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2014
Ben, E, Eilon V.  2014.  Spatial computation with gamma oscillations. Front Syst. Neuros. 8(165)
Roth, ZN, Zohary E.  2014.  Fingerprints of Learned Object Recognition Seen in the fMRI Activation Patterns of Lateral Occipital Complex. Cerebral Cortex. :bhu042.
Adam, Y, Livneh Y, Miyamichi K, Groysman M, Luo L, Mizrahi A.  2014.  Functional transformations of odor inputs in the mouse olfactory bulb. Frontiers in Neural Circuits. 8 Abstract
Sensory inputs from the nasal epithelium to the olfactory bulb (OB) are organized as a discrete map in the glomerular layer (GL). This map is then modulated by distinct types of local neurons and transmitted to higher brain areas via mitral and tufted cells. Little is known about the functional organization of the circuits downstream of glomeruli. We used in vivo two-photon calcium imaging for large scale functional mapping of distinct neuronal populations in the mouse OB, at single cell resolution. Specifically, we imaged odor responses of mitral cells (MCs), tufted cells (TCs) and glomerular interneurons (GL-INs). Mitral cells population activity was heterogeneous and only mildly correlated with the olfactory receptor neuron (ORN) inputs, supporting the view that discrete input maps undergo significant transformations at the output level of the OB. In contrast, population activity profiles of TCs were dense, and highly correlated with the odor inputs in both space and time. Glomerular interneurons were also highly correlated with the ORN inputs, but showed higher activation thresholds suggesting that these neurons are driven by strongly activated glomeruli. Temporally, upon persistent odor exposure, TCs quickly adapted. In contrast, both MCs and GL-INs showed diverse temporal response patterns, suggesting that GL-INs could contribute to the transformations MCs undergo at slow time scales. Our data suggest that sensory odor maps are transformed by TCs and MCs in different ways forming two distinct and parallel information streams.
Porat, Y, Orlov T, McKyton A, Zohary E.  2014.  Sensitivity to spatiotopic location in the human visual system. Journal of Vision. 14:1230–1230.
Moreh, E, Malkinson T S, Zohary E, Soroker N.  2014.  Visual Memory in Unilateral Spatial Neglect: Immediate Recall versus Delayed Recognition.
2013
Avital, A, Shiran K, Inna F, Yifat P, Hagai B.  2013.  Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons.. Front Syst. Neurosci.. 7(47) Abstract
The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs), and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs), which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs), presumably parvalbumin (PV) expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation). TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.
Renana, E, Reuben S, Eduard L, Ovadya R, Shay M, Tamir B-H, Hagai B, Zvi I.  2013.  Asymmetric right/left encodind of emotions in the human subthalamic nucleus. Front Syst. Neurosci.. 7(69) Abstract
Emotional processing is lateralized to the non-dominant brain hemisphere. However, there is no clear spatial model for lateralization of emotional domains in the basal ganglia. The subthalamic nucleus (STN), an input structure in the basal ganglia network, plays a major role in the pathophysiology of Parkinson's disease (PD). This role is probably not limited only to the motor deficits of PD, but may also span the emotional and cognitive deficits commonly observed in PD patients. Beta oscillations (12-30 Hz), the electrophysiological signature of PD, are restricted to the dorsolateral part of the STN that corresponds to the anatomically defined sensorimotor STN. The more medial, more anterior and more ventral parts of the STN are thought to correspond to the anatomically defined limbic and associative territories of the STN. Surprisingly, little is known about the electrophysiological properties of the non-motor domains of the STN, nor about electrophysiological differences between right and left STNs. In this study, microelectrodes were utilized to record the STN spontaneous spiking activity and responses to vocal non-verbal emotional stimuli during deep brain stimulation (DBS) surgeries in human PD patients. The oscillation properties of the STN neurons were used to map the dorsal oscillatory and the ventral non-oscillatory regions of the STN. Emotive auditory stimulation evoked activity in the ventral non-oscillatory region of the right STN. These responses were not observed in the left ventral STN or in the dorsal regions of either the right or left STN. Therefore, our results suggest that the ventral non-oscillatory regions are asymmetrically associated with non-motor functions, with the right ventral STN associated with emotional processing. These results suggest that DBS of the right ventral STN may be associated with beneficial or adverse emotional effects observed in PD patients and may relieve mental symptoms in other neurological and psychiatric diseases.
