Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA
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Abstract |
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Introduction |
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DA can affect synaptic responses by controlling glutamate synaptic transmission (Brown and Arbuthnott, 1983; Pennartz et al., 1992
; O'Donnell and Grace, 1994
; Nicola et al., 1996
), but also by acting on ion currents in the postsynaptic neuron. The nature of this modulation depends on factors such as the receptor subtype involved and the membrane potential of the target cell. In an elegant series of studies, Michael Levine and colleagues have shown, for example, that D1 receptors may enhance striatal neuron response to NMDA receptor activation, whereas D2 receptors may decrease responses to non-NMDA receptors (Levine et al., 1996a
,b
; Cepeda and Levine, 1998
; Cepeda et al., 1998
). Furthermore, D1 receptor activation has also been shown to prolong a persistent voltage-gated Na+ current (INa,p) in PFC neurons (Yang and Seamans, 1996
) and L-type Ca2+ channels in striatal (Hernández-López et al., 1997
) and PFC (Yang et al., 1998
) neurons. Such modulation by DA may have an impact on transitions between membrane potential states that depend on such currents.
Neocortical pyramidal neurons exhibit in vivo a bistable membrane potential. A very negative resting membrane potential (down state) is interrupted by plateau depolarizations (up state) (Cowan et al., 1994; Cowan and Wilson, 1994
). Up and down membrane potential states have also been observed in PFC neurons (Branchereau et al., 1996
), as well as in medium spiny neurons in the striatum (Wilson and Groves, 1981
; Wilson, 1993
; Wilson and Kawaguchi, 1996
) and nucleus accumbens (NAcc) (O'Donnell and Grace, 1995
, 1998
). Up events are driven by excitatory inputs (O'Donnell and Grace, 1995
; Wilson and Kawaguchi, 1996
), but they may be modulated by ion currents. The down state is maintained by a strong inwardly rectifying K+ current (Wilson, 1993
). Once strong excitatory inputs depolarize the neuron to a point at which this current shuts down, the membrane potential can rapidly move to a more depolarized value, the up state. This depolarization can be maintained by Ca2+ currents and INa,p (Wilson, 1993
) and the extent of depolarization may be limited by another K+ current, the slow A-current (Gabel and Nisenbaum, 1998
). Furthermore, at the very negative membrane potential of the down state, NMDA receptors are effectively blocked by Mg2+, and therefore a D1NMDA interaction would not be expressed. On the other hand, during the depolarized up state, the Mg2+ blockade of NMDA receptors would be partially removed. One prediction that can arise from in vitro studies on DANMDA interactions (Levine et al., 1996a
,b
; Cepeda and Levine, 1998
; Cepeda et al., 1998
) is that D1 receptors may contribute to stabilizing the up state in neurons with a bistable membrane potential. This hypothesis was addressed in this study with in vivo intracellular recordings from PFC pyramidal neurons by stimulating the VTA. The role of D1 receptors in mediating the responses was assessed by repeating the stimulation in the presence of a selective antagonist. Parts of this work have been presented in abstract form (Lewis and O'Donnell, 1999
).
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Materials and Methods |
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In vivo intracellular recordings were performed from 73 neurons in 51 SpragueDawley male adult rats (245415 g). All experimental procedures were carried out according to the USPHS Guide for the Care and Use of Laboratory Animals and approved by the Albany Medical College Institutional Animal Care and Use Committee. Animals were anesthetized with chloral hydrate (400 mg/kg, i.p.) and placed on a stereotaxic apparatus. Supplemental anesthesia (chloral hydrate, 2430 mg/h) was continuously delivered during the recording session via a cannula inserted i.p. and a minipump. Bupivacaine (0.25%) was applied s.c. before any skin incision was made. Burr holes were drilled in the skull for electrode placement; stimulating electrodes were located in the mediodorsal (MD) thalamic nucleus (rostrocaudal: bregma 2.8 mm, lateral: 0.51.0 mm; vertical: 5.3 mm from brain surface), VTA (bregma 5.8 mm; lateral: 0.5 mm; 8.3 mm from brain surface), and either the ventral subiculum (bregma 5.8 mm; lateral: 3.5 mm; 8.4 mm from surface) or the fimbriafornix system (bregma 1.6 mm; lateral: 2.0 mm; 3.6 mm from surface), which carries the hippocampal afferents to the PFC.
