part of the task, the rats were injected before each trial with idazoxan, a drug which increases the firing rate of neurons in the locus coeruleus and the release of ...
Behavioural
Brain
Research,
39
19
(1990) 19-23
Elsevier BBR 01065
Activation of the noradrenergic system facilitates an attentional shift in the rat Valerie Devauges and Susan J. Sara Department
de Psychophysiologie,
Laboratoire
de Physiologic Nerveuse, GijkuYvette (France)
Centre
(Received 8 November 1989) (Revised version received 13 February (Accepted 19 February 1990) Key
words:
Attention;
Attentional
shift; Noradrenaline;
Nationale
de la Recherche
Scientifique,
1990)
Locus coeruleus; Idazoxan
The noradrenergic system was pharmacologically activated with the ~1~receptor antagonist, idazoxan (2 mg/kg i.p.), during the acquisition of a complex appetitive task requiring a shift in attention to stimulus dimension and in response strategy. Rats first learned a fixed path of 6 successive choices in a linear maze. The task was then changed to a visual discrimination task in which the spatial configuration of the correct path was indicated by visual cues and changed on each daily trial. During this part of the task, the rats were injected before each trial with idazoxan, a drug which increases the firing rate of neurons in the locus coeruleus and the release of noradrenaline in the cortex and hippocampus. Two control experiments showed that the drug treatment had no effect on the acquisition of either component of the task - the successive place learning or the visual discrimination. The drug was found to be effective only during the shift phase of the experiment, the idazoxan-treated rats taking fewer trials to reach criterion than the saline. A second experiment showed that idazoxan increased the amount of time spent investigating novel and unexpected objects in a familiar hole board. These results implicate the noradrenergic system in problem-solving which requires an attentional shift or a shift in responding from familiar to novel stimuli.
INTRODUCTION
Activation of the noradrenergic nucleus locus coeruleus (LC), with consequent release of noradrenaline (NA), facilitates evoked neuronal liring in many brain regions involved in receiving and processing information: cochlear nucleus2’, lateral geniculate nucleus35, visual cortex23, cerebellum and somatosensory cortex54, and hippocampus 46. In all of these structures, NA has been shown to inhibit or not affect spontaneous activity and to enhance or inhibit relatively less evoked responses, thus increasing signal-to-noise ratio. This action of NA in enhancing the selectivity and
Correspondence:
S.J. Sara, Dept. de Psychophysiologie,
0166-4328/90/$03.50
relative amplitude of neuronal responses to stimuli has led these authors and others to propose that the LC-NA system is implicated in attention and those cognitive processes dependent upon attention (see also refs. 16, 17, 42). This attentional hypothesis has been tested in many different behavioral paradigms with rats depleted of NA. The impairments produced by NA lesions are very subtle and occur only in certain paradigms. There is no clear effect of electrolytic or chemical lesion to the LC-cortical projection on simple acquisition of many tasks, although impairments do appear in tasks particularly difficult for normal rats, such as discrimi-
Lab. de Physiologie Nerveuse, C.N.R.S., Gif-sur-Yvette,
0 1990 Elsevier Science Publishers B.V. (Biomedical
Division)
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20 nation between lights or tones of different frequencies 12,32,34. Early studies showed an absence of latent inhibition and increased resistance to extinction in NA-depleted rats, which were interpreted as an inability to ignore irrelevant stimuli22,24. In more recent studies, the lesion of the ascending noradrenergic dorsal bundle was found to produce impairments in spontaneous alternation in a T-maze, habituation to novel stimuli3’ and sensory preconditioning3. These animals also appear to be sensitive to distracting stimuli when not previously habituated to them (see ref. 32). A common feature of these experiments is that behavioral deficits occur when novel stimuli must be evaluated for their relative significance, and then attended to or ignored. There are several reports, on the other hand, of lack of impairment in non-reversal shift tasks29,30*33. Some investigators have even reported facilitation in this paradigm after noradrenergic lesions26. We have found that rats severely depleted of NA are facilitated in reversal of a spatial discrimination task, with no effect of the lesion on the original acquisition37. These increasingly contradictory and paradoxical effects of lesions to the noradrenergic system have led several leading behavioral investigators in the field to call for a re-examination of the hypothesis that the coeruleo-cortical noradrenergic system is involved in selective attention (see refs. 7, 18,3 1). At the same time the evidence that NA is involved in modulation of signal/noise ratios and in gating of signals in the brain continues to accrue53, strongly suggesting that this system biases selected sensory input and, thereby, modulates selective attention. An explanation for such apparently contradictory behavioral data may be found in partial and variable recovery of function after NA lesion. This recovery involves such processes as modification of NA receptor sensitivity, rate of synthesis or activity of enzymes involved in NA synthesis, hyperactivity of surviving cells, and/or collateral or peripheral sympathetic sprouting 1,6,8,13-15,21,51,55.Moreover, other systerns might compensate for NA deficits (see ref. 37 for discussion). In the light of the remarkable plasticity of the
