Pergamon Press
Life Sciences, Vol . 25, pp . 395-400 Printed in the U .S .A .
MULTIPLE AND INTERRELATED FUNCTIONAL ASYMMETRIES IN RAT BRAIN S .D . flick, R .C . Meibach, R .D . Cox and S . Maayani Department of Pharmacology Mount Sinai School of Medicine of the City University of New York One Gustave L . Levy Place New York, New York 10029 (Received in final form June 11, 1979) Summary Normal rats rotate (turn in circles) at night and to response to drugs (e .g . d-amphetamine) during the day . Rats with known circling biases were injected with [1,2- 3 H]-deoXy-d-glucose, decapitated and glucose utilization was assessed in several brain structures . Most structures showed evidence of functional brain asymmetry . Asymmetries were of three different kinds : (1) a difference in activity between sides of the brain contralateral and ipsilateral to the direction of rotation (midbrain, striatum) ; (2) a difference in activity between left and right sides (frontal cortex, hippocampus) ; and (3) an absolute difference in activity between sides that was correlated to the rate of either rotation (thalamus, hypothalamus) or random movement (cerebellum) . Amphetamine, administered 15 minutes before a deoxyglucose injection in other rats, altered some asymmetries (striatum, frontal cortex, hippocampus) but not others (midbrain, thalamus, hypothalamus, cerebellum) . Different asymmetries appear to be organized along different dimensions in both the rat and human brains . Cerebral functional asymmetry has, until recently, been considered a unique characteristic of the human brain (1) . In the last several years, however, neuroanatomical, biochemical and/or functional evidence of asymmetry has been demonstrated in the brains of various animal species, including other primates (2), cats (3), rodents (4), and songbirds (5) . Research conducted in the present laboratory has established that normal rats have an as,Ymrnetry in nigrostriatal function ; asymmetries in striatal dopamine content (6 , striatal dopamine metabolism and dopamine-stimulated adenylate cyclase activity (7) have been related to spontaneous side preferences (6) and nocturnal (B) and druginduced (9) circling behavior . Although the composite substrate for such spatial biases has been presumed to include other neuroanatomical and neurochemical systems (10), investigations of the latter have, until now, been limited to providing general indications of specificity of nigrostriatal involvement (11) . In the present study we have assessed potential asymmetries in several brain regions by measuring local rates of glucose utilization (12) in the brains of rats with known circling biases .
0024-3205/79/040395-05$02 .00/0 Copyright (c) 1979 Pergamoa Press Ltd
396
Asymmetries in Rat Brain
Vol . 25, No. 4, 1979
Materials and Methods Thirty-three naive female Sprague-Dawley rats, approximately three months old, were initially administered d-amphetamine sulfate (1 .0 mg/kg, i .p .) and placed individually in an automated apparatus (13) in which circling behavior (or rotation} was measured for one hour . In addition to recording the dominant direction of turning, the net magnitude of rotation (the difference between full 360° turns in the dominant and non-dominant directions), the per cent preference (dominant full turns multiplied by 100 and divided by total full turns) and the amount of random or non-directional activity (extra quarter turns, determined by subtracting four times the number of full turns from the total number of quarter turns) were quantitated . Seven to 10 days after testing (8,9}, rats were anesthetized with methohexital and cannulas were implanted in the external jugular vein (14) . Approximately 24 hours later, rats received an intraperitoneal injection of either d-amphetamine sulfate (1 .0 mg/kg) or saline (1 ml/kg) followed, in 15 minutes, by an intravenous injection of [1 ,2- 3 H]-deoxyd-glucose (50 uCi New England Nuclear, Boston, Mass .) . Thirty minutes after the latter injection, rats were killed by decapitation and the left and right sides of the brains were each dissected into eight parts : cerebellum, thalamus, hypothalamus, caudate, frontal cortex, midbrain, hippocampus and posterior cortex . Each part of each side of the brain was individually homo enized in 1 ml of O .1M phosphate buffer (pH 7 .4) . Each of four aliquots (100 ul~ of each sam le was dissolved in 10 ml of scintillation