Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208 and , 1 NIMH, Clinical Brain Disorders Branch, Bethesda, MD 20892, USA
Address correspondence to Patricio ODonnell, Albany Medical College (MC-136), Center for Neuropharmacology and Neuroscience, 47 New Scotland Ave, Albany, NY 12208, USA. Email: odonnep{at}mail.amc.edu.
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Abstract |
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Introduction |
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Pyramidal neurons in the PFC exhibit a bistable membrane potential. A very negative resting membrane potential (down state) is periodically interrupted by plateau depolarizations (up state). Up states are believed to be driven by excitatory inputs (Amzica and Steriade, 1995; Wilson and Kawaguchi, 1996
) and can be modulated by activation of VTA afferents (Lewis and ODonnell, 2000
). Given the heavy hippocampalPFC projection, it is conceivable that up states can be affected by a ventral hippocampal lesion. Also, the output of the hippocampus controls activity in the VTA (Floresco et al., 2001
). A developmental lesion of the hippocampus could affect PFC cell properties and the activity of mesocortical DA projections, possibly resulting in abnormal responses of PFC neurons to VTA stimulation. Here we have evaluated PFC neuronal function in the lesioned animal using electrophysiological techniques and focusing on the nature of responses to VTA and thalamic afferent stimulation.
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Materials and Methods |
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Pregnant SpragueDawley rats were obtained at 18 days of gestation from Taconic Farms (Germantown, NY). At postnatal day 6 (PD6), male pups (1419 g) were separated into two groups. They were either lesioned with ibotenic acid or received a sham injection of artificial cerebrospinal fluid (aCSF). Four to nine pups were used for every surgery. A group of 11 rats (290440 g) also received a lesion as adults. All experimental protocols were performed according to the USPHS Guide for the Care and Use of Laboratory Animals and had been approved by Albany Medical College Institutional Animal Care and Use Committee.
Lesions
Pups were anesthetized with hypothermia by placing them in wet ice. They were secured to a platform on a stereotaxic apparatus (D. Kopf, Tujunga, CA) and an incision was made through the skin. A cannula was lowered into the ventral hippocampus (AP, 3.0 mm; ML, ± 3.5 mm; DV, 5.0 mm; all relative to bregma) and 0.3 µl of ibotenic acid in aCSF (10 µg/µl) were delivered by a minipump at a rate of 0.15 µl/min. The procedure was repeated in the contralateral hippocampus. Sham-operated animals received 0.3 µl of aCSF on each side. The cannula was left in place for an additional 3 min. Animals were warmed up and returned to their cages, where they remained undisturbed until weaning.
A group of adult animals received similar lesions. These rats were anesthetized with equithesin (3 ml/kg, i.p.) and placed in a stereotaxic apparatus (D. Kopf). A cannula placed into the ventral hippocampus (AP, 4.4 mm; ML, ± 5.0 mm; DV, 8.0 and 6.0 mm; all relative to bregma) was used to deliver 0.6 µl of ibotenic acid (10 µg/µl) or 0.6 µl of vehicle, delivered at a rate of 0.2 µl/min. Upon recovery from anesthesia, the animals were returned to their cages and recording sessions were conducted 13 weeks later.
Recording
A subset of animals was tested before puberty (PD 2835) and others were tested as adults (PD56 and older). Recording procedures were as described elsewhere (Lewis and ODonnell, 2000). Briefly, animals were anesthetized with chloral hydrate (400 mg/kg, i.p.) before being placed on a stereotaxic apparatus (D. Kopf). Recording and stimulating electrodes were lowered in the medial PFC (infralimbic and prelimbic areas), MD thalamus and VTA. Recording electrodes were glass micro-pipettes pulled with a Flaming-Brown puller (Sutter P-97) and filled with 3 M potassium acetate with 2% neurobiotin. Electrical signals were acquired with an amplifier (Neurodata IR-283), digitized with an interface board (DAP 3215; Microstar) and fed into a computer. Baseline recording and responses to electrical stimulation of VTA and MD were recorded. Following completion of the procedures, neurobiotin was injected into the neuron by applying positive current pulses (1 nA, 200 ms at 2 Hz for 5 min). Following histochemical procedures, this allowed for identification of cell type and location. Only neurons recorded from animals with a bilateral lesion and with recording and stimulating electrodes located in the intended sites were included in the analysis.
