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Chapter 22 The prefrontal system: a smorgasbord
F. Bloom (Editor) Progress in Brain Research, Vol. 100 0 1994 Elsevier Science B.V. All rights reserved
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CHAPTER 22
The prefrontal system: a smorgasbord Ivan Divac Department of Medical Physiologx Panum Institute, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark
Introduction Three decades ago, Rosvold’ and Szwarcbart (1 964) published a paper in which they argued that in addition to sensory and motor systems, there is the prefrontal system (PFS) in the brain consisting of the prefrontal cortex (PFC) and a set of anatomically and functionally related formations. The concept of PFS was based mainly on the results of neurobehavioral and anatomical studies on rhesus monkeys. Joint functioning of the components of PFS was inferred from impaired performance in delayed response-type tasks following lesions or electrical stimulation anywhere in the system. The neostriatal region innervated by PFC was one such component. This notion was just hatched when I arrived to Rosvold’s laboratory in early 1963, a short time after my graduation. In retrospect, it is obvious that I became “imprinted” in Rosvold’s laboratory since a large portion of my work has been devoted to the PFS, especially to relations between PFC and the neostriatum. During my stay at NIH, we obtained evidence that PFS can be divided in subsystems (Divac et al., 1967). In 1965, I came to the Nencki Institute in Warsaw where Konorski and his group had been studying functions of the PFC in cats and dogs. There, I acquired my second major line of interest: the comparative approach. Comparisons of PFS demand a definition of PFC that is useful across species. Attempts at such a definition are as old as the term PFC itself (Divac, 1988).
’ This paper is dedicated to H.E. Rosvold
According to the definition I accepted, PFC is the cortical projection area of the thalamic mediodorsal nucleus (MD) (to appreciate the complexity of this issue, see Divac and Oberg (1990) and Divac et al. (1993)). This definition of PFC obviously requires in turn a useful definition of MD. Neither topography, currently the main criterion, nor presently available chemical markers are reliable (Regidor and Divac, 1987) but hodology seems promising. A discussion of what is an entity in the thalamus has been discussed elsewhere (Divac, 1979). Our work on the rat demonstrated the usefulness of defining PFC by MD projections to the cortex: The cortical area in rats outlined by Leonard2 on the basis of thalamo-cortical connections was shown to mediate delayed response-type behavior, just as cortical areas, defined in the same way, do in any tested species, e.g. monkeys, dogs and cats (Divac, 1971). My studies of the PFS provided data relevant for the neostriatum as well as the PFC. The studies which focused on the neostriatum have been reviewed elsewhere (Divac, 1984). Presently, I would like to review my work that focused on PFC. The decision to get involved in any of the studies reviewed here was made on the basis of existing data and opportunities. Opportunities mostly arose when I encountered people who shared my interest, usually with the contribution of a technical expertise that I did not possess. Availability of funds often determined certain undertakings. Thanks to generous donors I have been able to study
*
The influential studies from other laboratories will not be cited here; they are accessible in the relevant papers discussed in this review.
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feral cats in Norway, wild rats on Hawaii, pigeons in Italy and echidnas in Australia. Predictably, sometimes the available data and opportunities caused whimsical turns in this line of my research. My early neuropsychological studies in cats (Divac, 1968, 1972) and rats (Divac, 1971; Wikmark et al., 1973) established the generality of the concept of PFS across mammalian species. Much later, 2-deoxyglucose was used to visualize the PFS in rats (Divac and Diemer, 1980). The results of that study showed coactivation of the PFC and many subcortical structures listed by Rosvold and Szwarcbart (1964). In a related experiment, delayed alternation impairment was observed after neostriatal lesions made by kainic acid. In these animals, PFC connections remained demonstrably preserved and functionally viable (Divac et al., 1978~).These two experiments dispersed (at least my) doubt that behavioral impairments seen after neostriatal lesions could be the consequence of accidental damage to cortical connections. In conclusion, the PFC and a part of the neostriatum do share the same functions and therefore do belong to the same system.
Anatomy of the prefrontal cortex Good agreement between morphological and functional data obtained in the rat and the exciting discovery of dopaminergic innervation of the cortical area described by Leonard as prefrontal, suggested a study in which American opossums, tree shrews and rats were compared. The results showed a good overlap of the projection from the thalamic mediodorsal nucleus and dopamine-containing fibers originating in the ventral tegmental area in each species. Interestingly, the cortical area which receives this overlapping projection has different topography in each of these species (Divac et al., 1978a). These observations suggested that a dense dopaminergic innervation might be used to outline the prefrontal cortex instead of the projection from MD. On the basis of this generalization, an attempt was made to identify the bird equivalent of the PFC. Histochemical (Divac and Mogensen, 1985), biochemical (Divac et al., 1985) and behavioral data (Mogensen and Divac, 1982, 1993a) suggested
that the postero-dorso-lateral “neostriatum” in pigeons could be considered equivalent to the PFC in mammals. A later discovery, by immunohistochemical techniques, of a dense network of tyrosine hydroxylaseand dopamine-containing fibers also in non-prefiontal cortical areas in primates has restricted the use of cortical dopamine as an indicator of the presence and position of the PFC to the species with a steep gradient of distribution of dopamine in the cortex. Thus far, high density of dopaminergic innervation of the prefrontal area remains unchallenged as an indicator of PFC in non-primate brains. (The perirhinal and entorhinal areas, also densely innervated with dopaminecontaining fibers, are not neocortical areas.) Although dens@ of dopamine-containing fibers in the motor area of primates appears higher than in the PFC, biochemical measurements in samples of cortical tissue indicate that both the amount of dopamine (e.g. Bjorklund et al., 1978), and binding of spiroperidol to dopamine receptors (Divac et al., 1981) are at the highest level in the PFC. The differences in dopaminergic innervation of the cerebral cortex might offer a test of evolutionary position of a particular species, e.g. among prosimians. One line of my research aimed to establish the localization and size of PFC in different species. We used mainly horseradish peroxidase as the tracer. This approach confirmed results from other laboratories that, in rats (Divac et al., 1978b, 1993), and probably in hedgehogs (I. Divac and J. Regidor, unpublished), the PFC is split into mesial and suprarhinal parts by a ventral cortical strip innervated by thalamic nucleus submedius and dorsally by cortex innervated by the nucleus ventralis lateralis. This “primitive” arrangement differs from the fronto-polar position of PFC found in tree shrews (Divac et al., 1978a; Divac and Passingham, 1980) and cats (Markowitsch et al., 1978). The same fronto-polar localization, but with a larger relative size of the PFC, exists in dogs and simians. Some evidence suggests that the same arrangement exists in echidnas (Tachyglossus aculeatus), the species with proportionally the largest PFC among mammals, including humans (Divac et a]., 1987a,b). In bush-babies, PFC has a unique position and shape:
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MD projects to the ventral surface of the frontal lobe and to the mesial, fronto-polar and lateral surfaces. A large part of the lateral frontal surface, reaching far rostrally, is not innervated by MD (Markowitsch et al., 1980). These observations suggest that PFC has undergone considerable changes during the evolution. Unfortunately, the sample of different species available so far is too small for a reliable and revealing typology. Further anatomical studies on PFS revealed: (a) intricate patterns of numerous subcortico-cortical connections to the PFC in rats (Divac et al., 1978b, Divac, 1979) and cats (Markowitsch et al., 1978); (b) sources of cortical projections to the PFC in cats (Markowitsch et al., 1979); and (c) sources of afferents to the MD in tree shrews (Sapawi and Divac, 1978). Since MD projections define PFC, information about inputs to MD is expected to contribute to understanding the functional role of PFC. In a few experiments, neurochemical techniques revealed interesting features of PFC: First, the capacity of glia to take up glutamate varied with the brain region from which the glia was cultured; the glia cultured from PFC showed a stronger uptake rate than that cultured from the visual cortex or cerebellum (Schousboe and Divac, 1979). Second, the performance of behaviors mediated by PFS did influence the turnover of synapses in rat PFC (Mogensen et al., 1982) but not the turnover of dopamine (Divac et al., 1984a; Mogensen et al., 1992). Functional analysis of the prefrontal cortex My studies of functional properties of PFC had the following general objectives: (i) to map PFS neurobehaviorally in different species; (ii) to analyze the relations between the PFC and its related neostriatal region; and (iii) to improve understanding of behavioral roles played by PFS. A part of the neurobehavioral work on mapping PFS in cats, rats and pigeons has been reviewed above. Other experiments showed that in monkeys, the same small part of the PFC is essential for delayed responding and delayed alternation (Warren and Divac, 1972). Later, we showed that also in rats only a part of
the PFC mediates delayed alternation (Larsen and Divac, 1978). Neurobehavioral comparisons of different species showed essentially the same functions of PFS in such widely different animals as nocturnal omnivores (rats), solitary hunters (cats), pack hunters (dogs) and aboreal, daylight fruit gatherers (monkeys). Yet, one difference is striking: rats, dogs and cats can relearn delayed response type behavior, whereas monkeys do not. We showed that this difference cannot be attributed to differences either in test situations (Divac and Warren, 1971) or in completeness of the prefrontal ablations (Divac, 1973). In some experiments, I attempted to see whether cats with PFC ablations succeed in relearning delayed responding by positioning andor “sustained attention” in the presumed absence of short-term memory. In this attempt, two approaches were taken. In the first, lesioned cats which relearned delayed responding were trained under the following modifications of the task: during the delay period, the wire cage was covered with an opaque cylinder which had a small hole turned towards the experimenter. Through this hole, a syringe with meat paste was inserted into the cage and the cat was allowed to lick the food for about 10 s in the middle of the 30 s delay. The visual isolation and distraction had a negligible effect; no drastic and longlasting relapse of impairment was seen (Divac, 1968). In the second approach, cats were blinded by bilateral transection of the optic nerve and after 10 weeks taught delayed responding. Retest after ablations of PFC produced the same degree of impairment as seen in cats with preserved vision. This result did not support either the hypothesis of distractibility as an important element in the impairment (blind cats would be less distracted and thus perform better than sighted cats) nor the hypothesis of compensation by visual imagery (blind cats should be more impaired in the absence of the possibility to make use of visual spatial orientation) (Divac, 1969). In rats, we looked for a brain formation which takes over the hnctions after PFC ablations and established that the brain formation which mediates the performance in rats with PFC ablations is neither the parietal cortical area (Wortwein et al., 1993) nor the entire
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dorsolateral isocortex (Wortwein et al., 1994). The latter study also shows that PFC can mediate delayed alternation in absence of the cortico-cortical input. In several experiments on cats (reviewed in more detail in Divac, 1984), it was shown that PFC and the associated part of the neostriatum are serially related. Once a cat relearns delayed responding after a lesion of either of these two structures, additional lesion of the remaining structure has no effect on the performance (Wikmark and Divac, 1973; Divac, 1974). Furthermore, combined lesion of the two formations did not induce a larger impairment than a lesion of either of them alone (Divac, 1968). The roles of PFC in situations that mimic real life of some species were studied neurobehaviorally. Ablations of mesial PFC did not affect fear behavior in wild rats (Divac et al., 1984b) nor flight and defence behaviors in feral cats (Ursin and Divac, 1975). These results should be reconciled with the effects of frontal lesions on “emotional behaviors” in humans. Other experiments showed that no lesion in the rat frontal lobes had an effect on sexual performance of male rats (Larsson et al., 1980); that ablation only of the ventral part of the PFC in rats induced transient aphagia without adipsia (Mogensen and Divac, 1993b); and that ablation of the pigeon equivalent of the mammalian PFC impaired homing from unfamiliar sites, but not from familiar sites (Gagliardo and Divac, 1993). In rats, the mesial, but not suprarhinal, PFC lesions impaired spontaneous alternation behavior (Divac et al., 1975b). A later experiment showed an interaction between the lesion localization and behavioral situation; the impairment was found only in animals with dorsal mesial lesions and only if the arms of the Tmaze were made different by black or white walls (Mogensen and Divac, 1993b). The impairment in spontaneous alternation, when compared to that of delayed spatial alternation, demonstrates that neither the type of reinforcement nor the kind of learning interact essentially with PFC functioning. Nauta has suggested that PFC mediates “interoceptive gnosis”. This hypothesis was tested by taste aversion conditioning. No ablation within PFC affected taste aversion (Divac et al., 1975a; Mogensen and Divac 1993b).