cocktail (New England Nuclear 950A~ and 1 ml of water and counted in a Beckman LS9000 scintillation counter (30% efficiency) . The deoxy-d-glucose (DDG) technique as introduced by Sokoloff and his associates (15) utilizes 14 C glucose to attain direct visualization of glucose utilization (GU) throughout the brain . Preliminary experiments in this laboratory adhered to their protocol ; however, certain limits of the technique became apparent . For instance, small changes in GU were undetectable even with the use of a densitometer . Therefore we decided to determine directly the amount of label in various brain regions by dissection and subsequent counting in a scintillation counter . This modification is advantageous in that (1) even the smallest changes in GU are detectable, (2) side to side and structure to structure differences become quantifiable, and (3) the less expensive trititum labeled DDG can be substituted for 14 C (control experiments involving double label counting with 14 C and 3H DDG demonstrated identical patterns of distribution} . Results As shown in Table 1, significant asymmetries in deoxyglucose metabolism were found for several structures . Asymmetries were computed in three different ways : as an absolute (high/low} difference, as a left or right bias (left/right} and with reference to the direction of rotation (contralateral/ipsilateral) . Generally, the results in the drug and control groups were similar . The major exceptions were (1) that whereas the frontal cortex and the hippocampus were more active on the left than on the right in control rats, these asymmetries were reversed under the influence of d-amphetamine ; and (2) a striatal contralateral/ipsilateral asymmetry was only significant after d-amphetamine . Analysis of the raw data showed that d-amphetamine selectively increased deoxyglucose activity in the contralateral striatum (t-test, p < .05) . There were no other significant differences between drug and control groups in deoxyglucose activity per se . Different asymmetries appear to have different roles in behavior . Whereas the direction of rotation was consistently related to an asymmetry in the midbrain and to a striatal asymmetry after d-amphetamine, neither of the latter was predictive of the magnitude of rotation . However, the absolute asymmetries in the hypothalamus and thalamus were quantitatively correlated with the amount of
397
Asymmetries in Rat Brain
Vol. 25, No . 4, 1979
TABLE I Asymmetry ratios were computed in three Asymmetires in deoXyglucose metabolism . ways : side having higher activity versus side having lower activity, left side versus right side and side contralateral to the direction of rotation versus side ipsilateral to the direction of rotation . Asymmetries (mean ± S .D .) in Control Rats *** High/Low*
Structure Cerebellum Thalamus Hypothalamus Frontal Cortex Striatum Midbrain Hippocampus Posterior Cortex
1 .10 1 .16 1 .14 1 .08 1 .06 1 .06 1 .05 1 .04
± .11 ± .17 ± .19 t .08 t .07 ± .05 ± .05 ± .06
Left/Right 1 .00 .98 .98 1 .05 1 .00 1 .02 1 .03 1 .02
± ± ± ± ± ± ± ±
.13 .17 .17 .05~ .09 .08 .04** .09
Contralateral/Ipsilateral 1 .02 .98 .96 .99 .97 .95 1 .00 1 .01
± .10 ± .19 ± .16 t .08 ± .08 ± .05~ ± .06 ± .09
Asymmetries (mean ± S .D .) in d-Amphetamine-treated Rats *** Structure Cerebellum Thalamus Hypothalamus Frontal Cortex Striatum Midbrain Hippocampus Posterior Cortex
High/Low * 1 .09 1 .12 1 .14 1 .05 1 .06 1 .07 1 .06 1 .04
t .12 ± .13 t .10 t .02 ± .04 t .06 ± .12 ± .05
Left/Right .97 .98 .97 .96 1 .00 .98 .95 1 .02
Contralateral/Ipsilateral
t .12 ± ± ± ± ± ± ±
.13 .14 .04** .07 .08 .07*"' .15
1 1 1 1
.98 .97 .05 .01 .05 .95 .02 .97
± ± ± ±
t ±
t ±
.12 .13 .14 .05 .04 ** .05** .14 .12
*All high/low asymmetries were significant at p < 02- .01 (paired t-tests) . Analyses of variance indicated significant (p < .02) differences between structures . In both control and d-amphetamine-treated groups, the asymmetries in cerebellum, thalamus and hypothalamus were each greater (paired t-tests, p < .05) than that in posterior cortex . In the control group, the asymmetry in frontal cortex was also greater (p < .05) than that in posterior cortex . ** Significant at p < .05 (paired t-tests) . * 11/22 rats in the control group and 6/11 rats in the d-amphetamine group rotated to the left, the remaining rats rotating to the right . Mean (t S .D .) behavioral measures for the two groups, respectively, were