EXPERIMENTAL
NEUROLOGY
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Lateral Hypothalamus Destruction in Infant Rats Produces Consummatory Deficits without Sensory Neglect or Attenuated Arousal C. ROBERT ALMLI, Department Received
ROBIN
of Psychology, January
S. FISHER, AND DAVID Ohio
University,
22, 1979; revision
Athens,
received
May
Ohio
L. HILL’ 45701
15, 1979
Male and female albino rats sustained bilateral electrolytic destruction of the lateral hypothalamic area (LHA) at 10 days of age. After brain damage, physical growth, the ontogeny of sensorimotor behavioral capacity, and consummatory behavioral responses to specific regulatory challenges were repeatedly and systematically assessed for as long as 375 days of age. Bilateral LHA damage caused immediate cessation of suckling from the dam and necessitated maintenance by hand and tube feeding. The infant LHA rats were incapable of regulating body weight by intake of dry food and water alone when killed at 70 or 375 days of age. Although they eventually could maintain body weight by ad libitum intake of highly palatable wet diets, these rats displayed severe body weight reduction, impaired linear growth, and permanent consummatory deficits to specific regulatory challenges. Multimodal sensorimotor tests failed to reveal “sensory neglect” or “attenuated arousal” in the brain-damaged rats; however, a transient syndrome of motor deficits and hyperreactivity consistently appeared. These findings were in sharp contrast to the sensorimotor deficits seen in animals which sustain LHA damage after weaning or in adulthood. These data argue that sensory neglect or attenuated arousal is not necessary to production of consummatory deficits and, taken with other research, suggest that damage to intrinsic LHA neurons causes consummatory deficits whereas damage to fibers of passage causes sensorimotor impairment.
INTRODUCTION Recent research has begun to explicate the role of the lateral hypothalamic area (LHA) of the rat in the ontogenetic development of Abbreviation: LHA-lateral hypothalamic area. 1 This research was supported by Ohio University Research Center grant 520 to C. R. Almli. R. S. Fisher is now at Department of Biological Sciences, Purdue University, West Lafayette, IN 47907. Address reprint requests to Dr. Almli. 146 0014-4886/79/100146-12$02.00/O Copyright All rights
8 1979 by Academic Press, Inc. of reproduction in any form reserved.
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consummatory behaviors (1,3-5,7,8, 14, 19-21). During the preweaning period, infant rats make the transition between suckling from the dam to mature forms of independent feeding and drinking behaviors concurrently with postnatal maturation of the LHA as evidenced by growth of endogenous LHA neurons (20,21), rapid increases in catecholamines (12, 18), and changes in LHA unit electrophysiologic characteristics (8, 14). Even with these developmental changes in the LHA and consummatory behaviors, bilateral destruction of the LHA in lo-day-old rats (3, 5, 19) produced severe and persistent consummatory deficits which were equivalent to the consummatory deficits associated with LHA damage in postweaning (e.g., 25 days of age) rats (5, 19) and adult rats (9, 11, 13). However, LHA destruction in rats 25 days of age and older also produced sensory, motor, and arousal dysfunction, in addition to consummatory deficits (9, 13, 17, 22, 26, 27). These other behaviors were not systematically evaluated in the earlier research on the effects of LHA destruction sustained by lo-day-old rats because of the lack of an appropriate testing procedure for infant rats, and because of the emphasis upon maintaining life of infant rats that had completely ceased suckling from the dam. Both problems have been overcome, as Almli and Fisher (2) have developed a sensorimotor testing battery for infant rats, and they have significantly improved the maintenance techniques for nonsuckling rats. Thus, the present study was designed to evaluate the sensorimotor capacity of lo-day-old rats sustaining LHA destruction. This knowledge is important, as Teitelbaum and co-workers (17, 22) suggested that aphagia following LHA destruction in adult rats was due to sensory neglect, and that recovery of consummatory behaviors was associated with abatement of neglect; furthermore, Stricker and Zigmond (26) proposed that the residual regulatory deficits of adults with LHA lesions were related to arousal dysfunction. The present study examined the association between sensory neglect and attenuated arousal and the consummatory deficits of infant rats sustaining bilateral LHA destruction. METHODS The animal housing conditions, surgical procedures, postoperative maintenance procedures, and measures of growth and consummatory behaviors were described in detail in previous reports (l-3, 5) and are therefore presented in abbreviated form in this study. Animals, Surgery, and Regulatory Measures. Infant albino rats of the Charles River CD strain were housed eight pups per litter under standard laboratory conditions (2, 3, 5). The rats were transferred to individual rack-mounted cages at 30 days of age.
