bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the Human Medial Frontal Cortex in Task Switching: A Combined fMRI and TMS Study
Authors: Rushworth M.F.S. , Hadland K. A. , Paus T. , Sipila P. K.
Published: December 2017

We used event-related functional magnetic resonance imaging (fMRI) to measure brain activity when subjects were performing identical tasks in the context of either a task-set switch or a continuation of earlier performance. The context, i.e., switching or staying with the current task, influenced medial frontal cortical activation; the medial frontal cortex is transiently activated at the time that subjects switch from one way of performing a task to another. Two types of task-set-switching paradigms were investigated. In the response-switching (RS) paradigm, subjects switched between different rules for response selection and had to choose between competing responses. In the visual-switching (VS) paradigm, subjects switched between different rules for stimulus selection and had to choose between competing visual stimuli. The type of conflict, sensory (VS) or motor (RS), involved in switching was critical in determining medial frontal activation. Switching in the RS paradigm was associated with clear blood-oxygenation-level-dependent signal increases (“activations”) in three medial frontal areas: the rostral cingulate zone, the caudal cingulate zone, and the presupplementary motor area (pre-SMA). Switching in the VS task was associated with definite activation in just one medial frontal area, a region on the border between the pre-SMA and the SMA. Subsequent to the fMRI session, we used MRI-guided frameless stereotaxic procedures and repetitive transcranial magnetic stimulation (rTMS) to test the importance of the medial frontal activations for task switching. Applying rTMS over the pre-SMA disrupted subsequent RS performance but only when it was applied in the context of a switch. This result shows, first, that the pre-SMA is essential for task switching and second that its essential role is transient and limited to just the time of behavioral switching. The results are consistent with a role for the pre-SMA in selecting between response sets at a superordinate level rather than in selecting individual responses. The effect of the rTMS was not simply due to the tactile and auditory artifacts associated with each pulse; rTMS over several control regions did not selectively disrupt switching. Applying rTMS over the SMA/pre-SMA area activated in the VS paradigm did not disrupt switching. This result, first, confirms the limited importance of the medial frontal cortex for sensory attentional switching. Second, the VS rTMS results suggest that just because an area is activated in two paradigms does not mean that it plays the same essentialrole in both cases.
Selective Modulation of Tonic and Phasic Inhibitions in Dentate Gyrus Granule Cells
Authors: Nusser Zoltan , Mody Istvan
Published: December 2017

In some nerve cells, activation of GABAA receptors by GABA results in phasic and tonic conductances. Transient activation of synaptic receptors generates phasic inhibition, whereas tonic inhibition originates from GABA acting on extrasynaptic receptors, like in cerebellar granule cells, where it is thought to result from the activation of extrasynaptic GABAA receptors with a specific subunit composition (α6βxδ). Here we show that in adult rat hippocampal slices, extracellular GABA levels are sufficiently high to generate a powerful tonic inhibition in δ subunit–expressing dentate gyrus granule cells. In these cells, the mean tonic current is approximately four times larger than that produced by spontaneous synaptic currents occurring at a frequency of ∼10 Hz. Antagonizing the GABA transporter GAT-1 with NO-711 (2.5 μM) selectively enhanced tonic inhibition by 330% without affecting the phasic component. In contrast, by prolonging the decay of inhibitory postsynaptic currents (IPSCs), the benzodiazepine agonist zolpidem (0.5 μM) augmented phasic inhibition by 66%, while leaving the mean tonic conductance unchanged. These results demonstrate that a tonic GABAA receptor–mediated conductance can be recorded from dentate gyrus granule cells of adult rats in in vitro slice preparations. Furthermore, we have identified distinct pharmacological tools to selectively modify tonic and phasic inhibitions, allowing future studies to investigate their specific roles in neuronal function.
Role of Arcuate Frontal Cortex of Monkeys in Smooth Pursuit Eye Movements. II. Relation to Vector Averaging Pursuit
Authors: Tanaka Masaki , Lisberger Stephen G.
Published: December 2017

