bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonin Effects on Frequency Tuning of Inferior Colliculus Neurons
Authors: Hurley Laura M. , Pollak George D.
Published: December 2017

We investigated the modulatory effects of serotonin on the tuning of 114 neurons in the central nucleus of the inferior colliculus (ICc) of Mexican free-tailed bats and how serotonin-induced changes in tuning influenced responses to complex signals. We obtained a “response area” for each neuron, defined as the frequency range that evoked discharges and the spike counts evoked by those frequencies at a constant intensity. We then iontophoretically applied serotonin and compared response areas obtained before and during the application of serotonin. In 58 cells, we also assessed how serotonin-induced changes in response areas correlated with changes in the responses to brief frequency-modulated (FM) sweeps whose structure simulated natural echolocation calls. Serotonin profoundly changed tone-evoked spike counts in 60% of the neurons (68/114). In most neurons, serotonin exerted a gain control, facilitating or depressing the responses to all frequencies in their response areas. In many cells, serotonergic effects on tones were reflected in the responses to FM signals. The most interesting effects were in those cells in which serotonin selectively changed the responsiveness to only some frequencies in the neuron's response area and had little or no effect on other frequencies. This caused predictable changes in responses to the more complex FM sweeps whose spectral components passed through the neurons' response areas. Our results suggest that serotonin, whose release varies with behavioral state, functionally reconfigures the circuitry of the IC and may modulate the perception of acoustic signals under different behavioral states.
The Duncker Illusion and Eye–Hand Coordination
Authors: Soechting John F. , Engel Kevin C. , Flanders Martha
Published: December 2017

A moving background alters the perceived direction of target motion (the Duncker illusion). To test whether this illusion also affects pointing movements to remembered/extrapolated target locations, we constructed a display in which a target moved in a straight line and disappeared behind a band of moving random dots. Subjects were required to touch the spot where the target would emerge from the occlusion. The four directions of random-dot motion induced pointing errors that were predictable from the Duncker illusion. Because it has been previously established that saccadic direction is influenced by this illusion, gaze was subsequently recorded in a second series of experiments while subjects performed the pointing task and a similar task with eye-tracking only. In the pointing task, subjects typically saccaded to the lower border of the occlusion zone as soon as the target disappeared and then tried to maintain fixation at that spot. However, it was particularly obvious in the eye-tracking-only condition that horizontally moving random dots generally evoked an appreciable ocular following response, altering the gaze direction. Hand-pointing errors were related to the saccadic gaze error but were more highly correlated with final gaze errors (resulting from the initial saccade and the subsequent ocular following response). The results suggest a model of limb control in which gaze position can provide the target signal for limb movement.
High I h Channel Density in the Distal Apical Dendrite of Layer V Pyramidal Cells Increases Bidirectional Attenuation of EPSPs
Authors: Berger Thomas , Larkum Matthew E. , Lüscher Hans-R.
Published: December 2017

Despite the wealth of recent research on active signal propagation along the dendrites of layer V neocortical pyramidal neurons, there is still little known regarding the traffic of subthreshold synaptic signals. We present a study using three simultaneous whole cell recordings on the apical dendrites of these cells in acute rat brain slices to examine the spread and attenuation of spontaneous excitatory postsynaptic potentials (sEPSPs). Equal current injections at each of a pair of sites separated by ∼500 μm on the apical dendrite resulted in equal voltage transients at the other site (“reciprocity”), thus disclosing linear behavior of the neuron. The mean apparent “length constants” of the apical dendrite were 273 and 446 μm for somatopetal and somatofugal sEPSPs, respectively. Trains of artificial EPSPs did not show temporal summation. Blockade of the hyperpolarization-activated cation current ( I h) resulted in less attenuation by 17% for somatopetal and by 47% for somatofugal sEPSPs. A pronounced location-dependent temporal summation of EPSP trains was seen. The subcellular distribution and biophysical properties of I h were studied in cell-attached patches. Within less than ∼400 μm of the soma, a low density of ∼3 pA/μm2 was found, which increased to ∼40 pA/μm2 in the apical distal dendrite. I h showed activation and deactivation kinetics with time constants faster than 40 ms and half-maximal activation at −95 mV. These findings suggest that integration of synaptic input to the apical tuft and the basal dendrites occurs spatially independently. This is due to a high I h channel density in the apical tuft that increases the electrotonic distance between these two compartments in comparison to a passive dendrite.
Propagation of Action Potentials in Dendrites Depends on Dendritic Morphology
Authors: Vetter Philipp , Roth Arnd , Häusser Michael
Published: December 2017

