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Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat
Brain Research 759 Ž1997. 251–258
Research report
Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat Jon C. Horvitz a
a, )
, Tripp Stewart b , Barry L. Jacobs
b
Department of Psychology, Columbia UniÕersity, Room 406, 1190 Amsterdam AÕe., New York, NY 10027, USA b Program in Neuroscience, Department of Psychology, Princeton UniÕersity, Princeton, NJ 08544, USA Accepted 11 February 1997
Abstract In light of evidence implicating dopamine in the pathophysiology of attention deficit disorder and schizophrenia, diseases involving attentional or sensory processing abnormalities, it was of interest to determine whether and how dopamine neurons in the ventral tegmental area respond to sensory stimuli. The single-unit responses of ventral tegmental dopamine neurons were recorded in freely-moving cats during the presentation of brief, non-conditioned auditory and visual stimuli. Both auditory and visual stimuli produced neuronal excitation, involving a greater than 5-fold increase in the probability of burst firing followed by a period of burst inhibition. The burst nature of the single-unit response suggests that sensory-induced dopamine release at target sites was disproportionally large relative to the discharge frequency. While characteristics of the dopaminergic sensory response were similar for auditory and visual stimuli, the response latency was longer for visual stimuli. The results demonstrate that dopamine neurons in the ventral tegmental area, the site of origin for mesolimbocortical dopamine neurons, are reliably activated by non-conditioned auditory and visual stimuli. Keywords: Dopamine; Attention; Sensory; Single-unit; Ventral tegmental area ŽVTA.; Mesolimbic
1. Introduction Studies investigating the behavioral functions of dopamine ŽDA. have focused largely upon a DA role in reinforcement andror motoric processes w1,14,24,48x. From this literature, a conceptual framework has emerged in which nigrostriatal DA neurons are assigned a motoric function w23,25x, and mesolimbic DA cells, originating in the VTA and projecting to the nucleus accumbens and other limbic structures w45x, are assigned a role in reinforcement or incentive motivational processes w7,12,26,47x. However, other evidence suggests an important DA role in sensory or attentional processes. Dopamine depletions produce sensory inattention, characterized by decreased orientation to visual, tactile, and olfactory stimuli w30,32,33x. Conversely, rats administered DA agonist drugs show an enhanced behavioral response to auditory stimuli under conditions when the response to such stimuli would normally be inhibited w5,11,46x. Similar sensory gating deficits are observed in schizophrenic patients w20x, a population believed to suffer abnormalities in DA trans)
Corresponding author. Fax: q1 Ž212. 854-3609.
mission w6,28x. Further, attention deficit disorder has been associated with dopamine abnormalities w21,34x, and recent evidence suggests that the disorder may be associated with a mutation in the dopamine transporter gene w10x. Consistent with the view that DA neurons play a role in sensory processing, single-unit studies have found that midbrain DA neurons in the monkey respond to conditioned stimuli signalling behaviorally-relevant events w35,37,38x, and that DA neurons in the substantia nigra ŽSN. of the cat and rat respond, more generally, to a large variety of non-conditioned sensory stimuli w8,17,41–43x. The finding that SN DA cells respond to sensory events is consistent with the view that the nigrostriatal system plays a role in sensory-motor processes w32,33x. The mesolimbic DA pathway, originating in the ventral tegmental area ŽVTA. is generally conceptualized as a reward system w7,26,47x, transmitting reward signals to target areas. It is therefore of particular interest to determine whether VTA DA cells also respond to non-reward, non-conditioned, sensory events. The purpose of the present study was to determine whether and how DA neurons in the ventral tegmental area ŽVTA., the site of origin for mesolimbocortical DA neu-
0006-8993r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 0 0 6 - 8 9 9 3 Ž 9 7 . 0 0 2 6 5 - 5
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rons w45x, respond to auditory and visual stimuli. We report here that: Ž1. VTA DA neurons in the freely-moving cat, like those of the SN w41x, respond to non-conditioned sensory stimuli, Ž2. individual VTA DA cells show similar sensory responses regardless of stimulus modality, although the latency of the dopaminergic response is longer for visual than for auditory stimuli, and Ž3. VTA DA cells typically respond to these sensory events with neuronal excitation, often involving a high probability of burst firing, followed by a period during which burst probability is reduced.
