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Exp Brain Res (2001) 139:116–119 DOI 10.1007/s002210100760 RESEARCH NOTE Nan-Hui Chen · Ilsun M. White · Steven P. Wise Neuronal activity in dorsomedial frontal cortex and prefrontal cortex reflecting irrelevant stimulus dimensions Received: 27 February 2001 / Accepted: 22 March 2001 / Published online: 11 May 2001 © Springer-Verlag 2001 Abstract Previous studies of the dorsomedial frontal cortex (DMF) and the prefrontal cortex (PF) have shown that, when monkeys respond to nonspatial features of a discriminative stimulus (e.g., color) and the stimulus appears at a place unrelated to the movement target, neurons nevertheless encode stimulus location. This observation could support the idea that these neurons always encode stimulus location, regardless of its relevance to an instrumentally conditioned behavior. Past studies, however, leave open the possibility that activity observed during one operant task might reflect the contingencies of a different task, performed at different times. To test these alternatives, we examined the activity of DMF and PF neurons in two rhesus monkeys conditioned to perform an operant eye-movement task in which only the color and shape of visual stimuli served as salient discriminative features. Each of eight stimuli was associated with a response to a different eye-movement target. The location of these stimuli varied from trial to trial but was of no behavioral relevance, and the monkeys did not perform any operant task in which stimulus location controlled behavior. A substantial minority of neurons in both DMF and PF nevertheless encoded stimulus location, which indicates that this property does not depend on its relevance in an instrumentally conditioned behavior. N.-H. Chen KunMing Institute of Zoology, 32 JiaoChang DongLu, KunMing, YunNan 650223, P.R. China I.M. White Behavioral Neurobiology, Institute of Toxicology, Swiss Federal Institute of Technology Zurich, 8603 Schwerzenbach, Switzerland S.P. Wise (✉) Section on Neurophysiology, Laboratory of Systems Neuroscience, National Institute of Mental Health, National Institute of Health, 49 Convent Drive, MSC 4401, Building 49/Room B1EE17, Bethesda, MD 20892-4401, USA e-mail: [email protected] Tel.: +1-301-4025481, Fax: +1-301-4025441 Keywords Visually guided movement · Supplementary eye field · Frontal cortex · Medial eye field · Monkey Introduction A persistent issue in behavioral neurophysiology is the extent to which neuronal activity reflects operant conditioning. For example, Mann et al. (1988) have concluded that the properties of the dorsomedial frontal cortex (DMF), also known as the supplementary eye field, changed dramatically to reflect the task that a monkey had been conditioned to perform. Notwithstanding more recent results (Tehovnik and Slocum 2000), the possibility that instrumental conditioning determines the response properties of cortical neurons remains an open issue, one with special importance to frontal cortex physiology. Stimulus location has been consistently shown to affect activity in both DMF (Olson et al. 2000; White and Wise 1999) and prefrontal cortex (PF) neurons (Asaad et al. 2000; Hoshi et al. 1998; White and Wise 1999), even in operant tasks involving responding exclusively to nonspatial stimulus dimensions such as color and shape. This finding suggests that these frontal networks process spatial information regardless of its relevance to an operant behavior. An alternative hypothesis, tested here, is that stimulus location affects neuronal activity because that feature is relevant in other operant tasks that the subjects perform at different times. Materials and methods Two male rhesus monkeys (Macaca mulatta), 6–8 kg, sat in a primate chair facing a video screen. The study was approved by the NIMH ACUC and conformed with the Guide for the care and use of laboratory animals (NIH publication, 1996). The head of each monkey was fixed and eye movements monitored at 200 samples/s with an infrared oculomotor (Bois Instruments). The first monkey pressed a bar to initiate a trial, which began with the presentation of a fixation spot (0.4°, 5° window) at screen center. The monkey needed to fixate that spot for 0.75–3.25 s, 117 Fig. 1 A Stimuli used, in monochromatic form, placed at the target location that each stimulus signaled. Each stimulus could appear at any of nine places: one of the eight targets or the fixation point (FP). B Example stimulus and response (arrow). C Spatial tuning for saccade direction, mean ± SEM discharge rate, in a PF neuron. Saccade direction is indicated vectorially, below. Note the preference for saccades with upward and leftward components. D Activity of a different PF neuron, showing preference for leftward stimulus locations. (X central location) otherwise the trial was aborted. If fixation was maintained, a stimulus appeared at either the central fixation point or one of eight potential saccade targets 10° from center (Fig. 1B) for 0.12–0.20 s. There were eight stimuli, each measuring ~2.5° (Fig. 1A) and composed of two elements of various shapes, hues, orientations, and sizes. Each stimulus, selected and located pseudorandomly, signaled a correct eye movement or, equivalently, a response target. Stimulus location was irrelevant. Next, the eight potential response targets appeared simultaneously. The monkey had to make a saccade to the correct target within 2.75 s and maintain gaze (2° window) for 0.6–2.7 