Altered local cerebral glucose utilization by unilateral frontal cortical ablations in rats

Brai~ Re.~earch,343 i ]9~5) ,~- 15 BRE 10986

Altered Local Cerebral Glucose Utilization by Unilateral Frontal Cortical Ablations in Rats SHINICHI HOSOKAWA, MOTOHIRO KATO, YASUTAKA AIKO and FUMIO SHIMA

Department of Neurophysiology, NeurologicalInstitute, Facultyof Medicine, Kyushu University, Fukuoka 812 (Japan) (Accepted December t lth, 1984)

Key words."cortical ablation - - frontal cortex - - local cerebral glucose utilization - [14C]deoxyglucose method - - rat - - corticofugal influence

Alterations in local cerebral glucose utilization (LCGU) foUowingablations of the unilateral frontal cortex in rats were studied to elucidate the effect of the lesion on the functional activity in the related cerebral structures. Frontal cortical ablations (areas 2, 4, 6 and 10) were made by aspiration on the left side, and LCGU was evaluated at 7 days after the operation, using the [14C]deoxyglucose method. Significant decreases in LCGU in rats with unilateral frontal cortical ablations, were observed in the ipsilateral thalamic nuclei (ventroanterior-ventrolateral(VAL), ventrobasal (VB), reticular), red nucleus and pontine nucleus, The ipsitate~'alglobus pallidus showed a significant LCGU increase. The contralateral cerebellar cortex showed a tendency toward a decrease in LCGU. The striatum, which receives direct projections from the frontal cortex, showed no LCGU change. These results indicated that ablations of unilateral frontal cortex in rats produced LCGU changes in the cerebral structures which have direct or indirect neuronal:connections with the ablated area. These LCGU changes were, for the most part, brought about by alteration in the neuronal activity; Particularly, the LCGU increase in the gtobus pallidus which receives transsynaptic neuronal input from the frontal cortex, without changes in the striatum, which receives direct projection, was attributed to the functional alteration of the globus pallidus produced by the cortical ablation. Destructive lesion of a cerebral structure, therefore, does not necessarily cause functional depressions in the pertinent structures, but it may enhance the function of some sti'uctures, depending on the functional characteristics of each neuronal connectionand functional organization of those structures. INTRODUCTION Functional alterations can occur even at some distant pertinent structures following a localized cerebral lesion 30. This ' r e m o t e effect' has been docum e n t e d not only by clinical observations~S,19,22,30, but also by experimental studies using both electrophysiologicaP 6 and metabolic s methods. Although this effect has b e e n thought to be mediated by n e u r o n a l fiber connections16, the exact underlying mechanism has not b e e n clearly defined. While m a n y studies 18A9,22,30 have shown that a localized cerebral lesion induces functional depressions in the pertinent structures, functional e n h a n c e m e n t s have not been well documented. Since the d e v e l o p m e n t of the [14C]deoxyglucose method27, local cerebral glucose utilization ( L C G U ) has been successfully used as a parameter of local

brain activities. In order to document 'remote effect' of a localized alteration of the cerebral function, under experimental conditions, the [14C]deoxygtucose method has proved to be a potential tool 5-6.8A1,12.2~. These studies revealed L C G U changes in the cerebral structures which are functionally related t o the area of original dysfunction. Stimulations o f localized areas of brain structure and inductions of focal seizures caused increases in LCGUS.6,11,12,251 and destructive lesions usually led to decreases in L C G U in the pertinent structures 8.2~. In our foregoing study 13, we observed L C G U changes following unilateral electrolytic lesions in the striatum, together with their approximate time course. The L C G U changes were most remarkable at 7 days after the lesion. They consisted of L C G U increases in the ipsilaterai globus pallidus, entopeduncular nucleus, and substantia nigra pars reticutata

Correspondence: S. Hosokawa, Department of Neurophysiology, Neurological Institute, Faculty of Medicine, Kyushu University 60, Higashi-ku, Fukuoka 812, Japan. 0006-8993/85/$03.30© 1985 Elsevier Science Publishers B.V. (Biomedical Division)

along with decreases in LCGU in the ipsilateral thalamic nuclei and lateral habenula. These LCGU increases may result from an increased neuronal firing as a result of a decreased inhibitory neuronal input from the striatum, which is mediated by GABA t3`15,3e. However, the possibility of metabolic changes accompanying reinnervation after lesions or glial hyperfunction has not been completely ruled out.

