Publications by authors named "Noa Regev"

9 Publications

  • Page 1 of 1

Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep.

Sci Adv 2020 04 8;6(15):eaaz4232. Epub 2020 Apr 8.

Department Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.
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http://dx.doi.org/10.1126/sciadv.aaz4232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141817PMC
April 2020

Sleep Differentially Affects Early and Late Neuronal Responses to Sounds in Auditory and Perirhinal Cortices.

J Neurosci 2020 04 18;40(14):2895-2905. Epub 2020 Feb 18.

Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel, 69978,

A fundamental feature of sleep is reduced behavioral responsiveness to external events, but the extent of processing along sensory pathways remains poorly understood. While responses are comparable across wakefulness and sleep in auditory cortex (AC), neuronal activity in downstream regions remains unknown. Here we recorded spiking activity in 435 neuronal clusters evoked by acoustic stimuli in the perirhinal cortex (PRC) and in AC of freely behaving male rats across wakefulness and sleep. Neuronal responses in AC showed modest (∼10%) differences in response gain across vigilance states, replicating previous studies. By contrast, PRC neuronal responses were robustly attenuated by 47% and 36% during NREM sleep and REM sleep, respectively. Beyond the separation according to cortical region, response latency in each neuronal cluster was correlated with the degree of NREM sleep attenuation, such that late (>40 ms) responses in all monitored regions diminished during NREM sleep. The robust attenuation of late responses prevalent in PRC represents a novel neural correlate of sensory disconnection during sleep, opening new avenues for investigating the mediating mechanisms. Reduced behavioral responsiveness to sensory stimulation is at the core of sleep's definition, but it is still unclear how the sleeping brain responds differently to sensory stimuli. In the current study, we recorded neuronal spiking responses to sounds along the cortical processing hierarchy of rats during wakefulness and natural sleep. Responses in auditory cortex only showed modest changes during sleep, whereas sleep robustly attenuated the responses of neurons in high-level perirhinal cortex. We also found that, during NREM sleep, the response latency predicts the degree of sleep attenuation in individual neurons above and beyond their anatomical location. These results provide anatomical and temporal signatures of sensory disconnection during sleep and pave the way to understanding the underlying mechanisms.
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http://dx.doi.org/10.1523/JNEUROSCI.1186-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117904PMC
April 2020

Drinking Desalinated Water that Lack Calcium and Magnesium Has No Effect on Mineral Content of Enamel and Dentin in Primary Teeth.

J Clin Pediatr Dent 2020 ;44(1):47-51

The present study compared the mineral contents of enamel and dentin of primary teeth from children exposed to desalinated water with those from children drinking ground water. The study comprised of two groups of teeth, seven primary teeth from children living in areas supplied exclusively with desalinated water and seven primary teeth from children that have been exposed solely to ground water from in-utero until the teeth were either extracted or naturally shed. Mineral content of three tooth regions was determined by scanning electron microscopy with an energy dispersive X-ray spectrometer (EDS). The main ion content of each region was calculated. Children exposed to ground water presented higher levels of magnesium in pre- and post- natal enamel than children living in areas supplied exclusively with desalinated water but without significant differences. The same was found for calcium levels. Excluding post-natal enamel calcium level (of borderline statistical significance), no significant differences were found in magnesium and calcium levels of primary teeth enamel and dentin of children exposed to desalinated water in comparison to children exposed to ground water. Mineral content of enamel and dentin in primary teeth is not affected by consuming desalinated water.
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http://dx.doi.org/10.17796/1053-4625-44.1.8DOI Listing
January 2020

A DJ-1 Based Peptide Attenuates Dopaminergic Degeneration in Mice Models of Parkinson's Disease via Enhancing Nrf2.

PLoS One 2015 29;10(5):e0127549. Epub 2015 May 29.

Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel.

Drugs currently used for treating Parkinson's disease patients provide symptomatic relief without altering the neurodegenerative process. Our aim was to examine the possibility of using DJ-1 (PARK7), as a novel therapeutic target for Parkinson's disease. We designed a short peptide, named ND-13. This peptide consists of a 13 amino acids segment of the DJ-1-protein attached to 7 amino acids derived from TAT, a cell penetrating protein. We examined the effects of ND-13 using in vitro and in vivo experimental models of Parkinson's disease. We demonstrated that ND-13 protects cultured cells against oxidative and neurotoxic insults, reduced reactive oxygen species accumulation, activated the protective erythroid-2 related factor 2 system and increased cell survival. ND-13 robustly attenuated dopaminergic system dysfunction and in improved the behavioral outcome in the 6-hydroxydopamine mouse model of Parkinson's disease, both in wild type and in DJ-1 knockout mice. Moreover, ND-13 restored dopamine content in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model. These findings validate DJ-1 as a promising therapeutic target in Parkinson's disease and identify a novel peptide with clinical potential, which may be significant for a broader range of neurological diseases, possibly with an important impact for the neurosciences.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127549PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449207PMC
March 2016

Mechanical properties of different airway stents.

