bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphorylation of Transcription Factor CREB in Rat Spinal Cord after Formalin-Induced Hyperalgesia: Relationship toc-fosInduction
Authors: Ji Ru-Rong , Rupp Fabio 
Published: April 2018

The involvement of cAMP-responsive element-binding protein (CREB) signaling in tissue injury-induced inflammation and hyperalgesia has been characterized by measuring phosphorylation of CREB at serine-133 (CREB Ser133) using a specific antibody. In the unstimulated state, unphosphorylated CREB was observed in most nuclei of spinal neurons except for motor neurons, where only a small portion of neurons were stained. A few dorsal root ganglion (DRG) neurons were also CREB-positive. After a unilateral injection of formalin into the hindpaw, a strong and bilateral phosphorylation of CREB Ser133 was induced, as assessed by both immunohistochemistry and Western blot. PhosphoCREB (pCREB)-positive neurons were found in laminae I, II, V, and X of spinal cord on both sides. CREB phosphorylation was very rapid and reached peak levels within 10 min of formalin treatment, whereas few pCREB-positive neurons were seen in unstimulated spinal cord. The induction of pCREB was predominantly postsynaptic, because only 5% of DRG neurons were labeled after inflammation. In contrast to CREB phosphorylation, the induction of c-Fos expression reached peak levels 2 hr after formalin treatment and c-Fos induction was mainly ipsilateral. Both formalin-evoked CREB phosphorylation and c-Fos expression in the spinal cord were suppressed by pretreatment with the NMDA receptor antagonist MK-801 (3.5 mg/kg, i.p.) or halothane anesthesia.These results suggest that CREB signaling may play a role in the long-term facilitation of spinal cord neurons after hyperalgesia. Furthermore, our results indicate that CREB phosphorylation may be necessary but not sufficient forc-fosinduction.
Opposite Membrane Potential Changes Induced by Glucose Deprivation in Striatal Spiny Neurons and in Large Aspiny Interneurons
Authors: Calabresi Paolo , Ascone Carlos Magarinos , Centonze Diego , Pisani Antonio , Sancesario Giuseppe , D’Angelo Vincenza , Bernardi Giorgio 
Published: April 2018

We have studied the electrophysiological effects of glucose deprivation on morphologically identified striatal neurons recorded from a corticostriatal slice preparation. The large majority of the recorded cells were spiny neurons and responded to aglycemia with a slow membrane depolarization coupled with a reduction of the input resistance. In voltage-clamp experiments aglycemia caused an inward current. This current was associated with a conductance increase and reversed at −40 mV. The aglycemia-induced membrane depolarization was not affected by tetrodotoxin (TTX) or 6-cyano-7-nitroquinoxaline-2,3-dione plus aminophosphonovalerate, antagonists acting respectively on AMPA and NMDA glutamate receptors. Also, the intracellular injection of bis(2-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid, a calcium (Ca2+) chelator, and low Ca2+/high Mg2+-containing solutions failed to reduce this phenomenon. Conversely, it was reduced by lowering external sodium (Na+) concentration.A minority of the recorded cells had the morphological characteristics of large aspiny interneurons and the electrophysiological properties of “long-lasting afterhyperpolarization (LA) cells.” These cells responded to aglycemia with a membrane hyperpolarization/outward current that was coupled with an increased conductance. This current was not altered by TTX, blockers of ATP-dependent potassium (K+) channels, and adenosine A1 receptor antagonists, whereas it was reduced by solutions containing low Ca2+/high Mg2+. This current reversed at −105 mV and was blocked by barium, suggesting the involvement of a K+conductance. We suggest that the opposite membrane responses of striatal neuronal subtypes to glucose deprivation might account for their differential neuronal vulnerability to aglycemia and ischemia.
Amyloid Fibrils Activate Tyrosine Kinase-Dependent Signaling and Superoxide Production in Microglia
Authors: McDonald Douglas R. , Brunden Kurt R. , Landreth Gary E. 
Published: April 2018

