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R A Pearce

Publications and source records attributed to R A Pearce.

34 records · Page 2Linked to original sources
PubMed1997

GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells.

GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells. J. Neurophysiol. 78: 2531-2545, 1997. A recent study in piriform (olfactory) cortex provided evidence that, as in hippocampus and neocortex, gamma-aminobutyric acid-A (GABAA)-mediated inhibition is generated in dendrites of pyramidal cells, not just in the somatic region as previously believed. This study examines selected properties of GABAA inhibitory postsynaptic currents (IPSCs) in dendritic and somatic regions that could provide insight into their functional roles. Pharmacologically isolated GABAA-mediated IPSCs were studied by whole cell patch recording in slices. To compare properties of IPSCs in distal dendritic and somatic regions, local stimulation was carried out with tungsten microelectrodes, and spatially restricted blockade of GABAA-mediated inhibition was achieved by pressure-ejection of bicuculline from micropipettes. The results revealed that largely independent circuits generate GABAA inhibition in distal apical dendritic and somatic regions. With such independence, a selective decrease in dendritic-region inhibition could enhance integrative or plastic processes in dendrites while allowing feedback inhibition in the somatic region to restrain system excitability. This could allow modulatory fiber systems from the basal forebrain or brain stem, for example, to change the functional state of the cortex by altering the excitability of interneurons that mediate dendritic inhibition without increasing the propensity for regenerative bursting in this highly epileptogenic system. As in hippocampus, GABAA-mediated IPSCs were found to have fast and slow components with time constants of decay on the order of 10 and 40 ms, respectively, at 29 degrees C. Modeling analysis supported physiological evidence that the slow time constant represents a true IPSC component rather than an artifactual slowing of the fast component from voltage clamp of a dendritic current. The results indicated that, whereas both dendritic and somatic-region IPSCs have both fast and slow GABAA components, there is a greater proportion of the slow component in dendrites. In a companion paper, the hypothesis is explored that the resulting slower time course of the dendritic IPSC increases its capacity to regulate the N-methyl--aspartate component of EPSPs. Finally, evidence is presented that the slow GABAA-mediated IPSC component is regulated by presynaptic GABAB inhibition whereas the fast is not. Based on the requirement for presynaptic GABAB-mediated block of inhibition for expression of long-term potentiation, this finding is consistent with participation of the slow GABAA component in regulation of synaptic plasticity. The lack of susceptibility of the fast GABAA component to the long-lasting, activity-induced suppression mediated by presynaptic GABAB receptors is consistent with a protective role for this process in preventing seizure activity.

Animals↗
PubMed1996

Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology.

Glial fibrillary acidic protein (GFAP) is a member of the family of intermediate filament structural proteins and is found predominantly in astrocytes of the central nervous system (CNS). To assess the function of GFAP, we created GFAP-null mice using gene targeting in embryonic stem cells. The GFAP-null mice have normal development and fertility, and show no gross alterations in behavior or CNS morphology. Astrocytes are present in the CNS of the mutant mice, but contain a severely reduced number of intermediate filaments. Since astrocyte processes contact synapses and may modulate synaptic function, we examined whether the GFAP-null mice were altered in long-term potentiation in the CA1 region of the hippocampus. The GFAP-null mice displayed enhanced long-term potentiation of both population spike amplitude and excitatory post-synaptic potential slope compared to control mice. These data suggest that GFAP is important for astrocyte-neuronal interactions, and that astrocyte processes play a vital role in modulating synaptic efficacy in the CNS. These mice therefore represent a direct demonstration that a primary defect in astrocytes influences neuronal physiology.

Animals↗
PubMed1996

Volatile anaesthetic enhancement of paired-pulse depression investigated in the rat hippocampus in vitro.

