Department of Physiology and Neuroscience, Medical University of South Carolina, 173 Ashley Ave, Suite 403, Charleston, SC 29425, USA
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Abstract |
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Introduction |
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Persistent activity is not unique to the PFC since spontaneous rhythmic shifts in membrane potential from a hyperpolarized down-state to a depolarized up-state have been observed in a variety of brain regions during various stages of the natural sleepwake cycle and in reduced cortical slabs or organotypic cultures (Steriade et al., 1993a,b; O'Donnell and Grace, 1995
; Plenz and Aertsen, 1996
; Plenz and Kitai, 1996
; Stern et al., 1998
; Lewis and O'Donnell, 2000
; Timofeev et al., 2000
, 2001; Steriade, 2001
; West and Grace, 2002
). These up-states share similar characteristics in that they are driven by synaptic input, show a transition in membrane potential to
60 mV for hundreds of milliseconds to tens of seconds, exhibit strong fluctuations in membrane potential and intermittent firing at 210 Hz and are synchronous in pairs of cells but evoke asynchronous firing. The similarities in these features across studies suggest that persistent activity may be common property of intact neural circuits. While up-states and the persistent activity underlying working memory could be different, they may share the basic common mechanisms that can be studied in more convenient reduced preparations.
In vivo, cortical up-states of persistent activity may be spontaneous or initiated by stimulation of the hippocampus or neuromodulatory midbrain or brain stem regions (Steriade et al., 1993a; O'Donnell and Grace, 1995
; Lewis and O'Donnell, 2000
). Moreover, up-states can be modulated by neuromodulatory inputs as well as input from the medial temporal lobe (Fuster, 1998
). Stimulation of neuromodulatory inputs produce much more prolonged up-states than those occurring spontaneously in cortex and evoke neural activity that is similar to natural brain state of arousal (Steriade et al., 1993a
). In computational models, extrinsic input to realistically simulated deep layer PFC neurons also evokes robust prolonged persistent activity that is critically dependent upon synaptic currents, such as the sustained NMDA current and GABAergic currents (Wang, 1999
; Durstewitz et al., 2000
). Given the ubiquity of persistent activity and its possible links to working memory processes in PFC, it is of interest to understand the synaptic basis of self-sustained activity evoked by various afferents to PFC such as those arising in the ventral tegmental area (VTA) and hippocampus.
Here we examined the synaptic basis of persistent activity in PFC using in vivo intracellular recordings and whole-cell patch-clamp recordings from PFC neurons in organotypic co-cultures. Persistent activity was evoked by limbic or neuromodulatory afferents to PFC (Steriade et al., 1993a; Lewis and O'Donnell, 2000
). Evoked persistent activity in PFC was mediated by a complex interplay of glutamatergic and GABAergic currents, with glutamatergic currents providing sustained depolarization and GABAA currents bombarding the neuron with IPSCs that produced characteristic membrane fluctuations. These unexpected mechanisms allowed groups of PFC neurons to maintain depolarization near threshold for many seconds.
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Methods |
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Recordings under current-clamp were obtained from neurons within the prelimbic cortex (coordinates from Bregma: AP 3.2 mm; L 0.6 mm; V 3.25.0 mm @ 10° head inclination) of male rats (300400 g, >p60) anesthetized with an i.p. injection of chloral hydrate (400 mg/kg) and placed in a stereotaxic apparatus. The temperature of the animal was maintained at 36°C with a heating pad. Supplemental anesthesia (as needed) and glutamatergic drugs were delivered via a lateral tail vein catheter. Bipolar concentric electrodes were positioned in the VTA. Sharp intracellular pipettes were pulled from 1 mm Omegadot borosilicate glass tubing using a FlamingBrown puller, and filled with 1.5% biocytin in 3 M K+ acetate and attached to a head stage connected to a Neurodata amplifier. Custom-made software (Neuroscope; Labview) was used for data collection, storage and analysis.