Action potential propagation links information processing in different regions of the dendritic tree. To examine the contribution of dendritic morphology to the efficacy of propagation, simulations were performed in detailed reconstructions of eight different neuronal types. With identical complements of voltage-gated channels, different dendritic morphologies exhibit distinct patterns of propagation. Remarkably, the range of backpropagation efficacies observed experimentally can be reproduced by the variations in dendritic morphology alone. Dendritic geometry also determines the extent to which modulation of channel densities can affect propagation. Thus in Purkinje cells and dopamine neurons, backpropagation is relatively insensitive to changes in channel densities, whereas in pyramidal cells, backpropagation can be modulated over a wide range. We also demonstrate that forward propagation of dendritically initiated action potentials is influenced by morphology in a similar manner. We show that these functional consequences of the differences in dendritic geometries can be explained quantitatively using simple anatomical measures of dendritic branching patterns, which are captured in a reduced model of dendritic geometry. These findings indicate that differences in dendritic geometry act in concert with differences in voltage-gated channel density and kinetics to generate the diversity in dendritic action potential propagation observed between neurons. They also suggest that changes in dendritic geometry during development and plasticity will critically affect propagation. By determining the spatial pattern of action potential signaling, dendritic morphology thus helps to define the size and interdependence of functional compartments in the neuron.
Cerebral Cortical Representation of Automatic and Volitional Swallowing in Humans
Authors: Martin Ruth E. , Goodyear Bradley G. , Gati Joseph S. , Menon Ravi S.
Published: December 2017

Although the cerebral cortex has been implicated in the control of swallowing, the functional organization of the human cortical swallowing representation has not been fully documented. Therefore, the present study determined the cortical representation of swallowing in fourteen healthy right-handed female subjects using single-event-related functional magnetic resonance imaging (fMRI). Subjects were scanned during three swallowing activation tasks: a naı̈ve saliva swallow, a voluntary saliva swallow, and a water bolus swallow. Swallow-related laryngeal movement was recorded simultaneously from the output of a bellows positioned over the thyroid cartilage. Statistical maps were generated by computing the difference between the magnitude of the voxel time course during 1) a single swallowing trial and 2) the corresponding control period. Automatic and volitional swallowing produced activation within several common cortical regions, the most prominent and consistent being located within the lateral precentral gyrus, lateral postcentral gyrus, and right insula. Activation foci within the superior temporal gyrus, middle and inferior frontal gyri, and frontal operculum also were identified for all swallowing tasks. In contrast, activation of the caudal anterior cingulate cortex was significantly more likely in association with the voluntary saliva swallow and water bolus swallow than the naı̈ve swallow. These findings support the view that, in addition to known brain stem areas, human swallowing is represented within a number of spatially and functionally distinct cortical loci which may participate differentially in the regulation of swallowing. Activation of the insula was significantly lateralized to the right hemisphere for the voluntary saliva swallow, suggesting a functional hemispheric dominance of the insula for the processing of swallowing.
Neurons in the Thalamic CM-Pf Complex Supply Striatal Neurons With Information About Behaviorally Significant Sensory Events
Authors: Matsumoto Naoyuki , Minamimoto Takafumi , Graybiel Ann M. , Kimura Minoru
Published: December 2017

The projection from the thalamic centre médian–parafascicular (CM-Pf) complex to the caudate nucleus and putamen forms a massive striatal input system in primates. We examined the activity of 118 neurons in the CM and 62 neurons in the Pf nuclei of the thalamus and 310 tonically active neurons (TANs) in the striatum in awake behaving macaque monkeys and analyzed the effects of pharmacologic inactivation of the CM-Pf on the sensory responsiveness of the striatal TANs. A large proportion of CM and Pf neurons responded to visual (53%) and/or auditory beep (61%) or click (91%) stimuli presented in behavioral tasks, and many responded to unexpected auditory, visual, or somatosensory stimuli presented outside the task context. The neurons fell into two classes: those having short-latency facilitatory responses (SLF neurons, predominantly in the Pf) and those having long-latency facilitatory responses (LLF neurons, predominantly in the CM). Responses of both types of neuron appeared regardless of whether or not the sensory stimuli were associated with reward. These response characteristics of CM-Pf neurons sharply contrasted with those of TANs in the striatum, which under the same conditions responded preferentially to stimuli associated with reward. Many CM-Pf neurons responded to alerting stimuli such as unexpected handclaps and noises only for the first few times that they occurred; after that, the identical stimuli gradually became ineffective in evoking responses. Habituation of sensory responses was particularly common for the LLF neurons. Inactivation of neuronal activity in the CM and Pf by local infusion of the GABAA receptor agonist, muscimol, almost completely abolished the pause and rebound facilitatory responses of TANs in the striatum. Such injections also diminished behavioral responses to stimuli associated with reward. We suggest that neurons in the CM and Pf supply striatal neurons with information about behaviorally significant sensory events that can activate conditional responses of striatal neurons in combination with dopamine-mediated nigrostriatal inputs having motivational value.
Müller Cell Ca2+ Waves Evoked by Purinergic Receptor Agonists in Slices of Rat Retina
Authors: Li Yang , Holtzclaw Lynne A. , Russell James T.
Published: December 2017