Ablation of the orbital part of the PFC in monkeys and dogs induces “response disinhibition”. We replicated the experiment using rats in which orbital cortex was removed. We saw no sign of any response disinhibition (Mogensen and Divac, 1993b). Efforts to understand the function of the PFC have often emphasized the role of the spatial factor (as in egocentric orientation) in the tasks that reveal impairments after PFC lesions. We tested such hypotheses first by applying differential reinforcement for low response rates to rats with PFC ablations. The task does not require differential spatial responding but only withholding responses for a predetermined interval. Ablation of the PFC did impair performance in this task thus showing that PFC also plays a role in situations where the spatial factor is considerably reduced if not entirely eliminated (Rosenkilde and Divac, 1975). Another study along the same lines led to the design of a task in which the informing cue had no spatial localization; cats were supposed to guide their responses to spatially separated feeders on the basis of the duration of confinement under a cage. Again, ablations of the PFC induced a clear impairment (Rosenkilde and Divac, 1976). This result confirms the conclusion that PFC also plays a role in behaviors with reduced spatial requirements. Some authors postulated involvement of PFC in sequential behaviors. Instead of observing a complex behavior such as maternal, we trained animals to manipulate two objects sequentially in an operant test chamber. Against the prediction, orbital ablation impaired sequencing much more strongly than did a dorsomedial lesion (Mogensen and Divac, 1984). It is likely that the essential part of the PFC for sequential behavior is the medial part of the orbital area (ventral part of the mesial PFC in rats). Conclusions
Demonstration of the existence of the PFC in a number of species from different orders offers a solid basis for extrapolation to other species, including humans. An extrapolation based on results obtained in a single species is more risky even when this species is consid-
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ered to be closely related to humans. Indeed, participation of a part of the neostriatum in prefiontal hnctions inferred from animal studies, has also been found in humans studied with PET and functional MR scanning. In my attempts to study functions of PFC, negative results were obtained at least as frequently as positive ones. We know now that the entire dorsolateral neocortex in rats plays no role in the recovery of delayed response-type behavior (Wortwein et al., 1994); that cats after PFC lesions do nor relearn delayed responding through body positioning or “sustained attention” (Divac, 1968); that the PFC does not mediate “visceral gnosis” (Divac et al., 1975a); that the PFC is unnecessary for sexual performance of rats (Larsson et al., 1980); that large parts of the PFC either in cats (Ursin and Divac, 1975) or rats (Divac et al., 1984b) are not essentially involved in “emotional behaviors”. On the other hand, no species with lesions in the PFC has escaped impairment of delayed response-type behaviors. Across species, this lesion consequence is more reliable than limb paralysis after motor cortical lesions. Unfortunately, no stringent a priori description of such tasks is available. Sometimes a task which apparently belongs to this group is performed successfully by animals with lesions in the PFS (Mogensen et al., 1987). In the long run, careful analysis of task differences sensitive or insensitive to PFS lesions may provide hints about critical features of situations in which PFS lesions induce impairments. The presence of the impairments in delayed response-type tasks by all species tested so far with PFC lesions contrasts with the different effects of the same lesions in other behavioral situations. Some conspicuous examples are first, as already mentioned, the inability of monkeys to relearn this performance after PFS lesions. Secondly, following prefiontal ablations, an exceptionally high behavioral activity is seen in Old World monkeys in comparison with other species, including squirrel monkeys. Thirdly, an established “response disinhibition” found after orbital PFC lesions in Old World monkeys could not be replicated in rats in spite of efforts to create similar behavioral requirements (Mogensen and Divac, 1993b). Of course, one can always wonder whether the identical situation
in the judgement of humans is also the same for two other different species. These few examples illustrate the problems of neurobehavioral analysis of PFC. A partial explanation of apparent inconsistencies and contradictions probably lies in the different functions of different subdivisions of PFC. This requires a parcellation of the PFC (and MD) comparable across species. References Bjijrklund. A., Divac, 1. and Lindvall, 0. (1978) Regional distribution of catecholamines in monkey cerebral cortex. Evidence for a dopaminergic innervation of the primate prefrontal cortex. Neurosci. Lett., 7: 115-1 19. Divac, 1. (1968) Effects of prefrontal and caudate lesions on delayed response in cats. Arta Biol. Exp. (Warsaw), 28: 149167. Divac, I. (1969) Delayed response in blind cats before and after prefrontal ablation. Physiol. Behav., 4: 795-800. Divac, I. (1971) Frontal lobe system and spatial reversal in the rat. Neuropsychologia, 9: 175-183. Divac, 1. (1972) Delayed alternation in cats with lesions of the prefrontal cortex and the caudate nucleus. Physiol. Behav., 8: 519522. Divac, I. (1973) Delayed response in cats after frontal lesions extending beyond the gyms proreus. Physiol. Behav., 10: 717720. Divac, 1. (1974) Caudate nucleus and relearning of delayed alternation in cats. Physiol. Psychol., 104-106. Divac, 1. (1979) Patterns of subcortico-cortical projections as revealed by somatopetal horseradish peroxidase tracing. Neuroscience, 4: 455-461. Divac, I. (1984) The neostriatum viewed orthogonally. In: Functions of fhe Basal Ganglia, CIBA Foundation Symposium 107, Pitman, London, pp. 201-215. Divac, 1. (1988) A note on the h i s t o j of the term ‘prefrontal’. IBRO News, 16: No 2. Divac, 1. and Diemer, N.H. (1980) The prefrontal system in the rat visualized by means of labelled deoxyglucose. Further evidence for functional heterogeneity of the neostriatum. J. Comp. Neurol., 190: 1-13. Divac, 1. and Mogensen, J. (1985) The prefrontal ‘cortex’ in the pigeon. Catecholamine histofluorescence. Neuroscience, 15 : 677-682. Divac, I. and Oberg, R.G.E. (1990) Prefrontal cortex: The name and the thing. In: W. Schwerdtfeger and P. Germroth (Eds.), Sfrucfure and Development of the Forebrain in Lower Vertebrates, Experimenfal Bruin Research Series, Springer-Verlag, Berlin, pp. 213-220. Divac, 1. and Passingham, R.E. (1980) Connections of the mediodorsal nucleus of the thalamus in the tree shrew. 11. Efferent connections. Neurosci. Letf.,19: 21-26. Divac, I. and Warren, J.M. (1971) Delayed response by frontal monkeys in the Nencki Testing Situation. Neuropsychologia, 9: 209-2 17.