s, after which the target spot dimmed. Then the monkey was required to release the bar quickly to receive reinforcement, a 0.1 to 0.3-ml drop of water. The task for the second monkey differed somewhat. There was no bar to press; each trial began automatically. The discriminative stimuli were divided into two sets of four, those with targets separated by 90°. One of these two sets was associated with targets in the cardinal directions from center (0°, 90°, 180°, and 270°), the other with the intermediate target locations (45°, 135°, 225°, and 315°). On each trial, only the targets associated with that set appeared, and reinforcement was given for the fixation contingencies alone. Cranial implantation was performed aseptically and with the monkeys under isofluorane anesthesia (1%–3%). The monkeys received banamine (0.5 mg/kg i.m.) postoperatively. Glass-coated, platinum-iridium electrodes (1–2 MΩ measured at 1 kHz) recorded frontal cortex activity. Single-unit potentials were filtered with a Table 1 Numbers of neurons showing significant effects of stimulus location and saccade direction (one-way ANOVA, P<0.05). A neuron can contribute to both stimulus location and saccade direction tabulations. (N number of task related units, DMF dorsomedial frontal cortex, PF prefrontal cortex) Subject area bandpass of 600 Hz to 6 kHz, amplified and discriminated using a multi-spike detector (Alpha-Omega Engineering). The location of DMF was confirmed with intracortical microstimulation. Trains of 11 cathodal constant-current pulses were delivered at 350 pulses/s, using a stimulus isolation unit (PSIU-6; Grass Instruments). Each pulse was 200–350 µs in duration. A ball electrode was used for less precise localization. Near the end of physiological data collection, electrolytic lesions (15 µA for 10 s, anodal current) were made along five tracks in the first monkey, six in the second. After the monkey was perfused with 10% formol-saline, marking pins were inserted. Each brain was sectioned on a freezing microtome at 40 µm thickness, mounted on glass slides, and stained with thionin. We plotted recording sites by reference to the electrolytic lesions and pin locations. For each neuron’s activity, spatial tuning was evaluated by separate one-way ANOVAs (P<0.05) for the effects of saccade direction and stimulus location. Reaction time was tested similarly. A significant task relationship was examined separately for neurons showing significant spatial tuning. Modulations above referenceperiod activity levels were tested by a one-way ANOVA, comparing reference-period activity (100–500 ms before stimulus onset) and the poststimulus response (50–500 ms after stimulus onset). Results Task performance was 95% and 91% correct, for the first and second monkey, respectively. The first monkey responded with a mean saccadic reaction time of 372±45 ms (SD), the second at 642±303 ms. Reaction time varied by saccade direction and stimulus location, but the differences were small. Figure 1C, D shows the spatial tuning properties of two PF neurons. The properties of DMF neurons were similar. One of the illustrated cells showed significant spatial tuning for saccade direction, regardless of the location of the discriminative stimulus (Fig. 1C), but no spatial tuning for stimulus location (not shown). The other PF neuron was spatially tuned to stimulus location (Fig. 1D), notwithstanding the fact that the location of each discriminative stimulus was behaviorally irrelevant. The spatial tuning for saccade direction was complex, but also statistically significant, in this neuron (not shown). Table 1 presents the numbers of neurons with significant spatial tuning for saccade direction and for stimulus location in both DMF and PF. Although more neurons in both areas showed selectivity for saccade direction, a significant minority was affected by stimulus location. Overall, the spatial tuning functions resembled those reported previously in both DMF (Schall 1991) and PF (Funahashi et al. 1991). Monkey 1 (N=112) Monkey 2 (N=87) Total (N=199) Stimulus location Stimulus location Saccade direction Stimulus location Saccade direction Saccade direction DMF PF 8 6 27 23 4 5 29 7 12 11 56 30 Total n % 14 13 50 45 9 10 36 41 23 12 86 43 118 Fig. 2A, B Electrode penetration sites. A Significant stimuluslocation effects (squares) or both saccade-direction and stimuluslocation effects (crosses). Symbol size indicates the number of neurons of the indicated class at each coordinate. B Significant saccade-direction effects (squares) or both effects (crosses). The filled circles indicate the location of marking pins in the first monkey. All plots are two-monkey composites referenced to the PA landmark. (Arc arcuate sulcus, PA posterior limit of the arcuate sulcus, Prin principal sulcus) Figure 2 shows the recording sites in a composite map based on bilateral recordings from DMF and unilateral recordings from PF. Figure 2B shows that neurons with statistically significant effects of saccade direction predominated in both DMF and PF (see also Table 1). Figure 2A shows the location of the smaller number of cells, in both areas, showing stimulus-location effects. A proportion of neurons showed significant effects of both stimulus location and saccade direction (Fig. 2A, B), but most saccade-direction cells lacked stimulus-location effects. Cells with activity reflecting stimulus location were scattered throughout the sampled area, with no evidence of segregation. Discussion