bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interneurons Containing Calretinin Are Specialized to Control Other Interneurons in the Rat Hippocampus
Authors: Gulyás Attila I. , Hájos Norbert , Freund Tamás F. 
Published: April 2018

Spine-free calretinin-immunoreactive (CR-IR) interneurons form a subpopulation of GABAergic cells in the rat hippocampus. A characteristic feature of these cells—located in all areas and layers—is the frequent dendro-dendritic and axo-dendritic contacts they form with each other. In this study we examined in detail the connectivity of these neurons by reconstructing their dendritic and axonal arbor and by identifying their postsynaptic targets.Radially running dendrites of CR-IR cells, located in different layers, intermingled into long braids. An average cell was in contact with dendrites of three to seven other CR-IR cells. Reconstruction of the dendritic trees from six consecutive sections demonstrated that at least 15 cells may participate in a dendro-dendritically connected cluster. Electron microscopical examination revealed that regularly spaced zonula adherentia connect the touching dendrites.The postsynaptic targets of CR-IR neurons have been examined using postembedding immunogold staining for GABA. CR-containing GABA-immunoreactive axons of local origin formed multiple symmetrical synaptic contacts (two to five) exclusively on GABAergic dendrites (CR-negative as well as CR-positive). Two to 10 CR-IR axons may converge onto a single CR-IR neuron, often from cells belonging to the same dendro-dendritically connected cluster. Using double immunocytochemistry, CR-IR cells were shown to heavily innervate calbindin D28k-containing interneurons and VIP-containing basket cells but avoided the parvalbumin-containing basket and axo-axonic cells.The unique connectivity of CR-IR cells may enable them to play a crucial role in the generation of synchronous, rhythmic hippocampal activity by controlling other interneurons terminating on different dendritic and somatic compartments of principal cells.
Nucleus-Specific Expression of GABAAReceptor Subunit mRNAs in Monkey Thalamus
Authors: Huntsman M. M. , Leggio M. G. , Jones E. G. 
Published: April 2018

Expression of 10 GABAAreceptor subunit genes was examined in monkey thalamus byin situhybridization using cRNA probes specific for α1, α2, α3, α4, α5, β1, β2, β3, γ1, and γ2subunit mRNAs. These displayed unique hybridization patterns with significant differences from rodents. α1, β2, and γ2transcripts were expressed at high levels in all dorsal thalamic nuclei, but expression was significantly higher in sensory relay nuclei—especially the dorsal lateral geniculate nucleus. Other transcripts showed nucleus-specific differences in levels of expression and in the range expressed. α5and α4subunit transcripts were expressed in all nuclei except the intralaminar nuclei. Levels of α2, α3, β1, β3, and γ1expression were very low, except in intralaminar nuclei. In the reticular nucleus, most subunit transcripts were not expressed, and only γ2transcripts were consistently detected at modest levels. Thalamic GABAAreceptors may be assembled from nucleus-specific groupings of subunit polypeptides.
Identification and Characterization of a 47 Base Pair Activity-Dependent Enhancer of the Rat Nicotinic Acetylcholine Receptor δ-Subunit Promoter
Authors: Walke Wade , Xiao Guozhi , Goldman Daniel 
Published: April 2018

Nicotinic acetylcholine receptor (nAChR) genes are regulated by muscle electrical activity. E-box sequences found in their promoters are necessary for this regulation. However, many muscle genes contain E-boxes, yet are not regulated by muscle depolarization. This suggests that other elements are necessary, perhaps working in conjunction with E-boxes, to confer depolarization-dependent control onto promoter activity. We have used direct DNA injection into muscle as anin vivoassay to identify and characterize these additional elements. Mutagenesis and expression assays identified multiple elements within the first 81 base pairs (bp) of the nAChR δ-subunit promoter that contribute to its regulation by muscle electrical activity. Within this 81 bp sequence, two regions of DNA were identified that were capable of conferring activity-dependent regulation onto a heterologous promoter. The stronger of these two putative enhancers was characterized further. It is a 47 bp sequence that contains an E-box along with sequences similar to the SV40 core enhancer and an SP1 site. Site-directed mutagenesis identified residues within each of these sequences that were necessary for enhancer activity. Furthermore, methylation interference DNA footprinting assays showed increased nuclear protein binding to sequences within both these enhancers after muscle denervation, and this pattern of binding was very similar to that observed with nuclear protein isolated from myotube extracts. These latter results suggest that similar mechanisms may mediate increased nAChR expression during muscle development and after muscle denervation.
Synchronous GABA-Mediated Potentials and Epileptiform Discharges in the Rat Limbic SystemIn Vitro
Authors: Avoli Massimo , Barbarosie Michaela , Lücke Anne , Nagao Takeki , Lopantsev Valeri , Köhling Rüdiger 
Published: April 2018

