bluuebunny/crossref_metadata_2025 huggingface dataset:
Multisegmental Aδ- and C-Fiber Input to Neurons in Lamina I and the Lateral Spinal Nucleus
Authors: Pinto Vítor , Szucs Peter , Lima Deolinda , Safronov Boris V.
Published: February 2010

Spinal lamina I and the lateral spinal nucleus (LSN) receive and integrate nociceptive primary afferent inputs to project through diverse ascending pathways. The pattern of the afferent supply of individual lamina I and LSN neurons through different segmental dorsal roots is poorly understood. Therefore, we recorded responses of lamina I and LSN neurons in spinal segments L4 and L3 to stimulation of six ipsilateral dorsal roots (L1–L6). The neurons were viewed through the overlying white matter in the isolated spinal cord preparation using the oblique infrared LED illumination technique. Orientation of myelinated fibers in the white matter was used as a criterion to distinguish between the LSN and lamina I. Both types of neurons received mixed (monosynaptic and polysynaptic) excitatory Aδ- and C-fiber input from up to six dorsal roots, with only less than one-third of it arising from the corresponding segmental root. The largest mixed input arose from the dorsal root of the neighboring caudal segment. Lamina I and LSN neurons could fire spikes upon the stimulation of up to six different dorsal roots. We also found that individual lamina I neurons can receive converging monosynaptic Aδ- and/or C-fiber inputs from up to six segmental roots. This study shows that lamina I and LSN neurons function as intersegmental integrators of primary afferent inputs. We suggest that broad monosynaptic convergence of Aδ- and C-afferents onto a lamina I neuron is important for the somatosensory processing.
CSF Biomarkers in Prediction of Cerebral and Clinical Change in Mild Cognitive Impairment and Alzheimer's Disease
Authors: Fjell Anders M. , Walhovd Kristine B. , Fennema-Notestine Christine , McEvoy Linda K. , Hagler Donald J. , Holland Dominic , Brewer James B. , Dale Anders M. ,   for the Alzheimer's Disease Neuroimaging Initiative
Published: February 2010

Brain atrophy and altered CSF levels of amyloid β (Aβ42) and the microtubule-associated protein tau are potent biomarkers of Alzheimer's disease (AD)-related pathology. However, the relationship between CSF biomarkers and brain morphometry is poorly understood. Thus, we addressed the following questions. (1) Can CSF biomarker levels explain the morphometric differences between normal controls (NC) and patients with mild cognitive impairment (MCI) or AD? (2) How are CSF biomarkers related to atrophy across the brain? (3) How closely are CSF biomarkers and morphometry related to clinical change [clinical dementia rating sum of boxes (CDR-sb)]? Three hundred seventy participants (105 NC, 175 MCI, 90 AD) from the Alzheimer's Disease Neuroimaging Initiative were studied, of whom 309 were followed for 1 year and 176 for 2 years. Analyses were performed across the entire cortical surface, as well as for 30 cortical and subcortical regions of interest. Results showed that CSF biomarker levels could not account for group differences in brain morphometry at baseline but that CSF biomarker levels showed moderate relationships to longitudinal atrophy rates in numerous brain areas, not restricted to medial temporal structures. Baseline morphometry was at least as predictive of atrophy as were CSF biomarkers. Even MCI patients with levels of Aβ42comparable with controls and of p-tau lower than controls showed more atrophy than the controls. Morphometry predicted change in CDR-sb better than did CSF biomarkers. These results indicate that morphometric changes in MCI and AD are not secondary to CSF biomarker changes and that the two types of biomarkers yield complementary information.
A Subpopulation of Neuronal M4Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors
Authors: Jeon Jongrye , Dencker Ditte , Wörtwein Gitta , Woldbye David P. D. , Cui Yinghong , Davis Albert A. , Levey Allan I. , Schütz Günther , Sager Thomas N. , Mørk Arne , Li Cuiling , Deng Chu-Xia , Fink-Jensen Anders , Wess Jürgen
Published: February 2010

Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M1–M5mAChRs). Like other mAChR subtypes, the M4mAChR is widely expressed in different regions of the forebrain. Interestingly, M4mAChRs are coexpressed with D1dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M4mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M4mAChRs only in D1dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D1dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M4mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance.
Neural Representation of Natural Images in Visual Area V2
Authors: Willmore Ben D. B. , Prenger Ryan J. , Gallant Jack L.
Published: February 2010

Area V2 is a major visual processing stage in mammalian visual cortex, but little is currently known about how V2 encodes information during natural vision. To determine how V2 represents natural images, we used a novel nonlinear system identification approach to obtain quantitative estimates of spatial tuning across a large sample of V2 neurons. We compared these tuning estimates with those obtained in area V1, in which the neural code is relatively well understood. We find two subpopulations of neurons in V2. Approximately one-half of the V2 neurons have tuning that is similar to V1. The other half of the V2 neurons are selective for complex features such as those that occur in natural scenes. These neurons are distinguished from V1 neurons mainly by the presence of stronger suppressive tuning. Selectivity in these neurons therefore reflects a balance between excitatory and suppressive tuning for specific features. These results provide a new perspective on how complex shape selectivity arises, emphasizing the role of suppressive tuning in determining stimulus selectivity in higher visual cortex.
Interaction between Facilitation and Depression at a Large CNS Synapse Reveals Mechanisms of Short-Term Plasticity
Authors: Müller Martin , Goutman Juan D. , Kochubey Olexiy , Schneggenburger Ralf
Published: February 2010

