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Nature Nov 2018Genetically modified mice are commonly generated by the microinjection of pluripotent embryonic stem (ES) cells into wild-type host blastocysts, producing chimeric...
Genetically modified mice are commonly generated by the microinjection of pluripotent embryonic stem (ES) cells into wild-type host blastocysts, producing chimeric progeny that require breeding for germline transmission and homozygosity of modified alleles. As an alternative approach and to facilitate studies of the immune system, we previously developed RAG2-deficient blastocyst complementation. Because RAG2-deficient mice cannot undergo V(D)J recombination, they do not develop B or T lineage cells beyond the progenitor stage: injecting RAG2-sufficient donor ES cells into RAG2-deficient blastocysts generates somatic chimaeras in which all mature lymphocytes derive from donor ES cells. This enables analysis, in mature lymphocytes, of the functions of genes that are required more generally for mouse development. Blastocyst complementation has been extended to pancreas organogenesis, and used to generate several other tissues or organs, but an equivalent approach for brain organogenesis has not yet been achieved. Here we describe neural blastocyst complementation (NBC), which can be used to study the development and function of specific forebrain regions. NBC involves targeted ablation, mediated by diphtheria toxin subunit A, of host-derived dorsal telencephalic progenitors during development. This ablation creates a vacant forebrain niche in host embryos that results in agenesis of the cerebral cortex and hippocampus. Injection of donor ES cells into blastocysts with forebrain-specific targeting of diphtheria toxin subunit A enables donor-derived dorsal telencephalic progenitors to populate the vacant niche in the host embryos, giving rise to neocortices and hippocampi that are morphologically and neurologically normal with respect to learning and memory formation. Moreover, doublecortin-deficient ES cells-generated via a CRISPR-Cas9 approach-produced NBC chimaeras that faithfully recapitulated the phenotype of conventional, germline doublecortin-deficient mice. We conclude that NBC is a rapid and efficient approach to generate complex mouse models for studying forebrain functions; this approach could more broadly facilitate organogenesis based on blastocyst complementation.
Topics: Animals; Blastocyst; Chimera; DNA-Binding Proteins; Doublecortin Domain Proteins; Female; Genetic Complementation Test; Germ Cells; Hippocampus; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Mouse Embryonic Stem Cells; Neocortex; Neurons; Neuropeptides; Organogenesis; Phenotype; Prosencephalon
PubMed: 30305734
DOI: 10.1038/s41586-018-0586-0 -
Journal of Perinatal Medicine 1991
Review
Topics: Brain; Gestational Age; Humans; Myelin Sheath; Neural Tube Defects; Neurons; Prosencephalon
PubMed: 1779374
DOI: 10.1515/jpme.1991.19.s1.29 -
Discharge patterns of neurons in cholinergic regions of the basal forebrain during waking and sleep.Behavioural Brain Research Nov 2000A subset of neurons recorded in the magnocellular basal forebrain (mBF) of cats and rats exhibit elevated discharge rates during waking and REM sleep, and diminished... (Review)
Review
A subset of neurons recorded in the magnocellular basal forebrain (mBF) of cats and rats exhibit elevated discharge rates during waking and REM sleep, and diminished discharge during sleep with cortical EEG synchrony (nonREM sleep). This pattern is observed in mBF neurons in cats with identified ascending projections, and in neurons located in cholinergic regions of the rat mBF. However, the cholinergic versus noncholinergic nature of recorded cells could not be determined with the extracellular recording method employed. During waking, discharge of mBF neurons is strongly movement-related. Peak discharge rates occur during a variety of head and limb movements. Discharge rates during waking immobility are reduced by >50% compared to rates during waking movement. The absence of movement accounts for more of the variance in discharge across the sleep-wake cycle than does the presence of cortical EEG synchronization. Several factors participate in the regulation of mBF neuronal activity across arousal states. Tonic inhibition mediated by adenosine appears to be present during both waking and sleep. In some mBF neurons, increased GABAergic inhibition contributes to nonREM sleep-related reductions in discharge rate. Fluctuations in mBF cell activity during waking behaviors may reflect changing excitatory input from neurons in the pontine and midbrain tegmentum.