Stimulation
Concentric bipolar electrodes (NEX-100; Rhodes Medical Instruments) with 0.5 mm between the tips were employed for electrical stimulation. Electrodes were placed in the VTA (5.8 mm caudal to bregma; 0.5 mm lateral; 8.3 mm from skull surface) and the MD thalamic nucleus (2.8 mm caudal to bregma; 0.5 mm lateral; 5.3 mm from skull surface). All coordinates were taken from a stereotaxic atlas (Paxinos and Watson, 1998). Current pulses were generated by stimulus isolation units driven by a Master 8 Stimulator (AMPI, Jerusalem, Israel) controlled by a computer. Electrical stimulation of the VTA and MD was 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 five pulses at 20 Hz to mimic DA cell burst firing. This procedure was shown to evoke DA release in the nucleus accumbens (Gonon, 1997
) and transitions to the up state in PFC neurons (Lewis and ODonnell, 2000
).
Lesion Analysis
The extent of damage was estimated roughly in all animals. Nissl staining was conducted in as many sections were necessary to include the entire rostrocaudal extent of the lesion. Areas with cell loss or cell disorganization were deemed as lesioned and lesion sizes were estimated roughly as the area at the coronal section in which they were largest, by measuring the diameter of damage extent. Since the lesion contours were irregular and in most cases difficult to determine precisely, there was some inaccuracy in the calculations. However, this was sufficient to separate animals with very discrete damage from animals with large lesions.
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Results |
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Stimulation of the VTA, the source of DA innervation to the PFC, with trains of pulses mimicking DA cell burst firing resulted in a prolonged transition to the up state in most neurons (Fig. 4), similar to a response dependent on D1 receptor activation reported in intact animals (Lewis and ODonnell, 2000
). In normal animals, this prolonged up state was typically accompanied by a suppression of PFC cell firing (Lewis and ODonnell, 2000
). Similarly, animals with the sham neonatal lesion tested in adulthood and animals with neonatal lesions tested before puberty revealed a VTA-evoked prolonged up state with suppression in cell firing (Fig. 4
). In animals with an adult ventral hippocampal lesion, VTA stimulation failed to evoke a prolonged up state (Fig. 5
). In animals lesioned as neonates and tested in adulthood, however, a prolonged up state was evoked and it was accompanied by increased cell firing (6.5 ± 2.2 Hz, Table 1
, Fig. 4
). This was significantly different from all other groups (ANOVA, F = 19.72, P < 0.00001), which consistently exhibited firing suppression with VTA train stimulation (Table 1
). There was no correlation between lesion size and the nature of the VTA-evoked responses. All groups included animals with small and large lesions; animals with a neonatal lesion showed increased VTA-evoked firing regardless of lesion size and none of the other groups showed such effect, regardless of lesion size. Thus, although VTA stimulation in neonatally lesioned animals elicited prolonged up events in PFC neurons, these neurons appeared to be dysfunctional.