Recordings
Recording electrodes were made of 1 mm o.d. Omegadot borosilicate glass tubing pulled with a P-97 Flaming-Brown puller (Sutter Instrument Co.). Electrodes were filled with 3 M potassium acetate and 2% Neurobiotin and had a resistance of 44110 M. Recording electrodes were lowered in the PFC (bregma +2.3 to +3.2 mm; lateral: 0.50.8 mm; recordings were attempted between 3 and 6 mm below brain surface). These electrodes were advanced using a hydraulic manipulator while monitoring activity on an oscilloscope. Signals were amplified using an IR-283 Neurodata amplifier (Cygnus Technology), filtered at 0.33 kHz with an eight-pole Bessel filter, and digitized with an interface board (DAP3215a, Microstar Labs) at 10 kHz and fed into a computer for data storage and offline analysis. All data handling was performed using custom-written software (Neuroscope). Once a stable cell was recorded for 5 min, the data were stored and stimulation protocols were carried out. Only neurons showing at least 55 mV membrane potential and 45 mV spike amplitude measured from threshold were analyzed and included in the study.
Electrical Stimulation
Concentric bipolar electrodes with 0.5 mm between tips were employed for electrical stimulation. Current pulses were generated by stimulus isolation units driven by a Master 8 Stimulator (AMPI, Jerusalem, Israel). Stimulation protocols were controlled by the computer using Neuroscope. Electrical stimulation of the VTA, MD and fimbriafornix or ventral subiculum were performed by delivering current pulses 0.5 ms in duration and 0.11 mA in amplitude every 10 s. The VTA was also stimulated with trains of 5 pulses at 20 Hz or 10 pulses at 5 Hz to mimic DA cell burst firing (Chiodo and Bunney, 1983; White and Wang, 1983
) [reviewed by White (White, 1996
)]. In some cases, after evoked responses were recorded, the entire procedure was repeated following administration of the D1 receptor antagonist SCH 23390 (0.3 mg/kg) via a cannula placed i.p.
In a subset of experiments the VTA was chemically, rather than electrically, stimulated (n = 4). Instead of the stimulating electrode, a 30-gauge cannula was lowered in the VTA. After recording baseline activity from a PFC neuron, 30 nl of a solution containing 100 µM NMDA were injected in the VTA with the aid of a syringe pump. As a control, in three experiments 30 nl of 0.9% saline were injected instead.
Histology
After completion of the recordings, Neurobiotin was injected into the cell by passing positive current (1.0 nA, 200 ms pulses at 2 Hz) for at least 5 min. At the end of the experiment, the animals were given a lethal dose of pentobarbital, and transcardially perfused with ice-cold saline followed by 4% paraformaldehyde. Neurobiotin-filled neurons were evidenced by standard histochemical techniques. Brains were cryoprotected in 30% sucrose and sectioned using a freezing microtome. Serial 30 µm thick sections were cut coronally through the medial PFC. Sections were incubated in 0.4% Triton X-100 in phosphate-buffered saline for 12 h, followed by 2 h in Vectastain Elite ABC reagent (Vector Laboratories). Following a series of rinses, sections were reacted with 3,3'-diamino-benzidine and ureahydrogen peroxide (Sigma FAST DAB set). Sections were then rinsed, mounted on gelatin-coated slides, air-dried for 24 h, cleared in xylene, coverslipped in Permount and examined on an Olympus CH30 microscope. Neurons were identified morphologically and localized according to the atlas of Paxinos and Watson (Paxinos and Watson, 1998).
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Results |
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Discussion |
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In the NAcc, up events are dependent on hippocampal input (O'Donnell and Grace, 1995). However, activation of hippocampal afferents failed to elicit transitions to the up state in PFC neurons. This may be due to differences in synaptic organization between these structures. In the NAcc, 510% of hippocampal terminals contact proximal dendrites and cell bodies (Meredith et al., 1990
), and therefore are positioned to exert a strong influence over NAcc neuron membrane potential. Such an arrangement has not been observed in PFC pyramidal neurons (Carr and Sesack, 1996
). Furthermore, ongoing experiments in our laboratory indicate that a hippocampal lesion fails to alter the frequency or duration of up events in the PFC (O'Donnell et al., 1999
). Thus, neither hippocampal nor thalamic afferents alone may be sufficient to drive PFC neuron up states. The excitatory inputs responsible for these transitions may be a combined set of sources, probably including cortico-cortical projections.