1. A prominent in vivo effect of general anaesthetics, including volatile anaesthetics such as halothane, is the prolonging of paired-pulse depression of the hippocampal CA1 population spike. The mechanisms by which volatile anaesthetics produce this effect were investigated in the hippocampal brain slice preparation by testing the effect of halothane on several long-lasting inhibitory processes, including the calcium-activated potassium current that underlies the slow after-hyperpolarization (IAHP), the GABAB-mediated potassium current that underlies the late IPSP, and the fast and slow components of the early GABAA-mediated IPSP. 2. Halothane produced a dose-dependent block of IAHP at concentrations between 0.5 and 1.5%. This block was manifested as a reduction in spike frequency adaptation, a reduction in the amplitude of the slow after-hyperpolarization following a train of action potentials, and a reduction in the amplitude of the voltage-clamped current following a calcium spike elicited in the presence of tetraethylammonium and tetrodotoxin. The effect did not appear to be caused by blockade of voltage-sensitive calcium channels, since halothane markedly reduced IAHP at a concentration (1.5%) that had little effect on the depolarization-evoked calcium spike. 3. Halothane reduced the amplitude of the late GABAB-mediated IPSP by approximately 50% at concentrations between 1 and 2%. Similar results were obtained for polysynaptic and monosynaptic responses, and with current-clamp and voltage-clamp recordings. However, halothane, at concentrations up to 3%, had no effect on the presynaptic GABAB response, as indicated by no reduction in paired-pulse depression of the monosynaptic GABAA response. 4. Halothane (2%) and enflurane (4%) prolonged the decay phase of the slow component of the monosynaptic GABAA-mediated IPSC approximately twofold, but did not alter the amplitude of the response. Halothane also prolonged the decay phase of the fast component of the GABAA-mediated IPSC, with no effect on the amplitude. However, enflurane markedly reduced the amplitude of the fast component of the GABAA IPSC, so that only a small slow current remained in response to a selective stimulus. 5. It is concluded that the effects of halothane on IAHP and on GABAB responses cannot account for its effects on paired-pulse depression, but that volatile anaesthetics enhance paired-pulse depression by prolonging the decay of the slow dendritic GABAA response. Furthermore, it is speculated that the proconvulsant property of enflurane is related to its depression of the fast somatic component of GABAA inhibition.

Action Potentials↗
PubMed1995

Different mechanisms for use-dependent depression of two GABAA-mediated IPSCs in rat hippocampus.

1. The mechanisms involved in the use-dependent depression of GABAA,fast and GABAA,slow, two GABAA-mediated IPSCs in the rat hippocampal slice preparation, were investigated by observing the effects of paired-pulse depression and of baclofen and CGP 35348 on monosynaptic inhibitory currents recorded from CA1 pyramidal neurons. 2. The second of a pair of evoked responses that consisted of both inhibitory components was depressed and decayed more rapidly compared to the first at an interpulse interval (IpI) of 200 ms. This effect was due to a decrease in the amplitude of GABAA,slow, with no effect on the time constant of decay or on the amplitude or time constant of GABAA,fast. 3. The time course of paired-pulse depression of both components at IpIs ranging from 5 to 2560 ms was compared. GABAA,slow was depressed maximally by 55% at IpIs of 80-160 ms. GABAA,fast was depressed maximally by 38% at 5 ms, and recovered exponentially with a time constant of 130 ms. 4. GABAA,slow was more sensitive than GABAA,fast to depression by baclofen. GABAA,slow was susceptible to complete block, with an ED50 of approximately 200 nM for (+/-)-baclofen and 100 nM for the active enantiomer, (R)-(+)-baclofen. GABAA,fast was blocked by only 50% by the highest concentrations of baclofen tested (10-100 microM (R)-(+)-baclofen), with an ED50 of approximately 2 microM for (+/-)-baclofen and 1 microM for (R)-(+)-baclofen. Paired-pulse depression of GABAA,fast was not occluded by 10 or 100 microM (R)-(+)-baclofen. 5. The GABAB antagonist CGP 35348 (0.4-1 mM), prevented paired-pulse depression of GABAA,slow at IpIs of 160 to 200 ms, and reversed the depression of GABAA,fast by baclofen, but had no effect on paired-pulse depression of GABAA,fast at IpIs of 20 to 40 ms. 6. It is concluded that use-dependent depression of GABAA,slow, but not GABAA,fast, is mediated by a presynaptic GABAB receptor. It is speculated that use-dependent depression of GABAA,fast, which occurs only over a much faster time scale, may be due to rapid postsynaptic GABAA receptor desensitization.

Animals↗
PubMed1993

Physiological evidence for two distinct GABAA responses in rat hippocampus.

The gamma-aminobutyric acid(A) (GABAA) receptor is a ligand-gated ionophore involved in synaptic inhibition. Biochemical and molecular biological studies indicate that considerable receptor heterogeneity exists, but physiological differences between inhibitory GABAA synaptic responses have not been identified in the brain. The present report describes two anatomically segregated GABAA-mediated synaptic currents in the hippocampal CA1 region that have distinct physiological, pharmacological, and functional properties. GABAA,fast enters at or near the cell body, decays rapidly (3-8 ms), is blocked by furosemide, and rapidly curtails the excitatory response. GABAA,slow enters far from the cell body, decays slowly (30-70 ms), is not blocked by furosemide, and underlies the conventionally recognized early inhibitory postsynaptic potential. The receptors producing these responses may represent subtypes of the GABAA receptor.

