bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noisy Juxtacellular StimulationIn VivoLeads to Reliable Spiking and Reveals High-Frequency Coding in Single Neurons
Authors: Doose Jens , Doron Guy , Brecht Michael , Lindner Benjamin 
Published: October 2016

Single cells in the motor and somatosensory cortex of rats were stimulatedin vivowith broadband fluctuating currents applied juxtacellularly. Unlike the DC current steps used previously, fluctuating stimulation currents reliably evoked spike trains with precise timing of individual spikes. Fluctuating currents resulted in strong cellular responses at stimulation frequencies beyond the inverse membrane time constant and the mean firing rate of the neuron. Neuronal firing was associated with high rates of information transmission, even for the high-frequency components of the stimulus. Such response characteristics were also revealed in additional experiments with sinusoidal juxtacellular stimulation. For selected cells, we could reproduce these statistics with compartmental models of varying complexity. We also developed a method to generate Gaussian stimuli that evoke spike trains with prescribed spike times (under the constraint of a certain rate and coefficient of variation) and exemplify its ability to achieve precise and reliable spiking in cortical neuronsin vivo. Our results demonstrate a novel method for precise control of spike timing by juxtacellular stimulation, confirm and extend earlier conclusions fromex vivowork about the capacity of cortical neurons to generate precise discharges, and contribute to the understanding of the biophysics of information transfer of single neuronsin vivoat high frequencies.SIGNIFICANCE STATEMENTNanostimulation of single identified neuronsin vivocan control spike frequency parametrically and, surprisingly, can even bias the animal's behavioral response. Here, we extend this stimulation protocol to time-dependent broadband noise stimulation in sensory and motor cortices of rat. In response to such stimuli, we found increased temporal spike-time reliability. The information transmission properties reveal, both experimentally and theoretically, that the neurons support high-frequency stimulation beyond the inverse membrane time. Generating a stimulus using the neuron's response properties, we could evoke prescribed spike times with high precision. Our work helps to establish a novel method for precise temporal control of single-cell spiking and provides a simplified biophysical description of single-neuron spiking under time-dependentin vivo-like stimulation.
Nogo Receptor 1 Confines a Disinhibitory Microcircuit to the Critical Period in Visual Cortex
Authors: Stephany Céleste-Élise , Ikrar Taruna , Nguyen Collins , Xu Xiangmin , McGee Aaron W. 
Published: October 2016

A characteristic of the developing mammalian visual system is a brief interval of plasticity, termed the “critical period,” when the circuitry of primary visual cortex is most sensitive to perturbation of visual experience. Depriving one eye of vision (monocular deprivation [MD]) during the critical period alters ocular dominance (OD) by shifting the responsiveness of neurons in visual cortex to favor the nondeprived eye. A disinhibitory microcircuit involving parvalbumin-expressing (PV) interneurons initiates this OD plasticity. The gene encoding theneuronal nogo-66-receptor 1(ngr1/rtn4r) is required to close the critical period. Here we combined mouse genetics, electrophysiology, and circuit mapping with laser-scanning photostimulation to investigate whether disinhibition is confined to the critical period byngr1. We demonstrate thatngr1mutant mice retain plasticity characteristic of the critical period as adults, and thatngr1operates within PV interneurons to restrict the loss of intracortical excitatory synaptic input following MD in adult mice, and this disinhibition induces a “lower PV network configuration” in both critical-period wild-type mice and adultngr1−/−mice. We propose thatngr1limits disinhibition to close the critical period for OD plasticity and that a decrease in PV expression levels reports the diminished recent cumulative activity of these interneurons.SIGNIFICANCE STATEMENTLife experience refines brain circuits throughout development during specified critical periods. Abnormal experience during these critical periods can yield enduring maladaptive changes in neural circuits that impair brain function. In the developing visual system, visual deprivation early in life can result in amblyopia (lazy-eye), a prevalent childhood disorder comprising permanent deficits in spatial vision. Here we identify that thenogo-66 receptor 1gene restricts an early and essential step in OD plasticity to the critical period. These findings link the emerging circuit-level description of OD plasticity to the genetic regulation of the critical period. Understanding how plasticity is confined to critical periods may provide clues how to better treat amblyopia.
A Decline in Response Variability Improves Neural Signal Detection during Auditory Task Performance
Authors: von Trapp Gardiner , Buran Bradley N. , Sen Kamal , Semple Malcolm N. , Sanes Dan H. 
Published: October 2016

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity.SIGNIFICANCE STATEMENTThe detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds.
A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca2+Release During Axonal Specification
Authors: Wilson Carlos , Muñoz-Palma Ernesto , Henríquez Daniel R. , Palmisano Ilaria , Núñez M. Tulio , Di Giovanni Simone , González-Billault Christian 
Published: October 2016

