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S A Deadwyler

Publications and source records attributed to S A Deadwyler.

At least 19 recordsLinked to original sources
PubMed1997

Cellular mechanisms underlying reinforcement-related processing in the nucleus accumbens: electrophysiological studies in behaving animals.

Numerous investigations have implicated the nucleus accumbens (NA) as an important neural substrate involved in mediating reinforcement-related processing. Electrophysiological studies in behaving animals enable a direct examination of cellular mechanisms underlying this process via characterization of NA activity at critical times during responding for food, water, or drug reward. Electrophysiological studies are reported that examined the activity of NA neurons during water- and cocaine-reinforced responding in rats. These studies reveal that some NA neurons exhibit changes (increases or decreases) in firing rate synchronized to the response-contingent delivery of water or cocaine. Furthermore, the sampled population of NA neurons exhibited less synchronized cell firing during the response for cocaine than for the water reward. NA activity during cocaine self-administration was explicitly coupled to the behavioral state of the animal and was markedly influenced by the stimulus context in which the drug was delivered. These findings are discussed with respect to the dynamic properties of NA activity and its importance as an underlying cellular substrate mediating reinforcement-related events in the behaving animal.

Animals↗
PubMed1997

The significance of neural ensemble codes during behavior and cognition.

The development of techniques to record from populations of neurons has made it possible to ask questions concerning the encoding of task-relevant information in awake, behaving animals. The issue of how groups of neurons within different brain structures register and retrieve representations of behaviorally significant events can now be addressed using multineuron-recording techniques. This review examines recent studies employing simultaneous recording of ten or more individual neurons in the mammalian brain. A major issue discussed is whether ensemble information content reconstructed from single-neuron recordings may be underestimated if compared to ensembles where those same neurons were recorded simultaneously. The mechanics of ensemble information encoding in the hippocampus is illustrated from population statistical analyses of ensemble activity during performance of a delay task. Detailed descriptions of methods of extracting ensemble information, as well as cross-correlational analyses, are discussed in the context of emergent issues regarding interpretation of ensemble data.

Animals↗
PubMed1996

Effects of chronic treatment with delta9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPgammaS autoradiography in rat brain.

Chronic Delta9-tetrahydrocannabinol (Delta9-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study uses in vitro autoradiography of agonist-stimulated [35S]GTPgammaS binding to localize cannabinoid receptor-activated G-proteins after chronic Delta9-THC treatment. Cannabinoid (WIN 55212-2)-stimulated [35S]GTPgammaS binding was performed in brain sections from rats treated chronically with 10 mg/kg Delta9-THC for 21 d. Control animals received saline or an acute injection of Delta9-THC. Acute Delta9-THC treatment had no effect on basal or WIN 55212-2-stimulated [35S]GTPgammaS binding. After chronic Delta9-THC treatment, net WIN 55212-2-stimulated [35S]GTPgammaS binding was reduced significantly (up to 70%) in most brain regions, including the hippocampus, caudate-putamen, perirhinal and entorhinal cortex, globus pallidus, substantia nigra, and cerebellum. In contrast, chronic Delta9-THC treatment had no effect on GABAB-stimulated [35S]GTPgammaS binding. In membranes and brain sections, Delta9-THC was a partial agonist, stimulating [35S]GTPgammaS by only 20% of the level stimulated by WIN 55212-2 and inhibiting WIN 55212-2-stimulated [35S]GTPgammaS at high concentrations. Because the EC50 of WIN 55212-2-stimulated [35S]GTPgammaS binding and the KD of cannabinoid receptor binding were unchanged by chronic Delta9-THC treatment, the partial agonist actions of Delta9-THC did not produce the decrease in cannabinoid-stimulated [35S]GTPgammaS binding. These results suggest that profound desensitization of cannabinoid-activated signal transduction mechanisms occurs after chronic Delta9-THC treatment.

Animals↗
PubMed1996

Ensemble codes involving hippocampal neurons are at risk during delayed performance tests.