NA system after damage, perhaps a more appropriate way to study its role in cognitive processes may be to reversibly activate or to inhibit it, instead of destroying it. Surprisingly, very few behavioral studies have used this strategy. Facilitatory effect of direct electrical stimulation of LC on successive discrimination reversals, with no effect on the simple acquisition of the task47 has been reported. Memory retrieval can also be facilitated with pre-test electrical stimulation of LC after forgetting of a complex linear maze39. Similar effects in the same paradigm were found with pre-test injection of drugs activating the NA system37,43,44, and more specifically with the a2 antagonist idazoxan 4o. Since these treatments did not have any effect on the acquisition of the task or on its long-term retention when administered prior to or right after training, we attributed the attenuation of forgetting to NA-induced enhancement of selective attention to relevant cues in the retrieval environment. The present series of experiments examines the effect of pharmacologically enhancing NA function in a behavioral paradigm in which demands on attentional processes are more explicit than in our previous studies. During the course of performance of an appetitively motivated maze task, new visual discriminanda are added and have to be taken into account for the acquisition of a new rule. The rat must shift attention to these visual discriminanda and modify its response strategy. To test the hypothesis that the noradrenergic system is particularly implicated in behavioral tasks which require shifts in attention, the following experiments were run to compare the effect of the pharmacological activation during an imposed shift in attention, with the effect on simple acquisition of each aspect of the task. EXPERIMENT Materials
I
and Methods
Pharmacological treatment The activity of the noradrenergic neurons can be enhanced by antagonists of a2 autoreceptors. These receptors are located on LC cell bodies and axon terminals, and their activation inhibits cell
21 tiring and release of NA2,49. Systemic injection of the highly selective CI* receptor antagonist, idazoxan, at a dose well below the threshold of effect on spontaneous behavior (2 mg/kg), increases the firing rate of the LC cells by about 80% 9 and the turnover rate of NA in cortex and hippocampus5. Postsynaptic effects as measured by evoked field potentials in the hippocampus are optimal at this dose of idazoxan4i. Animals A total number of 118 male Sprague-Dawley rats weighing approximately 240 g on arrival in the laboratory were used in these experiments. They were housed in pairs in wire mesh cages, in a well-ventilated room under a 12-h light-dark cycle (lights on 08.00-20.00 h). Experiments were carried out between 10.00 and 17.00 h. The rats were given food and water ad libitum. Before pretraining, food was gradually restricted to maintain the animals at approximately 85% of their free-feeding weight ( k 15 g of dry food/day). The daily ration was given at 13.30 or 17.00 h, depending on whether the animal was run in the morning or the afternoon. Each animal was run at approximately the same time each day. Apparatus The 6-unit linear maze has been described in detail”. It consists of six 50 x 40 cm units with 35 cm high walls, separated from a start box and a goal box (25 x 25 x 35 cm) by a sliding door. In each unit, a clear Plexiglas barrier was placed on the left or right. During the first part of the training, the rats learned a fixed path (LRRLLR or RLLRRL, L: left, R: right). In the second part of the experiment, the path was changed for each trial and two pairs of visual cues (7.5 x 32 and 10.5 x 35 cm) were added in each unit of the maze: a pair of black stimulus cards was put on the side with barrier, whereas a pair of white stimulus cards indicated the correct path. Three white cues (21.4 x 35 cm) were also added in the goal box. Thus each rat learned to follow the white discriminanda to find the correct new path each day. In two control experiments, the effect of idazoxan was tested either on the acquisition of a
