An Olfactory Cortex T.

TANABE,

Projection

Area in Orbitofrontal

of the Monkey H.

YARITA,

M.

IINO,

Y. OOSHIMA,

Department of Physiology, School of‘ Medicine, Gunma Prejbctuw, Japan

Gunma

AND

S. F. TAKAGI

University, Madnshi

City,

PHYSIOLOGICAL STUDY of the olfactory sponses of single neurons in the prefronprojection area in the prefrontal cortex tal olfactory area, while applying eight was reported in 1940 by Allen (3, 5). He kinds of odors, are examined, and the refound that the ventrolateral portion of sponse patterns are compared with those the frontal lobe is related to olfaction in of the OB, AP, and the medial portion of both ablation and electrophysiological ex- the amygdala (MA) (44). Preliminary reperiments on dogs. Since Nauta (27, 28) ports of these findings were published states that development of the frontal lobe elsewhere (4 l-43). is incomplete in the dog, it appears that Allen’s experiments to prove an olfactory METHODS area in the frontal lobe are far from conclusive. Animals Since then no further physiological In the acute experiments, 46 monkeys work has appeared on the prefrontal ol- (Macaca mdatta) of 2.5-5 kg from Indonesia were anesthetized with infactory area. However, there have been a were used. They Nembutal (30-35 mg/kg) and, if number of studies of the olfactory system. tramuscular needed, 10 mg of Ketalar (ketamine hydA projection from the pyriform cortex to was added. After the head was the medial nuclei of the thalamus has rochloride) fixed in a stereotaxic instrument, the brain was been shown by several investigators (15, widely exposed. The rectal temperature was 21, 22, 3 1, 36). A projection from the constantly measured, using a thermistor. In thalamic medial nucleus to the orbitofronthe chronic experiments, after monkeys were tal area has been reported (IO, 11, 14, 2 1, anesthetized with Nembutal (30-35 mg/kg), 24-26, 32, 33, 46, 48). Together, these the scalp was incised and a hole was opened observations suggested a pathway from bilaterally just above eac,h of the prefrontal the olfactory bulb (OB) to the anterior cortices with a dental drill. After the dura pyriform (prepyriform) cortex (AP) and mater was incised and the target brain region removed by an aspirator, the inthence, through the thalamic medial nuc- was carefully cised scalp was sewn up. The operation was lei to the orbitofrontal cortex. However, aseptically. this route has never been subjected to a performed physiological study. E let trodes The present study is concerned with the For stimulation, bipolar electrodes were olfactory area in the prefrontal cortex in made of stainless tubes (diameter: 0.4-0.5 mm) the monkey. The location and extent of or tungsten wires with a diameter of 300 pm the area has been determined, and an af- and a tip distance of l-2 mm. Concentric elecferent route to it from the olfactory bulb trodes were made of stainless tubes (diameter: has been traced, using stimulation and 0.6 or 0.7 mm) with an insulated wire in the of each. These electrodes were insuablation techniques. Finally, odor dis- center lated with polyurethan except for the tip part crimination has been compared before of about 0.5 mm. They were used for recordand after the ablation of the prefrontal Using electronic olfactory area. In the next paper, re- ing as well as for stimulation.

A

Received

for

publication

October

29,

19’74.

stimulators (MSE-SR, square pulses of 2-8

Nihon Kohden V and 0.0 l-O.5 ms

Co.) were

1269

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TANABE

applied. The microelectrodes used were made from glass tubing with a diameter of 3 mm, filled with 3 M KCl, and having resistances of 2-10 Ma. Recording Sites of recording were determined by reference to Snider and Lee’s Atlas (39). For recording evoked potentials in the lateroposterior portion of the orbitofrontal cortex, a recording electrode was inserted at about the posterior end of the sulcus principalis (Fig. 1A) to a depth of 1 l- 14 mm from the brain surface. Particularly at the depth of I2- 13 mn, evoked potentials were recorded most strikingly (Fig. 1B). Evoked potentials were recorded in the following sites: in the AP and MA, an electrode was inserted at about the points: A = 13-15 mm (mainly at A = 14 mm) and L = 4-6 mm. Depths were 34-35 mm from the brain surface ( l-2 mm above the cranial floor) in the AI’, and 28-33 m m from the entry point (7-8 mm above the cranial floor) in the MA. These two structures could also be differentiated by changes in the shape of the evoked potentials. In the hypothalamus, an electrode was inserted at A = 13-15 mm and L = O-2 mm to a depth of 23-26 mm; in the MD nucleus of the thalamus, at A = 5.5-9.5 mm and L = O-2 mm to a depth of 16-18 mm; in the entorhinal area (ER), at A = 4-8 mm and L = 6-8 mm to a depth of 32-35 mm. The evoked potentials at ER could easily be differentiated from those at AP by their much longer delays. For recording evoked potentials in the OB an electrode was inserted vertically at. points l-2 mm caudal from the tip of the frontal lobe, and l-2 mm lateral to the midline. The depths were 13-14 mm (l-2 mm above the cranial floor). The points of stimulation in the OB were selected so that the largest amplitude evoked potentials might be obtained in the AP. Histological localization elf recording sites In order to locate the sites where evoked potentials were obtained, DC Currents of 2-5 mA were passed for 5-l 0 s through the recording electrodes for electrocoagulation. After most of the experiments, a potassium ferricyanide solution was topically applied. If necessary, the solution was injected into the common carotid artery after an injection of Ringer solution. The recording sites were marked by a blue stain. In order to destroy a part of the brain tissue, the tube and the internal wire of a concentric electrode inserted were connected and both were made an anode. A silver plate