Multielectrode recording techniques were used to record ensemble activity from 10 to 16 simultaneously active CA1 and CA3 neurons in the rat hippocampus during performance of a spatial delayed-nonmatch-to-sample task. Extracted sources of variance were used to assess the nature of two different types of errors that accounted for 30% of total trials. The two types of errors included ensemble "miscodes" of sample phase information and errors associated with delay-dependent corruption or disappearance of sample information at the time of the nonmatch response. Statistical assessment of trial sequences and associated "strength" of hippocampal ensemble codes revealed that miscoded error trials always followed delay-dependent error trials in which encoding was "weak," indicating that the two types of errors were "linked." It was determined that the occurrence of weakly encoded, delay-dependent error trials initiated an ensemble encoding "strategy" that increased the chances of being correct on the next trial and avoided the occurrence of further delay-dependent errors. Unexpectedly, the strategy involved "strongly" encoding response position information from the prior (delay-dependent) error trial and carrying it forward to the sample phase of the next trial. This produced a miscode type error on trials in which the "carried over" information obliterated encoding of the sample phase response on the next trial. Application of this strategy, irrespective of outcome, was sufficient to reorient the animal to the proper between trial sequence of response contingencies (nonmatch-to-sample) and boost performance to 73% correct on subsequent trials. The capacity for ensemble analyses of strength of information encoding combined with statistical assessment of trial sequences therefore provided unique insight into the "dynamic" nature of the role hippocampus plays in delay type memory tasks.

Action Potentials↗
PubMed1996

Role of cyclic AMP in the actions of cannabinoid receptors.

Cannabinoids, including delta 9-tetrahydrocannabinol (THC), bind to receptors that couple to Gi/o-proteins and inhibit adenylyl cyclase. However, like other G-protein-coupled receptors, cannabinoid receptors are also coupled to other effector systems. This review examines the characteristics of the cannabinoid-G-protein-adenylyl cyclase system, and explores the role of cyclic AMP in mediating effects of these drugs. Several conclusions emerge from this research. First, the principal actions of cannabinoids are mediated through G-protein-coupled receptors, and the intracellular signaling mechanism that initiates cellular response of cannabinoids is activation of G-proteins. Second, cannabinoid-inhibited adenylyl cyclase is only one of several different effectors coupled to these receptors, and different effectors may be used for different types of responses. Third, cannabinoid inhibition of adenylyl cyclase plays an important role in several aspects of cannabinoid function, including modulating conductance at a voltage-dependent K+ channel ("A" current) in the hippocampus, thus providing an effective rationale for behavioral effects of cannabinoids mediated in this region. Other functions of this system may include production of long-term changes in gene expression by inhibition of cyclic AMP response elements on strategic genes, and inhibition of anandamide synthesis, thus mediating some of the long-term effects of cannabinoids on neuronal function.

Animals↗
PubMed1996

Hippocampal place fields: relationship between degree of field overlap and cross-correlations within ensembles of hippocampal neurons.

The capacity to record from multiple neurons in awake freely moving animals provides a means for characterizing organizational principles of place field encoding within ensembles of hippocampal neurons. In this study, cross-correlations between pairs of hippocampal place cells and degree of overlap between their respective place fields were analyzed during behavioral performance of delayed matching (DMS) or non-matching sample (DNMS) tasks, or while the same rats chased pellets in a different environment. The relationship between field overlap and cross-correlations of neural spike activity within ensembles was shown to be a positive, exponentially increasing, function. Place fields from the same neurons were markedly "remapped" between the Delay and Pellet-chasing tasks, with respect to physical location and size of fields. However individual pairs of place cells within each ensemble retained nearly the same degree of overlap and cross-correlation even though the spatial environment and the tasks differed markedly. This suggested that place cells were organized in functional "clusters" which exhibited the same inter-relations with respect to place field overlap and cross-correlations, irrespective of actual field of location. When cross-correlations between place cells were compared to placement of the array recording electrodes within the hippocampus, the strongest correlations were found along previously defined posterior-projecting fiber gradients between CA3 and CA1 subfields (Ishizuka et al. [1990], J Comp Neurol 295:580-623; Li et al. [1994] (J Comp Neurol 339:181-208). These findings suggest that the functional organization of place fields conforms to anatomical principles suspected to operate within hippocampal ensembles.