Animals↗
PubMed1993

Hyperpolarization-activated cation current (Ih) in neurons of the medial nucleus of the trapezoid body: voltage-clamp analysis and enhancement by norepinephrine and cAMP suggest a modulatory mechanism in the auditory brain stem.

1. Principal cells in the medial nucleus of the trapezoid body (MNTB) are part of a circuit in the superior olivary complex (SOC) that processes binaural information important for sound localization. MNTB cells have two voltage-dependent currents active near rest that contribute to these cells' highly nonlinear membrane properties and shape their responses to synaptic input. One of these currents, a low-threshold, 4-aminopyridine (4-AP)-sensitive K+ current, has been studied previously under current clamp. Using the single-electrode voltage-clamp technique, we have investigated the other of these currents, a hyperpolarization-activated, mixed cation current (Ih), in brain slices of the rat SOC. 2. Ih is responsible for a prominent "sag" in the voltage response to a steady hyperpolarizing current recorded under current clamp in MNTB cells. In voltage-clamp recordings, hyperpolarizing voltage steps from the resting potential elicited a large inward current that activated and deactivated with biexponential kinetics. Activation time constants were voltage dependent, with tau 1 and tau 2 = 246 and 1620 ms at -75 mV and 107 and 560 ms at -100 mV. 3. Ih was blocked by 1-5 mM cesium and had a reversal potential of -43 mV. Steady-state activation curves derived from tail currents yielded a half-activation voltage of -75.7 mV and slope factor of 5.7 mV, corresponding to < 10% activation of Ih at rest. 4. Application of norepinephrine (15-20 microM) or 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) (1 mM) caused a depolarizing shift in the steady-state activation curve and decreased the activation time constants. The shift in the activation curve resulted in a large increase in the activation of Ih at rest, an inward shift in the holding current, and an increase in the resting membrane conductance. In current-clamp recordings, this increase in the resting activation level of Ih resulted in membrane depolarization of 2-3 mV in the absence of 4-AP, and 5-10 mV in the presence of 4-AP, an increase in the input conductance, and a reduction in the voltage sag in response to hyperpolarizing currents. 5. The resulting change in the resting point of MNTB cells exposed to norepinephrine or 8-Br-cAMP is likely to alter the responses of these cells to synaptic input, both via the direct effect on the resting membrane conductance and by changing the activation of the low-threshold, 4-AP-sensitive potassium current.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗
PubMed1989

Retrotrapezoid nucleus in the rat.

The retrotrapezoid nucleus (RTN), recently described in the cat, is an anatomically identified cell group of the ventral medulla. It is of interest because of its possible role in the generation or control of breathing. The present investigation confirms the existence in the rat of an analogous cell group, as identified by retrograde transport of rhodamine microbeads from an injection site in the ventral respiratory group of the ventral medulla. Electrophysiological recordings from the region of RTN reveal individual units with respiratory related activity. These results support a possible role for the RTN in the control of breathing.

Airway Resistance↗
PubMed1989

Effect of volatile anesthetics on synaptic transmission in the rat hippocampus.

The synaptic effects of halothane, isoflurane, and enflurane were examined in the rat hippocampus in vivo and compared with the effects of ketamine and urethane. Actions of the agents on excitatory amino acid-mediated neurotransmission were studied by observing evoked responses and long-term potentiation in the stratum pyramidale of CA1 with stimulation of the contralateral CA3 region. Long-term potentiation is a long-lasting increase in synaptic efficacy, which follows a brief stimulus train. It has been shown to be established through activation of the NMDA subclass of excitatory amino acid receptors and is thought to be involved in memory processing. Volatile anesthetics had no effect on evoked excitatory responses or on long-term potentiation. Actions of the anesthetics on inhibitory processes in the hippocampus were studied by pairing stimuli at a range of interpulse intervals. The first stimulus activated inhibitory processes that caused the response to the second stimulus to be smaller than the initial response, a phenomenon termed paired pulse depression. Paired pulse depression was significantly prolonged by the volatile anesthetics compared with that under urethane or ketamine. These results indicate that the mechanism of action of the volatile anesthetics at the hippocampal CA1 synapse does not involve amino acid-mediated excitation but does involve enhancement of inhibition.

Animals↗
PubMed1988

A model for intersegmental coordination in the leech nerve cord.