To obtain further insight into the underlying mechanism of the alterations in LCGU after striatal lesions l-~, the present study was designed to examine the effect of a localized cerebral lesion on LCGU in the target structures which receive mostly excitatory neuronal input from the lesioned area. Therefore, we investigated the effect of ablations of the unilateral frontal cortex upon LCGU in the pertinent structures in the rat brain, and compared the findings with those of striatal lesions 13. The frontal cortex presumably sends a glutamate-mediated excitatory input to the striatum 2°, and is one of the major sources of neuronal input into the basal ganglia. The results were evaluated at 7 days after the cortical ablation, the same interval as in the case of striatal lesions 13. MATERIALS AND METHODS

Ten male Sprague-Dawley albino rats, weighing between 265 and 315 g, were used. Ablations of the unilateral frontal cortex were made in 5, and the other 5 served as the controls. The control rats received scalp incision and bone removal on the frontal area 7 days before the LCGU study. When the frontal cortex ablations were to be made, the rats were anesthetized with pentobarbital, 30 mg/kg, i.p. and placed in a stereotaxic apparatus. After the scalp incision and bone removal, the frontal cortex was ablated by aspiration with a blunted 20gauge hypodermic needle under an operating microscope. The ablation was made from the frontal pole to the bregma, from the midline to the most lateral part of the cortex. The lesioned area was protected with Gelfoam after the aspiration, and the scalp was closed by stainless steel clips. LCGU was measured at 7 days after the operation. The method of LCGU determination has been described in detail by Sokoloff et al. 27. In brief, the animals were deprived of food for at least 10 h prior to

the study, then were anesthetized with halothane. Polyethylene catheters were placed in the femoral vein and artery for intravenous administration of the isotope, and for blood sampling, respectively. The rats were then restrained with a loose-fitting cast placed around the lower abdomen, pelvis and legs, and were allowed to recover from anesthesia for at least 2 h. LCGU determination was conducted with the animal fully alert. A bolus of 2-deoxy-D-[1-14C]glucose ([14C]DG) (200 uCi/kg) (Amersham, 59 mCi/nmol) was injected through the femoral vein catheter. Timed arterial blood samples were collected into heparinized microfuge tubes. The sequential plasma concentration of [14C]DG was measured by a liquid scintillation counter and the plasma glucose concentration by a Beckman glucose analyzer. Forty-five minutes after the [14C]DG injection, the animals were decapitated, and the brains were immediately removed, and frozen instantaneously by dipping into isopentane chilled to -25 °C with dry ice. Later, the frozen brain was serially sectioned at 30 /~m thickness in a coronal plane, using a cryomicrotome (American Optical, Cryocut I1) at -30 °C. At every fifth slice, the section was taken on microscope slides, and dried immediately at 50 °C. These sections were placed on single-coated X-ray film (Sakura Medical X-ray Film, type C) along with standard disc plates in which the concentration of 14C had been calibrated. Exposure time was about 14 days. Selected sections corresponding to the autoradiographs, were stained with Nissl's and Bodian staining. The optic density of autoradiographs was measured bilaterally in 21 cerebral structures with a microphotometer (Sakura PDS-15). The autoradiographs thus obtained were analyzed visually and by quantitative measurement of LCGU. LCGU was calculated from the brain concentration of 14C and the plasma concentrations of [14C]DG and glucose, according to the equation developed by Sokoloff et al. 27. The value of the lumped constant used in this study was 0.48. Statistical analysis of LCGU values was made using Student's t-test. RESULTS

Behavioral changes Within a few hours after unilateral frontal neocor-

10

tical ablations, the rats were able to support their weight and to walk. All animals showed compulsive circling movement which was directed ipsilaterally to the side of neocortical lesion. Signs of motor paralysis were absent. The circling movement disappeared within 2-3 days after the operation, thereafter the animals behaved quite normally. At the time of L C G U study, at 7 days after the lesion, any asymmetry of placing and grasping reactions, and of the muscle was absent. Asymmetry of the response to sensory stimulation, or the preferred use of the unilateral limb was never evident.

Histological changes In all the rats at 7 days after the ablations, the major area of ablation was confined to the cortex in the left frontal lobe. Cytoarchitectonic areas 2, 4, 6 and 10 (after Krieg 17) were ablated in most of the animals (Fig. 1). Areas 1 and 3 were also included in some animals. The ablated cortical area was sharply demarcated, and tissue damage or gliosis was not evident in the surrounding area of the lesion. In the ventroanterior-ventrolateral (VAL), ventrobasal (VB) and reticular thalamic nuclei, the number of large nerve cells was reduced, and several spots of gliosis, composed of microglia and astrocytes, were observed on the lesioned side (Fig. 2). There was no evidence of

edema in any structure, and no obvious histological changes in the striatum, globus pallidus, red nucleus, pontine nucleus and cerebellar cortex, in the Nissl's and Bodian stained sections.