Organotypic Cultures and Patch-clamp Recordings
P1P3 rats were anesthetized by placing them on ice for 23 min. Sections (350 µm) of the prelimbic region of the PFC and the midbrain (containing the VTA), and/or the hippocampus or the basal forebrain (containing the septum) were obtained in oxygenated, sucrose-substituted solution (Seamans et al., 2001) using a Leica vibratome. Slices were placed next to each other on a Millipore millicell insert in a six-well culture dish. One milliliter of serum-based media fed the slices from below. The plating media contained: 50% basal medium Eagle, 25% Earles balanced salt solution, 25% horse serum plus 6.5 mg/ml glucose, 25 mM HEPESNaOH (pH 7.2), 100 µg/ml streptomycin and Glutamax for first 3 days. Every 34 days thereafter inserts were placed in a fresh six-well dish with 850 µl of media as above except 70% basal medium Eagle, 25% Earles balanced salt solution and 5% horse serum was substituted. After 15 days, 10 µl of 5-fluoro-2-deoxyuridine (0.08 mM) plus uridine (0.2 mM) in MEM was added to the media to prevent cell division. After an average of 24 ± 1 days in culture a cutout of the tissue with attached Millipore membrane was placed under an upright Zeiss FS2 microscope and viewed using DICIR optics. Recordings were made in whole-cell current- or voltage-clamp mode using a HEKA EPC9/3 amplifier running TIDA software. Capacitance and series resistance (520 M
, 70% compensated) artifacts were compensated automatically and optimized manually. Glass pipettes had tip resistances of 37 M
when filled with internal solution containing in mM; 110135 K-gluconate, KMeSO4 or 75110 K2SO4, 210 KCl, 2 MgCl2, 10 HEPES, 1 EGTA, 4 Na-ATP, 0.3 TrisGTP, 14 phosphocreatine and sometimes 2 QX-314. Liquid junction potentials were corrected when possible. Bathing media, containing in mM 125 NaCl, 3.8 KCl, 25 NaHCO3, 1.2 CaCl2, 1 MgCl2, 10 dextrose and 0.4 ascorbic acid (pH 7.4), was saturated with 95% O25% CO2 and maintained at 3336°C. This modified physiological ACSF not only has Ca2+ and Mg2+ concentrations closer to the in vivo conditions (Sanchez-Vives and McCormick, 2000
), but also Cl concentrations that are close native chloride concentrations in the brain. The Cl reversal potential was calculated based on this external solution and 14 mM [Cl]i. CNQX (10 µM), bicuculline (10 µM) and D-APV (50 µM) (Sigma, St Louis) were bath applied. N-Methyl-D-aspartate (NMDA,100 µM, 10 ms) was applied via a puffer pipette in the relevant ACSF. A stimulating electrode was placed in the afferent tissue next to the PFC slice and high (>20 mA) or low (<20 mA) intensity square wave (0.2 ms) pulses were delivered. The intensity necessary to produce an up-state varied greatly across preparations. The location of the stimulating electrode relative to the septum was verified by locating acetylcholine-containing neurons in the septal-PFC co-cultures optically using fluorescence for the 192IgG-congugated-Cy3 antibody (1:100) against the P75 receptor (Hartig et al., 1998
) that was bath-applied for 30 min at the end of the experiments. The septum was chosen because it is the main source of acetylcholine specifically to the medial PFC/prelimbic cortex as 192IgG-sapporin lesions of the septum most effectively eliminated AchE staining in prelimbic, but not dorsal PFC (Nieto-Escamez et al., 2002
; J. Conner, personal communication). For PFC-midbrain co-cultures, the location of the VTA was verified after recordings by processing the tissue for tyrosine hydroxylase (TH) (Gomez-Urquijo et al., 1999
). At the end of the recordings, the co-cultures were removed from the Millicell membrane and fixed in 4% paraformaldehyde dissolved in 10 mM phosphate-buffered saline (PBS) for at least 4 h and then placed in PBS. The tissue was pre-incubated in 2% Triton-X in PBS for 24h, and then rinsed again 3 x 5 min in PBS. The tissue was incubated in 1:5000 rabbit TH (New England Biolabs) in 0.1% BSA/PBS for 24 h at 4°C on a shaker. The tissue was rinsed in PBS for 10 min, and incubated in CY3 1:1000 for 1 h followed by 3 x 10 min rinses in PBS, dried and mounted. Alternatively, an avidinbiotin complex was used instead of CY3 and tissue was developed for diaminobenzadine.