When monkeys view two targets moving in different directions and are given no cues about which to track, the initiation of smooth pursuit is a vector average of the response evoked by each target singly. In the present experiments, double-target stimuli consisted of two identical targets moving in opposite directions along the preferred axis of pursuit for the neuron under study for 200 ms, followed by the continued motion for 800 ms of one target chosen randomly. Among the neurons that showed directional modulation during pursuit, recordings revealed three groups. The majority (32/60) showed responses that were intermediate to, and statistically different from, the responses to either target presented alone. Another large group (22/60) showed activity that was statistically indistinguishable from the response to the target moving in the preferred ( n = 15) or opposite ( n = 7) direction of the neuron under study. The minority (6/60) showed statistically higher firing during averaging pursuit than for either target presented singly. We conclude that many pursuit-related neurons in the frontal pursuit area (FPA) carry signals related to the motor output during averaging pursuit, while others encode the motion of one target or the other. Microstimulation with 200-ms trains of pulses at 50 μA while monkeys performed the same double-target tasks biased the averaging eye velocity in the direction of evoked eye movements during fixation. The effect of stimulation was compared with the predictions of three different models that placed the site of vector averaging upstream from, at, or downstream from the sites where the FPA regulates the gain of pursuit. The data were most consistent with a site for pursuit averaging downstream from the gain control, both for double-target stimuli that presented motion in opposite directions and in orthogonal directions. Thus the recording and stimulation data suggest that the FPA is both downstream and upstream from the sites of vector averaging. We resolve this paradox by suggesting that the site of averaging is really downstream from the site of gain control, while feedback of the eye velocity command from the brain stem and/or cerebellum is responsible for the firing of FPA neurons in relation to the averaged eye velocity. We suggest that eye velocity feedback allows FPA neurons to continue firing during accurate tracking, when image motion is small, and that the persistent output from the FPA is necessary to keep the internal gain of pursuit high and permit accurate pursuit.
Protein Synthesis Is Required for the Enhancement of Long-Term Potentiation and Long-Term Memory by Spaced Training
Authors: Scharf Matthew T. , Woo Newton H. , Lattal K. Matthew , Young Jennie Z. , Nguyen Peter V. , Abel Ted
Published: December 2017

Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.
Prefrontal Cortex Acetylcholine Release, EEG Slow Waves, and Spindles Are Modulated by M2 Autoreceptors in C57BL/6J Mouse
Authors: Douglas Christopher L. , Baghdoyan Helen A. , Lydic Ralph
Published: December 2017

Recent evidence suggests that muscarinic cholinergic receptors of the M2 subtype serve as autoreceptors modulating acetylcholine (ACh) release in prefrontal cortex. The potential contribution of M2 autoreceptors to excitability control of prefrontal cortex has not been investigated. The present study tested the hypothesis that M2 autoreceptors contribute to activation of the cortical electroencephalogram (EEG) in C57BL/6J (B6) mouse. This hypothesis was evaluated using microdialysis delivery of the muscarinic antagonist AF-DX116 (3 nM) while simultaneously quantifying ACh release in prefrontal cortex, number of 7- to 14-Hz EEG spindles, and EEG power spectral density. Mean ACh release in prefrontal cortex was significantly increased ( P < 0.0002) by AF-DX116. The number of 7- to 14-Hz EEG spindles caused by halothane anesthesia was significantly decreased ( P < 0.0001) by dialysis delivery of AF-DX116 to prefrontal cortex. The cholinergically induced cortical activation was characterized by a significant ( P < 0.05) decrease in slow-wave EEG power. Together, these neurochemical and EEG data support the conclusion that M2 autoreceptor enhancement of ACh release in prefrontal cortex activates EEG in contralateral prefrontal cortex of B6 mouse. EEG slow-wave activity varies across mouse strains, and the results encourage comparative phenotyping of cortical ACh release and EEG in additional mouse models.
Cyclooxygenase-2 Regulates Prostaglandin E2Signaling in Hippocampal Long-Term Synaptic Plasticity
Authors: Chen Chu , Magee Jeffery C. , Bazan Nicolas G.
Published: December 2017

The functional significance of cyclooxygenases (COX-1 and -2), the key enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in brain, is unclear, although they have been implicated in cellular functions and in some neurologic disorders, including stroke, epilepsy, and Alzheimer's disease. Recent evidence that COX-2 is expressed in postsynaptic dendritic spines (which are specialized structures involved in synaptic signaling) and is regulated by synaptic activity implies participation of COX-2 in neuronal plasticity. However, direct evidence is lacking. Here we demonstrate that selective COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating dendritic action potential-associated Ca2+influx, and long-term potentiation (LTP) induction in hippocampal dentate granule neurons, while a COX-1 inhibitor is ineffective. All of these actions were effectively reversed by exogenous application of PGE2but not of PGD2or PGF2α. Our results indicate that COX-2-generated PGE2regulates membrane excitability and long-term synaptic plasticity in hippocampal perforant path-dentate gyrus synapses.
Long-Term Modulation of Respiratory Network Activity Following Anoxia In Vitro
Authors: Blitz Dawn M. , Ramirez Jan-Marino
Published: December 2017

Neural networks that produce rhythmic behaviors require flexibility to respond to changes in the internal and external state of the animal. It is important to not only understand how a network responds during such perturbations but also how the network recovers. For example, the respiratory network needs to respond to and recover from temporary changes in oxygen level that can occur during sleep, exercise, and respiratory disorders. During a temporary decrease in oxygen level, there is an increase in respiratory frequency followed by a depression that can lead to complete apnea. Here we used a mouse brain stem slice preparation as a model system to examine the recovery of respiratory network activity after brief episodes of anoxia. We found the respiratory network recovers from a single anoxic episode with a transient increase in fictive respiratory frequency. Although repetitive anoxia does not elicit a greater frequency increase, it does elicit a longer lasting frequency increase persisting ≤90 min. Thus there is a centrally mediated long-lasting influence on the respiratory network elicited by decreased oxygen levels. This modulation occurs as a prolonged facilitation of fictive respiratory frequency after brief repetitive but not single anoxic exposure. These data are important to consider in the context of disorders such as sleep apnea in which brief periodic anoxic episodes are experienced.
Integrated Motor Cortical Control of Task-Related Muscles During Pointing in Humans
Authors: Devanne Hervé , Cohen Leonardo G. , Kouchtir-Devanne Nezha , Capaday Charles
Published: December 2017

