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White matter volume and white/gray matter ratio in mammalian species as a consequence of the universal scaling of cortical folding.
Mota B, Dos Santos SE, Ventura-Antunes L, Jardim-Messeder D, Neves K, Kazu RS, Noctor S, Lambert K, Bertelsen MF, Manger PR, Sherwood CC, Kaas JH, Herculano-Houzel S
(2019) Proc Natl Acad Sci U S A 116: 15253-15261
MeSH Terms: Animals, Artiodactyla, Cerebral Cortex, Connectome, Gray Matter, Humans, Neurons, Organ Size, Organ Specificity, Primates, Rodentia, Scandentia, White Matter
Show Abstract · Added March 30, 2020
Because the white matter of the cerebral cortex contains axons that connect distant neurons in the cortical gray matter, the relationship between the volumes of the 2 cortical compartments is key for information transmission in the brain. It has been suggested that the volume of the white matter scales universally as a function of the volume of the gray matter across mammalian species, as would be expected if a global principle of wiring minimization applied. Using a systematic analysis across several mammalian clades, here we show that the volume of the white matter does not scale universally with the volume of the gray matter across mammals and is not optimized for wiring minimization. Instead, the ratio between volumes of gray and white matter is universally predicted by the same equation that predicts the degree of folding of the cerebral cortex, given the clade-specific scaling of cortical thickness, such that the volume of the gray matter (or the ratio of gray to total cortical volumes) divided by the square root of cortical thickness is a universal function of total cortical volume, regardless of the number of cortical neurons. Thus, the very mechanism that we propose to generate cortical folding also results in compactness of the white matter to a predictable degree across a wide variety of mammalian species.
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Actin assembly and non-muscle myosin activity drive dendrite retraction in an UNC-6/Netrin dependent self-avoidance response.
Sundararajan L, Smith CJ, Watson JD, Millis BA, Tyska MJ, Miller DM
(2019) PLoS Genet 15: e1008228
MeSH Terms: Actin Cytoskeleton, Actin-Related Protein 2-3 Complex, Actins, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dendritic Cells, Membrane Proteins, Myosin Heavy Chains, Nerve Tissue Proteins, Netrins, Neurons, Nonmuscle Myosin Type IIB
Show Abstract · Added March 3, 2020
Dendrite growth is constrained by a self-avoidance response that induces retraction but the downstream pathways that balance these opposing mechanisms are unknown. We have proposed that the diffusible cue UNC-6(Netrin) is captured by UNC-40(DCC) for a short-range interaction with UNC-5 to trigger self-avoidance in the C. elegans PVD neuron. Here we report that the actin-polymerizing proteins UNC-34(Ena/VASP), WSP-1(WASP), UNC-73(Trio), MIG-10(Lamellipodin) and the Arp2/3 complex effect dendrite retraction in the self-avoidance response mediated by UNC-6(Netrin). The paradoxical idea that actin polymerization results in shorter rather than longer dendrites is explained by our finding that NMY-1 (non-muscle myosin II) is necessary for retraction and could therefore mediate this effect in a contractile mechanism. Our results also show that dendrite length is determined by the antagonistic effects on the actin cytoskeleton of separate sets of effectors for retraction mediated by UNC-6(Netrin) versus outgrowth promoted by the DMA-1 receptor. Thus, our findings suggest that the dendrite length depends on an intrinsic mechanism that balances distinct modes of actin assembly for growth versus retraction.
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Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling.
Snyder AE, Salimando GJ, Winder DG, Silberman Y
(2019) Alcohol Clin Exp Res 43: 1695-1701
MeSH Terms: Adrenergic Neurons, Animals, Corticotropin-Releasing Hormone, Ethanol, Excitatory Amino Acid Antagonists, Gene Knock-In Techniques, Glutamic Acid, Kynurenic Acid, Male, Membrane Potentials, Mice, Norepinephrine, Picrotoxin, Propranolol, Restraint, Physical, Septal Nuclei, Substance Withdrawal Syndrome
Show Abstract · Added March 30, 2020
BACKGROUND - Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.
METHODS - Adult male CRF-tomato reporter mice were treatment-naïve, or either exposed to CIE for 2 weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques.
RESULTS - We found that NE depolarized BNST CRF neurons in naïve mice in a β-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE- or stress-exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α-AR-dependent.
CONCLUSIONS - Altogether, these findings suggest that stress and CIE interact with β-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β-AR balance of BNST CRF neuronal excitability. Restoration of α/β-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.