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Results |
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Stimulation of neuromodulatory inputs providing cholingergic or dopaminergic input to cortex have been shown to produce persistent activity patterns that were much more prolonged than those occurring spontaneously, sometimes lasting tens of seconds (Steriade et al., 1993a; O'Donnell and Grace, 1995
; Lewis and O'Donnell, 2000
). In the present study, low intensity single-pulse stimulation of the mibrain region containing the ventral tegmental area (VTA) subthreshold for an up-state, evoked a fast depolarizing response followed by a prolonged hyperpolarization (Fig. 1b). Similar depolarizing-hyperpolarizing responses following VTA, fornix, cortico-cortico or whisker stimulation have been observed in cortical neurons recorded in vivo (O'Donnell and Grace, 1995
; Zhu and Connors, 1999
; Lewis and O'Donnell, 2000
) and appears to be a common effect of activating cortical networks. In the present study, VTA stimulation at higher intensities or with burst patterns (510 pulses/20 Hz), effectively produced persistent activity (Fig. 1c) that was 51% longer than that occurring spontaneously in VTAPFC co-cultures (spontaneous = 3.7 ± 0.5 s, VTA induced = 7.19 ± 0.5 s) and that often outlasted the sampling period of 10s in vivo. However, there was considerable variability across preparations. Persistent activity could also be evoked by other types of stimulation, including the septum in PFCbasal forebrain co-cultures (n = 13; see Methods), stimulation of the CA1 region in hippocampalVTAPFC triple cultures (n = 30) or focal application of NMDA in PFC (n = 6, Fig. 2ad).
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Persistent activity that appeared as unitary phenomenon under current-clamp was composed of multiple components revealed under voltage-clamp (Fig. 3). In cells where spontaneous and evoked persistent activity was of similar duration, direct comparison revealed similar components (Fig. 3a,b), and in fact these components were observed regardless of the initiating stimulus. The three main components were: (i) an initial EPSC and large amplitude response that reversed with membrane depolarization (component 1); (ii) a second slower response that was maintained throughout the depolarization (component 2); on which rode (iii) many small asynchronous synaptic events (component 3).
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One counter-intuitive aspect of the NMDA contribution to up-states is that robust up-states are routinely observed in animals anesthetized with ketamine (Steriade et al., 1993a,b; Stern et al., 1998
) which is an NMDA antagonist. As a test of the hypothesis that NMDA receptors are involved in up-states, Steriade et al. (1993b)
showed that a supplemental dose of ketamine (2.5 mg/kg) to animals anesthetized with urethane dramatically reduced up-state duration and spike frequency. But what happens in the case of animals anesthetized with ketamine? We also observed robust up-states in PFC neurons from five rats anesthetized with ketamine (20 mg/kg) and xlyazine (6 mg/kg). In these animals, when a supplemental injection of ketamine (1.5 mg/kg) was delivered a rapid and potent decrease in up-state duration (Fig. 5e) and amplitude was observed. Furthermore, subsequent application of CPP 10 min after the supplemental ketamine injection further reduced up-states, as shown in Figure 5a,e. When viewed in light of the data presented in Figure 5, it suggests that the amount of NMDA blockade by ketamine anesthesia is incomplete, and that the NMDA component of up-states can be reduced further by supplemental application of ketamine or the more selective NMDA antagonist CPP.