Visual inspection of the autoradiographs In the cerebral cortex, the widespread cortical area surrounding the lesion showed decreases in L C G U in 3 out of 5 rats, which extended to the ipsilateral parietal and temporal cortices. These cortical L C G U decreases were minimal and restricted in two rats. The striatum, which receives direct projections from the cerebral cortex, showed no change in L C G U pattern, in all the areas including the rostral and caudal parts, compared with the contralateral intact side and the controls. However, the ipsilateral globus pallidus, which receives projections from the striatum, showed an obvious L C G U increase, compared with the contralateral intact side (Fig. 3). In the thalamus, most of the ipsilateral VAL and VB and reticular thalamic nuclei showed L C G U decreases, compared with the contralaterat side. However, the small spotted-like activated areas were observed in these nuclei, which corresponded to the area of gliosis in the histological section. The ipsilateral red nucleus and pontine nucleus also showed L C G U decreases, in all the animals, compared with the contralateral side. In the cerebellum, the contralateral paravermal area, especially the granular layer, showed lower L C G U than the ipsilateral side in two out of 5 rats. Other brain structures, such as hippocampus, amygdala, substantia nigra, subthalamic nucleus appeared normal in rats with frontal cortical ablations.

Quantitative analysis of L C G U

Fig. 1. Schematic drawing of the dorsal aspect of rat brain showing the extent of ablated cytological areas (after Krieg~7) in the left frontal cortex.

The mean L C G U values for the control rats and those with frontal cortical ablations are shown in Table I. Significant decreases in LCGU in the ablated rats, in comparison to the controls, were observed in the VAL (P < 0.05), VB (P < 0.05) and reticular (P < 0.001) thalamic nuclei, pontine nucleus (P < 0.01), all on the ablated side. The ipsilateral globus pallidus, on the other hand. showed a significant L C G U increase (P < 0.05), compared with the controls. The ipsilateral red nucleus showed significantly lower L C G U values than the contratateral intact side (P < 0.0017, although comparisons with the

11

Fig. 2. Nissl-stained histology in the ventral thalamus (A, B), and globus pallidus (GP) (C, D) in coronal planes of rats brain with unilateral frontal cortical ablations. The ventroanterior-ventrolateral (VAL) and ventrobasal (VB) thalamic nuclei (arrows) on the side of lesion (left side) (A) show some neuronal loss and glial proliferation, compared with the contralateral intact side (right side) (B). The globus pallidus on the lesioned side (left) shows no apparent histological change (C), compared with the contralateral intact side (right) (D). x 24.

controls did not reach to the significant level in these structures. The contralateral cerebellar cortex showed a tendency toward lower L C G U values (P < 0.1), compared to the ipsilateral side. In all other structures on the ipsilateral side, including the striatum, and all structures on the contralateral side, except for the cerebellar cortex, there were no alterations in L C G U , as compared with the controls. DISCUSSION

Effects of ablations of the unilateral frontal cortex on LCGU The present study clearly revealed metabolic changes in several pertinent cerebral structures following ablations of the unilateral frontal cortex. This result supports our previous observation13 that a lo-

calized cerebral lesion induces L C G U changes in structures which receive neuronal input directly or indirectly from the lesioned area. L C G U changes in most of the structures were probably mediated by orthodromic or antidromic monosynaptic neuronal connections from the frontal cortex ( V A L 24, VB 9 and reticular t4 thalamic nuclei, red nucleus 4, pontine nucleus2). However, a significant L C G U increase in the ipsilateral globus pallidus, and a tendency toward a decrease in the contralateral cerebellar cortex were attributed only to polysynaptic connections. Most of these structures showing L C G U changes are in good agreement with changes seen with motor cortex stimulation25, and with experimental focal motor seizures originating from the motor cortexS,6. Our previous study 13 showed that, after unilateral electrolytic lesions in the striatum, L C G U increased

12 in the ipsilateral globus pallidus, e n t o p e d u n c u l a r nucleus and substantia nigra pars reticulata, and decreased in the ipsilateral thalamus ( V A L / V M ) and lateral habenula at 7 days after operation, the same interval as in this study. The c o m m o n findings between the present and the previous study are the

L C G U changes in the globus pallidus and V A L thalamic nucleus. This indicates that the L C G U changes in the two structures after the cortical ablation were mediated through functional changes in the striatum. Increased L C G U in the entopeduncular nucleus and substantia nigra pars reticulata were observed only

