PubMed Health⌕ Search

Biomedical subjects

Patricio O'Donnell

Publications and source records attributed to Patricio O'Donnell.

At least 19 recordsLinked to original sources
PubMed2007

Post-pubertal disruption of medial prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia.

BACKGROUND: A neonatal ventral hippocampal lesion (NVHL) induces behavioral and physiological anomalies mimicking pathophysiological changes of schizophrenia. Because prefrontal cortical (PFC) pyramidal neurons recorded from adult NVHL rats exhibit abnormal responses to activation of the mesocortical dopaminergic (DA) system, we explored whether these changes are due to an altered DA modulation of pyramidal neurons. METHODS: Whole-cell recordings were used to examine the effects of DA and glutamate agonists on cell excitability in brain slices obtained from pre- (postnatal day [PD] 28-35) and post-pubertal (PD > 61) sham and NVHL animals. RESULTS: N-methyl d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA), and the D(1) agonist SKF38393 increased excitability of deep layer pyramidal neurons in a concentration-dependent manner. The opposite effect was observed with the D(2) agonist quinpirole. The effects of NMDA (but not AMPA) and SKF38393 on cell excitability were significantly higher in slices from NVHL animals, whereas quinpirole decrease of cell excitability was reduced. These differences were not observed in slices from pre-pubertal rats, suggesting that PFC DA and glutamatergic systems become altered after puberty in NVHL rats. CONCLUSIONS: A disruption of PFC dopamine-glutamate interactions might emerge after puberty in brains with an early postnatal deficit in hippocampal inputs, and this disruption could contribute to the manifestation of schizophrenia-like symptoms.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Turning off cortical ensembles stops striatal Up states and elicits phase perturbations in cortical and striatal slow oscillations in rat in vivo.

In vivo, cortical neurons and striatal medium spiny neurons (MSN) display robust subthreshold depolarizations (Up states) during which they are enabled to fire action potentials. In the cortex, Up states are believed to occur simultaneously in a neuronal ensemble and to be sustained by local network interactions. It is known that MSN are impelled into the Up state by extra-striatal (primarily cortical) inputs, but the mechanisms that sustain and determine the end of striatal Up states are still debated. Furthermore, it has not been established if brisk perturbations of ongoing cortical oscillations alter rhythmic transitions between Up and Down states in striatal neurons. Here we report that MSN Up states terminate abruptly when persistent activity in cortical ensembles providing afferents to a given striatal region is turned off by local electrical stimulation or ends spontaneously. In addition, we found that phase perturbations in MSN membrane potential slow oscillations induced by cortical stimulation replicate the stimulus-induced dynamics of spiking activity in cortical ensembles. Overall, these results suggest that striatal Up states are single-cell subthreshold representations of episodes of persistent spiking in cortical ensembles. A precise spatial and temporal alignment between episodes of cortical persistent activity and striatal Up states would allow MSN to detect specific cortical inputs embedded within a more general cortical signal.

Action Potentials↗
PubMed2006

Dopamine modulation of prefrontal cortical interneurons changes during adolescence.

Adolescence is marked by profound psychological and neuroendocrine changes. Cognitive functions that depend on the prefrontal cortex and dopamine (DA), such as decision making, are acquired or refined during adolescence; yet, little is known about how neural circuits mature in the transition to adulthood. Here, we conducted electrophysiological recordings in rat brain slices, unveiling an enhancement of the excitability of interneurons, which are important for cortical network activity, by D(1) and D(2) DA receptors. The D(2) effect was observed in slices from adult (postnatal day [PD] > 50) but not preadolescent (PD < 36) animals suggesting a possible neural substrate for the maturation of DA-dependent prefrontal cortical functions during or after adolescence and identifying a critical neural population that could be involved in the periadolescent onset of neuropsychiatric disorders, such as schizophrenia.

Adaptation, Physiological↗
PubMed2006

Altered prefrontal cortical metabolic response to mesocortical activation in adult animals with a neonatal ventral hippocampal lesion.