As reviewed in detail (Tehovnik et al. 2000), DMF has been viewed as an oculomotor area (Schall 1991), although possible skeletomotor functions have received increased attention recently (Mushiake et al. 1996; Schlag et al. 1998). DMF represents space in both objectcentered (Olson and Gettner 1999; Olson and Tremblay 2000) and craniocentric coordinates (Lee and Tehovnik 1995; Schlag and Schlag-Rey 1987; Tehovnik and Lee 1993). However, DMF cells also respond to nonspatial stimuli (Chen and Wise 1995; Olson et al. 2000). PF has properties generally similar to DMF in that its cells, including those in the posterior region of PF sampled here, respond to both nonspatial and spatial aspects of visual stimuli (Rainer et al. 1998; Rao et al. 1997) and are affected by both nonspatial and spatial rules (Asaad et al. 2000; Hoshi et al. 1998; White and Wise 1999). The present study examined whether activity in DMF and PF was affected by stimulus location, even when that stimulus dimension was behaviorally irrelevant. Previous studies of both PF (Rainer et al. 1998; Rao et al. 1997; White and Wise 1999) and DMF (Olson et al. 2000; White and Wise 1999) have shown that stimulus location influences neuronal activity in nonspatially guided operant tasks. However, in each of those studies, the monkeys alternated between tasks in which cue location was the relevant stimulus dimension and other tasks in which it was not. Under such circumstances, one might argue that cells in DMF and PF were affected by stimulus location in nonspatially guided tasks because spatial factors controlled responding in other tasks. The present experiment overcame that problem because stimulus location was never a differential discriminative stimulus for responding. We found that stimulus location was nevertheless encoded in a minority of DMF and PF neurons. Of course, it is impossible to rule out the possibility that this finding resulted from the monkeys’ experience in their home cage, in which the location of objects was highly relevant to behavior. But DMF, at least, appears to be specialized for operantly conditioned behavior. Its cells are modulated in relation to eye movements made for juice reinforcement, but not when monkeys make saccades without primary reinforcement (Bon and Lucchetti 1992; Lee and Tehovnik 1995). DMF neurons also respond to juice delivery only in the context of instrumental behavior, not when juice is delivered randomly (Mann et al. 1988). Accordingly, we think it unlikely that unconditioned cage behavior underlies the encoding of stimulus location. Although this discussion emphasizes stimulus-location effects, such signals were relatively rare in both DMF and PF. The activity of most tuned cells reflected saccade direction and its correlated variables instead (Table 1). We note the existence of covariates because the present study did not entail any attempt to distinguish whether neuronal selectivity reflected features of the discriminative stimuli, the fixation targets or the saccadic eye movements. We assume, however, that the spatial factors predominate, in accordance with the spatial tuning of cells in both DMF (Schall 1991; Schlag and Schlag-Rey 1985, 1987; Schlag et al. 1998; Tehovnik et al. 2000) and the parts of PF sampled here (Funahashi et al. 1991), as well as with the presumed role of these areas in the selection of goals and the guidance of movement. In comparison with previous reports, the present results suggest that the irrelevancy of stimulus location led to a paucity of neurons encoding that dimension of the stimulus. This idea complements a finding from the frontal eye field, where cells show increased selectivity for nonspatial aspects of a visual stimulus after monkeys have been trained to respond to those features (Bichot et al. 1996). We conclude that neurons in DMF and PF reflect features of the sensory environment that are encountered during operant conditioning, but that are irrelevant to the 119 conditioned behavior and to the function of DMF and PF in the guidance of that behavior. Alternatively, it remains possible that this minority of cells might use stimulus location as a signal that the task does not call for analyzing this variable. The former possibility might shed some light on recent findings of unexpected signals in the primary motor cortex (M1). Signals have been found in M1 that reflect variables such as relative vibrotactile frequency (Mountcastle et al. 1992; Salinas and Romo 1998) and the ordinal rank of visual cues (Carpenter et al. 1999). In those studies, monkeys had been operantly conditioned for extensive periods. Perhaps M1 neurons, like the DMF and PF cells described here, also reflect information encountered during operant conditioning, even if that information is irrelevant to its function. Acknowledgements Author contributions: experimental design and animal training (S.W., I.W., N.-H.C.), data collection (N.-H.C.), data analysis (N.-H.C.). We thank Mr. Robert Gelhard for preparing the histological material. References Asaad WF, Rainer G, Miller EK (2000) Task-specific neural activity in the primate prefrontal cortex. J Neurophysiol 84: 451–459 Bichot NP, Schall JD, Thompson KG (1996) Visual feature selectivity in frontal eye fields induced by experience in mature macaques. Nature 381:697–699 Bon L, Lucchetti C (1992) The dorsomedial frontal cortex of the macaca monkey: fixation and saccade-related activity. 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