The two fundamental forms of short-term plasticity, short-term depression and facilitation, coexist at most synapses, but little is known about their interaction. Here, we studied the interplay between short-term depression and facilitation at calyx of Held synapses. Stimulation at a “low” frequency of 10 or 20 Hz, which is in the range of the spontaneous activity of these auditory neuronsin vivo, induced synaptic depression. Surprisingly, an instantaneous increase of the stimulation frequency to 100 or 200 Hz following the low-frequency train uncovered a robust facilitation of EPSCs relative to the predepressed amplitude level. This facilitation decayed rapidly (∼30 ms) and depended on presynaptic residual Ca2+, but it was not caused by Ca2+current facilitation. To probe the release probability of the remaining readily releasable vesicles following the low-frequency train we made presynaptic Ca2+uncaging experiments in the predepressed state of the synapse. We found that low-frequency stimulation depletes the fast-releasable vesicle pool (FRP) down to ∼40% of control and that the remaining FRP vesicles are released with ∼2-fold slower release kinetics, indicating a hitherto unknown intrinsic heterogeneity among FRP vesicles. Thus, vesicles with an intrinsically lower release probability predominate after low frequency stimulation and undergo facilitation during the onset of subsequent high-frequency trains. Facilitation in the predepressed state of the synapse might help to stabilize the amount of transmitter release at the onset of high-frequency firing at these auditory synapses.
Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior
Authors: Blundell Jacqueline , Blaiss Cory A. , Etherton Mark R. , Espinosa Felipe , Tabuchi Katsuhiko , Walz Christopher , Bolliger Marc F. , Südhof Thomas C. , Powell Craig M.
Published: February 2010

Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonistd-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
Reduced Laterality as a Trait Marker ofSchizophrenia—Evidence from Structural and Functional Neuroimaging
Authors: Oertel Viola , Knöchel Christian , Rotarska-Jagiela Anna , Schönmeyer Ralf , Lindner Michael , van de Ven Vincent , Haenschel Corinna , Uhlhaas Peter , Maurer Konrad , Linden David E. J.
Published: February 2010

Laterality is a characteristic principle of the organization of the brain systems for language, and reduced hemispheric asymmetry has been considered a risk factor for schizophrenia. Here we sought support for the risk factor hypothesis by investigating whether reduced asymmetry of temporal lobe structure and function is also present in unaffected relatives. Sixteen schizophrenia patients, 16 age-matched first-degree relatives, and 15 healthy controls underwent high-resolution three-dimensional anatomical imaging and functional magnetic resonance imaging during auditory stimulation. Both the overall auditory cortex and planum temporale volumes and the lateralization to the left hemisphere were markedly reduced in patients. The decrease of lateralization correlated with increased severity of symptoms. In addition, both the overall functional activation in response to auditory stimulation and its asymmetry were reduced in the patients. Relatives had intermediate values between patients and controls on both structural and functional measures. This study provides added support for the idea that reduced hemispheric asymmetry is a biological risk factor for schizophrenia.
Cell Type-Specific Control of Neuronal Responsiveness by Gamma-Band Oscillatory Inhibition
Authors: Otte Stephani , Hasenstaub Andrea , Callaway Edward M.
Published: February 2010

Neocortical networks are composed of diverse populations of cells that differ in their chemical content, electrophysiological characteristics, and connectivity. Gamma-frequency oscillatory activity of inhibitory subnetworks has been hypothesized to regulate information processing in the cortex as a whole. Inhibitory neurons in these subnetworks synchronize their firing and selectively innervate the perisomatic compartments of their target neurons, generating both tonic and rapidly fluctuating inhibition. How do different types of cortical neurons respond to changes in the level and structure of perisomatic inhibition? What accounts for response heterogeneity between cell types, and are these response properties fixed or flexible? To answer these questions, we usein vitrowhole-cell recording and dynamic-clamp somatic current injection to study six distinct types of cortical neurons. We demonstrate that different types of neurons systematically vary in their receptiveness to fast changes in the structure of inhibition and the range over which changes in inhibitory tone affect their output. Using simple neuron models and model neuron hybrids (dynamic clamp), we determine which intrinsic differences between cell types lead to these variations in receptiveness. These results suggest important differences in the way cell types are affected by gamma-frequency inhibition, which may have important circuit level implications. Although intrinsic differences observedin vitroare useful for the elucidation of basic cellular properties and differences between cell types, we also investigate how the integrative properties of neurons are likely to be rapidly modulated in the context of active networksin vivo.
High-Frequency Stimulation of the Subthalamic Nucleus and l-3,4-Dihydroxyphenylalanine InhibitIn VivoSerotonin Release in the Prefrontal Cortex and Hippocampus in a Rat Model of Parkinson's Disease
Authors: Navailles Sylvia , Benazzouz Abdelhamid , Bioulac Bernard , Gross Christian , De Deurwaerdère Philippe
Published: February 2010