BACKGROUND: Adult animals with a neonatal ventral hippocampal lesion (NVHL) exhibit deficits in working memory and sensorimotor gating similar to those observed in schizophrenia. As cognitive deficits in this disorder are typically associated with changes in cortical metabolic levels, we investigated here whether an NVHL affects metabolic responses to ventral tegmental area (VTA) activation, a procedure that elicits abnormal cell firing in the prefrontal cortex (PFC) of NVHL animals. METHODS: Prefrontal cortex metabolic activity was determined by measuring cytochrome oxidase I (CO-I) staining. Cytochrome oxidase I levels were quantified by densitometry in pre- and postpubertal sham-operated and lesioned rats that received one or three series of fifteen 20-Hz trains of VTA stimuli every 20 seconds. RESULTS: Ventral tegmental area stimulation yielded higher levels of PFC CO-I in NVHL animals when compared with the sham-operated group, an effect that appeared only after puberty. Increasing the series of burst stimulations further elevated CO-I in sham-operated, but not in NVHL animals. CONCLUSIONS: Increased PFC CO-I activity after VTA burst stimulation in NVHL rats highlights the enhanced energy demand that could be linked to the exaggerated response to stress observed in these animals. The inability to further increase the response with higher mesocortical activity, as observed in sham-operated animals, could be expression of a reduced PFC functional capacity in lesioned animals. Thus, a hyperexcitable PFC with a reduced ability to further increase activity could be a plausible pathophysiological scenario for schizophrenia. Human functional studies could be interpreted in the light of this conceptual framework.

Analysis of Variance↗
PubMed2006

Dopaminergic modulation of striatal plateau depolarizations in corticostriatal organotypic cocultures.

RATIONALE: It has been proposed that dopamine (DA) sustains up states in striatal medium spiny neurons (MSN). Testing this hypothesis requires an in vitro preparation, but up states are typically only observed in vivo. OBJECTIVES: In this study, we used corticostriatal organotypic cocultures, a preparation in which up states have been previously observed, to test the DA control of cortically-driven plateau depolarizations. RESULTS: After 7-21 days in vitro in serum-free conditions, plateau depolarizations resembling up states were only observed in cultures with a critical extent of striatal DA innervation. These plateaus were completely blocked by the non-NMDA antagonist CNQX and significantly shortened by the NMDA antagonist APV or the D(1) antagonist SCH23390. Intracellular interruption of Ca(++) or protein-kinase A (PKA) signaling also eliminated the plateaus. The D(2) antagonist eticlopride failed to disrupt the plateaus, but significantly increased MSN excitability. CONCLUSIONS: These results suggest that coincident activation of corticostriatal glutamatergic and mesostriatal DA transmission may set ensembles of MSN into prolonged depolarizations through a D(1) enhancement of striatal NMDA function in a Ca(++) and PKA-dependent manner.

Action Potentials↗
PubMed2006

Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo.

Prefrontal cortical (PFC) pyramidal neurons (PN) and fast spiking interneurons (FSI) receive dopaminergic (DA) and non-DA inputs from the ventral tegmental area (VTA). Although the responses of PN to VTA stimulation and DA administration have been extensively studied, little is known about the response of FSI to mesocortical activation. We explored this issue using single and double in vivo juxtacellular recordings of medial PFC PN and FSI with chemical VTA stimulation. Electrophysiological characteristics combined with Neurobiotin staining and parvalbumin immunohistochemistry allowed identification of recorded cells as FSI or PN. NMDA injection into the VTA increased firing in all FSI tested (n = 7), whereas most PN (7/11) responded with an inhibition. Furthermore, FSI excitation matching the temporal course of PN inhibition was observed with FSI-PN paired recordings (n = 5). These divergent electrophysiological responses to mesocortical activation could reflect PFC GABAergic interneurons contributing to silencing PN. Thus, the mesocortical system could provide a critical control of PFC circuits by simultaneously affecting FSI and PN firing.

Action Potentials↗
PubMed2005

NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron.

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an "up" state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of "up" and "down" state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be approximately 20% of the "up" state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.

Animals↗
PubMed2005

Selective disruption of nucleus accumbens gating mechanisms in rats behaviorally sensitized to methamphetamine.

Behavioral sensitization of psychostimulant-induced locomotor activity in rats has been proposed as a model of addiction and is accompanied by neuroadaptations in the nucleus accumbens and related circuits. Here, we used in vivo intracellular recordings to examine electrophysiological properties of accumbens neurons from animals that did or did not exhibit behavioral sensitization after repeated methamphetamine (5.0 mg/kg; 5 d). Although spontaneous activity of accumbens neurons was virtually unchanged, multiple synaptic interactions controlling membrane potential states were disrupted in sensitized animals. For example, stimulation of the ventral tegmental area attenuated accumbens responses to prefrontal cortex activation in nonsensitized and saline-treated animals, but not in sensitized animals. Acute methamphetamine (0.5 mg/kg) abolished accumbens up and down states in nonsensitized and saline-treated animals, suggesting a disruption of normal information processing in this area. However, acute methamphetamine failed to affect this pattern in accumbens neurons from sensitized animals. These results suggest that both acute and repeated methamphetamine administration can disrupt synaptic interactions in the nucleus accumbens; however, the nature of these alterations depends critically on the extent of behavioral sensitization. It is speculated that the response to acute methamphetamine in nonsensitized and saline-treated animals may be functionally adaptive, whereas the neuroadaptations observed in sensitized animals may be maladaptive and detrimental to accumbens information processing.