VTA stimulation with train pulses mimicking DA cell burst firing evoked a prolonged depolarization resembling the up state. Its duration was reduced by a selective D1 antagonist. The actual VTA-evoked transition had a short latency and was not blocked by SCH 23390. These results indicate that although the onset of up events may not involve DA receptor activation, their maintenance could depend on D1 receptors. Thus, DA contribution to this response may be to maintain the depolarization via a state-stabilizing action (O'Donnell, 1999). Chemical VTA stimulation with NMDA also resulted in a prolonged up state. NMDA receptors are known to activate DA cells in the VTA (Mercuri et al., 1992
; Wang and French, 1993
), evoking burst firing (Seutin et al., 1994
). Since this procedure has been shown to evoke DA release in the NAcc (Suaud-Chagny et al., 1992
), it is likely to also cause DA release in the PFC. The involvement of DA in the prolonged depolarization is also supported by in vitro studies showing that DA can maintain depolarization during tetanic stimulation of glutamate afferents in rat PFC slices (Otani et al., 1998
). An extracellular electrode located in the PFC was able to detect a long-lasting field potential response. Since this was only a few microvolts in amplitude, it is unlikely that it would contribute significantly to the intracellular depolarization, which ranges between 8 and 22 mV. Rather, the negative DC shifts may result from synchronous depolarizations to the up state in a population of PFC neurons.
Along with the prolonged up state, VTA stimulation also decreased PFC neuron firing. This response had been previously observed with extracellular recordings (Ferron et al., 1984; Jay et al., 1995
). Furthermore, early intracellular studies reported a reduction in firing along with depolarization in PFC neurons by DA iontophoresis (Bernardi et al., 1978
, 1982
); membrane potential states, however, were not addressed in those studies. Depolarization and decrease in firing may be due to independent mechanisms. Indeed, in vitro studies reported DA-mediated depolarizations that were not mimicked by combined D1 and D2 agonists in PFC (Shi et al., 1997
) and NAcc (O'Donnell and Grace, 1996
) slices. On the other hand, DA may decrease firing rate via its action on voltage-gated Na+ channels as demonstrated in the NAcc (Zhang et al., 1998
) and PFC (F.J. White, personal communication), or by uncoupling dendritic input zones in apical dendrites from basal dendritic-somatic areas (Yang et al., 1999
).
Some components of the responses observed may involve non-DA mechanisms. A few neurons responded with shortlatency hPSPs to VTA stimulation. These could be due to activation of GABA projection cells (Steffensen et al., 1998), which comprise a large proportion of VTA neurons. These responses have been typically observed during PFC neuron up states, bringing the membrane potential to a value around 70 mV. It is possible that the dPSPs observed with VTA stimulation during the down state were also GABA-mediated, since these depolarizations brought the membrane to a value similar to that of hPSPs evoked during the up state, which is at the presumed level of an in vivo Cl reversal potential. Alternatively, dPSPs may have a different source. DA cells have the capacity to release glutamate in vitro (Sulzer et al., 1998
); if this holds true for the in vivo condition, it could explain the VTA-evoked dPSPs in the PFC, particularly those observed at depolarized membrane potentials that cannot be accounted for by GABA. In any event, a fast component in the VTA-evoked response may be responsible for the transition to the up state, only to be maintained by the simultaneous release of DA.