We have measured agonist evoked Ca2+ waves in Müller cells in situ within freshly isolated retinal slices. Using an eye cup dye loading procedure we were able to preferentially fill Müller glial cells in retinal slices with calcium green. Fluorescence microscopy revealed that bath perfusion of slices with purinergic agonists elicits Ca2+ waves in Müller cells, which propagate along their processes. These Ca2+ signals were insensitive to tetrodotoxin (TTX, 1.0 μM) pretreatment. Cells were readily identified as Müller cells by their unique morphology and by subsequent immunocytochemical labeling with glial fibrillary acidic protein antibodies. While cells never exhibited spontaneous Ca2+ oscillations, purinoreceptor agonists, ATP, 2 MeSATP, ADP, 2 MeSADP, and adenosine readily elicited Ca2+ waves. These waves persisted in the absence of [Ca2+]o but were abolished by thapsigargin pretreatment, suggesting that the purinergic agonists tested act by releasing Ca2+ from intracellular Ca2+ stores. The rank order of potency of different purines and pyrimidines for inducing Ca2+ signals was 2 MeSATP = 2MeSADP > ADP > ATP ≫ αβmeATP = uridine triphosphate (UTP) > uridine diphosphate (UDP). The Ca2+signals evoked by ATP, ADP, and 2 MeSATP were inhibited by reactive blue (100 μM) and suramin (200 μM), and the adenosine induced signals were abolished only by 3,7-dimethyl-1-propargylxanthine (200 μM) and not by 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine) or 8-cyclopentyl-1,3-dipropylxanthine at the same concentration. Based on these pharmacological characteristics and the dose-response relationships for ATP, 2 MeSATP, 2 MeSADP, ADP, and adenosine, we concluded that Müller cells express the P1A2 and P2Y1 subtypes of purinoceptors. Analysis of Ca2+ responses showed that, similar to glial cells in culture, wave propagation occurred by regenerative amplification at specialized Ca2+ release sites (wave amplification sites), where the rate of Ca2+ release was significantly enhanced. These data suggest that Müller cells in the retina may participate in signaling, and this may serve as an extra-neuronal signaling pathway.
Temporal Coding of Contrast in Primary Visual Cortex: When, What, and Why
Authors: Reich Daniel S. , Mechler Ferenc , Victor Jonathan D.
Published: December 2017

How do neurons in the primary visual cortex (V1) encode the contrast of a visual stimulus? In this paper, the information that V1 responses convey about the contrast of static visual stimuli is explicitly calculated. These responses often contain several easily distinguished temporal components, which will be called latency, transient, tonic, and off. Calculating the information about contrast conveyed in each component and in groups of components makes it possible to delineate aspects of the temporal structure that may be relevant for contrast encoding. The results indicate that as much or more contrast-related information is encoded into the temporal structure of spike train responses as into the firing rate and that the temporally coded information is manifested most strongly in the latency to response onset. Transient, tonic, and off responses contribute relatively little. The results also reveal that temporal coding is important for distinguishing subtle contrast differences, whereas firing rates are useful for gross discrimination. This suggests that the temporal structure of neurons' responses may extend the dynamic range for contrast encoding in the primate visual system.
β-NAAG Rescues LTP From Blockade by NAAG in Rat Dentate Gyrus via the Type 3 Metabotropic Glutamate Receptor
Authors: IV Paul M. Lea , Wroblewska Barbara , Sarvey John M. , Neale Joseph H.
Published: December 2017

N-Acetylaspartylglutamate (NAAG) is an agonist at the type 3 metabotropic glutamate receptor (mGluR3), which is coupled to a Gi/o protein. When activated, the mGluR3 receptor inhibits adenylyl cyclase and reduces the cAMP-mediated second-messenger cascade. Long-term potentiation (LTP) in the medial perforant path (MPP) of the hippocampal dentate gyrus requires increases in cAMP. The presence of mGluR3 receptors and NAAG in neurons of the dentate gyrus suggests that this peptide transmitter may inhibit LTP in the dentate gyrus. High-frequency stimulation (100 Hz; 2 s) of the MPP resulted in LTP of extracellularly recorded excitatory postsynaptic potentials at the MPP-granule cell synapse of rat hippocampal slices. Perfusion of the slice with NAAG (50 and 200 μM) blocked LTP. Neither 50 nor 200 μM NAAG produced N-methyl-d-aspartate receptor currents in the granule cells of the acute hippocampal slice. The group II mGluR antagonist ethyl glutamate (100 μM) and a structural analogue of NAAG, β-NAAG (100 μM), prevented the blockade of LTP by NAAG. Paired-pulse depression of the excitatory postsynaptic potential at 20- and 80-ms interpulse intervals (IPI) was not affected by NAAG or β-NAAG. β-NAAG did not affect inositol trisphosphate production stimulated by the agonist glutamate in cells expressing the group I mGluR1α or mGluR5. β-NAAG blocked the decrease in forskolin-stimulated cAMP by the group II mGluR agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) but not the group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid in cerebellar granule cells. In cells transfected with mGluR3, but not mGluR2, β-NAAG blocked forskolin-stimulated cAMP responses to glutamate, NAAG, the nonspecific group I, II agonist trans-ACPD, and the group II agonist DCG-IV. We conclude that β-NAAG is a selective mGluR antagonist capable of differentiating between mGluR2 and mGluR3 subtypes and that the mGluR3 receptor functions to regulate activity-dependent synaptic potentiation in the hippocampus.
Temporal Representation of Iterated Rippled Noise as a Function of Delay and Sound Level in the Ventral Cochlear Nucleus
Authors: Wiegrebe Lutz , Winter Ian M.
Published: December 2017

