Biomedical subjects

T W Berger

Publications and source records attributed to T W Berger.

At least 37 records · Page 2Linked to original sources

PubMed1993

Na+ influx through Ca2+ channels can promote striatal GABA efflux in Ca(2+)-deficient conditions in response to electrical field depolarization.

Electrical field depolarization releases gamma-aminobutyric acid (GABA) in rat striatal slices in the absence of external Ca2+. omega-Conotoxin GVIA (omega-CgTx; 1-50 nM), a neuronal Ca2+ channel blocker, inhibits electrically evoked efflux of newly taken up [3H]GABA in a concentration-dependent manner in either normal or Ca(2+)-free medium. This suggests that ion influx occurs through Ca2+ channels in the absence of external Ca2+ and contributes to the efflux of GABA. Reducing external Na+ concentration to 27.25 mM (low [Na+]o medium) by equimolarly substituting choline chloride for sodium chloride has differential effects on electrically evoked GABA efflux depending on the external Ca2+ concentrations. In normal Ca2+ medium, electrically evoked GABA efflux increases whereas, in Ca(2+)-free medium, it is greatly inhibited when [Na+]o is reduced to 27.25 mM. In low [Na+]o medium, GABA efflux is largely tetrodotoxin (TTX)-sensitive, however, spike firing evoked by antidromic stimulation of striatal cells is inhibited. In Na(+)-free medium, resting GABA efflux increases 17-fold whereas evoked GABA efflux diminishes. In Ca(2+)-free medium, 70 min of incubation with 1-2-bis-(1-aminophenoxy)ethane-N,N,N',N' tetraacetoxy methyl ester (BATPA-AM, 1 microM), an intracellular calcium chelator, increases both resting GABA efflux and electrically evoked GABA overflow by approximately 100%. These results suggest that: (1) in Ca(2+)-free conditions, Na+ permeability of cells increases via Ca2+ channels and this profoundly affects GABA efflux. (2) Electrical field depolarization is likely to release GABA by directly depolarizing axon terminals. (3) Ca(2+)-independent GABA efflux is not promoted by an increase in intracellular free Ca2+ concentration via Na+/Ca2+ exchange processes from internal pools.

Animals↗

PubMed1993

Recovery of hippocampal dentate granule cell responsiveness to entorhinal cortical input following norepinephrine depletion.

Hippocampal dentate granule cell responsivity to excitatory input from entorhinal perforant path fibers was examined in the chronic rabbit preparation following norepinephrine (NE) depletion induced with the neurotoxin DSP4. To examine granule cell responsivity as a function of perforant path activation, constant low frequency stimulation (0.1 Hz) was applied to the perforant path using an ascending intensity series. To examine granule cell responsivity to more complex patterns of stimulation, a train of impulses, with a random interstimulus interval (Poisson distribution; mean frequency of 2 Hz), was applied to the perforant path. Both single impulse and random interval impulse stimulation revealed that NE depletion increased the average amplitude of the perforant path-granule cell population spike. The random interval impulse stimulation revealed that NE depletion also increased the magnitude and duration of second order inhibitory interactions. These changes were transient, however, and recovered over the 21 day test period. Hippocampal NE levels were reduced an average of 80% between 23 and 38 days post-DSP4. The activity of the rate-limiting enzyme for NE synthesis, tyrosine hydroxylase (TH), was reduced an average of 60%. That NE levels were reduced to a greater extent than was TH activity is suggestive of increased NE synthesis within the remaining nerve terminals. Such an increase in NE synthesis may reflect a compensatory response underlying the functional recovery of electrophysiological responsiveness following partial NE depletion.

Adrenergic Agents↗

PubMed1993

Depression of glutamatergic and GABAergic synaptic responses in striatal spiny neurons by stimulation of presynaptic GABAB receptors.