A large body of compelling but indirect evidence suggests that the motor cortex controls the different forelimb segments as a whole rather than individually. The purpose of this study was to obtain physiological evidence in behaving human subjects on the mode of operation of the primary motor cortex during coordinated movements of the forelimb. We approached this problem by studying a pointing movement involving the shoulder, elbow, wrist, and index finger as follows. Focal transcranial magnetic stimulation (TMS) was used to measure the input-output (I/O) curves—a measure of the corticospinal pathway excitability—of proximal (anterior deltoid, AD, and triceps brachii, TB) and distal muscles (extensor carpi radialis, ECR, and first dorsal interosseus, 1DI) during isolated contraction of one of these muscles or during selective co-activation with other muscles involved in pointing. Compared to an isolated contraction of the ECR, the plateau-level of the ECR sigmoid I/O curve increased markedly during co-activation with the AD while pointing. In contrast, the I/O curve of AD was not influenced by activation of the more distal muscles involved in pointing. Moreover, the 1DI I/O curve was not influenced by activation of the more proximal muscles. Three arguments argue for a cortical site of facilitation of ECR motor potentials. First, ECR motor potentials evoked by a near threshold TMS stimulus were facilitated when the AD and ECR were co-activated during pointing but not those in response to a near threshold anodal electrical stimulus. Second, the ECR H reflex was not found to be task dependent, indicating that the recruitment gain of the ECR α-motoneuron pool did not differ between tasks. Finally, in comparison with an isolated ECR contraction, intracortical inhibition tested at the ECR cortical site was decreased during pointing. These results suggest that activation of shoulder, elbow, and wrist muscles involved in pointing appear to involve, at least in part, common motor cortical circuits. In contrast, at least in the pointing task, the motor cortical circuits involved in activation of the 1DI appear to act independently.
Color Processing in Macaque Striate Cortex: Relationships to Ocular Dominance, Cytochrome Oxidase, and Orientation
Authors: Landisman Carole E. , Ts'o Daniel Y.
Published: December 2017

We located clusters of color-selective neurons in macaque striate cortex, as mapped with optical imaging and confirmed with electrophysiological recordings. By comparing responses to an equiluminant red/green stimulus versus a high-contrast luminance stimulus, we were able to reveal a patchy distribution of color selectivity. Other color imaging protocols, when compared with electrophysiological data, did not reliably indicate the location of functional structures. The imaged color patches were compared with other known functional subdivisions of striate cortex. There was a high degree of overlap of the color patches with the cytochrome-oxidase (CO) blobs. The patches were often larger than a single blob in size, however, and in some instances spanned two neighboring blobs. More than one-half (56%) of the color-selective patches seen in optical imaging were not confined to one ocular dominance (OD) column. Almost one-quarter of color patches (23%) extended across OD columns to encompass two blobs of different eye preference. We also compared optical images of orientation selectivity to maps of color selectivity. Results indicate that the layout of orientation and color selectivity are not directly related. Specifically, despite having similar scales and distributions, the maps of orientation and color selectivity were not in consistent alignment or registration. Further, we find that the maps of color selectivity and of orientation are each only loosely related to maps of OD. This description stands in contrast to a common depiction of color-selective regions as identical to CO blobs, appearing as pegs in the centers of OD columns in the classical “ice cube” model. These results concerning the pattern of color selectivity in V1 support the view (put forth in previous imaging studies of the organization of orientation and ocular dominance) that there is not a fundamental registration of functional hypercolumns in V1.
Inhibitor of Glutamate Transport Alters Synaptic Transmission at Sensorimotor Synapses inAplysia
Authors: Chin Jeannie , Burdohan John A. , Eskin Arnold , Byrne John H.
Published: December 2017

Aplysia sensory neurons possess high-affinity glutamate uptake activity that is regulated by serotonin. To gain insight into the physiological role of glutamate uptake in sensory neurons, we examined whether blockade of glutamate transport altered synaptic transmission. We also examined whether glutamate transport affected homosynaptic depression and posttetanic potentiation (PTP). In the presence of dl-threo-β-hydroxyaspartic acid (THA), previously shown to block glutamate uptake in Aplysia, the duration of unitary excitatory postsynaptic potentials (EPSPs) was significantly increased and their amplitude was significantly reduced. Similar effects were observed in the properties of summated EPSPs. However, no effect on the induction of homosynaptic depression or PTP was observed. Although it is unclear whether THA exerted its effect by modulating neuronal and/or glial mechanisms, at least one target of THA was neuronal, as the duration of unitary EPSPs measured in cultured sensorimotor synapses was also increased in the presence of THA. These results support the hypotheses that glutamate is the transmitter released by the sensory neurons and that glutamate transport plays an important role in regulating features of synaptic transmission in Aplysia.
Posthatching Locomotor Experience Alters Locomotor Development in Chicks
Authors: Muir G. D. , Chu T. K.
Published: December 2017