Ofek, K, Soreq H.  2013.  Cholinergic involvement and manipulation approaches in multiple system disorders. 11th International Meeting on Cholinesterases. 203(1):113-119. Abstract
Within the autonomic system, acetylcholine signaling contributes simultaneously and interactively to cognitive, behavioral, muscle and immune functions. Therefore, manipulating cholinergic parameters such as the activities of the acetylcholine hydrolyzing enzymes in body fluids or the corresponding transcript levels in blood leukocytes can change the global status of the autonomic system in treated individuals. Specifically, cholinesterase activities are subject to rapid and effective changes. The enzyme activity baseline increases with age and body mass index and depends on gender and ethnic origin. Also, the corresponding DNA (for detecting mutations) and RNA (for measuring specific mRNA transcripts) of cholinergic genes present individual variability. In leukocytes, acetylcholine inhibits the production of pro-inflammatory cytokines, suggesting relevance of cholinergic parameters to both the basal levels and to disease-induced inflammation. Inversely, acetylcholine levels increase under various stress stimuli, inducing changes in autonomic system molecules (e.g., pro-inflammatory cytokines) which can penetrate the brain; therefore, manipulating these levels can also effect brain reactions, mainly of anxiety, depression and pain. Additionally, neurodegenerative diseases often involve exacerbated inflammation, depression and anxiety, providing a focus interest group for cholinergic manipulations. In Alzheimer’s disease, the systemic cholinergic impairments reflect premature death of cholinergic neurons. The decline of cholinesterases in the serum of Parkinson’s disease and post- stroke patients, discovery of the relevant microRNAs and the growing range of use of anticholinesterase medications all call for critical re-inspection of established and novel approaches for manipulating cholinergic parameters.
Miyamichi, K, Shlomai-Fuchs Y, Shu M, Weissbourd B, Luo L, Mizrahi A.  2013.  Dissecting Local Circuits: Parvalbumin Interneurons Underlie Broad Feedback Control of Olfactory Bulb Output. Neuron. :-. Abstract
In the mouse olfactory bulb, information from sensory neurons is extensively processed by local interneurons before being transmitted to the olfactory cortex by mitral and tufted (M/T) cells. The precise function of these local networks remains elusive because of the vast heterogeneity of interneurons, their diverse physiological properties, and their complex synaptic connectivity. Here we identified the parvalbumin interneurons (PVNs) as a prominent component of the M/T presynaptic landscape by using an improved rabies-based transsynaptic tracing method for local
Labarrera, C, London M, Angelo K.  2013.  Tonic inhibition sets the state of excitability in olfactory bulb granule cells. The Journal of Physiology. 591(7):1841-1850. Abstract
• Granule cells are the main source of inhibition in the olfactory bulb (i.e. the first station of odour processing in the mammalian brain), but very little is known about the inhibition that acts upon them.• Using in vivo whole cell patch clamp recordings in anaesthetized mice we report the following new findings:• We found odour-evoked responses to be rare (seen only in 18% of the odour presentations, and only in cells that showed also evoked excitatory responses to odours).• We report for the first time the presence of tonic inhibition in the olfactory bulb.• We show that tonic inhibition dominates over phasic synaptic inhibition evoked by odours, thereby being the key regulator shaping the granule cells spike output.• Preliminary (in vivo) evidence suggests that sensory evoked phasic inhibition onto granule cells is provided by deep short axon cells in the olfactory bulb.GABAergic granule cells (GCs) regulate, via mitral cells, the final output from the olfactory bulb to piriform cortex and are central for the speed and accuracy of odour discrimination. However, little is known about the local circuits in which GCs are embedded and how GCs respond during functional network activity. We recorded inhibitory and excitatory currents evoked during a single sniff-like odour presentation in GCs in vivo. We found that synaptic excitation was extensively activated across cells, whereas phasic inhibition was rare. Furthermore, our analysis indicates that GCs are innervated by a persistent firing of deep short axon cells that mediated the inhibitory evoked responses. Blockade of GABAergic synaptic input onto GCs revealed a tonic inhibitory current mediated by furosemide-sensitive GABAA receptors. The average current associated with this tonic GABAergic conductance was 3-fold larger than that of phasic inhibitory postsynaptic currents. We show that the pharmacological blockage of tonic inhibition markedly increased the occurrence of supra-threshold responses during an odour-stimulated sniff. Our findings suggest that GCs mediate recurrent or lateral inhibition, depending on the ambient level of extracellular GABA.