fixed path in the linear maze (as during the first part of the previous task) or on the acquisition of the visual part of the task (as during the second part of the previous task). Behavioral procedure The first 2 days consisted of a pretraining period during which the animals were habituated to the experimenter, the maze and the experimental conditions. On day 1, rats explored for 10 min, two at a time, the last two maze units, in the absence of barriers, and were permitted to eat food pellets in the goal box. On day 2, rats were placed individually in the last unit and the sliding door was closed when the goal box was entered. The first part of the training began on day 3 and lasted 5 days with one daily trial. In the spatial task, barriers were placed at the appropriate points and the path was changed to its mirror configuration after every two rats, in an attempt to evenly distribute animal odors inside the maze. Each rat was placed in the start box and the sliding door was immediately opened. Performances were recorded as the time to reach the goal box, the number of errors and the number of retracings (i.e. return to preceding units). The animals were removed from the goal box after two minutes during which they could eat the pellets. After 5 trials, rats making more than two errors on the last two days of training were eliminated (n = 11). Thirty rats were retained for the second phase of the experiment which began on day 8 and lasted 18 days, with one daily trial. Visual discriminanda were added in the maze and the path was changed for each trial. Black cards were always associated with barriers, whereas white cards always indicated the correct path. Thus, the animals were required to attend to these visual stimuli and to change their strategy to a visual one, in order to find the correct new path each day. Rats were trained to a criterion of zero or one error on two consecutive days. Those animals not reaching criterion after 18 days were assigned a ceiling score of 18. During this phase, rats were injected 30 min before each daily trial with the a2 antagonist, idazoxan (2 mg/kg i.p.), (n = 16) or with saline (n = 14), (see Fig. 1 for the experimental design).
22
SPATIAL DlSCRlMlNATlON
VISUAL
SHIFT
Fig. 1. Experimental design and procedure, Expt. I. After two days ofpretraining, rats were trained with one daily trial to learn a fixed path (RLLRRL or LRRLLR) until they reached a performance of 2 errors or fewer on two consecutive days. Then visual cues were added in the maze, black cards always indicating barriers and white cards always indicating the correct path, the path being changed for each trial. The maze with or without cues is schematized on the right and the left of the figure respectively.
Control experiments Twenty-eight rats were used to test the effect of idazoxan on the simple acquisition of the spatial task in the linear maze. The procedure for pretraining and training in this experiment was the same as for the first part of the training in the previous experiment. Half of the group received daily pretrial injections of idazoxan (2 mg/kg i.p.) and one group daily saline injections. Rats were trained until they reached a criterion of zero or one error on two consecutive days, or for a maximum of 10 days. Forty-nine rats were used to test the effect of idazoxan on the acquisition of the visual part of the task. The 6-unit linear maze used for this experiment was the same as the one used before, except that black and white cards indicating, respectively, the carriers and the path were added, as in the second part of the training in the first experiment. After the pretraining period of two days, two groups were constituted. One group (n = 25) injected daily with idazoxan 30 min before each trial (2 mg/kg i.p.) and one saline control group (n = 24) injected with an equal volume of saline. Rats were trained in the same manner as during the second part of the training in the shift task, until they reached a criterion of zero or one error, or a maximum of 21 trials.
Statistical analysis Since the number of the trials was arbitrarily limited to 18 (and to 10 and 21 respectively for the two control experiments) and those animals not attaining the criterion were assigned a maximum ceiling score, the data on this variable were analyzed with a non-parametric Mann-Whitney U-test. Results For the shift task, since the animals were initially trained on a fixed path in the maze and were then divided into matched groups according to their performance on the last training trial (in terms of number of errors and retracing time), for the second part of the experiment, there is no difference between these two groups in this first part of the experiment. During the second part of the training, 81% (n = 13/16) ofthe idazoxan-treated rats, and 50% (n = 7/14) of th e sal ine-treated rats had reached the criterion of zero or one error on two consecutive trials during the 18 days of training. The mean number of trials for those animals reaching this criterion was 11 for the idazoxan group and 15.5 for the saline group (see Fig. 2). This difference between the two groups concerning the
23
loo-
rp
20
0
M
IDAZOXAN
-
SALINE
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%“%4t 1
234567
8
9
10
11
12
13
14
15
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18
trtals
Fig. 2. Percent of rats reaching criterion as a function of number of trials during the visual shift, when black and white cues are added in the maze and the path changed for each trial (Expt. I). Rats treated with idazoxan (2 mg/kg 30 min before each trial) reached the criterion with significantly fewer trials than the saline-treated rats.