High-frequency stimulation of the subthalamic nucleus (STN-HFS) andl-3,4-dihydroxyphenylalanine (l-DOPA) medication are the most used therapeutic approaches in Parkinson's disease (PD), but their beneficial motor effects are burdened by the emergence of cognitive and depressive disorders. Although a reduced serotonergic function has been linked to the psychiatric effects of antiparkinsonian treatments, biochemical evidence supporting this hypothesis is still lacking. By using a microdialysis approach in anesthetized rats, we investigated the ability of STN-HFS (130 Hz, 30 μA, 20 min) andl-DOPA (6–12 mg/kg) to change extracellular levels of serotonin (5-HT) monitored simultaneously in the prefrontal cortex (PFC) and hippocampus (HIPP), two brain regions involved in the regulation of mood and cognition that receive a distinct 5-HT innervation. The results show that STN-HFS inhibited 5-HT levels in the PFC and HIPP of sham-lesioned and 6-hydroxydopamine (6-OHDA)-lesioned rats. The effect elicited by STN-HFS was blocked by the administration of the 5-HT1Aagonist 8-hydroxy-N,N-dipropyl-2-aminotetralin.l-DOPA (6 and 12 mg/kg) reduced 5-HT levels in the PFC and HIPP of 6-OHDA rats. STN-HFS did not further decrease 5-HT levels induced byl-DOPA, but attenuatedl-DOPA-induced dopamine release in the PFC and HIPP. These neurochemical data show that STN-HFS inhibits 5-HT release by modulating serotonergic neuron activity, while the decrease in 5-HT levels induced byl-DOPA may include its direct action inside serotonergic neurons. These results support the premise that antiparkinsonian treatments reduce central serotonergic transmission, which may favor the development of nonmotor side effects in PD.
Common Origins of Hippocampal Ivy and Nitric Oxide Synthase Expressing Neurogliaform Cells
Authors: Tricoire Ludovic , Pelkey Kenneth A. , Daw Michael I. , Sousa Vitor H. , Miyoshi Goichi , Jeffries Brian , Cauli Bruno , Fishell Gord , McBain Chris J.
Published: February 2010

GABAergic interneurons critically regulate cortical computation through exquisite spatiotemporal control over excitatory networks. Precision of this inhibitory control requires a remarkable diversity within interneuron populations that is largely specified during embryogenesis. Although interneurons expressing the neuronal isoform of nitric oxide synthase (nNOS) constitute the largest hippocampal interneuron cohort their origin and specification remain unknown. Thus, as neurogliaform cells (NGC) and Ivy cells (IvC) represent the main nNOS+interneurons, we investigated their developmental origins. Although considered distinct interneuron subtypes, NGCs and IvCs exhibited similar neurochemical and electrophysiological signatures, including NPY expression and late spiking. Moreover, lineage analyses, including loss-of-function experiments and inducible fate-mapping, indicated that nNOS+IvCs and NGCs are both derived from medial ganglionic eminence (MGE) progenitors under control of the transcription factor Nkx2-1. Surprisingly, a subset of NGCs lacking nNOS arises from caudal ganglionic eminence (CGE) progenitors. Thus, while nNOS+NGCs and IvCs arise from MGE progenitors, a CGE origin distinguishes a discrete population of nNOS−NGCs.
Ca2+/Calmodulin Disrupts AKAP79/150 Interactions with KCNQ (M-Type) K+Channels
Authors: Bal Manjot , Zhang Jie , Hernandez Ciria C. , Zaika Oleg , Shapiro Mark S.
Published: February 2010