Nelken, I, de Cheveigne A.  2013.  An ear for statistics. Nature Neuroscience.. 16(4):381-382.
Adler, A, Finkes I, Katabi S, Prut Y, Bergman H.  2013.  Encoding by Synchronization in the Primate Striatum. The Journal of Neuroscience. 33(11):4854-4866. Abstract
Information is encoded in the nervous system through the discharge and synchronization of single neurons. The striatum, the input stage of the basal ganglia, is divided into three territories: the putamen, the caudate, and the ventral striatum, all of which converge onto the same motor pathway. This parallel organization suggests that there are multiple and competing systems in the basal ganglia network controlling behavior. To explore which mechanism(s) enables the different striatal domains to encode behavioral events and to control behavior, we compared the neural activity of phasically active neurons [medium spiny neurons (MSNs), presumed projection neurons] and tonically active neurons (presumed cholinergic interneurons) across striatal territories from monkeys during the performance of a well practiced task. Although neurons in all striatal territories displayed similar spontaneous discharge properties and similar temporal modulations of their discharge rates to the behavioral events, their correlation structure was profoundly different. The distributions of signal and noise correlation of pairs of putamen MSNs were strongly shifted toward positive correlations and these two measures were correlated. In contrast, MSN pairs in the caudate and ventral striatum displayed symmetrical, near-zero signal and noise correlation distributions. Furthermore, only putamen MSN pairs displayed different noise correlation dynamics to rewarding versus neutral/aversive cues. Similarly, the noise correlation between tonically active neuron pairs was stronger in the putamen than in the caudate. We suggest that the level of synchronization of the neuronal activity and its temporal dynamics differentiate the striatal territories and may thus account for the different roles that striatal domains play in behavioral control.
Taubman, H, Vaadia E, Paz R, Chechik G.  2013.  A Bayesian approach for characterizing direction tuning curves in the supplementary motor area of behaving monkeys. Journal of Neurophysiology. Abstract
Neural responses are commonly studied in terms of "tuning curves", characterizing changes in neuronal response as a function of a continuous stimulus parameter. In the motor system, neural responses to movement-direction often follow a bell-shaped tuning curve, whose exact shape determines the properties of neuronal movement coding. Estimating the shape of that tuning curve robustly is hard, especially when directions are sampled unevenly and at a coarse resolution. Here we describe a Bayesian estimation procedure that improves the accuracy of curve-shape estimation, even when the curve is sampled unevenly and at a very coarse resolution. Using this approach we characterize the movement direction tuning curves in the supplementary motor area (SMA) of behaving monkeys. We compare the SMA tuning curves to tuning curves of neurons from the primary motor cortex (M1) of the same monkeys, showing that the tuning curves of the SMA neurons tend to be narrower and shallower. We also show that these characteristics do not depend on the specific location in each region.
Soreq, L, Bergman H, Israel Z, Soreq H.  2013.  OVERLAPPING MOLECULAR SIGNATURES IN PARKINSON'S PATIENT LEUKOCYTES BEFORE AND AFTER TREATMENT AND IN MOUSE MODEL BRAIN REGIONS.. CNS & neurological disorders drug targets. Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with worldwide increasing incidence. PD is the second most prevalent neurodegenerative disease and the first that involves motor symptoms. The great majority of cases, defined as sporadic with non-familial disease, show a highly variable risk of disease due to environmental and genetic factors that remain largely unknown. Furthermore, the neurodegenerative process typically initiates decades prior to the appearance of hallmark motor symptoms; therefore, clinical diagnosis is enabled only when most of the relevant neurons have died and current treatment is palliative at best. Here, we review the application of genomic scale microarray based research aimed to enable early diagnosis and identify novel targets for therapeutic intervention. We demonstrate that blood leukocytes can serve as a feasible and reliable tissue source to test for disease-induced and treatment-related transcript changes. We cover our reports of transcription and alternative splicing modifications in PD patient's leukocytes based on 3' and exon microarray analyses and the identified inflammatory modulations. We further describe the effects of deep brain stimulation (DBS) neurosurgery on the leukocyte transcripts as reflecting the patient's neurological status. A focus is gained on common genes identified both in the molecular signature of human PD leukocytes and in brain RNA from engineered PD mouse models subjected to risk and protection manipulations. Finally, we discuss potential future directions of high-throughput RNA research as facilitators of the PD knowledge base through next generation sequencing technologies of both short and long RNA transcripts including microRNAs.