174 Divac, I., Rosvold H.E., Szwarcbart, M. (1967) Behavioral effects of selective ablation of the caudate nucleus. J. Comp. PhysioLPsychol., 63: 184-190. Divac, I., Gade, A. and Wikmark, R.G.E. (1975a) Taste aversion in rats with lesions in the frontal lobes: no evidence for interoceptive agnosia. Physiol. Psychol., 3: 43-46. Divac, I., Wikmark, R.G.E. and Gade, A. (1975b) Spontaneous alternation in rats with lesions in the frontal lobes. An extension of the frontal lobe syndrome. Physiol. Psychol., 3: 3 9 4 2 . Divac, I., Bjdrklund, A., Lindvall, 0. and Passingham, R.E. (1 978a) Converging projections from the mediodorsal thalamic nucleus and mesencephalic dopaminergic neurons to the neocortex in three species. J. Comp. Neurol., 180: 59-72. Divac, I., Kosmal, A,, Bjdrklund, A. and Lindvall, 0. (1978b) Subcortical projections to the prefrontal cortex in the rat as revealed by the horseradish peroxidase technique. Neuroscience, 3: 785796. Divac, I., Markowitsch, H.J. and Pritzel, M. (1978~)Behavioral and anatomical consequences of small intrastriatal injections of kainic acid in the rat. Brain Res., 151: 523-532. Divac, I., Braestrup, C. and Nielsen, M. (1981) Spiroperidol, naloxone, diazepam and QNB binding in the monkey cerebral cortex. Brain Res. Bull., 7: 469-477. Divac, I., Lichtensteiger, W. and Gade, A. (1984a) Catecholamine microfluorometry of nigral perikarya and tyrosine hydroxylase assay in some telencephalic structures of rats exposed to different behavioral situations. Acta Neurobiol. Exp., 44: 263-272. Divac, I., Mogensen, J., Blanchard, R.J. and Blanchard, D.C. (1984b) Mesial cortical lesions and fear behavior in the wild rat. Physiol. Psychol., 12: 271-274. Divac, I., Mogensen, J. and BjOrklund, A. (1985) The prefrontal ‘cortex’ in the pigeon. Biochemical evidence. Bruin Res., 332: 365-368. Divac, I., Holst, M.-C., Nelson, J., McKenzie, J.S (1987a) Afferents of the frontal cortex in the echidna (Tachyglossus uculeatus). Indication of an outstandingly large prefrontal area. Bruin Behav. Evol., 30: 303-320. Divac, I., Pettigrew, J.D., Holst, M.-C. and McKenzie, J.S. (1987b) Efferent connections .of the prefrontal cortex of echidna (Tachyglossus aculeatus).Bruin Beha! Evol., 30: 321-327. Divac, I., Mogensen, J., Petrovic-Minic, B., Zilles, K., Regidor, J. (1993) Cortical projections of the thalamic mediodorsal nucleus in the rat. Definition of the prefrontal cortex. Actu Neurobiol. Exp., 53: 425-429. Gagliardo, A. and Divac, I. (1993) Effects of ablation of the presumed equivalent of the mammalian prefrontal cortex in pigeon homing. Behav. Neurosci., 107: 280-288. Larsen, J.K. and Divac, I. (1978) Selective ablations within the prefrontal cortex of the rat and performance of delayed alternation. Physiol. Psychol., 6: 15-17. Larsson, K., Oberg, R.G.E. and Divac, I. (1980) Frontal cortical ablations and sexual performance in male albino rats. Neurosci. Lett., Suppl. 5 : 319. Markowitsch, H.J., Pritzel, M. and Divac, I. (1978) The prefrontal cortex of the cat: anatomical subdivisions based on retrograde labelling of cells in the mediodorsal thalamic nucleus. Exp. Brain Res., 32: 335-344. Markowitsch, H.J., Pritzel, M. and Divac, I. (1979) Cortical aEer-
ents to the prefrontal cortex of the cat: a study with the horseradish peroxidase technique. Neurosci. Lett., 11: 115-120. Markowitsch, H.J., Pritzel, M., Wilson, M. and Divac, I. (1980) The prefrontal cortex of a prosimian (Gulugo senegalensis) defined as cortical projection area of the thalamic mediodorsal nucleus. Neuroscience, 5 : 1771-1779. Mogensen, J. and Divac, I. (1982) The prefrontal ‘cortex’ in the pigeon. Behavioral evidence. Brain Behm. Evol., 21 : 60-66. Mogensen, J. and Divac, I. (1984) Sequential behavior after modified prefrontal lesions in the rat. Physiol. Psychol., 12: 41-44. Mogensen, J. and Divac, I. (1993a) Behavioural effects of ablation of the pigeon-equivalent of the mammalian prefrontal cortex. B e h . Bruin Res., 55: 101-107. Mogensen, J. and Divac, I. (1993b) Behavioural changes after ablation of subdivisions of the rat prefrontal cortex. Acta Neurobiol. Exp., 53: 439449. Mogensen, J., Jmgensen, 0,s.and Divac, I. (1982) Synaptic proteins in frontal and control brain regions of rats after exposure to spatial problems. Behm Bruin Rex, 5 : 375-386. Mogensen, J., Ivenen, I.H. and Divac, I. (1987) Neostriatal lesions impaired rats’ delayed alternation performance in a T-maze but not in a two-key operant chamber. Acta Neurobiol. Exp., 47: 45-54. Mogensen, J., Bjdrklund, A. and Divac, I. (1992) Catecholamines and DOPAC in cortical and neostriatal regions during rats’ learning of delayed alternation. Actu Neurobiol. Exp., 52: 4956. Regidor, J. and Divac, 1. (1987) Architectonics of the thalamus in echidna (Tuchyglossus uculeutus): search for the mediodorsal nucleus. Bruin Behm. Evol., 30: 328-341. Rosenkilde, C.E. and Divac, I. (1975) DRL performance following anteromedial cortical ablations in rats. Bruin Res., 95: 142-146. Rosenkilde, C.E. and Divac, I. (1976) Time discrimination performance in cats with lesions in the prefrontal cortex and the caudate nucleus. J. Comp. Physiol. Psychol., 90: 343-352. Rosvold, H.E. and Szwarcbart, M.K. (1964) Neural structures involved in delayed-response performance. In: J.M. Warren and K. Akert (Eds.), The Frontal Granular Cortex and Behavior, McGraw-Hill, New York, pp. 1-15. Sapawi, R.R. and Divac, I. (1978) Connections of the mediodorsal nucleus of the thalamus in the tree shrew. I. Afferent connections. Neurosci. Lett., 7: 183-1 89. Schousboe, A. and Divac, I. (1979) Differences in glutamate uptake in astrocytes cultured from different brain regions. Brain Res., 177: 407-409. Ursin, H. and Divac, I. (1975) Emotional behavior in feral cats with ablations of the prefrontal cortex and subsequent lesions in amygdala. J. Comp. Physiol. Psychol., 88: 36-39. Warren, J.M. and Divac, I. (1972) Delayed response performance by rhesus monkeys with midprincipalis lesions. Psychonomic Sci., 8: 146-147. Wikmark, R.G.E. and Divac, I. (1973) Absence of effect of caudate lesions on delayed responses acquired after large frontal ablations in cats. Israeli J. Med. Sci., 9: 92-97. Wikmark, R.G.E., Divac, I. and Weiss, R. (1973) Retention of spatial delayed alternation in rats with lesions in the frontal lobes. Implications for a comparative neuropsychologyof the prefrontal system. Bruin B e h Evol., 8: 329-339.