We have previously demonstrated that, even though chicks are very precocial and can locomote within hours of hatching, they require a period of time to develop a mature stable walk. As an example, 1- to 2-day-old animals move with disproportionately small stride lengths compared with 10- to 14-day-old animals. The purpose of this study was to determine whether the maturation of walking, including the development of a mature stride length, depends on locomotor experience. We also investigated the development and experience-dependence nature of head bobbing, an optokinetic behavior that occurs during walking in birds. Chicks were randomly assigned to one of three groups receiving either increased locomotor experience (i.e., treadmill exercise), decreased locomotor experience (i.e., decreased housing space), or no alteration in locomotor experience. To assess the dependence of locomotor maturation on N-methyl-d-aspartate (NMDA)–type glutamate receptors, animals in each group were either given an NMDA antagonist (MK-801, 1 mg/kg intramuscularly daily) or saline control. Locomotor characteristics (stride length, leg support durations, horizontal head excursions) were quantified from videotaped recordings of chicks walking overground unrestrained on posthatching days 1 , 2, 4, 6, 8, and 10. Animals subject to exercise restriction for at least 6 days moved with shortened stride lengths compared with age-matched treadmill-exercised or control animals, a change that was maintained for the duration of the study. NMDA antagonism also resulted in shortened stride lengths. Head bobbing behavior matured during the same posthatching time period. The rate of this maturation was also decreased by exercise restriction. Thus locomotor experience is required for normal development of locomotor behavior, even in very precocial animals. These results are discussed in terms of the possible neuroanatomical and neurophysiological mechanisms underlying experience- and activity-dependent changes during motor development.
Acid-Activated Cation Currents in Rat Vallate Taste Receptor Cells
Authors: Lin Weihong , Ogura Tatsuya , Kinnamon Sue C.
Published: December 2017

Sour taste is mediated by acids with the degree of sourness a function of proton concentration. Recently, several members of the acid-sensing ion channel subfamily (ASICs) were cloned from taste cells and proposed to mediate sour taste. However, it is not known whether sour responses in taste cells resemble the responses mediated by ASICs. Using the whole cell patch-clamp technique and Na+imaging, we have characterized responses to acid stimuli in isolated rat vallate taste cells. Citric acid (pH 5) induced a large, rapidly activating inward current in most taste cells tested. The response showed various degrees of desensitization with prolonged stimulation. Current amplitudes were pH dependent, and adapting with acidic bath solutions reduced subsequent responses to acid stimulation. Amiloride (100–500 μM) partially and reversibly suppressed the acid-induced current. The current-voltage relationship showed reversal potential near the Na+equilibrium potential, suggesting that the current is carried predominantly by Na+. These data were consistent with Na+imaging experiments showing that acid stimulation resulted in increases in intracellular Na+. Taken together, these data indicate that acid-induced currents in vallate taste cells share general properties with ASICs expressed in heterologous cells and sensory neurons that express ASIC subunits. The large amplitude of the current and its existence in a high percentage of taste cells imply that ASICs or ASIC-like channels may play a prominent role in sour-taste transduction.
Differentiating Noxious- and Innocuous-Related Activation of Human Somatosensory Cortices Using Temporal Analysis of fMRI
Authors: Chen Jen-I , Ha Brian , Bushnell M. Catherine , Pike Bruce , Duncan Gary H.
Published: December 2017

The role of the somatosensory cortices (SI and SII) in pain perception has long been in dispute. Human imaging studies demonstrate activation of SI and SII associated with painful stimuli, but results have been variable, and the functional relevance of any such activation is uncertain. The present study addresses this issue by testing whether the time course of somatosensory activation, evoked by painful heat and nonpainful tactile stimuli, is sufficient to discriminate temporal differences that characterize the perception of these stimulus modalities. Four normal subjects each participated in three functional magnetic resonance imaging (fMRI) sessions, in which painful (noxious heat 45–46°C) and nonpainful test stimuli (brushing at 2 Hz) were applied repeatedly (9-s stimulus duration) to the left leg in separate experiments. Activation maps were generated comparing painful to neutral heat (35°C) and nonpainful brushing to rest. Directed searches were performed in SI and SII for sites reliably activated by noxious heat and brush stimuli, and stimulus-dependent regions of interest (ROI) were then constructed for each subject. The time course, per stimulus cycle, was extracted from these ROIs and compared across subjects, stimulus modalities, and cortical regions. Both innocuous brushing and noxious heat produced significant activation within contralateral SI and SII. The time course of brush-evoked responses revealed a consistent single peak of activity, approximately 10 s after the onset of the stimulus, which rapidly diminished upon stimulus withdrawal. In contrast, the response to heat pain in both SI and SII was characterized by a double-peaked time course in which the maximum response (the 2nd peak) was consistently observed ∼17 s after the onset of the stimulus (8 s following termination of the stimulus). This prolonged period of activation paralleled the perception of increasing pain intensity that persists even after stimulus offset. On the other hand, the temporal profile of the initial minor peak in pain-related activation closely matched that of the brush-evoked activity, suggesting a possible relationship to tactile components of the thermal stimulation procedure. These data indicate that both SI and SII cortices are involved in the processing of nociceptive information and are consistent with a role for these structures in the perception of temporal aspects of pain intensity.
Neural Activity in Human Primary Motor Cortex Areas 4a and 4p Is Modulated Differentially by Attention to Action
Authors: Binkofski F. , Fink G. R. , Geyer S. , Buccino G. , Gruber O. , Shah N. J. , Taylor J. G. , Seitz R. J. , Zilles K. , Freund H.-J.
Published: December 2017

