The effect of sequential lesioning in the basal forebrain on cerebral cortical glucose metabolism in rats. An animal positron emission tomography study

Brain Research 837 Ž1999. 75–82 www.elsevier.comrlocaterbres

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The effect of sequential lesioning in the basal forebrain on cerebral cortical glucose metabolism in rats. An animal positron emission tomography study Yukinori Katsumi a , Takashi Hanakawa b , Hidenao Fukuyama b, ) , Takuya Hayashi a , Yasuhiro Nagahama a , Hiroshi Yamauchi a , Yasuomi Ouchi c , Hideo Tsukada c , Hiroshi Shibasaki

b

a

b c

Department of Neurology, Faculty of Medicine, Kyoto UniÕersity, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan Department of Brain Pathophysiology, Faculty of Medicine, Kyoto UniÕersity, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8397, Japan Positron Medical Center, Hamamatsu Medical Center and Central Research Laboratory, Hamamatsu Photonics, Hamakita, Shizuoka, Japan Accepted 20 April 1999

Abstract We studied the effect of the cortical projection from the basal forebrain on the cerebral cortical metabolism using positron emission tomography ŽPET. with w18 F x fluorodeoxyglucose. Unilateral damage of the nucleus basalis magnocellularis ŽNBM. did not cause a permanent reduction of cortical metabolism: recovery was observed 4 weeks after the operation. Destruction of the contralateral side after recovery from unilateral damage produced persistent bilateral suppression of glucose metabolism, with partial recovery. We speculate that recovery from the unilateral NBM lesions is partly ascribable to the cholinergic projection from the contralateral NBM, and partly due to non-cholinergic systems, and conclude that bilateral damage might be responsible for persistent cortical glucose metabolism suppression. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Cholinergic neuron; Nucleus basalis magnocellularis; Positron emission tomography; Cerebral metabolic rate of glucose

1. Introduction The frontal and parietal cortices receive dense cholinergic projection from the nucleus basalis magnocellularis ŽNBM. w3,14,20,32,33x. Destruction of the NBM reduced the cerebral metabolic rate of glucose ŽCMRglc. and choline acetyltransferase ŽChAT. activity in the frontal and parietal cortices. The NBM in rats corresponds to the nucleus of Meynert in humans. Unilateral lesions of the NBM in rats decreases the CMRglc in the ipsilateral frontal cortex, but the CMRglc recovers over the course of a few weeks w7,8,19,22,24x. Considering the persistent CMRglc suppression in the cortex in Alzheimer’s disease, this temporary CMRglc suppression after cholinergic deprivation suggests that the pathology of the nucleus of Meynert may make a small contribution to the cerebral cortical metabolic suppression in Alzheimer’s disease w30,31,41x. Concerning the recovery of ChAT activities, various causes have been proposed, including compensation mechanisms involving the intrinsic cholinergic inner-

vation w6x, reorganization of cholinergic synapses in the cerebral cortex w7x, increased activities of nerve growth factor w36,37x, sprouting of spared axons from the lesions w11x, or contralateral hemispheric effect w5x. There have been no reports on the recovery mechanism of the CMRglc in the rats. In baboons, however, the possibility of the contralateral compensation via the corpus callosum was suggested w43x. In order to clarify whether the contralateral NBM plays an important role in cortical CMRglc recovery, we performed the following operations on rats: at first, unilateral lesions were made in the NBM, and the contralateral NBM was damaged 4 weeks later, when decreased cortical CMRglc had recovered to within the normal range. We measured the CMRglc of the frontal cortex of these rats 3 days and 4 weeks after the second operation using positron emission tomography ŽPET. with w18 F x fluorodeoxyglucose ŽFDG..

