bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomy, Physiology, and Synaptic Responses of Rat Layer V Auditory Cortical Cells and Effects of Intracellular GABAABlockade
Authors: Hefti Brenda J. , Smith Philip H.
Published: December 2017

The varied extracortical targets of layer V make it an important site for cortical processing and output, which may be regulated by differences in the pyramidal neurons found there. Two populations of projection neurons, regular spiking (RS) and intrinsic bursting (IB), have been identified in layer V of some sensory cortices, and differences in their inhibitory inputs have been indirectly demonstrated. In this report, IB and RS cells were identified in rat auditory cortical slices, and differences in thalamocortical inhibition reaching RS and IB cells were demonstrated directly using intracellular GABAA blockers. Thalamocortical synaptic input to RS cells was always a combination of excitation and both GABAA and GABAB inhibition. Stimulation seldom triggered a suprathreshold response. IB cell synaptic responses were mostly excitatory, and stimulation usually triggered action potentials. This apparent difference was confirmed directly using intracellular chloride channel blockers. Before intracellular diffusion, synaptic responses were stable and similar to control conditions. Subsequently, GABAA was blocked, revealing a cell's total excitatory input. On GABAAblockade, RS cells responded to synaptic stimulation with large, suprathreshold excitatory events, indicating that excitation, while always present in these cells, is masked by GABAA. In IB cells that had visible GABAA input, it often masked an excitatory postsynaptic potential (EPSP) that could lead to additional suprathreshold events. These findings indicate that IB cells receive less GABAA-mediated inhibitory input and are able to spike or burst in response to thalamocortical synaptic stimulation far more readily than RS cells. Such differences may have implications for the influence each cell type exerts on its postsynaptic targets.
Electrophysiological Properties of Cholinergic and Noncholinergic Neurons in the Ventral Pallidal Region of the Nucleus Basalis in Rat Brain Slices
Authors: Bengtson C. Peter , Osborne Peregrine B.
Published: December 2017

The ventral pallidum is a major source of output for ventral corticobasal ganglia circuits that function in translating motivationally relevant stimuli into adaptive behavioral responses. In this study, whole cell patch-clamp recordings were made from ventral pallidal neurons in brain slices from 6- to 18-day-old rats. Intracellular filling with biocytin was used to correlate the electrophysiological and morphological properties of cholinergic and noncholinergic neurons identified by choline acetyltransferase immunohistochemistry. Most cholinergic neurons had a large whole cell conductance and exhibited marked fast (i.e., anomalous) inward rectification. These cells typically did not fire spontaneously, had a hyperpolarized resting membrane potential, and also exhibited a prominent spike afterhyperpolarization (AHP) and strong spike accommodation. Noncholinergic neurons had a smaller whole cell conductance, and the majority of these cells exhibited marked time-dependent inward rectification that was due to an h-current. This current activated slowly over several hundred milliseconds at potentials more negative than −80 mV. Noncholinergic neurons fired tonically in regular or intermittent patterns, and two-thirds of the cells fired spontaneously. Depolarizing current injection in current clamp did not cause spike accommodation but markedly increased the firing frequency and in some cells also altered the pattern of firing. Spontaneous tetrodotoxin-sensitive GABAA-mediated inhibitory postsynaptic currents (IPSCs) were frequently recorded in noncholinergic neurons. These results show that cholinergic pallidal neurons have similar properties to magnocellular cholinergic neurons in other parts of the forebrain, except that they exhibit strong spike accommodation. Noncholinergic ventral pallidal neurons have large h-currents that could have a physiological role in determining the rate or pattern of firing of these cells.
Selective Depolarization of Interneurons in the Early Posttraumatic Dentate Gyrus: Involvement of the Na+/K+-ATPase
Authors: Ross Stephen T. , Soltesz Ivan
Published: December 2017

Interneurons innervating dentate granule cells are potent regulators of the entorhino-hippocampal interplay. Traumatic brain injury, a leading cause of death and disability among young adults, is frequently associated with rapid neuropathological changes, seizures, and short-term memory deficits both in humans and experimental animals, indicating significant posttraumatic perturbations of hippocampal circuits. To determine the pathophysiological alterations that affect the posttraumatic functions of dentate neuronal networks within the important early (hours to days) posttraumatic period, whole cell patch-clamp recordings were performed from granule cells and interneurons situated in the granule cell layer of the dentate gyrus of head-injured and age-matched, sham-operated control rats. The data show that a single pressure wave-transient delivered to the neocortex of rats (mimicking moderate concussive head trauma) resulted in a characteristic (∼10 mV), transient (<4 days), selective depolarizing shift in the resting membrane potential of dentate interneurons, but not in neighboring granule cells. The depolarization was not associated with significant changes in action potential characteristics or input resistance, and persisted in the presence of antagonists of ionotropic and metabotropic glutamate, and GABAAand muscarinic receptors, as well as blockers of voltage-dependent sodium channels and of the h-current. The differential action of the cardiac glycosides oubain and stophanthidin on interneurons from control versus head-injured rats indicated that the depolarization of interneurons was related to the trauma-induced decrease in the activity of the electrogenic Na+/K+-ATPase. In contrast, the Na+/K+-ATPase activity in granule cells did not change. Intracellular injection of Na+, Ca2+-chelator and ATP, as well as ATP alone, abolished the difference between the resting membrane potentials of control and injured interneurons. The selective posttraumatic depolarization increased spontaneous firing in interneurons, enhanced the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) in granule cells, and augmented the efficacy of depolarizing inputs to discharge interneurons. These results demonstrate that mechanical neurotrauma delivered to a remote site has highly selective effects on different cell types even within the same cell layer, and that the electrogenic Na+-pump plays a role in setting the excitability of hippocampal interneuronal networks after injury.
D1 Dopamine Receptor Activation Reduces GABAA Receptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade
Authors: Flores-Hernandez Jorge , Hernandez Salvador , Snyder Gretchen L. , Yan Zhen , Fienberg Allen A. , Moss Stephen J. , Greengard Paul , Surmeier D. James
Published: December 2017