Animals↗
PubMed2005

Social isolation rearing affects prefrontal cortical response to ventral tegmental area stimulation.

BACKGROUND: Animals reared in social isolation exhibit attentional deficits that parallel those found in schizophrenia patients. Such disturbances are frequently attributed to a dysfunction of the mesocortical system. Here we investigated whether electrophysiologic characteristics of prefrontal cortical pyramidal neurons or mesocortical responses were changed in isolated animals. METHODS: In vivo intracellular recordings were obtained from prefrontal cortical pyramidal neurons in animals raised in social isolation or in socialized control animals before and after ventral tegmental area stimulation mimicking dopamine cell burst firing. RESULTS: Prefrontal cortical pyramidal neurons recorded from isolated animals showed bimodal characteristics resembling those of their socialized littermates. Stimulation of the ventral tegmental area evoked plateau depolarizations in both groups, but this was accompanied by abnormal firing or a short hyperpolarization in most of the isolated animals. CONCLUSION: These findings suggest that social isolation rearing may affect mesocortical information processing.

Animals↗
PubMed2005

Prefrontal cortical cell firing during maintenance, extinction, and reinstatement of goal-directed behavior for natural reward.

The prefrontal cortex (PFC) is important for higher cognitive functioning and the processing of reward-related information. Here, electrophysiological recording procedures were used to examine cell firing in the PFC in rats (n = 12) during water reinforcement sessions consisting of three phases. In phase one (maintenance), animals pressed a lever (fixed ratio 1) for water reinforcement (0.05 ml/press) paired with an auditory stimulus. Of 62 neurons recorded during maintenance, 39 (63%) exhibited one of three types of patterned discharges relative to the reinforced response for water. Specifically, PFC neurons exhibited increases in firing rate within seconds preceding the response (type PR; n = 9 cells) or increases (type RFe; n = 16 cells) or decreases (type RFi; n = 14 cells) in firing rate immediately following response completion. The remaining neurons did not alter their firing profiles relative to the reinforced response (type nonphasic cells; n = 23 cells). In phase two (extinction), lever press responses had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, phase three (reinstatement) began, during which each lever press response was again associated with water reinforcement paired with the stimulus. Results indicate differential effects of extinction/reinstatement on cell firing rates and patterns dependent on cell type. These findings are discussed with respect to the adaptive nature of PFC activity during goal-directed behaviors for "natural" rewards, and are considered relative to prior studies that examined nucleus accumbens cell firing during a similar behavioral task.

Action Potentials↗
PubMed2004

Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation.

Dopamine-glutamate interactions may contribute to persistent electrical activity in the prefrontal cortex (PFC). We tested whether a D1 modulation of NMDA function can result in persistent depolarization in vitro. D1-NMDA co-activation yielded depolarizing plateaus resembling in vivo up states in PFC pyramidal neurons recorded in slices from adult (PD 45-65), but not pre-pubertal (PD 29-38) rats. These plateaus required intracellular Ca2+, activation of L-type Ca2+ channels and protein kinase A. These events were eliminated by intracellular administration of the voltage-gated Na+ channel blocker QX-314 or by interrupting synaptic activity with bath application of tetrodotoxin or the AMPA antagonist CNQX, suggesting that they require both intrinsic and synaptic mechanisms. These recurrent depolarizations could constitute important elements in cortical information processing, allowing synaptic plasticity and memory functions. Acquiring these PFC D1-NMDA interactions after puberty may be a critical element for developing mature cognitive abilities.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2004

Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms.

Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA-glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA-D1 synergism required postsynaptic intracellular Ca2+ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2-NMDA interaction was also blocked by the GABA(A) antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2-AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C-IP3 and intracellular Ca2+ at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABA(A) receptors, depending on the glutamate receptor subtypes involved.

Action Potentials↗
PubMed2004

Dopaminergic modulation of prefrontal cortical input to nucleus accumbens neurons in vivo.