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Wortwein, G., Mogensen, J. and Divac, I. (1993) Retention and relearning of spatial delayed alternation in rats after combined or sequental lesions of the prefrontai and parietal cortex. Actu Neurobiol. Exp., 53: 351-366.
Wartwein G, Mogensen J, Divac, 1. (1994) Retention and relearning of spatial delayed alternation in rats after ablation of the prefrontal cortex or total nonprefrontal isocortex. Behuv. Bruin Res., in press..
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CHAPTER 22
The prefrontal system: a smorgasbord Ivan Divac Department of Medical Physiologx Panum Institute, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark
Introduction Three decades ago, Rosvold’ and Szwarcbart (1 964) published a paper in which they argued that in addition to sensory and motor systems, there is the prefrontal system (PFS) in the brain consisting of the prefrontal cortex (PFC) and a set of anatomically and functionally related formations. The concept of PFS was based mainly on the results of neurobehavioral and anatomical studies on rhesus monkeys. Joint functioning of the components of PFS was inferred from impaired performance in delayed response-type tasks following lesions or electrical stimulation anywhere in the system. The neostriatal region innervated by PFC was one such component. This notion was just hatched when I arrived to Rosvold’s laboratory in early 1963, a short time after my graduation. In retrospect, it is obvious that I became “imprinted” in Rosvold’s laboratory since a large portion of my work has been devoted to the PFS, especially to relations between PFC and the neostriatum. During my stay at NIH, we obtained evidence that PFS can be divided in subsystems (Divac et al., 1967). In 1965, I came to the Nencki Institute in Warsaw where Konorski and his group had been studying functions of the PFC in cats and dogs. There, I acquired my second major line of interest: the comparative approach. Comparisons of PFS demand a definition of PFC that is useful across species. Attempts at such a definition are as old as the term PFC itself (Divac, 1988).
’ This paper is dedicated to H.E. Rosvold
According to the definition I accepted, PFC is the cortical projection area of the thalamic mediodorsal nucleus (MD) (to appreciate the complexity of this issue, see Divac and Oberg (1990) and Divac et al. (1993)). This definition of PFC obviously requires in turn a useful definition of MD. Neither topography, currently the main criterion, nor presently available chemical markers are reliable (Regidor and Divac, 1987) but hodology seems promising. A discussion of what is an entity in the thalamus has been discussed elsewhere (Divac, 1979). Our work on the rat demonstrated the usefulness of defining PFC by MD projections to the cortex: The cortical area in rats outlined by Leonard2 on the basis of thalamo-cortical connections was shown to mediate delayed response-type behavior, just as cortical areas, defined in the same way, do in any tested species, e.g. monkeys, dogs and cats (Divac, 1971). My studies of the PFS provided data relevant for the neostriatum as well as the PFC. The studies which focused on the neostriatum have been reviewed elsewhere (Divac, 1984). Presently, I would like to review my work that focused on PFC. The decision to get involved in any of the studies reviewed here was made on the basis of existing data and opportunities. Opportunities mostly arose when I encountered people who shared my interest, usually with the contribution of a technical expertise that I did not possess. Availability of funds often determined certain undertakings. Thanks to generous donors I have been able to study
*
The influential studies from other laboratories will not be cited here; they are accessible in the relevant papers discussed in this review.
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feral cats in Norway, wild rats on Hawaii, pigeons in Italy and echidnas in Australia. Predictably, sometimes the available data and opportunities caused whimsical turns in this line of my research. My early neuropsychological studies in cats (Divac, 1968, 1972) and rats (Divac, 1971; Wikmark et al., 1973) established the generality of the concept of PFS across mammalian species. Much later, 2-deoxyglucose was used to visualize the PFS in rats (Divac and Diemer, 1980). The results of that study showed coactivation of the PFC and many subcortical structures listed by Rosvold and Szwarcbart (1964). In a related experiment, delayed alternation impairment was observed after neostriatal lesions made by kainic acid. In these animals, PFC connections remained demonstrably preserved and functionally viable (Divac et al., 1978~).These two experiments dispersed (at least my) doubt that behavioral impairments seen after neostriatal lesions could be the consequence of accidental damage to cortical connections. In conclusion, the PFC and a part of the neostriatum do share the same functions and therefore do belong to the same system.