The mechanisms underlying attention to action are poorly understood. Although distracted by something else, we often maintain the accuracy of a movement, which suggests that differential neural mechanisms for the control of attended and nonattended action exist. Using functional magnetic resonance imaging (fMRI) in normal volunteers and probabilistic cytoarchitectonic maps, we observed that neural activity in subarea 4p (posterior) within the primary motor cortex was modulated by attention to action, while neural activity in subarea 4a (anterior) was not. The data provide the direct evidence for differential neural mechanisms during attended and unattended action in human primary motor cortex.
Cannabinoids Depress Inhibitory Synaptic Inputs Received by Layer 2/3 Pyramidal Neurons of the Neocortex
Authors: Trettel Joseph , Levine Eric S.
Published: December 2017

Using whole cell voltage-clamp recordings we investigated the effects of a synthetic cannabinoid (WIN55,212-2) on inhibitory inputs received by layer 2/3 pyramidal neurons in slices of the mouse auditory cortex. Activation of the type 1 cannabinoid receptor (CB1R) with WIN55,212-2 reliably reduced the amplitude of GABAergic inhibitory postsynaptic currents evoked by extracellular stimulation within layer 2/3. The suppression of this inhibition was blocked and reversed by the highly selective CB1R antagonist AM251, confirming a CB1R-mediated inhibition. Pairing evoked inhibitory postsynaptic currents (IPSCs) at short interstimulus intervals while applying WIN55,212-2 resulted in an increase in paired-pulse facilitation suggesting that the probability of GABA release was reduced. A presynaptic site of cannabinoid action was verified by an observed decrease in the frequency with no change in the amplitude or kinetics of action potential–independent postsynaptic currents (mIPSCs). When Cd2+ was added or Ca2+ was omitted from the recording solution, the remaining fraction of Ca2+-independent mIPSCs did not respond to WIN55,212-2. These data suggest that cannabinoids are capable of suppressing the inhibition of neocortical pyramidal neurons by depressing Ca2+-dependent GABA release from local interneurons.
17β-Estradiol Benzoate Decreases the AHP Amplitude in CA1 Pyramidal Neurons
Authors: Kumar Ashok , Foster Thomas C.
Published: December 2017

Disruption of Ca2+ homeostasis is hypothesized to mediate several electrophysiological markers of brain aging. Recent evidence indicates that estradiol can rapidly alter Ca2+-dependent processes in neurons through nongenomic mechanisms. In the current study, electrophysiological effects of 17β-estradiol benzoate (EB) on the Ca2+-activated afterhyperpolarization (AHP) were investigated using intracellular sharp electrode recording in hippocampal slices from ovariectomized Fischer 344 female rats. The AHP amplitude was enhanced in aged (22–24 mo) compared with young (5–8 mo) rats and direct application of EB (100 pM) reduced the AHP in aged rats. The age-related difference was due, in part, to the increased AHP amplitude of aged animals, since an EB-mediated decrease in the AHP could be observed in young rats when the extracellular Ca2+ was elevated to increase the AHP amplitude. In aged rats, bath application of EB occluded the ability of the L-channel blocker, nifedipine (10 μM), to attenuate the AHP. The results support a role for EB in modifying hippocampal Ca2+-dependent processes in a manner diametrically opposite that observed during aging, possibly through L-channel inhibition.
GDNF and NGF Reverse Changes in Repriming of TTX-Sensitive Na+ Currents Following Axotomy of Dorsal Root Ganglion Neurons
Authors: Leffler Andreas , Cummins Theodore R. , Dib-Hajj Sulayman D. , Hormuzdiar William N. , Black Joel A. , Waxman Stephen G.
Published: December 2017

