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Visual Neuroscience Mar 2014Anatomical and physiological approaches are beginning to reveal the synaptic origins of parallel ON- and OFF-pathway retinal circuits for the transmission of short (S-)... (Review)
Review
Anatomical and physiological approaches are beginning to reveal the synaptic origins of parallel ON- and OFF-pathway retinal circuits for the transmission of short (S-) wavelength sensitive cone signals in the primate retina. Anatomical data suggest that synaptic output from S-cones is largely segregated; central elements of synaptic triads arise almost exclusively from the "blue-cone" bipolar cell, a presumed ON bipolar, whereas triad-associated contacts derive primarily from the "flat" midget bipolar cell, a hyperpolarizing, OFF bipolar. Similarly, horizontal cell connectivity is also segregated, with only the H2 cell-type receiving numerous contacts from S-cones. Negative feedback from long (L-) and middle (M-) wavelength sensitive cones via the H2 horizontal cells elicits an antagonistic surround in S-cones demonstrating that S versus L + M or "blue-yellow" opponency is first established in the S-cone. However, the S-cone output utilizes distinct synaptic mechanisms to create color opponency at the ganglion cell level. The blue-cone bipolar cell is presynaptic to the small bistratified, "blue-ON" ganglion cell. S versus L + M cone opponency arises postsynaptically by converging S-ON and LM-OFF excitatory bipolar inputs to the ganglion cell's bistratified dendritic tree. The common L + M cone surrounds of the parallel S-ON and LM-OFF cone bipolar inputs appear to cancel resulting in "blue-yellow" antagonism without center-surround spatial opponency. By contrast, in midget ganglion cells, opponency arises by the differential weighting of cone inputs to the receptive field center versus surround. In the macula, the "private-line" connection from a midget ganglion cell to a single cone predicts that S versus L + M opponency is transmitted from the S-cone to the S-OFF midget bipolar and ganglion cell. Beyond the macula, OFF-midget ganglion cell dendritic trees enlarge and collect additional input from multiple L and M cones. Thus S-OFF opponency via the midget pathway would be expected to become more complex in the near retinal periphery as L and/or M and S cone inputs sum to the receptive field center. An important goal for further investigation will be to explore the hypothesis that distinct bistratified S-ON versus midget S-OFF retinal circuits are the substrates for human psychophysical detection mechanisms attributed to S-ON versus S-OFF perceptual channels.
Topics: Animals; Color Perception; Color Vision; Patch-Clamp Techniques; Primates; Retinal Bipolar Cells; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Retinal Neurons; Synapses
PubMed: 23895762
DOI: 10.1017/S0952523813000230 -
The International Journal of... Jun 2018Bipolar disorder is a mental health condition with progressive social and cognitive function disturbances. Most patients' treatments are based on polypharmacy, but with...
BACKGROUND
Bipolar disorder is a mental health condition with progressive social and cognitive function disturbances. Most patients' treatments are based on polypharmacy, but with no biological basis and little is known of the drugs' interactions. The aim of this study was to analyze the effects of lithium, valproate, quetiapine, and lamotrigine, and the interactions between them, on markers of inflammation, bioenergetics, mitochondrial function, and oxidative stress in neuron-like cells and microglial cells.
METHODS
Neuron-like cells and lipopolysaccharide-stimulated C8-B4 cells were treated with lithium (2.5 mM), valproate (0.5 mM), quetiapine (0.05 mM), and lamotrigine (0.05 mM) individually and in all possible combinations for 24 h. Twenty cytokines were measured in the media from lipopolysaccharide-stimulated C8-B4 cells. Metabolic flux analysis was used to measure bioenergetics, and real-time PCR was used to measure the expression of mitochondrial function genes in neuron-like cells. The production of superoxide in treated cells was also assessed.