2. Materials and methods )

Corresponding author. [email protected]

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q 81-75-751-3202;

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Eight male Wistar rats Žbody weight: 250–300 g. were used. In these rats, a unilateral Žleft side. NBM was first

0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 5 3 0 - 9

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injured by the injection of ibotenic acid. Based on our previous study w24x, CMRglc in the ipsilateral frontal cortex was expected to recover to within normal range by 4 weeks after the unilateral NBM destruction. Then the rats were divided into two groups. In Group 1 Ž n s 4., the contralateral NBM was damaged by the injection of ibotenic acid 4 weeks after the first operation. Group 2 Ž n s 4. were used as sham-operated control. 2.1. Injury of the NBM In the first injuring of the NBM, rats were placed in a stereotaxic apparatus Žincisor bar 3.3 mm below interaural line. under mild pentobarbital anesthesia Ž20 mgrkg.. Lesions of the NBM were made by stereotaxically injecting 0.1 ml of 2% ibotenic acid dissolved in 0.1 M phosphate buffered saline ŽPBS. with a Hamilton microsyringe. The coordinates were 1.4 mm posterior to the bregma, 2.8

mm lateral to the midline, and 6.9 mm beneath the surface of the brain, according to the rat brain atlas w26x. The needle was kept for 5 min at this point to avoid the backflow along the injected needle track and after that, the needle was slowly removed. In the second operation on the NBM in Group 1 rats, contralateral lesions were made in the same manner as in the first operation. Sham-operated rats of Group 2 were injected with 0.1 ml of 0.2 mM thiamine pyrophosphate dissolved in 0.1 M PBS. 2.2. PET studies PET with FDG was used to evaluate CMRglc in the cortex of rats 3 days and 4 weeks after the second operation in both groups. Rats were not fed for 24 h before the PET scan in order to stabilize the plasma glucose level. PET scan data consisting of seven slices were obtained

Fig. 1. Scheme of the experiment. Four weeks after the first operation on one side, we made a lesion on the contralateral basal forebrain nucleus by ibotenic acid ŽA. or thiamine pyrophosphate as the control ŽB.. PET was done 3 days and 4 weeks after the second operation.

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using SHR-2000 ŽHamamatsu Photonics, Hamakita, Japan. with a full width at half maximum ŽFWHM. of 3 mm in the transverse and 4.8 mm in the axial direction w40x. Under pentobarbital anesthesia, two polyethylene catheters Ž24-gauge. were inserted into a femoral artery and a femoral vein, respectively. The former was used for sampling arterial blood and monitoring the blood gas of the rats, and the latter for FDG administration. The head of the rat was positioned in the tomograph gantry using a customized head holder for fixing the head horizontally. Prior to FDG administration, a 20-min transmission scan with 68-Ger68-Ga was carried out for the attenuation correction. After intravenous administration of 37 MBq Ž1 mCi. of FDG, arterial blood sampling was done manually every 10 s for the first 1 min, and then at 1.5, 2, 3, 5, 10, 20, 30, 40, 50 and 60 min. Collected samples were centrifuged without delay, and used to measure plasma radioactivity and glucose concentration. Blood gas analysis was done periodically during the dynamic scan to monitor the physiological conditions, which were all within normal ranges, including PaO 2 and PaCO 2 . Body temperature was

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monitored using a rectal thermal electrode, and maintained at about 378C using a heating pad. The plasma glucose concentration was measured before and after the scan and the average value was adopted as the plasma glucose level. Dynamic scans were obtained over a period of 60 min, as a series of frames of 2-min duration just after the FDG administration. Scan data were prefiltered with Butterworth filter and reconstructed using Shepp–Logan filter. Images were reconstructed as a matrix of 50 = 50 with a pixel size of 1 = 1 mm. After the second PET scan, each brain was resected for histological examination. Serial brain tissue sections were stained with hematoxylin and eosin to check the position and the extent of the injury at the injection site. The time schedule of the operations and PET measurements is depicted in Fig. 1. 2.3. Determination of regions of interest (ROI) Before PET scanning, T2-weighted magnetic resonance imaging ŽMRI. Ž0.3 T MRP7000AD; Hitachi Medical,

Fig. 2. MRI and ROI. Upper image: MRI corresponding to PET slice. Middle: ROIs were determined on the averaged image of the last 20 min of the PET scan superimposed on the relevant MRI. Lower: three representative PET slices of the brain, which were calculated from dynamic scan images added for 20 min since 40 min after FDG injection. Note the high accumulation of FDG in Haderian glands Žsingle arrow. in the left side image. Parietal lobes were distorted by the ibotenic acid injection Ždouble arrow. in the middle of the image.