as follows : net rotation- 57 .2 ± 31 .9 and 49 .5 t 30 .5 ; % Dominance- 90 .1 t 15 .5 and 91 .3 ± 10 .4 ; Extra quarter turns- 217 .3 t 174 .0 and 235 .5 ± 188 .4 . net rotation (r = .51- .57 ; p s ,05- .01 in the control group and < .1 in the damphetamine group) . Though the frontal cortex, as well as the hippocampus, had a significant left-right asymmetry, the per cent preference during rotation was higher if frontal cortex activity was also higher on the contralateral side ; that is, there was a correlation between the contralateral/ipsilateral ratio in frontal cortex and % preference (r ~ .54 and .55 ; p < .O1 in the control group and < .l in the d-amphetamine group) . Interestingly, there was a very strong association between the cerebellum and non-directional activity ; the absolute
39 8
Asymmetries in Rat Brain
Vol . 25, No . 4, 1979
cerebellar asymmetry was highly correlated with the sum of extra quarter turns (r = 76 and .70 ; p < .001 in the control group and < .05 in the d-amphetamine group) . The posterior cortex was the only structure whose asymmetry was not related to any behavioral parameter . Interrelationships between asymmetries in different structures are also evident . Normally, in the control group, the midbrain and striata were asymmetric in the same direction (Chi square test, p < .05), as were the frontal cortex and hippocampus (Chi square test, p < .05} . Moreover, if the average of the striatal and midbrain asymmetries was higher on the ipsilateral side, the average of the frontal cortical and hippocampal asymmetries was usually higher on the left side and conversely (striatal and midbrain contralateral, frontal cortical and hippocampal right) . The latter generality applied to 20 of the 22 control rats, with the exceptions being the weakest rotaters ; the relationship was also quantitatively correlated (r = .56 ; p < .05), with a greater striatal and midbrain ipsilateral bias associated with a greater frontal cortical and hippocampal left bias and conversely . Under the influence of d-amphetamine, the midbrain and striata became asymmetric in opposite directions and a simple relationship with the frontal cortex and hippocampus was no longer discernable . Discussion The results of this study indicate that hemispheric asymmetry in the rat is more prevalent, as well as more complex, than previously thought . To the extent that "functional activity is . . .closely coupled to the local rate of energy metabolism," (12) the labeled deoxyglucose technique, as employed here, has provided evidence for three different kinds of cerebral functional asymmetry . Asymmetry related to the direction of a motor bias, involving the midbrain and striatum, is supportive of previous work with more specific neurochemical indices (4) . A left-right asymmetry in rat cortex has been suggested recently (16) . The present data confirm this suggestion, localize the asymmetry to frontal as opposed to posterior cortex and identify a similar asymmetry in hippocampus . The third or absolute kind of asymmetry is certainly the most curious and without precedent . In the case of the cerebellum, inasmuch as it contains bilateral intrinsic connections (17) and its efferents are both crossed (18} and uncrossed (19), one might speculate that its two sides operate in seesaw fashion with maximal inhibition of movement associated with perfect synchrony and vice-versa . An analogy between asymmetry in the rat brain and that in the human brain has previously been difficult to conceive . Asymmetry in the human brain had been characterized as left-right whereas the nigrostriatal asymmetry in rat brain had no such a riori predilection . It now appears that different asymmetries are organized a ong different dimensions in both the rat and the human brains . Indeed, within the human thalamus, asymmetries of norepinephrine content may vary in direction in different regions (20) . Although there is now a basis for comparison, it remains to be determined how closely asymmetries in animal and human brains resemble each other . Acknowledgem~en t Supported by NIDA grant DA 01044 and NIDA Research Scientist Development Award DA 70082 to S . D . Glick . References 1 . 2.
J . LEVY, Ann . N .Y . Acad . Sci . 29 9 264-272 (1975) . M . LEMAY and N . GESCHWIND, BrainBehav . Evol . 11 48-52 (1975) .
Vol . 25, No . 4, 1979
3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 .