Dopaminergic transmission in the nucleus accumbens has been proposed to modulate the effects of converging excitatory inputs from the cortex, hippocampus, and amygdala. Here, we used in vivo intracellular recording in anesthetized rats to examine the response of nucleus accumbens neurons to stimulation of the prefrontal cortex (PFC) and the ventral tegmental area (VTA). The EPSP elicited in accumbens neurons by PFC stimulation was attenuated by VTA train stimulation in a pattern mimicking dopamine cell burst firing. PFC-elicited EPSPs were smaller in amplitude and faster to decay after VTA stimulation. These changes could not be explained by membrane depolarization alone, because EPSPs evoked during the sustained depolarization after VTA stimulation were significantly smaller than EPSPs evoked during spontaneously occurring up states. Furthermore, no attenuation of PFC-elicited responses was observed during depolarization produced by positive current injection through the recording electrode. Administration of a D1 antagonist (SCH 23390; 0.5 mg/kg, i.p.) had no effect on the VTA reduction of PFC-elicited responses, whereas administration of a D2 antagonist (eticlopride; 0.5 mg/kg, i.p.) reversed the reduction of PFC inputs when the analysis was limited to comparisons with spontaneous up states. These results suggest that the ability of PFC inputs to drive accumbens neurons is dampened by dopamine acting primarily at D2 receptors. Along with previous reports of dopaminergic attenuation of limbic afferents to the accumbens, these findings support the hypothesis that dopamine mediates the selection and integration of excitatory inputs and thus shapes information processing in accumbens output neurons.

Animals↗
PubMed2004

Prefrontal lesion reverses abnormal mesoaccumbens response in an animal model of schizophrenia.

BACKGROUND: A neonatal hippocampal lesion induces postpubertal behavioral alterations resembling phenomena observed in schizophrenia. We have recently reported that nucleus accumbens neurons exhibit altered response to ventral tegmental area activation, but only when animals with this lesion reach adulthood. Because a prefrontal cortical lesion eliminates postpubertal abnormal behaviors in these animals, we investigated whether altered accumbens responses were reversed with this manipulation. METHODS: In vivo intracellular recordings were conducted in accumbens neurons in rats that had received neonatal hippocampal lesions combined with either adult prefrontal cortical lesion or sham treatment. Accumbens response to mesolimbic pathway activation was recorded in these animals. RESULTS: Accumbens neurons from animals with a neonatal hippocampal lesion and an adult prefrontal sham operation still showed altered accumbens response to mesolimbic stimulation. On the other hand, most animals with combined neonatal hippocampal and adult prefrontal lesions exhibited responses similar to those of naïve animals. CONCLUSIONS: This result suggests that abnormal behaviors in these animals might be related to excessive prefrontal drive of accumbens neurons upon dopamine activation.

Animals↗
PubMed2004

Prefrontal cortical up states are synchronized with ventral tegmental area activity.

The innervation of the prefrontal cortex (PFC) by the ventral tegmental area (VTA) has an important role in incentive-motivation and cognitive functions. Although this projection has been extensively studied, the precise actions of its transmitters, dopamine (DA) and GABA, on PFC pyramidal neurons remain to be determined. We have recently shown that VTA stimulation elicits a sustained depolarization in PFC pyramidal neurons resembling the periodic depolarizations (up states) these neurons exhibit. This response was shortened by a D1 antagonist, suggesting that DA may sustain depolarized up states in PFC neurons. Here, we tested whether spontaneous PFC up states in vivo require spontaneous VTA activity. Intracellular recordings from PFC neurons conducted simultaneously with VTA local field potentials (LFPs) revealed PFC membrane potential fluctuations occurring synchronously with VTA field potential transitions. Extracellular PFC recordings performed simultaneously with VTA LFPs also indicated a high coherence between these two regions, with VTA oscillations trailing PFC oscillations by a few milliseconds. Furthermore, blockade of VTA activity with lidocaine transiently eliminated PFC LFPs, but not PFC cell up states; instead, up states became irregular during intra-VTA lidocaine administration. These results suggest that baseline levels of VTA activity are necessary for synchronizing PFC pyramidal neurons in the up-down oscillations observed in the anesthetized preparation, allowing the emergence of slow EEG components.

Action Potentials↗
PubMed2003

Dopamine gating of forebrain neural ensembles.

Dopamine may exert different actions depending on a number of factors. A common view is that D1 receptors may be responsible for excitatory actions whereas D2 receptors are involved in inhibitory actions. However, this position cannot be reconciled with several findings indicating otherwise. The role of dopamine on forebrain neural ensembles may be better understood in the light of functional states of the system. Pyramidal cortical neurons and striatal medium spiny neurons alternate between two membrane potential states ('up' and 'down') that could shape dopamine actions. It is proposed that D1 receptors can act as state-stabilizers by sustaining up states and thereby facilitating plasticity mechanisms by providing postsynaptic depolarization and increasing NMDA function. In this way, dopamine can sustain activity in depolarized units. This action is accompanied by a decrease in cell firing (perhaps mediated by D2 receptors), which renders the cells responsive only to strong stimuli. The result would be a net increase in signal-to-noise ratio in a selected assembly of neurons.

Animals↗