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At 10 days of age the infant rats were anesthetized with diethyl ether, and a stainless-steel electrode (0.25mm diam, 0.5-mm uninsulated tip) was stereotaxically positioned at 3.5 mm anterior to lambda, ? 1.3 mm lateral to the sagittal suture, and 7.8 mm ventral to the skull surface (3-5). Anodal electrolytic lesions were produced with 1.5-mA current passed for 15 s. Thirteen rats (seven males and six females) sustained brain damage, and 17 rats (9 males and 8 females) served as controls (complete surgery and electrode penetration into the brain without passage of current). Body weight (g) was measured daily for all rats from 10 days of age until killing, and water intake (ml) was measured daily from 35 days of age until killing. Snout-anus body length (mm) was measured at 10,20, 30, and 70 days of age for all rats. After 50 days of age the rats received a variety of feeding and drinking tests to determine if “residual” regulatory deficits were present (2, 3, 5, 19). Sensorimotor Behaviors. Each brain-damaged and control rat was subjected to a comprehensive sensorimotor test battery at 10-20, 25, 30, and 60 days of age. The sensorimotor test battery is described in detail elsewhere (2). Briefly, this battery evaluated performance of the following behavior patterns during development: righting from a supine to prone position, air righting, forepaw and rear paw grasping, forepaw and lateral hopping, vibrisseal placing, forepaw and rear paw placing, rooting, spintwist reflex, ingestion of periorally applied Similac infant formula, edge aversion, visual orientation (tracking of moving object or light source with head), auditory orientation (tracking of sound source with head), olfactory orientation (behavioral reaction to odors of Mennen Skin Bracer and Similac), and somatosensory orientation (behavioral reaction after systematic tactile stimulation of the body surface from nose to tail with a 2-g pressure von Frey hair). In addition, posture, gait, grooming behaviors, and activity and reactivity levels were evaluated, and the presence of limb spasticity and tremor was noted (2). Histology. Eleven brain-damaged rats were killed at 70 days of age and two at 375 days of age. The rats were perfused intracardially with 0.87% NaCl followed by a 10% Formalin-saline solution. Frozen coronal sections were cut at 50 pm, and each section through the lesion was stained with cresyl violet. The locus and magnitude of neural damage were microscopically determined, and the sections were compared to atlas figures (16). RESULTS Histologic Analysis. Six rats (three males and three females) sustained extensive and complete bilateral destruction of the lateral hypothalamic
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area (bilateral rats), and the neural damage (absent, necrotic, and gliotic tissue zones) paralleled the anterior-posterior extent of the ventromedial nucleus of the hypothalamus. Tissue destruction extended medially to the fornix and mamillothalamic tract, and in some cases, the zone of damage approached the lateral edge of the ventromedial nucleus. The lateral spread of tissue damage included the medial portion of the internal capsule; dorsally, the damage spread to include portions of the fields of Forel, zona incerta, and medial lemniscus. Ventral spread of tissue destruction typically reached the base of the brain; however, for some rats, a narrow band of tissue was spared. Included in the bilateral group were two rats (one male and one female) which were studied until 375 days of age (long-term survival rats). Figure 1 presents photomicrographs of coronal sections through the centers of the lesions of bilateral rats killed at 70 days of age (A) and at 375 days of age (B). There was obvious lesion shrinkage from 70 to 375 days of age. There was also extensive shrinkage of lesion size between 10 and 70 days of age; however, most of this shrinkage was due to collapse of periventricular tissue laterally which resulted in ventricular dilation (7,10,29). Lateral hypothalamic destruction as extensive as shown in Fig. 1A produced severe and persistent growth and consummatory deficits when sustained by IO-day-old rats (3-5, 19), and equivalent damage sustained by rats at 25 days of age (5, 19) or as adults (9,11, 13, 17,22) produced growth and consummatory deficits as well as sensory neglect, hypoactivity, hyporeactivity, and motor dysfunction. Such neural destruction would include important fiber systems (e.g., nigrostriatal, trigeminal, reticular formation) which have been previously implicated in the etiology of behavioral deficits after lateral hypothalamic damage (2,6,23, 26-28,30). Another seven rats (four males and three females) sustained brain damage that differed slightly from that of the bilateral rats just described. These seven rats sustained damage on one side of the brain which duplicated that of the bilateral rats; however, the damage on the contralateral side of the brain had a slight dorsomedial bias. This bias resulted in damage of the dorsolateral fibrous zone of the ventromedial nucleus and extensive destruction of the fields of Fore1 and zona incerta. The lateral spread of damage ended at the medial edge of the internal capsule, and the ventral half of the lateral hypothalamic area was spared. Thus, these rats sustained incomplete bilateral damage of the lateral hypothalamic-medial forebrain bundle area (incomplete rats). All data analysis was carried out with analysis of variance, two-tailed t tests for independent groups, and x2 tests for independent samples (25). No gender differences were found on sensorimotor test performance within groups; therefore, data of both genders were pooled for analysis of sensorimotor capacity.
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FIG. 1. Photomicrographs of frontal sections through the centers of the lesions of rats sustaining bilateral destruction of the lateral hypothalamus (LHA) at 10 days of age. A-male rat (Bi-LHA group) killed at 70 days of age (60 days postlesion). B-male rat (Bi-LT group) killed at 375 days of age (365 days postlesion). Both rats were adipsic and consuming special wet diets at the time of killing. Brain sections were stained with cresyl violet and magnified x 10 (A) and x20 (B).
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Consummatory Behaviors and Growth. In replication of previous research (3-5, 19), bilateral LHA destruction sustained by lo-day-old rats resulted in complete cessation of suckling from the dam and severe consummatory and growth deficits which persisted for as long as 1 year postlesion. The bilateral rats never regained suckling behaviors after brain damage, and the rats were 32 to 45 days of age before they consumed sufficient “wet diet” (2) to survive without hand feeding. All bilateral rats were still adipsic and consuming only wet diets when killed at 70 or 375 days of age. When tested after 50 days of age, none of the bilateral rats drank water during food deprivation (P < 0.01) or after injection of hypertonic NaCl solution (Z’ < 0.01). The long-term survival rats (375 days of age) also failed to consume water after water deprivation or injection of polyethylene glycol solution. In addition, they failed to increase wet diet intake when injected with 2-deoxy-D-glucose, and they did not decrease wet diet intake when injected with amphetamine (3, 4, 19). At 70 days of age the bilateral males were 50 to 60% of control body weight (P < 0.05) and 66% of control body length (P < 0.05). The bilateral females were 70 to 80% of control body weight (P < 0.05) at 70 days of age, and they displayed a 22% reduction in body length (P < 0.05). When the two long-term