2. Materials and methods 2.1. Subjects Adult male cats Ž2.4–3.2 kg. obtained from Liberty Research ŽWaverly, NY. served as subjects. Animals were individually housed with free access to food and water in a temperature-controlled 14:10-h light:dark environment Žlights on at 07.00 h.. 2.2. Surgery Animals were anesthetized with pentobarbital Ž42 mgrkg, i.p.., placed in a stereotaxic instrument, and implanted with a moveable microdrive. The microdrive consisted of two outer cannulae, separated by 1 mm, which guided the dorsalrventral movement of two inner cannulae oriented in the anterior–posterior plane. The bottom tips of the inner cannulae were aimed 5 mm above the VTA. A bundle of 7 flexible insulated nichrome microwires Ž32 or 64 mm o.d., impedances 20–500 k V at 1 kHz. was lowered through each inner cannula to a position approximately 1 mm above the VTA. The target coordinates for the ventral tegmental area were A: 4.1–5.8, L: 0.8–1.5, H: Žy3.0. – Žy4.0. w2x. The microwire bundles were glued to the top of the inner cannulae, so that subsequent lowering of the inner cannulae resulted in ventral movement of the microwires. Cats were also implanted with gross electrodes for recording the electroencephalogram ŽEEG., electromyogram ŽEMG., and electrooculogram ŽEOG., although data regarding gross potentials are not presented here. All electrodes were soldered to a 25-pin connector and the entire assembly was secured to the skull with dental acrylic. The methods employed here for single-unit and gross electrode surgery have been previously described in detail w40x. 2.3. Apparatus Single-unit recording was conducted in an isolated, sound-attenuated recording chamber Ž65 = 65 = 95 cm.. Auditory stimuli Žclicks of 1 ms duration, 73 dB measured at the center of the chamber. were delivered through a
speaker mounted on the recording chamber wall, and visual stimuli Žlight flashes, 1.5 = 10 6 candle power, 1.9 = 10 7 lumens peak intensity. were delivered through a clear plexiglas window by means of a Grass PS 22B photic stimulator light source located 60 cm from the center of the chamber. Electrical potentials were led from the cat by means of a counter-weighted low-noise cable and slip-ring assembly. The microelectrode signals were amplified ŽGrass P511 AC preamp., filtered Žbandpass 0.3 to 3 kHz., and monitored on a storage oscilloscope. Neuronal activity was also monitored on a computer sampling at 40,000 Hz, with the waveform of each action potential overlaid on a software oscilloscope ŽData Wave Technologies. ensuring that single-units were isolated. The timestamp and waveform for each action potential was stored digitally on the computer. 2.4. Procedure Following 1 week of postsurgical recovery, animals were placed in the recording chamber and screened for the presence of isolated neuronal activity on one of the fourteen implanted microwires. Dopaminergic neurons Ž n s 18. were identified according to previously established criteria: long duration action potentials Ž) 2 ms., slow firing rate Ž2–8 spikesrs., and firing pattern characterized by single spikes, occasionally interspersed with bursts of decreasing amplitude w4,15x. As apomorphine has previously been shown to decrease the discharge rate of identified DA-containing neurons w39x, a subset of the neurons Ž n s 10. meeting the electrophysiological criteria above were observed following apomorphine Ž0.5 mgrkg. administration. All neurons tested showed at least 50% reductions in discharge rate. Upon isolation of a single-unit, baseline activity was monitored for approximately 10 min to assess action potential waveform and firing characteristics of the cell. The animal was then presented a series of 50 or 100 auditory and the same number of visual stimuli. Sensory stimuli were presented with a randomly varied interstimulus interval of 10–30 s, and the order of stimulus presentation was alternated from one experimental session to the next. 2.5. QuantitatiÕe methods Peristimulus time histograms and dot rasters provided graphic representation of neuronal activity occurring from 400 ms before to 600 ms after stimulus presentation. For peristimulus time histograms, trials were divided into 20 ms bins, and action potentials occurring within each bin were summed over all sensory trials. Significant excitatory or inhibitory poststimulus neuronal responses were identified as those bins whose counts were greater than two standard deviations above or below the baseline mean for at least 2 consecutive bins. The neuronal response latency was defined as the midpoint value of the first bin meeting
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the response criteria. Offset of the response was the midpoint of the first of two consecutive bins failing to meet the response criteria. Cells showing significant sensory responses were subjected to further analysis of response duration, latency to peak response, and peak response magnitude. The probability of neuronal firing as a function of stimulus presentation was calculated for each neuron by computing the proportion of sensory trials during which an action potential occurred during each consecutive 20 ms bin. The mean probability of DA neuron firing during each bin was calculated by computing the probability estimates at each time bin averaged across DA neurons. Poststimulus time bins showing changes in mean firing probability were subjected to t-tests to evaluate whether the probabilities were significantly different from the mean probability observed 100 ms prior to stimulus delivery. Finally, the probability of neuronal bursting was calculated as a function of stimulus presentation. To designate the occurrence of burst activity, a conservative criterion was employed, requiring 2 or more consecutive spikes with interspike intervals ŽISI. of less than 80 ms Žfor analysis of DA burst characteristics, see w18x.. In order to
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determine the timecourse of burst activity, overlapping 80 ms periods were examined Že.g., activity during 20–100 ms and during 40–120 ms., and for each of these periods it was determined whether or not the neuron was in burst mode. The probability of burst activity during a given 80 ms period was the proportion of sensory trials during which burst activity occurred during that 80 ms period. The use of overlapping bins allows for an estimation of probabilities within a given time bin, but not for the summation of probabilities across bins. 2.6. Histology At the conclusion of the experiment, animals were deeply anesthetized with sodium pentobarbital and a 20 mA anodal direct current was passed for 40 s through the electrodes from which units had been recorded. Cats were perfused intracardially with physiological saline, followed by 10% formalin, and 5% potassium ferrocyanide in formalin to produce a Prussian blue reaction. Following perfusion, brains were removed, 50 mm thick frozen sections were cut, and sections were mounted on slides. The slides were stained with neutral red to facilitate visualization of
Fig. 1. Peri-event time histograms and raster plots showing the response of an individual ventral tegmental dopamine neuron to an auditory click Žleft panel. and a light flash Žright panel.. Auditory and visual stimuli Žarrow. were of 1 ms duration.