Uninjured C-type rat dorsal root ganglion (DRG) neurons predominantly express slowly inactivating TTX-resistant (TTX-R) and slowly repriming TTX-sensitive (TTX-S) Na+ currents. After peripheral axotomy, TTX-R current density is reduced and rapidly repriming TTX-S currents emerge and predominate. The change in TTX-S repriming kinetics is paralleled by an increase in the level of transcripts and protein for the Nav1.3 sodium channel α-subunit, which is known to exhibit rapid repriming. Changes in Na+current profile and kinetics in DRG neurons may substantially alter neuronal excitability and could contribute to some states of chronic pain associated with injury of sensory neurons. In the present study, we asked whether glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF), which have been shown to prevent some axotomy-induced changes such as the loss of TTX-R Na+ current expression in DRG neurons, can ameliorate the axotomy-induced change in TTX-S Na+ current repriming kinetics. We show that intrathecally administered GDNF and NGF, delivered individually, can partially reverse the effect of axotomy on the repriming kinetics of TTX-S Na+ currents. When GDNF and NGF were co-administered, the repriming kinetics were fully rescued. We observed parallel effects of GDNF and NGF on the Nav1.3 sodium channel transcript levels in axotomized DRG. Both GDNF and NGF were able to partially reverse the axotomy-induced increase in Nav1.3 mRNA, with GDNF plus NGF producing the largest effect. Our data indicate that both GDNF and NGF can partially reverse an important effect of axotomy on the electrogenic properties of sensory neurons and that their effect is additive.
Linear Regression of Eye Velocity on Eye Position and Head Velocity Suggests a Common Oculomotor Neural Integrator
Authors: Goldman Mark S. , Kaneko Chris R. S. , Major Guy , Aksay Emre , Tank David W. , Seung H. S.
Published: December 2017

The oculomotor system produces eye-position signals during fixations and head movements by integrating velocity-coded saccadic and vestibular inputs. A previous analysis of nucleus prepositus hypoglossi (nph) lesions in monkeys found that the integration time constant for maintaining fixations decreased, while that for the vestibulo-ocular reflex (VOR) did not. On this basis, it was concluded that saccadic inputs are integrated by the nph, but that the vestibular inputs are integrated elsewhere. We re-analyze the data from which this conclusion was drawn by performing a linear regression of eye velocity on eye position and head velocity to derive the time constant and velocity bias of an imperfect oculomotor neural integrator. The velocity-position regression procedure reveals that the integration time constants for both VOR and saccades decrease in tandem with consecutive nph lesions, consistent with the hypothesis of a single common integrator. The previous evaluation of the integrator time constant relied upon fitting methods that are prone to error in the presence of velocity bias and saccades. The algorithm used to evaluate imperfect fixations in the dark did not account for the nonzero null position of the eyes associated with velocity bias. The phase-shift analysis used in evaluating the response to sinusoidal vestibular input neglects the effect of saccadic resets of eye position on intersaccadic eye velocity, resulting in gross underestimates of the imperfections in integration during VOR. The linear regression method presented here is valid for both fixation and low head velocity VOR data and is easy to implement.
Short- and Long-Term Changes in Joint Co-Contraction Associated With Motor Learning as Revealed From Surface EMG
Authors: Osu Rieko , Franklin David W. , Kato Hiroko , Gomi Hiroaki , Domen Kazuhisa , Yoshioka Toshinori , Kawato Mitsuo
Published: December 2017

In the field of motor control, two hypotheses have been controversial: whether the brain acquires internal models that generate accurate motor commands, or whether the brain avoids this by using the viscoelasticity of musculoskeletal system. Recent observations on relatively low stiffness during trained movements support the existence of internal models. However, no study has revealed the decrease in viscoelasticity associated with learning that would imply improvement of internal models as well as synergy between the two hypothetical mechanisms. Previously observed decreases in electromyogram (EMG) might have other explanations, such as trajectory modifications that reduce joint torques. To circumvent such complications, we required strict trajectory control and examined only successful trials having identical trajectory and torque profiles. Subjects were asked to perform a hand movement in unison with a target moving along a specified and unusual trajectory, with shoulder and elbow in the horizontal plane at the shoulder level. To evaluate joint viscoelasticity during the learning of this movement, we proposed an index of muscle co-contraction around the joint (IMCJ). The IMCJ was defined as the summation of the absolute values of antagonistic muscle torques around the joint and computed from the linear relation between surface EMG and joint torque. The IMCJ during isometric contraction, as well as during movements, was confirmed to correlate well with joint stiffness estimated using the conventional method, i.e., applying mechanical perturbations. Accordingly, the IMCJ during the learning of the movement was computed for each joint of each trial using estimated EMG-torque relationship. At the same time, the performance error for each trial was specified as the root mean square of the distance between the target and hand at each time step over the entire trajectory. The time-series data of IMCJ and performance error were decomposed into long-term components that showed decreases in IMCJ in accordance with learning with little change in the trajectory and short-term interactions between the IMCJ and performance error. A cross-correlation analysis and impulse responses both suggested that higher IMCJs follow poor performances, and lower IMCJs follow good performances within a few successive trials. Our results support the hypothesis that viscoelasticity contributes more when internal models are inaccurate, while internal models contribute more after the completion of learning. It is demonstrated that the CNS regulates viscoelasticity on a short- and long-term basis depending on performance error and finally acquires smooth and accurate movements while maintaining stability during the entire learning process.
Inhibitory Interactions Between Spiny Projection Neurons in the Rat Striatum
Authors: Tunstall Mark J. , Oorschot Dorothy E. , Kean Annabel , Wickens Jeffery R.
Published: December 2017