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Tokyo, Japan. was carried out to determine the ROI accurately on the frontal lobes ŽFig. 2.. The acquisition parameters of MRI were TR s 200 ms, TE s 23 ms, 458 flip angle, 2-mm slice thickness with no gap, producing a 256 = 256 matrix image. The anesthetized rat was placed in an MRI scanner fixed with the same head holder as that used for the PET scan. Marks were set using a capsule containing Vitamin E on the ear bar of the head holder to match the baseline of the MRI image with the PET data. After finishing the PET scan, MRI images were coregistered to the set of PET data using software that we developed w23x. ROIs were determined on the MRI image containing the frontal lobe. The ROI size was within the range of 28 = 28 pixels, 28–32 mm2 in actual size, and the ROIs were applied to the corresponding set of PET data, which consisted of 30 dynamic PET scans. Therefore, we obtained 30 serial brain activity measurements for each ROI, and these were utilized to calculate CMRglc. 2.4. Calculation of CMRglc We calculated the CMRglc using the Patlak graphical method w25x, because fitting by the non-linear least squares method in determining the metabolic rate constants produced unstable results in some cases w42x. The dynamic frame data divided by the plasma FDG radioactivity were plotted against the integrated plasma FDG radioactivity divided by the plasma FDG radioactivity for each time point. The slope of the line fitting on these plots provides the value of K 1U k 3rŽ k 2 q k 3 ., so we calculated the CMRglc using this value divided by the lumped constant Ž0.58. w18x and multiplied by the plasma glucose concentration. 2.5. Statistics We evaluated the differences between the CMRglc values of the frontal lobes by two-way analysis of variance ŽANOVA. with repeated measurements, namely, operated group vs. sham-operated control group, and injured side

vs. non-injured side, at the time of measurement at 3 days and 4 weeks after the second operation. Post hoc multiple comparisons among these categories were done using Scheffe’s F-test.

3. Results 3.1. Histological examination The histological study showed intense gliosis and sparse neurons in the NBM of the rats injected with ibotenic acid, which indicated the complete necrosis of the NBM caused by ibotenic acid ŽTable 1.. 3.2. CMRglc measurements The interaction of the two categories with respect to CMRglc, namely operated or sham-operated, and lesioned side or non-lesioned side, with repetition, was not significant, so we proceeded to analyze the CMRglc measurements by one-way ANOVA in each category at the two time points. The sham-operated control group showed no significant differences with regard to the side of needle insertion or the time of PET scan after the second operation ŽFig. 3.. The bilaterally operated group revealed a significant decrease in CMRglc 3 days after the second operation, but no significant difference was found between the operated side and non-operated side. Thus, the second unilateral operation suppressed the cortical glucose metabolism bilaterally. Four weeks after the second operation, we again found a significant reduction of CMRglc bilaterally compared to the sham-operated group, and no laterality of CMRglc was observed. We found a small but significant degree of improvement of CMRglc compared to that of 3 days after the operation on both sides of the frontal lobes. Therefore, the effects of the second operation remained

Table 1 The CMRglc in rats with lesioning of the basal forebrain Animal

Operated rats

Control rats

3 days

1 2 3 4 Mean S.D.