M-type channels are localized to neuronal, cardiovascular, and epithelial tissues, where they play critical roles in control of excitability and K+transport, and are regulated by numerous receptors via Gq/11-mediated signals. One pathway shown for KCNQ2 and muscarinic receptors uses PKC, recruited to the channels by A-kinase anchoring protein (AKAP)79/150. As M-type channels can be variously composed of KCNQ1-5 subunits, and M current is known to be regulated by Ca2+/calmodulin (CaM) and PIP2, we probed the generality of AKAP79/150 actions among KCNQ1-5 channels, and the influence of Ca2+/CaM and PIP2on AKAP79/150 actions. We first examined which KCNQ subunits are targeted by AKAP79 in Chinese hamster ovary (CHO) cells heterologously expressing KCNQ1-5 subunits and AKAP79, using fluorescence resonance energy transfer (FRET) under total internal reflection fluorescence (TIRF) microscopy, and patch-clamp analysis. Donor-dequenching FRET between CFP-tagged KCNQ1-5 and YFP-tagged AKAP79 revealed association of KCNQ2-5, but not KCNQ1, with AKAP79. In parallel with these results, CHO cells stably expressing M1receptors studied under perforated patch-clamp showed cotransfection of AKAP79 to “sensitize” KCNQ2/3 heteromers and KCNQ2-5, but not KCNQ1, homomers to muscarinic inhibition, manifested by shifts in the dose–response relations to lower concentrations. The effect on KCNQ4 was abolished by the T553A mutation of the putative PKC phosphorylation site. We then probed the role of CaM and PIP2in these AKAP79 actions. TIRF/FRET experiments revealed cotransfection of wild-type, but not dominant-negative (DN), CaM that cannot bind Ca2+, to disrupt the interaction of YFP-tagged AKAP791-153with CFP-tagged KCNQ2-5. Tonic depletion of PIP2by cotransfection of a PIP2phosphatase had no effect, and sudden depletion of PIP2did not delocalize GFP-tagged AKAP79 from the membrane. Finally, patch-clamp experiments showed cotransfection of wild-type, but not DN, CaM to prevent the AKAP79-mediated sensitization of KCNQ2/3 heteromers to muscarinic inhibition. Thus, AKAP79 acts on KCNQ2-5, but not KCNQ1-containing channels, with effects disrupted by calcified CaM, but not by PIP2depletion.
Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic–Ischemic Brain Injury
Authors: Ten Vadim S. , Yao Jun , Ratner Veniamin , Sosunov Sergey , Fraser Deborah A. , Botto Marina , Sivasankar Baalasubramanian , Morgan B. Paul , Silverstein Samuel , Stark Raymond , Polin Richard , Vannucci Susan J. , Pinsky David , Starkov Anatoly A.
Published: February 2010

Hypoxic–ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia–ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia–ischemia. Only C1q−/−mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q−/−brain mitochondria and preserved activity of the respiratory chain. Compared with C1q+/+neurons, cortical C1q−/−neurons exhibited resistance to oxygen–glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q−/−neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.
Attention Differentially Modulates Similar Neuronal Responses Evoked by Varying Contrast and Direction Stimuli in Area MT
Authors: Khayat Paul S. , Niebergall Robert , Martinez-Trujillo Julio C.
Published: February 2010

The effects of attention on the responses of visual neurons have been described as a scaling or additive modulation independent of stimulus features and contrast, or as a contrast-dependent modulation. We explored these alternatives by recording neuronal responses in macaque area MT to moving stimuli that evoked similar firing rates but varied in contrast and direction. We presented two identical pairs of stimuli, one inside the neurons' receptive field and the other outside, in the opposite hemifield. One stimulus of each pair always had high contrast and moved in the recorded cell's antipreferred direction (AP pattern), while the other (test pattern) could either move in the cell's preferred direction and vary in contrast, or have the same contrast as the AP pattern and vary in direction. For different stimulus pairs evoking similar responses, switching attention between the two AP patterns, or directing attention from a fixation spot to the AP pattern inside or outside the receptive field, produced a stronger suppression of responses to varying contrast pairs, reaching a maximum (∼20%) at intermediate contrast. For invariable contrast pairs, switching attention from the fixation spot to the AP pattern produced a modulation that ranged from 10% suppression when the test pattern moved in the cells preferred direction to 14% enhancement when it moved in a direction 90° away from that direction. Our results are incompatible with a scaling or additive modulation of MT neurons' response by attention, but support models where spatial and feature-based attention modulate input signals into the area normalization circuit.
Cortical Mechanisms for the Segregation and Representation of Acoustic Textures
Authors: Overath Tobias , Kumar Sukhbinder , Stewart Lauren , von Kriegstein Katharina , Cusack Rhodri , Rees Adrian , Griffiths Timothy D.
Published: February 2010

Auditory object analysis requires two fundamental perceptual processes: the definition of the boundaries between objects, and the abstraction and maintenance of an object's characteristic features. Although it is intuitive to assume that the detection of the discontinuities at an object's boundaries precedes the subsequent precise representation of the object, the specific underlying cortical mechanisms for segregating and representing auditory objects within the auditory scene are unknown. We investigated the cortical bases of these two processes for one type of auditory object, an “acoustic texture,” composed of multiple frequency-modulated ramps. In these stimuli, we independently manipulated the statistical rules governing (1) the frequency–time space within individual textures (comprising ramps with a given spectrotemporal coherence) and (2) the boundaries between textures (adjacent textures with different spectrotemporal coherences). Using functional magnetic resonance imaging, we show mechanisms defining boundaries between textures with different coherences in primary and association auditory cortices, whereas texture coherence is represented only in association cortex. Furthermore, participants' superior detection of boundaries across which texture coherence increased (as opposed to decreased) was reflected in a greater neural response in auditory association cortex at these boundaries. The results suggest a hierarchical mechanism for processing acoustic textures that is relevant to auditory object analysis: boundaries between objects are first detected as a change in statistical rules over frequency–time space, before a representation that corresponds to the characteristics of the perceived object is formed.
The P2Y2Receptor Sensitizes Mouse Bladder Sensory Neurons and Facilitates Purinergic Currents
Authors: Chen Xiaowei , Molliver Derek C. , Gebhart G. F.
Published: February 2010