rats were killed at 375 days of age, the male was 81% of control body weight and 89% of control body length. The long-term female was 123% of control body weight and 97% of control body length. The incomplete rats also ceased suckling after brain damage; however, these rats slowly recovered consummatory behaviors, and they were drinking water and feeding on dry pellets by 41 to 45 days of age. In spite of recovery of consummatory behaviors, the incomplete males had reduced body weights (55 to 60% of control, P < 0.05) and stunted linear growth (80 to 85% of control, P < 0.05) at 70 days of age. The incomplete females were 68 to 75% of control body weight P < 0.05) and 85 to 90% of control body length (P < 0.05) at 70 days of age. In response to the drinking tests, the incomplete rats did not differ from control for water intake after hypertonic NaCl solution injection or for water intake during food deprivation. Sensorimotor Behavior Ontogeny. The ontogenetic development of the various sensorimotor behaviors of the rats were classified into four categories on the basis of postlesion behavioral sequelae on each test. Behaviors could have normal response development, altered response development (persistence or substitution of response), delayed response development (temporal retardation of response onset relative to controls), or response abnormality (response was not observed during ontogenetic development of normal or control rats) (2). Behavioral dysfunctions were quantitatively estimated for consistency (percentage of group with dysfunction) and duration (temporal length of dysfunction of single rats
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within each group). The sham-operated control rats displayed normal sensorimotor response development on all tests and observations (2). Normal Response Development. In contrast to older rats sustaining LHA destruction (17, 22,26), the lo-day-old bilateral and incomplete rats in this study displayed normal sensorimotor development on the following tests: righting from a supine to prone position, air righting, forepaw and rear paw placing, forepaw and rear paw grasping, rooting, edge aversion, visual orientation, auditory orientation, olfactory orientation, and activity level in isolation. Delayed Response Development. As Table 1 indicates, some rats (0 to 57%) of the bilateral and incomplete groups displayed a l- to 3-day delay in the development of forepaw and lateral hopping, vibrisseal placing, and spin-twist reflex. The short durations of the delayed responses coupled with the finding that not all rats of any group displayed delayed responses indicated that these delayed responses might have been due to subtle differences in brain damage among rats. Altered Response Development. Response development on the somatosensory orientation test was altered in the bilateral and incomplete TABLE
1
Sensorimotor Behavior Dysfunction after Bilateral and Incomplete Destruction of the Lateral Hypothalamus at 10 Days of Age in the Rat” Symptom duration (days)
Percentage of group with symptom
Response class/test
Bilateral group
Incomplete tww
Delayed responses Forepaw hopping Lateral hopping Vibrisseal placing Spin-twist reflex
o-1 o-1 o-1 0
o-3 o-2 0 o-2
25 25 25 0
57 29 0 29
50
50
100
100
S-50 S-20 15-20 4-10 20-50
5-50 5-50 5-20 3-10 20-50
100 100 100 100 100
100 100 100 100 100
Altered responses Somatosensory Orientation Abnormal responses Posture Gait Spasticity Tremor Hyperreactivity
Bilateral group
Incomplete group
a Symptom duration expresses the maximum and minimum temporal extension of dysfunction in days after surgery.
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rats (see Table 1). Stimulation of the body surface of normal and sham-operated control rats (10 days of age and older) with a 2-g pressure von Frey hair (2) resulted in a turn of the head toward the site of stimulation in approximately 85 to 90% of the trials (turn response). On 5 to 10% of the trials, the rats turned their heads toward the site of stimulation and brushed at the stimulated body region with their hind limbs (turn-brush response), and on 5 to 10% of the trials the rats failed to orient to the stimulation (no response). The bilateral and incomplete rats differed from controls in that the brain-damaged rats displayed an increased frequency of turn-brush responses (bilateral = 25%, incomplete = 19%, control = 8%) and a decreased frequency of turn responses (bilateral = 70%, incomplete = 76%, control = 87%) during development. No-response to stimulation had a constant frequency of 5% for all groups. Chi square tests of statistical independence of these response frequency data revealed that there were no reliable differences between groups prior to brain damage at 10 days of age. However, after brain damage there were reliable differences between groups at 11 through 20 days of age (P < O.Ol), at 25 days of age (P < 0.05), but not at 30 days of age. Reliable differences were again found at 60 days of age (P < 0.05). The long-term survival rats displayed response frequencies equal to those of control rats when tested at 90 through 375 days of age which indicated that the effect was persistent but not permanent. Thus, the bilateral and incomplete rats exhibited an increased frequency of a normal response to tactile stimulation (turn-brush response) at the expense of another response (turn response) more typical of normal response development. However, it was important to note that the brain-damaged rats were responding to tactile stimulation and they did not display a change in frequency of no-response to stimulation; i.e., they were not “neglecting” the stimulation. Abnormal Responses. Brain-damaged rats had a consistent and persistent set of behavioral abnormalities after sustaining brain damage (see Table I). The following symptoms were observed postlesion in all brain-damaged rats: abnormal posture, abnormal gait, limb spasticity, tremor, and hyperreactivity. Control rats did not display these symptoms at any time during ontogeny. Postural abnormalities consisted of a “hunched” curvature of the spine, lowered head attitude, and an appearance of “tip-toe” standing. Abnormalities of gait were uncoordinated locomotion and hunched body position with abnormal extension of the extremities. Bilateral rats had slightly less persistent gait dysfunction than incomplete rats. These abnormalities of posture and gait were not observed in the long-term rats on or after 90 days of age. All brain-damaged rats also exhibited limb spasticity. This symptom consisted of limb rigidity and extension which may have contributed to the