Weizman, L, Helfer D, Ben Bashat D, Pratt L-T, Joskowicz L, Constantini S, Shofty B, Ben Sira L.  2013.  PNist: interactive volumetric measurements of plexiform neurofibromas in MRI scans.. International journal of computer assisted radiology and surgery. Abstract
Volumetric measurements of plexiform neurofibromas (PNs) are time consuming and error prone, as they require the delineation of the PN boundaries, which is mostly impractical in the daily clinical setup. Accurate volumetric measurements are seldom performed for these tumors mainly due to their great dispersion, size and multiple locations. This paper presents a semiautomatic method for segmentation of PN from STIR MRI scans.
Maharshak, N, Shenhar-Tsarfaty S, Aroyo N, Orpaz N, Guberman I, Canaani J, Halpern Z, Dotan I, Berliner S, Soreq H.  2013.  MicroRNA-132 Modulates Cholinergic Signaling and Inflammation in Human Inflammatory Bowel Disease.. Inflammatory bowel diseases. 19(7):1346-53. Abstract
: MicroRNA-132 (miR-132) targets acetylcholinesterase (AChE) and potentiates the cholinergic blockade of inflammatory reactions in cultured cells and experimental mice, but the implications of this interaction to human inflammatory disease remained unexplored. This study aimed to test whether miR-132 is causally involved in anti-inflammatory reactions of patients with inflammatory bowel disease (IBD) and modulates vagal tone and consequently inflammation in patients with IBD.
Rothschild, G, Cohen L, Mizrahi A, Nelken I.  2013.  Elevated correlations in neuronal ensembles of mouse auditory cortex following parturition.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(31):12851-61. Abstract
The auditory cortex is malleable by experience. Previous studies of auditory plasticity have described experience-dependent changes in response profiles of single neurons or changes in global tonotopic organization. However, experience-dependent changes in the dynamics of local neural populations have remained unexplored. In this study, we examined the influence of a dramatic yet natural experience in the life of female mice, giving birth and becoming a mother on single neurons and neuronal ensembles in the primary auditory cortex (A1). Using in vivo two-photon calcium imaging and electrophysiological recordings from layer 2/3 in A1 of mothers and age-matched virgin mice, we monitored changes in the responses to a set of artificial and natural sounds. Population dynamics underwent large changes as measured by pairwise and higher-order correlations, with noise correlations increasing as much as twofold in lactating mothers. Concomitantly, changes in response properties of single neurons were modest and selective. Remarkably, despite the large changes in correlations, information about stimulus identity remained essentially the same in the two groups. Our results demonstrate changes in the correlation structure of neuronal activity as a result of a natural life event.
Rothschild, G, Cohen L, Mizrahi A, Nelken I.  2013.  Elevated correlations in neuronal ensembles of mouse auditory cortex following parturition.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(31):12851-61. Abstract
The auditory cortex is malleable by experience. Previous studies of auditory plasticity have described experience-dependent changes in response profiles of single neurons or changes in global tonotopic organization. However, experience-dependent changes in the dynamics of local neural populations have remained unexplored. In this study, we examined the influence of a dramatic yet natural experience in the life of female mice, giving birth and becoming a mother on single neurons and neuronal ensembles in the primary auditory cortex (A1). Using in vivo two-photon calcium imaging and electrophysiological recordings from layer 2/3 in A1 of mothers and age-matched virgin mice, we monitored changes in the responses to a set of artificial and natural sounds. Population dynamics underwent large changes as measured by pairwise and higher-order correlations, with noise correlations increasing as much as twofold in lactating mothers. Concomitantly, changes in response properties of single neurons were modest and selective. Remarkably, despite the large changes in correlations, information about stimulus identity remained essentially the same in the two groups. Our results demonstrate changes in the correlation structure of neuronal activity as a result of a natural life event.
