We review the transport, synthesis and catabolism of glutathione in the brain as well as its compartmentation and biochemistry in different brain cells. The major reactions involving glutathione are ...reviewed and the factors limiting its availability in brain cells are discussed. We also describe and critique current methods for measuring glutathione in the human brain using magnetic resonance spectroscopy, and review the literature on glutathione measurements in healthy brains and in neurological, psychiatric, neurodegenerative and neurodevelopmental conditions In summary: Healthy human brain glutathione concentration is ∼1–2 mM, but it varies by brain region, with evidence of gender differences and age effects; in neurological disease glutathione appears reduced in multiple sclerosis, motor neurone disease and epilepsy, while being increased in meningiomas; in psychiatric disease the picture is complex and confounded by methodological differences, regional effects, length of disease and drug-treatment. Both increases and decreases in glutathione have been reported in depression and schizophrenia. In Alzheimer's disease and mild cognitive impairment there is evidence for a decrease in glutathione compared to age-matched healthy controls. Improved methods to measure glutathione in vivo will provide better precision in glutathione determination and help resolve the complex biochemistry of this molecule in health and disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Amorphous solids, or glasses, are distinguished from crystalline solids by their lack of long-range structural order. At the level of two-body structural correlations, glassformers show no ...qualitative change upon vitrifying from a supercooled liquid. Nonetheless the dynamical properties of a glass are so much slower that it appears to take on the properties of a solid. While many theories of the glass transition focus on dynamical quantities, a solid’s resistance to flow is often viewed as a consequence of its structure. Here we address the viewpoint that this remains the case for a glass. Recent developments using higher-order measures show a clear emergence of structure upon dynamical arrest in a variety of glass formers and offer the tantalising hope of a structural mechanism for arrest. However a rigorous fundamental identification of such a causal link between structure and arrest remains elusive. We undertake a critical survey of this work in experiments, computer simulation and theory and discuss what might strengthen the link between structure and dynamical arrest. We move on to highlight the relationship between crystallisation and glass-forming ability made possible by this deeper understanding of the structure of the liquid state, and emphasise the potential to design materials with optimal glassforming and crystallisation ability, for applications such as phase-change memory. We then consider aspects of the phenomenology of glassy systems where structural measures have yet to make a large impact, such as polyamorphism (the existence of multiple liquid states), ageing (the time-evolution of non-equilibrium materials below their glass transition) and the response of glassy materials to external fields such as shear.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The ascending cholinergic system dynamically regulates sensory perception and cognitive function, but it remains unclear how this modulation is executed in neocortical circuits. Here, we demonstrate ...that the cholinergic system controls the integrative operations of neocortical principal neurons by modulating dendritic excitability. Direct dendritic recordings revealed that the optogenetic-evoked release of acetylcholine (ACh) transformed the pattern of dendritic integration in layer 5B pyramidal neurons, leading to the generation of dendritic plateau potentials which powerfully drove repetitive action potential output. In contrast, the synaptic release of ACh did not positively modulate axo-somatic excitability. Mechanistically, the transformation of dendritic integration was mediated by the muscarinic ACh receptor-dependent enhancement of dendritic R-type calcium channel activity, a compartment-dependent modulation which decisively controlled the associative computations executed by layer 5B pyramidal neurons. Our findings therefore reveal a biophysical mechanism by which the cholinergic system controls dendritic computations causally linked to perceptual detection.
•Optogenetic release of ACh positively modulates neocortical principal neuron excitability•Optogenetic release of ACh selectively controls dendritic excitability•Dendritic excitability is transformed by a mAChR-mediated modulation of calcium channels•Cholinergic modulation impacts behaviorally relevant dendritic integration
Williams and Fletcher use optogenetic and high-resolution electrophysiological techniques to demonstrate that the cholinergic system directly controls the electrical excitability of the dendrites of neocortical principal neurons, through the modulation of calcium channels, to powerfully enhance behaviorally relevant associative computations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Active dendritic synaptic integration enhances the computational power of neurons. Such nonlinear processing generates an object-localization signal in the apical dendritic tuft of layer 5B cortical ...pyramidal neurons during sensory-motor behavior. Here, we employ electrophysiological and optical approaches in brain slices and behaving animals to investigate how excitatory synaptic input to this distal dendritic compartment influences neuronal output. We find that active dendritic integration throughout the apical dendritic tuft is highly compartmentalized by voltage-gated potassium (KV) channels. A high density of both transient and sustained KV channels was observed in all apical dendritic compartments. These channels potently regulated the interaction between apical dendritic tuft, trunk, and axosomatic integration zones to control neuronal output in vitro as well as the engagement of dendritic nonlinear processing in vivo during sensory-motor behavior. Thus, KV channels dynamically tune the interaction between active dendritic integration compartments in layer 5B pyramidal neurons to shape behaviorally relevant neuronal computations.
•Distal tuft input drives pyramidal neuron output by regulating dendritic spike width•Kv channels control the interaction between active integration compartments•High densities of Kv channels are expressed throughout the apical dendritic tree•Interactive integration engages Kv channels during sensory-motor behavior
How does synaptic input to distal dendrites influence neuronal output? Harnett et al. investigate excitability and integration in apical tuft dendrites of layer 5 cortical pyramidal neurons, demonstrating how K+ channels control computation in this compartment to modulate axonal firing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The structure of the neocortex varies across the neocortical mantle to govern the physical size of principal neurons. What impact such anatomical variation has on the computational operations of ...principal neurons remains unknown. Here, we demonstrate within a functionally defined area that neocortical thickness governs the anatomical, electrophysiological, and computational properties of the principal output neurons of the neocortex. We find that neocortical thickness and the size of layer 5B pyramidal neurons changes as a gradient across the rostro-caudal axis of the rat primary visual cortex. Simultaneous somato-dendritic whole-cell recordings and compartmental modeling revealed that the electrical architecture of principal neurons was not preserved; rather, primary visual cortex site-dependent differences in intracellular resistivity accentuated a gradient of the electrical behavior of layer 5B pyramidal neurons to influence the emergence of active dendritic computations. Our findings therefore reveal an exquisite relationship between neocortical structure and neuronal computation.