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abnormalities of posture and gait and the delayed response ontogeny of several measures such as forepaw and lateral hopping. Mild forms of whole body tremor were characteristic of the braindamaged rats in the initial phases of postsurgical recovery. In 83% of the bilateral rats and 71% of the incomplete rats, tremor abated within 1 day of the recovery of prelesion body weight. Tremor ceased within 3 days of the recovery of prelesion body weight in all brain-damaged rats. This symptom was the only sensorimotor behavioral measure that demonstrated any temporal association with any regulatory achievement; i.e., recovery of prelesion body weight. No residual tremor was found during maturity in the long-term rats. All brain-damaged rats displayed a similar and persistent form of hyperreactivity. Handling or gross tactile stimulation of the rats tended to evoke biting, vocalization, extreme struggle to escape, and rapid, uncoordinated locomotion. These rats were also hyperreactive while in the litter cage when they came in contact with littermates or the dam. However, these rats did not display high activity levels when in isolation, and some form of stimulation seemed necessary for the production of hyperactivity. DISCUSSION Extensive bilateral destruction of the LHA in adult rats was shown to produce consummatory deficits, postural and locomotor abnormality, sensory neglect, and attenuated arousal levels; and some investigators have suggested that the consummatory deficits were secondary to sensory and/or arousal dysfunction (9,11,13,17,22,26). This suggestion was based on demonstrations of the close temporal relationship between recovery from sensorimotor and consummatory deficits after LHA destruction in adults and on research showing that damage to fiber systems coursing through or near the LHA (e.g., nigrostriatal, trigeminal, reticular formation) produced sensory and/or arousal dysfunction in adults which yielded consummatory deficits (23, 26, 27, 30). However, in the present report, extensive bilateral destruction of the LHA in lo-day-old rats produced motor-postural abnormality and severe and persistent consummatory deficits that were not associated with sensory neglect or attenuated arousal levels. These results demonstrated that sensory neglect and/or attenuated arousal levels were not necessary for the production of consummatory deficits after LHA destruction; i.e., damage to the LHA produced primary consummatory deficits which were not accompanied by sensory neglect or attenuated arousal. The present demonstration of consummatory deficits without sensory neglect or attenuated arousal for LHA-damaged infant rats was supported
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by recent research with adult rats. Grossman et al. (15) found that kainic acid injections into the LHA of adult rats produced adipsia and aphagia without the persistent motor, sensorimotor, and arousal disturbances typically observed in adult rats sustaining electrolytic LHA lesions. Those authors (15) concluded that the consummatory deficits were related to destruction of neurons within the LHA, not damage to fiber systems (including dopaminergic fiber systems, which were spared) passing through the LHA. Infant rats with LHA destruction and adult rats with kainic acidproduced LHA lesions both demonstrated consummatory deficits without sensory neglect or attenuated arousal; however, the two preparations differed in that kainic acid lesions spared$bres en passage whereas those fibers were damaged in lo-day-old rats with extensive electrolytic LHA lesions. This apparent discrepancy can be resolved by consideration of recent developmental research. In contrast to adults, electrolytic lesions of the midbrain reticular formation (6) or neurotoxin dopamine depletion (24) of preweaning infant rats produced a postlesion period of hyperactivity and hyperreactivity. Thus, damage to these fiber systems in infant rats produced a paradoxical increase in activity and arousal levels, and damage to these fibers with the present infant LHA lesions would account for the postlesion period of hyperreactivity and stimulation-induced hyperactivity (in contrast to the sensory neglect and attenuated arousal produced with LHA lesions in adult rats). The differential behavioral effects of damage to endogenous LHA neurons versusfibres en passage would also account for the behavioral similarities and differences of the bilateral LHA and incomplete LHA rats of the present report. The incomplete rats had the lesion on one side of the brain biased in the dorsomedial direction and this lesion configuration would result in considerable bilateral damage to the nigrostriatal bundle, trigeminal lemniscus, and reticular formation fiber systems; however, there would be only partial bilateral damage to intrinsic LHA neurons, as the ventral half of the LHA was spared on one side of the brain. Thus, bilateral and incomplete rats shared nearly equivalent damage to the fiber systems mediating the motor abnormality and paradoxical hyperreactivity effect; however, the bilateral rats sustained more extensive bilateral damage of intrinsic LHA neurons, and therefore suffered more severe and persistent consummatory deficits than found for the incomplete rats. The present developmental report and the adult kainic acid research both yielded results which suggest that damage of endogenous LHA neurons resulted in consummatory deficits, whereas damage of fiber systems coursing through or near the LHA resulted in alteration of sensorimotor and/or arousal capacity. Also, the present results support the dopaminergic model of minimal brain dysfunction-childhood hyperactivity (24) and the
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proposed involvement of LHA neurons in diencephalic infancy-failure to thrive syndrome (1).
syndrome
of
REFERENCES 1. ALMLI, C. R. 1978. The ontogeny of feeding and drinking behaviors: effects of early brain damage. Neurosci. Biobehav. Rev. 2: 281-300. 2. ALMLI, C. R., AND R. S. FISHER. 1977. Infant rats: sensorimotor ontogeny and effects of substantia nigra destruction. Bruin Res. Bull. 2: 425-459. 3. ALMLI, C. R., AND G. T. GOLDEN. 1976. Preweanling rats: recovery from lateral hypothalamic damage. J. Camp. Physiol. 90: 1063-1074. 4. ALMLI, C. R., AND G. T. GOLDEN. 1976. Serial lateral hypothalamic destruction: infancy and adulthood. Exp. Neural. 53: 646-662. 5. ALMLI, C. R., AND G. T. GOLDEN. 1974. Infant rats: effects of lateral hypothalamic destruction. Physiol. Behav. 13: 81-90. 6. ALMLI, C. R., AND D. L. HILL. 1977. Infant rats: effects of central gustatory and reticular formation destruction upon the ontogeny of sensorimotor and regulatory behaviors. Sot. Neurosci. Abstr. 3: 421. 7. ALMLI, C. R., D. L. HILL, N. T. MCMULLEN, AND R. S. FISHER. 1979. Newborn rats: lateral hypothalamic damage and consummatory-sensorimotor ontogeny. Physiol. Behav.
22: 767-773.
8. ALMLI, C. R., N. T. MCMULLEN, AND G. T. GOLDEN. 1976. Infant rats: hypothalamic unit activity. Brain Res. Bull. 1: 543-552. 9. ALMLI, C. R., AND C. S. WEISS. 1974. Drinking behaviors: effects of lateral preoptic and lateral hypothalamic destruction. Physiol. Behav. 13: 527-538. 10. BERNARDIS, L. L. 1972. Delayed ventricular changes in the hypothalamus of the weanling rat following electrolytic lesions of the ventromedial nucleus. J. Neurovisc. Relat. 32: 347-354. 11. Cox, V. C., AND J. W. KAKOLEWSKI. 1970. Sex differences in body weight regulation in rats following lateral hypothalamic lesions. Camp. Behav. Biol. 5: 195-197. 12. COYLE, J. T. 1974. Development of the central catecholominergic neurons. Pages 877-884in F. 0. SCHMITT AND F. G. WORDEN, Eds., The Neurosciences: Third Study Program. MIT Press, Cambridge, Massachusetts. 13. EPSTEIN, A. N. 1971. The lateral hypothalamic syndrome: its implications for the physiologicalpsychologyofhungerand thirst. Pages 263-317in E. STELLAR AND J. M. SPRAGUE, Eds., Progress in Physiological Psychology, Vol. 4. Academic Press, New York/London. 14. FISHER, R. S., AND C. R. ALMLI. 1978. Infant rats: ontogeny of hypothalamic unit modulation by internal and external sensory input. Int. Sot. Develop. Psychobiol.: St. Louis, Missouri. 15. GROSSMAN, S. P., D. DACEY, A. E. HALARIS, T. COLLIER, AND A. ROUTTENBERG. 1978. Aphagia and adipsia after preferential destruction of nerve cell bodies in the hypothalamus. Science 202: 537-539. 16. KGNIG, J. F. R., AND R. KLIPPEL. 1963. Forebrain and Lower Parts of the Brain
The Rat Bruin: A Stereotaxic Stem. Williams & Wilkins,
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Baltimore. 17. LEVITT, D. R., AND P. TEITELBAUM. 1975. Somnolence, akinesia, and sensory activation of motivated behavior in the lateral hypothalamic syndrome. Proc. Natl. Acad Sci. U.S.A.