© 2019 by the Research Society on Alcoholism.
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Sex-Dependent Modulation of Anxiety and Fear by 5-HT Receptors in the Bed Nucleus of the Stria Terminalis.
Marcinkiewcz CA, Bierlein-De La Rosa G, Dorrier CE, McKnight M, DiBerto JF, Pati D, Gianessi CA, Hon OJ, Tipton G, McElligott ZA, Delpire E, Kash TL
(2019) ACS Chem Neurosci 10: 3154-3166
MeSH Terms: Animals, Anxiety, Behavior, Animal, Fear, Feeding Behavior, Female, Gene Knockdown Techniques, Male, Mice, Mice, Transgenic, Motor Activity, Neurons, Receptor, Serotonin, 5-HT1A, Septal Nuclei, Sex Factors
Show Abstract · Added June 28, 2019
Serotonin (5-hydroxytryptamine; 5-HT) coordinates behavioral responses to stress through a variety of presynaptic and postsynaptic receptors distributed across functionally diverse neuronal networks in the central nervous system. Efferent 5-HT projections from the dorsal raphe nucleus (DRN) to the bed nucleus of the stria terminalis (BNST) are generally thought to enhance anxiety and aversive learning by activating 5-HT receptor (5-HTR) signaling in the BNST, although an opposing role for postsynaptic 5-HT receptors has recently been suggested. In the present study, we sought to delineate a role for postsynaptic 5-HT receptors in the BNST in aversive behaviors using a conditional knockdown of the 5-HT receptor. Both males and females were tested to dissect out sex-specific effects. We found that male mice have significantly reduced fear memory recall relative to female mice and inactivation of 5-HT receptor in the BNST increases contextual fear conditioning in male mice so that they resemble the females. This coincided with an increase in neuronal excitability in males, suggesting that 5-HT receptor deletion may enhance contextual fear recall by disinhibiting fear memory circuits in the BNST. Interestingly, 5-HT receptor knockdown did not significantly alter anxiety-like behavior in male or female mice, which is in agreement with previous findings that anxiety and fear are modulated by dissociable circuits in the BNST. Overall, these results suggest that BNST 5-HT receptors do not significantly alter behavior under basal conditions, but can act as a molecular brake that buffer against excessive activation of aversive circuits in more threatening contexts.
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15 MeSH Terms
Mitochondrially targeted cytochrome P450 2D6 is involved in monomethylamine-induced neuronal damage in mouse models.
Chattopadhyay M, Chowdhury AR, Feng T, Assenmacher CA, Radaelli E, Guengerich FP, Avadhani NG
(2019) J Biol Chem 294: 10336-10348
MeSH Terms: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Cytochrome P-450 CYP2D6, Disease Models, Animal, Humans, Male, Methylamines, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Neuroblastoma, Neurons, Neurotoxins, Parkinson Disease, Tumor Cells, Cultured
Show Abstract · Added March 3, 2020
Parkinson's disease (PD) is a major human disease associated with degeneration of the central nervous system. Evidence suggests that several endogenously formed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mimicking chemicals that are metabolic conversion products, especially β-carbolines and isoquinolines, act as neurotoxins that induce PD or enhance progression of the disease. We have demonstrated previously that mitochondrially targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the conversion of MPTP to the toxic 1-methyl-4-phenylpyridinium ion. In this study, we show that the mitochondrially targeted CYP2D6 can efficiently catalyze MPTP-mimicking compounds, 2-methyl-1,2,3,4-tetrahydroisoquinoline, 2-methyl-1,2,3,4-tetrahydro-β-carboline, and 9-methyl-norharmon, suspected to induce PD in humans. Our results reveal that activity and respiration in mouse brain mitochondrial complex I are significantly affected by these toxins in WT mice but remain unchanged in Cyp2d6 locus knockout mice, indicating a possible role of CYP2D6 in the metabolism of these compounds both and These metabolic effects were minimized in the presence of two CYP2D6 inhibitors, quinidine and ajmalicine. Neuro-2a cells stably expressing predominantly mitochondrially targeted CYP2D6 were more sensitive to toxin-mediated respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Exposure to these toxins also induced the autophagic marker Parkin and the mitochondrial fission marker Dynamin-related protein 1 (Drp1) in differentiated neurons expressing mitochondrial CYP2D6. Our results show that monomethylamines are converted to their toxic cationic form by mitochondrially directed CYP2D6 and result in neuronal degradation in mice.