4 weeks

3 days

4 weeks

Lesion side

Non-lesion side

Lesion side

Non-lesion side

Lesion side

Non-lesion side

Lesion side

Non-lesion side

32.80 30.85 33.09 24.14 30.22 4.17

33.93 33.12 24.57 21.46 28.27 6.21

50.95 42.60 48.25 41.37 45.79 4.56

44.49 43.00 45.80 41.14 43.61 2.00

55.35 59.90 59.21 57.52 58.00 2.03

56.17 64.93 55.99 54.72 57.95 4.70

59.34 62.14 57.11 63.94 60.63 3.02

64.50 54.41 59.44 63.15 60.38 4.52

Data are expressed as mmol Ž100 g brain.y1 miny1. Operated rats were injected with ibotenic acid on the side contralateral to that first injured in the basal forebrain. Control rats were injected with thiamine pyrophosphate dissolved in 0.1 M PBS on the same side as the operated rats. The first operation destroyed the unilateral basal forebrain. Days and weeks indicate the times after the second operation.

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Fig. 3. The CMRglc in rats with basal forebrain lesions. Significant differences after multiple comparison correction are indicated by an asterisk Ž p - 0.05. and lines. Control: control group with sham operation; Operated: operated group; 3D: 3 days; 4W: 4 weeks after the second operation. Lesion: side operated on 4 weeks after the first operation. Non-lesion: contralateral to the side operated on 4 weeks after the first operation.

after 4 weeks, but there was some tendency to recover from the damage bilaterally ŽFig. 3..

4. Discussion 4.1. Calculation of CMRglc Although there are advantages to PET scanning in animals, such as the ease of the procedure of the scan, the large number of available tracers, and the ability to measure the cerebral blood flow or metabolism many times serially on the same animals, some technical problems have been pointed out. In small animals, the ROI size is critical in obtaining exact values, because partial volume effects may easily affect the results of the measurements. FDG becomes highly accumulated in the Harderian glands of the mouse w39x. The FDG radioactivity of Harderian glands in the rat was reported to affect the radioactivity of the frontal lobe, which suggested that CMRglc in the frontal cortex was overestimated by about two-fold in comparison with the true value in animals with small ROI size w17x. However, if the ROI size is greater than twice the size of the FWHM, the in-plane partial volume effect will be minimized w2,12x. Thus, we adopted an ROI size greater than twice that of FWHM, and therefore our CMRglc measurements are considered to be valid in this respect. However the partial volume effect in the axial direction is not predictable from the ROI size, and the Harderian glands effect from the anterior portion of the brain is large, so that we adopted a slice of the frontal cortex slightly posterior to that in the previous study w24x to minimize the partial volume effect of the Harderian

glands of the anterior portion. This ROI on the frontal lobe was confirmed to be valid by our recent study using the same PET scanner w9x. The cholinergic fibers from the NBM project to the frontal and parietal cortices, but the parietal cortex was excluded in the present study due to the possibility of being affected by the surgical procedure, and only CMRglc in the frontal cortex was targeted. In order to provide data relevant to Alzheimer’s disease, we should include the parietal or temporal cortices in the measurements, and therefore such experiments should be done on larger animals, such as cats or monkeys. We evaluated the CMRglc by the Patlak graphical method. We also calculated the metabolic rate constants from our data by the non-linear least squares method w10x, but there was no need to obtain each rate constant for the purpose of the present experiment, and the fitting process sometimes failed to converge, in contrast to the graphical method. This is partly because the graphical method is not affected by the brain radioactivity measurement obtained by PET in the early phase of dynamic scan, which is unstable because of the low radioactivities, nor influenced by the injected dose or speed of the injection of FDG, and furthermore, the graphical method precisely reflects the metabolic rate constant changes in the pathological tissues for the CMRglc determination w42x. The Patlak graphical method adopts the compartment model composed of three compartments and three parameters, not four parameters; therefore, the K 1U and kU3 values are smaller than those obtained using the four parameter model with the non-linear least squares method, resulting in a lower value of CMRglc compared with that obtained using the four parameter model. One of the reason why the three parameter model is more appropriate than four parameter model in