Previously it was suggested that during up-states associated with sleepwake cycles, neurons recorded intracellularly in vivo were bombarded by IPSPs (Timofeev et al., 2001). Accordingly, unitary synaptic events were present during the entire period of persistent activity (Fig. 6a). In the present experiments, most unitary events were eliminated by bicuculline (n = 8) indicating they were mainly mediated by asynchronous GABA-mediated Cl currents (Fig. 6b). However, it should be noted that in bicuclline the slice exhibited signs of epileptiform activity. Thus the reversal potentials of all events were analyzed in ACSF lacking bicuculline. All events tended to be inward (downward going) at potentials more negative than
60 mV. Figure 6d shows the data from all these responses recorded at potentials below 60 mV plus all outward events (upward going) recorded at potentials above 60 mV. Like component 1, reversal of these events (61.4 mV) obtained by fitting a line to the group data shown in Figure 6d, occurred near the predicted reversal potential for Cl (59.8), given the present Cl concentrations. The reversal potential measured here using patch-pipettes was very close to the reversal potential of 57 ± 4 mV for fluctuating events in somatosensory cortex recorded during up-states using sharp KAc filled electrodes that do not disrupt the [Cl]i (Plenz and Kitai, 1996
). This analysis therefore revealed mainly the inhibitory or Cl mediated unitary events during the up-state. At holding potentials above the reversal it was possible to dissociate inward (downward going) versus outward (upward going) events in order to determine the relative excitatory versus inhibitory drive. Analysis of up-states from 17 neurons clamped at 40 mV revealed that 69.6% (n = 1684) of all events were outward and 30.4% (n = 512) events were inward at this potential, suggesting that
70% of the asynchronous synaptic drive during persistent up-states was inhibitory.
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The offset of persistent activity was marked by a sharp drop in synaptic activity, supporting the claim that up-states are terminated by a lack of synaptic input (Contreras et al., 1996; Timofeev et al., 2001
).
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Discussion |
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Since persistent activity is a network phenomenon requiring sufficient connectivity between neurons it is not observed in acute brain slices from rats or primate PFC [but is present in ferret slices (Sanchez-Vives and McCormick, 2000)] where connections are removed during slicing, but is observed in cortical and subcortical tissue where sufficient connectivity is still present, such as in vivo or in organotypic slice preparations. In organotypic co-cultures of cortex and basal forebrain, thalamus or striatum, afferent fibers entered the cortical region and only formed connections within the layer in which connections normally formed in vivo, regardless of the orientation of the two slices in the culture (Yamamoto et al., 1992
; Bolz, 1994
; Gomez-Urquijo et al., 1999
; Klostermann and Wahle, 1999
; Molnar and Blakemore, 1999
). Physiological properties of pyramidal, interneurons and striatal neurons in organotypic mono- and co-cultures also closely match those of neurons characterized in vivo or in acute slice preparations (Plenz and Aertsen, 1996
; Plenz and Kitai, 1996
; Klostermann and Wahle, 1999
). These cultures maintain a well-balanced state of excitation and inhibition, suggesting that mechanisms intrinsic to cortex are sufficient for the expression of cell-type-specific electrophysiological properties and persistent activity. Specifically in the case of co-cultures containing the PFC and midbrain, they exhibit similar electrophysiological properties to those observed in vivo (e.g. Fig. 1). In midbrain containing co-cultures tyrosine hydroxylase positive midbrain fibers innervate mainly deep layers of the rat PFC (Gomez-Urquijo et al., 1999
; Trantham et al., 2002
) and release dopamine (Cragg et al., 1998
), similar to the in vivo situation [for a detailed histological description of VTAPFC co-cultures, see Gomez-Urquijo et al. (1999)
]. In both preparations PFC neurons also exhibit up-state behavior that can be initiated or prolonged by VTA stimulation (Lewis and O'Donnell, 2000
) (Fig. 1). Nevertheless, we do not presume that the co-culture is identical to the brain of a 24-day-old animal in every respect (see De Simoni et al., 2003
). Rather, it is a convenient reduced model system that allows investigation of persistent activity with greater experimental control than the in vivo preparation.