72: 2819-2823.
18. LOIZOU, L. A. 1972. The postnatal ontogeny of monoamine-containing central nervous system of the albino rat. Brain Res. 40: 395-418.
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19. LYTLE, L. D., AND B. A. CAMPBELL. 1975. Effects of lateral hypothalamic lesions on consummatory behavior in developing rats. Physiol. Behav. 15: 323-331. 20. MCMULLEN, N. T., AND C. R. ALMLI. 1979. Neuronal development in the medial forebrain bundle: a golgi study of preoptic and hypothalamic neurons in the rat. Fed. Proc. 38: 1397. 21. MCMULLEN, N. T., AND C. R. ALMLI. 1978. Golgi observations on medial forebrain bundle (MFB) neurons in newborn rats. Sot. Neurosci. Abstr. 4: 120. 22. MARSHALL, .I. F., AND P: TEITELBAUM. 1974. Further analysis of sensory inattention following lateral hypothalamic damage in rats. J. Camp. Physiol. Psychol. 86: 375-395. 23. PARKER, S. W., AND S. M. FELDMAN. 1967. Effects of mesencephalic lesions on feeding behavior in rats. Exp. Neural. 17: 313-326. 24. SHAYWITZ, B. A., R. D. YAGER, AND J. H. KLOPPER. 1976. Selective dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. Science 191: 305-308. 25. SIEGEL, S. 1956. Nonparametric Statistics. McGraw-Hill, New York. 26. STRICKER, E. M., AND M. J. ZIGMOND. 1976. Recovery of function after damage to central catecholamine-containing neurons: a neurochemical model for the lateral hypothalamic syndrome. Pages 121-188 in J. M. SPRAGUE AND A. N. EPSTEIN, Eds., Progress in Psychobiology and Physiological Psychology, Vol. 6. Academic Press, New York/London. 27. UNGERSTEDT, U. 1971. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-sttiatal dopamine system. Acta Physiol. Stand. Suppl. 367: 95- 122. 28. WOLF, G., AND L. V. DICARA. 1971. A third ascending hypothalamopetal pathway. Exp. Neurol.
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Lateral Hypothalamus Destruction in Infant Rats Produces Consummatory Deficits without Sensory Neglect or Attenuated Arousal C. ROBERT ALMLI, Department Received
ROBIN
of Psychology, January
S. FISHER, AND DAVID Ohio
University,
22, 1979; revision
Athens,
received
May
Ohio
L. HILL’ 45701
15, 1979
Male and female albino rats sustained bilateral electrolytic destruction of the lateral hypothalamic area (LHA) at 10 days of age. After brain damage, physical growth, the ontogeny of sensorimotor behavioral capacity, and consummatory behavioral responses to specific regulatory challenges were repeatedly and systematically assessed for as long as 375 days of age. Bilateral LHA damage caused immediate cessation of suckling from the dam and necessitated maintenance by hand and tube feeding. The infant LHA rats were incapable of regulating body weight by intake of dry food and water alone when killed at 70 or 375 days of age. Although they eventually could maintain body weight by ad libitum intake of highly palatable wet diets, these rats displayed severe body weight reduction, impaired linear growth, and permanent consummatory deficits to specific regulatory challenges. Multimodal sensorimotor tests failed to reveal “sensory neglect” or “attenuated arousal” in the brain-damaged rats; however, a transient syndrome of motor deficits and hyperreactivity consistently appeared. These findings were in sharp contrast to the sensorimotor deficits seen in animals which sustain LHA damage after weaning or in adulthood. These data argue that sensory neglect or attenuated arousal is not necessary to production of consummatory deficits and, taken with other research, suggest that damage to intrinsic LHA neurons causes consummatory deficits whereas damage to fibers of passage causes sensorimotor impairment.
INTRODUCTION Recent research has begun to explicate the role of the lateral hypothalamic area (LHA) of the rat in the ontogenetic development of Abbreviation: LHA-lateral hypothalamic area. 1 This research was supported by Ohio University Research Center grant 520 to C. R. Almli. R. S. Fisher is now at Department of Biological Sciences, Purdue University, West Lafayette, IN 47907. Address reprint requests to Dr. Almli. 146 0014-4886/79/100146-12$02.00/O Copyright All rights
8 1979 by Academic Press, Inc. of reproduction in any form reserved.
