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Neuron Oct 2012The mammalian retina consists of neurons of >60 distinct types, each playing a specific role in processing visual images. They are arranged in three main stages. The... (Review)
Review
The mammalian retina consists of neurons of >60 distinct types, each playing a specific role in processing visual images. They are arranged in three main stages. The first decomposes the outputs of the rod and cone photoreceptors into ∼12 parallel information streams. The second connects these streams to specific types of retinal ganglion cells. The third combines bipolar and amacrine cell activity to create the diverse encodings of the visual world--roughly 20 of them--that the retina transmits to the brain. New transformations of the visual input continue to be found: at least half of the encodings sent to the brain (ganglion cell response selectivities) remain to be discovered. This diversity of the retina's outputs has yet to be incorporated into our understanding of higher visual function.
Topics: Animals; Humans; Nerve Net; Neurons; Retina; Visual Pathways
PubMed: 23083731
DOI: 10.1016/j.neuron.2012.10.002 -
Neuron Apr 2019The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent... (Review)
Review
The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.
Topics: Animals; Antidepressive Agents; Brain; Cerebral Cortex; Depressive Disorder; Glutamic Acid; Hippocampus; Humans; Interneurons; Ketamine; Neurons; Sex Factors; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 30946828
DOI: 10.1016/j.neuron.2019.03.013 -
Cell Aug 2016Patterns of gene expression can be used to characterize and classify neuronal types. It is challenging, however, to generate taxonomies that fulfill the essential...
Patterns of gene expression can be used to characterize and classify neuronal types. It is challenging, however, to generate taxonomies that fulfill the essential criteria of being comprehensive, harmonizing with conventional classification schemes, and lacking superfluous subdivisions of genuine types. To address these challenges, we used massively parallel single-cell RNA profiling and optimized computational methods on a heterogeneous class of neurons, mouse retinal bipolar cells (BCs). From a population of ∼25,000 BCs, we derived a molecular classification that identified 15 types, including all types observed previously and two novel types, one of which has a non-canonical morphology and position. We validated the classification scheme and identified dozens of novel markers using methods that match molecular expression to cell morphology. This work provides a systematic methodology for achieving comprehensive molecular classification of neurons, identifies novel neuronal types, and uncovers transcriptional differences that distinguish types within a class.
Topics: Amacrine Cells; Animals; Cluster Analysis; Female; Genetic Markers; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Retinal Bipolar Cells; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic; Transcriptome
PubMed: 27565351
DOI: 10.1016/j.cell.2016.07.054 -
Nature Nov 2015Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit...
Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.
Topics: Action Potentials; Antipsychotic Agents; Bipolar Disorder; Calcium Signaling; Dentate Gyrus; Endophenotypes; Humans; Induced Pluripotent Stem Cells; Lithium Compounds; Male; Mitochondria; Neurons; Patch-Clamp Techniques
PubMed: 26524527
DOI: 10.1038/nature15526 -
Nature Dec 2023The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs. Retinal cell types may have evolved to accommodate... (Comparative Study)
Comparative Study
The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.
Topics: Animals; Humans; Neurons; Retina; Retinal Ganglion Cells; Single-Cell Gene Expression Analysis; Vertebrates; Vision, Ocular; Species Specificity; Biological Evolution; Amacrine Cells; Photoreceptor Cells; Ependymoglial Cells; Retinal Bipolar Cells; Visual Perception
PubMed: 38092908
DOI: 10.1038/s41586-023-06638-9 -
The Journal of Neuroscience : the... Oct 2012Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the...
Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the performance of GECIs. The state-of-the art single-wavelength GECI, GCaMP3, has been deployed in a number of model organisms and can reliably detect three or more action potentials in short bursts in several systems in vivo. Through protein structure determination, targeted mutagenesis, high-throughput screening, and a battery of in vitro assays, we have increased the dynamic range of GCaMP3 by severalfold, creating a family of "GCaMP5" sensors. We tested GCaMP5s in several systems: cultured neurons and astrocytes, mouse retina, and in vivo in Caenorhabditis chemosensory neurons, Drosophila larval neuromuscular junction and adult antennal lobe, zebrafish retina and tectum, and mouse visual cortex. Signal-to-noise ratio was improved by at least 2- to 3-fold. In the visual cortex, two GCaMP5 variants detected twice as many visual stimulus-responsive cells as GCaMP3. By combining in vivo imaging with electrophysiology we show that GCaMP5 fluorescence provides a more reliable measure of neuronal activity than its predecessor GCaMP3. GCaMP5 allows more sensitive detection of neural activity in vivo and may find widespread applications for cellular imaging in general.