ET

AL.

electrode was put o11 the superficial temporal muscles as a cathode. Through this circuit, DC currents of 5-l 0 IIIA were passed for 1 O-60 s. For aspirating a part of‘ the brain tissue, glass tubings with tip diameters of’ 1.5-2 mm connected to an aspirator were used. After the aspiration, the same experiment was made as to whether or not the evoked potential which had appeared in the LPOF before could still be elicited by OB stimulation. The brains were taken out and fixed in 10% buffered formalin solution to allow identification of the electrode tips and to confirm the locus aspirated. When necessary, the brain sections were stained with cresyl violet or hematoxylin-eosin. Olfnctory behavior Monkeys have a habit of smelling food before they eat, and they dislike food with a bitter taste. Taking advantage of’ these habits, monkeys were conditioned to avoid small pieces of bread with a bitter taste only by sniffing the smell. The bread pieces used were 1-cm cubes. 111 order to add odors to the pieces of‘ bread, they were dipped in one of the following solutions: a) &camphor solution. (10 -3 with 3% quinine (CQ), /I > isovaleric acid solution ( 10 -d) (V), c) yundecalactone solution ( 10 -‘I) (U), d) r~lethylcyclopentenoloI~e solution ( 10 -3 (C), e) scatol solution (10 +) (S). The original substances or solutions were dilu ted to the respective concentrations in odorless mineral oil, Nujol (Plough, Inc., Memphis, Tenn.). The concentrations used and the abbreviations of the names of the odors are shown in parentheses at the end of each solutio11.

Pieces of bread with the five odors were prepared. Monkeys were trained to discriminate a piece with CQ from a piece with one of the other four odors. 111 this training we were very careful to make certain that the monkeys could not use their sight in the discrimination of the bread pieces. All solutions were made colorless; bread pieces were made as equal in size as possible, and in each trial a piece of bread or two pieces with different odors were put on a tray behind a screen or behind the monkeys just before the tray was presented to them. After a period of training (usually 7-10 days) the monkeys became able to discard bitter pieces of bread by sniffing alone, taking the nonbitter ones into their mouths. In the behavioral studies, seven conditioned monkeys were used. Four groups of bread pieces, each having one of the following odor pairs, were prepared: I) CQ versus V (CQV), 2) Cc) ver4) CQ sus u (CQ:U),3) CQ versus C (CQC),

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OLFACTORY

PROJECTION

versus S (CQS). T wo kinds of tests were performed. The “select.ion of two test” consisted of presenting a monkey, at one time, two pieces of bread, each with one of the above paired odors. The right and left positions on a tray of th e two odorous pie ces were changed according to the Gellerman series. The “one piece test” consisted of presenting a monkey only one odorous piece on a tray at one time according to the Gellerman series. In the former test, the tray with two pieces was presented 10 times a day for 10 days. Therefore, a total of 100 trials were performed for each odor pair. The number of the successful answers was used as a score for that pair. In the latter test, 10 trials were repeated for 5 days and thus, in total, 50 trials were performed. The number of the successful answers shown was used as a score for each odor pair. After the behavioral tests were performed for the four odor pairs, the orbitofrontal cortex was partially ablated bilaterally. Approximately 2 wk after the ablation, the same conditioning tests were given to each monkey for a period longer than the days which were required for the first conditioning; then the real tests were started again. After all these tests were performed, the brains were removed and the parts ablated were examined and located exactly. Also, it was confirmed that there existed no pathological changes (such as a hematoma) which might have influenced the activities of the olfactory tract, the pyriform cortex, or other parts.

AREA

IN

PREFRONTAL

8

LOBE

1271 0

4-

6

-I FIG. 1. Orbitofrontal cortex. A: dorsal surface of hemisphere of monkey. SP: sulc us principalis; S A: sulcus arcua .tus . Area indicated bv hatched lines is where electrode was inserted. R: ‘frontal section of monkey brain at site of electrode insertion. Area indicated by hatched lines is where evoked potentials were recorded. C: diagram of orbitofrontal cortex seen from lower front. Numbers from lot0 I 4 indicate areas classified by Walker (47). Nu mbers from 1 to 6 and letters from a to h show sites of recording. Hatched area (lateroposterior orbitofrontal area or LPOF) is portion in which evoked potentials were obtained due to stimulation of olfactory bulb (OB) as indicated by arrow and S. D: records obtained at sites indicated in C. Evoked potentials are found from b to g and from 2 to 4. Calibrations are 40 ms and 100 pV.