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consummatory behaviors (1,3-5,7,8, 14, 19-21). During the preweaning period, infant rats make the transition between suckling from the dam to mature forms of independent feeding and drinking behaviors concurrently with postnatal maturation of the LHA as evidenced by growth of endogenous LHA neurons (20,21), rapid increases in catecholamines (12, 18), and changes in LHA unit electrophysiologic characteristics (8, 14). Even with these developmental changes in the LHA and consummatory behaviors, bilateral destruction of the LHA in lo-day-old rats (3, 5, 19) produced severe and persistent consummatory deficits which were equivalent to the consummatory deficits associated with LHA damage in postweaning (e.g., 25 days of age) rats (5, 19) and adult rats (9, 11, 13). However, LHA destruction in rats 25 days of age and older also produced sensory, motor, and arousal dysfunction, in addition to consummatory deficits (9, 13, 17, 22, 26, 27). These other behaviors were not systematically evaluated in the earlier research on the effects of LHA destruction sustained by lo-day-old rats because of the lack of an appropriate testing procedure for infant rats, and because of the emphasis upon maintaining life of infant rats that had completely ceased suckling from the dam. Both problems have been overcome, as Almli and Fisher (2) have developed a sensorimotor testing battery for infant rats, and they have significantly improved the maintenance techniques for nonsuckling rats. Thus, the present study was designed to evaluate the sensorimotor capacity of lo-day-old rats sustaining LHA destruction. This knowledge is important, as Teitelbaum and co-workers (17, 22) suggested that aphagia following LHA destruction in adult rats was due to sensory neglect, and that recovery of consummatory behaviors was associated with abatement of neglect; furthermore, Stricker and Zigmond (26) proposed that the residual regulatory deficits of adults with LHA lesions were related to arousal dysfunction. The present study examined the association between sensory neglect and attenuated arousal and the consummatory deficits of infant rats sustaining bilateral LHA destruction. METHODS The animal housing conditions, surgical procedures, postoperative maintenance procedures, and measures of growth and consummatory behaviors were described in detail in previous reports (l-3, 5) and are therefore presented in abbreviated form in this study. Animals, Surgery, and Regulatory Measures. Infant albino rats of the Charles River CD strain were housed eight pups per litter under standard laboratory conditions (2, 3, 5). The rats were transferred to individual rack-mounted cages at 30 days of age.
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At 10 days of age the infant rats were anesthetized with diethyl ether, and a stainless-steel electrode (0.25mm diam, 0.5-mm uninsulated tip) was stereotaxically positioned at 3.5 mm anterior to lambda, ? 1.3 mm lateral to the sagittal suture, and 7.8 mm ventral to the skull surface (3-5). Anodal electrolytic lesions were produced with 1.5-mA current passed for 15 s. Thirteen rats (seven males and six females) sustained brain damage, and 17 rats (9 males and 8 females) served as controls (complete surgery and electrode penetration into the brain without passage of current). Body weight (g) was measured daily for all rats from 10 days of age until killing, and water intake (ml) was measured daily from 35 days of age until killing. Snout-anus body length (mm) was measured at 10,20, 30, and 70 days of age for all rats. After 50 days of age the rats received a variety of feeding and drinking tests to determine if “residual” regulatory deficits were present (2, 3, 5, 19). Sensorimotor Behaviors. Each brain-damaged and control rat was subjected to a comprehensive sensorimotor test battery at 10-20, 25, 30, and 60 days of age. The sensorimotor test battery is described in detail elsewhere (2). Briefly, this battery evaluated performance of the following behavior patterns during development: righting from a supine to prone position, air righting, forepaw and rear paw grasping, forepaw and lateral hopping, vibrisseal placing, forepaw and rear paw placing, rooting, spintwist reflex, ingestion of periorally applied Similac infant formula, edge aversion, visual orientation (tracking of moving object or light source with head), auditory orientation (tracking of sound source with head), olfactory orientation (behavioral reaction to odors of Mennen Skin Bracer and Similac), and somatosensory orientation (behavioral reaction after systematic tactile stimulation of the body surface from nose to tail with a 2-g pressure von Frey hair). In addition, posture, gait, grooming behaviors, and activity and reactivity levels were evaluated, and the presence of limb spasticity and tremor was noted (2). Histology. Eleven brain-damaged rats were killed at 70 days of age and two at 375 days of age. The rats were perfused intracardially with 0.87% NaCl followed by a 10% Formalin-saline solution. Frozen coronal sections were cut at 50 pm, and each section through the lesion was stained with cresyl violet. The locus and magnitude of neural damage were microscopically determined, and the sections were compared to atlas figures (16). RESULTS Histologic Analysis. Six rats (three males and three females) sustained extensive and complete bilateral destruction of the lateral hypothalamic
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area (bilateral rats), and the neural damage (absent, necrotic, and gliotic tissue zones) paralleled the anterior-posterior extent of the ventromedial nucleus of the hypothalamus. Tissue destruction extended medially to the fornix and mamillothalamic tract, and in some cases, the zone of damage approached the lateral edge of the ventromedial nucleus. The lateral spread of tissue damage included the medial portion of the internal capsule; dorsally, the damage spread to include portions of the fields of Forel, zona incerta, and medial lemniscus. Ventral spread of tissue destruction typically reached the base of the brain; however, for some rats, a narrow band of tissue was spared. Included in the bilateral group were two rats (one male and one female) which were studied until 375 days of age (long-term survival rats). Figure 1 presents photomicrographs of coronal sections through the centers of the lesions of bilateral rats killed at 70 days of age (A) and at 375 days of age (B). There was obvious lesion shrinkage from 70 to 375 days of age. There was also extensive shrinkage of lesion size between 10 and 70 days of age; however, most of this shrinkage was due to collapse of periventricular tissue laterally which resulted in ventricular dilation (7,10,29). Lateral hypothalamic destruction as extensive as shown in Fig. 1A produced severe and persistent growth and consummatory deficits when sustained by IO-day-old rats (3-5, 19), and equivalent damage sustained by rats at 25 days of age (5, 19) or as adults (9,11, 13, 17,22) produced growth and consummatory deficits as well as sensory neglect, hypoactivity, hyporeactivity, and motor dysfunction. Such neural destruction would include important fiber systems (e.g., nigrostriatal, trigeminal, reticular formation) which have been previously implicated in the etiology of behavioral deficits after lateral hypothalamic damage (2,6,23, 26-28,30). Another seven rats (four males and three females) sustained brain damage that differed slightly from that of the bilateral rats just described. These seven rats sustained damage on one side of the brain which duplicated that of the bilateral rats; however, the damage on the contralateral side of the brain had a slight dorsomedial bias. This bias resulted in damage of the dorsolateral fibrous zone of the ventromedial nucleus and extensive destruction of the fields of Fore1 and zona incerta. The lateral spread of damage ended at the medial edge of the internal capsule, and the ventral half of the lateral hypothalamic area was spared. Thus, these rats sustained incomplete bilateral damage of the lateral hypothalamic-medial forebrain bundle area (incomplete rats). All data analysis was carried out with analysis of variance, two-tailed t tests for independent groups, and x2 tests for independent samples (25). No gender differences were found on sensorimotor test performance within groups; therefore, data of both genders were pooled for analysis of sensorimotor capacity.