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•Neocortical thickness varies as a gradient across the rat primary visual cortex•Neocortical structure governs apical dendritic morphology of V1 principal neurons•Principal neurons exhibit a gradient of dendritic information processing across V1•Neocortical structure and biophysics enforce a computational gradient across V1
Fletcher and Williams demonstrate that neuronal computations are determined by neocortical location. Dendritic integration in the primary visual cortex is governed by neuronal morphology and biophysics, creating a gradient of information processing that challenges the idea of stereotyped microcircuit operation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent spatial gene expression technologies enable comprehensive measurement of transcriptomic profiles while retaining spatial context. However, existing analysis methods do not address the limited ...resolution of the technology or use the spatial information efficiently. Here, we introduce BayesSpace, a fully Bayesian statistical method that uses the information from spatial neighborhoods for resolution enhancement of spatial transcriptomic data and for clustering analysis. We benchmark BayesSpace against current methods for spatial and non-spatial clustering and show that it improves identification of distinct intra-tissue transcriptional profiles from samples of the brain, melanoma, invasive ductal carcinoma and ovarian adenocarcinoma. Using immunohistochemistry and an in silico dataset constructed from scRNA-seq data, we show that BayesSpace resolves tissue structure that is not detectable at the original resolution and identifies transcriptional heterogeneity inaccessible to histological analysis. Our results illustrate BayesSpace's utility in facilitating the discovery of biological insights from spatial transcriptomic datasets.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Dendritic computations have a central role in neuronal function, but it is unknown how cell-class heterogeneity of dendritic electrical excitability shapes physiologically engaged neuronal and ...circuit computations. To address this, we examined dendritic integration in closely related classes of retinal ganglion cells (GCs) using simultaneous somato-dendritic electrical recording techniques in a functionally intact circuit. Simultaneous recordings revealed sustained OFF-GCs generated powerful dendritic spikes in response to visual input that drove action potential firing. In contrast, the dendrites of transient OFF-GCs were passive and did not generate dendritic spikes. Dendritic spike generation allowed sustained, but not transient, OFF-GCs to signal into action potential output the local motion of visual stimuli to produce a continuous wave of action potential firing in adjacent cells as images moved across the retina. Conversely, this representation was highly fragmented in transient OFF-GCs. Thus, a heterogeneity of dendritic excitability defines the computations executed by classes of GCs.
•Dendritic electrical excitability is cell-class-specific in rabbit retinal OFF-GCs•Visual stimuli initiate dendritic spikes in sustained but not in transient OFF-GCs•Dendritic spikes compute local motion in sustained OFF-GCs•OFF-GC classes signal distinct aspects of an approaching predator
Brombas et al. perform simultaneous electrical recordings from the soma and dendrites of rabbit OFF retinal ganglion cells to reveal that the differential expression of active dendritic integration defines cell-class-specific computations and the representation of moving visual stimuli.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Omega-3 polyunsaturated fatty acids (n-3 PUFA), enriched in fish oils, are increasingly recognized to have potential benefits for treating many human afflictions. Despite the importance of PUFA, ...their molecular mechanism of action remains unclear. One emerging hypothesis is that phospholipids containing n-3 PUFA acyl chains modify the structure and composition of membrane rafts, thus affecting cell signaling. In this study the two major n-3 PUFA found in fish oils, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, are compared. Using solid-state 2H NMR spectroscopy we explored the molecular organization of 1-2H31palmitoyl-2-eicosapentaenoylphosphatidylcholine (PEPC-d31) and 1-2H31palmitoyl-2-docosahexaenoylphosphatidylcholine (PDPC-d31) in mixtures with sphingomyelin (SM) and cholesterol (chol). Our results indicate that whereas both PEPC-d31 and PDPC-d31 can accumulate into SM-rich/chol-rich raftlike domains, the tendency for DHA to incorporate into rafts is more than twice as great as for EPA. We propose that DHA may be the more bioactive component of fish oil that serves to disrupt lipid raft domain organization. This mechanism represents an evolution in the view of how PUFA remodel membrane architecture.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives ...substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons.
Active dendritic integration is thought to enrich the computational power of central neurons. However, a direct role of active dendritic processing in the execution of defined neuronal computations ...in intact neural networks has not been established. Here we used multi-site electrophysiological recording techniques to demonstrate that active dendritic integration underlies the computation of direction selectivity in rabbit retinal ganglion cells. Direction-selective retinal ganglion cells fire action potentials in response to visual image movement in a preferred direction. Dendritic recordings revealed that preferred-direction moving-light stimuli led to dendritic spike generation in terminal dendrites, which were further integrated and amplified as they spread through the dendritic arbor to the axon to drive action potential output. In contrast, when light bars moved in a null direction, synaptic inhibition vetoed neuronal output by directly inhibiting terminal dendritic spike initiation. Active dendritic integration therefore underlies a physiologically engaged circuit-based computation in the retina.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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