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Fig. 2. Mean probability of VTA DA neuronal firing before and after the delivery of an auditory or visual stimulus Žarrow.. Probability estimates, at each time bin, were averaged across all DA neurons tested for an auditory ŽA. or visual ŽB. response. Asterisks mark the poststimulus time bins for each neuronal discharge for which neuronal discharge probability was significantly greater than that observed during the prestimulus baseline Ž ) P - 0.05, )) P - 0.01..
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Fig. 3. Mean probability of VTA DA burst mode activity as a function of auditory or visual stimulus presentation Žarrow.. Probability estimates, at each time bin, were averaged across all DA neurons tested for an auditory ŽA. or visual ŽB. response. Asterisks mark the poststimulus time bins for which burst probability was significantly greater than that observed during the prestimulus baseline Ž ) P - 0.05, ) ) P - 0.01..
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electrode tracks and blue-labelled recording sites. Histological analysis confirmed that 18 DA neurons meeting the electrophysiological criteria Žabove. were located within the VTA.
3. Results Action potential waveforms were examined for all recorded ventral tegmental DA neurons following each auditory and visual test. If, during the course of a sensory test, the DA action potential waveform did not remain clearly isolated from background noise, that sensory test was excluded from analysis. Significant auditory responses were observed in 13 of 15 ventral tegmental DA neurons Ž87%.. Most of these auditory-responsive cells showed neuronal excitation Ž11r13., while 2 cells were inhibited by the stimulus. The mean " SD latency of the excitatory response was 43 " 21 ms, with peak responses occurring 66 " 25 ms after stimulus presentation, and a response duration of 98 " 59 ms. The excitatory response was typically followed by a period of inhibition Ž8r11 cells. lasting approximately 180 " 53 ms. Visual responses were observed in 9 of 12 DA cells Ž75%.. Again, the predominant sensory response Ž8r9. was excitatory, with 1 cell inhibited by the visual stimulus. The mean Ž"SD. latency of the visual excitatory response was 68 Ž"20. ms, with peak response occurring at 105 Ž"30. ms, and a response duration of 120 Ž"52. ms. Fig. 1 shows the response of an individual VTA DA neuron to 50 presentations of the auditory stimulus and 50 presentations of the visual stimulus. As can be seen, similar excitatory responses were observed to auditory and visual stimuli. Within-cell comparisons of auditory and visual responses revealed that most Ž7. responded to both stimulus modalities, while 4 responded only to one modality Ž3 auditory, 1 visual.. Paired t-tests conducted on data from the cells that responded to both modalities revealed that while stimuli of the two sensory modalities produced no differences in excitatory response magnitude Ž P s n.s.. or duration Ž P s n.s.., the latency to peak visual response was significantly longer than that of auditory response, t6 s 3.67, P s 0.01. A marginal increase in the latency to visual relative to auditory response onset was also observed, t6 s 2.27, P s 0.06. In order to estimate the overall responsiveness of VTA DA cells to sensory stimuli, the mean probability of firing during each 20 ms bin during the pre- and poststimulus periods was averaged across all DA neurons analyzed for an auditory Ž n s 15; Fig. 2A. and visual Ž n s 12; Fig. 2B. response. As can be seen, the mean probability of firing during the prestimulus period ranged from 0.04 to 0.08, corresponding to a spontaneous firing rate of 2–4 spikesrs. Auditory and visual stimuli produced a greater than 4-fold
increase in probability of neuronal discharge, peaking 60– 80 ms after presentation of the auditory stimulus, and 80–100 ms after presentation of the visual stimulus. There is evidence to suggest that burst mode firing of DA neurons produces disproportionally large increases in DA release at target sites w16x. It was therefore of interest to ask whether the presentation of sensory stimuli was associated with burst mode activity. It should be noted that the increased probability of neuronal firing observed across consecutive 20 ms time bins following the presentation of a sensory stimulus does not, in itself, provide evidence for burst activity, since neurons could respond to sensory events with heightened probabilities of a single-spike discharge distributed across consecutive time bins. However, as can be seen in Fig. 3, the probability of burst mode firing is dramatically increased after presentation of either an auditory Ž3A. or visual Ž3B. stimulus. Excitatory neuronal responses for auditory Ž11. and visual Ž8. stimuli were collapsed and subjected to burst analysis. The probability of burst activity was significantly elevated during the first 200 ms following stimulus presentation compared to baseline t 18 s 4.45, P s 0.0003. During the subsequent 200 ms period Ž200–400 ms poststimulus., burst probability was reduced relative to baseline, t 18 s 2.28, P s 0.04.