Sensitization of bladder afferents is an underlying contributor to the development and maintenance of painful bladder syndrome/interstitial cystitis. Extracellular purines and pyrimidines (e.g., ATP and UTP), released during bladder distension or from damaged cells after tissue insult, are thought to play an important role in bladder physiological and pathological states by actions at ionotropic P2X and metabotropic P2Y receptors. In the present study, we examined the ability of P2Y receptors to sensitize and modulate P2X-mediated responses in mouse bladder sensory neurons. UTP (a P2Y2and P2Y4agonist) increased excitability of bladder neurons by depolarizing resting membrane potential, increasing action potential firing, and facilitating responses to suprathreshold current injection as well as to P2X agonist application. These effects of UTP on bladder neuron excitability were blocked by the P2Y2receptor antagonist suramin. UTP also facilitated bladder neuron homomeric P2X2sustained currents and homomeric P2X3fast currents. The facilitatory effect of UTP on P2X2sustained currents was mediated by a G-protein-coupled P2Y2receptor/PKC pathway, whereas the effect of UTP on P2X3fast currents was G-protein independent. We also examined P2X and P2Y receptor expression in bladder neurons. P2Y2and P2Y4transcripts were detected in ∼50 and ∼20% of bladder neurons, respectively. Approximately 50% of P2X2- and P2X3-positive bladder neurons expressed P2Y2transcripts, whereas ≤25% of the same bladder neurons expressed P2Y4transcripts. These results support involvement of P2Y2receptors in bladder sensation, suggesting an important contribution to bladder neuron excitability and hypersensitivity.
Mechanisms Underlying Lateral GABAergic Feedback onto Rod Bipolar Cells in Rat Retina
Authors: Chávez Andrés E. , Grimes William N. , Diamond Jeffrey S.
Published: February 2010

GABAergic feedback inhibition from amacrine cells shapes visual signaling in the inner retina. Rod bipolar cells (RBCs), ON-sensitive cells that depolarize in response to light increments, receive reciprocal GABAergic feedback from A17 amacrine cells and additional GABAergic inputs from other amacrine cells located laterally in the inner plexiform layer. The circuitry and synaptic mechanisms underlying lateral GABAergic inhibition of RBCs are poorly understood. A-type and ρ-subunit-containing (C-type) GABA receptors (GABAARs and GABACRs) mediate both forms of inhibition, but their relative activation during synaptic transmission is unclear, and potential interactions between adjacent reciprocal and lateral synapses have not been explored. Here, we recorded from RBCs in acute slices of rat retina and isolated lateral GABAergic inhibition by pharmacologically ablating A17 amacrine cells. We found that amacrine cells providing lateral GABAergic inhibition to RBCs receive excitatory synaptic input mostly from ON bipolar cells via activation of both Ca2+-impermeable and Ca2+-permeable AMPA receptors (CP-AMPARs) but not NMDA receptors (NMDARs). Voltage-gated Ca2+(Cav) channels mediate the majority of Ca2+influx that triggers GABA release, although CP-AMPARs contribute a small component. The intracellular Ca2+signal contributing to transmitter release is amplified by Ca2+-induced Ca2+release from intracellular stores via activation of ryanodine receptors. Furthermore, lateral nonreciprocal feedback is mediated primarily by GABACRs that are activated independently from receptors mediating reciprocal feedback inhibition. These results illustrate numerous physiological differences that distinguish GABA release at reciprocal and lateral synapses, indicating complex, pathway-specific modulation of RBC signaling.
Temporally Diverse Firing Patterns in Olfactory Receptor Neurons Underlie Spatiotemporal Neural Codes for Odors
Authors: Raman Baranidharan , Joseph Joby , Tang Jeff , Stopfer Mark
Published: February 2010

Odorants are represented as spatiotemporal patterns of spikes in neurons of the antennal lobe (AL; insects) and olfactory bulb (OB; vertebrates). These response patterns have been thought to arise primarily from interactions within the AL/OB, an idea supported, in part, by the assumption that olfactory receptor neurons (ORNs) respond to odorants with simple firing patterns. However, activating the AL directly with simple pulses of current evoked responses in AL neurons that were much less diverse, complex, and enduring than responses elicited by odorants. Similarly, models of the AL driven by simplistic inputs generated relatively simple output. How then are dynamic neural codes for odors generated? Consistent with recent results from several other species, our recordings from locust ORNs showed a great diversity of temporal structure. Furthermore, we found that, viewed as a population, many response features of ORNs were remarkably similar to those observed within the AL. Using a set of computational models constrained by our electrophysiological recordings, we found that the temporal heterogeneity of responses of ORNs critically underlies the generation of spatiotemporal odor codes in the AL. A test then performedin vivoconfirmed that, given temporally homogeneous input, the AL cannot create diverse spatiotemporal patterns on its own; however, given temporally heterogeneous input, the AL generated realistic firing patterns. Finally, given the temporally structured input provided by ORNs, we clarified several separate, additional contributions of the AL to olfactory information processing. Thus, our results demonstrate the origin and subsequent reformatting of spatiotemporal neural codes for odors.
The Developmental Stage of Dentate Granule Cells Dictates Their Contribution to Seizure-Induced Plasticity
Authors: Kron Michelle M. , Zhang Helen , Parent Jack M.
Published: February 2010

