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2017
Gal, E, London M, Globerson A, Ramaswamy S, Reimann MW, Muller E, Markram H, Segev I.  2017.  Rich cell-type-specific network topology in neocortical microcircuitry. Nature Neuroscience. 20(7) Abstract
Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ~0.3-mm 3 volume from juvenile rat somatosensory neocortex, comprising ~31,000 cells and ~36 million synapses. Using this reconstruction, we found a small-world topology with an average of 2.5 synapses separating any two cells and multiple cell-type-specific wiring features. Amounts of excitatory and inhibitory innervations varied across cells, yet pyramidal neurons maintained relatively constant excitation/inhibition ratios. The circuit contained highly connected hub neurons belonging to a small subset of cell types and forming an interconnected cell-type-specific rich club. Certain three-neuron motifs were overrepresented, matching recent experimental results. Cell-type-specific network properties were even more striking when synaptic strength and sign were considered in generating a functional topology. Our systematic approach enables interpretation of microconnectomics ‘big data’ and provides several experimentally testable predictions.
Mosheiff, N, Agmon H, Moriel A, Burak Y.  2017.  An efficient coding theory for a dynamic trajectory predicts non-uniform allocation of entorhinal grid cells to modules. PLoS Computational Biology. 13(6):e1005597.
Yarden-Rabinowitz, Y, Yarom Y.  2017.  In vivo analysis of synaptic activity in cerebellar nucleineurons unravels the efficacy of excitatory inputs. Journal of Physiology. 595(17) Abstract
It is commonly agreed that the main function of the cerebellar system is to providewell-timed signals used for the execution of motor commands or prediction of sensory inputs.This function is manifested as a temporal sequence of spiking that should be expressed in thecerebellar nuclei (CN) projection neurons. Whether spiking activity is generated by excitationor release from inhibition is still a hotly debated issue. In an attempt to resolve this debate,we recorded intracellularly from CN neurons in anaesthetized mice and performed an analysisof synaptic activity that yielded a number of important observations. First, we demonstratethat CN neurons can be classified into four groups. Second, shape-index plots of the excitatoryevents suggest that they are distributed over the entire dendritic tree. Third, the rise time ofexcitatory events is linearly related to amplitude, suggesting that all excitatory events contributeequally to the generation of action potentials (APs). Fourth, we identified a temporal patternof spontaneous excitatory events that represent climbing fibre inputs and confirm the resultsby direct stimulation and analysis on harmaline-evoked activity. Finally, we demonstrate thatthe probability of excitatory inputs generating an AP is 0.1 yet half of the APs are generated byexcitatory events. Moreover, the probability of a presumably spontaneous climbing fibre inputgenerating an AP is higher, reaching a mean population value of 0.15. In view of these results, themode of synaptic integration at the level of the CN should be re-considered.
Mongillo, G, Loewenstein Y.  2017.  Neuroscience: Formation of a Percept in the Rat Cortex. Current Biology. 27(11):1585-1596.e6. Abstractpdf
It has long been known that we subjectively experience longer stimuli as being more intense. A recent study sheds light on the neural mechanisms underlying this bias by tracking the formation of a percept of intensity in the rat brain.
Murakami, M, Shteingart H, Loewenstein Y, Mainen ZF.  2017.  Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal Cortex. Neuron. 94(4):908–919. Abstractmmc2.pdf
The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals.
Shaham, N, Burak Y.  2017.  Slow Diffusive Dynamics in a Chaotic Balanced Neural Network. PLoS Computational Biology. 13(5):e1005505.2017_shaham_burak.pdf
Dan, O, Hochner-Celnikier D, Solnica A RN, Loewenstein Y.  2017.  Association of Catastrophic Neonatal Outcomes With Increased Rate of Subsequent Cesarean Deliveries. Obstetrics & Gynecology. 129(4):671-675. Abstractpdf Supplemental Digital Content
OBJECTIVE: To evaluate whether full-term deliveries resulting in neonates diagnosed with hypoxic–ischemic encephalopathy are associated with a significant increase in the rate of subsequent unscheduled cesarean deliveries. METHODS: We conducted a retrospective chart review study and examined all deliveries in the Department of Obstetrics and Gynecology at Hadassah University Hospital, Mt. Scopus campus, Jerusalem, Israel, during 2009–2014. We reviewed all cases of hypoxic–ischemic encephalopathy in singleton, term, liveborn neonates and identified seven such cases, three of which were attributed to obstetric mismanagement and four that were not. We measured the rate of unscheduled cesarean deliveries before and after the events and their respective hazard ratio. RESULTS: Before a mismanaged delivery resulting in hypoxic–ischemic encephalopathy, the baseline rate of unscheduled cesarean deliveries was approximately 80 unscheduled cesarean deliveries for every 1,000 deliveries. In the first 4 weeks immediately after each of the three identified cases, there was a significant increase in the rate of unscheduled cesarean deliveries by an additional 48 unscheduled cesarean deliveries per 1,000 deliveries (95% confidence interval [CI] 27–70/1,000). This increase was transient and lasted approximately 4 weeks. We estimated that each case was associated with approximately 17 additional unscheduled cesarean deliveries (95% CI 8–27). There was no increase in the rate of unscheduled cesarean deliveries in cases of hypoxic–ischemic encephalopathy that were not associated with mismanagement. CONCLUSION: The increase in the rate of unscheduled cesarean deliveries after a catastrophic neonatal outcome may result in short-term changes in obstetricians' risk evaluation.