4. Discussion Dopamine neurons in the VTA, like those in the SN w41–43x, responded to both auditory and visual stimuli. While auditory and visual responses of VTA DA neurons were of similar magnitude and duration, the visual response latency was longer than that of the auditory response. For both auditory and visual stimuli, the VTA DA sensory response was characterized by a period of burst firing followed by a period during which burst activity had a reduced probability of occurrence. Midbrain DA neurons in the rat and cat have previously been found to exhibit occasional periods of burst firing interspersed among slow single-spike activity w3,4,43x. This burst activity is dependent upon excitatory amino acid input originating in the frontal cortex w19,44x. Of particular relevance, burst mode firing is associated with a disproportionally large release of DA at terminal regions, and may therefore play a significant role in modulating postsynaptic membrane potentials w16x. The present results suggest that, in freely moving animals, burst mode activity of VTA DA neurons is elicited by auditory and visual events. These results complement findings by Freeman and Bunney w15x, that burst firing of VTA DA neurons is seen following tactile stimulation of rat vibrissae. These investigators also made informal observations of VTA DA burst activity in the rat following sounds such as a whistle, clap, or hiss, and noted that during periods of DA burst firing the animals appear "overtly attentive". While this is a subjective observation, we have made similar informal
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observations that DA burst firing occurring during baseline periods coincides with the cat looking out of the plexiglass window of the cage or apparently attending to something. Given the considerable evidence that mesolimbic DA plays a critical role in reinforcement or reward processes w7,12,26,47x, it is somewhat surprising that dopamine neurons in the VTA, the site of origin for most mesolimbocortical DA cells w45x, are reliably activated by sensory events which are not associated with reward. Like the VTA DA neurons, SN DA neurons in the cat and rat respond to a variety of sensory stimuli, including flash, click, olfactory, and somatosensory stimulation, with neither primary nor conditioned reward properties w8,17,41–43x. SN DA responses to such stimuli are consistent with a nigrostriatal involvement in sensory-motor processes w32,33x. However, similar sensory responses in VTA DA cells suggests that the mesolimbic system, too, may play a role in sensory processing rather than a specific role in reward. In accordance with this view, while midbrain ŽSN and VTA. DA neurons in the monkey respond to food reward, these neurons also respond to novel stimuli such as door opening, which elicit an orienting response w29x. In DA neurons that respond to food or liquid reward, the DA neuronal response is lost after a CS predicting reward delivery had been established w29,35x. Mirenowicz and Schultz w35x suggest that the DA response to reward stimuli may require that the reward event be temporally unpredictable. It is our view that midbrain DA neurons respond to a large category of events that are salient to the animal, whether the salience derives from appetitive conditioned properties of the stimulus Žsuch as tones signalling reward delivery. or physical properties of the stimulus Žsuch as fast rise-time clicks and flashes.. It should be noted that Mirenowicz and Schultz w36x have provided recent evidence that aversive stimuli may fall outside the category of events which produce strong DA activation. While the aversive stimuli in their study were mild Žfor example, a mild air puff to the hand., the authors did attempt to set stimulus parameters such that appetitive and aversive stimuli were of comparable "motivational strength". Of particular interest is the question of how DA neurons might respond to increases in the intensity of an aversive stimulus. If DA neurons are unresponsive to aversive events, than an increase in the magnitude of the aversive stimulus should either be without effect or might even produce a decrease in the DA response. If, on the other hand, DA neurons respond to stimulus salience, then increases in the magnitude of an aversive stimulus should produce an increase in DA activity. The present results demonstrate that VTA DA neurons, like those in the SN, respond to non-conditioned auditory and visual events. However, the question remains as to what role this sensory-induced activation of the mesolimbic DA system plays in behavior. Several findings are relevant here. Increases in mesolimbic DA activity, pro-
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duce elevations in locomotor and exploratory behavior w22,31x, and investigative behavior is attenuated by lesions of mesolimbocortical DA neurons w13x. Further, DA-agonist induced hyperactivity is attenuated by lesions of mesolimbic DA neurons w9,27x. Such findings, taken together with those of the present study, point to the view that mesolimbic DA neurons are activated by sensory stimuli and that the output of these DA neurons at mesolimbic target regions promotes locomotor and investigative behavior. In accordance with this view, DA has been implicated in the pathophysiology of both attentional deficit disorder w21,10x and schizophrenia w6,28x, disorders associated with a hyper-responsiveness to sensory events or failure to "filter-out" irrelevant sensory stimuli w20,34x. The results of the present study indicate that VTA DA neurons are activated by auditory and visual events. The fact that these sensory responses are associated with increased burst probability suggests that these sensory events produce large increases in DA terminal release w16x. It is likely that this elevation in DA release at target sites promotes investigative behavior in animals w31,22,13x. One might speculate that, in humans, sensory-induced elevations in DA activity promote investigative behavior, and possibly, further processing of incoming sensory events. Accordingly, a pathological elevation in DA activity might be expected to produce exaggerated attentional responses to sensory events.
Acknowledgements We gratefully acknowledge Roger Gallegos, Casimir Fornal, Christine Metzler, and Luis Colon for their invaluable assistance in conducting this experiment.