Dentate granule cell (DGC) neurogenesis persists throughout life in the hippocampal dentate gyrus. In rodent temporal lobe epilepsy models, status epilepticus (SE) stimulates neurogenesis, but many newborn DGCs integrate aberrantly and are hyperexcitable, whereas others may integrate normally and restore inhibition. The overall influence of altered neurogenesis on epileptogenesis is therefore unclear. To better understand the role DGC neurogenesis plays in seizure-induced plasticity, we injected retroviral (RV) reporters to label dividing DGC progenitors at specific times before or after SE, or used x-irradiation to suppress neurogenesis. RV injections 7 weeks before SE to mark DGCs that had matured by the time of SE labeled cells with normal placement and morphology 4 weeks after SE. RV injections 2 or 4 weeks before seizure induction to label cells still developing during SE revealed normally located DGCs exhibiting hilar basal dendrites and mossy fiber sprouting (MFS) when observed 4 weeks after SE. Cells labeled by injecting RV after SE displayed hilar basal dendrites and ectopic migration, but not sprouting, at 28 d after SE; when examined 10 weeks after SE, however, these cells showed robust MFS. Eliminating cohorts of newborn DGCs by focal brain irradiation at specific times before or after SE decreased MFS or hilar ectopic DGCs, supporting the RV labeling results. These findings indicate that developing DGCs exhibit maturation-dependent vulnerability to SE, indicating that abnormal DGC plasticity derives exclusively from aberrantly developing DGCs. Treatments that restore normal DGC development after epileptogenic insults may therefore ameliorate epileptogenic network dysfunction and associated morbidities.
Hypocretins Regulate the Anxiogenic-Like Effects of Nicotine and Induce Reinstatement of Nicotine-Seeking Behavior
Authors: Plaza-Zabala Ainhoa , Martín-García Elena , de Lecea Luis , Maldonado Rafael , Berrendero Fernando
Published: February 2010

Emerging evidence suggests that the hypocretinergic system is involved in addictive behavior. In this study, we investigated the role of these hypothalamic neuropeptides in anxiety-like responses of nicotine and stress-induced reinstatement of nicotine-seeking behavior. Acute nicotine (0.8 mg/kg, s.c.) induced anxiogenic-like effects in the elevated plus-maze and activated the paraventricular nucleus of the hypothalamus (PVN) as revealed by c-Fos expression. Pretreatment with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 or preprohypocretin gene deletion blocked both nicotine effects. In the PVN, SB334867 also prevented the activation of corticotrophin releasing factor (CRF) and arginine-vasopressin (AVP) neurons, which expressed Hcrtr-1. In addition, an increase of the percentage of c-Fos-positive hypocretin cells in the perifornical and dorsomedial hypothalamic (PFA/DMH) areas was found after nicotine (0.8 mg/kg, s.c.) administration. Intracerebroventricular infusion of hypocretin-1 (Hcrt-1) (0.75 nmol/1 μl) or footshock stress reinstated a previously extinguished nicotine-seeking behavior. The effects of Hcrt-1 were blocked by SB334867, but not by the CRF1 receptor antagonist antalarmin. Moreover, SB334867 did not block CRF-dependent footshock-induced reinstatement of nicotine-seeking while antalarmin was effective in preventing this nicotine motivational response. Therefore, the Hcrt system interacts with CRF and AVP neurons in the PVN and modulates the anxiogenic-like effects of nicotine whereas Hcrt and CRF play a different role in the reinstatement of nicotine-seeking. Indeed, Hcrt-1 reinstates nicotine-seeking through a mechanism independent of CRF activation whereas CRF mediates the reinstatement induced by stress.
Detection of Low Salience Whisker Stimuli Requires Synergy of Tectal and Thalamic Sensory Relays
Authors: Cohen Jeremy D. , Castro-Alamancos Manuel A.
Published: February 2010