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D1 dopamine receptors in the regulation of postsynaptic GABAA receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D1 dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D1 dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D1 dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3′,5′ cyclic monophosphothioate) attenuated the response to D1 dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the β1 subunit of the GABAAreceptor—a known substrate of PKA—in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D1 dopamine receptor stimulation increased phosphorylation of GABAA receptor β1/β3 subunits. The D1dopamine receptor-induced phosphorylation of β1/β3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D1 dopamine receptor modulation of GABAA currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D1 dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABAA receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABAA receptor β1 subunits.
Thyroid Hormone Deficiency Before the Onset of Hearing Causes Irreversible Damage to Peripheral and Central Auditory Systems
Authors: Knipper Marlies , Zinn Christoph , Maier Hannes , Praetorius Mark , Rohbock Karin , Köpschall Iris , Zimmermann Ulrike
Published: December 2017

Both a genetic or acquired neonatal thyroid hormone (TH) deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and general success of delayed, corrective TH treatment was investigated by treating pregnant and lactating rats with the goitrogen methimazole (MMI). We observed that for the establishment of normal hearing ability, maternal TH, before fetal thyroid gland function on estrus days 17–18, is obviously not required. Within a crucial time between the onset of fetal thyroid gland function and the onset of hearing at postnatal day 12 ( P12), any postponement in the rise of TH-plasma levels, as can be brought about by treating lactating mothers with MMI, leads to permanent hearing defects of the adult offspring. The severity of hearing defects that were measured in 3- to 9-mo-old offspring could be increased with each additional day of TH deficiency during this critical period. Unexpectedly, the active cochlear process, assayed by distortion product otoacoustic emissions (DPOAE) measurements, and speed of auditory brain stem responses, which both until now were not thought to be controlled by TH, proved to be TH-dependent processes that were damaged by a delay of TH supply within this critical time. In contrast, no significant differences in the gross morphology and innervation of the organ of Corti or myelin gene expression in the auditory system, detected as myelin basic protein (MBP) and proteolipid protein (PLP) mRNA using Northern blot approach, were observed when TH supply was delayed for few days. These classical TH-dependent processes, however, were damaged when TH supply was delayed for several weeks. These surprising results may suggest the existence of different TH-dependent processes in the auditory system: those that respond to corrective TH supply (e.g., innervation and morphogenesis of the organ of Corti) and those that do not, but require T3 activity during a very tight time window (e.g., active cochlear process, central processes).
Time-Dependent Changes in Input Resistance of Rat Hypoglossal Motoneurons Associated with Whole-Cell Recording
Authors: Robinson David W. , Cameron William E.
Published: December 2017

The effect of cellular dialysis associated with whole-cell recording was studied in 24 developing hypoglossal motoneurons in a rat brainstem slice preparation. In all cases, establishing whole-cell continuity with the electrode solution resulted in an increase in the input resistance measured in current clamp. The mean magnitude of this increase was 39.7% and the time course of the maximum effect was quite variable. There was no correlation found between the time to maximum effect and the magnitude of the increase in resistance. These data indicate that the passive membrane properties are not constant during whole-cell recording in mammalian motoneurons.
Hippocampus–Entorhinal Cortex Loop and Seizure Generation in the Young Rodent Limbic System
Authors: Calcagnotto Maria Elisa , Barbarosie Michaela , Avoli Massimo
Published: December 2017