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Research report
Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat Jon C. Horvitz a
a, )
, Tripp Stewart b , Barry L. Jacobs
b
Department of Psychology, Columbia UniÕersity, Room 406, 1190 Amsterdam AÕe., New York, NY 10027, USA b Program in Neuroscience, Department of Psychology, Princeton UniÕersity, Princeton, NJ 08544, USA Accepted 11 February 1997
Abstract In light of evidence implicating dopamine in the pathophysiology of attention deficit disorder and schizophrenia, diseases involving attentional or sensory processing abnormalities, it was of interest to determine whether and how dopamine neurons in the ventral tegmental area respond to sensory stimuli. The single-unit responses of ventral tegmental dopamine neurons were recorded in freely-moving cats during the presentation of brief, non-conditioned auditory and visual stimuli. Both auditory and visual stimuli produced neuronal excitation, involving a greater than 5-fold increase in the probability of burst firing followed by a period of burst inhibition. The burst nature of the single-unit response suggests that sensory-induced dopamine release at target sites was disproportionally large relative to the discharge frequency. While characteristics of the dopaminergic sensory response were similar for auditory and visual stimuli, the response latency was longer for visual stimuli. The results demonstrate that dopamine neurons in the ventral tegmental area, the site of origin for mesolimbocortical dopamine neurons, are reliably activated by non-conditioned auditory and visual stimuli. Keywords: Dopamine; Attention; Sensory; Single-unit; Ventral tegmental area ŽVTA.; Mesolimbic
1. Introduction Studies investigating the behavioral functions of dopamine ŽDA. have focused largely upon a DA role in reinforcement andror motoric processes w1,14,24,48x. From this literature, a conceptual framework has emerged in which nigrostriatal DA neurons are assigned a motoric function w23,25x, and mesolimbic DA cells, originating in the VTA and projecting to the nucleus accumbens and other limbic structures w45x, are assigned a role in reinforcement or incentive motivational processes w7,12,26,47x. However, other evidence suggests an important DA role in sensory or attentional processes. Dopamine depletions produce sensory inattention, characterized by decreased orientation to visual, tactile, and olfactory stimuli w30,32,33x. Conversely, rats administered DA agonist drugs show an enhanced behavioral response to auditory stimuli under conditions when the response to such stimuli would normally be inhibited w5,11,46x. Similar sensory gating deficits are observed in schizophrenic patients w20x, a population believed to suffer abnormalities in DA trans)
Corresponding author. Fax: q1 Ž212. 854-3609.
mission w6,28x. Further, attention deficit disorder has been associated with dopamine abnormalities w21,34x, and recent evidence suggests that the disorder may be associated with a mutation in the dopamine transporter gene w10x. Consistent with the view that DA neurons play a role in sensory processing, single-unit studies have found that midbrain DA neurons in the monkey respond to conditioned stimuli signalling behaviorally-relevant events w35,37,38x, and that DA neurons in the substantia nigra ŽSN. of the cat and rat respond, more generally, to a large variety of non-conditioned sensory stimuli w8,17,41–43x. The finding that SN DA cells respond to sensory events is consistent with the view that the nigrostriatal system plays a role in sensory-motor processes w32,33x. The mesolimbic DA pathway, originating in the ventral tegmental area ŽVTA. is generally conceptualized as a reward system w7,26,47x, transmitting reward signals to target areas. It is therefore of particular interest to determine whether VTA DA cells also respond to non-reward, non-conditioned, sensory events. The purpose of the present study was to determine whether and how DA neurons in the ventral tegmental area ŽVTA., the site of origin for mesolimbocortical DA neu-
0006-8993r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 0 0 6 - 8 9 9 3 Ž 9 7 . 0 0 2 6 5 - 5
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rons w45x, respond to auditory and visual stimuli. We report here that: Ž1. VTA DA neurons in the freely-moving cat, like those of the SN w41x, respond to non-conditioned sensory stimuli, Ž2. individual VTA DA cells show similar sensory responses regardless of stimulus modality, although the latency of the dopaminergic response is longer for visual than for auditory stimuli, and Ž3. VTA DA cells typically respond to these sensory events with neuronal excitation, often involving a high probability of burst firing, followed by a period during which burst probability is reduced.