The influence of gamma-aminobutyric acidB (GABAB) receptor stimulation on the excitatory and inhibitory synaptic potentials and membrane properties of identified striatal spiny neurons was examined in a corticostriatal slice preparation. Stimulation of the subcortical white matter evoked a monosynaptic, excitatory postsynaptic potential (EPSP) and a polysynaptic, inhibitory postsynaptic potential (IPSP) in spiny neurons. The EPSP had two components: a large amplitude response which could be blocked by the kainate/quisqualate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), and a small amplitude, long-duration depolarization which could be blocked by the N-methyl-D-aspartate receptor antagonist, d-(-)-2-amino-5-phosphonovaleric acid (APV, 100 microM). The IPSP was observed as a membrane depolarization when recorded from neurons at resting membrane potential. However, when neurons were injected with the Na(+)-channel blocker, QX-314, allowing cells to be depolarized above their spike thresholds, a prominent hyperpolarizing IPSP was readily observed which could be blocked by the GABAA antagonist, bicuculline (10-50 microM). This bicuculline-sensitive IPSP was responsible for the inhibition of EPSP amplitude and probability of spike discharge revealed using paired stimulation of the subcortical white matter. The amplitude of both the EPSP and the IPSP were depressed by the GABAB receptor agonist, p-chlophenyl-GABA (baclofen, 0.5-100 microM) in a concentration-dependent manner. Baclofen also blocked paired stimulus inhibition of spike discharge. These effects of baclofen persisted in slices in which the cortex was removed and were reversed by the GABAB receptor antagonist, 3-amino-3-hydroxy-2-(4-chlorophenyl)-propanesulphonic acid (saclofen, 100-500 microM). In contrast to its profound influence on synaptic input, baclofen did not alter resting membrane potential, input resistance, membrane current-voltage relationship, or spike threshold of the cells recorded, and therefore did not appear to exert direct postsynaptic effects on the striatal spiny neurons. Taken together, these data indicate that the depressant effects of baclofen on EPSPs are mediated through GABAB receptors located on the terminals of glutamatergic afferents within the striatum. Moreover, the results suggest that the actions of baclofen on IPSPs and paired stimulus inhibition are produced by activation of GABAB receptors within the striatum at a site presynaptic to spiny neurons, either on the terminals of GABAergic afferents or on an interposed non-spiny GABAergic cell. Thus, GABAB hetero- and auto-receptors have the capacity to provide a negative feedback mechanism through which the major excitatory and inhibitory inputs to striatal spiny neurons are regulated.

2-Amino-5-phosphonovalerate↗

PubMed1992

Characterization in vivo of the NMDA receptor-mediated component of dentate granule cell population synaptic responses to perforant path input.

The NMDA receptor-mediated component of the hippocampal granule cell population excitatory postsynaptic potential response to low frequency (< 0.2 Hz) stimulation of the medial perforant path was characterized in vivo. Extracellular recordings were obtained from the dentate molecular layer in anesthetized rabbits, and glutamatergic and GABAergic antagonists were applied locally by pressure ejection. To measure the NMDA-mediated component, the NMDA receptor antagonist D-5-aminophosphonovalerate (APV) was applied during the constant ejection of physiological saline, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and/or bicuculline methiodide. In general agreement with the results of attempts by other investigators to identify NMDA responses in vivo, APV did not significantly reduce the response to a single stimulus impulse in the presence of saline. However, an NMDA-mediated response was revealed when alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate receptor-mediated current flow was eliminated by applying the non-NMDA receptor antagonist CNQX. The NMDA component was negative-going as predicted, but its duration was considerably less than indicated in other studies of the dentate in vitro. The relative magnitudes of the NMDA and non-NMDA components of the EPSP were found to vary as a function of stimulus intensity or frequency. The NMDA receptor-mediated component represented 12% of the control response and increased to over 25% in response to higher stimulus intensities. A brief, high-frequency burst of impulses evoked a larger NMDA component in the presence of CNQX and was able to evoke an NMDA component in the presence of saline. Surprisingly, short trains of stimulation at lower frequencies typically produced suppression of the NMDA component. In a final series of experiments, it was found that many characteristics of the NMDA component were substantially altered by GABAergic inhibition. In the presence of the GABAA antagonist bicuculline, the magnitude of NMDA receptor-mediated responses was increased and their duration was greatly extended. Additionally, in the presence of bicuculline, the NMDA component facilitated markedly in response to frequencies of stimulus input > 20 Hz. These results indicate in vivo that the initiation and duration of NMDA current flow depend strongly upon the intensity and frequency of perforant path stimulation. In addition, the NMDA response to a single impulse appears to be reduced and truncated by input from GABAA receptor-mediated feedback and/or feedforward inhibition, and this inhibition affects temporal summation of NMDA receptor-mediated responses over a wide range of input frequencies. It is suggested that such inhibition results from the activation of GABAA receptors located on granule cell dendritic shafts.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1992