Nitzan, E, Pfaltzgraff ER, Labosky PA, Kalcheim C.  2013.  Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3.. Proceedings of the National Academy of Sciences of the United States of America. 110(31):12709-14. Abstract
Skin melanocytes arise from two sources: either directly from neural crest progenitors or indirectly from neural crest-derived Schwann cell precursors after colonization of peripheral nerves. The relationship between these two melanocyte populations and the factors controlling their specification remains poorly understood. Direct lineage tracing reveals that neural crest and Schwann cell progenitor-derived melanocytes are differentially restricted to the epaxial and hypaxial body domains, respectively. Furthermore, although both populations are initially part of the Foxd3 lineage, hypaxial melanocytes lose Foxd3 at late stages upon separation from the nerve, whereas we recently found that epaxial melanocytes segregate earlier from Foxd3-positive neural progenitors while still residing in the dorsal neural tube. Gain- and loss-of-function experiments in avians and mice, respectively, reveal that Foxd3 is both sufficient and necessary for regulating the balance between melanocyte and Schwann cell development. In addition, Foxd3 is also sufficient to regulate the switch between neuronal and glial fates in sensory ganglia. Together, we propose that differential fate acquisition of neural crest-derived cells depends on their progressive segregation from the Foxd3-positive lineage.
Katz, B, Oberacker T, Richter D, Tzadok H, Peters M, Minke B, Huber A.  2013.  Drosophila TRP and TRPL are assembled as homomultimeric channels in vivo.. Journal of cell science. 126(Pt 14):3121-33. Abstract
Family members of the cationic transient receptor potential (TRP) channels serve as sensors and transducers of environmental stimuli. The ability of different TRP channel isoforms of specific subfamilies to form heteromultimers and the structural requirements for channel assembly are still unresolved. Although heteromultimerization of different mammalian TRP channels within single subfamilies has been described, even within a subfamily (such as TRPC) not all members co-assemble with each other. In Drosophila photoreceptors two TRPC channels, TRP and TRP-like protein (TRPL) are expressed together in photoreceptors where they generate the light-induced current. The formation of functional TRP-TRPL heteromultimers in cell culture and in vitro has been reported. However, functional in vivo assays have shown that each channel functions independently of the other. Therefore, the issue of whether TRP and TRPL form heteromultimers in vivo is still unclear. In the present study we investigated the ability of TRP and TRPL to form heteromultimers, and the structural requirements for channel assembly, by studying assembly of GFP-tagged TRP and TRPL channels and chimeric TRP and TRPL channels, in vivo. Interaction studies of tagged and native channels as well as native and chimeric TRP-TRPL channels using co-immunoprecipitation, immunocytochemistry and electrophysiology, critically tested the ability of TRP and TRPL to interact. We found that TRP and TRPL assemble exclusively as homomultimeric channels in their native environment. The above analyses revealed that the transmembrane regions of TRP and TRPL do not determine assemble specificity of these channels. However, the C-terminal regions of both TRP and TRPL predominantly specify the assembly of homomeric TRP and TRPL channels.
Roberson, D, Gudes S, Sprague JM, Patoski HAW, Robson VK, Blasl F, Duan B, Oh S B, Bean BP, Ma Q et al..  2013.  Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons.. Nature Neuroscience. 16(7):910-8. Abstractroberson_et_al_itch_nature_neuroscience_2013.pdf
The peripheral terminals of primary sensory neurons detect histamine and non-histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. Using a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker, we found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1(+) or TRPA1(+) neurons allowed allyl isothiocyanate or capsaicin, respectively, to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus.
Kay, KN, Winawer J, Mezer A, Wandell BA.  2013.  Compressive spatial summation in human visual cortex.. Journal of neurophysiology. 110(2):481-94. Abstract
Neurons within a small (a few cubic millimeters) region of visual cortex respond to stimuli within a restricted region of the visual field. Previous studies have characterized the population response of such neurons using a model that sums contrast linearly across the visual field. In this study, we tested linear spatial summation of population responses using blood oxygenation level-dependent (BOLD) functional MRI. We measured BOLD responses to a systematic set of contrast patterns and discovered systematic deviation from linearity: the data are more accurately explained by a model in which a compressive static nonlinearity is applied after linear spatial summation. We found that the nonlinearity is present in early visual areas (e.g., V1, V2) and grows more pronounced in relatively anterior extrastriate areas (e.g., LO-2, VO-2). We then analyzed the effect of compressive spatial summation in terms of changes in the position and size of a viewed object. Compressive spatial summation is consistent with tolerance to changes in position and size, an important characteristic of object representation.