Anatomy of the prefrontal cortex Good agreement between morphological and functional data obtained in the rat and the exciting discovery of dopaminergic innervation of the cortical area described by Leonard as prefrontal, suggested a study in which American opossums, tree shrews and rats were compared. The results showed a good overlap of the projection from the thalamic mediodorsal nucleus and dopamine-containing fibers originating in the ventral tegmental area in each species. Interestingly, the cortical area which receives this overlapping projection has different topography in each of these species (Divac et al., 1978a). These observations suggested that a dense dopaminergic innervation might be used to outline the prefrontal cortex instead of the projection from MD. On the basis of this generalization, an attempt was made to identify the bird equivalent of the PFC. Histochemical (Divac and Mogensen, 1985), biochemical (Divac et al., 1985) and behavioral data (Mogensen and Divac, 1982, 1993a) suggested
that the postero-dorso-lateral “neostriatum” in pigeons could be considered equivalent to the PFC in mammals. A later discovery, by immunohistochemical techniques, of a dense network of tyrosine hydroxylaseand dopamine-containing fibers also in non-prefiontal cortical areas in primates has restricted the use of cortical dopamine as an indicator of the presence and position of the PFC to the species with a steep gradient of distribution of dopamine in the cortex. Thus far, high density of dopaminergic innervation of the prefrontal area remains unchallenged as an indicator of PFC in non-primate brains. (The perirhinal and entorhinal areas, also densely innervated with dopaminecontaining fibers, are not neocortical areas.) Although dens@ of dopamine-containing fibers in the motor area of primates appears higher than in the PFC, biochemical measurements in samples of cortical tissue indicate that both the amount of dopamine (e.g. Bjorklund et al., 1978), and binding of spiroperidol to dopamine receptors (Divac et al., 1981) are at the highest level in the PFC. The differences in dopaminergic innervation of the cerebral cortex might offer a test of evolutionary position of a particular species, e.g. among prosimians. One line of my research aimed to establish the localization and size of PFC in different species. We used mainly horseradish peroxidase as the tracer. This approach confirmed results from other laboratories that, in rats (Divac et al., 1978b, 1993), and probably in hedgehogs (I. Divac and J. Regidor, unpublished), the PFC is split into mesial and suprarhinal parts by a ventral cortical strip innervated by thalamic nucleus submedius and dorsally by cortex innervated by the nucleus ventralis lateralis. This “primitive” arrangement differs from the fronto-polar position of PFC found in tree shrews (Divac et al., 1978a; Divac and Passingham, 1980) and cats (Markowitsch et al., 1978). The same fronto-polar localization, but with a larger relative size of the PFC, exists in dogs and simians. Some evidence suggests that the same arrangement exists in echidnas (Tachyglossus aculeatus), the species with proportionally the largest PFC among mammals, including humans (Divac et a]., 1987a,b). In bush-babies, PFC has a unique position and shape:
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MD projects to the ventral surface of the frontal lobe and to the mesial, fronto-polar and lateral surfaces. A large part of the lateral frontal surface, reaching far rostrally, is not innervated by MD (Markowitsch et al., 1980). These observations suggest that PFC has undergone considerable changes during the evolution. Unfortunately, the sample of different species available so far is too small for a reliable and revealing typology. Further anatomical studies on PFS revealed: (a) intricate patterns of numerous subcortico-cortical connections to the PFC in rats (Divac et al., 1978b, Divac, 1979) and cats (Markowitsch et al., 1978); (b) sources of cortical projections to the PFC in cats (Markowitsch et al., 1979); and (c) sources of afferents to the MD in tree shrews (Sapawi and Divac, 1978). Since MD projections define PFC, information about inputs to MD is expected to contribute to understanding the functional role of PFC. In a few experiments, neurochemical techniques revealed interesting features of PFC: First, the capacity of glia to take up glutamate varied with the brain region from which the glia was cultured; the glia cultured from PFC showed a stronger uptake rate than that cultured from the visual cortex or cerebellum (Schousboe and Divac, 1979). Second, the performance of behaviors mediated by PFS did influence the turnover of synapses in rat PFC (Mogensen et al., 1982) but not the turnover of dopamine (Divac et al., 1984a; Mogensen et al., 1992). Functional analysis of the prefrontal cortex My studies of functional properties of PFC had the following general objectives: (i) to map PFS neurobehaviorally in different species; (ii) to analyze the relations between the PFC and its related neostriatal region; and (iii) to improve understanding of behavioral roles played by PFS. A part of the neurobehavioral work on mapping PFS in cats, rats and pigeons has been reviewed above. Other experiments showed that in monkeys, the same small part of the PFC is essential for delayed responding and delayed alternation (Warren and Divac, 1972). Later, we showed that also in rats only a part of
the PFC mediates delayed alternation (Larsen and Divac, 1978). Neurobehavioral comparisons of different species showed essentially the same functions of PFS in such widely different animals as nocturnal omnivores (rats), solitary hunters (cats), pack hunters (dogs) and aboreal, daylight fruit gatherers (monkeys). Yet, one difference is striking: rats, dogs and cats can relearn delayed response type behavior, whereas monkeys do not. We showed that this difference cannot be attributed to differences either in test situations (Divac and Warren, 1971) or in completeness of the prefrontal ablations (Divac, 1973). In some experiments, I attempted to see whether cats with PFC ablations succeed in relearning delayed responding by positioning andor “sustained attention” in the presumed absence of short-term memory. In this attempt, two approaches were taken. In the first, lesioned cats which relearned delayed responding were trained under the following modifications of the task: during the delay period, the wire cage was covered with an opaque cylinder which had a small hole turned towards the experimenter. Through this hole, a syringe with meat paste was inserted into the cage and the cat was allowed to lick the food for about 10 s in the middle of the 30 s delay. The visual isolation and distraction had a negligible effect; no drastic and longlasting relapse of impairment was seen (Divac, 1968). In the second approach, cats were blinded by bilateral transection of the optic nerve and after 10 weeks taught delayed responding. Retest after ablations of PFC produced the same degree of impairment as seen in cats with preserved vision. This result did not support either the hypothesis of distractibility as an important element in the impairment (blind cats would be less distracted and thus perform better than sighted cats) nor the hypothesis of compensation by visual imagery (blind cats should be more impaired in the absence of the possibility to make use of visual spatial orientation) (Divac, 1969). In rats, we looked for a brain formation which takes over the hnctions after PFC ablations and established that the brain formation which mediates the performance in rats with PFC ablations is neither the parietal cortical area (Wortwein et al., 1993) nor the entire