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Discussion |
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In animals with a hippocampal lesion performed in adult-hood, PFC pyramidal cell membrane potential was affected. Up membrane potential states could not be detected. This indicates that hippocampal afferents may contribute significantly to the excitatory inputs that depolarize PFC neurons into the up state. In the nucleus accumbens, a transection of the fimbria-fornix also resulted in the disappearance of spontaneous up events (ODonnell and Grace, 1995). In that study, electrical fornix stimulation evoked a transition to the up state in accumbens neurons. More recently, we have shown that transitions to the up state in PFC neurons could not be evoked by ventral hippocampal or fornix stimulation (Lewis and ODonnell, 2000
). Thus, although the hippocampal afferents may not be as important in driving up states in PFC neurons as in accumbens neurons, their absence may impair synchronous excitatory activation, preventing spontaneous up states in PFC cells. In animals with a neonatal lesion, on the other hand, the presence of spontaneous up states suggests that, in the absence of functional hippocampal innervation, other excitatory inputs may contribute to drive PFC up states. Although speculative, it is probable that other cortico-cortical connections are recruited in this case.
In adult-lesioned rats, VTA stimulation did not evoke an increased firing rate as in neonatally lesioned rats and failed to evoke a membrane depolarization. This intriguing finding may indicate that VTA stimulation-dependent transitions to the up state are indeed the result of enhanced glutamatergic activity, perhaps from hippocampal terminals. The difference in PFC response to VTA stimulation between neonatal and adult-lesioned animals indicates that this response is sensitive to developmental conditions.
In all other groups, VTA stimulation evoked prolonged depolarizations in PFC neurons, resembling the up membrane potential state. This is similar to what we have observed in naïve animals (Lewis and ODonnell, 2000). In that study, we demonstrated that this response could be reduced (but not blocked) by a D1 antagonist. We interpreted such data as indication of DA having a role in sustaining the depolarization to the up state, an event dependent on synchronous excitatory inputs. The mechanisms involved in this action remain unclear. It is possible that VTA stimulation elicits a network change that enhances glutamatergic release causing a transition to the up state in PFC pyramidal cells, with DA acting via D1 receptors maintaining that up state. Indeed, we have demonstrated recently that D1 receptors can enhance NMDA-mediated responses in PFC pyramidal neurons recorded in vitro (Wang and ODonnell, 2001
). If there were such a role for DA in the PFC as to sustain up states, one would expect up events to occur synchronously with electrical activity in the VTA. We have preliminary evidence indicating that this is the case: simultaneous recordings from PFC pyramidal neurons and field potentials in the VTA yield PFC up states synchronous with VTA local field potentials (Peters and ODonnell, 2000
). Thus, in anesthetized animals electrical activity in the VTA can contribute to the periodic depolarizations that characterize the up state in PFC pyramidal neurons.
In all control groups, the prolonged depolarization evoked by VTA stimulation was accompanied by a marked decrease in firing. This is also similar to what we observed in naïve animals with similar VTA stimulation (Lewis and ODonnell, 2000). Chemical stimulation of the VTA had the same effect (Lewis and ODonnell, 2000
), indicating that the decrease in firing was dependent on activation of VTA projection neurons. A number of mechanisms can explain this finding. An early study (Bernardi et al., 1982
) reported that iontophoretic administration of DA in the PFC resulted in a depolarization concomitant with suppression in firing. This indicates that the suppression in firing may be an action dependent on DA in the PFC. DA released by VTA stimulation could act on pyramidal neurons or on GABAergic interneurons, resulting in interneuron-mediated inhibition of pyramidal cells. PFC GABA interneurons receive DA inputs (Sesack et al., 1995
) and possess DA receptors (Khan et al., 2001
). Another possibility would be that by stimulating the VTA we were activating GABA projection cells, which comprise a significant proportion of VTA neurons (Steffensen et al., 1998
; Carr and Sesack, 2000
) and can inhibit PFC neurons (Pirot et al., 1992
). The prolonged nature of this inhibition could be due activation of GABA-B receptors or to recruitment of a network of cortical interneurons. Thus, we believe three factors could contribute to the suppression in firing: activation of GABA projection neurons from the VTA; a DA effect on PFC GABA interneurons; and/or a direct action of DA on pyramidal neurons.