Topics: Animals; Basal Ganglia; Cats; Humans; Neurons; Parasympathetic Nervous System; Prosencephalon; Rats; Sleep; Wakefulness
PubMed: 11000419
DOI: 10.1016/s0166-4328(00)00257-6 -
Brain Research BulletinAn improved comparative interpretation of the teleostean forebrain suggests that the dorsal tier (Vd,Vc) and ventral tier (Vv,Vl) nuclei of the ventral telencephalic... (Comparative Study)
Comparative Study Review
An improved comparative interpretation of the teleostean forebrain suggests that the dorsal tier (Vd,Vc) and ventral tier (Vv,Vl) nuclei of the ventral telencephalic area (subpallium) represent the striatum and septum, respectively. Among other arguments, a dopaminergic innervation originating in the diencephalic posterior tubercle reaches Vd and dense efferents of Vv project to the midline hypothalamus in the adult zebrafish subpallium. The adult area dorsalis telencephali represents the teleostean pallium. Regulatory genes typically expressed in the early amniote subpallium (e.g., Dlx-1) are also restricted to the presumptive zebrafish ventral telencephalic area. Further, early Pax6 protein distribution in the zebrafish telencephalon corresponds to the migrating stream noted at the pallial-subpallial boundary in amniotes, but a ventricular, radial glia-based expression in the pallium is absent. The peripherally migrated, adult diencephalic preglomerular complex of the basal plate posterior tubercle (early: M2) provides sensory inputs to the pallium. Early Pax6 protein distribution indicates that at least part of M2 may directly originate from alar plate ventral thalamic Pax6-expressing cells. Dopaminergic cells of the basal plate posterior zebrafish forebrain (P1-P3) are restricted to the ventral thalamic prosomere (P3), including those forming the adult ascending dopaminergic system. Moreover, the latter likely depend developmentally on the dorsally adjacent alar plate Pax6-expressing cells.
Topics: Animals; Cell Division; Diencephalon; Dopamine; Eye Proteins; Fishes; Homeodomain Proteins; PAX6 Transcription Factor; Paired Box Transcription Factors; Prosencephalon; Repressor Proteins; Telencephalon
PubMed: 11922990
DOI: 10.1016/s0361-9230(01)00666-9 -
Progress in Brain Research 1996From all of the studies of developmentally regulated molecules as well as the impressive proliferation of cells within the SEZ, we would like to propose that the SEZ of... (Review)
Review
From all of the studies of developmentally regulated molecules as well as the impressive proliferation of cells within the SEZ, we would like to propose that the SEZ of the adult brain, from the lateral ventricles of the cerebrum to the central canal of the spinal cord, represents a potential "brain marrow" from which stem and progenitor cells can be further studied and exploited for cell replacement and circuitry repair paradigms for neurological disease. Without question the SEZ is not as regenerative or pleuripotential as bone marrow or other hematopoietic systems, but there are definitely some elements in common. Bone marrow contains a pleuripotent stem cell that under certain conditions (e.g. the presence of certain growth factors and cytokines) gives rise to erythroblasts and myeloblasts whose progeny include erythrocytes, monocytes, thrombocytes and macrophages. Different growth factors can likewise affect the proliferation as well as differentiation of adult CNS stem and progenitor cells, again contributing to diverse cellular phenotypes. The roles for matrix molecules in these events are yet to be discovered, however, there is evidence to suggest that matrix molecules, including tenascin, do interact with hematopoietic stem cells (Yoder and Williams, 1995) to possibly affect their proliferation and differentiation. Future studies might reveal a similar role for the dense ECM expression within the SEZ proliferative/migratory pathway.
Topics: Animals; Cell Death; Cell Division; Embryonic and Fetal Development; Neurons; Prosencephalon
PubMed: 8979813
DOI: No ID Found -
Pathologie-biologie May 2006
Topics: Adult; Animals; Brain; Brain Diseases; Cell Division; Humans; Neurons; Prosencephalon; Stem Cell Transplantation; Stem Cells
PubMed: 16530347
DOI: 10.1016/j.patbio.2006.01.009 -
Brain Research. Brain Research Reviews Sep 2003Recently, a multidisciplinary approach has provided new insights into the mechanisms of category learning. In this article, results from theoretical modeling,... (Review)
Review
Recently, a multidisciplinary approach has provided new insights into the mechanisms of category learning. In this article, results from theoretical modeling, experimental psychology, clinical neuropsychology, functional neuroimaging, and single-cell studies are reviewed. Although the results are not conclusive, some general principles have emerged. Areas localized in the sensory neocortex are responsible for the perceptual representation of category exemplars, whereas lateral and anterior prefrontal structures are necessary for the encoding of category boundaries and abstract rules. The prefrontal cortex may influence categorical representation in the sensory neocortex via top-down control. The neostriatum is important in stimulus-response mapping, and the orbitofrontal cortex/ventral striatum are related to stimulus-reward associations accompanying category learning. Many category learning tasks can be performed implicitly. In conclusion, category learning paradigms provide a unique opportunity to investigate cognitive processes such as perception, memory, and attention in a systematic and interactive manner. Category learning tasks are suitable for mapping damaged brain systems in clinical populations.