Application of the convulsant 4-aminopyridine (4AP, 50 μM) to adult mouse combined hippocampus–entorhinal cortex (EC) slices induces interictal and ictal discharges originating from CA3 and EC respectively. In this model of limbic seizures, ictal discharges disappear over time and are reestablished after Schaffer collateral cut, a procedure that blocks interictal propagation from CA3 to EC. Here we tested whether this form of network plasticity is operant in hippocampus–EC slices obtained from young (10–25 day-old) mice. In these experiments 4AP elicited interictal (duration = 100–250 ms; interval = 0.7 ± 0.2 s, mean ± SD, n = 20) and ictal (duration = 267 ± 37 s; interval = 390 ± 37 s, n = 20) discharges in both CA3 and EC. However, in young mouse slices the ictal events occurred throughout the experiment, whereas Schaffer collateral cut abolished CA3-driven interictal discharges in EC without influencing ictal activity ( n = 10). Perforant path lesion prevented the spread of EC-driven ictal events to CA3, where interictal and short ictal discharges (duration = 32 ± 11 s; interval = 92 ± 9.7 s, n = 8) continued to occur. Hence, two independent forms of ictal activity were seen in CA3 and in EC after separation of these structures. In intact hippocampus–EC slices, ictal discharges were reduced by an N-methyl-d-aspartate receptor antagonist ( n = 10). Under these conditions, Schaffer collateral cut abolished ictal activity in EC, not in CA3 ( n = 6). Thus the young mouse hippocampus–EC loop has different properties as compared with adult tissue. These differences, which include the inability of hippocampal outputs to control ictal discharge generation in EC and the ability of the loop to sustain ictal activity, may contribute to the low-seizure threshold seen in young individuals.
Bovine Versus Rat Adrenal Chromaffin Cells: Big Differences in BK Potassium Channel Properties
Authors: Lovell Peter V. , James Dustin G. , McCobb David P.
Published: December 2017

Both bovine and rat adrenal chromaffin cells have served as pioneering model systems in cellular neurophysiology, including in the study of large conductance calcium- and voltage-dependent K+(BK) channels. We now report that while BK channels dominate the outward current profile of both species, specific gating properties vary widely across cell populations, and the distributions of these properties differ dramatically between species. Although BK channels were first described in bovine chromaffin cells, rapidly inactivating ones were discovered in rat chromaffin cells. We report that bovine cells can also exhibit inactivating BK channels with varying properties similar to those in rat cells. However, a much smaller proportion of bovine cells exhibit inactivating BK current, the proportion of the total current that inactivates is usually smaller, and the rate of inactivation is often much slower. Other gating features differ as well; the voltage dependence of channel activation is much more positive for bovine cells, and their rates of activation and deactivation are faster and slower, respectively. Modeling studies suggest that channel heterogeneity is consistent with varying tetrameric combinations of inactivation-competent versus -incompetent subunits. The results suggest that chromaffin BK channel functional nuances represent an important level for evolutionary tailoring of autonomic stress responses.
Contralateral Movement and Extensor Force Generation Alter Flexion Phase Muscle Coordination in Pedaling
Authors: Ting Lena H. , Kautz Steven A. , Brown David A. , Zajac Felix E.
Published: December 2017

The importance of bilateral sensorimotor signals in coordination of locomotion has been demonstrated in animals but is difficult to ascertain in humans due to confounding effects of mechanical transmission of forces between the legs (i.e., mechanical interleg coupling). In a previous pedaling study, by eliminating mechanical interleg coupling, we showed that muscle coordination of a unipedal task can be shaped by interlimb sensorimotor pathways. Interlimb neural pathways were shown to alter pedaling coordination as subjects pedaling unilaterally exhibited increased flexion-phase muscle activity compared with bilateral pedaling even though the task mechanics performed by the pedaling leg(s) in the unilateral and bilateral pedaling tasks were identical. To further examine the relationship between contralateral sensorimotor state and ipsilateral flexion-phase muscle coordination during pedaling, subjects in this study pedaled with one leg while the contralateral leg either generated an extensor force or relaxed as a servomotor either held that leg stationary or moved it in antiphase with the pedaling leg. In the presence of contralateral extensor force generation, muscle activity in the pedaling leg during limb flexion was reduced. Integrated electromyographic activity of the pedaling-leg hamstring muscles (biceps femoris and semimembranosus) during flexion decreased by 25–30%, regardless of either the amplitude of force generated by the nonpedaling leg or whether the leg was stationary or moving. In contrast, rectus femoris and tibialis anterior activity during flexion decreased only when the contralateral leg generated high rhythmic force concomitant with leg movement. The results are consistent with a contralateral feedforward mechanism triggering flexion-phase hamstrings activity and a contralateral feedback mechanism modulating rectus femoris and tibialis anterior activity during flexion. Because only muscles that contribute to flexion as a secondary function were observed, it is impossible to know whether the modulatory effect also acts on primary, unifunctional, limb flexors or is specific to multifunctional muscles contributing to flexion. The influence of contralateral extensor-phase sensorimotor signals on ipsilateral flexion may reflect bilateral coupling of gain control mechanisms. More generally, these interlimb neural mechanisms may coordinate activity between muscles that perform antagonistic functions on opposite sides of the body. Because pedaling and walking share biomechanical and neuronal control features, these mechanisms may be operational in walking as well as pedaling.
Role of Muscle Pulleys in Producing Eye Position-Dependence in the Angular Vestibuloocular Reflex: A Model-Based Study
Authors: Thurtell Matthew J. , Kunin Mikhail , Raphan Theodore
Published: December 2017