number of trials necessary to reach criterion was significant (Mann-Whitney U-test, U = 30.5; P < 0.002, two-tailed). Moreover, performance of zero or one error occurred more frequently during the 18 trials for idazoxan-treated rats (x = 4.37; S.E.M. = 0.61) than for saline-treated rats (x = 3.14; S.E.M. = 0.46) (t,, = 3.36; P = 0.05). Control experiments The mean number of trials necessary to reach the criterion of zero or one error on two consecutive days on the spatial task was 7.1 for each group (Mann-Whitney U-test, U = 96; n.s.). There was no difference between the idazoxan- or saline-treated groups in the percentage of animals reaching criterion after 10 trials (58 y0 and 7 1 y0 respectively). The mean number of trials necessary to reach the criterion of zero or one error on two consecutive days on the visual task is 14.4 for the idazoxan-treated group and 14.5 for the saline control group; the difference is not significant (Mann-Whitney U-test, U = 275; z = - 0.5; P = 0.31). There was no difference in the percentage of animals in each group reaching criterion after 21 trials (96% idazoxan and 87% saline. Discussion The activation of the NA system clearly facilitates performance during the attentional shift in
Expt. I. The lack of effect of idazoxan on acquisition or performance of either component of the task supports the contention that the drug effect is on the shift aspect of the task. The results could conceivably be accounted for in terms of state dependency since the animals were trained on the task without the drug initially and the drug was administered only when the shift was initiated. If the internal state induced by the drug is recognized by the animal, then this could provide an additional cue to differentiate the two tasks, thus reducing interference from the spatial phase to the visual phase. Arguing against this possible account is the fact that idazoxan does not have stimulus properties at the dose used in this experiment 36. Furthermore, idazoxan facilitates test performance of the spatial version of this task, after a long retention interval, in animals trained without drug4’; any stimulus properties of the drug should produce an impairment in this case. These findings make it unlikely that the present results can be attributed to stimulus properties of idazoxan. Behavioral adaptation to the change in stimulus-response-reinforcement contingencies in this task involves several cognitive processes, any of which may be susceptible to modulation by the increased activity of neurons of the LC induced by blockade of a, autoreceptors. The behavioral facilitation observed during the shift could be due to NA facilitation of sensory
24 perception and/or discrimination at each daily trial. Indeed, it would be interesting to determine to what extent rats treated with idazoxan during the shift could maintain their visual discrimination performance without the drug. But such an explanation cannot entirely account for the facilitation, since there was no effect of the treatment on the performance of the spatial or visual discrimination aspect of the task alone (control expts.). The shift from running a fixed path based on spatial and proprioceptive cues, to changing the response sequence from trial to trial as a function of the visual discriminanda, requires cognitive and behavioral plasticity which could also involve NA function. Indeed, the increased resistance to extinction in rats with noradrenergic depletion might be due to a deficit in behavioral plasticity25. From a perceptual point of view, the second part of the task requires a shift in attention from stimuli in the proprioceptive modality (and perhaps olfactory and others) to the visual modality. The rat might be using visual cues to solve the fixed aspect of the task (we have evidence that some rats cheat on the ‘spatial’ task by using subtle intramaze visual cues in the form of shadow configurations); in this case the attentional shift would be within the visual modality, from the shadows to the newly relevant stimulus cards. Shadows are now irrelevant and should not be attended to. As many investigators have suggested (see Introduction), the postsynaptic effects of NA in modulating signal-to-noise ratios, especially in sensory pathways, might well be involved in facilitating this kind of ‘selective attention’, in response to change. EXPERIMENT
