Proceedings of The National Academy of Sciences, 1991
In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10to... more In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10to 50-Hz frequency range (persistent sodium conductance/conjunctive properties/cognition) ABSTRACT We report here the presence of fast subthreshold oscillatory potentials recorded in vitro from neurons within layer 4 of the guinea pig frontal cortex. Two types of oscillatory neurons were recorded: (i) One type exhibited subthreshold oscillations whose frequency increased with membrane depolarization and encompassed a range of 10-45 Hz.
A substantial amount of research has focused on determining the factors that alter the activity o... more A substantial amount of research has focused on determining the factors that alter the activity of substantia nigra dopamine neurons. Much of this research has indicated that several mechanisms that regulate dopamine neuron activity have the capability to maintain the baseline activity of dopamine cells at a fairly constant rate. For example, the intrinsic membrane conductances present on dopamine neurons, which generate the spike activity of these cells, appear to maintain the activity of spontaneously active neurons and suppress the induction of activity in quiescent cells. In addition, dopamine cell activity can be regulated by afferent systems that appear to be capable of preventing dopamine neurons from displaying sustained variations in electrophysiological activity. Specifically, inputs from the striatum or from the subthalamic nucleus may each exert opposing influences on dopamine cell activity via direct vs. indirect afferent projection pathways. In addition, the dendritic release of dopamine may provide negative feedback; dopamine cell firing may increase the dendritic release of dopamine within the substantia nigra, providing a local feedback inhibition of dopamine neuron activity. Factors such as the intrinsic membrane properties, afferent input, and the dendritic release of dopamine all work together in a complex manner to regulate the activity level of dopamine neurons.
1. The present experiments investigated the effects of gamma-amino-butyric acidB (GABAB) receptor... more 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)
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Correlations between substantia nigra (SN) dopamine (DA) cell activity and striatal extracellular... more Correlations between substantia nigra (SN) dopamine (DA) cell activity and striatal extracellular DA were examined using simultaneous extracellular single-unit recordings and in vivo microdialysis performed in drug-naive rats and in rats treated repeatedly with haloperidol (HAL). Intact rats treated with HAL for 21-28 d exhibited significantly fewer active DA cells, indicating the presence of depolarization block (DB) in these cells. However, in rats that received surgical implantation of the microdialysis probe followed by a 24 hr recovery period, HALinduced DA cell DB was reversed, as evidenced by a number of active DA neurons that was significantly higher than that in HAL-treated intact rats and similar to that of drug-naive rats. In contrast, using a modified probe implantation procedure that did not reverse SN DA neuron DB, we found striatal DA efflux to be significantly lower than in controls and significantly correlated with the reduction in DA neuron spike activity. Further-more, although basal striatal DA efflux was independent of SN DA cell burst-firing activity in control rats, these variables were significantly correlated in rats with HAL-induced DA cell DB. Therefore, HAL-induced DB of SN DA neurons is disrupted by implantation of a microdialysis probe into the striatum using standard procedures. However, a modified microdialysis method that allowed reinstatement of DA neuron DB revealed that the HAL-induced inactivation of SN DA neurons was associated with significantly lower extracellular DA levels in the striatum. Moreover, the residual extracellular DA maintained in the presence of DB may, in part, depend on the burst-firing pattern of the noninactivated DA neurons in the SN.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
The tonic influence of dopamine D 1 and D 2 receptors on the activity of striatal neurons in vivo... more The tonic influence of dopamine D 1 and D 2 receptors on the activity of striatal neurons in vivo was investigated by performing intracellular recordings concurrently with reverse microdialysis in chloral hydrate-anesthetized rats. Striatal neurons were recorded in the vicinity of the microdialysis probe to assess their activity during infusions of artificial CSF (aCSF), the D 1 receptor antagonist SCH 23390 (10 M), or the D 2 receptor antagonist eticlopride (20 M). SCH 23390 perfusion decreased the excitability of striatal neurons exhibiting electrophysiological characteristics of spiny projection cells as evidenced by a decrease in the maximal depolarized membrane potential, a decrease in the amplitude of up-state events, and an increase in the intracellular current injection amplitude required to elicit an action potential. Conversely, a marked depolarization of upand down-state membrane potential modes, a decrease in the amplitude of intracellular current injection required to elicit an action potential, and an increase in the number of spikes evoked by depolarizing current steps were observed in striatal neurons after local eticlopride infusion. A significant increase in maximal EPSP amplitude evoked by electrical stimulation of the prefrontal cortex was also observed during local eticlopride but not SCH 23390 infusion. These results indicate that in intact systems, ongoing dopaminergic neurotransmission exerts a powerful tonic modulatory influence on the up-and down-state membrane properties of striatal neurons and controls their excitability differentially via both D 1 -and D 2 -like receptors. Moreover, a significant component of D 2 receptor-mediated inhibition of striatal neuron activity in vivo occurs via suppression of excitatory synaptic transmission.