RESULTS
The results suggest major inhibitory effects on proinflammatory cytokine release as a therapeutic mechanism of these medications when used in combination. The various combinations of medications also caused overexpression of PGC1α and ATP5A1 in neuron-like cells. Quetiapine appears to have a proinflammatory effect in microglial cells, but this was reversed by the addition of lamotrigine independent of the drug combination.
CONCLUSION
Polypharmacy in bipolar disorder may have antiinflammatory effects on microglial cells as well as effects on mitochondrial biogenesis in neuronal cells.
Topics: Animals; Antimanic Agents; Bipolar Disorder; Cell Line; Cytokines; Drug Interactions; Gene Expression; Humans; Inflammation; Lipopolysaccharides; Mice; Microglia; Mitochondria; Neurons; Polypharmacy
PubMed: 29471411
DOI: 10.1093/ijnp/pyy014 -
Traffic (Copenhagen, Denmark) Dec 2020Radial glial cells (RGCs) are progenitors of the cerebral cortex which produce both neurons and glia during development. Given their central role in development, RGC... (Review)
Review
Radial glial cells (RGCs) are progenitors of the cerebral cortex which produce both neurons and glia during development. Given their central role in development, RGC dysfunction can result in diverse neurodevelopmental disorders. RGCs have an elongated bipolar morphology that spans the entire radial width of the cortex and ends in basal endfeet connected to the pia. The basal process and endfeet are important for proper guidance of migrating neurons and are implicated in signaling. However, endfeet must function at a great distance from the cell body. This spatial separation suggests a role for local gene regulation in endfeet. Endfeet contain a local transcriptome enriched for cytoskeletal and signaling factors. These localized mRNAs are actively transported from the cell body and can be locally translated in endfeet. Yet, studies of local gene regulation in RGC endfeet are still in their infancy. Here, we draw comparisons of RGCs with foundational work in anatomically and phylogenetically related cell types, neurons and astrocytes. Our review highlights a striking overlap in the types of RNAs localized, as well as principles of local translation between these three cell types. Thus, studies in neurons, astrocytes and RGCs can mutually inform an understanding of RNA localization across the nervous system.
Topics: Astrocytes; Cerebral Cortex; Ependymoglial Cells; Neuroglia; Neurons
PubMed: 33058331
DOI: 10.1111/tra.12769 -
Clinical & Experimental Optometry Sep 2005Retinal degenerative diseases that progress through loss of photoreceptors initiate a sequence of events that culminates in negative remodelling of the retina.... (Review)
Review
Retinal degenerative diseases that progress through loss of photoreceptors initiate a sequence of events that culminates in negative remodelling of the retina. Initially, photoreceptor loss ablates glutamatergic signalling to the neural retina and eliminates coordinate Ca++-coupled homeostatic signalling. Retinal neurons react to this loss of glutamatergic input through retinal rewiring and migration of neurons throughout the axis of the retina. All diseases that kill photoreceptors trigger retinal remodelling as the final common pathway and cell death is a common feature. Retinal remodelling resembles CNS pathologic remodelling and constitutes a major challenge to all rescue strategies.
Topics: Amacrine Cells; Animals; Disease Progression; Humans; Microscopy, Electron; Neuronal Plasticity; Retina; Retinal Bipolar Cells; Retinal Degeneration; Retinal Ganglion Cells
PubMed: 16255687
DOI: 10.1111/j.1444-0938.2005.tb06712.x -
Brain Structure & Function Nov 2022Neurogranin (Nrgn) is a neural protein that is enriched in the cerebral cortex and is involved in synaptic plasticity via its interaction with calmodulin. Recently we...