sake of simplicity, the above-indicated areas where the evoked potentials were recorded will be designated as the LPOF. Very similar evoked potentials were obtained in the LPOF when the AP was stimulated (Fig. 2b). However, these poRESULTS tentials were larger in magnitude and apPotentials evoked in orbitofrontal cortex peared with an average delay of 16.5 ms, by electrical stimulation of olfactory i .e., shorter than in the cask of the OB bulb and anterior pyrzyorm cortex stimulation in c. When the OB was stimulated with a Next, evoked potentials were recorded single electric pulse, evoked potentials in the LPOF while stimulating the OB, with an average delay of 24.1 ms and and a third electrode was inserted into the amplitudes of 30-l 10 PV were recorded AP. With this electrode made to act as an ipsilaterally with a concentric electrode in- anode, an electric current was passed to a serted into the lateroposterior area of the silver plate put on the temporal muscles orbitofrontal cortex (Fig. 2~). The sites as a cathode (see METHODS) and the AP where the evoked potentials could be re- (and probably a part of the MA in some corded (Fig. 1D) are shown with hatched cases) was electrocoagulated. After a lines in Fig. 1C. They include the posterior pause, the same electric-pulse was applied part of Walker’s area 12 and the lateropos- to the olfactory bulb, but the evoked poterior par: of area 13 and farther pos- tential was no longer observed in the teriorly, the junctional area between the LPOF (Fig. 2d). In order to confirm that frontal lobe and the temporal lobe and the this result was not due to a shock opercular region of the frontal lobe. How- phenomenon, evoked potentials in the ever, evoked potentials were not obtained lateral olfactory tract on-the electrocoaguin other parts of the frontal lobe. For the lated side and the potentials in the AP-on

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a

d FIG. ‘L. Evoked potentials in LPOF and anterior pyriform cortex (AP). a: evoked potential recorded in AP due to stimulation of OB. b and c: evoked potentials in LPOF due to stimulation of AP and OB, respectively. d: stimulation of the OB no longer elicits a potential in LPOF after AP has been electrically destroyed. Calibrations are 20 ms and 30 pV.

the contralateral side were recorded by stimulating the OB of the respective side. Both potentials appeared strikingly. The outcome of this experiment indicates that the olfactory afferent fibers from the OB to the LPOF pass through the AP (and probably the MA). Potentials evoked in orbitofrontal cortex by electrical stimulation of medial thalamic nucleus

In order to confirm whether or not the fibers projecting from the OB to the LPOF pass the thalamus, the following experiments were performed: stimulating the OB and inserting a recording electrode successively into the whole area of the thalamus of the same side, evoked poten tials were sought an teroposteriorly and mediolaterally at intervals of 1 mm and at the depth of every 1 mm. Evoked potentials were recorded in the mediodorsal (MD) nucleus of the thalamus (Fig. 3a). Actually, the evoked potentials were relativelv unstable and sometimes difficult to obtain. But when a glass capillary microelectrode was inserted into the MD nucieus, spike potentials were recorded from single cells there, with latencies of 8-36 ms. Figure 3c shows such a spike superimposed on the evoked potential and Fig. 3d indicates an increase in the number of spikes

FIG. 3. Evoked potentials in thalamus. a and b: evoked potentials in dorsomedial (MD) nucleus of thalamus due to stimulation of OB and AP, respectively. c and d: responses of single neuron in MD nucleus due to stimulation of OB. Calibrations are 20 ms and 30 PV in a and b, and 20 ms and 100 PV in c and d.

when the stimulus intensity was increased. Figure 3b illustrates the potentials evoked in the MD nucleus by stimulation of the AP with a bipolar electrode. These potentials had short latencies of 7-7.5 ms and could be recorded anteroposteriorly in a relatively broad extent of the medial thalamic region. Next, a bipolar electrode with tips 1.5 mm apart anteroposteriorly was inserted into the MD nucleus for stimulation, and evoked potentials were recorded in the orbitofrontal cortex. Figure 4 designates the site of stimulation of the thalamus in A, and the recording sites in the orbitofrontal cortex in B. In column C the potentials evoked by stimulation of the MD nucleus, and in columned the potentials evoked by stimulation of the OB are shown, respectively. When the MD nucleus was stimulate& evoked potentials were found in the

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OLFACTORY

cl -,-

C

PROJECTION

--

AREA

D

PO qr-

S’

t-

-

4. Stimulation of thalamic MD nucleus. A: frontal section of monkey brain. S indicates site of stimulation. B: sites of recording on the orbitofrontal cortex as indicated by letters. C: records are potentials from a to t due to stimulation of MD nucleus. D: records are potentials at the same sites due to stimulation of the OB. A large potential at n is the compound action potential of the lateral olfactory tract. Calibrations are 20 ms and 30 pV. FIG.

whole extent of Walker’s areas 10 and 11 and in the anterior part of areas 12 and 13 as seen in column C, while they were not observed in those areas indicated in column D. This showed that the projection area of the MD nucleus is the portion of the orbitofrontal cortex anterior and anteromedial to the LPOF. Thus, clear difference was made evident between the projection areas of the OB and those of the MD nucleus of the thalamus. In order to confirm the above result, the following experiment was performed to determine the influence which the destruction of the thalamus may have on the potential evoked in the LPOF by stimulation of the OB. The thalamus was removed by aspiration in three monkeys and was electrically destroyed in two other monkeys. During the course of the removal, an