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dorsolateral isocortex (Wortwein et al., 1994). The latter study also shows that PFC can mediate delayed alternation in absence of the cortico-cortical input. In several experiments on cats (reviewed in more detail in Divac, 1984), it was shown that PFC and the associated part of the neostriatum are serially related. Once a cat relearns delayed responding after a lesion of either of these two structures, additional lesion of the remaining structure has no effect on the performance (Wikmark and Divac, 1973; Divac, 1974). Furthermore, combined lesion of the two formations did not induce a larger impairment than a lesion of either of them alone (Divac, 1968). The roles of PFC in situations that mimic real life of some species were studied neurobehaviorally. Ablations of mesial PFC did not affect fear behavior in wild rats (Divac et al., 1984b) nor flight and defence behaviors in feral cats (Ursin and Divac, 1975). These results should be reconciled with the effects of frontal lesions on “emotional behaviors” in humans. Other experiments showed that no lesion in the rat frontal lobes had an effect on sexual performance of male rats (Larsson et al., 1980); that ablation only of the ventral part of the PFC in rats induced transient aphagia without adipsia (Mogensen and Divac, 1993b); and that ablation of the pigeon equivalent of the mammalian PFC impaired homing from unfamiliar sites, but not from familiar sites (Gagliardo and Divac, 1993). In rats, the mesial, but not suprarhinal, PFC lesions impaired spontaneous alternation behavior (Divac et al., 1975b). A later experiment showed an interaction between the lesion localization and behavioral situation; the impairment was found only in animals with dorsal mesial lesions and only if the arms of the Tmaze were made different by black or white walls (Mogensen and Divac, 1993b). The impairment in spontaneous alternation, when compared to that of delayed spatial alternation, demonstrates that neither the type of reinforcement nor the kind of learning interact essentially with PFC functioning. Nauta has suggested that PFC mediates “interoceptive gnosis”. This hypothesis was tested by taste aversion conditioning. No ablation within PFC affected taste aversion (Divac et al., 1975a; Mogensen and Divac 1993b).
Ablation of the orbital part of the PFC in monkeys and dogs induces “response disinhibition”. We replicated the experiment using rats in which orbital cortex was removed. We saw no sign of any response disinhibition (Mogensen and Divac, 1993b). Efforts to understand the function of the PFC have often emphasized the role of the spatial factor (as in egocentric orientation) in the tasks that reveal impairments after PFC lesions. We tested such hypotheses first by applying differential reinforcement for low response rates to rats with PFC ablations. The task does not require differential spatial responding but only withholding responses for a predetermined interval. Ablation of the PFC did impair performance in this task thus showing that PFC also plays a role in situations where the spatial factor is considerably reduced if not entirely eliminated (Rosenkilde and Divac, 1975). Another study along the same lines led to the design of a task in which the informing cue had no spatial localization; cats were supposed to guide their responses to spatially separated feeders on the basis of the duration of confinement under a cage. Again, ablations of the PFC induced a clear impairment (Rosenkilde and Divac, 1976). This result confirms the conclusion that PFC also plays a role in behaviors with reduced spatial requirements. Some authors postulated involvement of PFC in sequential behaviors. Instead of observing a complex behavior such as maternal, we trained animals to manipulate two objects sequentially in an operant test chamber. Against the prediction, orbital ablation impaired sequencing much more strongly than did a dorsomedial lesion (Mogensen and Divac, 1984). It is likely that the essential part of the PFC for sequential behavior is the medial part of the orbital area (ventral part of the mesial PFC in rats). Conclusions
Demonstration of the existence of the PFC in a number of species from different orders offers a solid basis for extrapolation to other species, including humans. An extrapolation based on results obtained in a single species is more risky even when this species is consid-
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ered to be closely related to humans. Indeed, participation of a part of the neostriatum in prefiontal hnctions inferred from animal studies, has also been found in humans studied with PET and functional MR scanning. In my attempts to study functions of PFC, negative results were obtained at least as frequently as positive ones. We know now that the entire dorsolateral neocortex in rats plays no role in the recovery of delayed response-type behavior (Wortwein et al., 1994); that cats after PFC lesions do nor relearn delayed responding through body positioning or “sustained attention” (Divac, 1968); that the PFC does not mediate “visceral gnosis” (Divac et al., 1975a); that the PFC is unnecessary for sexual performance of rats (Larsson et al., 1980); that large parts of the PFC either in cats (Ursin and Divac, 1975) or rats (Divac et al., 1984b) are not essentially involved in “emotional behaviors”. On the other hand, no species with lesions in the PFC has escaped impairment of delayed response-type behaviors. Across species, this lesion consequence is more reliable than limb paralysis after motor cortical lesions. Unfortunately, no stringent a priori description of such tasks is available. Sometimes a task which apparently belongs to this group is performed successfully by animals with lesions in the PFS (Mogensen et al., 1987). In the long run, careful analysis of task differences sensitive or insensitive to PFS lesions may provide hints about critical features of situations in which PFS lesions induce impairments. The presence of the impairments in delayed response-type tasks by all species tested so far with PFC lesions contrasts with the different effects of the same lesions in other behavioral situations. Some conspicuous examples are first, as already mentioned, the inability of monkeys to relearn this performance after PFS lesions. Secondly, following prefiontal ablations, an exceptionally high behavioral activity is seen in Old World monkeys in comparison with other species, including squirrel monkeys. Thirdly, an established “response disinhibition” found after orbital PFC lesions in Old World monkeys could not be replicated in rats in spite of efforts to create similar behavioral requirements (Mogensen and Divac, 1993b). Of course, one can always wonder whether the identical situation