Although midbrain containing cultures contain tyrosine hydroxylase and release dopamine, the contribution of dopamine to up-state initiation was not investigated here but is the subject of ongoing investigations (Trantham et al., 2002). However, as shown previously, VTA stimulation (Lewis and O'Donnell, 2000
) or stimulation of other neuromodulatory inputs to cortex such as the locus coeruleus or pedunculopontine nuclei (Steriade et al., 1993b
), are capable of initiating the complex mix of synaptic currents that underlie prolonged persistent activity. Thus traditionally neuromodulatory inputs to cortex may be capable of evoking persistent activity that is ultimately dependent upon glutamate and GABA currents. The present study focused not on how these neuromodulatory inputs initiate persistent activity, but rather exploited the fact that these subcortical regions are potent activators of such activity.
Persistent activity required non-NMDA currents (i.e. it was eliminated by NBQX or CNQX) to activate a large EPSP/IPSP component (component 1) and a prolonged inward current (component 2) with overlying asynchronous events (component 3). Approximately 70% of all asynchronous events recorded during the period of persistent activity reversed near 60 mV (Figs 3b and 6a) and were eliminated by bicuculline (Fig. 6b). It is not clear why the unitary EPSC rate did not increase significantly during up-states, especially in the presence of bicuculline where almost all events were eliminated. One reason may be that recordings were made from the soma where mostly inhibitory rather than excitatory inputs converge. Recently it was shown that in striatal neurons the Ca2+ signal recorded in dendrites correlated well with up-states recorded from the soma (Kerr and Plenz, 2002). Given the massive drop in input resistance during the up-state, EPSPs on electrotonically remote dendrites may have become invisible to the soma. Nevertheless, from the perspective of the soma (and presumably the axonal spike initiation zone), evoked persistent activity was characterized by a balance of a prolonged inward current and fast IPSPs and not by a balance of fast excitatory and inhibitory unitary events. Very similar results have also been observed in primary cortical cultures (Opitz et al., 2002
). Because the characteristic fluctuations in membrane potential were produced by the interplay of glutamate and GABA currents it explains why they were removed by CNQX, APV or bicuculline.
The periodic IPSPs tended to force the membrane potential towards the Cl reversal potential. In combination with intrinsic currents, these events may bring the mean Vm of up-states to near60 mV, as is commonly observed (Steriade et al., 1993a,b; O'Donnell and Grace, 1995
; Stern et al., 1998
; Destexhe and Pare, 1999
; Lewis and O'Donnell, 2000
; Timofeev et al., 2000
, 2001; Steriade, 2001
; West and Grace, 2002
). These data also highlight the importance of coordinated activity in PFC pyramidal and non-pyramidal neurons to persistent activity, as suggested previously (Goldman-Rakic, 1996
).
Both computational modeling (Wang, 1999; Durstewitz et al., 2000
) and in vivo intracellular recording studies (Steriade et al., 1993b
) have shown that the synaptic drive needed to maintain persistent activity depends strongly on NMDA currents. In support of this claim, the current underlying persistent activity was reduced or eliminated by NMDA antagonists. However, persistent activity was also eliminated by NBQX or CNQX, indicating that activation of NMDA receptors depended on activation of non-NMDA receptors. In many neurons the inward current did not possess the voltage dependence of a pure NMDA current, suggesting that the inward current that drove the up-state is composed of a mix of NMDA and non-NMDA synaptic currents (as well as intrinsic currents). Yet unlike AMPA receptors, NMDA receptors have a long decay time constant and produce a current that can outlast the period of agonist application by as much as 1000-fold (Spruston et al., 1995
) and as a result, are capable of producing sustained depolarizations for seconds. This explains how persistent depolarizations could be sustained for seconds despite the asynchronous and low firing rates (<5 Hz) recorded from individual neurons in the network and in spite of the massive inhibitory bombardment (Fig. 6) onto pyramidal cells that might otherwise terminate excitation dependent solely on recurrent firing and EPSPs. However, recurrent AMPA excitation may reinitiate activation of NMDA currents to prolong the period of persistent activity. Indeed the prolonged inward current (component 2) could very likely be the result of summed EPSPs that are smeared out to produce what looks like a large unitary inward current. In many cases, in the presence of bicuculline, massive EPSPs like those shown in Figure 4 were observed throughout the period of the normal up-state. These large EPSPs were of much lower frequency and larger amplitude than the spontaneous events analyzed in Figure 6 and therefore did not contribute to the membrane fluctuations. One possibility is that NMDA currents and possibly other prolonged inward currents bridge the gap between these large infrequent EPSPs to produce what looks like the smoothed EPSP shown in Figure 5. Thus, component 2 may be the result of large AMPA mediated EPSPs that are connected by prolonged NMDA currents.