The discharge patterns of single units in the ventral cochlear nucleus (VCN) of anesthetized guinea pigs were examined in response to iterated rippled noise (IRN) as a function of the IRN delay (which determines the IRN pitch) and the IRN sound level. Delays were varied over five octaves in half-octave steps, and sound levels were varied over a 30- or 50-dB range in steps of 5 dB. Neural responses were analyzed in terms of first-order and all-order inter-spike intervals (ISIs). The IRN quasi-periodicity was preserved in the all-order ISIs for most units independent of unit type or best frequency (BF). A deterioration of the temporal all-order code was found, however, when the neural response was influenced by inhibition. The IRN quasi-periodicity was also preserved in first-order ISIs for a limited range of IRN delays and levels. Sustained Chopper units (CS) in the VCN responded with very regular ISIs when the IRN delay corresponded to the unit's chopping period; i.e., the unit showed an increased proportion of intervals corresponding to the IRN delay (interval enhancement) relative to an equal-level, white-noise stimulation. This interval enhancement has a band-pass characteristic with a peak corresponding to the chopping period. Moreover, for CS units in rate saturation, the chopping period, and thus the interval enhancement to the IRN, did not vary with level. Units classified as onset-chopper also show a band-pass interval enhancement to the IRN stimuli; however, they show more level-dependent changes than CS units. Primary-like (PL) units also show level-dependent changes in their ability to code the IRN pitch in first-order intervals. The range of delays where PL units showed interval enhancement was broader and extended to shorter delays. Based on these findings, it is suggested that CS units may play an important role in pitch processing in that they transform a higher-order interval code into a first-order interval place code. Their limited dynamic range together with the preservation of the temporal stimulus features in saturation may serve as a physiological basis for the perceived level independence of pitch.
Spectro-Temporal Response Field Characterization With Dynamic Ripples in Ferret Primary Auditory Cortex
Authors: Depireux Didier A. , Simon Jonathan Z. , Klein David J. , Shamma Shihab A.
Published: December 2017

To understand the neural representation of broadband, dynamic sounds in primary auditory cortex (AI), we characterize responses using the spectro-temporal response field (STRF). The STRF describes, predicts, and fully characterizes the linear dynamics of neurons in response to sounds with rich spectro-temporal envelopes. It is computed from the responses to elementary “ripples,” a family of sounds with drifting sinusoidal spectral envelopes. The collection of responses to all elementary ripples is the spectro-temporal transfer function. The complex spectro-temporal envelope of any broadband, dynamic sound can expressed as the linear sum of individual ripples. Previous experiments using ripples with downward drifting spectra suggested that the transfer function is separable, i.e., it is reducible into a product of purely temporal and purely spectral functions. Here we measure the responses to upward and downward drifting ripples, assuming reparability within each direction, to determine if the total bidirectional transfer function is fully separable. In general, the combined transfer function for two directions is not symmetric, and hence units in AI are not, in general, fully separable. Consequently, many AI units have complex response properties such as sensitivity to direction of motion, though most inseparable units are not strongly directionally selective. We show that for most neurons, the lack of full separability stems from differences between the upward and downward spectral cross-sections but not from the temporal cross-sections; this places strong constraints on the neural inputs of these AI units.
Adrenergic Hyperactivity and Metanephrine Excess in the Nucleus Accumbens After Prefrontocortical Dopamine Depletion
Authors: Espejo Emilio F. , Miñano Javier
Published: December 2017

Selective dopamine depletion within the medial prefrontal cortex in rats is known to enhance dopamine and norepinephrine levels in the nucleus accumbens and to induce characteristic behavioral disturbances. The present study was designed to determine levels of adrenaline, apart from dopamine and norepinephrine, and metabolites in the nucleus accumbens after prefrontocortical dopamine depletion. Prefrontocortical dopamine depletion was carried out by injecting 6-hydroxydopamine, and it was validated through: the emergence of behavioral disturbances such as amphetamine-induced stereotypies, spontaneous motor hyperactivity, and enhanced “anxiety-like” responses and through postmortem quantification of catecholamine levels by using high-performance liquid chromatography. The findings indicated that lesioned rats exhibited more oral stereotypies after amphetamine, were hyperlocomotive, and showed more pronounced anxiety-like behaviors than controls. Following prefrontocortical dopamine depletion, postmortem concentrations of dopamine and norepinephrine, along with the metabolites 3,4-dihydroxyphenylacetic acid and vanillylmandelic acid, were reliably enhanced in the nucleus accumbens as expected, and dopamine turnover was decreased. Furthermore the nucleus accumbens contained higher levels of adrenaline and its transmethylated metabolite metanephrine. To sum up, prefrontocortical dopamine depletion induces motor and emotional disturbances in rats and alters the neurochemical profile of the nucleus accumbens, not only inducing dopaminergic and noradrenergic hyperactivity but also leading to adrenaline and metanephrine excess.
Is Persistent Activity of Calcium/Calmodulin-Dependent Kinase Required for the Maintenance of LTP?
Authors: Chen Huan-Xin , Otmakhov Nikolai , Strack Stefan , Colbran Roger J. , Lisman John E.
Published: December 2017