2. Materials and methods 2.1. Subjects Adult male cats Ž2.4–3.2 kg. obtained from Liberty Research ŽWaverly, NY. served as subjects. Animals were individually housed with free access to food and water in a temperature-controlled 14:10-h light:dark environment Žlights on at 07.00 h.. 2.2. Surgery Animals were anesthetized with pentobarbital Ž42 mgrkg, i.p.., placed in a stereotaxic instrument, and implanted with a moveable microdrive. The microdrive consisted of two outer cannulae, separated by 1 mm, which guided the dorsalrventral movement of two inner cannulae oriented in the anterior–posterior plane. The bottom tips of the inner cannulae were aimed 5 mm above the VTA. A bundle of 7 flexible insulated nichrome microwires Ž32 or 64 mm o.d., impedances 20–500 k V at 1 kHz. was lowered through each inner cannula to a position approximately 1 mm above the VTA. The target coordinates for the ventral tegmental area were A: 4.1–5.8, L: 0.8–1.5, H: Žy3.0. – Žy4.0. w2x. The microwire bundles were glued to the top of the inner cannulae, so that subsequent lowering of the inner cannulae resulted in ventral movement of the microwires. Cats were also implanted with gross electrodes for recording the electroencephalogram ŽEEG., electromyogram ŽEMG., and electrooculogram ŽEOG., although data regarding gross potentials are not presented here. All electrodes were soldered to a 25-pin connector and the entire assembly was secured to the skull with dental acrylic. The methods employed here for single-unit and gross electrode surgery have been previously described in detail w40x. 2.3. Apparatus Single-unit recording was conducted in an isolated, sound-attenuated recording chamber Ž65 = 65 = 95 cm.. Auditory stimuli Žclicks of 1 ms duration, 73 dB measured at the center of the chamber. were delivered through a
speaker mounted on the recording chamber wall, and visual stimuli Žlight flashes, 1.5 = 10 6 candle power, 1.9 = 10 7 lumens peak intensity. were delivered through a clear plexiglas window by means of a Grass PS 22B photic stimulator light source located 60 cm from the center of the chamber. Electrical potentials were led from the cat by means of a counter-weighted low-noise cable and slip-ring assembly. The microelectrode signals were amplified ŽGrass P511 AC preamp., filtered Žbandpass 0.3 to 3 kHz., and monitored on a storage oscilloscope. Neuronal activity was also monitored on a computer sampling at 40,000 Hz, with the waveform of each action potential overlaid on a software oscilloscope ŽData Wave Technologies. ensuring that single-units were isolated. The timestamp and waveform for each action potential was stored digitally on the computer. 2.4. Procedure Following 1 week of postsurgical recovery, animals were placed in the recording chamber and screened for the presence of isolated neuronal activity on one of the fourteen implanted microwires. Dopaminergic neurons Ž n s 18. were identified according to previously established criteria: long duration action potentials Ž) 2 ms., slow firing rate Ž2–8 spikesrs., and firing pattern characterized by single spikes, occasionally interspersed with bursts of decreasing amplitude w4,15x. As apomorphine has previously been shown to decrease the discharge rate of identified DA-containing neurons w39x, a subset of the neurons Ž n s 10. meeting the electrophysiological criteria above were observed following apomorphine Ž0.5 mgrkg. administration. All neurons tested showed at least 50% reductions in discharge rate. Upon isolation of a single-unit, baseline activity was monitored for approximately 10 min to assess action potential waveform and firing characteristics of the cell. The animal was then presented a series of 50 or 100 auditory and the same number of visual stimuli. Sensory stimuli were presented with a randomly varied interstimulus interval of 10–30 s, and the order of stimulus presentation was alternated from one experimental session to the next. 2.5. QuantitatiÕe methods Peristimulus time histograms and dot rasters provided graphic representation of neuronal activity occurring from 400 ms before to 600 ms after stimulus presentation. For peristimulus time histograms, trials were divided into 20 ms bins, and action potentials occurring within each bin were summed over all sensory trials. Significant excitatory or inhibitory poststimulus neuronal responses were identified as those bins whose counts were greater than two standard deviations above or below the baseline mean for at least 2 consecutive bins. The neuronal response latency was defined as the midpoint value of the first bin meeting
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the response criteria. Offset of the response was the midpoint of the first of two consecutive bins failing to meet the response criteria. Cells showing significant sensory responses were subjected to further analysis of response duration, latency to peak response, and peak response magnitude. The probability of neuronal firing as a function of stimulus presentation was calculated for each neuron by computing the proportion of sensory trials during which an action potential occurred during each consecutive 20 ms bin. The mean probability of DA neuron firing during each bin was calculated by computing the probability estimates at each time bin averaged across DA neurons. Poststimulus time bins showing changes in mean firing probability were subjected to t-tests to evaluate whether the probabilities were significantly different from the mean probability observed 100 ms prior to stimulus delivery. Finally, the probability of neuronal bursting was calculated as a function of stimulus presentation. To designate the occurrence of burst activity, a conservative criterion was employed, requiring 2 or more consecutive spikes with interspike intervals ŽISI. of less than 80 ms Žfor analysis of DA burst characteristics, see w18x.. In order to
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determine the timecourse of burst activity, overlapping 80 ms periods were examined Že.g., activity during 20–100 ms and during 40–120 ms., and for each of these periods it was determined whether or not the neuron was in burst mode. The probability of burst activity during a given 80 ms period was the proportion of sensory trials during which burst activity occurred during that 80 ms period. The use of overlapping bins allows for an estimation of probabilities within a given time bin, but not for the summation of probabilities across bins. 2.6. Histology At the conclusion of the experiment, animals were deeply anesthetized with sodium pentobarbital and a 20 mA anodal direct current was passed for 40 s through the electrodes from which units had been recorded. Cats were perfused intracardially with physiological saline, followed by 10% formalin, and 5% potassium ferrocyanide in formalin to produce a Prussian blue reaction. Following perfusion, brains were removed, 50 mm thick frozen sections were cut, and sections were mounted on slides. The slides were stained with neutral red to facilitate visualization of
Fig. 1. Peri-event time histograms and raster plots showing the response of an individual ventral tegmental dopamine neuron to an auditory click Žleft panel. and a light flash Žright panel.. Auditory and visual stimuli Žarrow. were of 1 ms duration.