IN

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1273

evoked potential elicited in the LPOF by stimulation of the OB was used as an indicator. Observing the potential, a glass aspirating pipette with tip diameter of about 1.5 mm was repeatedly inserted into the thalamus in the area from about 12 mm anterior to the intersection of the midline between both hemispheres and the central sulcus, to 2-3 mm posterior to the intersection, and laterally 4-5 mm on both sides. In this way, a considerable area of the thalamus was gradually aspirated, constantly observing whether or not the evoked potential was abolished. This aspiration was also performed in the other side of the brain. However, in none of the three monkeys did the evoked potential in the LPOF disappear. After these experiments, the monkeys were sacrificed and the extent of the thalamus removed was determined. In the first monkey, the anterior half of the thalamus was removed on both sides but the posterior half remained. In the second monkey, the thalamus on both sides was extensively removed except the medial and lateral geniculate bodies. Besides, the entorhinal cortex also was destroyed in the stimulated side (Fig. 5A). In the third monkey, the thalamus was again very extensively removed on both sides, leaving only small parts of the medial and lateral geniculate bodies. Moreover, a lesion was found even in the hypothalamic region in the stimulated side. This monkey will be referred to again in the next . section. In the next two monkeys, the thalamus was destroyed electrically. The concentric electrode was inserted at distances of 1 mm anteroposteriorly, mediolaterally, and vertically. At every insertion of 1 mm, the current was made to flow, examining whether or not the potential evoked in the LPOF by the olfactory bulb stimulation would disappear. However, the evoked potential neither disappeared nor decreased in size during the process of electrocoagulation. After the experiments it was confirmed in these two monkeys that the thalamus was extensively burned and destroyed and that the corpus callosum was partially burned (Fig. 5B). From these results it was concluded that

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evoked potentials could be obtained when the anterolateral portion and the dorsal portion of the posterior half of the hypothalamus were stimulated. In both portions, evoked potentials could be recorded when the OB was stimulated. A stimulating electrode was fixed at a site in the dorsoposterior hypothalamic region, because stimulation of this locus elicited a very clear evoked potential in the LPOF (Fig. 6A). While applying single electric pulses through the electrode, a concentric recording electrode was inserted into the orbitofrontal cortex and evoked potentials were sought, moving the recording electrode extensively (Fig.

C a a

A

FIG. 5. Photographs of sagittal sections of monkey brains. In A, the thalamus was removed by aspiration together with the adjacent part of the corpus callosum and the entorhinal area. The removed portion is outlined by a broken line. In B, the broad extent of the thalamus destroyed by electrocoagulation is shown. The thalamic portion is burned and discolored. Parts of the corpus callosum and cingulate gyrus are also destroyed. The extent of the destroyed area is outlined by a broken line.

the projection pathway from the OB to the LPOF does not pass through the thalamus. Potentials evoked in orbitofrontal area by electrical stimulation of hypothalamus

Applying single electric stimuli to the OB, evoked potentials were sought in the hypothalamus by inserting a concentric electrode. They were found in a rather broad region of the hypothalamus. Next, a recording electrode was inserted into the LPOF. Another electrode was inserted in the hypothalamus, and through this electrode single electric pulses were applied. Moving this stimulating electrode anteriorly or posteriorly, and medially or laterally, the sites of stimulation which could elicit the evoked potentials in the LPOF were sought. It was evident that the clearest

43

C

d

s

x jP

e f

9 h I j k I

m ” a P q r FIG. 6. Stimulation of hypothalamus. A indicates the site of stimulation in the frontal section of the hypothalamus. B is a diagram of the orbitofrontal cortex as seen from the lower front; 18 letters designate the sites of recording. C shows records obtained at sites shown in B. Evoked potentials are observed from I to r (especially at m and n). Calibrations are 20 ms and 30 pV.

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OLFACTORY

PROJECTION

6B, C). It was observed that evoked potentials appear mainly at the posterior portions of Walker’s areas 12 and 13 and only slightly at the medial portion of area 13 and the posterior portion of area 14. In other words, the area in which the evoked potentials are elicited by hypothalamic stimulation overlaps the area in which they are elicited by OB stimulation. Consequently, it is clear that the area of the orbitofrontal cortex in which potentials are elicited by stimulation of the thalamic MD nucleus (Fig. 4) does not respond to the stimulation of the hypothalamus. Next, while observing the potentials evoked in the LPOF by OB stimulation, electrolytic lesions were placed in the anterolateral or posterodorsal portion of the hypothalamus, i.e., the hypothalamic regions from which the largest amplitude potentials can be evoked in the LPOF. Aspiration of the posterior portion of the hypothalamus was also carried out. As a result, the evoked potential in the LPOF dramatically disappeared (Fig. 7). That this result was not due to a shock phenomenon was proved by means of an experiment showing that a large-

FIG. 7. Destruction of hypothalamus. a: photograph to show that the hypothalamic region was destroyed. When the portion indicated by the arrow was electrically destroyed, an evoked potential (shown by c on the right) disappeared completely. a: evoked potential in hypothalamus due to stimulation of OB. b: evoked potential in LPOF due to stimulation of hypothalamus. c and d: evoked potential in LPOF by OB stimulation in c, disappeared in d when the hypothalamic region was electrically destroyed. Calibrations are 20 ms and 30 pV.