Matias, S, Lottem E, Dugué GP, Mainen ZF.  2017.  Activity patterns of serotonin neurons underlying cognitive flexibility. Elife. Abstract
Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine–serotonin opponency with potential clinical implications.
Jaffe-Dax, S, Ahissar M.  2017.  In search for the relevant space of implicit memory deficit in dyslexia. Proceedings of the 39th annual conference of the cognitive science society. :2267-2272.
Gomez, J, Barnett MA, Natu V, Mezer A, Palomero-Gallagher N, Weiner KS, Amunts K, Zilles K, Grill-Spector K.  2017.  Microstructural proliferation in human cortex is coupled with the development of face processing. Science. Abstract
How does cortical tissue change as brain function and behavior improve from childhood to adulthood? By combining quantitative and functional magnetic resonance imaging in children and adults, we find differential development of high-level visual areas that are involved in face and place recognition. Development of face-selective regions, but not place-selective regions, is dominated by microstructural proliferation. This tissue development is correlated with specific increases in functional selectivity to faces, as well as improvements in face recognition, and ultimately leads to differentiated tissue properties between face- and place-selective regions in adulthood, which we validate with postmortem cytoarchitectonic measurements. These data suggest a new model by which emergent brain function and behavior result from cortical tissue proliferation rather than from pruning exclusively.
Jaffe-Dax, S, Frenkel O, Ahissar M.  2017.  Shorter neural adaptation to sounds accounts for dyslexics' abnormal perceptual and reading dynamics. eLife. 6glocal_tones_block1.txtglocal_tones_block2.txtglocal_tones_block3.txtglocal_tones_block4.txtcorrelationmartices.pngresulttable.txt
PA Correia, Lottem E, Banerjee D, Machado AS, Carey MR, Mainen ZF.  2017.  Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons. Elife. Abstract
Serotonin (5-HT) is associated with mood and motivation but the function of endogenous 5-HT remains controversial. Here, we studied the impact of phasic optogenetic activation of 5-HT neurons in mice over time scales from seconds to weeks. We found that activating dorsal raphe nucleus (DRN) 5-HT neurons induced a strong suppression of spontaneous locomotor behavior in the open field with rapid kinetics (onset ≤1 s). Inhibition of locomotion was independent of measures of anxiety or motor impairment and could be overcome by strong motivational drive. Repetitive place-contingent pairing of activation caused neither place preference nor aversion. However, repeated 15 min daily stimulation caused a persistent increase in spontaneous locomotion to emerge over three weeks. These results show that 5-HT transients have strong and opposing short and long-term effects on motor behavior that appear to arise from effects on the underlying factors that motivate actions.
Maoz, R, Garfinkel BP, Soreq H.  2017.  Alzheimer's Disease and ncRNAs. Adv Exp Med Biol. 978:337-361. Abstract
Alzheimer's disease is a devastating neurodegenerative disorder affecting a significant portion of the world's rapidly growing aging population. In spite of its prevalence, the etiology of the disease is still poorly understood, and effective therapy is all but unavailable. Over the past decade, noncoding RNA, including microRNA (miRNA), has emerged as a major class of regulatory molecules involved in virtually all physiological and disease states. The specificity provided by miRNA sequence complementarity, together with the ability of these molecules to regulate complex networks of genes, has made them exciting novel targets for therapeutic agents. In this chapter, we review recent progress on understanding the role of noncoding RNA in Alzheimer's disease (AD). The majority of available work has focused on miRNA, and we review the many studies implicating specific miRNAs in the development of the disease. More recently, several studies have tied other RNA classes to the disorder, including long noncoding RNA, circular RNA, and Y RNAs, and we review this fascinating field as well. Finally, we explore the potential promise of these findings for future therapeutic applications.