Application of 4-aminopyridine (4AP, 50 μm) to combined slices of adult rat hippocampus–entorhinal cortex-induced ictal and interictal epileptiform discharges, as well as slow field potentials that were abolished by the μ-opioid agonist [d-Ala2,N-Me-Phe4,Gly-ol5] enkephalin (DAGO, 10 μm) or the GABAAreceptor antagonist bicuculline methiodide (BMI, 10 μm); hence, they represented synchronous GABA-mediated potentials. Ictal discharges originated in the entorhinal cortex and propagated to the hippocampus, whereas interictal activity of CA3 origin was usually recorded in the hippocampus. The GABA-mediated potentials had no fixed site of origin or modality of propagation; they closely preceded (0.2–5 sec) and thus appeared to initiate ictal discharges. Only ictal discharges were blocked by the antagonist of the NMDA receptor 3,3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP, 10 μm), whereas the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 μm) abolished all epileptiform activities. The GABA-mediated potentials continued to occur synchronously in all regions even after concomitant application of CNQX and CPP. [K+]oelevations were recorded in the entorhinal cortex during the ictal discharge (peak values = 13.9 ± 0.9 mm) and the synchronous GABA-mediated potentials (peak values = 4.2 ± 0.1 mm); the latter increases were presumably attributable to postsynaptic GABAA-receptor activation because they were abolished by DAGO or BMI. Their role in initiating ictal activity was demonstrated by using DAGO, which abolished both GABA-mediated synchronous potentials and ictal discharges. These data indicate that NMDA-mediated ictal discharges induced by 4AP originate in the entorhinal cortex; such a conclusion is in line with clinical evidence obtained in temporal lobe epilepsy patients. 4AP also induces GABA-mediated potentials that spread within the limbic system when excitatory transmission is blocked and may play a role in initiating ictal discharge by increasing [K+]o.
A Dynamic Network Simulation of the Nematode Tap Withdrawal Circuit: Predictions Concerning Synaptic Function Using Behavioral Criteria
Authors: Wicks Stephen R. , Roehrig Chris J. , Rankin Catharine H. 
Published: April 2018

The nematode tap withdrawal reflex demonstrates several forms of behavioral plasticity. Although the neural connectivity that supports this behavior is identified (Integration of mechanosensory stimuli inCaenorhabditis elegans, Wicks and Rankin, 1995, J Neurosci 15:2434–2444), the neurotransmitter phenotypes, and hence whether the synapses in the circuit are excitatory or inhibitory, remain uncharacterized. Here we use a novel strategy to predict the polarity configuration, i.e., the array of excitatory and inhibitory connections, of the nematode tap withdrawal circuit using an anatomically and physiologically justifiable dynamic network simulation of that circuit. The output of the modeled circuit was optimized to the behavior of animals, which possessed circuits altered by surgical ablation by exhaustively enumerating an array of synaptic signs that constituted the modeled circuit. All possible polarity configurations were then compared, and a statistical analysis was used to determine whether, for a given synaptic class, a particular polarity was associated with a good fit to behavioral data. The results from four related experiments were used to predict the polarities of seven of the nine cell classes of the tap withdrawal circuit. In addition, the model was used to assess possible roles for two novel mechanosensory integration neurons: DVA and PVD.
Functional Mapping of Human Learning: A Positron Emission Tomography Activation Study of Eyeblink Conditioning
Authors: Blaxton Teresa A. , Zeffiro Thomas A. , Gabrieli John D. E. , Bookheimer Susan Y. , Carrillo Maria C. , Theodore William H. , Disterhoft John F. 
Published: April 2018