In vivo modulation of N-methyl-D-aspartate receptor-dependent long-term potentiation by the glycine modulatory site.

The role of the glycine modulatory site in N-methyl-D-aspartate receptor function was examined by determining the effect of the glycine site antagonist, 7-chlorokynurenic acid, on the induction of long-term potentiation at the commissural-CA1 synapse in anesthetized rats. Robust long-term potentiation of population excitatory postsynaptic potentials and population spike responses recorded extracellularly in the stratum pyramidale and in stratum radiatum of CA1 developed after high frequency stimulation (100 Hz for 1 s) of commissural fibers during continuous intrahippocampal administration of vehicle solution (0.15 M NaCl). In contrast, infusion of either 7-chlorokynurenic acid (400 microM) or of the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonovaleric acid (100 microM), significantly attenuated or completely blocked the development of long-term potentiation. When 7-chlorokynurenic acid was infused together with the glycine analog, D-serine (1 mM), long-term potentiation developed that was comparable to that observed in control animals. Intrahippocampal administration of D-serine alone was associated with slightly greater magnitude of long-term potentiation than observed in control animals. Collectively, these findings establish that in intact hippocampus, activity at the glycine modulatory site is necessary for activation of the N-methyl-D-aspartate receptor complex. Furthermore, these results suggest that the glycine modulatory site may not be fully saturated in vivo, and thus can serve to regulate N-methyl-D-aspartate receptor function.

2-Amino-5-phosphonovalerate↗

PubMed1992

Functionally distinct subpopulations of striatal neurons are differentially regulated by GABAergic and dopaminergic inputs--I. In vivo analysis.

Two subpopulations of striatal neurons, Type I and Type II, are distinguished by their contrasting electrophysiological responses to paired impulse stimulation of cortical afferents. Although both Type I and Type II striatal neurons are excited by the first impulse of any pair of impulses, in response to short interstimulus intervals (10-30 ms) Type I neurons display an increase in probability of spike discharge to the second impulse (facilitation), whereas Type II neurons exhibit a decrease in probability of discharge (inhibition); in response to longer interstimulus intervals (50-250 ms) Type I cells display inhibition, whereas Type II cells show facilitation. The present experiments investigated the possibility that the unique paired impulse responses of Type I and Type II neurons reflect differential regulation by GABAergic and dopaminergic afferents. Extracellular recording techniques were combined with micropressure ejection of specific antagonists for GABAA (bicuculline), GABAB (phaclofen), D1 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-IH-3-benzazepin+ ++-7-ol; SCH23390) or D2 (sulpiride) receptors; the role of dopamine was also examined using the specific neurotoxin, 6-hydroxydopamine. Results showed that bicuculline (250-500 microM) reduced stimulation threshold for spike discharge of both Type I and Type II neurons and completely antagonized the paired impulse inhibition in response to short interstimulus intervals characteristic of Type II neurons. In contrast, phaclofen (2-30 mM) had only a variable influence on spike threshold for Type II cells and no effect on the paired impulse responses of either Type I or Type II neurons. Micropressure ejection of SCH23390 (1 mM) decreased spike thresholds for both cell types and attenuated the inhibition of spike discharge to long interstimulus intervals distinctive of Type I neurons, an effect which was mimicked by dopaminergic denervation. In contrast, sulpiride (1 mM) had little effect on spike thresholds, and no influence on the paired impulse responses of either cell type. These results indicate that the excitability of both Type I and Type II neurons is tonically inhibited by GABAergic and dopaminergic input via stimulation of GABAA and D1 receptors, respectively. Moreover, the bicuculline sensitivity of Type II neurons suggests that GABAergic input to this cell class arises from neurons within a cortically driven feedforward and/or feedback loop, whereas Type I cells receive input from neurons which lie outside of such a loop. In addition, the inhibition to longer interstimulus intervals characteristic of Type I cells is, at least in part, dependent on dopaminergic input through D1 receptor stimulation.