Calcium/calmodulin-dependent protein kinase II (CaMKII) is concentrated in the postsynaptic density (PSD) and plays an important role in the induction of long-term potentiation (LTP). Because this kinase is persistently activated after the induction, its activity could also be important for LTP maintenance. Experimental tests of this hypothesis, however, have given conflicting results. In this paper we further explore the role of postsynaptic CaMKII in induction and maintenance of LTP. Postsynaptic application of a CaMKII inhibitor [autocamtide-3 derived peptide inhibitor (AC3-I), 2 mM] blocked LTP induction but had no detectable affect on N-methyl-d-aspartate (NMDA)-mediated synaptic transmission, indicating that the primary function of CaMKII in LTP is downstream from NMDA channel function. We next explored various methodological factors that could account for conflicting results on the effect of CaMKII inhibitors on LTP maintenance. In contrast to our previous work, we now carried out experiments at higher temperature (33°C), used slices from adult animals, and induced LTP using a tetanic stimulation. However, we still found that LTP maintenance was not affected by postsynaptic application of AC3-I. Furthermore the inhibitor did not block LTP maintenance under conditions designed to enhance the Ca2+-dependent activity of protein phosphatases 1 and 2B (elevated Ca2+, calmodulin, and an inhibitor of protein kinase A). We also tested the possibility that CaMKII inhibitor might not be able to affect CaMKII once it was inserted into the PSD. In whole-brain extracts, AC3-I blocked autophosphorylation of both soluble and particulate/PSD CaMKII with similar potencies although the potency of the inhibitor toward other CaMKII substrates varied. Thus we were unable to demonstrate a functional role of persistent Ca2+-independent CaMKII activity in LTP maintenance. Possible explanations of the data are discussed.
Characterization of Outward Currents Induced by 5-HT in Neurons of Rat Dorsolateral Septal Nucleus
Authors: Yamada Kei , Hasuo Hiroshi , Ishimatsu Masaru , Akasu Takashi
Published: December 2017

Properties of the 5-hydroxytryptamine (5-HT)-induced current ( I5-HT) were examined in neurons of rat dorsolateral septal nucleus (DLSN) by using whole cell patch-clamp techniques. I5-HTwas associated with an increase in the membrane conductance of DLSN neurons. The reversal potential of I5-HTwas −93 ± 6 (SE) mV ( n = 7) in the artificial cerebrospinal fluid (ACSF) and was changed by 54 mV per decade change in the external K+concentration, indicating that I5-HTis carried exclusively by K+. Voltage dependency of the K+conductance underlying I5-HTwas investigated by using current-voltage relationship. I5-HTshowed a linear I-V relation in 63%, inward rectification in 21%, and outward rectification in 16% of DLSN neurons. (±)-8-Hydroxy-dipropylaminotetralin hydrobromide (30 μM), a selective 5-HT1Areceptor agonist, also produced outward currents with three types of voltage dependency. Ba2+(100 μM) blocked the inward rectifier I5-HTbut not the outward rectifier I5-HT. In I5-HTwith linear I-Vrelation, blockade of the inward rectifier K+current by Ba2+(100 μM) unmasked the outward rectifier current in DLSN neurons. These results suggest that I5-HTwith linear I-Vrelation is the sum of inward rectifier and outward rectifier K+currents in DLSN neurons. Intracellular application of guanosine-5′- O-(3-thiotriphosphate) (300 μM) and guanosine-5′- O-(2-thiodiphosphate) (5 mM), blockers of G protein, irreversibly depressed I5-HT. Protein kinase C (PKC) 19-36 (20 μM), a specific PKC inhibitor, depressed the outward rectifier I5-HTbut not the inward rectifier I5-HT. I5-HTwas depressed by N-ethylmaleimide, which uncouples the G-protein-coupled receptor from pertussis-toxin-sensitive G proteins. H-89 (10 μM) and adenosine 3′,5′-cyclic monophosphothioate Rp-isomer (300 μM), protein kinase A inhibitors, did not depress I5-HT. Phorbol 12-myristate 13-acetate (10 μM), an activator of PKC, produced an outward rectifying K+current. These results suggest that both 5-HT-induced inward and outward rectifying currents are mediated by a G protein and that PKC is probably involved in the transduction pathway of the outward rectifying I5-HTin DLSN neurons.
Role of Primate Magnocellular Red Nucleus Neurons in Controlling Hand Preshaping During Reaching to Grasp
Authors: Van Kan Peter L. E. , McCurdy Martha L.
Published: December 2017

Reaching to grasp is of fundamental importance to primate motor behavior and requires coordinating hand preshaping with limb transport and grasping. We aimed to clarify the role of cerebellar output via the magnocellular red nucleus (RNm) to the control of reaching to grasp. Rubrospinal fibers originating from RNm constitute one pathway by which cerebellar output influences spinal circuitry directly. We recorded discharge from individual forelimb RNm neurons while monkeys performed a reach-to-grasp task and two tasks that were similar to the reach-to-grasp task in trajectory, amplitude, and direction but did not include a grasp. One of these, the device task, elicited reaches while holding a handle, and the other, the free-reach task, elicited reaches that did not require any specific hand use for task performance. The results demonstrate that coordinated whole-limb reaching movements are associated with large discharge modulations of RNm neurons predominantly when hand use is included. Therefore RNm neurons can at best only make a minor contribution to the control of reaching movements that lack hand use. We evaluated relations between the discharge of individual RNm neurons and electromyographic (EMG) activity of forelimb muscles during the reach-to-grasp task by comparing times of peak RNm discharge to times of peak EMG activity. The results are consistent with the view that RNm discharge may contribute to EMG activity of both distal and proximal muscles during reaching to grasp especially digit extensor and limb elevation muscles. Relations between the discharge of individual RNm neurons and movements of the metacarpi-phalangeal (MCP), wrist, elbow, and shoulder joints during individual trials of task performance were quantified by parametric correlation analyses on a subset of neurons studied during the reach-to-grasp and free-reach tasks. The results indicate that MCP extensions were consistently preceded by bursts of RNm discharge, and strong correlations were observed between parameters of discharge and the duration, velocity, and amplitude of corresponding MCP extensions. In contrast, relations between discharge and movements of proximal joints were poorly represented, and RNm discharge was not related to the speed of limb transport. Based on our data and those of others, we hypothesize that cerebellar output via RNm is specialized for controlling hand use and conclude that RNm may contribute to the control of hand preshaping during reaching to grasp by activating muscle synergies that produce the appropriate MCP extension at the appropriate phase of limb transport.
Neurotensin Excites Periaqueductal Gray Neurons Projecting to the Rostral Ventromedial Medulla
Authors: Li Allen H. , Hwang Hwa-Min , Tan Peter P. , Wu Tony , Wang Hung-Li
Published: December 2017