In animals with a neonatal hippocampal lesion, VTA stimulation evoked a dramatic increase in PFC cell firing. Although speculative, it is possible that any of the mechanisms mentioned above could become altered in animals that developed with an abnormal ventral hippocampus. There is evidence, for example, of altered GABA interneurons in this model (Lipska and Weinberger, 2000). Given that the VTA and PFC are reciprocally connected (Thierry et al., 1979
; Au-Young et al., 1999
), electrical stimulation of the VTA could evoke antidromic firing in the PFC. However, it is unlikely that the increased PFC firing in response to VTA stimulation observed in animals with a hippocampal lesion is due to antidromic activation, because it is only observed in neonatally lesioned animals. One could argue that the hippocampal lesion would predispose to spread of antidromic activation. If this were the case, the adult lesion should also show an increased firing. Furthermore, antidromic responses typically involve a constant, short latency and are able to follow high-frequency stimulation (Seitun et al., 1979
). As illustrated in Figure 4A
, no antidromic spikes were observed following the stimuli in the train. Therefore, we are confident that the increased firing observed in these animals is a synaptically mediated event. The source of such activation remains to be unveiled. The presence of a prolonged VTA-evoked depolarization in these animals, an effect dependent on D1 receptors (Lewis and ODonnell, 2000
), indicates that this lesion may not affect PFC D1 receptors. It is possible that changes in D2 receptors or GABA interneurons are responsible for the increase in firing. In summary, the basis for the delayed emergence of this electrophysiological abnormality may involve protracted postnatal developmental changes in PFC cytoarchitecture and DA innervation (Lambe et al., 2000
).
The altered response to VTA stimulation was present in all animals with neonatal ventral hippocampal damage, independently of lesion size. This observation was made in animals with a lesion encompassing most of the ventral and medial hippocampus, as well as in those with minimal lesion circumscribed to the ventral subiculum. Although this may seem surprising, there is a recent indication that a very subtle alteration in hippocampal activity (without lesion) by injection of tetrodotoxin (TTX) in neonates results in behavioral anomalies similar to those caused by the lesion (Lipska et al., 2002). Thus, either a small lesion or a transient inactivation in this critical developmental period may result in changes in adult, but not prepubertal animals.
The increased firing during VTA-evoked up events observed in neonatally lesioned animals may result in a loss of the filtering function DA exerts within this circuit (ODonnell et al., 1999). The effect of VTA stimulation in normal animals i.e. a depolarization concomitant with a decrease in firing (Lewis and ODonnell, 2000
) may provide a mechanism that brings PFC pyramidal neurons to a ready-to-fire state upon phasic activation of their DA afferents, but decreases baseline (or irrelevant) firing. Such a mechanism may contribute to the proposed role of DA systems in attributing salience to stimuli (Solomon and Staton, 1982
; Schultz et al., 1993
). An increased firing evoked by VTA stimulation when the firing should have been reduced may result in inappropriate activation of PFC neurons. This could explain unusual responses of PFC to amphetamine in monkeys with neonatal medial temporal lobe lesions (Saunders et al., 1998
). In normal monkeys, caudate DA release was down-regulated after intra-PFC amphetamine injection, consistent with the electrophysiological data that after DA receptor activation in the PFC, pyramidal cell firing is reduced and, in turn, excitatory drive from PFC to brainstem DA neurons should be diminished. In contrast, the neonatally lesioned monkeys exhibited an increase in caudate DA release under these conditions. Our current data would predict precisely this result, as DA cell firing appears to be controlled by PFC inputs (Taber et al., 1995
) and a disrupted PFC may in turn alter DA systems projecting to the caudate (Bertolino et al., 2000
). Thus, animals that develop without proper hippocampal input exhibit disorganized PFC firing in response to DA. This may lead to recruitment of DA cells into excessive burst firing, and a vicious circle of cortical dysfunction and DA dysregulation that may characterize psychosis (Laruelle, 2000
). In conclusion, this is the first direct evidence for a delayed physiological alteration in the VTAPFC system following a neonatal hippocampal lesion.
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Acknowledgments |
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