Animals↗

PubMed1992

Functionally distinct subpopulations of striatal neurons are differentially regulated by GABAergic and dopaminergic inputs--II. In vitro analysis.

In the companion report [Nisenbaum and Berger (1992) Neuroscience 48, 561-578] the contrasting paired impulse responses to stimulation of the corticostriatal pathway which define the Type I and Type II subpopulations of striatal neurons were shown to reflect differential regulation by GABAergic and dopaminergic inputs. More specifically, the decreased probability of spike discharge (inhibition) to long interstimulus intervals (60-260 ms) characteristic of Type I neurons was found to be dependent on dopaminergic input via D1 receptor activation, whereas the inhibition to short interstimulus intervals (10-20 ms) distinctive of Type II neurons was found to be mediated by GABAergic input acting through GABAA receptor stimulation. The present experiments have further investigated the contribution of GABAergic and dopaminergic feedforward and/or feedback circuits to the functional identities of Type I and Type II neurons using an in vitro corticostriatal slice preparation. In this preparation, the cortical afferents to the striatum are preserved, allowing for activation of striatal cells in a manner similar to that used in vivo; however, all axons arising from midbrain and brainstem structures including the substantia nigra are transected, and intrastriatal GABAergic pathways are reduced. Consistent with the predicted effect of disrupting these two neurotransmitter pathways, the paired impulse responses of striatal neurons recorded in vitro were not similar to the responses of either Type I or Type II neurons recorded in vivo. Indeed, the paired impulse profiles of striatal neurons recorded in vitro were relatively homogeneous in that virtually all cells displayed an increased probability of spike discharge (facilitation) to the second impulse of all interstimulus intervals (10-500ms) tested. Low concentrations of allosteric agonists for the GABAA receptor, pregnanolone (5 microM) and pentobarbital (50 microM), selectively inhibited spike discharge in response to short interstimulus intervals (10-20 ms) for approximately 40% of the neurons sampled, but produced no change in facilitation to longer interstimulus intervals (30-500 ms). The agonist-induced inhibition to short interstimulus intervals was blocked by bicuculline (10-20 microM), and was not mimicked by the GABAB receptor agonist, baclofen (1-5 microM). In addition, application of dopamine (5-10 microM) or the D1 receptor agonist, SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 5 microM), inhibited spike discharge to longer interstimulus intervals (40-500 ms) for approximately 10% of striatal cells recorded. The inhibition to longer interstimulus intervals was blocked by the D1 receptor antagonist, SCH23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin+ ++-7-ol], but not the D2 antagonist, sulpiride.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1992

Instantaneous characterization of time-varying nonlinear systems.

A nonlinear system may be characterized by an orthogonal functional power series (FPS) computed from cross correlations between input and output variables. "Is the response changing over the course of the experiment?" is a fundamental question encountered in the analysis of both FPS and evoked potentials (EP's). Regression on closed-form functions of time produces a time-varying FPS or EP. Evaluation of these functions at a specified time point produces a system characterization for that instant.