AREA

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PREFRONTAL

127.5

LOBE

amplitude potential could be evoked in the pyriform lobe by stimulation of the OB. In the third monkey, in which the thalamus was extensively aspirated (see above), the evoked potential continued to appear. However, when the aspirating pipette was advanced more deeply and anteriorly into the hypothalamic region of the same side, the evoked potential suddenly disappeared. The same finding, that the evoked potential in the LPOF disappears by aspirating or electrocoagulating the hypothalamic region, was obtained in the other four monkeys. From these experiments it was concluded that the projection pathway from the OB to the LPOF passes through the hypothalamic region. Relation between orbitofrontal and entorhinal cortex

cortex

When the ER was electrically stimulated with a bipolar electrode, evoked potentials were recorded at various sites throughout the whole of Walker’s areas 12 and 13 in the orbitrofrontal cortex (Fig. 8B, c-e and g-j). But they were never recorded in the areas 10 and 11 in which large amplitude evoked potentials were obtained by stimulation of the thalamic MD nucleus. When the recording electrode was moved from the anterior end backward to the posterior end of the pyriform cortex, while electrically stimulating the OB, single-peak evoked potentials with latenties of 3.5-7.5 were observed initially (Fig. 8C, a). Such potentials continued to appear until the electrode was moved backward to a certain intermediate point, where the potential suddenly became “double peaked” (Fig. 8 C, b). When the recording electrode was moved farther backward and entered the posterior portion of the pyriform cortex, the first peak disappeared and the second one remained (Fig. 8C, c). The latency of the second peak was as long as 25-40 ms. The recording sites at which only the second peak was obtained corresponded with the ER. From the long latencies of the second peak, it is quite clear that the entorhinal cortex receives no afferents directly from the OB.

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TANABE

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B

B

0 1

b

a

W

b

-

c

-

c

-

d

-

d

-

e

-

f

-

g

7

h

-

i

0

Stimulation of entorhinal cortex (ER) and recording in LPOF in A and L3. B: records obtained at sites designated by letters on the orbitofrontal cortex in A. Evoked potentials are found from c to e and g to j. The site of stimulation is indicated by E. Calibrations are 20 ms and 30 pV. C: evoked potentials in the anterior pyriform and the entorhinal cortices due to stimulation of OB. C, a: evoked potential FIG. 9. Stimulation of LPOF. A: sites of stimularecorded at AP. C, b: evoked potentials in the midcortex with letdle section of pyriform cortex. C, c: evoked potential tion are shown on the orbitofrontal ters; two poles of a bipolar electrode were put in ER. Full explanation in text. Calibrations are 20 mediolaterally. B: records obtained at E in entorhims and 30 pV. nal cortex by stimulation of above sites. Calibrations are 20 ms and 30 +. Further explanation in text. FIG.

8.

’ -+m -I

When these latencies were compared with those of the evoked potentials in the LPOF (24.1 ms), it was found that the former latencies are longer than the latter ones. Besides, it was made clear that the potentials evoked in the LPOF by stimulation of the OB continued to appear even when the ER was ablated. Next, instead of the OB, the various sites (Fig. 9A) of the orbitofrontal cortex were stimulated with a bipolar electrode, and the evoked potentials were recorded in the ER (at E in Fig. 9A). Figure 9B shows that potentials could be evoked by stimulation of points f-m. Since f coincides with the lateral olfactory tract, a large potential elicited by stimulation ofthis site could be easily judged to be different from the other evoked potentials in B. It was shown, therefore, that

evoked potentials appear in the ER only when Walker’s areas 12 and 13 were stimulated in the orbitofrontal cortex. Then, a broad extent of the orbitofrontal area, including these Walker’s areas 12 and 13, were aspirated. In spite of this, potentials in the ER could still be evoked by OB stimulation (Fig. SC, c). From these results it was concluded that there exist reciprocal connections between the entorhinal cortex and Walker’s areas 12 and 13, including the LPOF, and furthermore that the afferent pathway from the OB to the LPOF does not involve the entorhinal cortex, whereas impulse conduction from the OB to entorhinal cortex is independent of the LPOF.

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OLFACTORY

Effects of partial ablation of oditofrontal cortex on olfactory

PROJECTION

AREA

behavior

Since an afferent pathway from the OB to the LPOF was found, the role which the LPOF plays in olfaction was examined in the following experiments: Figure 10 indicates the ablated parts in the frontal lobes of the six monkeys of seven used in this experiment. In M I-M 4, a part of the orbitofrontal cortex was ablated; and in M, and M 7, a part of the dorsal portion of the frontal lobe was removed. In Table 1, the abilities of these monkeys to discriminate odor pairs (see METHODS) are illustrated by comparing preoperative with postoperative scores. The differences between these two values in each odor pair show the decline of discriminative ability. At the bottom of each column, the rate of decrease in such abilities is shown in percent as rate of failure (Q/o)for each of the odor pairs. The abilities were examined in the two tests, selection of two and one piece test, which were explained in the METHODS. As control experiments, the dorsal porMl

M2

M3

M7

FIG. 10. Ablated parts of the monkey brains of M ,-M 7, excepting M 5. Shading indicates resected parts in the prefrontal cortices. All the resected parts except in the case of M5 were confirmed with the naked eye after behavioral experiments. It is seen that parts of the LPOF were adequately removed in M,. In MS, which is not shown here, resection of the same parts as in M, was tried, but not confirmed later. All resections were made with an aspirator. Further explanation in text.