It is well established that the head and eye velocity axes do not always align during compensatory vestibular slow phases. It has been shown that the eye velocity axis systematically tilts away from the head velocity axis in a manner that is dependent on eye-in-head position. The mechanisms responsible for producing these axis tilts are unclear. In this model-based study, we aimed to determine whether muscle pulleys could be involved in bringing about these phenomena. The model presented incorporates semicircular canals, central vestibular pathways, and an ocular motor plant with pulleys. The pulleys were modeled so that they brought about a rotation of the torque axes of the extraocular muscles that was a fraction of the angle of eye deviation from primary position. The degree to which the pulleys rotated the torque axes was altered by means of a pulley coefficient. Model input was head velocity and initial eye position data from passive and active yaw head impulses with fixation at 0°, 20° up and 20° down, obtained from a previous experiment. The optimal pulley coefficient required to fit the data was determined by calculating the mean square error between data and model predictions of torsional eye velocity. For active head impulses, the optimal pulley coefficient varied considerably between subjects. The median optimal pulley coefficient was found to be 0.5, the pulley coefficient required for producing saccades that perfectly obey Listing's law when using a two-dimensional saccadic pulse signal. The model predicted the direction of the axis tilts observed in response to passive head impulses from 50 ms after onset. During passive head impulses, the median optimal pulley coefficient was found to be 0.21, when roll gain was fixed at 0.7. The model did not accurately predict the alignment of the eye and head velocity axes that was observed early in the response to passive head impulses. We found that this alignment could be well predicted if the roll gain of the angular vestibuloocular reflex was modified during the initial period of the response, while pulley coefficient was maintained at 0.5. Hence a roll gain modification allows stabilization of the retinal image without requiring a change in the pulley effect. Our results therefore indicate that the eye position–dependent velocity axis tilts could arise due to the effects of the pulleys and that a roll gain modification in the central vestibular structures may be responsible for countering the pulley effect.
MST Responses to Pursuit Across Optic Flow With Motion Parallax
Authors: Upadhyay Urmen D. , Page William K. , Duffy Charles J.
Published: December 2017

Self-movement creates the patterned visual motion of optic flow with a focus of expansion (FOE) that indicates heading direction. During pursuit eye movements, depth cues create a retinal flow field that contains multiple FOEs, potentially complicating heading perception. Paradoxically, human heading perception during pursuit is improved by depth cues. We have studied medial superior temporal (MST) neurons to see whether their heading selectivity is also improved under these conditions. The responses of 134 MST neurons were recorded during the presentation of optic flow stimuli containing one or three speed-defined depth planes. During pursuit, multiple depth-plane stimuli evoked larger responses (71% of neurons) and stronger heading selectivity (70% of neurons). Responses to the three speed-defined depth-planes presented separately showed that most neurons (54%) preferred one of the planes. Responses to multiple depth-plane stimuli were larger than the averaged responses to the three component planes, suggesting enhancing interactions between depth-planes. Thus speed preferences create selective responses to one of many depth-planes in the retinal flow field. The presence of multiple depth-planes enhances those responses. These properties might improve heading perception during pursuit and contribute to relative depth perception.
Novel Mechanism for Presynaptic Inhibition: GABAAReceptors Affect the Release Machinery
Authors: Parnas I. , Rashkovan G. , Ravin R. , Fischer Y.
Published: December 2017

Presynaptic inhibition is produced by increasing Cl− conductance, resulting in an action potential of a smaller amplitude at the excitatory axon terminals. This, in turn, reduces Ca2+ entry to produce a smaller release. For this mechanism to operate, the “inhibitory” effect of shunting should last during the arrival of the “excitatory” action potential to its terminals, and to achieve that, the inhibitory action potential should precede the excitatory action potential. Using the crayfish neuromuscular preparation which is innervated by one excitatory axon and one inhibitory axon, we found, at 12°C, prominent presynaptic inhibition when the inhibitory action potential followed the excitatory action potential by 1, and even 2, ms. The presynaptic excitatory action potential and the excitatory nerve terminal current (ENTC) were not altered, and Ca2+imaging at single release boutons showed that this “late” presynaptic inhibition did not result from a reduction in Ca2+ entry. Since 50 μM picrotoxin blocked this late component of presynaptic inhibition, we suggest that γ-aminobutyric acid-A (GABAA) receptors reduce transmitter release also by a mechanism other than affecting Ca2+ entry.
The Open- and Closed-Loop Gain-Characteristics of the Cone/Horizontal Cell Synapse in Goldfish Retina
Authors: Kraaij D. A. , Spekreijse H. , Kamermans M.
Published: December 2017