Med Eng Phys 2015 Apr 5;37(4):408-15. Epub 2015 Mar 5.

Afeka, Tel-Aviv Academic College of Engineering, Medical Engineering Department, Tel Aviv 69107, Israel.

Airway stents improve pulmonary function and quality of life in patients suffering from airway obstruction. The aim of this study was to compare main types of stents (silicone, balloon-dilated metal, self-expanding metal, and covered self-expanding metal) in terms of their mechanical properties and the radial forces they exert on the trachea. Mechanical measurements were carried out using a force gauge and specially designed adaptors fabricated in our lab. Numerical simulations were performed for eight different stent geometries, inserted into trachea models. The results show a clear correlation between stent diameter (oversizing) and the levels of stress it exerts on the trachea. Compared with uncovered metal stents, metal stents that are covered with less stiff material exert significantly less stress on the trachea while still maintaining strong contact with it. The use of such stents may reduce formation of mucosa necrosis and fistulas while still preventing stent migration. Silicone stents produce the lowest levels of stress, which may be due to weak contact between the stent and the trachea and can explain their propensity for migration. Unexpectedly, stents made of the same materials exerted different stresses due to differences in their structure. Stenosis significantly increases stress levels in all stents.
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http://dx.doi.org/10.1016/j.medengphy.2015.02.008DOI Listing
April 2015

The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2-S6 in the pore module of target sodium channels.

Biochem J 2014 Oct;463(2):271-7

*Department of Plant Molecular Biology & Ecology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.

Av3 is a peptide neurotoxin from the sea anemone Anemonia viridis that shows specificity for arthropod voltage-gated sodium channels (Navs). Interestingly, Av3 competes with a scorpion α-toxin on binding to insect Navs and similarly inhibits the inactivation process, and thus has been classified as 'receptor site-3 toxin', although the two peptides are structurally unrelated. This raises questions as to commonalities and differences in the way both toxins interact with Navs. Recently, site-3 was partly resolved for scorpion α-toxins highlighting S1-S2 and S3-S4 external linkers at the DIV voltage-sensor module and the juxtaposed external linkers at the DI pore module. To uncover channel determinants involved in Av3 specificity for arthropods, the toxin was examined on channel chimaeras constructed with the external linkers of the mammalian brain Nav1.2a, which is insensitive to Av3, in the background of the Drosophila DmNav1. This approach highlighted the role of linker DI/SS2-S6, adjacent to the channel pore, in determining Av3 specificity. Point mutagenesis at DI/SS2-S6 accompanied by functional assays highlighted Trp404 and His405 as a putative point of Av3 interaction with DmNav1. His405 conservation in arthropod Navs compared with tyrosine in vertebrate Navs may represent an ancient substitution that explains the contemporary selectivity of Av3. Trp404 and His405 localization near the membrane surface and the hydrophobic bioactive surface of Av3 suggest that the toxin possibly binds at a cleft by DI/S6. A partial overlap in receptor site-3 of both toxins nearby DI/S6 may explain their binding competition capabilities.
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http://dx.doi.org/10.1042/BJ20140576DOI Listing
October 2014

Regulation of neuronal M-channel gating in an isoform-specific manner: functional interplay between calmodulin and syntaxin 1A.

J Neurosci 2011 Oct;31(40):14158-71

Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.

Whereas neuronal M-type K(+) channels composed of KCNQ2 and KCNQ3 subunits regulate firing properties of neurons, presynaptic KCNQ2 subunits were demonstrated to regulate neurotransmitter release by directly influencing presynaptic function. Two interaction partners of M-channels, syntaxin 1A and calmodulin, are known to act presynaptically, syntaxin serving as a major protein component of the membrane fusion machinery and calmodulin serving as regulator of several processes related to neurotransmitter release. Notably, both partners specifically modulate KCNQ2 but not KCNQ3 subunits, suggesting selective presynaptic targeting to directly regulate exocytosis without interference in neuronal firing properties. Here, having first demonstrated in Xenopus oocytes, using analysis of single-channel biophysics, that both modulators downregulate the open probability of KCNQ2 but not KCNQ3 homomers, we sought to resolve the channel structural determinants that confer the isoform-specific gating downregulation and to get insights into the molecular events underlying this mechanism. We show, using optical, biochemical, electrophysiological, and molecular biology analyses, the existence of constitutive interactions between the N and C termini in homomeric KCNQ2 and KCNQ3 channels in living cells. Furthermore, rearrangement in the relative orientation of the KCNQ2 termini that accompanies reduction in single-channel open probability is induced by both regulators, strongly suggesting that closer N-C termini proximity underlies gating downregulation. Different structural determinants, identified at the N and C termini of KCNQ3, prevent the effects by syntaxin 1A and calmodulin, respectively. Moreover, we show that the syntaxin 1A and calmodulin effects can be additive or blocked at different concentration ranges of calmodulin, bearing physiological significance with regard to presynaptic exocytosis.
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http://dx.doi.org/10.1523/JNEUROSCI.2666-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623657PMC
October 2011