Schizophrenia is comprised of several symptom subtypes, including positive symptoms, negative sym... more Schizophrenia is comprised of several symptom subtypes, including positive symptoms, negative symptoms, disorganization syndrome, and cognitive disturbances. Of these, evidence suggests that the positive symptoms are related to a dopaminergic hyperactivity within subcortical limbic regions, such as the nucleus accumbens. The accumbens itself receives overlapping inputs from several limbic areas, including the hippocampus subiculum and the amygdala, as well as afferents from the prefrontal cortex. Our studies show that the hippocampal input functions as a gate within the accumbens, modulating information flow along the prefrontal cortical-accumbens-pallidalthalamic-prefrontal cortical loop. It is suggested that the hippocampal subiculum may exert a context-dependent gating within this loop, serving to keep an organism focused on a task. In contrast, the amygdala exerts a very brief, event-related gating that is likely related to affective states. It is this balance between hippocampal-driven focus on task and affect-mediated emotional drive that preserves normal function; a balance that is in part maintained by the dopamine system. This interaction was examined in a developmental disruption model of schizophrenia. In this model, a mitotoxin is administered to pregnant rats during gestational day 17. The adult offspring exhibit several neuroanatomical, behavioral, and pharmacological responses consistent with an animal model of schizophrenia. Moreover, in these animals, electrophysiological studies show that gating within the accumbens is driven primarily by the amygdala, rather than the hippocampus. If such a condition is present in schizophrenia, it would suggest that such patients would react to stimuli primarily based on affective valence, being easily distracted from tasks and goal-directed behaviors. Dopamine D2 antagonists would act to restore this balance by augmenting prefrontal cortical input while diminishing amygdala drive. q
Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-... more 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.
Proceedings of The National Academy of Sciences, 1991
In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10to... more In vitro neurons in mammalian cortical layer 4 exhibit intrinsic oscillatory activity in the 10to 50-Hz frequency range (persistent sodium conductance/conjunctive properties/cognition) ABSTRACT We report here the presence of fast subthreshold oscillatory potentials recorded in vitro from neurons within layer 4 of the guinea pig frontal cortex. Two types of oscillatory neurons were recorded: (i) One type exhibited subthreshold oscillations whose frequency increased with membrane depolarization and encompassed a range of 10-45 Hz.
A substantial amount of research has focused on determining the factors that alter the activity o... more A substantial amount of research has focused on determining the factors that alter the activity of substantia nigra dopamine neurons. Much of this research has indicated that several mechanisms that regulate dopamine neuron activity have the capability to maintain the baseline activity of dopamine cells at a fairly constant rate. For example, the intrinsic membrane conductances present on dopamine neurons, which generate the spike activity of these cells, appear to maintain the activity of spontaneously active neurons and suppress the induction of activity in quiescent cells. In addition, dopamine cell activity can be regulated by afferent systems that appear to be capable of preventing dopamine neurons from displaying sustained variations in electrophysiological activity. Specifically, inputs from the striatum or from the subthalamic nucleus may each exert opposing influences on dopamine cell activity via direct vs. indirect afferent projection pathways. In addition, the dendritic release of dopamine may provide negative feedback; dopamine cell firing may increase the dendritic release of dopamine within the substantia nigra, providing a local feedback inhibition of dopamine neuron activity. Factors such as the intrinsic membrane properties, afferent input, and the dendritic release of dopamine all work together in a complex manner to regulate the activity level of dopamine neurons.