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Fig. 2. Mean probability of VTA DA neuronal firing before and after the delivery of an auditory or visual stimulus Žarrow.. Probability estimates, at each time bin, were averaged across all DA neurons tested for an auditory ŽA. or visual ŽB. response. Asterisks mark the poststimulus time bins for each neuronal discharge for which neuronal discharge probability was significantly greater than that observed during the prestimulus baseline Ž ) P - 0.05, )) P - 0.01..
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Fig. 3. Mean probability of VTA DA burst mode activity as a function of auditory or visual stimulus presentation Žarrow.. Probability estimates, at each time bin, were averaged across all DA neurons tested for an auditory ŽA. or visual ŽB. response. Asterisks mark the poststimulus time bins for which burst probability was significantly greater than that observed during the prestimulus baseline Ž ) P - 0.05, ) ) P - 0.01..
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electrode tracks and blue-labelled recording sites. Histological analysis confirmed that 18 DA neurons meeting the electrophysiological criteria Žabove. were located within the VTA.
3. Results Action potential waveforms were examined for all recorded ventral tegmental DA neurons following each auditory and visual test. If, during the course of a sensory test, the DA action potential waveform did not remain clearly isolated from background noise, that sensory test was excluded from analysis. Significant auditory responses were observed in 13 of 15 ventral tegmental DA neurons Ž87%.. Most of these auditory-responsive cells showed neuronal excitation Ž11r13., while 2 cells were inhibited by the stimulus. The mean " SD latency of the excitatory response was 43 " 21 ms, with peak responses occurring 66 " 25 ms after stimulus presentation, and a response duration of 98 " 59 ms. The excitatory response was typically followed by a period of inhibition Ž8r11 cells. lasting approximately 180 " 53 ms. Visual responses were observed in 9 of 12 DA cells Ž75%.. Again, the predominant sensory response Ž8r9. was excitatory, with 1 cell inhibited by the visual stimulus. The mean Ž"SD. latency of the visual excitatory response was 68 Ž"20. ms, with peak response occurring at 105 Ž"30. ms, and a response duration of 120 Ž"52. ms. Fig. 1 shows the response of an individual VTA DA neuron to 50 presentations of the auditory stimulus and 50 presentations of the visual stimulus. As can be seen, similar excitatory responses were observed to auditory and visual stimuli. Within-cell comparisons of auditory and visual responses revealed that most Ž7. responded to both stimulus modalities, while 4 responded only to one modality Ž3 auditory, 1 visual.. Paired t-tests conducted on data from the cells that responded to both modalities revealed that while stimuli of the two sensory modalities produced no differences in excitatory response magnitude Ž P s n.s.. or duration Ž P s n.s.., the latency to peak visual response was significantly longer than that of auditory response, t6 s 3.67, P s 0.01. A marginal increase in the latency to visual relative to auditory response onset was also observed, t6 s 2.27, P s 0.06. In order to estimate the overall responsiveness of VTA DA cells to sensory stimuli, the mean probability of firing during each 20 ms bin during the pre- and poststimulus periods was averaged across all DA neurons analyzed for an auditory Ž n s 15; Fig. 2A. and visual Ž n s 12; Fig. 2B. response. As can be seen, the mean probability of firing during the prestimulus period ranged from 0.04 to 0.08, corresponding to a spontaneous firing rate of 2–4 spikesrs. Auditory and visual stimuli produced a greater than 4-fold
increase in probability of neuronal discharge, peaking 60– 80 ms after presentation of the auditory stimulus, and 80–100 ms after presentation of the visual stimulus. There is evidence to suggest that burst mode firing of DA neurons produces disproportionally large increases in DA release at target sites w16x. It was therefore of interest to ask whether the presentation of sensory stimuli was associated with burst mode activity. It should be noted that the increased probability of neuronal firing observed across consecutive 20 ms time bins following the presentation of a sensory stimulus does not, in itself, provide evidence for burst activity, since neurons could respond to sensory events with heightened probabilities of a single-spike discharge distributed across consecutive time bins. However, as can be seen in Fig. 3, the probability of burst mode firing is dramatically increased after presentation of either an auditory Ž3A. or visual Ž3B. stimulus. Excitatory neuronal responses for auditory Ž11. and visual Ž8. stimuli were collapsed and subjected to burst analysis. The probability of burst activity was significantly elevated during the first 200 ms following stimulus presentation compared to baseline t 18 s 4.45, P s 0.0003. During the subsequent 200 ms period Ž200–400 ms poststimulus., burst probability was reduced relative to baseline, t 18 s 2.28, P s 0.04.