Under constant light-adapted conditions, vision seems to be rather linear. However, the processes underlying the synaptic transmission between cones and second-order neurons (bipolar cells and horizontal cells) are highly nonlinear. In this paper, the gain-characteristics of the transmission from cones to horizontal cells and from horizontal cells to cones are determined with and without negative feedback from horizontal cells to cones. It is shown that 1) the gain-characteristic from cones to horizontal cells is strongly nonlinear without feedback from horizontal cells, 2) the gain-characteristic between cones and horizontal cells becomes linear when feedback is active, and 3) horizontal cells feed back to cones via a linear mechanism. In a quantitative analysis, it will be shown that negative feedback linearizes the synaptic transmission between cones and horizontal cells. The physiological consequences are discussed.
Expression and Channel Properties of α-Bungarotoxin-Sensitive Acetylcholine Receptors on Chick Ciliary and Choroid Neurons
Authors: McNerney Mary Ellen , Pardi Desiree , Pugh Phyllis C. , Nai Qiang , Margiotta Joseph F.
Published: December 2017

Cell-specific expression of nicotinic acetylcholine receptors (AChRs) was examined using ciliary and choroid neurons isolated from chick ciliary ganglia. At embryonic days 13 and 14 (E13,14) the neurons can be distinguished by size, with ciliary neuron soma diameters exceeding those of choroid neurons by about twofold. Both neuronal populations are known to express two major AChR types: α3*-AChRs recognized by mAb35, that contain α3, α5, β4, and occasionally β2 subunits, and α-bungarotoxin (αBgt)-AChRs recognized and blocked by αBgt, that contain α7 subunits. We found that maximal whole cell current densities ( I/ C m) mediated by αBgt-AChRs were threefold larger for choroid compared with ciliary neurons, while α3*-AChR current densities were similar in the two populations. Different densities of total cell-surface αBgt-AChRs could not explain the distinct αBgt-AChR response densities associated with ciliary and choroid neurons. Ciliary ganglion neurons display abundant [125I]-αBgt binding (≈106 sites/neuron), but digital fluorescence measurements revealed equivalent site densities on both populations. AChR channel classes having single-channel conductances of ≈30, 40, 60, and 80 pS were present in patches excised from both ciliary and choroid neurons. Treating the neurons with αBgt selectively abolished the 60- and 80-pS events, identifying them as arising from αBgt-AChRs. Kinetic measurements revealed brief open and long closed durations for αBgt-AChR channel currents, predicting a very low probability of being open ( p o) when compared with 30- or 40-pS α3*-AChR channels. None of the channel parameters associated with the 60- and 80-pS αBgt-AChRs differed detectably, however, between choroid and ciliary neurons. Instead calculations based on the combined whole cell and single-channel results indicate that choroid neurons express approximately threefold larger numbers of functional αBgt-AChRs ( N F) per unit area than do ciliary neurons. Comparison with total surface [125I]-αBgt-AChR sites ( N T), reveals that N F/ N T≪ 1 for both neuron populations, suggesting that “silent” αBgt-AChRs predominate. Choroid neurons may therefore express a higher density of functional αBgt-AChRs by recruiting a larger fraction of receptors from the silent pool than do ciliary neurons.
EEG Correlation of the Discharge Properties of Identified Neurons in the Basal Forebrain
Authors: Duque A. , Balatoni B. , Detari L. , Zaborszky L.
Published: December 2017

The basal forebrain (BF) is a heterogeneous structure located in the ventral aspect of the cerebral hemispheres. It contains cholinergic as well as different types of noncholinergic corticopetal neurons and interneurons, including GABAergic and peptidergic cells. The BF constitutes an extrathalamic route to the cortex, and its activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with electroencephalographic (EEG) low-voltage fast activity (LVFA). However, the specific role of the different BF cell types has largely remained unknown due to the lack of chemical identification of the recorded neurons. Here we show that the firing rate of immunocytochemically identified cholinergic and parvalbumin-containing neurons increase during cortical LVFA. In contrast, increased neuropeptide Y neuron firing is accompanied by cortical slow waves. Our results, furthermore, indicate that BF neurons posses a distinct temporal relationship to different EEG patterns and suggest a more dynamic interplay within BF as well as between BF and cortical circuitries than previously proposed.
Context-Dependent Smooth Eye Movements Evoked by Stationary Visual Stimuli in Trained Monkeys
Authors: Tanaka Masaki , Lisberger Stephen G.
Published: December 2017

The appearance of a stationary but irrelevant cue triggers a smooth eye movement away from the position of the cue in monkeys that have been trained extensively to smoothly track the motion of moving targets while not making saccades to the stationary cue. We have analyzed the parameters that regulate the size of the cue-evoked smooth eye movement and examined whether presentation of the cue changes the initiation of pursuit for subsequent steps of target velocity. Cues evoked smooth eye movements in blocks of target motions that required smooth pursuit to moving targets, but evoked much smaller smooth eye movements in blocks that required saccades to stationary targets. The direction of the cue-evoked eye movement was always opposite to the position of the cue and did not depend on whether subsequent target motion was toward or away from the position of fixation. The latency of the cue-evoked smooth eye movement was near 100 ms and was slightly longer than the latency of pursuit for target motion away from the position of fixation. The size of the cue-evoked smooth eye movement was as large as 10°/s and decreased as functions of the eccentricity of the cue and the illumination of the experimental room. To study the initiation of pursuit in the wake of the cues, we used bilateral cues at equal eccentricities to the right and left of the position of fixation. These evoked smaller eye velocities that were consistent with vector averaging of the responses to each cue. In the wake of bilateral cues, the initiation of pursuit was enhanced for target motion away from the position of fixation, but not for target motion toward the position of fixation. We suggest that the cue-evoked smooth eye movement is related to a previously postulated on-line gain control for pursuit, and that it is a side-effect of sudden activation of the gain-controlling element.
Control of Membrane Sealing in Injured Mammalian Spinal Cord Axons
Authors: Shi Riyi , Asano Tomoko , Vining Neil C. , Blight Andrew R.
Published: December 2017