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FIG. 1. Photomicrographs of frontal sections through the centers of the lesions of rats sustaining bilateral destruction of the lateral hypothalamus (LHA) at 10 days of age. A-male rat (Bi-LHA group) killed at 70 days of age (60 days postlesion). B-male rat (Bi-LT group) killed at 375 days of age (365 days postlesion). Both rats were adipsic and consuming special wet diets at the time of killing. Brain sections were stained with cresyl violet and magnified x 10 (A) and x20 (B).
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Consummatory Behaviors and Growth. In replication of previous research (3-5, 19), bilateral LHA destruction sustained by lo-day-old rats resulted in complete cessation of suckling from the dam and severe consummatory and growth deficits which persisted for as long as 1 year postlesion. The bilateral rats never regained suckling behaviors after brain damage, and the rats were 32 to 45 days of age before they consumed sufficient “wet diet” (2) to survive without hand feeding. All bilateral rats were still adipsic and consuming only wet diets when killed at 70 or 375 days of age. When tested after 50 days of age, none of the bilateral rats drank water during food deprivation (P < 0.01) or after injection of hypertonic NaCl solution (Z’ < 0.01). The long-term survival rats (375 days of age) also failed to consume water after water deprivation or injection of polyethylene glycol solution. In addition, they failed to increase wet diet intake when injected with 2-deoxy-D-glucose, and they did not decrease wet diet intake when injected with amphetamine (3, 4, 19). At 70 days of age the bilateral males were 50 to 60% of control body weight (P < 0.05) and 66% of control body length (P < 0.05). The bilateral females were 70 to 80% of control body weight (P < 0.05) at 70 days of age, and they displayed a 22% reduction in body length (P < 0.05). When the two long-term rats were killed at 375 days of age, the male was 81% of control body weight and 89% of control body length. The long-term female was 123% of control body weight and 97% of control body length. The incomplete rats also ceased suckling after brain damage; however, these rats slowly recovered consummatory behaviors, and they were drinking water and feeding on dry pellets by 41 to 45 days of age. In spite of recovery of consummatory behaviors, the incomplete males had reduced body weights (55 to 60% of control, P < 0.05) and stunted linear growth (80 to 85% of control, P < 0.05) at 70 days of age. The incomplete females were 68 to 75% of control body weight P < 0.05) and 85 to 90% of control body length (P < 0.05) at 70 days of age. In response to the drinking tests, the incomplete rats did not differ from control for water intake after hypertonic NaCl solution injection or for water intake during food deprivation. Sensorimotor Behavior Ontogeny. The ontogenetic development of the various sensorimotor behaviors of the rats were classified into four categories on the basis of postlesion behavioral sequelae on each test. Behaviors could have normal response development, altered response development (persistence or substitution of response), delayed response development (temporal retardation of response onset relative to controls), or response abnormality (response was not observed during ontogenetic development of normal or control rats) (2). Behavioral dysfunctions were quantitatively estimated for consistency (percentage of group with dysfunction) and duration (temporal length of dysfunction of single rats
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within each group). The sham-operated control rats displayed normal sensorimotor response development on all tests and observations (2). Normal Response Development. In contrast to older rats sustaining LHA destruction (17, 22,26), the lo-day-old bilateral and incomplete rats in this study displayed normal sensorimotor development on the following tests: righting from a supine to prone position, air righting, forepaw and rear paw placing, forepaw and rear paw grasping, rooting, edge aversion, visual orientation, auditory orientation, olfactory orientation, and activity level in isolation. Delayed Response Development. As Table 1 indicates, some rats (0 to 57%) of the bilateral and incomplete groups displayed a l- to 3-day delay in the development of forepaw and lateral hopping, vibrisseal placing, and spin-twist reflex. The short durations of the delayed responses coupled with the finding that not all rats of any group displayed delayed responses indicated that these delayed responses might have been due to subtle differences in brain damage among rats. Altered Response Development. Response development on the somatosensory orientation test was altered in the bilateral and incomplete TABLE
1
Sensorimotor Behavior Dysfunction after Bilateral and Incomplete Destruction of the Lateral Hypothalamus at 10 Days of Age in the Rat” Symptom duration (days)
Percentage of group with symptom
Response class/test
Bilateral group
Incomplete tww
Delayed responses Forepaw hopping Lateral hopping Vibrisseal placing Spin-twist reflex
o-1 o-1 o-1 0
o-3 o-2 0 o-2
25 25 25 0
57 29 0 29
50
50
100
100
S-50 S-20 15-20 4-10 20-50
5-50 5-50 5-20 3-10 20-50
100 100 100 100 100
100 100 100 100 100
Altered responses Somatosensory Orientation Abnormal responses Posture Gait Spasticity Tremor Hyperreactivity
Bilateral group
Incomplete group
a Symptom duration expresses the maximum and minimum temporal extension of dysfunction in days after surgery.