Alzheimer’s disease (AD) is a devastating neurological disorder characterized by loss of cognitive skills and progressive dementia. The pathological hallmark of AD is the presence of numerous senile plaques throughout the hippocampus and cerebral cortex associated with degenerating axons, neurofibrillary tangles, and gliosis. The core of the senile plaque primarily is composed of the 39–43 amino acid β-amyloid peptide (Aβ), which forms fibrils of β-pleated sheets. Although considerable genetic evidence implicates Aβ in the pathogenesis of AD, a direct causal link remains to be established.Senile plaques are foci of local inflammatory processes, as evidenced by the presence of numerous activated microglia and acute phase proteins. Aβ has been shown to elicit inflammatory responses in microglia; however, the intracellular events mediating these effects are largely unknown. We report that exposure of microglia and THP1 monocytes to fibrillar Aβ led to time- and dose-dependent increases in protein tyrosine phosphorylation of a population of proteins similar to that elicited by classical immune stimuli such as immune complexes. The tyrosine kinases Lyn, Syk, and FAK were activated on exposure of microglia and THP1 monocytes to Aβ, resulting in the tyrosine kinase-dependent generation of superoxide radicals. The present data support a role for oxidative damage in the pathogenesis of AD, provide an important mechanistic link between Aβ and the generation of reactive oxygen intermediates, and identify molecular targets for therapeutic intervention in AD.
Development of Multisensory Neurons and Multisensory Integration in Cat Superior Colliculus
Authors: Wallace Mark T. , Stein Barry E. 
Published: April 2018

The development of multisensory neurons and multisensory integration was examined in the deep layers of the superior colliculus of kittens ranging in age from 3 to 135 d postnatal (dpn). Despite the high proportion of multisensory neurons in adult animals, no such neurons were found during the first 10 d of postnatal life. Rather, all sensory-responsive neurons were unimodal. The first multisensory neurons (somatosensory–auditory) were found at 12 dpn, and visually responsive multisensory neurons were not found until 20 dpn. Early multisensory neurons responded weakly to sensory stimuli, had long latencies, large receptive fields, and poorly developed response selectivities. Most surprising, however, was their inability to integrate combinations of sensory cues to produce significant response enhancement (or depression), a characteristic feature of the adult. Responses to combinations of sensory cues differed little from responses to their modality-specific components.At 28 dpn an abrupt physiological change was noted. Some multisensory neurons now integrated combinations of cross-modality cues and exhibited significant response enhancements when these cues were spatially coincident and response depressions when the cues were spatially disparate. During the next 2 months the incidence of multisensory neurons, and the proportion of these neurons capable of adult-like multisensory integration, gradually increased. Once multisensory integration appeared in a given neuron, its properties changed little with development. Even the youngest integrating neurons showed superadditive enhancements and spatial characteristics of multisensory integration that were indistinguishable from the adult. Nevertheless, neonatal and adult multisensory neurons differed in the manner in which they integrated temporally asynchronous stimuli, a distribution that may reflect the very different behavioral requirements at different ages. The possible maturational role of corticotectal projections in the abrupt gating of multisensory integration is discussed.
Apomorphine-Susceptible and Apomorphine-Unsusceptible Wistar Rats Differ in Their Susceptibility to Inflammatory and Infectious Diseases: A Study on Rats with Group-Specific Differences in Structure and Reactivity of Hypothalamic–Pituitary–Adrenal Axis
Authors: Kavelaars Annemieke , Heijnen Cobi J. , Ellenbroek Bart , van Loveren Henk , Cools Alexander 
Published: April 2018