The process of sealing of damaged axons was examined in isolated strips of white matter from guinea pig spinal cord by recording the “compound membrane potential,” using a sucrose-gap technique, and by examining uptake of horseradish peroxidase (HRP). Following axonal transection, exponential recovery of membrane potential occurred with a time constant of 20 ± 5 min, at 37°C, and extracellular calcium activity ([Ca2+]o) of 2 mM. Most axons excluded HRP by 30 min following transection. The rate of sealing was reduced by lowering calcium and was effectively blocked at [Ca2+]o≤ 0.5 mM, under which condition most axons continued to take up HRP for more than 1 h. Sealing at higher [Ca2+]owas blocked by calpain inhibitors (calpeptin and calpain inhibitor-1) indicating a requirement for type II (mM) calpain in the sealing process. Following compression injury, the amplitude of the maximal compound action potential conducted through the injury site was reduced. The extent of amplitude reduction was increased when the tract was superfused with calcium-free Krebs' solution (Ca2+replaced by Mg2+). These results suggest that the fall in [Ca2+]oseen following injury in vivo is sufficient to prevent membrane sealing and may paradoxically contribute to axonal dieback, retrograde cell death, and “secondary” axonal disruption.
Effects of Inactivation of the Anterior Interpositus Nucleus on the Kinematic and Dynamic Control of Multijoint Movement
Authors: Cooper Scott E. , Martin John H. , Ghez Claude
Published: December 2017

We previously showed that inactivating the anterior interpositus nucleus in cats disrupts prehension; paw paths, normally straight and accurate, become curved, hypometric, and more variable. In the present study, we determined the joint kinematic and dynamic origins of this impairment. Animals were restrained in a hammock and trained to reach and grasp a cube of meat from a narrow food well at varied heights; movements were monitored using the MacReflex analysis system. The anterior interpositus nucleus was inactivated by microinjection of the GABA agonist muscimol (0.25–0.5 μg in 0.5 μL saline). For each joint, we computed the torque due to gravity, inertial resistance (termed self torque), interjoint interactions (termed interaction torque), and the combined effects of active muscle contraction and passive soft tissue stretch (termed generalized muscle torque). Inactivation produced significant reductions in the amplitude, velocity, and acceleration of elbow flexion. However, these movements continued to scale normally with target height. Shoulder extension was reduced by inactivation but wrist angular displacement and velocity were not. Inactivation also produced changes in the temporal coordination between elbow, shoulder, and wrist kinematics. Dynamic analysis showed that elbow flexion both before and during inactivation was produced by the combined action of muscle and interaction torque, but that the timing depended on muscle torque. Elbow interaction and muscle torques were scaled to target height both before and during inactivation. Inactivation produced significant reductions in elbow flexor interaction and muscle torques. The duration of elbow flexor muscle torque was prolonged to compensate for the reduction in flexor interaction torque. Shoulder extension was produced by extensor interaction and muscle torques both before and during inactivation. Inactivation produced a reduction in shoulder extension, primarily by reduced interaction torque, but without compensation. Wrist plantarflexion, which occurred during elbow flexion, was driven by plantarflexor interaction and gravitational torques both before and during inactivation. Muscle torque acted in the opposite direction with a phase lead to restrain the plantarflexor interaction torque. During inactivation, there was a reduction in plantarflexor interaction torque and a loss of the phase lead of the muscle torque. Our findings implicate the C1/C3 anterior interpositus zone of the cerebellum in the anticipatory control of intersegmental dynamics during reaching, which zone is required for coordinating the motions of the shoulder and wrist with those of the elbow. In contrast, this cerebellar zone does not play a role in scaling the movement to match a target.
β-Adrenergic Receptor-Mediated Presynaptic Facilitation of Inhibitory GABAergic Transmission at Cerebellar Interneuron-Purkinje Cell Synapses
Authors: Saitow Fumihito , Satake Shin'Ichiro , Yamada Junko , Konishi Shiro
Published: December 2017