Regional cerebral blood flow (rCBF) was measured using positron emission tomography during eyeblink conditioning in young adults. Subjects were scanned in three experimental conditions: delay conditioning, in which binaural tones preceded air puffs to the right eye by 400 msec; pseudoconditioning, in which presentations of tone and air puff stimuli were not correlated in time; and fixation rest, which served as a baseline control. Compared with fixation, pseudoconditioning produced rCBF increases in frontal and temporal cortex, basal ganglia, left hippocampal formation, and pons. Learning-specific activations were observed in conditioning as compared with pseudoconditioning in bilateral frontal cortex, left thalamus, right medial hippocampal formation, left lingual gyrus, pons, and bilateral cerebellum; decreases in rCBF were observed for bilateral temporal cortex, and in the right hemisphere in putamen, cerebellum, and the lateral aspect of hippocampal formation. Blood flow increased as the level of learning increased in the left hemisphere in caudate, hippocampal formation, fusiform gyrus, and cerebellum, and in right temporal cortex and pons. In contrast, activation in left frontal cortex decreased as learning increased. These functional imaging results implicate many of the same structures identified by previous lesion and recording studies of eyeblink conditioning in animals and humans and suggest that the same brain regions in animals and humans mediate multiple forms of associative learning that give meaning to a previously neutral stimulus.
Laminar Localization, Morphology, and Physiological Properties of Pyramidal Neurons that Have the Low-Threshold Calcium Current in the Guinea-Pig Medial Frontal Cortex
Authors: de la Peña Elvira , Geijo-Barrientos Emilio 
Published: April 2018

One of the several types of ionic currents present in central neurons is the low-threshold, or T-type calcium current (LTCC). This current is responsible for the firing of low-threshold calcium spikes (LTS) and participates in the generation of rhythmic activity and bursts of action potentials in several brain nuclei. We have studied the distribution and properties of pyramidal neurons recorded from the guinea-pig medial frontal cortex that have this calcium current. Pyramidal neurons were recorded in anin vitroslice preparation using either current clamp or single-electrode voltage-clamp recording. Pyramidal neurons that generated LTS or had the LTCC were found only between 500 mm from the pial surface and the white matter (approximately layers V/VI) and were absent in more superficial layers. All pyramidal neurons that fired LTS or had the LTCC were characterized as regular spiking and had some important morphological and physiological differences from the rest of the pyramidal neurons studied. This group of neurons had shorter and less complex apical dendritic arbors, fired action potentials of lower amplitude and longer duration, and were the only type of pyramidal neurons able to generate bursts of action potentials. In addition, the inhibitory synaptic potentials elicited by stimulation of layer I were more powerful in this group of neurons. This research provides new evidence for the presence of the LTCC in subsets of cortical pyramidal neurons, which have specific and well defined morphological and physiological properties.
Stoichiometry of a Recombinant GABAAReceptor
Authors: Chang Yongchang , Wang Ruoping , Barot Sonal , Weiss David S. 
Published: April 2018

GABA is the main inhibitory neurotransmitter in the mammalian brain. The postsynaptic GABAAreceptor/pore complex is presumed to be a pentamer typically composed of a combination of α, β, and γ subunits, although the stoichiometry remains controversial. We probed the stoichiometry of the GABAAreceptor by site-directed mutagenesis of a conserved leucine (to serine) in the putative second membrane-spanning domain of the rat α1(αL263S), β2(αL259S), and γ2(αL274S) subunit isoforms. Coexpression of wild-type and mutant subunits of each class (e.g., α and αL263S), along with their wild-type counterparts (e.g., β and γ), inXenopus laevisoocytes resulted in mixed populations of receptors with distinct GABA sensitivities. This is consistent with the interpretation that the leucine mutation increased the GABA sensitivity in proportion to the number of incorporated mutant subunits. The apparent number of incorporated subunits for each class (α, β, and γ) could then be determined from the number of components comprising the compound GABA dose–response relationships. Using this approach, we conclude that the recombinant α1β2γ2 GABAAreceptor is a pentamer composed of two α subunits, two β subunits, and one γ subunit.
Evidence for Differential Control of Posterior Hypothalamic, Supramammillary, and Medial Mammillary Theta-Related Cellular Discharge by Ascending and Descending Pathways
Authors: Kirk Ian J. , Oddie Scott D. , Konopacki Jan , Bland Brian H. 
Published: April 2018

