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Conditional Bistability, a Generic Cellular Mnemonic Mechanism for Robust and Flexible Working Memory Computations.
Rodriguez, G, Sarazin, M, Clemente, A, Holden, S, Paz, JT, Delord, B
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2018;(22):5209-5219
Abstract
Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain the fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust and generic. and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability, and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the subthreshold input it requires, and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory.SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property: conditional bistability. We show that, thanks to its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability (1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that (2) it accounts for essential neurodynamical features for the organization and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models.
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Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons.
Welcome, MO, Mastorakis, NE
Neuromolecular medicine. 2018;(3):281-300
Abstract
The astrocyte-neuron lactate shunt (ANLS) hypothesis is the most widely accepted model of brain glucose metabolism. However, over the past decades, research has shown that neuronal and astrocyte plasma membrane receptors, in particular, GLUT2, Kir6.2 subunit of the potassium ATP-channel, SGLT-3 acting as glucosensors, play a pivotal role in brain glucose metabolism. Although both ANLS hypothesis and glucosensor model substantially improved our understanding of brain glucose metabolism, the latter appears to be gaining more attention in the scientific community as the former could not account for new research data indicating that hypothalamic and brainstem neurons may not require astrocyte-derived lactate for energy. More recently, emerging evidences suggest a crucial role of sweet taste receptors in brain glucose metabolism. Furthermore, a couple of intracellular molecules acting as glucosensors have been identified in central astrocytes and neurons. This review integrates new data on the mechanisms of brain glucose sensing and metabolism. The role of the glucosensors including the sweet taste T1R2 + T1R3-mediated brain glucose-sensing and metabolism in brain glucose metabolic disorders is discussed. Possible role of glucose sensors (GLUT2, K-ATPKir6.2, SGLT3, T1R2 + T1R3) in brain diseases involving metabolic dysfunctions and the therapeutic significance in targeting central glucosensors for the treatment of these brain diseases are also discussed.
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3.
Electrophysiological Mechanism of Peripheral Hormones and Nutrients Regulating Energy Homeostasis.
Huang, Z, Xiao, K
Advances in experimental medicine and biology. 2018;:183-198
Abstract
In organism, energy homeostasis is a biological process that involves the coordinated homeostatic regulation of energy intake (food intake) and energy expenditure. The human brain, particularly the hypothalamic proopiomelanocortin (POMC)- and agouti-related protein/neuropeptide Y (AgRP/NPY)-expressing neurons in the arcuate nucleus, plays an essential role in regulating energy homeostasis. The regulation process is mainly dependent upon peripheral hormones such as leptin and insulin, as well as nutrients such as glucose, amino acids, and fatty acids. Although many studies have attempted to illustrate the exact mechanisms of glucose and hormones action on these neurons, we still cannot clearly see the full picture of this regulation action. Therefore, in this review we will mainly discuss those established theories and recent progresses in this area, demonstrating the possible physiological mechanism by which glucose, leptin, and insulin affect neuronal excitability of POMC and AgRP neurons. In addition, we will also focus on some important ion channels which are expressed by POMC and AgRP neurons, such as KATP channels and TRPC channels, and explain how these channels are regulated by peripheral hormones and nutrients and thus regulate energy homeostasis.
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4.
Mechanisms of carnosine-induced activation of neuronal cells.
Yamashita, S, Sato, M, Matsumoto, T, Kadooka, K, Hasegawa, T, Fujimura, T, Katakura, Y
Bioscience, biotechnology, and biochemistry. 2018;(4):683-688
Abstract
Carnosine (β-Ala-l-His), an imidazole dipeptide, is known to have many functions. Recently, we demonstrated in a double-blind randomized controlled trial that carnosine is capable of preserving cognitive function in elderly people. In the current study, we assessed the ability of carnosine to activate the brain, and we tried to clarify the molecular mechanisms behind this activation. Our results demonstrate that carnosine permeates the blood brain barrier and activates glial cells within the brain, causing them to secrete neurotrophins, including BDNF and NGF. These results point to a novel mechanism of carnosine-induced neuronal activation. Our results suggest that carnosine should be recognized as a functional food factor that helps achieve anti-brain aging.
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5.
Voltage-Sensitive Potassium Channels of the BK Type and Their Coding Genes Are Alcohol Targets in Neurons.
Dopico, AM, Bukiya, AN, Bettinger, JC
Handbook of experimental pharmacology. 2018;:281-309
Abstract
Among all members of the voltage-gated, TM6 ion channel superfamily, the proteins that constitute calcium- and voltage-gated potassium channels of large conductance (BK) and their coding genes are unique for their involvement in ethanol-induced disruption of normal physiology and behavior. Moreover, in vitro studies document that BK activity is modified by ethanol with an EC50~23 mM, which is near blood alcohol levels considered legal intoxication in most states of the USA (0.08 g/dL = 17.4 mM). Following a succinct introduction to our current understanding of BK structure and function in central neurons, with a focus on neural circuits that contribute to the neurobiology of alcohol use disorders (AUD), we review the modifications in organ physiology by alcohol exposure via BK and the different molecular elements that determine the ethanol response of BK in alcohol-naïve systems, including the role of an ethanol-recognizing site in the BK-forming slo1 protein, modulation of accessory BK subunits, and their coding genes. The participation of these and additional elements in determining the response of a system or an organism to protracted ethanol exposure is consequently analyzed, with insights obtained from invertebrate and vertebrate models. Particular emphasis is put on the role of BK and coding genes in different forms of tolerance to alcohol exposure. We finally discuss genetic results on BK obtained in invertebrate organisms and rodents in light of possible extrapolation to human AUD.