Physiological levels of ROS support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shape neurons remain unknown. Ca2+, a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca2+release from the endoplasmic reticulum, mediated by both the IP3R1 and ryanodine receptor (RyR) channels, requires physiological ROS levels that are mainly sustained by the NADPH oxidase (NOX) complex. In this work, we explore the contribution of the link between NOX and RyR-mediated Ca2+release toward axonal specification of rat hippocampal neurons. Using genetic approaches, we find that NOX activation promotes both axonal development and Rac1 activation through a RyR-mediated mechanism, which in turn activates NOX through Rac1, one of the NOX subunits. Collectively, these data suggest a feedforward mechanism that integrates both NOX activity and RyR-mediated Ca2+release to support cellular mechanisms involved in axon development.SIGNIFICANCE STATEMENTHigh levels of ROS are frequently associated with oxidative stress and disease. In contrast, physiological levels of ROS, mainly sustained by the NADPH oxidase (NOX) complex, promote neuronal development and axonal growth. However, the mechanisms by which ROS shape neurons have not been described. Our work suggests that NOX-derived ROS promote axonal growth by regulating Rac1 activity, a molecular determinant of axonal growth, through a ryanodine receptor (RyR)-mediated Ca2+release mechanism. In addition, Rac1, one of the NOX subunits, was activated after RyR-mediated Ca2+release, suggesting a feedforward mechanism between NOX and RyR. Collectively, our data suggest a novel mechanism that is instrumental in sustaining physiological levels of ROS required for axonal growth of hippocampal neurons.
Genetically Targeted All-Optical Electrophysiology with a Transgenic Cre-Dependent Optopatch Mouse
Authors: Lou Shan , Adam Yoav , Weinstein Eli N. , Williams Erika , Williams Katherine , Parot Vicente , Kavokine Nikita , Liberles Stephen , Madisen Linda , Zeng Hongkui , Cohen Adam E. 
Published: October 2016

Recent advances in optogenetics have enabled simultaneous optical perturbation and optical readout of membrane potential in diverse cell types. Here, we develop and characterize aCre-dependent transgenic Optopatch2 mouse line that we call Floxopatch. The animals expressed a blue-shifted channelrhodopsin, CheRiff, and a near infrared Archaerhodopsin-derived voltage indicator, QuasAr2, via targeted knock-in at the rosa26 locus. In Optopatch-expressing animals, we tested for overall health, genetically targeted expression, and function of the optogenetic components. In offspring of Floxopatch mice crossed with a variety ofCredriver lines, we observed spontaneous and optically evoked activityin vitroin acute brain slices andin vivoin somatosensory ganglia. Cell-type-specific expression allowed classification and characterization of neuronal subtypes based on their firing patterns. The Floxopatch mouse line is a useful tool for fast and sensitive characterization of neural activity in genetically specified cell types in intact tissue.SIGNIFICANCE STATEMENTOptical recordings of neural activity offer the promise of rapid and spatially resolved mapping of neural function. Calcium imaging has been widely applied in this mode, but is insensitive to the details of action potential waveforms and subthreshold events. Simultaneous optical perturbation and optical readout of single-cell electrical activity (“Optopatch”) has been demonstrated in cultured neurons and in organotypic brain slices, but not in acute brain slices orin vivo. Here, we describe a transgenic mouse in which expression of Optopatch constructs is controlled by the Cre-recombinase enzyme. This animal enables fast and robust optical measurements of single-cell electrical excitability in acute brain slices and in somatosensory gangliain vivo, opening the door to rapid optical mapping of neuronal excitability.
α2δ2 Controls the Function and Trans-Synaptic Coupling of Cav1.3 Channels in Mouse Inner Hair Cells and Is Essential for Normal Hearing
Authors: Fell Barbara , Eckrich Stephanie , Blum Kerstin , Eckrich Tobias , Hecker Dietmar , Obermair Gerald J. , Münkner Stefan , Flockerzi Veit , Schick Bernhard , Engel Jutta 
Published: October 2016