Elucidation of the molecular basis of selective recognition uncovers the interaction site for the core domain of scorpion alpha-toxins on sodium channels.

J Biol Chem 2011 Oct 8;286(40):35209-17. Epub 2011 Aug 8.

Department of Plant Molecular Biology and Ecology, George S Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.

Neurotoxin receptor site-3 at voltage-gated Na(+) channels is recognized by various peptide toxin inhibitors of channel inactivation. Despite extensive studies of the effects of these toxins, their mode of interaction with the channel remained to be described at the molecular level. To identify channel constituents that interact with the toxins, we exploited the opposing preferences of LqhαIT and Lqh2 scorpion α-toxins for insect and mammalian brain Na(+) channels. Construction of the DIV/S1-S2, DIV/S3-S4, DI/S5-SS1, and DI/SS2-S6 external loops of the rat brain rNa(v)1.2a channel (highly sensitive to Lqh2) in the background of the Drosophila DmNa(v)1 channel (highly sensitive to LqhαIT), and examination of toxin activity on the channel chimera expressed in Xenopus oocytes revealed a substantial decrease in LqhαIT effect, whereas Lqh2 was as effective as at rNa(v)1.2a. Further substitutions of individual loops and specific residues followed by examination of gain or loss in Lqh2 and LqhαIT activities highlighted the importance of DI/S5-S6 (pore module) and the C-terminal region of DIV/S3 (gating module) of rNa(v)1.2a for Lqh2 action and selectivity. In contrast, a single substitution of Glu-1613 to Asp at DIV/S3-S4 converted rNa(v)1.2a to high sensitivity toward LqhαIT. Comparison of depolarization-driven dissociation of Lqh2 and mutant derivatives off their binding site at rNa(v)1.2a mutant channels has suggested that the toxin core domain interacts with the gating module of DIV. These results constitute the first step in better understanding of the way scorpion α-toxins interact with voltage-gated Na(+)-channels at the molecular level.
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http://dx.doi.org/10.1074/jbc.M111.259507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186375PMC
October 2011

Selective interaction of syntaxin 1A with KCNQ2: possible implications for specific modulation of presynaptic activity.

PLoS One 2009 Aug 13;4(8):e6586. Epub 2009 Aug 13.

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.

KCNQ2/KCNQ3 channels are the molecular correlates of the neuronal M-channels, which play a major role in the control of neuronal excitability. Notably, they differ from homomeric KCNQ2 channels in their distribution pattern within neurons, with unique expression of KCNQ2 in axons and nerve terminals. Here, combined reciprocal coimmunoprecipitation and two-electrode voltage clamp analyses in Xenopus oocytes revealed a strong association of syntaxin 1A, a major component of the exocytotic SNARE complex, with KCNQ2 homomeric channels resulting in a approximately 2-fold reduction in macroscopic conductance and approximately 2-fold slower activation kinetics. Remarkably, the interaction of KCNQ2/Q3 heteromeric channels with syntaxin 1A was significantly weaker and KCNQ3 homomeric channels were practically resistant to syntaxin 1A. Analysis of different KCNQ2 and KCNQ3 chimeras and deletion mutants combined with in-vitro binding analysis pinpointed a crucial C-terminal syntaxin 1A-association domain in KCNQ2. Pull-down and coimmunoprecipitation analyses in hippocampal and cortical synaptosomes demonstrated a physical interaction of brain KCNQ2 with syntaxin 1A, and confocal immunofluorescence microscopy showed high colocalization of KCNQ2 and syntaxin 1A at presynaptic varicosities. The selective interaction of syntaxin 1A with KCNQ2, combined with a numerical simulation of syntaxin 1A's impact in a firing-neuron model, suggest that syntaxin 1A's interaction is targeted at regulating KCNQ2 channels to fine-tune presynaptic transmitter release, without interfering with the function of KCNQ2/3 channels in neuronal firing frequency adaptation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006586PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721677PMC
August 2009