II
The following experiment more explicitly examines the effect of idazoxan on response to change in the environment in order to lend support to the interpretation of the previous experiment in terms of selective attention. Rats are familiarized with an apparatus containing small holes into which they can poke their noses. When novel objects are placed in these holes, the animals markedly increase the time spent investigating the holes. If
an effect of idazoxan is indeed to increase attention to novelty and change, it might be expected that rats treated with idazoxan will show an even greater interest in the holes containing the objects than control animals. Materials and Methods Animals Twenty two male Sprague-Dawley rats weighing between 200 and 220 g at their arrival in the laboratory were used in this experiment. They were housed in the same conditions as already described in Expt. I, and were given water and food ad libitum. They were handled for 5 min, two at a time, the day after arrival, and alone the following day. Apparatus The apparatus consisted of a box constructed of heavy beige plastic (60 x 60 x 35 cm) with 9 holes (4 cm diameter) symmetrically cut in the floor. Photoelectric cells detected total lateral exploration (XY), rearings, location, number and duration of visits to the different holes. Data were collected through a specially designed interface and stored by an Apple II computer. Behavioral procedure Each trial lasted 9 min during which the rat was allowed to freely explore the hole-board. Location, number and duration of holes visited, XY exploration and rearings were recorded for 3 periods of 3 min each. There were 3 days of habituation. On the fourth day, objects were added in 4 holes and rats were injected 30 min before the trial with either idazoxan (2 mg/kg) or saline (1 ml/kg). Objects were one small orange plastic horse, two red alphabetic letters, S and J, and one white sheep. Experimental and control groups were formed by matching pairs of animals according to their scores on all the activity measures on day 3 of habituation. Rats defecating during the session were also equally distributed in each group. Data analysis The differences between the total time spent investigating each hole on day 3 and on day 4
25 were the dependent variables. A between-within analysis of variance formed on these data, the between factor drug treatment and the within factor individual holes.
two-way was perbeing the being the
Results and Discussion
There was no change in total exploration time for those holes without objects (Fig. 3). There was a marked increase in the time spent investigating those holes containing objects on day 4. Analysis of variance showed that the factor holes showed a highly significant difference (F8,iG0 = 15.254; P < 0.001). Inspection of Fig. 3 shows that there was an increase in time spent visiting all holes containing objects and a decrease in time visiting holes with no objects. There was no effect at all of idazoxan on the time spent investigating holes without objects and the main effect of drug was not significant (F,,Z, = 2.14; P = 0.155). Those animals treated with idazoxan tended to explore the holes with objects even more. The drug x hole interaction (F8,i6,, = 1.939; P = 0.057) was due to the marked preference for a hole containing a horse shown by idazoxantreated animals (see left of Fig. 3). This was the only planned comparison which was significant (t = 4.2; P < 0.001). The reason for such a prefer-
t3 ida 0
-
Sal
no objects
2
Fig. 3. Difference between the total time spent investigating each hole on day 4 and on day 3 (sal: saline, ida: idazoxan). Rats spent more time visiting holes with objects than holes without objects. Idazoxan increases the time spent visiting holes with objects, especially the hole with the most complex object, a galloping horse; there is no effect on the time spent visiting holes without objects.