4. Discussion Dopamine neurons in the VTA, like those in the SN w41–43x, responded to both auditory and visual stimuli. While auditory and visual responses of VTA DA neurons were of similar magnitude and duration, the visual response latency was longer than that of the auditory response. For both auditory and visual stimuli, the VTA DA sensory response was characterized by a period of burst firing followed by a period during which burst activity had a reduced probability of occurrence. Midbrain DA neurons in the rat and cat have previously been found to exhibit occasional periods of burst firing interspersed among slow single-spike activity w3,4,43x. This burst activity is dependent upon excitatory amino acid input originating in the frontal cortex w19,44x. Of particular relevance, burst mode firing is associated with a disproportionally large release of DA at terminal regions, and may therefore play a significant role in modulating postsynaptic membrane potentials w16x. The present results suggest that, in freely moving animals, burst mode activity of VTA DA neurons is elicited by auditory and visual events. These results complement findings by Freeman and Bunney w15x, that burst firing of VTA DA neurons is seen following tactile stimulation of rat vibrissae. These investigators also made informal observations of VTA DA burst activity in the rat following sounds such as a whistle, clap, or hiss, and noted that during periods of DA burst firing the animals appear "overtly attentive". While this is a subjective observation, we have made similar informal
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observations that DA burst firing occurring during baseline periods coincides with the cat looking out of the plexiglass window of the cage or apparently attending to something. Given the considerable evidence that mesolimbic DA plays a critical role in reinforcement or reward processes w7,12,26,47x, it is somewhat surprising that dopamine neurons in the VTA, the site of origin for most mesolimbocortical DA cells w45x, are reliably activated by sensory events which are not associated with reward. Like the VTA DA neurons, SN DA neurons in the cat and rat respond to a variety of sensory stimuli, including flash, click, olfactory, and somatosensory stimulation, with neither primary nor conditioned reward properties w8,17,41–43x. SN DA responses to such stimuli are consistent with a nigrostriatal involvement in sensory-motor processes w32,33x. However, similar sensory responses in VTA DA cells suggests that the mesolimbic system, too, may play a role in sensory processing rather than a specific role in reward. In accordance with this view, while midbrain ŽSN and VTA. DA neurons in the monkey respond to food reward, these neurons also respond to novel stimuli such as door opening, which elicit an orienting response w29x. In DA neurons that respond to food or liquid reward, the DA neuronal response is lost after a CS predicting reward delivery had been established w29,35x. Mirenowicz and Schultz w35x suggest that the DA response to reward stimuli may require that the reward event be temporally unpredictable. It is our view that midbrain DA neurons respond to a large category of events that are salient to the animal, whether the salience derives from appetitive conditioned properties of the stimulus Žsuch as tones signalling reward delivery. or physical properties of the stimulus Žsuch as fast rise-time clicks and flashes.. It should be noted that Mirenowicz and Schultz w36x have provided recent evidence that aversive stimuli may fall outside the category of events which produce strong DA activation. While the aversive stimuli in their study were mild Žfor example, a mild air puff to the hand., the authors did attempt to set stimulus parameters such that appetitive and aversive stimuli were of comparable "motivational strength". Of particular interest is the question of how DA neurons might respond to increases in the intensity of an aversive stimulus. If DA neurons are unresponsive to aversive events, than an increase in the magnitude of the aversive stimulus should either be without effect or might even produce a decrease in the DA response. If, on the other hand, DA neurons respond to stimulus salience, then increases in the magnitude of an aversive stimulus should produce an increase in DA activity. The present results demonstrate that VTA DA neurons, like those in the SN, respond to non-conditioned auditory and visual events. However, the question remains as to what role this sensory-induced activation of the mesolimbic DA system plays in behavior. Several findings are relevant here. Increases in mesolimbic DA activity, pro-
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duce elevations in locomotor and exploratory behavior w22,31x, and investigative behavior is attenuated by lesions of mesolimbocortical DA neurons w13x. Further, DA-agonist induced hyperactivity is attenuated by lesions of mesolimbic DA neurons w9,27x. Such findings, taken together with those of the present study, point to the view that mesolimbic DA neurons are activated by sensory stimuli and that the output of these DA neurons at mesolimbic target regions promotes locomotor and investigative behavior. In accordance with this view, DA has been implicated in the pathophysiology of both attentional deficit disorder w21,10x and schizophrenia w6,28x, disorders associated with a hyper-responsiveness to sensory events or failure to "filter-out" irrelevant sensory stimuli w20,34x. The results of the present study indicate that VTA DA neurons are activated by auditory and visual events. The fact that these sensory responses are associated with increased burst probability suggests that these sensory events produce large increases in DA terminal release w16x. It is likely that this elevation in DA release at target sites promotes investigative behavior in animals w31,22,13x. One might speculate that, in humans, sensory-induced elevations in DA activity promote investigative behavior, and possibly, further processing of incoming sensory events. Accordingly, a pathological elevation in DA activity might be expected to produce exaggerated attentional responses to sensory events.
Acknowledgements We gratefully acknowledge Roger Gallegos, Casimir Fornal, Christine Metzler, and Luis Colon for their invaluable assistance in conducting this experiment.
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