Vinograd, A, Fuchs-Shlomai Y, Stern M, Mukherjee D, Gao Y, Citri A, Davison I, Mizrahi A.  2017.  Functional Plasticity of Odor Representations during Motherhood. Cell Reports. 21:351-365. Abstract
Summary Motherhood is accompanied by new behaviors aimed at ensuring the wellbeing of the offspring. Olfaction plays a key role in guiding maternal behaviors during this transition. We studied functional changes in the main olfactory bulb (OB) of mothers in mice. Using in vivo two-photon calcium imaging, we studied the sensory representation of odors by mitral cells (MCs). We show that MC responses to monomolecular odors become sparser and weaker in mothers. In contrast, responses to biologically relevant odors are spared from sparsening or strengthen. MC responses to mixtures and to a range of concentrations suggest that these differences between odor responses cannot be accounted for by mixture suppressive effects or gain control mechanisms. In vitro whole-cell recordings show an increase in inhibitory synaptic drive onto MCs. The increase of inhibitory tone may contribute to the general decrease in responsiveness and concomitant enhanced representation of specific odors.
2016
Garfinkel, BP, Arad S, Neuner SM, Netser S, Wagner S, Kaczorowski CC, Rosen CJ, Gal M, Soreq H, Orly J.  2016.  HP1BP3 expression determines maternal behavior and offspring survival. Genes Brain Behav. 15:678-88. Abstract
Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process.
Meydan, C, Shenhar-Tsarfaty S, Soreq H.  2016.  MicroRNA Regulators of Anxiety and Metabolic Disorders. Trends Mol Med. 22:798-812. Abstract
Anxiety-related and metabolic disorders are under intense research focus. Anxiety-induced microRNAs (miRNAs) are emerging as regulators that are not only capable of suppressing inflammation but can also induce metabolic syndrome-related processes. We summarize here evidence linking miRNA pathways which share regulatory networks in metabolic and anxiety-related conditions. In particular, miRNAs involved in these disorders include regulators of acetylcholine signaling in the nervous system and their accompanying molecular machinery. These have been associated with anxiety-prone states in individuals, while also acting as inflammatory suppressors. In peripheral tissues, altered miRNA pathways can lead to dysregulated metabolism. Common pathways in metabolic and anxiety-related phenomena might offer an opportunity to reclassify 'healthy' and 'unhealthy', as well as metabolic and anxiety-prone biological states, and inform putative strategies to treat these disorders.
Hanan, M, Soreq H, Kadener S.  2016.  CircRNAs in the brain. RNA Biol. :1-7. Abstract
Circular RNAs (circRNAs) are highly abundant and evolutionarily conserved non-coding RNAs produced by circularization of specific exons. Since their re-discovery as potential regulators of gene expression, thousands of circRNAs were detected in different tissues and cell types across most organisms. Accumulating data suggest key roles for them in the central nervous system. Neuronal-expressed RNAs are diverted to yield highly enriched CircRNAs in human, mouse, pig and flies, with many of them enriched in neuronal tissues. CircRNA levels are dynamically modulated in neurons, both during differentiation and following bursts of electrical activity, and accumulate with age, and many of them are enriched in synapses. Together, available data suggest that circRNAs have important roles in synaptic plasticity and neuronal function. This review covers current advances in the field and lays out hypotheses regarding functions of circRNAs in the brain as well as their putative involvement in initiation and progression of neurodegenerative processes.
Dotan, I, Levy-Nissenbaum E, Chowers Y, Fich A, Israeli E, Adar T, Shteingart S, Soreq H, Goldin E.  2016.  Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective Open-Label, Multicenter Phase II Trial. Dig Dis Sci. 61:3246-3254. Abstract
BACKGROUND: Treatment of active ulcerative colitis is associated with incomplete efficacy, adverse events, and loss of response. Toll-like receptor-9 mediates innate and adaptive immune response toward intestinal microorganisms. The oral synthetic oligonucleotide toll-like receptor-9 modulator has demonstrated anti-inflammatory properties in colitis murine models and a satisfactory safety profile in humans. AIM: To evaluate the efficacy and safety of BL-7040 (a Toll-like receptor-9 modulator) in patients with moderately active ulcerative colitis. METHODS: Moderately active ulcerative colitis patients were included in this multicenter, open-label phase IIa trial. Concomitant mesalamine and steroids at a stable dose were allowed. Clinical outcome was evaluated using the Mayo score, histology, and mucosal cytokine levels. Side effects were registered. RESULTS: Sixteen out of 22 patients completed a 5-week treatment course and 2-week follow-up. Six patients discontinued the study, three of them due to adverse events. Clinical remission was observed in two patients (12.5 %), and clinical response as well as mucosal healing were achieved in half (50 %) of the patients, while all others remained stable. Furthermore, mucosal neutrophil (p = 0.002) and mucosal interleukin-6 levels (p = 0.046) were significantly reduced in responders compared to non-responders. Toll-like receptor-9 was well tolerated with only one unrelated to study drug serious adverse event (hemoglobin decrease) and 29 mild-to-moderate adverse events. CONCLUSIONS: Oral administration of the Toll-like receptor-9 agonist BL-7040 appeared efficacious, safe and well tolerated in patients with moderately active ulcerative colitis.