1. The present experiments investigated the effects of gamma-amino-butyric acidB (GABAB) receptor... more 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)
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Correlations between substantia nigra (SN) dopamine (DA) cell activity and striatal extracellular... more Correlations between substantia nigra (SN) dopamine (DA) cell activity and striatal extracellular DA were examined using simultaneous extracellular single-unit recordings and in vivo microdialysis performed in drug-naive rats and in rats treated repeatedly with haloperidol (HAL). Intact rats treated with HAL for 21-28 d exhibited significantly fewer active DA cells, indicating the presence of depolarization block (DB) in these cells. However, in rats that received surgical implantation of the microdialysis probe followed by a 24 hr recovery period, HALinduced DA cell DB was reversed, as evidenced by a number of active DA neurons that was significantly higher than that in HAL-treated intact rats and similar to that of drug-naive rats. In contrast, using a modified probe implantation procedure that did not reverse SN DA neuron DB, we found striatal DA efflux to be significantly lower than in controls and significantly correlated with the reduction in DA neuron spike activity. Further-more, although basal striatal DA efflux was independent of SN DA cell burst-firing activity in control rats, these variables were significantly correlated in rats with HAL-induced DA cell DB. Therefore, HAL-induced DB of SN DA neurons is disrupted by implantation of a microdialysis probe into the striatum using standard procedures. However, a modified microdialysis method that allowed reinstatement of DA neuron DB revealed that the HAL-induced inactivation of SN DA neurons was associated with significantly lower extracellular DA levels in the striatum. Moreover, the residual extracellular DA maintained in the presence of DB may, in part, depend on the burst-firing pattern of the noninactivated DA neurons in the SN.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
The tonic influence of dopamine D 1 and D 2 receptors on the activity of striatal neurons in vivo... more The tonic influence of dopamine D 1 and D 2 receptors on the activity of striatal neurons in vivo was investigated by performing intracellular recordings concurrently with reverse microdialysis in chloral hydrate-anesthetized rats. Striatal neurons were recorded in the vicinity of the microdialysis probe to assess their activity during infusions of artificial CSF (aCSF), the D 1 receptor antagonist SCH 23390 (10 M), or the D 2 receptor antagonist eticlopride (20 M). SCH 23390 perfusion decreased the excitability of striatal neurons exhibiting electrophysiological characteristics of spiny projection cells as evidenced by a decrease in the maximal depolarized membrane potential, a decrease in the amplitude of up-state events, and an increase in the intracellular current injection amplitude required to elicit an action potential. Conversely, a marked depolarization of upand down-state membrane potential modes, a decrease in the amplitude of intracellular current injection required to elicit an action potential, and an increase in the number of spikes evoked by depolarizing current steps were observed in striatal neurons after local eticlopride infusion. A significant increase in maximal EPSP amplitude evoked by electrical stimulation of the prefrontal cortex was also observed during local eticlopride but not SCH 23390 infusion. These results indicate that in intact systems, ongoing dopaminergic neurotransmission exerts a powerful tonic modulatory influence on the up-and down-state membrane properties of striatal neurons and controls their excitability differentially via both D 1 -and D 2 -like receptors. Moreover, a significant component of D 2 receptor-mediated inhibition of striatal neuron activity in vivo occurs via suppression of excitatory synaptic transmission.
Schizophrenia is comprised of several symptom subtypes, including positive symptoms, negative sym... more Schizophrenia is comprised of several symptom subtypes, including positive symptoms, negative symptoms, disorganization syndrome, and cognitive disturbances. Of these, evidence suggests that the positive symptoms are related to a dopaminergic hyperactivity within subcortical limbic regions, such as the nucleus accumbens. The accumbens itself receives overlapping inputs from several limbic areas, including the hippocampus subiculum and the amygdala, as well as afferents from the prefrontal cortex. Our studies show that the hippocampal input functions as a gate within the accumbens, modulating information flow along the prefrontal cortical-accumbens-pallidalthalamic-prefrontal cortical loop. It is suggested that the hippocampal subiculum may exert a context-dependent gating within this loop, serving to keep an organism focused on a task. In contrast, the amygdala exerts a very brief, event-related gating that is likely related to affective states. It is this balance between hippocampal-driven focus on task and affect-mediated emotional drive that preserves normal function; a balance that is in part maintained by the dopamine system. This interaction was examined in a developmental disruption model of schizophrenia. In this model, a mitotoxin is administered to pregnant rats during gestational day 17. The adult offspring exhibit several neuroanatomical, behavioral, and pharmacological responses consistent with an animal model of schizophrenia. Moreover, in these animals, electrophysiological studies show that gating within the accumbens is driven primarily by the amygdala, rather than the hippocampus. If such a condition is present in schizophrenia, it would suggest that such patients would react to stimuli primarily based on affective valence, being easily distracted from tasks and goal-directed behaviors. Dopamine D2 antagonists would act to restore this balance by augmenting prefrontal cortical input while diminishing amygdala drive. q
Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-... more 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.
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