The neuronal circuits that generate swimming movements in the leech were simulated by a chain of coupled harmonic oscillators. Our model incorporates a gradient of rostrocaudally decreasing cycle periods along the oscillator chain, a finite conduction delay for coupling signals, and multiple coupling channels connecting each pair of oscillators. The interactions mediated by these channels are characterized by sinusoidal phase response curves. Investigations of this model were carried out with the aid of a digital computer and the results of a variety of manipulations were compared with data from analogous physiological experiments. The simulations reproduced many aspects of intersegmental coordination in the leech, including the findings that: 1) phase lags between adjacent ganglia are larger near the caudal than the rostral end of the leech nerve cord; 2) intersegmental phase lags increase as the number of ganglia in nerve cord preparations is reduced; 3) severing one of the paired lateral connective nerves can reverse the phase lag across the lesion and 4) blocking synaptic transmission in midganglia of the ventral nerve cord reduces phase lags across the block.

Animals↗
PubMed1987

Neural mechanisms generating the leech swimming rhythm: swim-initiator neurons excite the network of swim oscillator neurons.

This paper describes newly identified excitatory connections linking the segmentally iterated swim-initiator interneurons with the network of oscillator neurons that generates the leech swimming rhythm. Apparently monosynaptic excitatory chemical connections are made from one class of swim-initiator neurons (cells 204/205) to several members of the swim oscillator network, including cells 28, 115 and, as described by Weeks (1982c), cell 208. A second class of swim-initiator neurons, cells 21 and 61, also excites this subset of the oscillator neurons. The unpaired swim oscillator neuron, cell 208, also chemically excites cells 28 and 115, apparently directly. Thus, in addition to its role as a member of the swim oscillator, the excitatory output from cell 208 to the swim oscillator adds to that provided by the swim-initiator neurons. The results of this paper enlarge the subset of identified swim oscillator neurons synaptically excited by the swim-initiator neurons. These newly described targets of the swim-initiators strengthen the hypotheses that: 1) the swim-initiator neurons supply much of the tonic excitatory drive responsible for activation and maintenance of the swim central motor program, and 2) the two classes of swim-initiators, cells 204/205 and cells 21/61, act synergistically to initiate and maintain swimming.

Animals↗
PubMed1985

2,3-Dihydroxybenzoic acid. Effect on mortality rate in a septic rat model.

Neutrophil-derived oxygen-free radicals may play a role in organ dysfunction associated with generalized sepsis. A rat model was used to test the effects of two free radical scavengers, dimethyl sulfoxide (DMSO) and 2,3-dihydroxybenzoic acid (2,3-DHB), on mortality from intra-abdominal sepsis produced by cecal ligation and perforation. Being an iron-chelating agent, 2,3-DHB may have an additional bacteriostatic effect. Therapeutic regimens included no treatment; gentamicin sulfate (2 mg given intraperitoneally [IP] every eight hours); DMSO (2 g/24 hr given IP every eight hours in divided doses); 2,3-DHB (35 mg/kg given IP every eight hours); and combinations of gentamicin with each free radical scavenger. No statistically significant improvement in survival was obtained by therapeutic intervention with gentamicin alone, DMSO alone, 2,3-DHB alone, or gentamicin in combination with DMSO. When used in combination with gentamicin, 2,3-DHB yielded a statistically significant improvement in survival when compared with gentamicin alone or with no treatment. These results show that 2,3-DHB when used in combination with gentamicin has a beneficial effect on mortality following intra-abdominal sepsis in this model.

Abdomen↗
PubMed1985

Intersegmental coordination of the leech swimming rhythm. I. Roles of cycle period gradient and coupling strength.

The isolated leech nervous system generates a metachronally coordinated rhythmic output that is the neuronal correlate of swimming activity. We investigated two factors that contribute to intersegmental coordination: the swim-cycle periods expressed by segmental ganglia and the strength of neuronal coupling between ganglia. To determine the regional variation in swim-cycle periods, we severed both of the lateral intersegmental connectives. We left intact the median connective, which conveys tonic excitation but little phasic information. We obtained a reduction in intersegmental coupling strength by severing a single lateral intersegmental connective. Cycle periods were manipulated by cooling restricted sections of the nerve cord. Our experiments revealed an anterior-posterior gradient of cycle periods in ganglia of the isolated nerve cord; that is, chains of ganglia obtained from the anterior nerve cord exhibited longer cycle periods than those obtained from the posterior end of the cord. This gradient extends posteriorly to approximately ganglion 12 and may reverse posterior to ganglion 13. Increasing local cycle periods by cooling restricted sections of the nerve cord caused delay in activity cycles in the cooled ganglia, relative to the cycles of ganglia at the control temperature. This finding demonstrates that the observed gradient in cycle period provides for smaller intersegmental phase lags than would occur if there were no period gradients. Reduction of coupling strength by severing a lateral connective led to altered phase relationships across the lesion, both at the motor and oscillator levels. For those ganglion chains in which the anterior ganglia had greater periods, the reduced coupling led to reduced or even reversed phase relationships across the lesion but left unchanged the phase lag between the ends of the chain. In contrast, reduced coupling between halves of a chain in which the posterior ganglia had greater cycle periods led to increased phase lags across the lesion and between the ends. These altered phase relationships arise from a relative increase in the contribution of period differences when coupling strength is decreased. We conclude that the anterior-to-posterior progression of neuronal activity in the isolated leech nerve cord during swimming activity is provided by the intersegmental coupling signals. Furthermore, the period gradient expressed in our preparations acts to provide for smaller phase lags than would be generated by these coupling signals in the absence of such a gradient.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Intersegmental coordination of the leech swimming rhythm. II. Comparison of long and short chains of ganglia.