The auxiliary subunit α2δ2 modulates the abundance and function of voltage-gated calcium channels. Here we show that α2δ2 mRNA is expressed in neonatal and mature hair cells. A functional α2δ2-null mouse, the ducky mouse (du), showed elevated auditory brainstem response click and frequency-dependent hearing thresholds. Otoacoustic emissions were not impaired pointing to normal outer hair cell function. Peak Ca2+and Ba2+currents of mature du/du inner hair cells (IHCs) were reduced by 30–40%, respectively, and gating properties, such as the voltage of half-maximum activation and voltage sensitivity, were altered, indicating that Cav1.3 channels normally coassemble with α2δ2 at IHC presynapses. The reduction of depolarization-evoked exocytosis in du/du IHCs reflected their reduced Ca2+currents. Ca2+- and voltage-dependent K+(BK) currents and the expression of the pore-forming BKα protein were normal. Cav1.3 and Cavβ2 protein expression was unchanged in du/du IHCs, forming clusters at presynaptic ribbons. However, the close apposition of presynaptic Cav1.3 clusters with postsynaptic glutamate receptor GluA4 and PSD-95 clusters was significantly impaired in du/du mice. This implies that, in addition to controlling the expression and gating properties of Cav1.3 channels, the largely extracellularly localized α2δ2 subunit moreover plays a so far unknown role in mediating trans-synaptic alignment of presynaptic Ca2+channels and postsynaptic AMPA receptors.SIGNIFICANCE STATEMENTInner hair cells possess calcium channels that are essential for transmitting sound information into synaptic transmitter release. Voltage-gated calcium channels can coassemble with auxiliary subunit α2δ isoforms 1–4. We found that hair cells of the mouse express the auxiliary subunit α2δ2, which is needed for normal hearing thresholds. Using a mouse model with a mutant, nonfunctional α2δ2 protein, we showed that the α2δ2 protein is necessary for normal calcium currents and exocytosis in inner hair cells. Unexpectedly, the α2δ2 protein is moreover required for the optimal spatial alignment of presynaptic calcium channels and postsynaptic glutamate receptor proteins across the synaptic cleft. This suggests that α2δ2 plays a novel role in organizing the synapse.
Connectional Modularity of Top-Down and Bottom-Up Multimodal Inputs to the Lateral Cortex of the Mouse Inferior Colliculus
Authors: Lesicko Alexandria M.H. , Hristova Teodora S. , Maigler Kathleen C. , Llano Daniel A. 
Published: October 2016

The lateral cortex of the inferior colliculus receives information from both auditory and somatosensory structures and is thought to play a role in multisensory integration. Previous studies in the rat have shown that this nucleus contains a series of distinct anatomical modules that stain for GAD-67 as well as other neurochemical markers. In the present study, we sought to better characterize these modules in the mouse inferior colliculus and determine whether the connectivity of other neural structures with the lateral cortex is spatially related to the distribution of these neurochemical modules. Staining for GAD-67 and other markers revealed a single modular network throughout the rostrocaudal extent of the mouse lateral cortex. Somatosensory inputs from the somatosensory cortex and dorsal column nuclei were found to terminate almost exclusively within these modular zones. However, projections from the auditory cortex and central nucleus of the inferior colliculus formed patches that interdigitate with the GAD-67-positive modules. These results suggest that the lateral cortex of the mouse inferior colliculus exhibits connectional as well as neurochemical modularity and may contain multiple segregated processing streams. This finding is discussed in the context of other brain structures in which neuroanatomical and connectional modularity have functional consequences.SIGNIFICANCE STATEMENTMany brain regions contain subnuclear microarchitectures, such as the matrix-striosome organization of the basal ganglia or the patch-interpatch organization of the visual cortex, that shed light on circuit complexities. In the present study, we demonstrate the presence of one such micro-organization in the rodent inferior colliculus. While this structure is typically viewed as an auditory integration center, its lateral cortex appears to be involved in multisensory operations and receives input from somatosensory brain regions. We show here that the lateral cortex can be further subdivided into multiple processing streams: modular regions, which are targeted by somatosensory inputs, and extramodular zones that receive auditory information.
Behavioral and Neural Signatures of Reduced Updating of Alternative Options in Alcohol-Dependent Patients during Flexible Decision-Making
Authors: Reiter Andrea M.F. , Deserno Lorenz , Kallert Thomas , Heinze Hans-Jochen , Heinz Andreas , Schlagenhauf Florian 
Published: October 2016