Evoked Potentials↗

PubMed1992

Presynaptic modulation by GABAB receptors of glutamatergic excitation and GABAergic inhibition of neostriatal neurons.

1. The present experiments investigated the effects of gamma-amino-butyric acidB (GABAB) receptor stimulation on the excitatory and inhibitory responses of neostriatal neurons evoked by stimulation of the subcortical white matter in a rat neostriatal slice preparation. 2. Intracellular recordings showed that single-impulse stimulation of the corpus callosum evoked monosynaptic, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive excitatory postsynaptic potentials (EPSPs) that were attenuated by the GABAB receptor agonist, p-chlorophenyl-GABA (baclofen, 0.5-10 microM) in a concentration-dependent manner. Baclofen also blocked the GABAA-mediated inhibition of neostriatal cell responses, which were revealed by paired-impulse stimulation of the subcortical white matter. Both of these effects persisted in slices in which the anterior cortex was removed, indicating that the site of action for baclofen was intrinsic to the neostriatum. The GABAB antagonist 3-amino-2-hydroxy-2-(4-chlorophenyl)-propanesulfonic acid (saclofen, 250-500 microM) reversed the depressant actions of baclofen on both the excitatory and inhibitory responses of neostriatal cells. 3. Concentrations of baclofen as high as 100 microM, which markedly attenuated EPSP amplitude, did not exert direct effects on resting membrane potential, current-voltage relationship, input resistance, or spike threshold and thus appeared to have no postsynaptic effect on the population of neurons recorded. 4. These results indicate that, in contrast to other regions of the CNS, the depressant effects of baclofen on glutamate-dependent EPSPs are mediated exclusively through GABAB receptors located presynaptically on the terminals of glutamatergic afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1992

Isolated NMDA receptor-mediated synaptic responses express both LTP and LTD.

1. The possibility of use-dependent, long-lasting modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission was examined by intracellular recordings from granule cells of the hippocampal dentate gyrus in vitro. In the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinaxaline-2,3-dione (CNQX, 10 microM) robust, long-term potentiation (LTP) of NMDA receptor-mediated synaptic potentials was induced by brief, high (50 Hz) and lower (10 Hz) frequency tetanic stimuli of glutamatergic afferents (60 +/- 6%, n = 8, P less than 0.001 and 43 +/- 12%, n = 3, P less than 0.05, respectively). 2. Hyperpolarization of granule cell membrane potential to -100 mV during 50-Hz tetanic stimuli reversibly blocked the induction of LTP (-6 +/- 2%, n = 6, P greater than 0.05) indicating that simultaneous activation of pre- and postsynaptic elements is a prerequisite for potentiation of NMDA receptor-mediated synaptic transmission. In contrast, hyperpolarization of the granule cell membrane potential to -100 mV during 10-Hz tetanic stimuli resulted in long-term depression (LTD) of NMDA receptor-mediated synaptic potentials (-34 +/- 8%, n = 8, P less than 0.01). 3. We also studied the role of [Ca2+]i in the induction of LTP and LTD of NMDA receptor-mediated synaptic responses. Before tetanization, [Ca2+]i was buffered by iontophoretic injections of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA). BAPTA completely blocked the induction of LTP (3 +/- 5%, n = 13) and partially blocked LTD (-14.8 +/- 6%, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1991

Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. I. Effects on linear and non-linear response characteristics.