Lin, T, Simchovitz A, Shenhar-Tsarfaty S, Vaisvaser S, Admon R, Hanin G, Hanan M, Kliper E, Bar-Haim Y, Shomron N et al..  2016.  Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction. Transl Psychiatry. 6:e801. Abstract
Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome-neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility.
Kolisnyk, B, Al-Onaizi M, Soreq L, Barbash S, Bekenstein U, Haberman N, Hanin G, Kish MT, Souza da Silva J, Fahnestock M et al..  2016.  Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology. Cereb Cortex. Abstract
The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Abeta1-42 This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia.
Kolisnyk, B, Al-Onaizi MA, Xu J, Parfitt GM, Ostapchenko VG, Hanin G, Soreq H, Prado MA, Prado VF.  2016.  Cholinergic Regulation of hnRNPA2/B1 Translation by M1 Muscarinic Receptors. J Neurosci. 36:6287-96. Abstract
Cholinergic vulnerability, characterized by loss of acetylcholine (ACh), is one of the hallmarks of Alzheimer's disease (AD). Previous work has suggested that decreased ACh activity in AD may contribute to pathological changes through global alterations in alternative splicing. This occurs, at least partially, via the regulation of the expression of a critical protein family in RNA processing, heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins. These proteins regulate several steps of RNA metabolism, including alternative splicing, RNA trafficking, miRNA export, and gene expression, providing multilevel surveillance in RNA functions. To investigate the mechanism by which cholinergic tone regulates hnRNPA2/B1 expression, we used a combination of genetic mouse models and in vivo and in vitro techniques. Decreasing cholinergic tone reduced levels of hnRNPA2/B1, whereas increasing cholinergic signaling in vivo increased expression of hnRNPA2/B1. This effect was not due to decreased hnRNPA2/B1 mRNA expression, increased aggregation, or degradation of the protein, but rather to decreased mRNA translation by nonsense-mediated decay regulation of translation. Cell culture and knock-out mice experiments demonstrated that M1 muscarinic signaling is critical for cholinergic control of hnRNPA2/B1 protein levels. Our experiments suggest an intricate regulation of hnRNPA2/B1 levels by cholinergic activity that interferes with alternative splicing in targeted neurons mimicking deficits found in AD. SIGNIFICANCE STATEMENT: In Alzheimer's disease, degeneration of basal forebrain cholinergic neurons is an early event. These neurons communicate with target cells and regulate their long-term activity by poorly understood mechanisms. Recently, the splicing factor hnRNPA2/B, which is decreased in Alzheimer's disease, was implicated as a potential mediator of long-term cholinergic regulation. Here, we demonstrate a mechanism by which cholinergic signaling controls the translation of hnRNPA2/B1 mRNA by activation of M1 muscarinic type receptors. Loss of cholinergic activity can have profound effects in target cells by modulating hnRNPA2/B1 levels.
Waiskopf, N, Ben-Shahar Y, Galchenko M, Carmel I, Moshitzky G, Soreq H, Banin U.  2016.  Photocatalytic Reactive Oxygen Species Formation by Semiconductor-Metal Hybrid Nanoparticles. Toward Light-Induced Modulation of Biological Processes. Nano Lett. 16:4266-73. Abstract
Semiconductor-metal hybrid nanoparticles manifest efficient light-induced spatial charge separation at the semiconductor-metal interface, as demonstrated by their use for hydrogen generation via water splitting. Here, we pioneer a study of their functionality as efficient photocatalysts for the formation of reactive oxygen species. We observed enhanced photocatalytic activity forming hydrogen peroxide, superoxide, and hydroxyl radicals upon light excitation, which was significantly larger than that of the semiconductor nanocrystals, attributed to the charge separation and the catalytic function of the metal tip. We used this photocatalytic functionality for modulating the enzymatic activity of horseradish peroxidase as a model system, demonstrating the potential use of hybrid nanoparticles as active agents for controlling biological processes through illumination. The capability to produce reactive oxygen species by illumination on-demand enhances the available peroxidase-based tools for research and opens the path for studying biological processes at high spatiotemporal resolution, laying the foundation for developing novel therapeutic approaches.