Single-unit discharge was recorded from cells in the posterior hypothalamic nucleus (PH), supramammillary nucleus (SuM), and medial mammillary nucleus (MM) during hippocampal theta (θ) elicited by stimulation of the reticular nucleus pontis oralis (RPO). In agreement with previously published work, θ-related cells in the PH (12 cells) were all classified as tonic θ-ON (increased tonic discharge rate during hippocampal θ), whereas those in the SuM (9 cells) and MM (15 cells) were all classified as phasic θ-ON (rhythmic discharge, in phase with ongoing θ). The effect of RPO stimulation on cell discharge was tested after hippocampal θ was abolished by infusion of procaine into the medial septum/vertical limb of the diagonal band. The RPO-elicited discharge patterns of all PH tonic θ-ON cells and all SuM phasic θ-ON cells survived septal procaine infusion. Further, the discharge rate of PH cells and the frequency of burst discharge of SuM cells during RPO stimulation both increased after the infusion. In contrast, septal procaine infusion abolished the RPO-elicited rhythmic discharge pattern in MM phasic θ-ON cells and attenuated their discharge rates. These results indicate that the PH and SuM form parts of an ascending system mediating hippocampal θ, whereas the MM receives (and perhaps relays to other parts of the limbic system) rhythmic input descending from the septo-hippocampal system. In addition, PH and SuM receive descending inputs that limit the discharge rates of their θ-related cells during hippocampal θ.
Emotional and Behavioral Correlates of Mediodorsal Thalamic Neurons during Associative Learning in Rats
Authors: Oyoshi Tatsuki , Nishijo Hisao , Asakura Tetsuhiko , Takamura Yusaku , Ono Taketoshi 
Published: April 2018

Neuronal activity was recorded from the mediodorsal thalamic nucleus (MD) of behaving rats that were trained to lick a protruding spout just after a conditioned stimulus to obtain reward or to avoid shock. Conditioned stimuli included both elemental (auditory or visual stimuli) and configural (simultaneous presentation of auditory and visual stimuli predicting reward outcome opposite that predicted by each stimulus presented alone) stimuli. Of 122 MD neurons responding during the task, the activity of 13 increased just before licking only during the task, but not before spontaneous licking during the intertrial interval (conditioned behavior related). These conditioned behavior-related neurons were located mainly in the lateral MD, which has intimate anatomical connections with motor-related areas such as anterior cingulate and striatum. The activity of the other 109 neurons was related to conditioned stimulation (conditioned stimulus related). Most of these neurons responded differentially to both elemental and configural stimuli in terms of reward contingency, and also changed their responses during extinction and relearning trials. Conditioned stimulus-related neurons with latencies <300 msec were located mainly in the rostromedial MD, which receives afferents from the basolateral nucleus of the amygdala in which sensory information from various sources converge. Furthermore, most differential neurons that were tested responded during the delay period in a reward task in which a delay was imposed between the conditioned stimulus and reward delivery. The present results, along with previous anatomical studies, suggest the existence of two limbic circuits: anterior cingulate–striatum–lateral MD (motor) and amygdala–medial MD–orbital prefrontal cortex (short-term memory/emotion).
A Missense Mutation in the Sodium Channel Scn8a Is Responsible for Cerebellar Ataxia in the Mouse Mutantjolting
Authors: Kohrman David C. , Smith Marianne R. , Goldin Alan L. , Harris John , Meisler Miriam H. 
Published: April 2018

The voltage-gated sodium channel Scn8a is broadly distributed in brain and spinal cord. We have identified a missense mutation in Scn8a that is associated with cerebellar ataxia in thejoltingmutant, a mild allele of the “motor endplate disease” locus. Thejoltingmutation results in substitution of Thr for an evolutionarily conserved Ala residue in the cytoplasmic S4–S5 linker of domain III. Introduction of the corresponding mutation into the rat brain IIA sodium channel shifted the voltage dependence of activation by 14 mV in the depolarizing direction, without affecting the kinetics of fast inactivation or recovery from inactivation. A shift in the threshold of the Scn8a channel could account for the reduced spontaneous activity of Purkinje cells, reduced inhibitory output from the cerebellum, and loss of motor control observed injoltingmice.
Modulation of High Voltage-Activated Calcium Channels by Somatostatin in Acutely Isolated Rat Amygdaloid Neurons
Authors: Viana Félix , Hille Bertil 
Published: April 2018