Asytmmetriea in Rat Brain
399
W .G . WEBSTER, Lateralization in the Nervous System , S . Harnad, R .W . Doty, L . Goldstein, J . Jaynes and G . Krauthamer, pp . 471-480, Academic Press, New York (1977) . S .D . GLICK, T . P . JERUSSI and B . ZIMMERBERG, ibid , pp . 213-249 . F . NOTTEBOHM, ibid , pp . 23-44 . B . ZIMMERBERG, S .D . GLICK and T . P . JERUSSI, Science 185 623-625 (1974) . T .P . JERUSSI, S .D . GLICK and C .L . JOHNSON, Brain Res . _129 385-388 (1977) . S .D . GLICK and R .D . COX, Brain Res . 150 149-161 (1978) T .P . JERUSSI and S .D . GLICK, Psychopiarmacology 47 249-260 (1976) . S .D . GLICK, T .P . JERUSSI and L .N . FLEISHER, Life~ci . 18 889-896 (1976) . S .D . GLICK, T .P . JERUSSI, D .H . WATERS and J .P . GREEN, Biochem . Pharmacol . _23 3223-3225 (1974) . L . SOKOLOFF, Neurochem . 29 13-26 (1977) . S . GREENSTEIN and S .D . GLÎCK, Pharmacol . Biochem . Behav . 3 507-510 (1975) . J .R . WEEKS, Methods in Ps chobiolo , Vol . 2 , R .D . Myers, pp . 155-168, Academic Press, New Yorc 2 . L . SOKOLOFF, M . REIVICH, C . KENNEDY, H .M . DES ROSIERS, C .S . PATLAK, K .D . PETTIGREW, 0 . SAKURADA and M . SHINOHARA, J . Neurochem . 28 897-916 (1977) . V .H . DENENBERG, J . GARBANATI, G . SHERMAN, D .A . YUTZEYand R . KAPLAN, Science 201 1150-1152 (1978) . D.E. HAINES, J . Comp . Neurol . 67 170-179 (1976) . K .A . CAUGHELL and B .A . FLUMERFELT, J . Comp . Neurol . 295 176-188 (1977) . R . R . BATTON III, A . JAYARAMAN, D . RUGGIERO and M .D . CÂRPENTER, J . Comp . Neurol . 174 281-291 (1977) . A . OKÉ, R . KELLER, I . MEFFORD and R .N . ADAMS, Science 200 1411-1413 (1978) .
Life Sciences, Vol . 25, pp . 395-400 Printed in the U .S .A .
MULTIPLE AND INTERRELATED FUNCTIONAL ASYMMETRIES IN RAT BRAIN S .D . flick, R .C . Meibach, R .D . Cox and S . Maayani Department of Pharmacology Mount Sinai School of Medicine of the City University of New York One Gustave L . Levy Place New York, New York 10029 (Received in final form June 11, 1979) Summary Normal rats rotate (turn in circles) at night and to response to drugs (e .g . d-amphetamine) during the day . Rats with known circling biases were injected with [1,2- 3 H]-deoXy-d-glucose, decapitated and glucose utilization was assessed in several brain structures . Most structures showed evidence of functional brain asymmetry . Asymmetries were of three different kinds : (1) a difference in activity between sides of the brain contralateral and ipsilateral to the direction of rotation (midbrain, striatum) ; (2) a difference in activity between left and right sides (frontal cortex, hippocampus) ; and (3) an absolute difference in activity between sides that was correlated to the rate of either rotation (thalamus, hypothalamus) or random movement (cerebellum) . Amphetamine, administered 15 minutes before a deoxyglucose injection in other rats, altered some asymmetries (striatum, frontal cortex, hippocampus) but not others (midbrain, thalamus, hypothalamus, cerebellum) . Different asymmetries appear to be organized along different dimensions in both the rat and human brains . Cerebral functional asymmetry has, until recently, been considered a unique characteristic of the human brain (1) . In the last several years, however, neuroanatomical, biochemical and/or functional evidence of asymmetry has been demonstrated in the brains of various animal species, including other primates (2), cats (3), rodents (4), and songbirds (5) . Research conducted in the present laboratory has established that normal rats have an as,Ymrnetry in nigrostriatal function ; asymmetries in striatal dopamine content (6 , striatal dopamine metabolism and dopamine-stimulated adenylate cyclase activity (7) have been related to spontaneous side preferences (6) and nocturnal (B) and druginduced (9) circling behavior . Although the composite substrate for such spatial biases has been presumed to include other neuroanatomical and neurochemical systems (10), investigations of the latter have, until now, been limited to providing general indications of specificity of nigrostriatal involvement (11) . In the present study we have assessed potential asymmetries in several brain regions by measuring local rates of glucose utilization (12) in the brains of rats with known circling biases .