Simchovitz, A, Soreq L, Soreq H.  2016.  Transcriptome profiling in Parkinson's leukocytes: from early diagnostics to neuroimmune therapeutic prospects. Curr Opin Pharmacol. 26:102-9. Abstract
Parkinson's disease (PD) involves motor symptoms reflecting the progressive degeneration of dopaminergic neurons in the substantia nigra. However, diagnosis is only enabled late in the disease, limiting treatment to palliative assistance. Here, we review recently generated transcriptional profiling datasets from blood and brain RNA of human PD cohorts and animal models that may offer unprecedented progress in PD research. Specifically, advanced analysis techniques demonstrated functionally inter-related underlying impairments of RNA metabolism and neuroimmune signalling processes. Identifying novel biomarkers in serum and nucleated blood cells, including protein networks and non-coding RNAs can drive discovery of the molecular mechanisms involved and reveal new targets for therapeutic intervention, posing a dual diagnosis/treatment opportunity for limiting the exacerbation of neuroinflammatory events in PD.
Shenhar-Tsarfaty, S, Shapira I, Toker S, Rogowski O, Berliner S, Ritov Y, Soreq H.  2016.  Weakened cholinergic blockade of inflammation associates with diabetes-related depression. Mol Med. 22 Abstract
Emerging evidence demonstrates association of depression with both immune malfunctioning and worsened course of diverse aging-related diseases, but there is no explanation for the pathway(s) controlling this dual association. Here, we report that in post-reproductive and evolutionarily 'blind' years, depression may weaken pathogen-host defense, compatible with the antagonistic pleiotropy hypothesis. In 15,532 healthy volunteers, depression scores associated with both inflammatory parameters and with increased circulation cholinesterase activities, implicating debilitated cholinergic blockade of inflammation as an underlying mechanism; furthermore, depression, inflammation and cholinesterase activities all increased with aging. In the entire cohort, combined increases in inflammation and the diabetic biomarker hemoglobin A1c associated with elevated depression. Moreover, metabolic syndrome patients with higher risk of diabetes showed increased cholinesterase levels and pulse values, and diabetics presented simultaneous increases in depression, inflammation and circulation cholinesterase activities, suggesting that cholinergic impairment precedes depression. Our findings indicate that dys-functioning cholinergic regulation weakens the otherwise protective link between depression and pathogen-host defense, with global implications for aging-related diseases.
Weiner, B, Hertz S, Perets N, London M.  2016.  Social Ultrasonic Vocalization in Awake Head-Restrained Mouse.. Frontiers in Behavioral Neuroscience. 10:236. Abstract
Numerous animal species emit vocalizations in response to various social stimuli. The neural basis of vocal communication has been investigated in monkeys, songbirds, rats, bats, and invertebrates resulting in deep insights into motor control, neural coding, and learning. Mice, which recently became very popular as a model system for mammalian neuroscience, also utilize ultrasonic vocalizations (USVs) during mating behavior. However, our knowledge is lacking of both the behavior and its underlying neural mechanism. We developed a novel method for head-restrained male mice (HRMM) to interact with non-restrained female mice (NRFM) and show that mice can emit USVs in this context. We first recorded USVs in a free arena with non-restrained male mice (NRMM) and NRFM. Of the NRMM, which vocalized in the free arena, the majority could be habituated to also vocalize while head-restrained but only when a female mouse was present in proximity. The USVs emitted by HRMM are similar to the USVs of NRMM in the presence of a female mouse in their spectral structure, inter-syllable interval distribution, and USV sequence length, and therefore are interpreted as social USVs. By analyzing the vocalizations of NRMM, we established criteria to predict which individuals are likely to vocalize while head fixed based on the USV rate and average syllable duration. To characterize the USVs emitted by HRMM, we analyzed the syllable composition of HRMM and NRMM and found that USVs emitted by HRMM have a higher proportion of USVs with complex spectral representation, supporting previous studies showing that mice social USVs are context dependent. Our results suggest a way to study the neural mechanisms of production and control of social vocalization in mice using advanced methods requiring head fixation.