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tion of the prefrontal lobe was partially removed on both sides in M 6 and M 7. After the operation, the monkey M7 displayed hyperactivity and aggressiveness which, however, disappeared after a week. Only in this M 7 animal was lesion found to invade partly into the superior frontal gyrus on the left side (indicated by an arrow in Fig. 10). In the other monkeys, neither that nor any other behavioral changes were observed. The rates of decline in the odor-discrimination performance of these animals were only 3.2 and 5.7%, respectively, in M 6 and 8.1 and 10.4%, respectively, in M 7 , far less than the respective values in the other monkeys (Table 1). In monkey M4 in which the LPOF was adequately ablated (Fig. lo), the rates of failure averaged 66.8% in the selection of two test and 76.1% in the one piece test (Table 1). In MS, a very similar case of removal of the LPOF, the rates of failure were 62.6 and 680/o, respectively. These rates of failure were remarkably higher than those of M 1, M 2, and M 3 in which parts of LPOF had been spared on one or both sides. Even in M4 and M 5, the discrimination between &camphor and scat01 was impaired much less than was that between other odor pairs. For instance, in M4 the failure to discriminate between &camphor and scat01 (CQS) in the two tests amounted to 38.4 and 42.9%, respectively, as compared with the average loss values of 76.3 and 87.1% for the other three odor pairs (Table 1). In M 5, the rates of failure between the two odors (CQS) were 42.4 and 59.1%, as compared with the averaged values of 69.3 and 71.0% for the other three odor pairs. The significance of these results is considered in the DISCUSSION. In monkey Ml, in which a portion anterior to the LPOF was bilaterally removed (Fig. lo), the rates of postoperative decline in the ability of discrimination were generally small in the two tests, i.e., 20.1 and 19.2% in average, respectively. In monkey M2, in which an intermediate portion between the ablated portions of M, and those of M4, as well as part of the LPOF, was bilaterally removed. the rates

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TABLE

1.

Scores of olfactory

behavior

%

%

%

%

%

%

%

AL.

tests

Selection

M f Preop score Postop score Difference Rate of failure, M 2 Preop score Postop score Difference Rate of failure, M 3 Preop score Postop score Difference Rate of failure, Ma Preop score Postop score Difference Rate of failure, M s Preop score Postop score Difference Rate of failure, M 6 Preop score Postop score Difference Rate of failure, M 7 Preop score Postop score Difference Rate of failure,

ET

of Two

CQ:V

CQ:U

CQ:C

CQ:S

88 84 4 4.5 89 56 33 37.1 92 67 25 27.2 83 20 63 75.9 92 12 80 87.0 98 94 4 4.1 94 86 8 8.5

84 68 16 19.0 80 54 26 32.5 91 57 34 37.4 79 30 49 62.0 76 29 47 61.8 90 86 4 4.4 93 81 12 12.9

85 50 35 41.2 81 70 11 13.6 90 72 18 20.0 88 8 80 90.9 93 38 55 59.1 95 94 1 1.1 90 83 7 7.8

89 75 14 15.7 67 32 35 52.2 98 80 18 18.4 73 45 28 38.4 92 53 39 42.4

One Avg

20.1

33.9

66.8

62.6

3.2 93 90 3 3.2

CQ:V

CQ:U

CQ:C

CQ:S

43 33 10 23.3 44 25 19 43.2 48 31

33 28 5 15.2 35 24 11 31.4 41 29 12 29.3 46 9 37 80.4 37 15 22 59.5 45 41 4 8.9 44 39 5 11.4

40 32 8 20.0 38 32 6 15.8 42 29 13 31.0 42 2 40 95.2 44 13 31 70.6 49 47 2 4.1 40 38 2 5.0

44 36 8 18.2 33 14 19 57.6 48 34 14 29.2 35 20 15 42.9 44 18 26 59.1

17 25.8

8.1

Piece Test

35.4 42 6 36 85.7 35 6 29 82.9 48 46 2 4.2 40 36 4 10.0

Avts

19.2

37.0

31.2

76.1

68.0

5.7 46 39 7 15.2

10.4

The preoperative scores show the number of the successful selections before the respective operations, and the postoperative scores show the number after the operation. The difference is the balance between the preoperative and postoperative scores. The rate of failure is the difference divided by the preoperative score. Further explanations are in METHODS and other text. The columns from M , to M 5 show the scores of monkeys with parts of the orbitofrontal cortices ablated. The columns of M 6 and M, show those of monkeys from which parts of the dorsal portion of the prefrontal cortex were resected. See also Fig. 10.

were found to be 33.9 and 37.0%, respectively. These values were worse than the rates of 20.1 and 19.2%, in Ml, but better than the rates of 66.8 and 76.1% in M 4. In M,, in which the left LPOF was completely removed and a part of the right LPOF was ablated (Fig. lo), the rates of failure in the two tests were 25.8 and (Table 1). Con31.2%, respectively sequently, the values of M2 and M3 indicate that the discriminative ability is rather well preserved, as long as a considerable portion of the LPOF is conserved at least on one side. From these experiments, it was concluded that lesions of the orbitofrontal cortex significantly impair olfactory discrimination only when the lesions destroy

the LPOF bilaterally. Further details concerning the olfactory function of the LPOF will be presented in a following paper (44). DISCUSSION

Olfactory projection orbitofrontal cortex

area in

The present experiments disclosed that evoked potentials appear in the area designated as the LPOF of the orbitofrontal cortex of the monkey when the OB or the AP was electrically stimulated (Fig. 1C). Moreover, it was observed that bilateral ablation of the LPOF markedly impairs the monkey’s olfactory discrimination. As mentioned in the beginning, Allen