Norepinephrine (NE) has been shown to elicit long-term facilitation of GABAergic transmission to rat cerebellar Purkinje cells (PCs) through β-adrenergic receptor activation. To further examine the locus and adrenoceptor subtypes involved in the NE-induced facilitation of GABAergic transmission, we recorded inhibitory postsynaptic currents (IPSCs) evoked by focal stimulation with paired-pulse (PP) stimuli from PCs in rat cerebellar slices by whole cell recordings and analyzed the PP ratio of the IPSC amplitude. NE increased the IPSC amplitude with a decease in the variance of the PP ratio, which was mimicked by presynaptic manipulation of the transmission caused by increasing the extracellular Ca2+ concentration, confirming that the presynaptic adrenergic receptors are responsible for the facilitation. Pharmacological tests showed that the β2-adrenoceptor antagonist, ICI118,551, but not the β1-adrenoceptor antagonist, CGP20712A, blocked the NE-induced IPSC facilitation, suggesting that the β2-adrenoceptors on cerebellar interneurons, basket cells (BCs), mediate the noradrenergic facilitation of GABAergic transmission. Double recordings were performed from BCs and PCs to further characterize the regulation of the GABAergic synapses. First, on-cell recordings from BCs showed that the β-agonist isoproterenol (ISP) increased the frequencies of the spontaneous spikes in BCs and the spike-triggered IPSCs in PCs recorded with the whole cell mode. The amplitude of the spike-triggered IPSCs decreased or increased depending on the individual GABAergic synapses examined. Forskolin invariably increased both the amplitude and the frequency of the spike-triggered IPSCs. Double whole cell recordings from BC-PC pairs showed that ISP mainly caused an increase in the amplitude of the IPSCs evoked in the PCs by an action current in the BCs produced in response to voltage steps from −60 to −10 mV. Our data suggest that the noradrenergic facilitation of GABAergic transmission in the rat cerebellar cortex is mediated, at least in part, by depolarization and action potential discharges in the BCs through activation of the β2-adrenoceptors in BCs coupled to intracellular cyclic AMP formation.
Modeling Inhibitory Plasticity in the Electrosensory System of Mormyrid Electric Fish
Authors: Roberts Patrick D.
Published: December 2017

Mathematical analyses and computer simulations are used to study the adaptation induced by plasticity at inhibitory synapses in a cerebellum-like structure, the electrosensory lateral line lobe (ELL) of mormyrid electric fish. Single-cell model results are compared with results obtained at the system level in vivo. The model of system level adaptation uses detailed temporal learning rules of plasticity at excitatory and inhibitory synapses onto Purkinje-like neurons. Synaptic plasticity in this system depends on the time difference between pre- and postsynaptic spikes. Adaptation is measured by the ability of the system to cancel a reafferent electrosensory signal by generating a negative image of the predicted signal. The effects of plasticity are tested for the relative temporal correlation between the inhibitory input and the sensory input, the gain of the sensory signal, and the presence of shunting inhibition. The model suggests that the presence of plasticity at inhibitory synapses improves the function of the system if the inhibitory inputs are temporally correlated with a predictable electrosensory signal. The functional improvements include an increased range of adaptability and a higher rate of system level adaptation. However, the presence of shunting inhibition has little effect on the dynamics of the model. The model quantifies the rate of system level adaptation and the accuracy of the negative image. We find that adaptation proceeds at a rate comparable to results obtained from experiments in vivo if the inhibitory input is correlated with electrosensory input. The mathematical analysis and computer simulations support the hypothesis that inhibitory synapses in the molecular layer of the ELL change their efficacy in response to the timing of pre- and postsynaptic spikes. Predictions include the rate of adaptation to sensory stimuli, the range of stimulus amplitudes for which adaptation is possible, the stability of stored negative images, and the timing relations of a temporal learning rule governing the inhibitory synapses. These results may be generalized to other adaptive systems in which plasticity at inhibitory synapses obeys similar learning rules.
Computational Model of the Role of Sensory Disorganization in Focal Task-Specific Dystonia
Authors: Sanger Terence D. , Merzenich Michael M.
Published: December 2017

We present a new computational model for the development of task-specific focal dystonia. The purpose of the model is to explain how altered sensory representations can lead to abnormal motor behavior. Dystonia is described as the result of excessive gain through a sensorimotor loop. The gain is determined in part by the sensory cortical area devoted to each motor function, and behaviors that lead to abnormal increases in sensory cortical area are predicted to lead to dystonia. Properties of dystonia including muscular co-contraction, overflow movements, and task specificity are predicted by properties of a linear approximation to the loop transformation. We provide simulations of several different mechanisms that can cause the gain to exceed 1 and the motor activity to become sustained and uncontrolled. The model predicts that normal plasticity mechanisms may contribute to worsening of symptoms over time.
Floccular Modulation of Vestibuloocular Pathways and Cerebellum-Related Plasticity: An In Vitro Whole Brain Study
Authors: Babalian Alexander L. , Vidal Pierre-Paul
Published: December 2017