© 2019 Chattopadhyay et al.
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Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice.
Anacker AMJ, Moran JT, Santarelli S, Forsberg CG, Rogers TD, Stanwood GD, Hall BJ, Delpire E, Veenstra-VanderWeele J, Saxe MD
(2019) Autism Res 12: 732-743
MeSH Terms: Animals, Autistic Disorder, Behavior, Animal, Disease Models, Animal, Electrophysiological Phenomena, Male, Mice, Mice, Knockout, Neurons, Prefrontal Cortex, Social Dominance
Show Abstract · Added March 18, 2020
The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2 mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2 mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2 mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes. Autism Research 2019, 12: 732-743. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors.
© 2019 International Society for Autism Research, Wiley Periodicals, Inc.
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Functional Coupling of K-Cl Cotransporter (KCC) to GABA-Gated Cl Channels in the Central Nervous System of Drosophila melanogaster Leads to Altered Drug Sensitivities.
Chen R, Prael FJ, Li Z, Delpire E, Weaver CD, Swale DR
(2019) ACS Chem Neurosci 10: 2765-2776
MeSH Terms: Animals, Central Nervous System, Chloride Channels, Drosophila Proteins, Drosophila melanogaster, Insecticide Resistance, Neurons, Signal Transduction, Symporters, Synaptic Transmission, gamma-Aminobutyric Acid
Show Abstract · Added April 10, 2019
GABAergic signaling is the cornerstone for fast synaptic inhibition of neural signaling in arthropods and mammals and is the molecular target for insecticides and pharmaceuticals, respectively. The K-Cl cotransporter (KCC) is the primary mechanism by which mature neurons maintain low intracellular Cl concentration, yet the fundamental physiology, comparative physiology, and toxicological relevance of insect KCC is understudied. Considering this, we employed electrophysiological, genetic, and pharmacological methods to characterize the physiological underpinnings of KCC function to the Drosophila CNS. Our data show that genetic ablation or pharmacological inhibition of KCC results in an increased spike discharge frequency and significantly ( P < 0.05) reduces the CNS sensitivity to γ-aminobutyric acid (GABA). Further, simultaneous inhibition of KCC and ligand-gated chloride channel (LGCC) complex results in a significant ( P < 0.001) increase in CNS spontaneous activity over baseline firing rates that supports functional coupling of KCC to LGCC function. Interestingly, 75% reduction in KCC mRNA did not alter basal neurotransmission levels indicating that only a fraction of the KCC population is required to maintain the Cl ionic gradient when at rest, but prolonged synaptic activity increases the threshold for GABA-mediated inhibition and reduces nerve sensitivity to GABA. These data expand current knowledge regarding the physiological role of KCC in a model insect and provides the necessary foundation to develop KCC as a novel biochemical target of insecticides, as well as complements existing research to provide a holistic understanding of the plasticity in mammalian health and disease.
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11 MeSH Terms
VU0810464, a non-urea G protein-gated inwardly rectifying K (K 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K 3 channels and reduces stress-induced hyperthermia in mice.
Vo BN, Abney KK, Anderson A, Marron Fernandez de Velasco E, Benneyworth MA, Daniels JS, Morrison RD, Hopkins CR, Weaver CD, Wickman K
(2019) Br J Pharmacol 176: 2238-2249
MeSH Terms: Animals, Anxiety, Behavior, Animal, Brain, Cells, Cultured, Female, Fever, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Sinoatrial Node, Stress, Psychological
Show Abstract · Added April 10, 2019
BACKGROUND AND PURPOSE - G protein-gated inwardly rectifying K (K 3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal K 3 channels consist of K 3.1 and K 3.2 subtypes, while cardiac K 3 channels consist of K 3.1 and K 3.4 subtypes. Previously, we identified a family of urea-containing K 3 channel activators, but these molecules exhibit suboptimal pharmacokinetic properties and modest selectivity for K 3.1/3.2 relative to K 3.1/3.4 channels. Here, we characterize a non-urea activator, VU0810464, which displays nanomolar potency as a K 3.1/3.2 activator, improved selectivity for neuronal K 3 channels, and improved brain penetration.