Shaltiel, G, Hanan M, Wolf Y, Barbash S, Kovalev E, Shoham S, Soreq H.  2013.  Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target.. Brain structure & function. 218(1):59-72. Abstract
Diverse stress stimuli induce long-lasting cognitive deficits, but the underlying molecular mechanisms are still incompletely understood. Here, we report three different stress models demonstrating that stress-inducible increases in microRNA-132 (miR-132) and consequent decreases in its acetylcholinesterase (AChE) target are causally involved. In a mild model of predator scent-induced anxiety, we demonstrate long-lasting hippocampal elevation of miR-132, accompanied by and associated with reduced AChE activity. Using lentiviral-mediated suppression of "synaptic" AChE-S mRNA, we quantified footshock stress-inducible changes in miR-132 and AChE and its corresponding cognitive damages. Stressed mice showed long-lasting impairments in the Morris water maze. In contrast, pre-stress injected AChE-suppressing lentivirus, but not a control virus, reduced hippocampal levels of both miR-132 and AChE and maintained similar cognitive performance to that of naïve, non-stressed mice. To dissociate between miR-132 and synaptic AChE-S as potential causes for stress-inducible cognitive deficits, we further used engineered TgR mice with enforced over-expression of the soluble "readthrough" AChE-R variant without the 3'-untranslated region binding site for miR-132. TgR mice displayed excess AChE-R in hippocampal neurons, enhanced c-fos labeling and correspondingly intensified reaction to the cholinergic agonist pilocarpine. They further showed excessive hippocampal expression of miR-132, accompanied by reduced host AChE-S mRNA and the GTPase activator p250GAP target of miR-132. At the behavioral level, TgR mice showed abnormal nocturnal locomotion patterns and serial maze mal-performance in spite of their reduced AChE-S levels. Our findings attribute stress-inducible cognitive impairments to cholinergic-mediated induction of miR-132 and consequently suppressed ACHE-S, opening venues for intercepting these miR-132-mediated damages.
Nitzan, E, Kalcheim C.  2013.  Neural crest and somitic mesoderm as paradigms to investigate cell fate decisions during development.. Development, growth & differentiation. 55(1):60-78. Abstract
The dorsal domains of the neural tube and somites are transient embryonic epithelia; they constitute the source of neural crest progenitors that generate the peripheral nervous system, pigment cells and ectomesenchyme, and of the dermomyotome that develops into myocytes, dermis and vascular cells, respectively. Based on the variety of derivatives produced by each type of epithelium, a classical yet still highly relevant question is whether these embryonic epithelia are composed of homogeneous multipotent progenitors or, alternatively, of subsets of fate-restricted cells. Growing evidence substantiates the notion that both the dorsal tube and the dermomyotome are heterogeneous epithelia composed of multipotent as well as fate-restricted precursors that emerge as such in a spatio-temporally regulated manner. Elucidation of the state of commitment of the precedent progenitors is of utmost significance for deciphering the mechanisms that regulate fate segregation during embryogenesis. In addition, it will contribute to understanding the nature of well documented neural crest-somite interactions shown to modulate the timing of neural crest cell emigration, their segmental migration, and myogenesis.
Soreq, L, Bergman H, Israel Z, Soreq H.  2013.  Overlapping molecular signatures in Parkinson's patients' leukocytes before and after treatment and in mouse model brain regions.. CNS & neurological disorders drug targets. 12(8):1086-93. Abstract
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with worldwide increasing incidence. PD is the second most prevalent neurodegenerative disease and the first that involves motor symptoms. The great majority of cases, defined as sporadic with non-familial disease, show a highly variable risk of disease due to environmental and genetic factors that remain largely unknown. Furthermore, the neurodegenerative process typically initiates decades prior to the appearance of hallmark motor symptoms; therefore, clinical diagnosis is enabled only when most of the relevant neurons have died and current treatment is palliative at best. Here, we review the application of genomic scale microarray based research aimed to enable early diagnosis and identify novel targets for therapeutic intervention. We demonstrate that blood leukocytes can serve as a feasible and reliable tissue source to test for disease-induced and treatment-related transcript changes. We cover our reports of transcription and alternative splicing modifications in PD patient's leukocytes based on 3' and exon microarray analyses and the identified inflammatory modulations. We further describe the effects of deep brain stimulation (DBS) neurosurgery on the leukocyte transcripts as reflecting the patient's neurological status. A focus is gained on common genes identified both in the molecular signature of human PD leukocytes and in brain RNA from engineered PD mouse models subjected to risk and protection manipulations. Finally, we discuss potential future directions of high-throughput RNA research as facilitators of the PD knowledge base through next generation sequencing technologies of both long and short RNA transcripts including microRNAs.