Microinjection of neurotensin into the midbrain periaqueductal gray (PAG) produces a potent and naloxone-insensitive analgesic effect. To test the hypothesis that neurotensin induces the analgesic effect by activating the PAG-rostral ventromedial medulla (RVM) descending antinociceptive pathway, PAG neurons that project to RVM (PAG-RVM) were identified by microinjecting DiIC18, a retrograde tracing dye, into the rat RVM. Subsequently, fluorescently labeled PAG-RVM projection neurons were acutely dissociated and selected for whole cell patch-clamp recordings. During current-clamp recordings, neurotensin depolarized retrogradely labeled PAG-RVM neurons and evoked action potentials. Voltage-clamp recordings indicated that neurotensin excited PAG-RVM neurons by opening the voltage-insensitive and nonselective cation channels. Both SR 48692, a selective NTR-1 antagonist, and SR 142948A, a nonselective antagonist of NTR-1 and NTR-2, failed to prevent neurotensin from exciting PAG-RVM neurons. Neurotensin failed to evoke cationic currents after internally perfusing PAG-RVM projection neurons with GDP-β-S or anti-Gαq/11antiserum. Cellular Ca2+fluorescence measurement using fura-2 indicated that neurotensin rapidly induced Ca2+release from intracellular stores of PAG-RVM neurons. Neurotensin-evoked cationic currents were blocked by heparin, an IP3receptor antagonist, and 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid (BAPTA), a fast chelator of Ca2+. These results suggest that by activating a novel subtype of neurotensin receptors, neurotensin depolarizes and excites PAG-RVM projection neurons through enhancing Ca2+-dependent nonselective cationic conductance. The coupling mechanism via Gαq/11proteins is likely to involve the production of IP3, and subsequent IP3-evoked Ca2+release leads to the opening of nonselective cation channels.
Depression of Windup of Spinal Neurons in the Neonatal Rat Spinal Cord In Vitro by an NK3 Tachykinin Receptor Antagonist
Authors: Barbieri Mario , Nistri Andrea
Published: December 2017

The effects of the NK3 tachykinin receptor antagonist SR 142801 on synaptic transmission and spike windup induced by trains of stimuli applied to a dorsal root were investigated with intra- and extracellular recording from the neonatal rat spinal cord in vitro. SR 142801 (10 μM) reduced the depolarization (recorded from lumbar ventral roots) induced by senktide (an NK3 agonist) more strongly than the one evoked by substance P methyl ester (SPMeO; an NK1 agonist). Nevertheless, after a long (>2 h) application time, SR 142801 largely depressed the response to SPMeO as well. When NK1 or NK3 receptors were blocked by >50% in the presence of SR 142801, there was also a significant reduction in the cumulative depolarization induced by repeated stimuli to a single dorsal root. This blocking action by SR 142801 was also observed in the presence of the N-methyl-d-aspartate (NMDA) receptor antagonist d-aminophosphonovalerate (APV) and the calcium channel blocker nifedipine. Intracellular data from lumbar motoneurons showed that the spike windup was the first and most sensitive target for the SR 142801 blocking effect. Increasing stimulus strength to dorsal root fibers could partly surmount such a block. SR 142801 per se had no direct action on fast synaptic transmission, membrane potential, or input resistance. These findings indicate that SR 142801 could lead to an early, large reduction in the windup of action potential discharge by motoneurons, suggesting its ability to suppress the reflex component of central sensitization evoked by repeated dorsal root stimuli.
Frontal Eye Field Sends Delay Activity Related to Movement, Memory, and Vision to the Superior Colliculus
Authors: Sommer Marc A. , Wurtz Robert H.
Published: December 2017