Epileptiform activity is known to alter both excitatory and inhibitory circuits within the network of neurons that comprise the hippocampal formation. In the present experiment, kindling-induced alterations in the functional properties of the rabbit perforant path-dentate circuit were analyzed using non-linear system analytic procedures. System input consisted of a random train of impulses applied to the perforant path. System output was the perforant path-granule cell population spike amplitude evoked by each impulse in the train. The results of non-linear systems analysis were compared with the results from twin impulse analysis of kindling-induced alterations within the hippocampal dentate gyrus. Compared to twin impulse procedures, non-linear systems analytic procedures revealed a reduced duration and magnitude of kindling-induced inhibitory interactions to interstimulus intervals of 10-200 ms. The increased magnitude of inhibitory interactions did not decay to prekindled magnitude until 16 weeks postkindling. In contrast, kindling-induced potentiation of the population spike had decayed within 10 weeks of the last stage 5 seizure. Despite the decay of electrophysiological responses to prekindled levels, only a few kindling stimulations were required to evoke fully kindled seizures. Thus, electrophysiological alterations within the first synaptic relay of the hippocampal trisynaptic circuit, the dentate gyrus, cannot explain the long duration of the kindling effect.

Animals↗

PubMed1990

Lesions of the dopaminergic nigrostriatal system in neonatal rats: effects on the electrophysiological activity of striatal neurons recorded during adulthood.

The spontaneous activity of single striatal neurons was recorded extracellularly from 3-4-month-old adult rats that had been given dopamine (DA)-depleting brain lesions 3 days after birth. Behavioral observations made prior to recording indicated no gross sensorimotor deficits, yet subsequent biochemical analyses revealed that animals had sustained near-total DA depletions (greater than 99%). Electrophysiological results showed that the firing rates of type II striatal cells were greatly increased relative to control levels. This finding contrasts sharply with the effects of DA-depleting brain lesions given to adult animals, in which similarly high levels of striatal cell activity are invariably associated with akinesia.

Aging↗

PubMed1990

Compensations after lesions of central dopaminergic neurons: some clinical and basic implications.

Parkinson's disease is associated with degeneration of the dopaminergic component of the nigrostriatal pathway. However, the neurological symptoms of this disorder do not emerge until the degenerative process is almost complete. A comparable phenomenon can be observed in animal models of Parkinson's disease produced by the administration of the selective neurotoxin, 6-hydroxydopamine (6-OHDA). Studies using such models suggest that the extensive loss of dopaminergic neurons is compensated, in large part, by increased synthesis and release of dopamine (DA) from those DA neurons that remain, together with a reduced rate of DA inactivation. These findings may have important implications for the diagnosis and treatment of a variety of neurological and psychiatric diseases, as well as for our understanding of plasticity in monoaminergic systems.

Adaptation, Physiological↗

PubMed1990

Feedforward excitation of the hippocampus by afferents from the entorhinal cortex: redefinition of the role of the trisynaptic pathway.

For the past 3 decades, functional characterizations of the hippocampus have emphasized its intrinsic trisynaptic circuitry, which consists of successive excitatory projections from the entorhinal cortex to the dentate gyrus, from granule cells of the dentate to the CA3/4 pyramidal cell region, and from CA3/4 to the CA1/2 pyramidal cell region. Despite unequivocal anatomical evidence for a monosynaptic projection from entorhinal to CA3 and CA1/2, few in vivo electrophysiological studies of the direct pathway have been reported. In the experiments presented here, we stimulated axons of entorhinal cortical neurons in vivo and recorded evoked single unit and population spike responses in the dentate, CA3, and CA1 of hippocampus, to determine if pyramidal cells are driven primarily via the monosynaptic or trisynaptic pathways. Our results show that neurons within the three subfields of the hippocampus discharge simultaneously in response to input from a given subpopulation of entorhinal cortical neurons and that the initial monosynaptic excitation of pyramidal cells then is followed by weaker excitatory volleys transmitted through the trisynaptic pathway. In addition, we found that responses of CA3 pyramidal cells often precede those of dentate granule cells and that excitation of CA3 and CA1 pyramidal cells can occur in the absence of granule cell excitation. In total, these results argue for a different conceptualization of the functional organization of the hippocampus with respect to the propagation of activity through its intrinsic pathways: input from the entorhinal cortex initiates a two-phase feedforward excitation of pyramidal cells, with the dentate gyrus providing feedforward excitation of CA3, and with both the dentate and CA3 providing feedforward excitation of CA1.