in the judgement of humans is also the same for two other different species. These few examples illustrate the problems of neurobehavioral analysis of PFC. A partial explanation of apparent inconsistencies and contradictions probably lies in the different functions of different subdivisions of PFC. This requires a parcellation of the PFC (and MD) comparable across species. References Bjijrklund. A., Divac, 1. and Lindvall, 0. (1978) Regional distribution of catecholamines in monkey cerebral cortex. Evidence for a dopaminergic innervation of the primate prefrontal cortex. Neurosci. Lett., 7: 115-1 19. Divac, 1. (1968) Effects of prefrontal and caudate lesions on delayed response in cats. Arta Biol. Exp. (Warsaw), 28: 149167. Divac, I. (1969) Delayed response in blind cats before and after prefrontal ablation. Physiol. Behav., 4: 795-800. Divac, I. (1971) Frontal lobe system and spatial reversal in the rat. Neuropsychologia, 9: 175-183. Divac, 1. (1972) Delayed alternation in cats with lesions of the prefrontal cortex and the caudate nucleus. Physiol. Behav., 8: 519522. Divac, I. (1973) Delayed response in cats after frontal lesions extending beyond the gyms proreus. Physiol. Behav., 10: 717720. Divac, 1. (1974) Caudate nucleus and relearning of delayed alternation in cats. Physiol. Psychol., 104-106. Divac, 1. (1979) Patterns of subcortico-cortical projections as revealed by somatopetal horseradish peroxidase tracing. Neuroscience, 4: 455-461. Divac, I. (1984) The neostriatum viewed orthogonally. In: Functions of fhe Basal Ganglia, CIBA Foundation Symposium 107, Pitman, London, pp. 201-215. Divac, 1. (1988) A note on the h i s t o j of the term ‘prefrontal’. IBRO News, 16: No 2. Divac, 1. and Diemer, N.H. (1980) The prefrontal system in the rat visualized by means of labelled deoxyglucose. Further evidence for functional heterogeneity of the neostriatum. J. Comp. Neurol., 190: 1-13. Divac, 1. and Mogensen, J. (1985) The prefrontal ‘cortex’ in the pigeon. Catecholamine histofluorescence. Neuroscience, 15 : 677-682. Divac, I. and Oberg, R.G.E. (1990) Prefrontal cortex: The name and the thing. In: W. Schwerdtfeger and P. Germroth (Eds.), Sfrucfure and Development of the Forebrain in Lower Vertebrates, Experimenfal Bruin Research Series, Springer-Verlag, Berlin, pp. 213-220. Divac, 1. and Passingham, R.E. (1980) Connections of the mediodorsal nucleus of the thalamus in the tree shrew. 11. Efferent connections. Neurosci. Letf.,19: 21-26. Divac, I. and Warren, J.M. (1971) Delayed response by frontal monkeys in the Nencki Testing Situation. Neuropsychologia, 9: 209-2 17.
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ents to the prefrontal cortex of the cat: a study with the horseradish peroxidase technique. Neurosci. Lett., 11: 115-120. Markowitsch, H.J., Pritzel, M., Wilson, M. and Divac, I. (1980) The prefrontal cortex of a prosimian (Gulugo senegalensis) defined as cortical projection area of the thalamic mediodorsal nucleus. Neuroscience, 5 : 1771-1779. Mogensen, J. and Divac, I. (1982) The prefrontal ‘cortex’ in the pigeon. Behavioral evidence. Brain Behm. Evol., 21 : 60-66. Mogensen, J. and Divac, I. (1984) Sequential behavior after modified prefrontal lesions in the rat. Physiol. Psychol., 12: 41-44. Mogensen, J. and Divac, I. (1993a) Behavioural effects of ablation of the pigeon-equivalent of the mammalian prefrontal cortex. B e h . Bruin Res., 55: 101-107. Mogensen, J. and Divac, I. (1993b) Behavioural changes after ablation of subdivisions of the rat prefrontal cortex. Acta Neurobiol. Exp., 53: 439449. Mogensen, J., Jmgensen, 0,s.and Divac, I. (1982) Synaptic proteins in frontal and control brain regions of rats after exposure to spatial problems. Behm Bruin Rex, 5 : 375-386. Mogensen, J., Ivenen, I.H. and Divac, I. (1987) Neostriatal lesions impaired rats’ delayed alternation performance in a T-maze but not in a two-key operant chamber. Acta Neurobiol. Exp., 47: 45-54. Mogensen, J., Bjdrklund, A. and Divac, I. (1992) Catecholamines and DOPAC in cortical and neostriatal regions during rats’ learning of delayed alternation. Actu Neurobiol. Exp., 52: 4956. Regidor, J. and Divac, 1. (1987) Architectonics of the thalamus in echidna (Tuchyglossus uculeutus): search for the mediodorsal nucleus. Bruin Behm. Evol., 30: 328-341. Rosenkilde, C.E. and Divac, I. (1975) DRL performance following anteromedial cortical ablations in rats. Bruin Res., 95: 142-146. Rosenkilde, C.E. and Divac, I. (1976) Time discrimination performance in cats with lesions in the prefrontal cortex and the caudate nucleus. J. Comp. Physiol. Psychol., 90: 343-352. Rosvold, H.E. and Szwarcbart, M.K. (1964) Neural structures involved in delayed-response performance. In: J.M. Warren and K. Akert (Eds.), The Frontal Granular Cortex and Behavior, McGraw-Hill, New York, pp. 1-15. Sapawi, R.R. and Divac, I. (1978) Connections of the mediodorsal nucleus of the thalamus in the tree shrew. I. Afferent connections. Neurosci. Lett., 7: 183-1 89. Schousboe, A. and Divac, I. (1979) Differences in glutamate uptake in astrocytes cultured from different brain regions. Brain Res., 177: 407-409. Ursin, H. and Divac, I. (1975) Emotional behavior in feral cats with ablations of the prefrontal cortex and subsequent lesions in amygdala. J. Comp. Physiol. Psychol., 88: 36-39. Warren, J.M. and Divac, I. (1972) Delayed response performance by rhesus monkeys with midprincipalis lesions. Psychonomic Sci., 8: 146-147. Wikmark, R.G.E. and Divac, I. (1973) Absence of effect of caudate lesions on delayed responses acquired after large frontal ablations in cats. Israeli J. Med. Sci., 9: 92-97. Wikmark, R.G.E., Divac, I. and Weiss, R. (1973) Retention of spatial delayed alternation in rats with lesions in the frontal lobes. Implications for a comparative neuropsychologyof the prefrontal system. Bruin B e h Evol., 8: 329-339.
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Wartwein G, Mogensen J, Divac, 1. (1994) Retention and relearning of spatial delayed alternation in rats after ablation of the prefrontal cortex or total nonprefrontal isocortex. Behuv. Bruin Res., in press..