Topics: Animals; Brain Injuries; Cognition Disorders; Corpus Striatum; Humans; Learning; Models, Neurological; Neural Pathways; Prefrontal Cortex; Prosencephalon
PubMed: 14499464
DOI: 10.1016/s0165-0173(03)00204-2 -
Annals of the New York Academy of... Jun 1999Two recent papers have questioned the concept of the amygdala as a functional and anatomically separate entity. Swanson and Petrovich go so far as to state that "the... (Review)
Review
Two recent papers have questioned the concept of the amygdala as a functional and anatomically separate entity. Swanson and Petrovich go so far as to state that "the amygdala is neither a structural nor a functional unit." This novel concept is derived from the fact that the amygdala is a structure whose anatomical connections and neurochemical features are more strongly interrelated to adjacent parts of the temporal lobe and basal forebrain than to unique characteristics of its own. This is an emerging hypothetical concept of the "amygdala" that seems to repeat itself in many parts of this volume and merits further examination in the future. The basal forebrain and cortical circuitry described here seem to be critical for a set of behaviors/processes that could be collectively described as cognitive-emotive. For example, this would include arousal, attention, sensory processing, reinforcement, and finally associative learning, decision making, and memory. Collectively this circuitry influences the emotional, motivational, and cognitive state of an organism. More and more studies are demonstrating that small and localized manipulations of the brain can result in equally subtle and specific deficits that are associated with definable parts of the anatomical circuitry, neurotransmitters, and receptors of basal forebrain structures. These studies have been guided and influenced by the refined neuroanatomical and neurochemical investigations of Lennart Heimer and his colleagues. Interpretations of these studies are beginning to uncover distinct deficits that suggest explanations and potential treatments for many psychiatric and pathological degenerative disorders.
Topics: Amygdala; Animals; Cerebral Cortex; Corpus Striatum; Humans; Models, Neurological; Neural Pathways; Prosencephalon
PubMed: 10415663
DOI: 10.1111/j.1749-6632.1999.tb09281.x -
Experimental Neurology Jun 2007The mammalian brain has been perceived as a quiescent organ incapable of postnatal neurogenesis for many years. Most recently, several studies have demonstrated that the... (Review)
Review
The mammalian brain has been perceived as a quiescent organ incapable of postnatal neurogenesis for many years. Most recently, several studies have demonstrated that the adult mammalian brain is indeed capable of neurogenesis and that the process is primarily confined to the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the hippocampus. Of these regions, the SVZ is the largest niche of neurogenesis in the adult mammalian brain. Within this niche resides a subpopulation of astrocytes with stem cell-like features of self-renewal and multipotentiality. Interestingly, there is also a subpopulation of cells within brain tumors that possess these same characteristics. Based on these findings, the emerging hypothesis is that brain tumor stem cells may be derived from neural stem cells and that both of these populations may originate from the SVZ. This possible connection stresses the importance of studying and understanding the role that the human SVZ plays in not only harboring neural and brain tumor stem cells, but how this microenvironment may support both neurogenesis and tumorigenesis. Furthermore, the obvious differences in the SVZ between humans and other animals make it important to understand the human model when studying human disease. Such an understanding may lead to novel therapeutic strategies for both neurodegenerative diseases and currently intractable brain tumors.
Topics: Animals; Brain Neoplasms; Disease Progression; Humans; Neoplastic Stem Cells; Prosencephalon
PubMed: 17459377
DOI: 10.1016/j.expneurol.2007.03.016 -
The Anatomical Record Sep 1998Previous studies have demonstrated that extracellular matrix glycoconjugates, shown by lectin-histochemistry with Vicia villosa agglutinin (VVA) and peanut agglutinin...
Previous studies have demonstrated that extracellular matrix glycoconjugates, shown by lectin-histochemistry with Vicia villosa agglutinin (VVA) and peanut agglutinin (PNA) as so-called perineuronal nets, play an important role in brain maturation. Concanavalin A (ConA) binding to neuronal surface glycoconjugates may be a marker of synaptic junctions. The present study was done to demonstrate the binding sites of these lectins in two functionally related nuclei of the prosencephalon, the basal nucleus (Meynert) and the hypothalamic tuberomamillary nucleus. Fetal brains of 16-36 weeks of gestation were examined by using VVA, PNA, and ConA to determine appearance and distribution patterns of specific lectin-binding sites on glycoconjugates during fetal brain development. The basal nucleus and the tuberomamillary nucleus showed a characteristic "cellular staining" that may have been due to cytoplasmatic labeling, surface labeling, or both. Lectin-staining occurred much earlier in the basal nucleus than in the tuberomamillary nucleus. Although all three lectins were bound to neurons of the basal nucleus, only ConA-positive neurons were observed in the tuberomamillary nucleus. In conclusion, lectin-labeled cells most probably represent projection neurons that are GABAergic (tuberomamillary nucleus) or cholinergic (basal nucleus). Labeling with the three lectins demonstrated nuclear-specific staining patterns that occur early in fetal development and gradually increase. Binding sites for lectins characterizing perineuronal nets (VVA, PNA) occurred only in the basal nucleus, whereas binding sites for ConA on neuronal-surface glycoconjugates, which seem to play a role in early synaptogenesis, were present in the basal and the tuberomamillary nucleus. The basal nucleus, however, expressed ConA binding sites distinctly earlier, probably indicating early arriving afferents.
Topics: Cell Nucleus; Concanavalin A; Extracellular Matrix; Fetus; Glycoconjugates; Humans; Hypothalamus; Lectins; Peanut Agglutinin; Plant Lectins; Prosencephalon; Staining and Labeling; Substantia Innominata
PubMed: 9737751
DOI: 10.1002/(SICI)1097-0185(199809)252:1<149::AID-AR13>3.0.CO;2-O