0024-3205/79/040395-05$02 .00/0 Copyright (c) 1979 Pergamoa Press Ltd
396
Asymmetries in Rat Brain
Vol . 25, No. 4, 1979
Materials and Methods Thirty-three naive female Sprague-Dawley rats, approximately three months old, were initially administered d-amphetamine sulfate (1 .0 mg/kg, i .p .) and placed individually in an automated apparatus (13) in which circling behavior (or rotation} was measured for one hour . In addition to recording the dominant direction of turning, the net magnitude of rotation (the difference between full 360° turns in the dominant and non-dominant directions), the per cent preference (dominant full turns multiplied by 100 and divided by total full turns) and the amount of random or non-directional activity (extra quarter turns, determined by subtracting four times the number of full turns from the total number of quarter turns) were quantitated . Seven to 10 days after testing (8,9}, rats were anesthetized with methohexital and cannulas were implanted in the external jugular vein (14) . Approximately 24 hours later, rats received an intraperitoneal injection of either d-amphetamine sulfate (1 .0 mg/kg) or saline (1 ml/kg) followed, in 15 minutes, by an intravenous injection of [1 ,2- 3 H]-deoxyd-glucose (50 uCi New England Nuclear, Boston, Mass .) . Thirty minutes after the latter injection, rats were killed by decapitation and the left and right sides of the brains were each dissected into eight parts : cerebellum, thalamus, hypothalamus, caudate, frontal cortex, midbrain, hippocampus and posterior cortex . Each part of each side of the brain was individually homo enized in 1 ml of O .1M phosphate buffer (pH 7 .4) . Each of four aliquots (100 ul~ of each sam le was dissolved in 10 ml of scintillation cocktail (New England Nuclear 950A~ and 1 ml of water and counted in a Beckman LS9000 scintillation counter (30% efficiency) . The deoxy-d-glucose (DDG) technique as introduced by Sokoloff and his associates (15) utilizes 14 C glucose to attain direct visualization of glucose utilization (GU) throughout the brain . Preliminary experiments in this laboratory adhered to their protocol ; however, certain limits of the technique became apparent . For instance, small changes in GU were undetectable even with the use of a densitometer . Therefore we decided to determine directly the amount of label in various brain regions by dissection and subsequent counting in a scintillation counter . This modification is advantageous in that (1) even the smallest changes in GU are detectable, (2) side to side and structure to structure differences become quantifiable, and (3) the less expensive trititum labeled DDG can be substituted for 14 C (control experiments involving double label counting with 14 C and 3H DDG demonstrated identical patterns of distribution} . Results As shown in Table 1, significant asymmetries in deoxyglucose metabolism were found for several structures . Asymmetries were computed in three different ways : as an absolute (high/low} difference, as a left or right bias (left/right} and with reference to the direction of rotation (contralateral/ipsilateral) . Generally, the results in the drug and control groups were similar . The major exceptions were (1) that whereas the frontal cortex and the hippocampus were more active on the left than on the right in control rats, these asymmetries were reversed under the influence of d-amphetamine ; and (2) a striatal contralateral/ipsilateral asymmetry was only significant after d-amphetamine . Analysis of the raw data showed that d-amphetamine selectively increased deoxyglucose activity in the contralateral striatum (t-test, p < .05) . There were no other significant differences between drug and control groups in deoxyglucose activity per se . Different asymmetries appear to have different roles in behavior . Whereas the direction of rotation was consistently related to an asymmetry in the midbrain and to a striatal asymmetry after d-amphetamine, neither of the latter was predictive of the magnitude of rotation . However, the absolute asymmetries in the hypothalamus and thalamus were quantitatively correlated with the amount of