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6.
POMC Neurons: Feeding, Energy Metabolism, and Beyond.
Zhan, C
Advances in experimental medicine and biology. 2018;:17-29
Abstract
The central melanocortin system is a well-established neuronal pathway involved in regulating energy metabolism. Pro-opiomelanocortin (POMC) neurons, agouti gene-related protein (AgRP) neurons, and their downstream cells expressing the melanocortin-3 (MC3R) and melanocortin-4 receptors (MC4R) are three key components of the central melanocortin pathway. This chapter focuses on the Pomc gene and the POMC neural system. First, I summarize the established role of this system in inhibiting food intake. Second, in light of new cutting-edge techniques, our understanding of how POMC neurons function to regulate energy homeostasis has been refined during the last few years. I describe some recent advances and discuss bidirectional effects of POMC neurons on feeding. Finally, the physiological significance beyond energy metabolism, in particular for reward and sex, is also discussed.
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Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors.
Bähring, R
Channels (Austin, Tex.). 2018;(1):187-200
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Abstract
Kv channel-interacting proteins (KChIPs) belong to the neuronal calcium sensor (NCS) family of Ca2+-binding EF-hand proteins. KChIPs constitute a group of specific auxiliary β-subunits for Kv4 channels, the molecular substrate of transient potassium currents in both neuronal and non-neuronal tissues. Moreover, KChIPs can interact with presenilins to control ER calcium signaling and apoptosis, and with DNA to control gene transcription. Ca2+ binding via their EF-hands, with the consequence of conformationl changes, is well documented for KChIPs. Moreover, the Ca2+ dependence of the presenilin/KChIP complex may be related to Alzheimer's disease and the Ca2+ dependence of the DNA/KChIP complex to pain sensing. However, only in few cases could the Ca2+ binding to KChIPs be directly linked to the control of excitability in nerve and muscle cells known to express Kv4/KChIP channel complexes. This review summarizes current knowledge about the Ca2+ binding properties of KChIPs and the Ca2+ dependencies of macromolecular complexes containing KChIPs, including those with presenilins, DNA and especially Kv4 channels. The respective physiological or pathophysiolgical roles of Ca2+ binding to KChIPs are discussed.
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8.
Stress enhanced calcium kinetics in a neuron.
Kant, A, Bhandakkar, TK, Medhekar, NV
Biomechanics and modeling in mechanobiology. 2018;(1):169-180
Abstract
Accurate modeling of the mechanobiological response of a Traumatic Brain Injury is beneficial toward its effective clinical examination, treatment and prevention. Here, we present a stress history-dependent non-spatial kinetic model to predict the microscale phenomena of secondary insults due to accumulation of excess calcium ions (Ca[Formula: see text]) induced by the macroscale primary injuries. The model is able to capture the experimentally observed increase and subsequent partial recovery of intracellular Ca[Formula: see text] concentration in response to various types of mechanical impulses. We further establish the accuracy of the model by comparing our predictions with key experimental observations.
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Equivalent Circuit of the Neuro-Electronic Junction for Signal Recordings From Planar and Engulfed Micro-Nano-Electrodes.
Massobrio, G, Martinoia, S, Massobrio, P
IEEE transactions on biomedical circuits and systems. 2018;(1):3-12
Abstract
In the latest years, several attempts to develop extracellular microtransducers to record electrophysiological activity of excitable cells have been done. In particular, many efforts have been oriented to increase the coupling conditions, and, thus, improving the quality of the recorded signal. Gold mushroom-shaped microelectrodes (GMμE) are an example of nano-devices to achieve those requirements. In this study, we developed an equivalent electrical circuit of the neuron-microelectrode system interface to simulate signal recordings from both planar and engulfed micro-nano-electrodes. To this purpose, models of the neuron, planar, gold planar microelectrode, and GMμE, neuro-electronic junction (microelectrode-electrolyte interface, cleft effect, and protein-glycocalyx electric double layer) are presented. Then, neuronal electrical activity is simulated by Hspice software, and analyzed as a function of the most sensitive biophysical models parameters, such as the neuron-microelectrode cleft width, spreading and seal resistances, ion-channel densities, double-layer properties, and microelectrode geometries. Results are referenced to the experimentally recorded electrophysiological neuronal signals reported in the literature.
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Iron-mediated oxidative cell death is a potential contributor to neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia.
Viktorinova, A
Archives of biochemistry and biophysics. 2018;:185-193
Abstract
The review article discusses current knowledge of iron-mediated oxidative cell death (ferroptosis) and its potential role in the pathogenesis of neuronal dysfunction induced by neonatal hemolytic hyperbilirubinemia. The connection between metabolic conditions related to hemolysis (iron and bilirubin overload) and iron-induced lipid peroxidation is highlighted. Neurotoxicity of iron and bilirubin is associated with their release from destructed erythrocytes in response to hemolytic disease. Iron overload initiates lipid peroxidation through the reactive oxygen species production resulting to oxidative damage to cells. Excessive loading of immature brain cells by iron-induced formation of reactive oxygen species contributes to the development of various neurodevelopmental disorders. The causal relationship between iron overload and susceptibility of brain cells to oxidative damage by ferroptosis appears to be associated not only with the amount of redox-active iron involved in oxidative cell damage but also with the degree of maturity of the neonatal brain. Neuronal dysfunction induced by neonatal hemolytic disease can represent a specific model of ferroptosis. The mechanism by which iron overload triggers ferroptosis is not completely explained. However, hemolysis of neonatal red blood cells appears to be a determining factor. Potential therapeutic strategy with iron-chelating agents to inhibit ferroptosis has a promising future in postnatal care.