Although NMDA antagonists CPP, APV and phencyclidine (PCP) (O'Donnell and Grace, 1998) have been shown to block evoked persistent activity, potent spontaneous up-states have been recorded routinely in the presence of ketamine anesthesia (Steriade et al., 1993b
; Destexhe and Pare, 1999
; Timofeev et al., 2000
, 2001). However, supplemental ketamine delivered to anesthetized animals has been shown to significantly reduce up-states (Steriade et al., 1993b
). We replicated this observation and found that in animals anesthetized with ketamine/xylazine, up-states were prominent yet were greatly reduced in duration by an additional supplemental dose of ketamine. Since supplemental ketamine to ketamine anesthetized animals reduced up-states, it suggests that the block of NMDA receptors needed for anesthesia was not complete. The differences in the effectiveness of ketamine and phencyclidine versus CPP and APV in eliminating up-states likely reflects the fact the former agents have potent effects on other neurotransmitter systems including dopamine and GABA (Moghaddam et al., 1997
; Yonezawa et al., 1998
). Furthermore, because PCP and ketamine-like compounds inhibit the NMDA-induced release of GABA in cortex (Drejer and Honore, 1987
; Pin et al., 1988
), the reduced GABAergic tone might actually facilitate up-state initiation.
During evoked persistent activity, PFC neurons display synchronous depolarizations, not synchronous firing. Therefore the present study actually described a mechanism for producing persistent depolarizations in PFC. Maintaining cortical neurons near threshold in the presence of strong membrane fluctuations is an especially effective means of producing reliable action potential initiation (Mainen and Sejnowski, 1995; Ho and Destexhe, 2000
). The prolonged depolarization may produce a ready state near threshold, allowing PFC neurons to effectively respond to even small inputs. Sufficiently strong inputs from the VTA or hippocampus that encode information relating to behavioral significance (Schultz, 1997
) or context respectively could place working memory buffers into this ready-state. During this period, PFC neurons may or may not fire (e.g. Fig. 2). However, given a ready state has been evoked, other sources of input perhaps from other cortices, could then effectively cause sustained firing on top of this persistent depolarization. If we extend on these ideas it would imply that during the encoding of behaviorally significant stimuli by VTA neurons, working memory buffers in the PFC should more effectively encode recently acquired information as persistent activity. This is in addition to the prolonged neuromodulatory action of dopamine in the PFC that stabilizes persistent activity, once it is evoked (Durstewitz et al., 2000
). Therefore, while persistent activity can be initiated by a variety of extrinsic and intrinsic sources (Fig. 2), the VTA may be unique in that it exerts an additional neuromodulatory control that increases the stability and robustness of already initiated up-states (Durstewitz et al., 2000
).
The present findings might also shed light on aspects of PFC dysfunction. As highlighted by Goldman-Rakic (1999) and others (Egan and Weinberger, 1997
), schizophrenia is characterized by a dysregulation of PFC function and working memory. The neurobiological deficiencies associated with schizophrenia are exactly those we propose would disrupt sustained activity, namely alterations in midbrain and limbic inputs to PFC, and disruptions in GABAergic and NMDA function in the PFC (Moghaddam, 1994
; Egan and Weinberger, 1997
; Lewis et al., 1999
). Thus, strategies aimed at GABA and NMDA systems that would produce more robust persistent activity patterns in PFC evoked from the VTA or limbic regions may prove beneficial in the treatment of this disease.
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Notes |
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Address correspondence to Jeremy K. Seamans, Department of Physiology and Neuroscience, Medical University of South Carolina, 173 Ashley Ave, Suite 403, Charleston, SC 29425, USA. Email: seamans{at}musc.edu.
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