Afferent Pathways↗

PubMed1989

Kindling facilitates acquisition of discriminative responding but disrupts reversal learning of the rabbit nictitating membrane response.

The effect of kindling the hippocampal perforant path-dentate projection on subsequent discrimination-reversal conditioning of the rabbit nictitating membrane (NM) response was examined. Kindling facilitated acquisition of the initial discriminative response but severely impaired performance during reversal training. The facilitative effect on initial acquisition is highly similar to previously reported effects of long-term potentiation on NM discrimination learning, and thus may reflect a kindling-induced increase in perforant path-dentate synaptic strength. The learning deficit during reversal training is similar to the effects of hippocampal ablation; i.e. characterized by a continued high response rate to the CS- rather than an inability to respond to the CS +. These findings demonstrate that kindling-induced seizures can have profound effects on associative learning. The effects are different for the discrimination and reversal phases of the task, however, which may reflect the multi-dimensional effects of kindling at the cellular level.

Animals↗

PubMed1989

Compensatory responses to nigrostriatal bundle injury. Studies with 6-hydroxydopamine in an animal model of parkinsonism.

Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-total destruction of the dopamine (DA)-containing neurons of the nigrostriatal bundle. The dysfunctions in animals with these lesions show many parallels with those present in Parkinsonian patients. Among these are the extensive loss of DA neurons in the basal ganglia, neurological impairments including akinesia, paradoxical kinesia in response to activating conditions, and improved sensory-motor function after the administration of DOPA. Moreover, as with patients with preclinical Parkinsonism, 6-HDA-treated rats with less extensive lesions show few or no behavioral dysfunctions, but are unusually sensitive to the akinesia-inducing effects of stress and dopaminergic antagonists. In this review, we summarize the behavioral effects of 6-HDA-induced depletion of striatal DA in the rat and then focus on the compensatory changes that may underlie the preclinical stage of the disorder. These compensations appear to include an increase in the number of active DA neurons, an increase in the release of DA per impulse from residual terminals, and a decrease in the amount of DA inactivated by high affinity uptake. Collectively, these alterations permit a few residual DA neurons to maintain a normal level of control over cellular activity in the striatum.

Animals↗

PubMed1988

Spontaneous activity of type II but not type I striatal neurons is correlated with recovery of behavioral function after dopamine-depleting brain lesions.

The relation between the spontaneous firing of Type I striatal neurons and recovery of behavioral function after near-total dopamine depletions of the rat striatum was investigated. The results demonstrate that the activity of Type I neurons remains elevated in recovered animals, which contrasts with our previous finding that the firing rates of Type II striatal neurons return to normal levels in association with behavioral recovery.

Action Potentials↗

PubMed1988

A systems theoretic approach to the study of CNS function.

This paper presents a paradigm for using a general systems theoretic approach to study central nervous system function. Neuronal systems are conceptualized as consisting of different populations of neurons, each of which may be treated as a unit with its own dynamic properties. These dynamic properties of each population are determined by fundamental characteristics of its constituent neurons. Different populations interact with each other through the network structure in which they are embedded. We are modeling the linear and nonlinear properties of these systems using a theoretical framework based on two complementary approaches. First, a functional power series is used to characterize the input/output properties of the system. Second, a state-variable approach is used to characterize the internal structure and function of the system and to identify specific relationships among physiological variables. We have extensively investigated the functional power series approach to study the cat somatosensory system and the rabbit hippocampal formation. Both of these systems exhibit nonlinear properties in their response to electrical stimulation, and these nonlinear properties are characterized by the high-order kernels of the functional power series. State-variable models are being formulated to map these input/output properties onto internal models of the systems.

Animals↗