Topics: Animals; Astrocytes; Caenorhabditis elegans; Calcium Signaling; Crystallography, X-Ray; Drosophila melanogaster; Female; Fluorescent Dyes; Fluorometry; Genes, Synthetic; Genetic Vectors; Green Fluorescent Proteins; HEK293 Cells; Hippocampus; Humans; Larva; Lasers; Mice; Models, Molecular; Mutagenesis, Site-Directed; Neuroimaging; Neuromuscular Junction; Neurons; Neuropil; Olfactory Receptor Neurons; Peptides; Photic Stimulation; Protein Conformation; Rats; Recombinant Fusion Proteins; Retinal Bipolar Cells; Synaptic Transmission; Zebrafish
PubMed: 23035093
DOI: 10.1523/JNEUROSCI.2601-12.2012 -
Current Neuropharmacology 2018Accumulating evidence has shown the importance of glial cells in the neurobiology of bipolar disorder. Activated microglia and inflammatory cytokines have been pointed... (Review)
Review
Accumulating evidence has shown the importance of glial cells in the neurobiology of bipolar disorder. Activated microglia and inflammatory cytokines have been pointed out as potential biomarkers of bipolar disorder. Indeed, recent studies have shown that bipolar disorder involves microglial activation in the hippocampus and alterations in peripheral cytokines, suggesting a potential link between neuroinflammation and peripheral toxicity. These abnormalities may also be the biological underpinnings of outcomes related to neuroprogression, such as cognitive impairment and brain changes. Additionally, astrocytes may have a role in the progression of bipolar disorder, as these cells amplify inflammatory response and maintain glutamate homeostasis, preventing excitotoxicity. The present review aims to discuss neuron-glia interactions and their role in the pathophysiology and treatment of bipolar disorder.
Topics: Animals; Bipolar Disorder; Cell Communication; Cytokines; Humans; Neuroglia; Neurons
PubMed: 28847296
DOI: 10.2174/1570159X15666170828170921 -
Developmental Biology Aug 2021Synapses in the outer retina are the first information relay points in vision. Here, photoreceptors form synapses onto two types of interneurons, bipolar cells and... (Review)
Review
Synapses in the outer retina are the first information relay points in vision. Here, photoreceptors form synapses onto two types of interneurons, bipolar cells and horizontal cells. Because outer retina synapses are particularly large and highly ordered, they have been a useful system for the discovery of mechanisms underlying synapse specificity and maintenance. Understanding these processes is critical to efforts aimed at restoring visual function through repairing or replacing neurons and promoting their connectivity. We review outer retina neuron synapse architecture, neural migration modes, and the cellular and molecular pathways that play key roles in the development and maintenance of these connections. We further discuss how these mechanisms may impact connectivity in the retina.
Topics: Animals; Humans; Interneurons; Photoreceptor Cells; Retina; Retinal Cone Photoreceptor Cells; Retinal Horizontal Cells; Synapses; Vision, Ocular
PubMed: 33848537
DOI: 10.1016/j.ydbio.2021.04.001 -
Current Psychiatry Reports Apr 2020We review the ways in which stem cells are used in psychiatric disease research, including the related advances in gene editing and directed cell differentiation. (Review)
Review
PURPOSE OF REVIEW
We review the ways in which stem cells are used in psychiatric disease research, including the related advances in gene editing and directed cell differentiation.
RECENT FINDINGS
The recent development of induced pluripotent stem cell (iPSC) technologies has created new possibilities for the study of psychiatric disease. iPSCs can be derived from patients or controls and differentiated to an array of neuronal and non-neuronal cell types. Their genomes can be edited as desired, and they can be assessed for a variety of phenotypes. This makes them especially interesting for studying genetic variation, which is particularly useful today now that our knowledge on the genetics of psychiatric disease is quickly expanding. The recent advances in cell engineering have led to powerful new methods for studying psychiatric illness including schizophrenia, bipolar disorder, and autism. There is a wide array of possible applications as illustrated by the many examples from the literature, most of which are cited here.
Topics: Bipolar Disorder; Humans; Induced Pluripotent Stem Cells; Neurons; Phenotype; Schizophrenia
PubMed: 32318888
DOI: 10.1007/s11920-020-01148-1 -
Cells Jan 2021Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack... (Review)
Review
Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron-glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron-glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron-glia interactions.
Topics: Animals; Bipolar Disorder; Cell Communication; Estrogens; Humans; Induced Pluripotent Stem Cells; Models, Biological; Neuroglia; Neurons; Schizophrenia
PubMed: 33494281
DOI: 10.3390/cells10020209