Animals↗
PubMed1996

Hippocampal ensemble activity during spatial delayed-nonmatch-to-sample performance in rats.

Multiple-cell recording from specially designed arrays of microwire electrodes allowed analysis of anatomically defined ensemble activity from 10 different locations within the hippocampus of rats (n = 7) performing a two-lever operant version of a spatial delayed-nonmatch-to-sample task (DNMS). Application of population analysis procedures to ensembles of single-neuron activity within the CA1 and CA3 fields revealed firing patterns related to task-relevant events within a DNMS trial. The patterns were extracted via a canonical discriminant analysis in the form of "roots" that represented sources of variance in firing within the ensemble, such as phase of the task (Sample or Nonmatch), spatial position of the lever press response (left or right), and correct versus error trials. Comparison of the ensemble firing on correct versus error trials revealed important insight into ensemble information encoding, such as "miscoding" of the response position and lack of distinct encoding of the response in the Sample phase, which became increasingly vulnerable to error as a function of the duration of delay interval. The extracted discriminant scores were reflective of multiple representations within ensembles and suggested that "conjunctions" of task-relevant features could be represented effectively by small numbers of hippocampal neurons. The findings support the long-held supposition that hippocampal neurons play a critical role in the encoding and retrieval of information in recognition memory tasks.

Animals↗
PubMed1996

Dose-dependent transitions in nucleus accumbens cell firing and behavioral responding during cocaine self-administration sessions in rats.

At the initiation of cocaine self-administration sessions, neurons in the rat nucleus accumbens (NA) exhibit a spontaneous transition in firing rate from activity unrelated to the reinforced response to one of four types of patterned discharges. This transition in NA activity is accompanied by a shift from high response rates at the start of the session ("Load-Up" behavior) to a lower rate for the remainder of the session. In this study, the relationship between transitions in behavioral responding and NA activity was examined further by changing the dose of cocaine per session (0.66, 0.50, 0.33, 0.16 or 0.08 mg/inf). Results show that the number of Load-Up responses significantly increased at lower cocaine doses [0.16, 0.08 mg/infusion (inf)] and decreased at higher doses (0.33, 0.50, 0.66 mg/inf). Thereafter, animals responded either with regularly spaced interinfusion intervals (INTs) at high doses (0.33, 0.50 and 0.66 mg/inf), or frequent bursts and pauses in responding at low doses (0.16 and 0.08 mg/inf. NA neurons exhibited a spontaneous transition in firing rate that was significantly correlated with this shift in behavioral responding across different doses of cocaine. Pretreatment with the dopamine D1 receptor antagonist SCH23390 (5 or 10 microgram/kg) prolonged the onset of NA patterned discharges, similar to responding for low doses of cocaine (0.08 and 0.16 mg/inf. These findings are discussed in terms of a functional role of the NA in mediating the reinforcing properties of cocaine.

Animals↗
PubMed1995

Cannabinoids selectively decrease paired-pulse facilitation of perforant path synaptic potentials in the dentate gyrus in vitro.

Perforant path synaptic potentials recorded from the outer molecular layer of the dentate gyrus were tested for paired-pulse potentiation and stimulus sensitivity in the presence and absence of the potent cannabinoid receptor ligand, WIN 55,212-2. Extracellular perforant path synaptic potential amplitudes were increased by 51% in 2 mM Ca2+ medium and 60% in 3 mM Ca2+ medium at a conditioning-test (C-T) interval of 10 ms, decreasing to 10-15% facilitation at an 80 ms C-T interval. Exposure to the potent cannabinoid receptor ligand WIN 55,212-2 produced a marked and dose-dependent reduction in the amplitude of the facilitated perforant path synaptic potentials. Maximum paired-pulse facilitation was reduced to 35% and 25% in 2.0 and 5.0 microM WIN 55,212-2 respectively. The effect was selective for potentials facilitated at C-T intervals of 10-60 ms. Input/output (I/O) curves of perforant path field potentials were shifted to the right in a dose-dependent (2.0 and 5.0 microM) manner by WIN 55,212-2. Significant differences in peak amplitudes of perforant path potentials were obtained at all suprathreshold stimulus intensities. A comparison of WIN 55,212-2 (5 microM) with the GABAB receptor agonist baclofen (200 microM) showed that when both drugs were administered independently each produced similar decreases in perforant path paired-pulse potentiation. However when administered together at these concentrations baclofen and WIN failed to potentiate each other, suggesting nonadditivity due to effects on a common process.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium "A-current" in cultured rat hippocampal neurons.

Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (IA) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of IA. Specific activators of PKA produced a negative shift in voltage dependence of IA, whereas PKA inhibitors produced a positive shift in IA voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in IA induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in IA voltage dependence. This partial effect of PKA inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of IA.

Animals↗
PubMed1995

Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process.

Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (IA) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on IA. The specific issue of whether cannabinoid receptor modulation of voltage-dependent IA acts via a cAMP-dependent process was investigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cyclase stimulant forskolin, produced concentration-dependent shifts in IA that were opposite those produced by cannabinoid receptor ligands. Moreover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also produced a marked negative shift in the steady-state voltage dependence of IA and increased the effect of forskolin on IA. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased IA via a decrease in steady-state voltage-dependent inactivation of IA. WIN 55,212-2 also reversed the effects of forskolin on IA. The electrophysiological studies were paralleled by direct assays of cAMP in these cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that pertussis toxin-sensitive cannabinoid receptor-mediated changes in IA were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of IA conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.

1-Methyl-3-isobutylxanthine↗
PubMed1994

A comparison of nucleus accumbens neuronal firing patterns during cocaine self-administration and water reinforcement in rats.

The firing patterns of nucleus accumbens (NA) neurons in the rat were recorded during cocaine self-administration and responding for water. Recordings were obtained from permanently implanted multiple-electrode arrays (eight microwires) inserted bilaterally into rostral portions of the NA in subjects (n = 18) exhibiting stable cocaine self-administration (0.33 mg/infusion), and during stable responding for water reinforcement. Electronically isolated and identified NA neurons exhibited four distinct patterns of phasic activity relative to the reinforced response. Three of these firing patterns were observed during both cocaine self-administration and water reinforcement sessions. Response-related activity was categorized by cells that showed an anticipatory increase in firing rate during the preresponse phase (type PR), and by cells that were excited (type RFE) or inhibited (type RFI) following the response in the reinforcement phase. PR and RFE cells showed significantly reduced peak firing during cocaine self-administration, compared to similar cells in water reinforcement sessions. A fourth type of NA firing pattern (type PR+RF) was observed only in cells recorded during cocaine self-administration sessions (Carelli et al., 1993b). PR+RF neurons exhibited two distinct peaks, one preceding the response and terminating at response completion (like PR cells), and a second peak immediately following the response (like RFE cells) with an inhibitory period between the two peaks (like RFI cells). The findings are discussed in terms of the role of the NA in mediating the reinforcing properties of both cocaine and water.

Animals↗
PubMed1993

Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats.

The firing patterns of neurons in the nucleus accumbens (NA) were recorded in rats trained to self-administer cocaine via response contingent intravenous drug infusions. Recordings were obtained from permanently implanted multiple electrode arrays (8 microwires) inserted bilaterally into the NA and/or ventral striatum (NA-VS) in animals exhibiting stable responding (inter-infusion intervals, INT) during test sessions consisting of 16-30 drug delivery episodes. Electronically isolated and identified NA-VS neurons showed distinct patterns of phasic increases in firing relative to the occurrence of the reinforced lever press. Two particular firing patterns, however, were repeatedly encountered in different animals. In one type, a marked increase was observed in discharge following response contingent drug delivery. A second firing pattern showed two distinct temporally separated brief firing peaks (bursts), one immediately prior to the initiation of responding, and the other a brief discharge commencing within 200 ms after the initiation of drug delivery. The time between firing peaks was found to be modifiable by changing the response/reward (FR) ratio for drug delivery. A third finding was that the correlates of the self-administration response were not solely the result of drug infusion since, (1) phasic firing increases were not observed when the drug was delivered non-contingently during the same session and, (2) the emergence of patterns was frequently delayed within the session until after drug self-administration behavior stabilized at regular INTs. The findings are discussed in terms of the significance of NA-VS neuron firing correlates for the initiation and maintenance of cocaine self-administration.