A number of potential confounds need to be addressed. First, some of the responses could be due to antidromic electrical activation of PFCVTA neurons that leave collaterals in the pyramidal cell being recorded. We believe this is unlikely because chemical activation of the VTA with local administration of NMDA (a procedure that would not result in antidromic activation) also evoked a prolonged depolarization. Second, anesthesia levels could affect membrane potential states. In a previous study, we reported that NAcc neurons would go into a prolonged down state at near-lethal doses of anesthesia (O'Donnell and Grace, 1995). To avoid changes in anesthesia levels, we used a continuous delivery with a syringe pump and an i.p. cannula. Neurons with a bistable membrane potential have been observed in the presence of a variety of anesthetic agents, including chloral hydrate (O'Donnell and Grace, 1995
, 1998
) and urethane (Wilson and Kawaguchi, 1996
). Another issue derived from the use of an anesthetized preparation relates to whether up and down membrane potential states are expression of sleep patterns. In a recent study, a strongly periodical 5 Hz oscillation was observed in cortical and striatal neurons (Charpier et al., 1999
), similar to what we observed in this study and to what had been reported in the NAcc (O'Donnell and Grace, 1995
). The strong periodicity of these oscillations is an indication that they may be related to the also very periodical sleep patterns. Indeed, the 5 Hz oscillation was in phase with EEG cortical spindles (Charpier et al., 1999
) in barbiturate-anesthetized animals. On the other hand, the alternation between up and down states should not be defined as an oscillation, given its very weak periodicity (Stern et al., 1997
). It is possible that during certain sleep stages updown transitions may become synchronized and increase their periodicity, contributing to a slow (<1 Hz) EEG oscillation (Steriade et al., 1993
; Amzica and Steriade, 1998
). However, intracellular recordings from striatal neurons in unanesthetized or locally anesthetized animals have also shown up and down membrane potential states (Hull et al., 1970
; Wilson and Groves, 1981
), even if sensory afferents were stimulated to ensure the animals were awake (Wilson and Groves, 1981
). Given the correlation between cortical and striatal up states (Stern et al., 1997
), it is possible that cortical updown transitions are not related to sleep. This issue will only be solved with intracellular recordings from awake animals.
Together, our results indicate that activation of VTA neurons depolarizes PFC neurons, bringing them to the up state (an effect probably not mediated by DA), which is then maintained by DA acting on D1 receptors. Thus, DA cell burst firing may maintain the up state in a population of neurons. This could be an important mechanism involved in PFC function and plasticity. For example, D1 DA receptors in the PFC are necessary for accurate performance in working memory tasks (Sawaguchi and Goldman-Rakic, 1994; Williams and Goldman-Rakic, 1995
). Thérèse Jay has shown that it is easier to elicit long-term potentiation (LTP) in the PFC by hippocampal stimulation following a train of stimuli to the VTA (Jay et al., 1996
), even though PFC neurons decreased their firing rate and synaptic responses to hippocampal stimulation were reduced following VTA stimulation (Jay et al., 1995
). These findings, at first sight incongruent, could be explained by our observations. A long-lasting VTA-evoked up state may provide a PFC neuron depolarization that is sufficient to facilitate NMDA-dependent LTP (by virtue of a removal of the Mg2+ blockade of the NMDA channel), while at the same time PFC neuronal firing is reduced. Furthermore, the observed decrease in firing may actually be a mechanism filtering activity unrelated to ongoing behavior. It has been proposed that VTA cell firing may be related to attention and motivational mechanisms (Schultz, 1992
). The involvement of DA in these functions may be achieved by its reinforcement of up events in an ensemble of PFC neurons, with ensembles defined as a distributed set of neurons in the up state (O'Donnell, 1999
). Irrelevant activity would be filtered by the reduced firing, and strong or coincident excitatory inputs may be gated by the prolonged up state. In this way, VTA projections may reinforce behaviorally relevant assemblies in the PFC by this coincidence-detection mechanism. Although speculative, this could be a general operating principle of DA systems, and pathological conditions in which there is a decrease in DA, such as Parkinson's disease and perhaps negative symptoms of schizophrenia, may result in a poor ensemble-reinforcement with dramatic consequences in the motor and cognitive spheres respectively. On the other hand, an increased mesolimbic DA activity may result in inappropriate ensembles being reinforced, which is likely to result in positive symptoms of schizophrenia.
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Note |
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Address correspondence to Patricio O'Donnell, MD, Ph.D., Albany Medical College (MC-136), Center for Neuropharmacology and Neuroscience, Albany, NY 12208, USA. Email: odonnep{at}mail.amc.edu.
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