The spiny projection neurons are by far the most numerous type of striatal neuron. In addition to being the principal projection neurons of the striatum, the spiny projection neurons also have an extensive network of local axon collaterals by which they make synaptic connections with other striatal projection neurons. However, up to now there has been no direct physiological evidence for functional inhibitory interactions between spiny projection neurons. Here we present new evidence that striatal projection neurons are interconnected by functional inhibitory synapses. To examine the physiological properties of unitary inhibitory postsynaptic potentials (IPSPs), dual intracellular recordings were made from pairs of spiny projection neurons in brain slices of adult rat striatum. Synaptic interactions were found in 9 of 45 pairs of neurons using averages of 200 traces that were triggered by a single presynaptic action potential. In all cases, synaptic interactions were unidirectional, and no bidirectional interactions were detected. Unitary IPSPs evoked by a single presynaptic action potential had a peak amplitude ranging from 157 to 319 μV in different connections (mean: 277 ± 46 μV, n = 9). The percentage of failures of single action potentials to evoke a unitary IPSP was estimated and ranged from 9 to 63% (mean: 38 ± 14%, n = 9). Unitary IPSPs were reversibly blocked by bicuculline ( n = 4) and had a reversal potential of −62.4 ± 0.7 mV ( n = 5), consistent with GABA-mediated inhibition. The findings of the present study correlate very well with anatomical evidence for local synaptic connectivity between spiny projection neurons and suggest that lateral inhibition plays a significant role in the information processing operations of the striatum.
Ryanodine Receptors Contribute to cGMP-Induced Late-Phase LTP and CREB Phosphorylation in the Hippocampus
Authors: Lu Yun-Fei , Hawkins Robert D.
Published: December 2017

We previously found that the nitric oxide (NO)-cGMP-cGMP-dependent protein kinase (PKG) signaling pathway acts in parallel with the cAMP-cAMP-dependent protein kinase (PKA) pathway to produce protein and RNA synthesis-dependent late-phase long-term potentiation (L-LTP) and cAMP response element-binding protein (CREB) phosphorylation in the CA1 region of mouse hippocampus. We have now investigated the possible involvement of a downstream target of PKG, ryanodine receptors. L-LTP can be induced by either multiple-train tetanization, NO or 8-Br-cGMP paired with one-train tetanization, or the cAMP activator forskolin, and all three types of potentiation are accompanied by an increase in phospho-CREB immunofluorescence in the CA1 cell body area. Both the potentiation and the increase in phospho-CREB immunofluorescence induced by multiple-train tetanization or 8-Br-cGMP paired with one-train tetanization are reduced by prolonged perfusion with ryanodine, which blocks Ca2+release from ryanodine-sensitive Ca2+stores. By contrast, neither the potentiation nor the increase in immunofluorescence induced by forskolin are reduced by depletion of ryanodine and inositol-1,4,5-triphosphate (IP3)-sensitive Ca2+stores. These results suggest that NO, cGMP, and PKG cause release of Ca2+from ryanodine-sensitive stores, which in turn causes phosphorylation of CREB in parallel with PKA during the induction of L-LTP.
PACAP Potentiates L-Type Calcium Channel Conductance in Suprachiasmatic Nucleus Neurons by Activating the MAPK Pathway
Authors: Dziema Heather , Obrietan Karl
Published: December 2017

The endogenous pacemaker activity of the suprachiasmatic nuclei (SCN; the master clock in mammals) is regulated by photic information relayed from the retina to the SCN via the retinohypothalamic tract (RHT). Recent work has revealed that glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) are stored in RHT nerve terminals and function in a coordinated manner to regulate clock timing. To address this interaction on a cellular level, Fura-2 Ca2+digital imaging was employed and the effects of PACAP on glutamate evoked Ca2+transients in SCN neurons were examined. Pretreatment of SCN neurons with PACAP markedly potentiated Ca2+transients elicited by both exogenous glutamate application and synaptically released glutamate. Many neurons became responsive to glutamate only after PACAP administration, suggesting that PACAP sets the lower concentration threshold required for glutamate to initiate a robust rise in postsynaptic cytosolic Ca2+. Facilitation of glutamate-induced Ca2+transients was inhibited by nimodipine, indicating that PACAP potentiates L-type Ca2+channel activity. The modulatory actions of PACAP were inhibited by antagonizing signaling via the p42/44 mitogen-activated protein kinase (MAPK) signal transduction cascade. Immunocytochemistry and Western analysis confirmed that PACAP stimulates MAPK activity at doses and time points shown to potentiate Ca2+influx. Down-regulation of protein kinase C (PKC) with the phorbol ester 12- O-tetradecanoyl phorbol 13-acetate (TPA) or PKC inhibition with bisindolylmaleimide attenuated the actions of PACAP, indicating that PKC also couples PACAP to potentiation of depolarization-induced Ca2+transients. The data presented here identify potentially important mechanisms by which PACAP regulates SCN physiology.
GAT-1 and Reversible GABA Transport in Bergmann Glia in Slices
Authors: Barakat L. , Bordey A.
Published: December 2017