Action Potentials↗
PubMed1993

Hippocampal cell firing correlates of delayed-match-to-sample performance in the rat.

Hippocampal CA1 and CA3 neurons were recorded in rats performing a delayed-match-to-sample (DMTS) task. Complex spike cells showed significant firing peaks following sample and match responses and during delivery of water reward. Individual cells were classified into 4 subtypes according to the presence or absence of firing in each of these 3 phases. There were significant differences in delay interval firing among the 4 subtypes, but firing during the delay did not predict the correct response: 34% of the cells showed a linear change in firing during the delay. Further analyses revealed significant lever position firing biases in approximately 70% of the cells tested irrespective of subtype. The complexity of firing correlates of the neurons recorded in this DMTS task suggests that the hippocampus divides specific aspects of the performance demands of the task across different cell subtypes, which together provide sufficient information to resolve the matching-to-sample problem on any given trial.

Animals↗
PubMed1993

Cannabinoids modulate potassium current in cultured hippocampal neurons.

Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significance. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, levonantradol and WIN 55,212-2) on cultured neurons from hippocampus, a brain region that exhibits high cannabinoid receptor density. The electrophysiological effects of cannabinoids were determined by whole-cell patch clamp recordings of voltage-dependent potassium currents. The voltage dependence of the rapidly inactivating potassium A current (IA), characteristic of hippocampal neurons, was significantly altered in a concentration-dependent manner by cannabinoid analogs. Decreased inactivation, which led to an increased activation of IA near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on IA while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid analogs was similar to that observed with respect to binding at cannabinoid receptors in brain membranes. The concentration-related effectiveness of cannabinoid analogs in modulating IA was similar to their potency in stimulating low Km GTPase in cell membranes isolated from the cannabinoid receptor-rich dentate gyrus. These data support the conclusion that cannabinoid effects on IA are mediated through G-protein-coupled receptors. This cannabinoid-induced shift in the voltage dependence of IA could serve to counteract fast, transient, depolarizing events such as action potentials and synaptic currents in hippocampal neurons.

Action Potentials↗
PubMed1993

Cannabinoid receptors: G-protein-mediated signal transduction mechanisms.

The recent discovery and cloning of cannabinoid receptors has provided a major breakthrough in the understanding of the biochemical mechanisms of action of delta 9-tetrahydrocannibinol (delta 9-THC). Cannabinoid receptors are coupled to G-proteins and inhibit adenylyl cyclase in a variety of systems. In the brain, cannabinoid-inhibited adenylyl cyclase and the receptors are particularly prevalent in the cerebellum, where they are localized to cerebellar granule cells (Fig. 1). In these cells, cannabinoid receptors are co-localized with other Gi/o-linked receptors such as gamma-aminobutyric acid (GABAB) receptors, where they share common effector systems (adenylyl cyclase catalytic units) but not common G-proteins. This sharing of effectors leads to the phenomenon of receptor convergence, in which agonists of different receptor types can produce the same biological response in certain cells. In cultured hippocampal neurons, cannabinoids also act through G-proteins to increase potassium conductance. In these cells, the predominant electrophysiological response at relatively low (microM) concentrations of cannabinoids is mediated through a voltage-sensitive potassium A current (IA) (Fig. 1). The action of cannabinoid receptors in this system is to shift the voltage sensitivity of IA channels to higher voltage ranges, thus increasing K+ conductance at lower membrane potentials and decreasing the probability of multiple action potentials. When combined with data from other groups showing a cannabinoid receptor-mediated decrease in calcium conductance, along with the unique localization of cannabinoid receptors in the brain, it is clear that these receptor-effector combinations are well situated to mediate many of the well-known neurobiological effects of delta 9-THC.

Animals↗