EXPERIMENTAL APPROACH - We used whole-cell electrophysiology to measure the efficacy and potency of VU0810464 in neurons and the selectivity of VU0810464 for neuronal and cardiac K 3 channel subtypes. We tested VU0810464 in vivo in stress-induced hyperthermia and elevated plus maze paradigms. Parallel studies with ML297, the prototypical activator of K 3.1-containing K 3 channels, were performed to permit direct comparisons.
KEY RESULTS - VU0810464 and ML297 exhibited comparable efficacy and potency as neuronal K 3 channel activators, but VU0810464 was more selective for neuronal K 3 channels. VU0810464, like ML297, reduced stress-induced hyperthermia in a K 3-dependent manner in mice. ML297, but not VU0810464, decreased anxiety-related behaviour as assessed with the elevated plus maze test.
CONCLUSION AND IMPLICATIONS - VU0810464 represents a new class of K 3 channel activator with enhanced selectivity for K 3.1/3.2 channels. VU0810464 may be useful for examining K 3.1/3.2 channel contributions to complex behaviours and for probing the potential of K 3 channel-dependent manipulations to treat neurological disorders.
© 2019 The British Pharmacological Society.
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14 MeSH Terms
V1 microcircuit dynamics: altered signal propagation suggests intracortical origins for adaptation in response to visual repetition.
Westerberg JA, Cox MA, Dougherty K, Maier A
(2019) J Neurophysiol 121: 1938-1952
MeSH Terms: Adaptation, Physiological, Animals, Evoked Potentials, Visual, Female, Geniculate Bodies, Macaca radiata, Male, Neurons, Visual Cortex
Show Abstract · Added August 27, 2020
Repetitive visual stimulation profoundly changes sensory processing in the primary visual cortex (V1). We show how the associated adaptive changes are linked to an altered flow of synaptic activation across the V1 laminar microcircuit. Using repeated visual stimulation, we recorded layer-specific responses in V1 of two fixating monkeys. We found that repetition-related spiking suppression was most pronounced outside granular V1 layers that receive the main retinogeniculate input. This repetition-related response suppression was robust to alternating stimuli between the eyes, in line with the notion that repetition-related adaptation is predominantly of cortical origin. Most importantly, current source density (CSD) analysis, which provides an estimate of local net depolarization, revealed that synaptic processing during repeated stimulation was most profoundly affected within supragranular layers, which harbor the bulk of cortico-cortical connections. Direct comparison of the temporal evolution of laminar CSD and spiking activity showed that stimulus repetition first affected supragranular synaptic currents, which translated into a reduction of stimulus-evoked spiking across layers. Together, these results suggest that repetition induces an altered state of intracortical processing that underpins visual adaptation. Our survival depends on our brains rapidly adapting to ever changing environments. A well-studied form of adaptation occurs whenever we encounter the same or similar stimuli repeatedly. We show that this repetition-related adaptation is supported by systematic changes in the flow of sensory activation across the laminar cortical microcircuitry of primary visual cortex. These results demonstrate how adaptation impacts neuronal interactions across cortical circuits.
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Phenotypes of primary retinal macroglia: Implications for purification and culture conditions.
Backstrom JR, Sheng J, Fischer RA, Sappington RM, Rex TS
(2019) Exp Eye Res 182: 85-92
MeSH Terms: Animals, Astrocytes, Cell Communication, Cell Culture Techniques, Cell Differentiation, Culture Media, Neuroglia, Phenotype, Rats, Rats, Sprague-Dawley, Retina, Retinal Neurons
Show Abstract · Added April 2, 2019
Many neurodegenerations, including those of the visual system, have complex etiologies that include roles for both neurons and glia. In the retina there is evidence that retinal astrocytes play an important role in neurodegeneration. There are several approaches for isolating and growing primary retinal astrocytes, however, they often lead to different results. In this study, we examined the influence of culture conditions on phenotypic maturation of primary, purified retinal glia. We compared retinal astrocytes and Müller glia purified by immunomagnetic separation, as differentiation between these astrocyte subtypes is critical and immuno-based methods are the standard practice of purification. We found that while time in culture impacts the health and phenotype of both astrocytes and Müller glia, the phenotypic maturation of retinal astrocytes was most impacted by serum factors. These factors appeared to actively regulate intermediate filament phenotypes in a manner consistent with the induction of astrocyte-mesenchymal transition (AMT). This propensity for retinal astrocytes to shift along an AMT continuum should be considered when interpreting resulting data. Our goal is that this study will help standardize the field so that studies are replicable, comparable, and as accurate as possible for subsequent interpretation of findings.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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12 MeSH Terms