Variability in susceptibility to diseases is a well known phenomenon that has been attributed to genetic and environmental factors. At the level of the immune system, the reactivity of two types of T helper cells (Th1 and Th2 cells) plays an important role in determining disease susceptibility. Inflammatory (autoimmune) diseases are stimulated by cytokines produced by Th1 cells. Th2 cytokines stimulate antibody production (e.g., IgE) and eosinophilia as observed in allergic reactions or during parasitic infections. We describe here that the reactivity in a Th1 or a Th2 disease model significantly differs between individual rats that show group-specific differences in reactivity of the hypothalamic–pituitary–adrenal (HPA) axis, as well as in their behavioral responses to stress.We used two outbred lines of Wistar rats, apomorphine-susceptible rats that have a relatively hyperreactive HPA axis (APO-SUS) and apomorphine-unsusceptible rats that have a relatively hyporeactive HPA axis (APO-UNSUS). APO-SUS, but not APO-UNSUS, rats generated a vigorous, Th2-dependent IgE response after infection with the nematodeTrichinella spiralis. In contrast, APO-UNSUS, but not APO-SUS, rats were susceptible for Th1-mediated experimental autoimmune encephalomyelitis. Investigation of cytokine responses of splenocytes revealed that the ratio of mRNA expression for Th1-derived interferon (IFN)-γ and mRNA expression of Th2-derived interleukin-4 (IL-4) was significantly smaller in APO-SUS than in APO-UNSUS rats.In conclusion, individual differences in structure and reactivity of the neuroendocrine system co-occur with group-specific differences in susceptibility to inflammatory and infectious diseases.
Transporters Buffer Synaptically Released Glutamate on a Submillisecond Time Scale
Authors: Diamond Jeffrey S. , Jahr Craig E. 
Published: April 2018

The role of transporters in clearing free glutamate from the synaptic cleft was studied in rat CA1 hippocampal neurons cultured on glial microislands. The time course of free glutamate in the cleft during a synaptic event was estimated by measuring the extent to which the rapidly dissociating AMPA receptor antagonist kynurenate (KYN) was replaced by glutamate during a synaptic response. Dose inhibition of the AMPA receptor EPSC by KYN was less than predicted by the equilibrium affinity of the antagonist, and the rise time of AMPA receptor miniature EPSCs (mEPSCs) was slowed by KYN. Both results indicated that KYN dissociated from AMPA receptors and was replaced by synaptically released transmitter. When transporters were blocked byd,l-threo-β-hydroxyaspartic acid (THA) or Li+, the mEPSC rise time in the presence of KYN was slowed further, indicating that transporters affect the glutamate concentration in the first few hundred microseconds of the synaptic response.The glutamate transient necessary to cause these effects was determined by developing a detailed kinetic model of the AMPA receptor. The model replicated the effects of KYN on the amplitude and rise time of the synaptic responses when driven by glutamate transients that were similar to previous estimates (Clements et al., 1992; Clements, 1996). The effects of THA were replicated by slowing and enlarging the slower phase of the dual component transient by about 20% or by prolonging the single component by almost 40%. Because transport is too slow to account for these effects, it is concluded that transporters buffer glutamate in the synaptic cleft.
Local Release of GABAergic Inhibition in the Motor Cortex Induces Immediate-Early Gene Expression in Indirect Pathway Neurons of the Striatum
Authors: Berretta Sabina , Parthasarathy Hemai B. , Graybiel Ann M. 
Published: April 2018

The neocortex is thought to exert a powerful influence over the functions of the basal ganglia via its projection to the striatum. It is not known, however, whether corticostriatal effects are similar across different types of striatal projection neurons and interneurons or are unique for cells having different functions within striatal networks. To examine this question, we developed a method for focal synchronous activation of the primary motor cortex (MI) of freely moving rats by local release of GABAergic inhibition. With this method, we monitored cortically evoked activation of two immediate-early gene protein products, c-Fos and JunB, in phenotypically identified striatal neurons. We further studied the influence of glutamate receptor antagonists on the stimulated expression of c-Fos, JunB, FosB, and NGFI-A.Local disinhibition of MI elicited remarkably selective induction of c-Fos and JunB in enkephalinergic projection neurons. These indirect pathway neurons, through their projections to the globus pallidus, can inhibit thalamocortical motor circuits. The dynorphin-containing projection neurons of the direct pathway, with opposite effects on the thalamocortical circuits, showed very little induction of c-Fos or JunB. The gene response of striatal interneurons was also highly selective, affecting principally parvalbumin- and NADPH diaphorase-expressing interneurons. The glutamate NMDA receptor antagonist MK-801 strongly reduced the cortically evoked striatal gene expression in all cell types for each gene examined. Because the gene induction that we found followed known corticostriatal somatotopy, was dose-dependent, and was selectively sensitive to glutamate receptor antagonists, we suggest that the differential activation patterns reflect functional specialization of cortical inputs to the direct and indirect pathways of the basal ganglia and functional plasticity within these circuits.
Time Course of Cortical Activations in Implicit and Explicit Recall
Authors: Badgaiyan Rajendra D. , Posner Michael I. 
Published: April 2018