Preparations of the nearly isolated leech nerve cord containing as few as two ganglia are sufficient to generate intersegmentally coordinated swim oscillations, provided that they receive tonic excitation from other segments via the median connective (Faivre's nerve). Due to their greatly reduced complexity, these preparations should provide useful experimental models of neuronal coordination. As a step in the development of such models, we have characterized the intersegmental coordination of nerve-cord chains ranging from 2 to 18 ganglia in length. We found that increases in swim-cycle period give rise to increases in intersegmental delay between homologous motoneuron bursts. Thus the intersegmental phase relationships are nearly independent of period. The relationship between intersegmental delay and period is approximately linear and extrapolates to intersect the period axis at approximately 0.3 s. This value is in close agreement with the analogous measure derived from tension measurements in the intact swimming leech. Chain length (number of connected ganglia in a preparation) has a pronounced influence on the magnitude of intersegmental phase lag. The longest chains (18 ganglia) exhibited phase lags of approximately 8 degrees per segment, whereas for pairs of ganglia the phase lag was approximately 40 degrees per segment. This dependence of phase lags on chain length was apparent at both the motor and oscillator levels. The intersegmental phase lag is not the same in all parts of the nerve cord. Rather, it increases steadily toward the posterior end of the chain, providing a deceleration in the rearward progression of the metachronal activity. The rearward increase in intersegmental phase lag is paralleled by a propensity of chains taken from more posterior sections of the nerve cord to exhibit larger phase lags. That is, there appears to be a phase-lag gradient intrinsic to the nerve cord to account for the deceleration of activity. The anterior and posterior ends of an isolated nerve cord continue to exhibit phase-locked bursting when an intervening section of five ganglia is bathed in elevated Mg2+ saline. Thus, information sufficient to coordinate oscillations in separate ganglia travels at least six segments. The phase lag across the blocked section is reduced but within each unblocked section is increased so that the phase lag between extreme ends is nearly unchanged. This altered burst pattern is due to a combination of synaptic block in segmental ganglia and conduction block in through-fibers.

Animals↗
PubMed1984

Intersegmental coordination of leech swimming: comparison of in situ and isolated nerve cord activity with body wall movement.

Recordings of motoneuron activity during swimming, obtained from leech ventral nerve cords in situ, were compared with films of swimming leeches and with recordings of motoneuron activity from isolated nerve cords. It was found that the intersegmental phase lag in body movement is greater than the phase lag of in situ neuronal activity, which is in turn greater than the phase lag of isolated nerve cord activity. We conclude that peripheral neuronal or mechanical effects, as well as sensory feedback to the central pattern generator, contribute to the movement pattern of the intact swimming leech.

Animals↗
PubMedDate not supplied

Measurement of rCBF by H2 clearance: theoretical analysis of diffusion effects.

Although experimental evidence now indicates that diffusion of hydrogen can influence the measured clearance curves from which local blood flow is inferred, its exact role has not yet been well defined. For this reason we have developed a theoretical treatment of the effects of diffusion near a boundary separating regions of inhomogeneous perfusion (e.g. the gray-matter interface), and reexamined the appropriateness of the currently used bi-exponential model. Using our model, we confirmed empirical estimates of important diffusion effects up to approximately 2 mm from an inhomogeneity, and further refined the concept of spatial resolution. We also showed that fitting data to bi-exponential curves may be incorrect and lead to inaccurate results. We conclude from these studies that diffusion does indeed have an important effect on the clearance curves measured near an inhomogeneity.

Blood Flow Velocity↗