Detection of a sensory stimulus depends on its psychophysical saliency; the higher the saliency, the easier the detection. But it is not known whether sensory relay nuclei differ in their ability to detect low salient whisker stimuli. We found that reversible lesions of either the somatosensory thalamus or superior colliculus blocked detection of a low salience whisker conditioned stimulus (WCS) in an active avoidance task, without affecting detection of a high salience WCS. Thus, thalamic and tectal sensory relays work synergistically to detect low salient stimuli during avoidance behavior, but are redundant during detection of highly salient stimuli. We also recorded electrophysiological responses evoked by high and low salience stimuli in the superior colliculus and barrel cortex of freely behaving animals during active exploration, awake immobility, and sensory detection in the active avoidance task. Field potential (FP) responses evoked in barrel cortex and superior colliculus by high intensity stimuli are larger and adapt more to frequency than those evoked by low-intensity stimuli. FP responses are also more suppressed and adapt less during active exploration, and become further suppressed in barrel cortex during successful detection of either high or low salient stimuli in the active avoidance task. In addition, unit recordings revealed that firing rate increases in superior colliculus during active exploration and especially during successful detection of either high or low salient stimuli in the active avoidance task. We conclude that detection of low salient stimuli is achieved by a sparse neural code distributed through multiple sensory relays.
GRK2: A Novel Cell-Specific Regulator of Severity and Duration of Inflammatory Pain
Authors: Eijkelkamp Niels , Heijnen Cobi J. , Willemen Hanneke L. D. M. , Deumens Ronald , Joosten Elbert A. J. , Kleibeuker Wendy , den Hartog Ilona J. M. , van Velthoven Cindy T. J. , Nijboer Cora , Nassar Mohammed A. , Dorn Gerald W. , Wood John N. , Kavelaars Annemieke
Published: February 2010

Chronic pain associated with inflammation is a common clinical problem, and the underlying mechanisms have only begun to be unraveled. GRK2 regulates cellular signaling by promoting G-protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism.GRK2+/−mice with an ∼50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using Cre–Lox technology. Carrageenan- or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Nav1.8 nociceptors.In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitization.In vivo, CCL3-induced acute hyperalgesia inGRK2+/−mice was mediated via TRPV1. Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia inGRK2+/−mice was associated with ongoing microglial activation and increased phospho-p38 and tumor necrosis factor α (TNF-α) in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-α activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia inGRK2+/−mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the pathophysiological relevance of microglial GRK2. Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia.
Keeping It Together: Mechanisms of Intersegmental Coordination for a Flexible Locomotor Behavior
Authors: Puhl Joshua G. , Mesce Karen A.
Published: February 2010

The coordination of multiple neural oscillators is key for the generation of productive locomotor movements. In the medicinal leech, we determined that activation and coordination of the segmental crawl oscillators, or unit burst generators, are dependent on signals descending from the cephalic ganglion. In nearly intact animals, removing descending input (reversibly with a sucrose block) prevented overt crawling, but not swimming. Cephalic depolarization was sufficient for coordination. To determine whether descending signals were necessary for the generation and maintenance of posterior-directed intersegmental phase delays, we induced fictive crawling in isolated whole nerve cords using dopamine (DA) and blocked descending inputs. After blockade, we observed a significant loss of intersegmental coordination. Appropriate phase delays were also absent in DA-treated chains of ganglia. In chains, when one ganglion was removed from its neighbors, crawling in that ganglion emerged robust and stable, underscoring that these oscillators operate best with either all or none of their intersegmental inputs. To study local oscillator coupling, we induced fictive crawling (with DA) in a single oscillator within a chain. Although appropriate intersegmental phase delays were always absent, when one ganglion was treated with DA, neighboring ganglia began to show crawl-like bursting, with motoneuron spikes/burst greatest in untreated posterior ganglia. We further determined that this local excitatory drive excluded the swim-gating cell, 204. In conclusion, both long-distance descending and local interoscillator coupling contribute to crawling. This dual contribution helps to explain the inherent flexibility of crawling, and provides a foundation for understanding other dynamic locomotor behaviors across animal groups.
Endocannabinoid Signaling Mediates Psychomotor Activation by Adenosine A2AAntagonists
Authors: Lerner Talia N. , Horne Eric A. , Stella Nephi , Kreitzer Anatol C.
Published: February 2010

Adenosine A2Areceptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A2Aantagonistin vivois greatly attenuated by antagonizing cannabinoid CB1receptor signaling or by administration to CB1−/−mice. To determine the locus of increased endocannabinoid signaling, we measured the amount of anandamide [AEA (N-arachidonoylethanolamine)] and 2-arachidonoylglycerol (2-AG) in brain tissue from striatum and cortex. We find that 2-AG is selectively increased in striatum after acute blockade of A2Areceptors, which are highly expressed by striatal indirect-pathway medium spiny neurons (MSNs). Using targeted whole-cell recordings from direct- and indirect-pathway MSNs, we demonstrate that A2Areceptor antagonists potentiate 2-AG release and induction of long-term depression at indirect-pathway MSNs, but not direct-pathway MSNs. Together, these data outline a molecular mechanism by which A2Aantagonists reduce excitatory synaptic drive on the indirect pathway through CB1receptor signaling, thus leading to increased psychomotor activation.
Increased circulating adiponectin levels and decreased leptin/soluble leptin receptor ratio throughout puberty in female ballet dancers: association with body composition and the delay in puberty
Authors: Donoso M A , Muñoz-Calvo M T , Barrios V , Garrido G , Hawkins F , Argente J
Published: February 2010

Introduction

Ballet dancers (BDs) have a negative energy balance related to physical training that results in alterations in body composition, sexual development, and adipokine secretion. Our aims were to study anthropometric parameters, body composition, and their relationship with adipokines throughout pubertal development.