397
Asymmetries in Rat Brain
Vol. 25, No . 4, 1979
TABLE I Asymmetry ratios were computed in three Asymmetires in deoXyglucose metabolism . ways : side having higher activity versus side having lower activity, left side versus right side and side contralateral to the direction of rotation versus side ipsilateral to the direction of rotation . Asymmetries (mean ± S .D .) in Control Rats *** High/Low*
Structure Cerebellum Thalamus Hypothalamus Frontal Cortex Striatum Midbrain Hippocampus Posterior Cortex
1 .10 1 .16 1 .14 1 .08 1 .06 1 .06 1 .05 1 .04
± .11 ± .17 ± .19 t .08 t .07 ± .05 ± .05 ± .06
Left/Right 1 .00 .98 .98 1 .05 1 .00 1 .02 1 .03 1 .02
± ± ± ± ± ± ± ±
.13 .17 .17 .05~ .09 .08 .04** .09
Contralateral/Ipsilateral 1 .02 .98 .96 .99 .97 .95 1 .00 1 .01
± .10 ± .19 ± .16 t .08 ± .08 ± .05~ ± .06 ± .09
Asymmetries (mean ± S .D .) in d-Amphetamine-treated Rats *** Structure Cerebellum Thalamus Hypothalamus Frontal Cortex Striatum Midbrain Hippocampus Posterior Cortex
High/Low * 1 .09 1 .12 1 .14 1 .05 1 .06 1 .07 1 .06 1 .04
t .12 ± .13 t .10 t .02 ± .04 t .06 ± .12 ± .05
Left/Right .97 .98 .97 .96 1 .00 .98 .95 1 .02
Contralateral/Ipsilateral
t .12 ± ± ± ± ± ± ±
.13 .14 .04** .07 .08 .07*"' .15
1 1 1 1
.98 .97 .05 .01 .05 .95 .02 .97
± ± ± ±
t ±
t ±
.12 .13 .14 .05 .04 ** .05** .14 .12
*All high/low asymmetries were significant at p < 02- .01 (paired t-tests) . Analyses of variance indicated significant (p < .02) differences between structures . In both control and d-amphetamine-treated groups, the asymmetries in cerebellum, thalamus and hypothalamus were each greater (paired t-tests, p < .05) than that in posterior cortex . In the control group, the asymmetry in frontal cortex was also greater (p < .05) than that in posterior cortex . ** Significant at p < .05 (paired t-tests) . * 11/22 rats in the control group and 6/11 rats in the d-amphetamine group rotated to the left, the remaining rats rotating to the right . Mean (t S .D .) behavioral measures for the two groups, respectively, were as follows : net rotation- 57 .2 ± 31 .9 and 49 .5 t 30 .5 ; % Dominance- 90 .1 t 15 .5 and 91 .3 ± 10 .4 ; Extra quarter turns- 217 .3 t 174 .0 and 235 .5 ± 188 .4 . net rotation (r = .51- .57 ; p s ,05- .01 in the control group and < .1 in the damphetamine group) . Though the frontal cortex, as well as the hippocampus, had a significant left-right asymmetry, the per cent preference during rotation was higher if frontal cortex activity was also higher on the contralateral side ; that is, there was a correlation between the contralateral/ipsilateral ratio in frontal cortex and % preference (r ~ .54 and .55 ; p < .O1 in the control group and < .l in the d-amphetamine group) . Interestingly, there was a very strong association between the cerebellum and non-directional activity ; the absolute
39 8
Asymmetries in Rat Brain
Vol . 25, No . 4, 1979
cerebellar asymmetry was highly correlated with the sum of extra quarter turns (r = 76 and .70 ; p < .001 in the control group and < .05 in the d-amphetamine group) . The posterior cortex was the only structure whose asymmetry was not related to any behavioral parameter . Interrelationships between asymmetries in different structures are also evident . Normally, in the control group, the midbrain and striata were asymmetric in the same direction (Chi square test, p < .05), as were the frontal cortex and hippocampus (Chi square test, p < .05} . Moreover, if the average of the striatal and midbrain asymmetries was higher on the ipsilateral side, the average of the frontal cortical and hippocampal asymmetries was usually higher on the left side and conversely (striatal and midbrain contralateral, frontal cortical and hippocampal right) . The latter generality applied to 20 of the 22 control rats, with the exceptions being the weakest rotaters ; the relationship was also quantitatively correlated (r = .56 ; p < .05), with a greater striatal and midbrain ipsilateral bias associated with a