Fig. 3. Representative autoradiographs in rats at 7 days after ablations of the left frontal cortex. The striatum, globus pallidus, thalamus (VAL, VB), red nucleus, pontine nucleus, and cerebellar cortex are indicated by arrows in A, B, C, D, E and F; respectively. The left sides of the brain are represented by the left side in the autoradiographs. The darker areas indicate higher LCGU. Note the de: creased LCGU in the ipsilateral thalamus (VAL, VB), red nucleus, and pontine nucleus, compared with the contralateral intact side, and also the decreased LCGU in the contralateral Cerebellar cortex. The ipsilateral globus pallidus rather shows a LCGU increase~ compared with the contralateral side. The striatum does not show any LCGU change (A, B).

13 TABLE I Altered local cerebral glucose utilization (umol/lO0 g/rnin) in rats with ablations o f unilateral frontal cortex ( 7 days alter lesions)

Values represent the means _+ S.E.M. of LCGU (umol/100 g/min). VAL, ventrolateral-ventroanterior nuclear complex: VB. ventrobasal nucleus; MD, mediodorsal nucleus. Control (n = 5)

Sensorimotor cortex Nucleus accumbens Striatum Globus pallidus Entopeduncular n. Subthalamic nucleus Substantia nigra Pars reticulata Pars compacta Red nucleus Thalamus VAL VB MD Reticular n. Lateral habenula Amygdala Hippocampus Superior colliculus Cerebellum Cortex Nuclei Pontine nucleus Internal capsule

Frontal ablations (n = 5~

Right

Left

Intact side

115+3 80 _+ 3 90+8 56_+ 3 45_+4 87-+3

116+6 84 + 3 94-+7 56 _+ 3 43_+4 89_+3

l18_+N 79 _+ 7 99_+7 60 -+ 2 4724 91 _+2

73 ± 5 92+9 84 _+ 8~f 5326 91 _+2

70 ± 4 76 -+ 5 85 + 7

69 -+ 4 76 _+ 5 85 + 4

74 -+ 4 78 -+ 5 97_+ 5

69 _+4 77 _+4 S0 _+ 3a

113_+4 112_+ 3 109 _+ 10

112_+3 110_+ 3 108 _+ 9

97+_5 ~.,' 92 _+ 5~,c 96 _+ 5 872 2 ~'d 145 _+ 5 86 + 7 91 ± 8 99+4 74 _+ 3 136 + 5 7 0 + 5 t'~' 27± 1

114_+4

115-+2

148 ± 6 77 -+ 3 86_+4 96±6

152 + 5 77 + 2 85_+3 98±5

122_+5 120 +_ 5 103 -+ 4 120_+5 1,15 ± 7 93 ± 7 89_+5 95+ 7

70 _+ 8 146_+ 13 93_+2 25_+ 1

70 _+ 8 149 ± 14 92+_ 1 25_+2

63 _+ 3 133 + 3 93_+2 27+2

Lesion side

P < 0.001; b p < 0.01; c p < 0.05 (significant difference from controls). d p < O.tlO1; c p < 0.01 : f P < 0.05 (significant difference from contralateral intact side).

with the striatal, and not with the cortical lesions.

out the overall L C G U changes in this nucleus. O n the

T h e s e findings suggest that the t r a n s s y n a p t i c n e u r o -

o t h e r hand, cellular c o m p o s i t i o n of the globus palli-

nal input f r o m the frontal c o r t e x t h r o u g h the s t r i a t u m

dus a p p e a r s to be simpler. M o s t of its input c o m e s

is m a i n l y t r a n s m i t t e d to the globus pallidus and V A L

f r o m the s t r i a t u m and its o u t p u t is t r a n s f e r r e d to the

t h a l a m i c nucleus, and the t r a n s m i s s i o n to the o t h e r

t h a l a m u s and to the m i d b r a i n >. Similar findings w e r e

nuclei in the basal ganglia is r a t h e r m i n o r .

r e p o r t e d by o t h e r w o r k e r s 31. A unilateral lesion of

L C G U changes did not a p p e a r in the s t r i a t u m , but

the substantia nigra by perinigral i n j e c t i o n of 6-hy-

L C G U significantly i n c r e a s e d in the globus pallidus.

d r o x y d o p a m i n e caused L C G U increases in the glob-

This was r a t h e r surprising, b e c a u s e the s t r i a t u m re-

us pallidus but not in the s t r i a t u m which r e c e i v e s di-

ceives direct e x c i t a t o r y input f r o m the frontal cor-

rect p r o j e c t i o n f r o m the substantia nigra.