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(5) recorded evoked potentials in the ventrolateral portion of the frontal lobe when stimulating the pyriform cortex in the dog, but he did not try to delineate this apparent olfactory projection area. So far no one has confirmed his data. It appears that our present experiments in the monkey have confirmed Allen’s observations for the first time, and have also succeeded in outlining the frontal olfactory area (LPOF) from other parts of the orbitofrontal cortex, the ablation of which does not affect odor discrimination. Allen (3) reported the interesting observation that dogs with bilateral ablation of the frontal cortex, despite a severely impaired capacity to discriminate the odor of cloves from that of asafetida, retained their ability to locate meat by smell. Such selective retention of the olfactory recognition of an odor associated with the animal’s needs is reminiscent of Pfaff and Gregory’s (30) finding that a high proportion of cells in the olfactory bulb and preoptic area of the rat respond more readily to urine odors than to artificial nonurine odors. In the present experiments a similar selectiveness was noted; among the odors applied, scat01 can be reasonably assumed to be the most common and familiar to monkeys. Our findings in monkeys with bilateral LPOF ablation showed the ability to discriminate scat01 from &camphor to be comparatively well preserved. Thus, it was thought that the odors which are related to the instincts on food and sex can be discriminated in lower odor olfactory areas, while those not related to these instincts need further processing and can be differentiated only when the LPOF is intact. Although the LPOF has been shown to be an olfactory area in the orbitofrontal there still remains a problem cortex, whether or not this area is specifically related to olfactory function. Allen (4) showed that the ability of conditioned dogs to discriminate auditory stimuli as well as general cutaneous stimuli remained unchanged after the prefrontal lobectomy. As will be shown in a subsequent paper (44), the cells in the LPOF which selectively responded to odors

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never responded to light or sound. Besides, it was shown that the afferent pathway to the LPOF never involved the nonspecific thalamic nuclei, but did pass through the hypothalamus. All these data indicate that the LPOF is a projection area specific to the olfactory modality. The posteromedial region adjoining the LPOF on the medial side has been known as an inhibitory area of the respiratory movement and as a control area of blood pressure (6, 17-19, 34, 40). It is interesting that the inhibitory respiratory area in the orbitofrontal lobe is just ad.jacent to the olfactory area, because smell sensations are well known to modify the respiratory movement and to affect the blood pressure of animals and humans. Thalamoprefrontal

connection

It has long been believed that among the sensory systems, the olfactory system is the only one which reaches the cerebral cortex without passing through the thalamus. Recently, Powell et al. (31) and others (15, 2 1, 22, 36) demonstrated a direct projection from the pyriform cortex to the MD nucleus of the thalamus. In accordance with these findings, responses of single cells in the mediodorsal thalamic nucleus to electrical stimulation of the OB or to odorous stimuli were recorded by us and several other investigators (9, 16, 20, 22) In the MD nucleus the following three cytoarchitectural subdivisions are generally recognized (2, 2 1, 29): 1) A pars magnocellularis is situated in the most medial portion. Benjamin and Jackson (9) and Jackson and Benjamin ( 16) recorded responses of single cells to OB stimulation exclusively in this medial region of the nucleus in both the squirrel monkey and rabbit. The latencies of the spike potentials in the squirrel monkey were 4-50 ms (14 ms in average) in their experiments, and in our experiments in the macaque varied between 8 and 36 ms. Since thev found that these cells did not respond to visual, auditory, or somatosensory stimuli, they concluded that the magnocellular portion of the MD nucleus is a specific locus for olfaction. In this

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connection it is important to recall that this subdivision of the nucleus projects to the orbitofrontal cortex (10, 32). 2) A pars multiformis is situated in the most lateral portion of the nucleus. This subdivision projects to area 8, the “frontal eyefield,” and consequently has been presumed to be related to vision (2, 2 1, 32, 35) 3) A pars parvocellularis occupies the large intermediate region of the MD nucleus. It projects to the dorsolateral convexity of the prefrontal cortex (area 9) (2, 2 1, 32), and may be related to the somatic sensorium (9; cf. ref 12, 13). The aforementioned demonstration of a projection from the pyriform cortex to the medial part of the MD nucleus had led us to expect evidence that the LPOF receives its olfactory input by way of this transthalamic pathway. We were therefore surprised that our findings indicated otherwise; massive destruction of the medial thalamus in our experiments did not block impulse conduction from the olfactory bulb to the LPOF and, moreover, electrical stimulation of the MD nucleus elicited no evoked responses in the LPOF, even though such responses were recorded in orbitofron tal cortical regions anterior and anteromedial to LPOF. The question thus arises as to whether the LPOF receives any projection from the MD at all. The “prefrontal cortex” had been defined as that part of the frontal lobe which receives direct projection from the thalamic MD nucleus (27, 33). The present experiment, however, indicates that there exists an area which is an exception to this definition. It is of interest to recall in this connection that negative findings in retrograde-degeneration studies have led several investigators to suggest that not all regions of the prefrontal cortex receive MD projections (2, 10, 32). Projection prefrontal

of hypothalamic cortex

jibers

to

Histological studies on the olfactory projection to the hypothalamus have been performed by several investigators (7, 3 1, 36). After making a lesion in the AP

