubMed: 37148369
DOI: 10.1007/s10548-023-00955-y -
World Neurosurgery May 2020The thalamus is a deep cerebral structure that is crucial for proper neurological functioning as it transmits signals from nearly all pathways in the body. Insult to the... (Review)
Review
The thalamus is a deep cerebral structure that is crucial for proper neurological functioning as it transmits signals from nearly all pathways in the body. Insult to the thalamus can, therefore, result in complex syndromes involving sensation, cognition, executive function, fine motor control, emotion, and arousal, to name a few. Specific territories in the thalamus that are supplied by deep cerebral arteries have been shown to correlate with clinical symptoms. The aim of this review is to enhance our understanding of the arterial anatomy of the thalamus and the complications that can arise from lesions to it by considering the functions of known thalamic nuclei supplied by each vascular territory.
Topics: Anterior Thalamic Nuclei; Basilar Artery; Brain Infarction; Circle of Willis; Geniculate Bodies; Humans; Lateral Thalamic Nuclei; Mediodorsal Thalamic Nucleus; Posterior Cerebral Artery; Pulvinar; Thalamus; Ventral Thalamic Nuclei
PubMed: 32036065
DOI: 10.1016/j.wneu.2020.01.237 -
Current Biology : CB Nov 2021To understand what makes sleep vulnerable in disease, it is useful to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is...
To understand what makes sleep vulnerable in disease, it is useful to look at how wake-promoting mechanisms affect healthy sleep. Wake-promoting neuronal activity is inhibited during non-rapid-eye-movement sleep (NREMS). However, sensory vigilance persists in NREMS in animals and humans, suggesting that wake promotion could remain functional. Here, we demonstrate that consolidated mouse NREMS is a brain state with recurrent fluctuations of the wake-promoting neurotransmitter noradrenaline on the ∼50-s timescale in the thalamus. These fluctuations occurred around mean noradrenaline levels greater than the ones of quiet wakefulness, while noradrenaline (NA) levels declined steeply in REMS. They coincided with a clustering of sleep spindle rhythms in the forebrain and with heart-rate variations, both of which are correlates of sensory arousability. We addressed the origins of these fluctuations by using closed-loop optogenetic locus coeruleus (LC) activation or inhibition timed to moments of low and high spindle activity during NREMS. We could suppress, lock, or entrain sleep-spindle clustering and heart-rate variations, suggesting that both fore- and hindbrain-projecting LC neurons show coordinated infraslow activity variations in natural NREMS. Noradrenergic modulation of thalamic, but not cortical, circuits was required for sleep-spindle clustering and involved NA release into primary sensory and reticular thalamic nuclei that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. Noradrenergic signaling by LC constitutes a vigilance-promoting mechanism that renders mammalian NREMS vulnerable to disruption on the close-to-minute timescale through sustaining thalamocortical and autonomic sensory arousability. VIDEO ABSTRACT.
Topics: Animals; Electroencephalography; Mammals; Mice; Norepinephrine; Prosencephalon; Sleep; Thalamus; Wakefulness
PubMed: 34648731
DOI: 10.1016/j.cub.2021.09.041 -
Science (New York, N.Y.) Oct 2019The circadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription, protein abundance, and function. Circadian...
The circadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription, protein abundance, and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24 hours, accurately quantifying almost 8000 phosphopeptides. Half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function through phosphorylation, including synaptic transmission, cytoskeleton reorganization, and excitatory/inhibitory balance. Sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Male; Mice; Mice, Inbred C57BL; Phosphoproteins; Phosphorylation; Phosphotransferases; Prosencephalon; Sleep; Synapses; Wakefulness
PubMed: 31601740
DOI: 10.1126/science.aav3617 -
Cell Stem Cell Oct 2021During embryogenesis, optic vesicles develop from the diencephalon via a multistep process of organogenesis. Using induced pluripotent stem cell (iPSC)-derived human...
During embryogenesis, optic vesicles develop from the diencephalon via a multistep process of organogenesis. Using induced pluripotent stem cell (iPSC)-derived human brain organoids, we attempted to simplify the complexities and demonstrate formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day 30, brain organoids attempt to assemble optic vesicles, which develop progressively as visible structures within 60 days. These optic vesicle-containing brain organoids (OVB-organoids) constitute a developing optic vesicle's cellular components, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. OVB-organoids also display synapsin-1, CTIP-positive myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photosensitive activity of OVB-organoids, and light sensitivities could be reset after transient photobleaching. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow interorgan interaction studies within a single organoid.
Topics: Cell Differentiation; Embryonic Development; Humans; Induced Pluripotent Stem Cells; Organogenesis; Organoids; Prosencephalon
PubMed: 34407456
DOI: 10.1016/j.stem.2021.07.010 -
Nature Oct 2023The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain, which has been challenging to study at...
The assembly of cortical circuits involves the generation and migration of interneurons from the ventral to the dorsal forebrain, which has been challenging to study at inaccessible stages of late gestation and early postnatal human development. Autism spectrum disorder and other neurodevelopmental disorders (NDDs) have been associated with abnormal cortical interneuron development, but which of these NDD genes affect interneuron generation and migration, and how they mediate these effects remains unknown. We previously developed a platform to study interneuron development and migration in subpallial organoids and forebrain assembloids. Here we integrate assembloids with CRISPR screening to investigate the involvement of 425 NDD genes in human interneuron development. The first screen aimed at interneuron generation revealed 13 candidate genes, including CSDE1 and SMAD4. We subsequently conducted an interneuron migration screen in more than 1,000 forebrain assembloids that identified 33 candidate genes, including cytoskeleton-related genes and the endoplasmic reticulum-related gene LNPK. We discovered that, during interneuron migration, the endoplasmic reticulum is displaced along the leading neuronal branch before nuclear translocation. LNPK deletion interfered with this endoplasmic reticulum displacement and resulted in abnormal migration. These results highlight the power of this CRISPR-assembloid platform to systematically map NDD genes onto human development and reveal disease mechanisms.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cell Movement; CRISPR-Cas Systems; Gene Editing; Interneurons; Neurodevelopmental Disorders; Organoids; Endoplasmic Reticulum; Prosencephalon; Active Transport, Cell Nucleus
PubMed: 37758944
DOI: 10.1038/s41586-023-06564-w -
Cell Stem Cell Feb 2022Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration...
Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca1.2. Here, we find that acute pharmacological modulation of Ca1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced γ-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by interneuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.
Topics: Autistic Disorder; Cell Movement; Cerebral Cortex; Humans; Interneurons; Long QT Syndrome; Prosencephalon; Syndactyly
PubMed: 34990580
DOI: 10.1016/j.stem.2021.11.011