Many neurons within prefrontal cortex exhibit a tonic discharge between visual stimulation and motor response. This delay activity may contribute to movement, memory, and vision. We studied delay activity sent from the frontal eye field (FEF) in prefrontal cortex to the superior colliculus (SC). We evaluated whether this efferent delay activity was related to movement, memory, or vision, to establish its possible functions. Using antidromic stimulation, we identified 66 FEF neurons projecting to the SC and we recorded from them while monkeys performed a Go/Nogo task. Early in every trial, a monkey was instructed as to whether it would have to make a saccade (Go) or not (Nogo) to a target location, which permitted identification of delay activity related to movement. In half of the trials (memory trials), the target disappeared, which permitted identification of delay activity related to memory. In the remaining trials (visual trials), the target remained visible, which permitted identification of delay activity related to vision. We found that 77% (51/66) of the FEF output neurons had delay activity. In 53% (27/51) of these neurons, delay activity was modulated by Go/Nogo instructions. The modulation preceded saccades made into only part of the visual field, indicating that the modulation was movement-related. In some neurons, delay activity was modulated by Go/Nogo instructions in both memory and visual trials and seemed to represent where to move in general. In other neurons, delay activity was modulated by Go/Nogo instructions only in memory trials, which suggested that it was a correlate of working memory, or only in visual trials, which suggested that it was a correlate of visual attention. In 47% (24/51) of FEF output neurons, delay activity was unaffected by Go/Nogo instructions, which indicated that the activity was related to the visual stimulus. In some of these neurons, delay activity occurred in both memory and visual trials and seemed to represent a coordinate in visual space. In others, delay activity occurred only in memory trials and seemed to represent transient visual memory. In the remainder, delay activity occurred only in visual trials and seemed to be a tonic visual response. In conclusion, the FEF sends diverse delay activity signals related to movement, memory, and vision to the SC, where the signals may be used for saccade generation. Downstream transmission of various delay activity signals may be an important, general way in which the prefrontal cortex contributes to the control of movement.
Electrophysiological Characteristics of Reactive Astrocytes in Experimental Cortical Dysplasia
Authors: Bordey A. , Lyons S. A. , Hablitz J. J. , Sontheimer H.
Published: December 2017

Neocortical freeze lesions have been widely used to study neuronal mechanisms underlying hyperexcitability in dysplastic cortex. Comparatively little attention has been given to biophysical changes in the surrounding astrocytes that show profound morphological and biochemical alterations, often referred to as reactive gliosis. Astrocytes are thought to aid normal neuronal function by buffering extracellular K+. Compromised astrocytic K+buffering has been proposed to contribute to neuronal dysfunction. Astrocytic K+buffering is mediated, partially, by the activity of inwardly rectifying K+channels ( KIR) and may involve intracellular redistribution of K+through gap-junctions. We characterized K+channel expression and gap-junction coupling between astrocytes in freeze-lesion-induced dysplastic neocortex. Whole cell patch-clamp recordings were obtained from astrocytes in slices from postnatal day (P) 16–P24 rats that had received a freeze-lesion on P1. A marked increase in glial fibrillary acidic protein immunoreactivity was observed along the entire length of the freeze lesion. Clusters of proliferative (bromo-deoxyuridine nuclear staining, BrdU+) astrocytes were seen near the depth of the microsulcus. Astrocytes in cortical layer I surrounding the lesion were characterized by a significant reduction in KIR. BrdU-positive astrocytes near the depth of the microsulcus showed essentially no expression of KIRchannels but markedly enhanced expression of delayed rectifier K+( KDR) channels. These proliferative cells showed virtually no dye coupling, whereas astrocytes in the hyperexcitable zone adjacent to the microsulcus displayed prominent dye-coupling as well as large KIRand outward K+currents. These findings suggest that reactive gliosis is accompanied by a loss of KIRcurrents and reduced gap junction coupling, which in turn suggests a compromised K+buffering capacity.
Functional Organization of Squirrel Monkey Primary Auditory Cortex: Responses to Pure Tones
Authors: Cheung Steven W. , Bedenbaugh Purvis H. , Nagarajan Srikantan S. , Schreiner Christoph E.
Published: December 2017

The spatial organization of response parameters in squirrel monkey primary auditory cortex (AI) accessible on the temporal gyrus was determined with the excitatory receptive field to pure tone stimuli. Dense, microelectrode mapping of the temporal gyrus in four animals revealed that characteristic frequency (CF) had a smooth, monotonic gradient that systematically changed from lower values (0.5 kHz) in the caudoventral quadrant to higher values (5–6 kHz) in the rostrodorsal quadrant. The extent of AI on the temporal gyrus was ∼4 mm in the rostrocaudal axis and 2–3 mm in the dorsoventral axis. The entire length of isofrequency contours below 6 kHz was accessible for study. Several independent, spatially organized functional response parameters were demonstrated for the squirrel monkey AI. Latency, the asymptotic minimum arrival time for spikes with increasing sound pressure levels at CF, was topographically organized as a monotonic gradient across AI nearly orthogonal to the CF gradient. Rostral AI had longer latencies (range = 4 ms). Threshold and bandwidth co-varied with the CF. Factoring out the contribution of the CF on threshold variance, residual threshold showed a monotonic gradient across AI that had higher values (range = 10 dB) caudally. The orientation of the threshold gradient was significantly different from the CF gradient. CF-corrected bandwidth, residual Q10, was spatially organized in local patches of coherent values whose loci were specific for each monkey. These data support the existence of multiple, overlying receptive field gradients within AI and form the basis to develop a conceptual framework to understand simple and complex sound coding in mammals.
Calcium Dynamics and Electrophysiological Properties of Cerebellar Purkinje Cells in SCA1 Transgenic Mice
Authors: Inoue Takafumi , Lin Xi , Kohlmeier Kristi A. , Orr Harry T. , Zoghbi Huda Y. , Ross William N.
Published: December 2017