The distinction between implicit and explicit retrieval of learned material is central to recent thinking about the neural systems underlying memory. Word stem completion is one task in which subjects can be instructed either to make a deliberate recall (explicit instruction) or to be told to complete the stem with any appropriate word (implicit instruction). Positron emission tomography (PET) studies have indicated that during implicit retrieval, there is reduced blood flow in right posterior areas, whereas some tasks of explicit retrieval involve frontal and hippocampal activation. However, there is no information about the timing of these activations or how implicit and explicit retrieval might be related.We used word stem completion tasks similar to those used in the PET studies, but used high-density electrical recording designed to allow localization of the regions involved in the tasks and to provide temporal information. We found reduced activity for primed words in right posterior cortex corresponding to previous PET results. The reduction occurred within the first 200 msec after input, suggesting early interaction with the information stored in this area. Similar reductions observed during explicit recall of the previously presented words indicate that priming is similar under implicit and explicit conditions. In addition, when priming was not an adequate basis for response, then frontal areas were active. Retrieval of unprimed words under implicit instruction elicited right frontal activation, whereas explicit retrieval activated frontal areas bilaterally. Left frontal and hippocampal activations appear to occur only when the retrieval involved use of the words from the list studied previously.
Slow Kinetics of Miniature IPSCs during Early Postnatal Development in Granule Cells of the Dentate Gyrus
Authors: Hollrigel Greg S. , Soltesz Ivan 
Published: April 2018

Whole-cell patch-clamp recordings were used to investigate the properties of GABAAreceptor-mediated postsynaptic currents during development in dentate gyrus granule cells from neonatal [postnatal day 0 (P0)] to adult rats in brain slices. The frequency of miniature IPSCs (mIPSCs) was low at birth and increased progressively with age. The mIPSCs of all ages could be satisfactorily fitted with the sum of a single exponential rise and single exponential decay. From P0 to P14, both the rise time and the decay time constants were significantly longer than in the adult. The mIPSC rise and decay kinetics did not change during the first 2 postnatal weeks, but during the third week the kinetics sped up and by P21 attained adult values. In contrast, the amplitude of the mIPSCs did not change during development. The synaptic GABAAreceptors in immature and adult cells showed differential sensitivity to modulators. The subunit-specific benzodiazepine agonist zolpidem increased the decay time constant of the IPSCs of immature granule cells with a reduced potency compared with the adult. Furthermore, zinc decreased the amplitude and decay time constant of mIPSCs from developing granule cells, whereas it had no effect on mIPSCs in adult neurons.The results reveal for the first time that until the end of the second postnatal week the synaptic GABAAreceptor-mediated currents in dentate granule cells display slower rise and decay kinetics but similar amplitudes compared with adult, resulting in a net decrease in synaptic charge transfer during development.
α-Conotoxin MII Blocks Nicotine-Stimulated Dopamine Release in Rat Striatal Synaptosomes
Authors: Kulak Jennifer M. , Nguyen Thu A. , Olivera Baldomero M. , McIntosh J. Michael 
Published: April 2018

Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) can induce the release of neurotransmitters such as dopamine and norepinephrine in the CNS. Accumulating evidence suggests that distinct nAChR subtypes are involved; however, it has been difficult to determine the subunit composition of these receptors, in part because of the lack of a sufficient variety of selective nAChR ligands. We present experimental data that at least two different nAChR complexes are involved in dopamine release, one of which has an α3/β2 subunit interface.The recently discovered peptide α-conotoxin MII is a potent and selective inhibitor of rat nAChRs containing an interface formed by α3 and β2 subunits. We used this peptide to examine nicotine-stimulated release of dopamine from rat striatal synaptosomes and of norepinephrine from hippocampal synaptosomes. MII (100 nm) blocks 34–49% of the nicotine-stimulated dopamine release, but not dopamine release evoked by elevated [K+]. Furthermore, two peptides structurally related to α-conotoxin MII, namely α-conotoxin MI (selective for α1β1γδ nAChRs) and α-conotoxin ImI (selective for α7-containing nAChRs), have no effect on nicotine-stimulated dopamine release. The results indicate that one third to half of the dopamine release in the striatal preparation is mediated by nAChRs with an α3/β2 subunit interface. In contrast, ≤10% of nicotine-stimulated release of norepinephrine from hippocampal synaptosomes is modulated by nAChRs with α3/β2 subunit interfaces.
Nucleus Reuniens Thalami Modulates Activity in Hippocampal Field CA1 through Excitatory and Inhibitory Mechanisms
Authors: Dolleman-Van der Weel M. J. , Lopes da Silva F. H. , Witter M. P. 
Published: April 2018

The nucleus reuniens thalami (RE) originates dense projections to CA1, forming asymmetrical synapses on spines (50%) and dendrites (50%). The hypothesis that RE input modulates transmission in CA1 through excitation of both pyramidal cells and interneurons was tested using electrophysiological methods in the anesthetized rat. The RE–CA1 afferents were selectively stimulated at their origin; evoked field potentials and unit activity were recorded in CA1. RE-evoked depth profiles showed a prominent negative deflection in the stratum lacunosum-moleculare and a positive one in the stratum radiatum. The lacunosum-moleculare sink–radiatum source configuration is compatible with RE-elicited depolarization of apical dendrites of pyramidal cells. Despite a consistent and robust paired pulse facilitation of RE-evoked field potentials, population spikes in the stratum pyramidale were not detected at any tested condition. This indicates the inability of RE–CA1 input to discharge pyramidal cells. However, stimulation of RE-elicited spiking of extracellularly recorded units in strata oriens/alveus and distal radiatum, indicative of the activation of local interneurons. Thus, RE seems to modulate transmission in CA1 through a (subthreshold) depolarization of pyramidal cells and a suprathreshold excitation of putative inhibitory oriens/alveus and radiatum interneurons.RE-evoked monosynaptic or disynaptic field potentials were associated with stimulation of rostral or caudal RE, respectively. Anatomically, a projection from caudal to rostral RE was demonstrated that can account for the disynaptic RE–CA1 input. Because caudal RE receives input from the hippocampus via the subiculum, we propose the existence of a closed RE–hippocampal circuit that allows RE to modulate the activity in CA1, depending on hippocampal output.
Murine Astrocytes Express a Functional Chemokine Receptor
Authors: Tanabe Shigeyuki , Heesen Michael , Berman Michael A. , Fischer Michael B. , Yoshizawa Izumi , Luo Yi , Dorf Martin E. 
Published: April 2018

Elevated levels of chemokines have been observed in various diseases of the CNS. Little is known, however, about how these chemokines affect parenchymal cells of the CNS. The current studies examine astrocyte chemotaxis to the mouse chemokine macrophage inflammatory protein-1α (MIP-1α). Murine astrocytes demonstrate directed migration along a chemical gradient in response to 10−10–10−8mMIP-1α. Peak chemotactic responses are noted at 10−9m. MIP-1α-induced astrocyte migration is specifically inhibitable with pertussis toxin, suggesting a role for Gαiproteins in the signaling process.RT-PCR andin situhybridization were used to identify expression of the murine CCR1 MIP-1α receptor on astrocytes. Astrocytes contain mRNA for CCR1, but messages for CCR4 and the orphan chemokine receptor MIP-1αR-like#1 were not detected. The combined results suggest that a functional chemokine receptor is expressed on resident cells of the CNS. We speculate that the interactions of chemokines with astrocytes are involved in inflammatory reactions of the CNS.