ET

AL.

of the rat, Powell et al. (31) traced degeneration of the afferent fibers to the en tire an teropos terior extent of the hypothalamus via the medial forebrain bundle. Scott and Leonard (36) obtained a similar result in the rat. Furthermore, electrophysiological studies proved the existence of such an olfactory projection to the hypothalamus; responses of single neurons were evoked in the hypothalamus by applying odors to the nostrils or electric pulses to the OB (8, 20, 36-38.) Heimer (15) in a degeneration experiment on the rat could not find fibers projecting from the AP to the hypothalamic region. His findings, although arguing against a direct connection between these two areas, do not disprove the possibility of multisynaptic olfactohypothalamic connections. Since our experiment proved that evoked potentials are recorded extensively from the anterior to the posterior portion of the hypothalamus by electrical stimulation of the OB, we must conclude that there exists such a connection between the OB and the hypothalamus via the AP. Projection of fibers from the hypothalamus to the thalamic MD nucleus has long been known (11, 23). Consequently, it is conceivable that the olfactory afferent fibers enter the hypothalamus, and then proceed to the LPOF via the thalamic MD nucleus. However, this was found not to be the case because our experiment ruled out projection of fibers from the MD nucleus to the LPOF. On the other hand, the present experiment proved that stimulation of the hypothalamus evoked potentials in the LPOF. It is supposed, therefore, that the hypothalamus has a fiber connection with the LPOF without passing the MD nucleus. Olfactory pathway from olfactory bulb to LPOF The present findings suggest a conduction pathway passing from the olfactory bulb to the anterior pyriform cortex (and probably the medial region of the amygdala) and thence, sequentially, to the hypothalamus and the orbitofrontal olfactory area (LPOF). The mediodorsal nucleus of the thalamus appears not to be an essential link in this olfactofrontal connec-

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tion, even though there is good anatomical (15, 2 1, 22, 3 1, 36) and physiological (9, 16) evidence that the medial, magnocellular subdivision of the nucleus receives a substantial projection from the pyriform cortex. All of the available evidence suggests that this olfactothalamic connection is part of a subsidiary olfactory conduction channel leading to regions of the orbitofrontal cortex that lie anterior and anteromedial to the LPOF and appear to be much less essential than the latter for odor discrimination. Connection of LPOF with entorhinal area It is well known that the entorhinal area (ER) projects heavily to the hippocampus and dentate gyrus. The anatomical studies of Van Hoesen et al. (45) indicated three cortical areas as direct sources of afferents to the ER. Besides afferents from the prepyriform cortex and ventral parts of the temporal neocortex, a third afferent system was shown to originate in Walker’s areas 12 and 13. Accordingly, our experiments showed that stimulation of these areas 12 and 13 evokes potentials in the ER, whereas stimulation of the other areas in the orbitofrontal cortex does not. The findings of Van Hoesen et al. (45) also indicated that the ER is a final cortical link in the conduction routes from the sensory systems of the neocortex to the hippocampus and the dentate gyrus of the limbic system. Since the LPOF was proved to be an olfactory area in our experiments, it may be said that the ER is a relay area which conveys information from a high-order olfactory area to the limbic system (1). However, since the present experiments indicate that the ER is not involved in the main and specific olfactory pathway, it appears that the entorhinal area does not play a primary role in olfaction.

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tion of the orbitofrontal cortex (LPOF). However, those potentials disappeared when the anterior pyriform cortex (AP) (probably together with the medial portion of the amygdala (MA)) was aspirated or electrically destroyed. 2. In nearly the entire hypothalamic region, evoked potentials were recorded by the same stimulation of the OB. When the hypothalamic region was stimulated, evoked potentials were recorded in the LPOF. 3. The evoked potentials in the LPOF due to the OB stimulation never disappeared even when the thalamus was extensively aspirated or destroyed electrically, but they did disappear when the anterolateral and dorsoposterior portions of the hypothalamus were absorbed or electrocoagulated. 4. Evoked potentials in the mediodorsal nucleus (MD) of the thalamus were recorded when the OB was stimulated. When this nucleus was stimulated, evoked potentials were observed in the broad extent of the orbitofrontal cortex anterior to the LPOF, but never in the LPOF itself. 5. Monkeys were conditioned to discriminate two odors. When the LPOF was removed, such ability strikingly decreased; but when other areas in the prefrontal cortex were removed, the ability decreased only slightly. 6. It was concluded that there exists an olfactory pathway from the OB to the LPOF through the AP (and probably the MA) and the hypothalamus, but none through the thalamus, and that the LPOF plays an important role in the discrimination of odors. 7. It was proved that the entorhinal cortex (ER) is neither located as an intermediate olfactory area nor is it situated as a higher area than the LPOF in the newly found olfactory pathway stated above. It may be a link between the high olfactory area and the limbic system.

SUMMARY

An olfactory projection area was studied in monkeys anesthetized with Nembutal. 2. Evoked potentials were recorded when the olfactory bulb (OB) was electrically stimulated in the lateroposterior por-

ACKNOWLEDGMENTS

We thank Miss Toshi Yajma for preparation the figures and the table, and Reverend Joseph rhardt, O.F.M. for correcting our English. This study was supported by a grant from Ministry of Education of Japan.

of Ehthe

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