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calculating CMRglc is that kU4 in the 4-constant model represents the rate constant for dephosphorylation by glucose-6-phosphatase activity was assumed to exist in solving metabolic compartment analysis without experimental confirmation w34x. It was also reported that the better dynamic fits to tissue radioactivity obtained with the addition of a kU4 reflects not glucose-6-phosphatase activity but the effects of tissue heterogeneity and the consequences of trying to fit a set of rate constants that should apply only to a single compartment to a heterogeneous mixture of compartments w35x. 4.2. Procedures for introducing lesions in the NBM We adopted ibotenic acid to destroy the NBM, which might also have influenced the non-cholinergic systems at the basal forebrain as well as the cholinergic system. We previously used bromopyruvate to inhibit the synthesis of acetylcholine without destroying other neuronal systems w24x, and found similar effects on the frontal lobe CMRglc suppression with bromopyruvate and ibotenic acid. However, the effect of bromopyruvate was transient because it inhibits the synthesis of acetylcholine at the time of injection, but acetylcholine is synthesized normally afterwards when the bromopyruvate effect disappears. Therefore, we considered bromopyruvate to be inappropriate for the present long-term experimental design. We could not completely prevent the destruction of basal forebrain structures other than the cholinergic neurons so long as we used ibotenic acid. Thus our results can not exclude the possibility of extra-cholinergic effects on the frontal CMRglc. In recent years, immunotoxins to cholinergic neurons, such as 192-IgG saporin, have been used to selectively and completely destroy cholinergic neurons, and such immunotoxins produce somewhat different results from the classical glutamatergic receptor stimulants. Although we examined the damaged tissue histologically and found extensive gliosis, we could not confirm the completeness of the NBM destruction. The partial recovery at 4 weeks may be ascribed to residual neuronal sprouting onto the frontal lobe. 4.3. The effects of NBM lesions on frontal CMRglc London et al. w19x first reported that rats with acute ibotenate lesions of the NBM showed decreased CMRglc in the ipsilateral cerebral cortex as measured by the w14 C xlabeled deoxyglucose technique, and they also showed that the reduced CMRglc recovered to within the normal range with time. Similar findings were reported in baboons w15,16x. The recovery time in rats varied somewhat in different studies, with reported values of 28–32 days w19x, 2 weeks w7x and 7 days w8x. It was 3 weeks in our previous study w24x, and the fact that the control group in this study showed similar CMRglc at 3 days and 4 weeks after the second operation indicates that CMRglc had recovered

completely at 4 weeks after the first unilateral operation. Therefore, the schedule of the second operation was thought to be appropriate with regard to the time of recovery from the unilateral lesion. We found that cortical CMRglc was decreased bilaterally without asymmetry by the second contralateral NBM lesion. This fact indicates the possibility that the CMRglc once reduced by the unilateral lesion recovered through the effect of the contralateral NBM projection. In a PET study using callosotomized baboons, there was no significant trend for recovery after unilateral basal forebrain damage w43x, and the authors speculated that the corpus callosum normally mediates cholinergic fibers contralaterally, so the recovery of glucose utilization after unilateral NBM destruction may in part be due to this transcallosal cholinergic system. There is a possibility that the unilateral destruction of the NBM affects the bilateral frontal cortices. In the baboon, unilateral destruction of the NBM reduced not only the CMRglc of the ipsilateral frontal cortex but also that of the contralateral frontal cortex w15,16x. It was speculated that this contralateral reduction was due to a transcallosal depression of function Ždiaschisis. as a result of the unilateral NBM lesion. There are cholinergic fibers from the unilateral NBM to the contralateral side, but these are too sparse to influence contralateral CMRglc in monkeys w27,29x. Transcallosal fibers usually originate from the pyramidal cells of layer three of the cerebral cortex in monkeys w13x, and transhemispheric functional suppression might be mediated through such fiber systems w1x. In rats, there have been no reports of bilateral CMRglc reduction after unilateral damage. There was a tendency of contralateral CMRglc reduction, but insignificant, in our previous study w24x. Even if there is a transcallosal suppression, we think that its influence is small or transient with respect to CMRglc in rats. With regard to the immunohistochemical studies on the effect of unilateral destruction of the NBM, the contralateral NBM showed a significant increase in size when compared with the normal mean value w28x. This phenomenon also supports the hypothesis that the contralateral NBM compensates for the unilateral NBM dysfunction. In contrast to the ipsilateral reduction of the cortical CMRglc by unilateral destruction of the NBM, Orzi et al. w22x reported that the reduction of metabolism caused by simultaneous bilateral lesions of the NBM was followed by complete, spontaneous recovery within 4 months. We found that there was a tendency to recover 4 weeks after the second operation in this study, but that the recovery was incomplete. Although the observation periods in these studies differ, our data are not necessarily consistent with those of Orzi et al. The 4-week time lag between the two operations may be responsible for this discrepancy. After the first operation on the NBM, the contralateral basal forebrain functions compensatorily, so that the second operation might have produced a more pronounced effect