Neurogranin (Nrgn) is a neural protein that is enriched in the cerebral cortex and is involved in synaptic plasticity via its interaction with calmodulin. Recently we reported its expression in the brain of the adult zebrafish (Alba-González et al. J Comp Neurol 530:1569-1587, 2022). In this study we analyze the development of Nrgn-like immunoreactivity (Nrgn-like-ir) in the brain and sensory structures of zebrafish embryos and larvae, using whole mounts and sections. First Nrgn-like positive neurons appeared by 2 day post-fertilization (dpf) in restricted areas of the brain, mostly in the pallium, epiphysis and hindbrain. Nrgn-like populations increased noticeably by 3 dpf, reaching an adult-like pattern in 6 dpf. Most Nrgn-like positive neurons were observed in the olfactory organ, retina (most ganglion cells, some amacrine and bipolar cells), pallium, lateral hypothalamus, thalamus, optic tectum, torus semicircularis, octavolateralis area, and viscerosensory column. Immunoreactivity was also observed in axonal tracts originating in Nrgn-like neuronal populations, namely, the projection of Nrgn-like immunopositive primary olfactory fibers to olfactory glomeruli, that of Nrgn-like positive pallial cells to the hypothalamus, the Nrgn-like-ir optic nerve to the pretectum and optic tectum, the Nrgn-like immunolabeled lateral hypothalamus to the contralateral region via the horizontal commissure, the octavolateralis area to the midbrain via the lateral lemniscus, and the viscerosensory column to the dorsal isthmus via the secondary gustatory tract. The late expression of Nrgn in zebrafish neurons is probably related to functional maturation of higher brain centers, as reported in the mammalian telencephalon. The analysis of Nrgn expression in the zebrafish brain suggests that it may be a useful marker for specific neuronal circuitries.
Topics: Animals; Zebrafish; Neurogranin; Brain; Neurons; Axons; Mammals
PubMed: 36018391
DOI: 10.1007/s00429-022-02550-6 -
Molecular Psychiatry Aug 2021Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in...
Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.
Topics: Animals; Bipolar Disorder; Humans; Insulin; Insulin Resistance; Mice; Neurons; Schizophrenia
PubMed: 33173197
DOI: 10.1038/s41380-020-00939-5 -
Prion 2013Neurons have highly developed Ca(2+) signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information... (Review)
Review
Neurons have highly developed Ca(2+) signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information processing and the changes in synaptic plasticity that underpin learning and memory. The tonic excitatory drive, which is activated by the ascending arousal system, is particularly important for processes such as sensory perception, cognition and consciousness. The Ca(2+) signaling pathway is a key component of this arousal system that regulates the neuronal excitability responsible for controlling the neural brain rhythms required for information processing and cognition. Dysregulation of the Ca(2+) signaling pathway responsible for many of these neuronal processes has been implicated in the development of some of the major neural diseases in man such as Alzheimer disease, bipolar disorder and schizophrenia. Various treatments, which are known to act by reducing the activity of Ca(2+) signaling, have proved successful in alleviating the symptoms of some of these neural diseases.
Topics: Alzheimer Disease; Animals; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Calcium; Calcium Signaling; Humans; Neurons; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 22895098
DOI: 10.4161/pri.21767 -
Annual International Conference of the... Nov 2021Partial vision restoration on degenerated retina can be achieved by electrically stimulating the surviving retinal ganglion cells via implanted electrodes to elicit a...
Partial vision restoration on degenerated retina can be achieved by electrically stimulating the surviving retinal ganglion cells via implanted electrodes to elicit a signal corresponding to the natural response of the cells. Realistic computational models of electrical stimulation of the retina can prove useful to test different stimulation strategies and improve the performance of retinal implants. Simulation of healthy retinal networks and their dynamical response to natural light stimulation may also help us understand how retinal processing takes place via a series of electrical signals flowing through different stages of retinal processing, ultimately giving rise to visual percepts. Such models may provide further insights on retinal network processing and thus guide the design of retinal prostheses and their stimulation protocols to generate more natural percepts. This work aims to characterize the photocurrent generated by healthy cone photoreceptors in response to a light flash stimulation and the resulting membrane potential for the photoreceptors and its postsynaptic cone bipolar cells. A simple network of ten cone photoreceptors synapsing with a cone bipolar cell is simulated using the NEURON environment and validated against patch-clamp recordings of cone photoreceptors and ON-type bipolar cells (ON-BC). The results presented will be valuable in modeling light-evoked or electrically stimulated retinal networks that comprise cone pathways. The computational models and methods developed in this work will serve as an integral building block in the development of large and realistic retinal networks.Clinical Relevance- Accurate computational model of a retinal neural network can help in predicting cell responses to electrical stimulation in vision restoration therapies using prostheses. It can be leveraged to optimize the stimulation parameters to match the natural light response of the network as closely as possible.