Addicted individuals continue substance use despite the knowledge of harmful consequences and often report having no choice but to consume. Computational psychiatry accounts have linked this clinical observation to difficulties in making flexible and goal-directed decisions in dynamic environments via consideration of potential alternative choices. To probe this in alcohol-dependent patients (n= 43) versus healthy volunteers (n= 35), human participants performed an anticorrelated decision-making task during functional neuroimaging. Via computational modeling, we investigated behavioral and neural signatures of inference regarding the alternative option. While healthy control subjects exploited the anticorrelated structure of the task to guide decision-making, alcohol-dependent patients were relatively better explained by a model-free strategy due to reduced inference on the alternative option after punishment. Whereas model-free prediction error signals were preserved, alcohol-dependent patients exhibited blunted medial prefrontal signatures of inference on the alternative option. This reduction was associated with patients' behavioral deficit in updating the alternative choice option and their obsessive-compulsive drinking habits. All results remained significant when adjusting for potential confounders (e.g., neuropsychological measures and gray matter density). A disturbed integration of alternative choice options implemented by the medial prefrontal cortex appears to be one important explanation for the puzzling question of why addicted individuals continue drug consumption despite negative consequences.SIGNIFICANCE STATEMENTIn addiction, patients maintain substance use despite devastating consequences and often report having no choice but to consume. These clinical observations have been theoretically linked to disturbed mechanisms of inference, for example, to difficulties when learning statistical regularities of the environmental structure to guide decisions. Using computational modeling, we demonstrate disturbed inference on alternative choice options in alcohol addiction. Patients neglecting “what might have happened” was accompanied by blunted coding of inference regarding alternative choice options in the medial prefrontal cortex. An impaired integration of alternative choice options implemented by the medial prefrontal cortex might contribute to ongoing drug consumption in the face of evident negative consequences.
The association of thyroid function and the risk of kidney function decline: a population-based cohort study
Authors: Chaker Layal , Sedaghat Sanaz , Hoorn Ewout J , Elzen Wendy P J Den , Gussekloo Jacobijn , Hofman Albert , Ikram M Arfan , Franco Oscar H , Dehghan Abbas , Peeters Robin P 
Published: October 2016

Objectives
Thyroid dysfunction has been associated with kidney function decline, but mainly in cross-sectional studies. Therefore, we aimed to determine the association between thyroid and kidney function in a prospective population-based cohort study longitudinally.

Design
Prospective cohort study.

Methods
Participants aged ≥45 years from the Rotterdam Study with thyroid and kidney function assessment were included. Kidney function and new onset chronic kidney disease (CKD) were defined using estimated glomerular filtration ate (eGFR), with CKD defined as eGFR <60 mL/min/1.73 m2 according to the CKD-EPI formula.

Results
We included 5103 participants (mean age of 63.6 years) with a mean follow-up of 8.1 years. Cross-sectionally, higher TSH levels were associated with lower eGFR (Beta (β): −1.75 mL/min; 95% confidence interval (CI): −2.17, −1.33), in multivariable models adjusting for several cardiovascular risk factors including smoking, hypertension and history of coronary heart disease among others. In contrast, longitudinally, higher TSH levels were associated with less annual eGFR decline (β: −0.06 mL/min; CI: −0.11, −0.01) and lower CKD incidence (odds ratio 0.85, CI; 0.75, 0.96). Compared with euthyroid participants, subclinical hyperthyroid individuals had an increased risk for CKD whereas hypothyroid individuals had a decreased risk (P for trend = 0.04).

Conclusions
Hyperactive thyroid function is associated with increased risk of kidney function decline while hypothyroidism is associated with a decreased CKD risk. More insight is needed in the pathophysiological pathways connecting high thyroid function and kidney function decline.
Genetic polymorphisms in asthmatic patients living at Krasnoyarsk
Authors: Cherkashina I. I. , Razvodovskaya A. V. , Nikulina S. Yu. , Shestovitskiy V. A. , Voevoda M. I. , Maksimov V. N. , Aver'yanov A. B. , Chernova A. A. 
Published: October 2016

The aim of the study was to evaluate a role of transforming growth factor"β1 (TGF"β1) gene rs1800470 single nucleotide polymorphisms (SNPs), cytotoxic T"lymphocyte"associated protein 4 (CTLA4) gene rs231775 SNPs and hedgehog"interacting protein (HHIP) gene rs1828591 SNP for predisposition to bronchial asthma (BA) in Krasnoyarsk residents.Methods. The study involved 100 asthma patients and 338 control subjects. The control group included a representative population sample of Siberian urban residents without respiratory diseases who had participated in the WHO MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) and the HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) projects.Results. There was a significant difference in genotype and allele frequency distribution of the TGFβ gene in patients with non"allergic BA vs controls. Therefore, A allele carriers with heterozygous genotype AG and homozygous genotype AA of rs1800470 polymorphism of the TGF"β1 gene were at high risk of non"allergic BA. We also found an increase in the GG genotype frequency in BA group compared to the control group. The GG genotype of CTLA4 gene rs231775 polymorphism was associated with high risk of allergic BA (ОR = 2.036; 95% CI = 1.16–3.58; р = 0.012). Genotype and allele frequency distribution of HHIP gene rs1828591 polymorphism did not differ significantly between BA patients and the control group.Conclusion. An association was revealed between BA, TGF"β1 gene rs1800470 SNPs and CTLA4 gene rs231775 SNPs. An association between BA and HHIP gene rs1828591 SNPs was not found.