The isolated whole brain (IWB) preparation of the guinea pig was used to investigate the floccular modulation of vestibular-evoked responses in abducens and oculomotor nerves and abducens nucleus; for identification of flocculus target neurons (FTNs) in the vestibular nuclei and intracellular study of some of their physiological properties; to search for possible flocculus-dependent plasticity at the FTN level by pairing of vestibular nerve and floccular stimulations; and to study the possibility of induction of long-term depression (LTD) in Purkinje cells by paired stimulation of the inferior olive and vestibular nerve. Stimulation of the flocculus had only effects on responses evoked from the ipsilateral (with respect to the stimulated flocculus) vestibular nerve. Floccular stimulation significantly inhibited the vestibular-evoked discharges in oculomotor nerves on both sides and the inhibitory field potential in the ipsilateral abducens nucleus while the excitatory responses in the contralateral abducens nerve and nucleus were free from such inhibition. Eleven second-order vestibular neurons were found to receive a short-latency monosynaptic inhibitory input from the flocculus and were thus characterized as FTNs. Monosynaptic inhibitory postsynaptic potentials from the flocculus were bicuculline sensitive, suggesting a GABAA-ergic transmission from Purkinje cells to FTNs. Two of recorded FTNs could be identified as vestibulospinal neurons by their antidromic activation from the cervical segments of the spinal cord. Several pairing paradigms were investigated in which stimulation of the flocculus could precede, coincide with, or follow the vestibular nerve stimulation. None of them led to long-term modification of responses in the abducens nucleus or oculomotor nerve evoked by activation of vestibular afferents. On the other hand, pairing of the inferior olive and vestibular nerve stimulation resulted in approximately a 30% reduction of excitatory postsynaptic potentials evoked in Purkinje cells by the vestibular nerve stimulation. This reduction was pairing-specific and lasted throughout the entire recording time of the neurons. Thus in the IWB preparation, we were able to induce a LTD in Purkinje cells, but we failed to detect traces of flocculus-dependent plasticity at the level of FTNs in vestibular nuclei. Although these data cannot rule out the possibility of synaptic modifications in FTNs and/or at other brain stem sites under different experimental conditions, they are in favor of the hypothesis that the LTD in the flocculus could be the essential mechanism of cellular plasticity in the vestibuloocular pathways.
Influence of Stimulus Eccentricity and Direction on Characteristics of Pro- and Antisaccades in Non-Human Primates
Authors: Bell A. H. , Everling S. , Munoz D. P.
Published: December 2017

The ability to inhibit reflexes in favor of goal-oriented behaviors is critical for optimal exploration and interaction with our environment. The antisaccade task can be used to investigate the ability of subjects to suppress a reflexive saccade (prosaccade) to a suddenly appearing visual stimulus and instead generate a voluntary saccade (antisaccade) to its mirror location. To understand the neural mechanisms required to perform this task, our lab has developed a non-human primate model. Two monkeys were trained on a task with randomly interleaved pro- and antisaccade trials, with the color of the central fixation point (FP) instructing the monkey to either make a prosaccade (red FP) or an antisaccade (green FP). In half of the trials, the FP disappeared 200 ms before stimulus presentation (gap condition) and in the remaining trials, the FP remained visible (overlap condition) during stimulus presentation. The effect of stimulus eccentricity and direction was examined by presenting the stimulus at one of eight different radial directions (0−360°) and five eccentricities (2, 4, 8, 10, and 16°). Antisaccades had longer saccadic reaction times (SRTs), more dysmetria, and lower peak velocities than prosaccades. Direction errors in the antisaccade task were more prevalent in the gap condition. The difference in mean SRT between correct pro- and antisaccades, the anti-effect, was greater in the overlap condition. The difference in mean SRT between the overlap and the gap condition, the gap effect, was larger for antisaccades than for prosaccades. The manipulation of stimulus eccentricity and direction influenced SRT and the proportion of direction errors. These results are comparable to human studies, supporting the use of this animal model for investigating the neural mechanisms subserving the generation of antisaccades.
Homeostasis of REM Sleep After Total and Selective Sleep Deprivation in the Rat
Authors: Ocampo-Garcés Adrián , Molina Enrique , Rodríguez Alberto , Vivaldi Ennio A.
Published: December 2017

During specific rapid eye movement (REM) sleep deprivation its homeostatic regulation is expressed by progressively more frequent attempts to enter REM and by a compensatory rebound after the deprivation ends. The buildup of pressure to enter REM may be hypothesized to depend just on the time elapsed without REM or to be differentially related to non-REM (NREM) and wakefulness. This problem bears direct implications on the issue of the function of REM and its relation to NREM. We compared three protocols that combined REM-specific and total sleep deprivation so that animals underwent similar 3-h REM deprivations but different concomitant NREM deprivations for the first 2 (2T1R), 1 (1T2R), or 0 (3R) hours. Deprivation periods started at hour 6 after lights on. Twenty-two chronically implanted rats were recorded. The median amount of REM during all three protocols was ∼1 min. The deficits of median amount of NREM in minutes within the 3-h deprivation periods as compared with their baselines were, respectively for 2T1R, 1T2R, and 3R, 35 (43%), 25 (25%), and 7 (7%). Medians of REM rebound in the three succeeding hours, in minutes above baseline, were, respectively, 8 (44%), 9 (53%), and 9 (50%), showing no significant differences among protocols. Attempted transitions to REM showed a rising trend during REM deprivations reaching a final value that did not differ significantly among the three protocols. These results support the hypothesis that the build up of REM pressure and its subsequent rebound is primarily related to REM absence independent of the presence of NREM.