ence might lie in the fact that this object was the most complex of the four, having many more contours and angles than the sheep or the letters of the alphabet. In summary, these data clearly indicate that idazoxan has no effect on general exploration of familiar places (holes without objects) and enhances interest in certain novel objects. GENERAL
DISCUSSION
The experiments presented here show that the behavioral response to a new stimulus and the acquisition of a new strategy based upon new discriminative stimuli is facilitated by activation of the noradrenergic system. Locus coeruleus cells increase their spontaneous firing rate in response to novelty or to change in the environment4. Recent experiments, in which the firing rate of single units of the LC were recorded during classical conditioning, showed that these cells fired to the to-be-conditioned stimulus (CS) when it was novel, after which the cellular response habituated. The cell again responded to the CS at the beginning of the conditioning trials, when the reinforcement was introduced. Again the cellular response disappeared as the training progressed. Immediately after the first extinction trial, the cellular response to the CS reappeared45,42. The lack of effect of idazoxan during simple acquisition in the two control experiments may be due to the fact that the NA-LC system is spontaneously activated to its most efficient level when the animals are placed in a new environment (in this case, the maze) and thus a ceiling effect prevents facilitatory action of NA-activating drugs. Indeed, the drug appears to have an effect only when changes appear in a very familiar environment. During Expt. I, the change in stimulus-response-reinforcement contingencies which may normally activate LC neurons, could still be potentiated by an NA-stimulating drug. In Expt. II, this activation may occur in response to the appearence of novel objects and may be at the origin of the spontaneous response to novel objects observed in saline-treated rats. The pharmacological treatment could then serve to poten-
26 tiate and to maintain this spontaneous neuronal response to change when it is not at its optimal level of efficiency. This would suggest that there is a critical period during the learning of these new contingencies when the NA-potentiating drug exerts its most effective action on behavior. It would be of interest to define this period so that the possibility of complex receptor regulation induced by daily drug treatment might be better controlled. It is well known that chronic pharmacological stimulation of the noradrenergic system may produce changes in a- or P-receptor density and/or sensitivity (see ref. 28 for review). To what extent the results depend upon this chronic treatment and possible receptor regulation cannot be determined within the present experimental design. We would suggest that the behavioral facilitation observed is directly mediated by the modulating influence of NA on target structures such as the sensory relays of the the hippocampus, thalamus and/or the sensory cortices. This might, however, be an overly simplistic view, since NA is known to interact with several other neurotransmitter systems through the a2 receptor. For example, the a, receptors located on cholinergic neurons inhibit the release of acetylcholine52; idazoxan, in blocking these receptors, could cause an increase in release of acetylcholine. The literature suggesting that cortical and hippocampal cholinergic systems play a role in learning and memory processes is abundant. Furthermore, there is a complex interaction between the activity of LC neurons and the hypothalamic neuroendrocrine and autonomic nervous system50,48. To cite just one example, NA facilitates release from hypothalamic tissue of vasopressin56, a hormone which has been implicated in learning and memory processes3’ (see ref. 11 for review). Finally, the systemic mode of administration requires consideration of peripheral mechanisms of action, which might involve changes in heart rate, cerebral blood flow or blood pressure (although we do know that the systemic dose used in this experiment has only a transient effect on blood pressure in the few minutes after injection in the anesthetized rat (Devauges and Sara, unpublished data).
While the results of this experiment leave open many possible interpretations concerning the mechanisms involved in the cognitive facilitation, they are certainly highly consistent with Kety’s remarkably intuitive hypotheses concerning the functional role of NA in the central nervous system. As early as 1972, he proposed that this system was involved in arousal and adaptive responses to environmental inputs which have survival significance20. The enhanced behavioral adaptation to the change in stimulus-responsereinforcement contingencies seen in idazoxantreated animals lends support to this suggestion. Kety further proposed that ‘the aroused state induced by novel stimuli, or by stimuli (genetically) recognized as significant, is pervasive and affects synapses throughout the central nervous system, supressing most, but permitting or even accentuating activity in those that are transmitting the novel or significant stimuli”‘. This action of noradrenaline has since been confirmed in many brain areas (see Introduction) and has recently been extended by the description of the gating action of NA in increasing the efficacy of synaptic transmission53. The present behavioral results (to the extent that they be mediated by the drug effects on LC) suggest that the functional signilicance of this gating action at a cognitive level might be found in enhanced selective attention to significant discriminative stimuli. ACKNOWLEDGEMENTS
This research was supported in part by grant 88CO581 from the ‘Ministere de la Recherche et de la Technologie’ to S.J.S. V.D. is a predoctoral fellow of the ‘Minis&e de la Recherche et de la Technologie’. The authors thank M. Dumas for her expert technical assistance in running the experiments. Idazoxan was a gift from Reckitt and Coleman, Kingston-upon-Hull, U.K. REFERENCES 1 Acheson, A.N. and Zigmond, M.J., Short- and long-term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons, J. Neurosci., 1 (1981) 493-504. 2 Andrade, R. and Aghajanian, G.K., Intrinsic regulation
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