Cortical projections of the
thalamic mediodorsal nucleus in
the rat. Definition of the
prefrontal cortex
Ivan Divac1,Jesper ~ogensen',Bosiljka
~ e t r o v i c - ~ i n iKarl
c ~ , zilles3 and Jose ~ e g i d o r ~
'Institute of Neurophysiology, School of Medicine, University of
Copenhagen, Denmark; On leave from Institute of Pathophysiology,
Medical Faculty of Beograd, Yugoslavia; Vogt Institute of Brain
4
Research, University of Diisseldorff, Germany On leave from
Universidad de Las Palmas de Gran Canaria, Spain
Address for correspondence:
Ivan Divac
Institute of Neurophysiology
Panum Institute
Blegdamsvej 3C
DK-2200 Copenhagen N.
Denmark
Abstract. Deposits of somatopetal tracers, that filled the entire
dorsolateral cortex of one hemisphere, labelled only a few cell bodies
in the thalamic mediodorsal nucleus (MD). Further experiments served
to confirm the existence of strong projections from MD to the mesial
and suprarhinal areas of the frontal cortex. Thus, only a very small
proportion of the MD neurones in the rat projects outside the cortical
areas described first by Leonard (1 969). We conclude that at least in
the rat, cortical projections of the MD are selective enough to be used
as the basis for definition of the prefrontal cortex.
Key words: prefrontal cortex, thalamic mediodorsal nucleus,
definition, comparative neurology
426
I. Divac et al.
The possibility to define different areas of the one discovered not only presence of labelled pericerebral cortex for comparative purposes by their karya within the boundaries of the MD after tracer
specific thalamic connections was suggested by injections into cortical areas which were not within
Bonin (1944) and McCulloch (1944). According- the "traditional" PFC boundaries, for example the
ly, Rose and Woolsey (1948) proposed to define insular cortex and the posterior parieto-temporal as"orbitofrontal" area (designating in nonprimate sociation area (review in Markowitsch and Pritzel
brains the equivalent of the primate prefrontal cor- 1979) but also that the area innervated by MD retex, PFC) by essential afferents from the mediodor- ceives afferents from other thalamic nuclei (e.g.
sal nucleus of the thalamus (MD). In comparative Divac et al. 1978). Such evidence lead Leonard
neuropsychology this definition proved useful (1972) to question, and Markowitsch and Pritzel
since thus outlined cortical area has been shown in (1979) to dismiss Rose and Woolsey's definition.
numerous species to mediate the same functions (as The latter authors proposed instead a program of
inferred from consequences of its lesions). Striking study which should make a polythetic definition
examples are studies on monkeys (review in Rosvold possible in the future.
and Szwarcbart 1964), dogs (Lawicka and Konorski
The aim of the present study was to compare
1961, Kosmal 1981), rats (Leonard 1969, Divac 1971), densities of cortical projections of MD to the mecats (Rose and Woolsey 1948, Lawicka and Konorski sial and suprarhinal areas with the projections to the
1965), tree shrews (Passingham 1978, Divac and Pa$- much larger dorsolateral area. We obtained inforsingham 1980) and guinea pigs (Markowitsch and mation about cortical projections of MD by means
Riess 1981).
of three approaches: First, like Krettek and Price
Rose and Woolsey (1948) recognized some (1977), we filled the MD with radioactively labelled
problems with their definition of PFC. First, one aminoacids, looking for the terminal fields in the
must define MD precisely and unequivocally, a cortex. Secondly, as reported previously (Divac et
task which has not been solved yet (Regidor and al. 1978), we filled the frontal lobe with horseradish
Divac 1987). Since cytoarchitecture of MD peroxidase (HRP) and, thirdly, we infiltrated the envaries in different species (e.g. Akert 1964), we tire dorsolateral cortex, excluding the mesial surdefine MD in mammals for comparative purpose face and the banks of the rhinal sulcus, with
as the cell group in the mediodorsal thalamic re- fluorescent somatopetal tracers (Divac et al. 1987),
gion, with rather well defined lateral and ventral and looked for labelling in the MD. The third apborders in the species with easily detectable lami- proach provides new information since in the prena medullaris thalami interna, and a vague caudal vious studies (reviewed in Markowitsch and Pritzel
border (Rose and Woolsey 1948). Secondly, the 1979) only small cortical areas were injected. In that
technique which Rose and Woolsey had used im- way, neurones having sparse projections over large
posed the distinctionbetween "essential"and "sustain- area could not be revealed. Out of a large material
ing" projections of MD: PFC was the area the ablation (Divac et al. 1978, 1987), we have selected three
of which caused degeneration in MD. Ablation of the representative cases to illustrate the relevant obsersurrounding cortex alone did not cause MD degener- vations obtained with three different approaches.