texS4 while the globus pallidus r e c e i v e s p r o j e c t i o n

This study also d e m o n s t r a t e d that the d i r e c t i o n of

f r o m the s t r i a t u m , not directly f r o m the cortex2% T h e

L C G U changes following the c e r e b r a l lesion is not

lack of L C G U

c h a n g e s in the s t r i a t u m m a y result

u n i f o r m . M o s t of the L C G U c h a n g e s f o l l o w i n g abla-

f r o m the c o m p l e x i t y of functional c o m p o s i t i o n of this

tions of the unilateral frontal c o r t e x w e r e d e c r e a s e s ,

nucleus m,:% A l t h o u g h the g l u t a m a t e - m e d i a t e d excitatory n e u r o n a l input f r o m the c o r t e x to the s t r i a t u m

e x c e p t in case of the globus pallidus. This diversity of

is a s s u m e d to d e c r e a s e in the p r e s e n c e of cortical le-

the d i r e c t i o n of L C G U changes is, again, in g o o d a g r e e m e n t with the case of striatal lesions~< T h e s e

sions, the e x c i t a t o r y and i n h i b i t o r y e v e n t s in v a r i o u s

findings indicate that a localized c e r e b r a l destructive

cellular c o m p o n e n t s within the s t r i a t u m m i g h t cancel

lesion does not necessarily depress the activity in the

14 pertinent structures, but it can enhance the activity in some structures. The cause of this diversity of LCGU changes may result from differences in functional characteristics of each neuronal connection, excitatory or inhibitory, or in the functional organization of that structure.

Mechanisms of LCGU changes following ablations of the unilateral frontal cortex We should consider several underlying processes for the mechanism of L C G U changes following ablations of the unilateral frontal cortex. Firstly, the metabolism underlying synaptic neuronal activity has been considered to play a major part in L C G U in that area 2~. Therefore, L C G U changes in a structure following the cortical ablation can be attributed to changes in either presynaptic or postsynaptic neuronal activity in that structure 3. Secondly, the metabolic changes secondary to the morphological alterations induced by the lesion, such as neuronal loss or gtial proliferation 7 have to be considered. Finally increases in metabolism may occur due to the process of reinnervation after lesions >. In the present study, the observed neuronal loss in the thalamic nuclei (VAL, VB) may account, in part, for the decreased L C G U in these areas. However, the absence of morphological changes in the other structures suggests that most of the L C G U changes following the cortical ablations primarily reflect alterations in neuronal activity in these areas. Moreover, in the absence of L C G U changes in the striatum which receives the direct cortical projection, LCGU increases in the globus pallidus and decreases in the other structures. These diversities in the direction of L C G U changes can be explained by differences in the functional characteristics of each neuronal connection or in the functional organization of that structure. In particular, increased L C G U in the globus pallidus which receives transsynaptic neuronal input from the frontal cortex, and without the changes in the striatum which receives direct projection, cannot be explained by the morphological or metabolic changes related to the reinnervation and

most probably reflects changes m the nemonal activity. Cooper et al. 7 reported an increase m 2-dcoxyglucose uptake in the ipsilateral thalamic nuclei al 2 weeks after neocortical ablations. However, since their study was done with rats under deep anesthesia. interpretation should be made with caution. As reported by Agranoff and Frey l, not only the primary site of injury but also its projection site is refractory to the suppressive effect that barbiturates have on normal neuropils, and which may reverse the asymmetry of LCGU. Therefore, to evaluate the L C G U changes following ablation of the frontal cortex, consideration has to be given to a number of other factors, including the type of lesion 21, use of anesthesia 7, and the interval after producing the lesion 26. In the present study, the cortical ablation was made by aspiration, and L C G U was measured 7 days following the ablation, in conscious rats. In conclusion, ablations of unilateral frontal cortex in rats produced LCGU changes in the cerebral structures which have direct or indirect neuronal connections with the ablated area. These LCGU changes were, for the most part, brought about by the alteration in the neuronal activity. Particularly, the LCGU increase in the globus pallidus, without the changes in the striatum which receives the direct projection. was attributed to the functional alteration of the globus pallidus produced by the cortical ablation. These destructive lesions of a cerebral structure do not necessarily cause functional depressions in the pertinent structures, but may enhance the function in some structures, depending on the functional characteristics of each neuronal connection and functional organization of the structures ACKNOWLEDGEMENTS This study was supported in part by grants from The Ministry of Education, Science and Culture (Dynamic Neural Mechanism of the Brain, Grants 58106003 and 59770555), Japan. We thank M. Yoneda and K. Hatanaka for technical assistance, and M. Ohara for reading the manuscript.

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