Topics: Computer Simulation; Retina; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Visual Prosthesis
PubMed: 34892214
DOI: 10.1109/EMBC46164.2021.9630642 -
Experimental & Molecular Medicine Apr 2018Bipolar disorder (BD) is a common psychiatric disorder characterized by recurrent mood swings between depression and mania, and is associated with high treatment costs.... (Review)
Review
Bipolar disorder (BD) is a common psychiatric disorder characterized by recurrent mood swings between depression and mania, and is associated with high treatment costs. The existence of manic episodes is the defining feature of BD, during which period, patients experience extreme elevation in activity, energy, and mood, with changes in sleep patterns that together severely impair their ability to function in daily life. Despite some limitations in recapitulating the complex features of human disease, several rodent models of mania have been generated and characterized, which have provided important insights toward understanding its underlying pathogenic mechanisms. Among the mechanisms, neuronal excitatory and inhibitory (E/I) synaptic dysfunction in some brain regions, including the frontal cortex, hippocampus, and striatum, is an emerging hypothesis explaining mania. In this review, we highlight recent studies of rodent manic models having impairments in the E/I synaptic development and function. We also summarize the molecular and functional changes of E/I synapses by some mood stabilizers that may contribute to the therapeutic efficacy of drugs. Furthermore, we discuss potential future directions in the study of this emerging hypothesis to better connect the outcomes of basic research to the treatment of patients with this devastating mental illness.
Topics: Affect; Animals; Animals, Genetically Modified; Antipsychotic Agents; Biomarkers; Bipolar Disorder; Disease Models, Animal; Gene Expression Regulation; Humans; Neurons; Synapses
PubMed: 29628501
DOI: 10.1038/s12276-018-0028-y -
Open Biology Jan 2023Microglia are very sensitive to changes in the environment and respond through morphological, functional and metabolic adaptations. To depict the modifications microglia...
Microglia are very sensitive to changes in the environment and respond through morphological, functional and metabolic adaptations. To depict the modifications microglia undergo under healthy and pathological conditions, we developed free access image analysis scripts to quantify microglia morphologies and phagocytosis. Neuron-glia cultures, in which microglia express the reporter tdTomato, were exposed to excitotoxicity or excitotoxicity + inflammation and analysed 8 h later. Neuronal death was assessed by SYTOX staining of nucleus debris and phagocytosis was measured through the engulfment of SYTOX particles in microglia. We identified seven morphologies: round, hypertrophic, fried egg, bipolar and three 'inflamed' morphologies. We generated a classifier able to separate them and assign one of the seven classes to each microglia in sample images. In control cultures, round and hypertrophic morphologies were predominant. Excitotoxicity had a limited effect on the composition of the populations. By contrast, excitotoxicity + inflammation promoted an enrichment in inflamed morphologies and increased the percentage of phagocytosing microglia. Our data suggest that inflammation is critical to promote phenotypical changes in microglia. We also validated our tools for the segmentation of microglia in brain slices and performed morphometry with the obtained mask. Our method is versatile and useful to correlate microglia sub-populations and behaviour with environmental changes.
Topics: Humans; Microglia; Phagocytosis; Inflammation; Cell Death; Neurons
PubMed: 36629019
DOI: 10.1098/rsob.220200