Subjects and methods

We carried out a prospective follow-up study of 22 female Caucasian BDs (Tanner II stage) followed throughout puberty. Nutritional status was determined by measurement of height, weight, and body mass index (BMI). We calculated growth velocity, bone maturity, and body composition at Tanner stages II, III, and V by dual energy X-ray absorptiometry. Circulating leptin, adiponectin, and soluble leptin receptor (sObR) levels were determined.

Results

BDs presented a delay in skeletal maturation during puberty, without affectation of final height. Energy intake was deficient according to their physical exercise, and they had a delay of 1 year in the mean age of menarche. Leptin levels were decreased, whereas sObR and adiponectin levels were increased throughout puberty. The percentage of trunk fat, total fat mass, and fat of the extremities was decreased throughout the study period (P<0.01). Lean mass was increased in the lower extremities, and bone mineral density was normal.

Conclusion

A negative energy balance together with maintained physical exercise induced modifications in body composition in BDs. Changes in leptin and adiponectin levels appear to be more related to total fat content than to BMI. Furthermore, the onset and delayed progress of puberty may be related with an inadequate energy balance due to increased exercise.
Acromegaly per se does not increase the risk for coronary artery disease
Authors: Akutsu Hiroyoshi , Kreutzer Jürgen , Wasmeier Gerald , Ropers Dieter , Rost Christian , Möhlig Matthias , Wallaschofski Henri , Buchfelder Michael , Schöfl Christof
Published: February 2010

Context

Information about the risk and course of coronary artery disease (CAD) in acromegaly is limited.

Objective

To evaluate CAD risk in acromegalic patients at diagnosis and after successful treatment during follow-up.

Subjects and methods

Twenty-five consecutive patients (age 45.1±10.6 years, 15 women) were studied at the time of diagnosis, and 19 patients were re-evaluated after 4.6±1.1 years. The European Society of Cardiology (ESC) risk score was calculated, and a cardiac computed tomography was performed for detection and quantification (Agatston score (AS)) of coronary artery calcium (CACs). Fifty age-, sex-, and CAD risk-matched subjects and CAC data from the population-based Heinz Nixdorf Recall (HNR) study served as controls.

Results

In 21 of the 25 patients, the 10-year risk of developing CAD according to the ESC risk score was low (<10%) and high (>20%) in four patients. The AS was lower than in controls (2.6±7.9 vs 66±182;P=0.014) and less patients had a positive CAC (AS>0) (20 vs 48%,P=0.024), which in the acromegalic patients was less than expected from the HNR study. The AS did not correlate with GH excess or disease duration. In 19 acromegalic patients, who were in remission and re-evaluated after 4.6±1.1 years, the ESC risk (P=0.102) and the AS (P=0.173) did not change significantly and no symptomatic CAD event occurred.

Conclusion

CAD risk in newly diagnosed acromegalic patients was low and remained stable after successful treatment. CAC was lower than in controls suggesting that GH excessper sedoes not carry an additional CAD risk.
Models to predict changes in serum IGF1 and body composition in response to GH replacement therapy in GH-deficient adults
Authors: Barbosa Edna J L , Koranyi Josef , Filipsson Helena , Bengtsson Bengt-Åke , Boguszewski Cesar Luiz , Johannsson Gudmundur
Published: February 2010

Objective

Clinical response to GH therapy in GH-deficient (GHD) adults varies widely. Good predictors of treatment response are lacking. The aim of the study was to develop mathematical models to predict changes in serum IGF1 and body composition (BC) in response to GH therapy in GHD adults.

Design and methods

One hundred and sixty-seven GHD patients (103 men, median age 50 years) were studied before and after 12 months of GH treatment. GH dose was tailored according to serum IGF1 concentrations. Good responders (GR) and poor responders (PR) to GH therapy were defined as patients with a response >60th and <40th percentile respectively, for changes in serum IGF1 levels (adjusted for GH cumulative dose) and in BC (lean body mass (LBM) and body fat determined using dual-energy X-ray absorptiometry). A logistic regression model was used to predict the probability of being a GR or PR.

Results

In the IGF1 prediction model, men (odds ratio (OR) 5.62: 95% confidence interval 2.59–12.18) and patients with higher insulin levels (OR 1.06: 1.00–1.12) were more likely to be GR. The accuracy of the prediction model was 70%. In the BC model, men (OR 10.72: 1.36–84.18) and GHD patients with lower LBM (OR 0.82: 0.73–0.92) and greater height (OR 1.23: 1.08–1.40) at baseline were more likely to be GR. The accuracy of the prediction model was 80%.

Conclusion

Accurate mathematical models to predict GH responsiveness in GHD adults were developed using gender, body height, baseline LBM, and serum insulin levels as the major clinical predictors.