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rats (see Table 1). Stimulation of the body surface of normal and sham-operated control rats (10 days of age and older) with a 2-g pressure von Frey hair (2) resulted in a turn of the head toward the site of stimulation in approximately 85 to 90% of the trials (turn response). On 5 to 10% of the trials, the rats turned their heads toward the site of stimulation and brushed at the stimulated body region with their hind limbs (turn-brush response), and on 5 to 10% of the trials the rats failed to orient to the stimulation (no response). The bilateral and incomplete rats differed from controls in that the brain-damaged rats displayed an increased frequency of turn-brush responses (bilateral = 25%, incomplete = 19%, control = 8%) and a decreased frequency of turn responses (bilateral = 70%, incomplete = 76%, control = 87%) during development. No-response to stimulation had a constant frequency of 5% for all groups. Chi square tests of statistical independence of these response frequency data revealed that there were no reliable differences between groups prior to brain damage at 10 days of age. However, after brain damage there were reliable differences between groups at 11 through 20 days of age (P < O.Ol), at 25 days of age (P < 0.05), but not at 30 days of age. Reliable differences were again found at 60 days of age (P < 0.05). The long-term survival rats displayed response frequencies equal to those of control rats when tested at 90 through 375 days of age which indicated that the effect was persistent but not permanent. Thus, the bilateral and incomplete rats exhibited an increased frequency of a normal response to tactile stimulation (turn-brush response) at the expense of another response (turn response) more typical of normal response development. However, it was important to note that the brain-damaged rats were responding to tactile stimulation and they did not display a change in frequency of no-response to stimulation; i.e., they were not “neglecting” the stimulation. Abnormal Responses. Brain-damaged rats had a consistent and persistent set of behavioral abnormalities after sustaining brain damage (see Table I). The following symptoms were observed postlesion in all brain-damaged rats: abnormal posture, abnormal gait, limb spasticity, tremor, and hyperreactivity. Control rats did not display these symptoms at any time during ontogeny. Postural abnormalities consisted of a “hunched” curvature of the spine, lowered head attitude, and an appearance of “tip-toe” standing. Abnormalities of gait were uncoordinated locomotion and hunched body position with abnormal extension of the extremities. Bilateral rats had slightly less persistent gait dysfunction than incomplete rats. These abnormalities of posture and gait were not observed in the long-term rats on or after 90 days of age. All brain-damaged rats also exhibited limb spasticity. This symptom consisted of limb rigidity and extension which may have contributed to the
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abnormalities of posture and gait and the delayed response ontogeny of several measures such as forepaw and lateral hopping. Mild forms of whole body tremor were characteristic of the braindamaged rats in the initial phases of postsurgical recovery. In 83% of the bilateral rats and 71% of the incomplete rats, tremor abated within 1 day of the recovery of prelesion body weight. Tremor ceased within 3 days of the recovery of prelesion body weight in all brain-damaged rats. This symptom was the only sensorimotor behavioral measure that demonstrated any temporal association with any regulatory achievement; i.e., recovery of prelesion body weight. No residual tremor was found during maturity in the long-term rats. All brain-damaged rats displayed a similar and persistent form of hyperreactivity. Handling or gross tactile stimulation of the rats tended to evoke biting, vocalization, extreme struggle to escape, and rapid, uncoordinated locomotion. These rats were also hyperreactive while in the litter cage when they came in contact with littermates or the dam. However, these rats did not display high activity levels when in isolation, and some form of stimulation seemed necessary for the production of hyperactivity. DISCUSSION Extensive bilateral destruction of the LHA in adult rats was shown to produce consummatory deficits, postural and locomotor abnormality, sensory neglect, and attenuated arousal levels; and some investigators have suggested that the consummatory deficits were secondary to sensory and/or arousal dysfunction (9,11,13,17,22,26). This suggestion was based on demonstrations of the close temporal relationship between recovery from sensorimotor and consummatory deficits after LHA destruction in adults and on research showing that damage to fiber systems coursing through or near the LHA (e.g., nigrostriatal, trigeminal, reticular formation) produced sensory and/or arousal dysfunction in adults which yielded consummatory deficits (23, 26, 27, 30). However, in the present report, extensive bilateral destruction of the LHA in lo-day-old rats produced motor-postural abnormality and severe and persistent consummatory deficits that were not associated with sensory neglect or attenuated arousal levels. These results demonstrated that sensory neglect and/or attenuated arousal levels were not necessary for the production of consummatory deficits after LHA destruction; i.e., damage to the LHA produced primary consummatory deficits which were not accompanied by sensory neglect or attenuated arousal. The present demonstration of consummatory deficits without sensory neglect or attenuated arousal for LHA-damaged infant rats was supported
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by recent research with adult rats. Grossman et al. (15) found that kainic acid injections into the LHA of adult rats produced adipsia and aphagia without the persistent motor, sensorimotor, and arousal disturbances typically observed in adult rats sustaining electrolytic LHA lesions. Those authors (15) concluded that the consummatory deficits were related to destruction of neurons within the LHA, not damage to fiber systems (including dopaminergic fiber systems, which were spared) passing through the LHA. Infant rats with LHA destruction and adult rats with kainic acidproduced LHA lesions both demonstrated consummatory deficits without sensory neglect or attenuated arousal; however, the two preparations differed in that kainic acid lesions spared$bres en passage whereas those fibers were damaged in lo-day-old rats with extensive electrolytic LHA lesions. This apparent discrepancy can be resolved by consideration of recent developmental research. In contrast to adults, electrolytic lesions of the midbrain reticular formation (6) or neurotoxin dopamine depletion (24) of preweaning infant rats produced a postlesion period of hyperactivity and hyperreactivity. Thus, damage to these fiber systems in infant rats produced a paradoxical increase in activity and arousal levels, and damage to these fibers with the present infant LHA lesions would account for the postlesion period of hyperreactivity and stimulation-induced hyperactivity (in contrast to the sensory neglect and attenuated arousal produced with LHA lesions in adult rats). The differential behavioral effects of damage to endogenous LHA neurons versusfibres en passage would also account for the behavioral similarities and differences of the bilateral LHA and incomplete LHA rats of the present report. The incomplete rats had the lesion on one side of the brain biased in the dorsomedial direction and this lesion configuration would result in considerable bilateral damage to the nigrostriatal bundle, trigeminal lemniscus, and reticular formation fiber systems; however, there would be only partial bilateral damage to intrinsic LHA neurons, as the ventral half of the LHA was spared on one side of the brain. Thus, bilateral and incomplete rats shared nearly equivalent damage to the fiber systems mediating the motor abnormality and paradoxical hyperreactivity effect; however, the bilateral rats sustained more extensive bilateral damage of intrinsic LHA neurons, and therefore suffered more severe and persistent consummatory deficits than found for the incomplete rats. The present developmental report and the adult kainic acid research both yielded results which suggest that damage of endogenous LHA neurons resulted in consummatory deficits, whereas damage of fiber systems coursing through or near the LHA resulted in alteration of sensorimotor and/or arousal capacity. Also, the present results support the dopaminergic model of minimal brain dysfunction-childhood hyperactivity (24) and the
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proposed involvement of LHA neurons in diencephalic infancy-failure to thrive syndrome (1).
syndrome
of
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