Cerebellar Purkinje cells (PCs) from spinocerebellar ataxia type 1 (SCA1) transgenic mice develop dendritic and somatic atrophy with age. Inositol 1,4,5-trisphosphate receptor type 1 and the sarco/endoplasmic reticulum Ca2+ATPase pump, which regulate [Ca2+]i, are expressed at lower levels in these cells compared with the levels in cells from wild-type (WT) mice. To examine PCs in SCA1 mice, we used whole-cell patch clamp recording combined with fluorometric [Ca2+]iand [Na+]imeasurements in cerebellar slices. PCs in SCA1 mice had Na+spikes, Ca2+spikes, climbing fiber (CF) electrical responses, parallel fiber (PF) electrical responses, and metabotropic glutamate receptor (mGluR)-mediated, PF-evoked Ca2+release from intracellular stores that were qualitatively similar to those recorded from WT mice. Under our experimental conditions, it was easier to evoke the mGluR-mediated secondary [Ca2+]iincrease in SCA1 PCs. The membrane resistance of SCA1 PCs was 3.3 times higher than that of WT cells, which correlated with the 1.7 times smaller cell body size. Most SCA1 PCs (but not WT) had a delayed onset (about 50–200 ms) to Na+spike firing induced by current injection. This delay was increased by hyperpolarizing prepulses and was eliminated by 4-aminopyridine, which suggests that this delay was due to enhancement of the A-like K+conductance in the SCA1 PCs. In response to CF stimulation, most PCs in mutant and WT mice had rapid, widespread [Ca2+]ichanges that recovered in <200 ms. Some SCA1 PCs showed a slow, localized, secondary Ca2+transient following the initial CF Ca2+transient, which may reflect release of Ca2+from intracellular stores. Thus, with these exceptions, the basic physiological properties of mutant PCs are similar to those of WT neurons, even with dramatic alteration of their morphology and downregulation of Ca2+handling molecules.
Isolation of the Kernel for Respiratory Rhythm Generation in a Novel Preparation: The Pre-Bötzinger Complex “Island”
Authors: Johnson Shereé M. , Koshiya Naohiro , Smith Jeffrey C.
Published: December 2017

The pre-Bötzinger complex (pre-BötC), a bilaterally distributed network of rhythmogenic neurons within the ventrolateral medulla, has been proposed to be the critical locus for respiratory rhythm generation in mammals. To date, thin transverse medullary slice preparations that capture the pre-BötC have served as the optimal experimental model to study the region's inherent cellular and network properties. We have reduced the thin slices to isolated pre-BötC “islands” to further establish whether the pre-BötC has intrinsic rhythmicity and is the kernel for rhythmogenesis in the slice. We recorded neuron population activity locally in the pre-BötC with macroelectrodes and fluorescent imaging of Ca2+ activities with Calcium Green-1AM dye before and after excising the island. The isolated island remained rhythmically active with a population burst profile similar to the inspiratory burst in the slice. Rhythmic population activity persisted in islands after block of GABAAergic and glycinergic synaptic inhibition. The loci of pre-BötC Ca2+ activity imaged in thin slices and islands were similar, and imaged pre-BötC neurons exhibited synchronized flashing after blocking synaptic inhibition. Population burst frequency increased monotonically as extracellular potassium concentration was elevated, consistent with mathematical models consisting entirely of an excitatory network of synaptically coupled pacemaker neurons with heterogeneous, voltage-dependent bursting properties. Our results provide further evidence for a rhythmogenic kernel in the pre-BötC in vitro and demonstrate that the islands are ideal preparations for studying the kernel's intrinsic properties.
Sensorimotor Integration Compensates for Visual Localization Errors During Smooth Pursuit Eye Movements
Authors: van Beers Robert J. , Wolpert Daniel M. , Haggard Patrick
Published: December 2017

To localize a seen object, the CNS has to integrate the object's retinal location with the direction of gaze. Here we investigate this process by examining the localization of static objects during smooth pursuit eye movements. The normally experienced stability of the visual world during smooth pursuit suggests that the CNS essentially compensates for the eye movement when judging target locations. However, certain systematic localization errors are made, and we use these to study the process of sensorimotor integration. During an eye movement, a static object's image moves across the retina. Objects that produce retinal slip are known to be mislocalized: objects moving toward the fovea are seen too far on in their trajectory, whereas errors are much smaller for objects moving away from the fovea. These effects are usually studied by localizing the moving object relative to a briefly flashed one during fixation: moving objects are then mislocalized, but flashes are not. In our first experiment, we found that a similar differential mislocalization occurs for static objects relative to flashes during pursuit. This effect is not specific for horizontal pursuit but was also found in other directions. In a second experiment, we examined how this effect generalizes to positions outside the line of eye movement. We found that large localization errors were found in the entire hemifield ahead of the pursuit target and were predominantly aligned with the direction of eye movement. In a third experiment, we determined whether it is the flash or the static object that is mislocalized ahead of the pursuit target. In contrast to fixation conditions, we found that during pursuit it is the flash, not the static object, which is mislocalized. In a fourth experiment, we used egocentric localization to confirm this result. Our results suggest that the CNS compensates for the retinal localization errors to maintain position constancy for static objects during pursuit. This compensation is achieved in the process of sensorimotor integration of retinal and gaze signals: different retinal areas are integrated with different gaze signals to guarantee the stability of the visual world.