greater frontal cortical and hippocampal left bias and conversely . Under the influence of d-amphetamine, the midbrain and striata became asymmetric in opposite directions and a simple relationship with the frontal cortex and hippocampus was no longer discernable . Discussion The results of this study indicate that hemispheric asymmetry in the rat is more prevalent, as well as more complex, than previously thought . To the extent that "functional activity is . . .closely coupled to the local rate of energy metabolism," (12) the labeled deoxyglucose technique, as employed here, has provided evidence for three different kinds of cerebral functional asymmetry . Asymmetry related to the direction of a motor bias, involving the midbrain and striatum, is supportive of previous work with more specific neurochemical indices (4) . A left-right asymmetry in rat cortex has been suggested recently (16) . The present data confirm this suggestion, localize the asymmetry to frontal as opposed to posterior cortex and identify a similar asymmetry in hippocampus . The third or absolute kind of asymmetry is certainly the most curious and without precedent . In the case of the cerebellum, inasmuch as it contains bilateral intrinsic connections (17) and its efferents are both crossed (18} and uncrossed (19), one might speculate that its two sides operate in seesaw fashion with maximal inhibition of movement associated with perfect synchrony and vice-versa . An analogy between asymmetry in the rat brain and that in the human brain has previously been difficult to conceive . Asymmetry in the human brain had been characterized as left-right whereas the nigrostriatal asymmetry in rat brain had no such a riori predilection . It now appears that different asymmetries are organized a ong different dimensions in both the rat and the human brains . Indeed, within the human thalamus, asymmetries of norepinephrine content may vary in direction in different regions (20) . Although there is now a basis for comparison, it remains to be determined how closely asymmetries in animal and human brains resemble each other . Acknowledgem~en t Supported by NIDA grant DA 01044 and NIDA Research Scientist Development Award DA 70082 to S . D . Glick . References 1 . 2.
J . LEVY, Ann . N .Y . Acad . Sci . 29 9 264-272 (1975) . M . LEMAY and N . GESCHWIND, BrainBehav . Evol . 11 48-52 (1975) .
Vol . 25, No . 4, 1979
3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 .
Asytmmetriea in Rat Brain
399
W .G . WEBSTER, Lateralization in the Nervous System , S . Harnad, R .W . Doty, L . Goldstein, J . Jaynes and G . Krauthamer, pp . 471-480, Academic Press, New York (1977) . S .D . GLICK, T . P . JERUSSI and B . ZIMMERBERG, ibid , pp . 213-249 . F . NOTTEBOHM, ibid , pp . 23-44 . B . ZIMMERBERG, S .D . GLICK and T . P . JERUSSI, Science 185 623-625 (1974) . T .P . JERUSSI, S .D . GLICK and C .L . JOHNSON, Brain Res . _129 385-388 (1977) . S .D . GLICK and R .D . COX, Brain Res . 150 149-161 (1978) T .P . JERUSSI and S .D . GLICK, Psychopiarmacology 47 249-260 (1976) . S .D . GLICK, T .P . JERUSSI and L .N . FLEISHER, Life~ci . 18 889-896 (1976) . S .D . GLICK, T .P . JERUSSI, D .H . WATERS and J .P . GREEN, Biochem . Pharmacol . _23 3223-3225 (1974) . L . SOKOLOFF, Neurochem . 29 13-26 (1977) . S . GREENSTEIN and S .D . GLÎCK, Pharmacol . Biochem . Behav . 3 507-510 (1975) . J .R . WEEKS, Methods in Ps chobiolo , Vol . 2 , R .D . Myers, pp . 155-168, Academic Press, New Yorc 2 . L . SOKOLOFF, M . REIVICH, C . KENNEDY, H .M . DES ROSIERS, C .S . PATLAK, K .D . PETTIGREW, 0 . SAKURADA and M . SHINOHARA, J . Neurochem . 28 897-916 (1977) . V .H . DENENBERG, J . GARBANATI, G . SHERMAN, D .A . YUTZEYand R . KAPLAN, Science 201 1150-1152 (1978) . D.E. HAINES, J . Comp . Neurol . 67 170-179 (1976) . K .A . CAUGHELL and B .A . FLUMERFELT, J . Comp . Neurol . 295 176-188 (1977) . R . R . BATTON III, A . JAYARAMAN, D . RUGGIERO and M .D . CÂRPENTER, J . Comp . Neurol . 174 281-291 (1977) . A . OKÉ, R . KELLER, I . MEFFORD and R .N . ADAMS, Science 200 1411-1413 (1978) .