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on the cortical metabolism compared than that produced by simultaneous bilateral destruction. Thus we concluded that bilateral NBM damage might be responsible for persistent cortical glucose metabolism suppression. Previous studies indicated that cortical CMRglc reduction is correlated with reduction of cortical ChAT activity w15,16,22x. However, with regard to the recovery of cortical CMRglc, a correlation with ChAT activity has not been clearly established. Some reports showed the recovery of ChAT activity with time, while others showed no recovery of ChAT activity after more than 3 months w4,5,21,38,44x. Although the present study did not include measurements of ChAT, the reported recovery of ChAT activity is likely to take a longer time than that of CMRglc irrespective of whether the lesions of NBM are unilateral or bilateral. Therefore, we speculated that the contralateral compensatory mechanism may not work only via cholinergic projections from the contralateral NBM, but also via intrinsic cholinergic neurons in the cerebral cortex or other non-cholinergic cortical activating systems. The study of the mechanism of recovery of the reduced cortical glucose metabolism caused by NBM lesions is very important because it may yield insights relevant to ameliorating the dementia in patients with basal forebrain cholinergic system dysfunction in conditions such as Alzheimer’s disease.

w7x

w8x

w9x

w10x

w11x

w12x

w13x

w14x

w15x

Acknowledgements This work is partly supported by the Grant-in-aid for Scientific Research ŽA. 08558083 from the Japan Ministry of Education, Science and Culture, and Research for the Future Program ŽRFTF. JSPS-RFTF97L00201 from The Japan Society for the Promotion of Science, and General Research Grant for Aging and Health ‘Analysis of aged brain function with neuroimaging’. References w1x R.J. Andrews, Transhemispheric diaschisis. A review and comment, Stroke 22 Ž1991. 943–949. w2x J.C. Baron, H. Miyazawa, 1991. Use of positron emission tomography to assess effects of brain lesions in experimental subhuman primates. In: P. Michaelconn ŽEd.., Methods of Neurosciences: Lesions and Transplantation, San Diego, Academic Press, pp. 429– 441. w3x V. Bigl, N.J. Woolf, L.L. Butcher, Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis, Brain Res. Bull. 8 Ž1982. 727–749. w4x M. Calaminici, F.A. Abdulla, J.D. Sinden, J.D. Stephenson, Plastic changes in the cholinergic innervation of the rat cerebral cortex after unilateral lesion of the nucleus basalis with alpha-amino-3-OH-4isoxozole propionic acid ŽAMPA.: effects of basal forebrain transplants into neocortex, Brain Res. Bull. 42 Ž1997. 79–93. w5x F. Casamenti, P.L. Di Patre, L. Bartolini, G. Pepeu, Unilateral and bilateral nucleus basalis lesions: differences in neurochemical and behavioural recovery, Neuroscience 24 Ž1988. 209–215. w6x P. Cossette, D. Umbriaco, N. Zamar, E. Hamel, L. Descarries,

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