ation but enhanced it when combined with the lesion
Distribution of radioactive label in the rat with inof the "core" area. The assumptions made in order to jection into MD is shown in Fig. 1A,B and C. The label
explain these observations were that some MD neu- is seen in the mesial and ventrolateral cortex of the
rons project not only to the core area but also to the sur- frontal lobe. Other cortical areas showed a density of
rounding cortical belt and that all axon collaterals must silver grains similar to the background level. The data
be cut if a perikaryon is to degenerate.
obtained with leucine and HRP confirm previous deThe somatopetal transport techniques dealt tailed descriptions of MD projections in rats (Leonard
blows to the Rose and Woolesy's definition when 1969, Krettek and Price 1977, Divac et al. 1978).
Fig. 1. Illustration of gross relations between the MD and the cerebral cortex. Left column: cortical efferents of MD; A and B, radioactively labelled mesial and
suprarhinal areas; C, the section with the maximal spread of injected radioactive aminoacids. The medial division of MD in both hemispheres is invaded leading to
bilateral labelling of the lateral PFC. Central column: retrograde labelling in the thalamus following a large injection of HRP into the frontal pole; D, the injection
site; E, a section including MD photographed in dark field; F, detail of the section E. Right column:retrograde labelling in the thalamus followingadeposit of Fluoro-Gold
into the dorsolateral isocortex; G, the extent of the deposit in the frontal lobe; H, a section including MD at approximately the same level as E; I, detail of section H.
428
I. Divac et al.
Earlier studies have indicated projections from
MD not only to its main cortical target but also to
insular, cingulate, parietotemporal "association"
areas, and more recently supplementary motor areas
(Markowitsch and Pritzel1979, Giguereand GoldmanRakic 1988). We are showing now that only a very
small proportion of the perikarya on the territory of
MD projects outside the main target area described
in the rat by Leonard (1969).
If PFC is defined as the cortical target of the MD
then, strictly speaking, all areas which receive MD
innervation, regardless of where they are, should be
considered as the PFC. On the other hand, some cortical zones in the rostral frontal cortex of rhesus
monkeys seem not to receive afferents from MD
(Giguere and Goldman-Rakic 1988), and therefore
are not PFC. Similar discontinuities of MD projections to the frontal cortex have not been seen in the
rat or tree shrew (Krettek and Price 1977, Divac and
Passingham 1980 and the present data) and may be
a primate specialization.
It is difficult to interprete the presence in the MD
of neurones with projections to cortical areas outside the main cortical target of MD. These neurones
may innervate the frontal eye field in the rat (Leonard 1969, Divac et al. 1978). Injection of HRP in
the rat anterodorsal cortex, 4 mm rostral to bregma
and 2 mm lateral to the midline, were found to label
some neurones in the posterolateral region of MD
(Cicirata et al. 1986). Electrical stimulation of the
same cortical spot in the same animals elicited
movements of vibrissae (Cicirata et al. 1986). The
same authors found no MD labelling in cases with
HRP injections in other parts of the somatosensorimotor cortex. The position of MD labelling in their
Figure 4 (Cicirata et al. 1986) is almost identical with
that seen in our Fig. 1H. It should be determined
whether these neurones differ from other MD neurones morphologically,chemically, or in terms of their
afferent innervation. If it turns out that topographically
defined MD consists of two subpopulations of neurones which differ from each other, one could eliminate
the problem of definition of PFC by redefining MD.
If grounds to subdivide MD neurons are not
found, one could define as "prefrontal" that cortical
area which receives afferents from the majority of
MD neurones. Our material shows that the density
gradient is very steep, making the suggested modification of Rose and Woolsey's definition of PFC
feasible.
In conclusion, comparative neurology demands
a way to compare presumably equivalent or at least
similar brain regions in different species. Therefore
a definition of a brain region or system which makes
species comparisons possible is valuable. Before a
polythetic definition becomes available, the definition of PFC as the target of the majority of MD neurons seems acceptable (for further discussion see
Divac and Oberg 1990)
ACKNOWLEDGEMENTS
We are thankful to the Danish Medical Research
Council, Fonden of 1870, Hasselblads Foundation,
Gangstedfonden, Foundation for Experimental Research in Neurology and Ib Henriksens Fond for
financial support, R.Gunilla E. Oberg for comments
on the manuscript, F. Riis for help with photography and M. LQvgreenfor secretarial help.
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Received 7 July 1992, accepted I I November 1992
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