We investigated actions of somatostatin (Som) on voltage-gated calcium channels in acutely isolated rat amygdaloid neurons. Somatostatin caused a dose-dependent inhibition of the high voltage-activated (HVA) Ca2+current, with little or no effect on the low voltage-activated (LVA) current. Nifedipine (2–10 μm) reduced the peak current by ∼15% without reducing inhibition of current by Som significantly, ruling out L-type channels as the target of modulation. The modulation appears to involve N- and P/Q-type calcium channels. After pretreatment with ω-conotoxin-GVIA (ω-CgTx) or ω-agatoxin-IVA, the inhibition was reduced but not abolished, whereas the combined application of both toxins nearly abolished the modulation. The Som analog BIM-23060 mimicked the effects of Som, whereas BIM-23058 had no effect, implicating Som type-2 receptors (SSTR-2). The inhibition was voltage-dependent, being minimal for small depolarizations, and was often accompanied by a slowing of the activation time course. Strong depolarizing prepulses partially relieved the inhibition and restored the time course of activation. Intracellular dialysis with GTPγS led to spontaneous inhibition and a slowing of the current like that with Som and occluded the effects of the peptide. Dialysis with GDPβS also diminished the inhibition. A short preincubation with 50 μmof the alkylating agentN-ethylmaleimide (NEM) prevented the action of somatostatin. These results suggest a role for NEM-sensitive G-proteins in the Som inhibition. Application of 8-CPT-cAMP and IBMX did not mimic or prevent the effects of Som.
Ventromedial Preoptic Prostaglandin E2 Activates Fever-Producing Autonomic Pathways
Authors: Scammell Thomas E. , Elmquist Joel K. , Griffin John D. , Saper Clifford B. 
Published: April 2018

Fever is thought to be initiated by pyrogenic cytokines inducing the production of prostaglandin E2 (PGE2) in the preoptic area (POA); PGE2 may act as a paracrine mediator that stimulates the neural pathways that raise body temperature. This essential role for prostaglandins in fever first was proposed 25 years ago, but the specific preoptic cell groups at which PGE2 acts and the pathways through which fever is produced remain poorly understood. To better define the role of preoptic PGE2 in fever, we developed a new method for combining acute brain injections with Fos immunohistochemistry. We microinjected a threshold dose of PGE2 to construct an anatomically detailed map of fever-producing preoptic sites. The most pyrogenic preoptic sites were clustered along the ventromedial aspect of the POA, surrounding and just anterior to the organum vasculosum of the lamina terminalis. We then used Fos immunohistochemistry to identify the pattern of neural activation induced by fever-producing preoptic injections of PGE2 and compared it with the Fos pattern seen after systemic immune stimulation. PGE2 fever was accompanied by Fos induction in the ventromedial POA and the parvicellular subnuclei of the paraventricular nucleus of the hypothalamus (PVH). In contrast to the Fos pattern seen after intravenous lipopolysaccharide administration, PGE2 injection did not induce Fos in the circumventricular organs or the magnocellular subnuclei of the PVH. These observations establish a potential site of PGE2 action during fever and help define candidate pathways through which fever occurs.
Aging Changes in Voltage-Gated Calcium Currents in Hippocampal CA1 Neurons
Authors: Campbell Lee W. , Hao Su-Yang , Thibault Olivier , Blalock Eric M. , Landfield Philip W. 
Published: April 2018

Previous current-clamp studies in rat hippocampal slice CA1 neurons have found aging-related increases in long-lasting calcium (Ca)-dependent and Ca-mediated potentials. These changes could reflect an increase in Ca influx through voltage-gated Ca channels but also could reflect a change in potassium currents. Moreover, if altered Ca influx is involved, it is unclear whether it arises from generally increased Ca channel activity, lower threshold, or reduced inactivation. To analyze the basis for altered Ca potentials, whole-cell voltage-clamp studies of CA1 hippocampal neurons were performed in nondissociated hippocampal slices of adult (3- to 5-month-old) and aged (25- to 26-month-old) rats. An aging-related increase was found in high-threshold Ca and barium (Ba) currents, particularly in the less variable, slowly inactivating (late) current at the end of a depolarization step. Input resistance of neurons did not differ between age groups. In steady-state inactivation and repetitive-pulse protocols, inactivation of Ca and Ba currents was not reduced and, in some cases, was slightly greater in aged neurons, apparently because of larger inward current. The current blocked by nimodipine was greater in aged neurons, indicating that some of the aging increase was in L-type currents. These results indicate that whole-cell Ca currents are increased with aging in CA1 neurons, apparently attributable to greater channel activity rather than to reduced inactivation. The elevated Ca influx seems likely to play a role in impaired function and enhanced susceptibility to neurotoxic influences.