Although glial GABA uptake and release have been studied in vitro, GABA transporters (GATs) have not been characterized in glia in slices. Whole cell patch-clamp recordings were obtained from Bergmann glia in rat cerebellar slices to characterize carrier-mediated GABA influx and efflux. GABA induced inward currents at −70 mV that could be pharmacologically separated into GABAAreceptor and GAT currents. In the presence of GABAA/B/Creceptor blockers, mean GABA-induced currents measured −48 pA at −70 mV, were inwardly rectifying between −70 and +50 mV, were inhibited by external Na+removal, and were diminished by reduction of external Cl−. Nontransportable blockers of GAT-1 (SKF89976-A and NNC-711) and a transportable blocker of all the GAT subtypes (nipecotic acid) reversibly reduced GABA-induced transport currents by 68 and 100%, respectively. A blocker of BGT-1 (betaine) had no effect. SKF89976-A and NNC-711 also suppressed baseline inward currents that likely result from tonic GAT activation by background GABA. The substrate agonists, nipecotic acid and β-alanine but not betaine, induced voltage- and Na+-dependent currents. With Na+and GABA inside the patch pipette or intracellular GABA perfusion during the recording, SKF89976-A blocked baseline outward currents that activated at −60 mV and increased with more depolarized potentials. This carrier-mediated GABA efflux induced a local accumulation of extracellular GABA detected by GABAAreceptor activation on the recorded cell. Overall, these results indicate that Bergmann glia express GAT-1 that are activated by ambient GABA. In addition, GAT-1 in glia can work in reverse and release sufficient GABA to activate nearby GABA receptors.
Postnatal Development of Rat Hippocampal Gamma Rhythm In Vivo
Authors: Lahtinen Hannele , Palva J. Matias , Sumanen Satu , Voipio Juha , Kaila Kai , Taira Tomi
Published: December 2017

Network oscillations in the gamma-frequency band (20–100 Hz) may have a central role in the timing and coordination of neural activity in the adult brain, yet their appearance in the course of development has remained unexplored. Moreover, electroencephalogram (EEG)-based classification of the vigilance states [active sleep (AS), quiet sleep (QS), or awake (W)] has been thought to be possible only after the second postnatal week. We now report the presence of spontaneous hippocampal gamma oscillations in the area CA3 of freely moving rats at postnatal days (P) 5–10. Initially, at P5, the gamma oscillations were seen in time-frequency analyses of intrahippocampal EEG recordings as brief (<500 ms) bursts at 20–30 Hz. The early gamma rhythmicity was most pronounced during periods of AS but was occasionally detected also during QS. Toward P10, the gamma oscillations gained amplitude and extended also to higher (≤60 Hz) frequencies. In parallel, the gamma oscillations were progressively more and more confined to AS. To further consolidate these findings, we compared amplitude spectra averaged within the behavioral categories. AS was characterized by the appearances of gamma (20–30 Hz) and theta (3–5 Hz) peaks at P6 and at P8, respectively. QS, on the other hand, had considerably smoother amplitude distributions between 1 and 100 Hz for P5–P10, with no peaks in gamma or theta bands. Hippocampal gamma rhythm thus seems to hallmark early AS. Our data provide the first in vivo evidence for both the presence and the behavioral correlate of spontaneous gamma oscillations in the newborn rat.
Endogenous and Network Properties ofLymnaeaFeeding Central Pattern Generator Interneurons
Authors: Straub Volko A. , Staras Kevin , Kemenes György , Benjamin Paul R.
Published: December 2017

Understanding central pattern generator (CPG) circuits requires a detailed knowledge of the intrinsic cellular properties of the constituent neurons. These properties are poorly understood in most CPGs because of the complexity resulting from interactions with other neurons of the circuit. This is also the case in the feeding network of the snail, Lymnaea, one of the best-characterized CPG networks. We addressed this problem by isolating the interneurons comprising the feeding CPG in cell culture, which enabled us to study their basic intrinsic electrical and pharmacological cellular properties without interference from other network components. These results were then related to the activity patterns of the neurons in the intact feeding network. The most striking finding was the intrinsic generation of plateau potentials by medial N1 (N1M) interneurons. This property is probably critical for rhythm generation in the whole feeding circuit because the N1M interneurons are known to play a pivotal role in the initiation of feeding cycles in response to food. Plateau potential generation in another cell type, the ventral N2 (N2v), appeared to be conditional on the presence of acetylcholine. Examination of the other isolated feeding CPG interneurons [lateral N1 (N1L), dorsal N2 (N2d), phasic N3 (N3p)] and the modulatory slow oscillator (SO) revealed no significant intrinsic properties in relation to pattern generation. Instead, their firing patterns in the circuit appear to be determined largely by cholinergic and glutamatergic synaptic inputs from other CPG interneurons, which were mimicked in culture by application of these transmitters. This is an example of a CPG system where the initiation of each cycle appears to be determined by the intrinsic properties of a key interneuron, N1M, but most other features of the rhythm are probably determined by network interactions.