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Age-related memory deficits in rats and mice: Enhancement with peripheral injections of epinephrine
BEHAVIORALAND NEURALBIOLOGY~4, 213--220 (1985)
Age-Related Memory Deficits in Rats and Mice: Enhancement with Peripheral Injections of Epinephrine DEBRA B . STERNBERG, *'1 JOE L . MARTINEZ, JR.,~: PAUL E . GOLD,:~ AND JAMES L . MCGAUGH *'2
*Center for the Neurobiology of Learning and Memory and Department of Psychobiology, University of California, Irvine, California 92717; ?Department of Psychology, University of California, Berkeley, California 94720; and CDepartment of Psychology, University of Virginia, Charlottesville, Virginia 22901 Epinephrine peripherally administered to rats and mice immediately following avoidance and/or appetitive training enhances later memory retention in both young and old animals. These findings suggest a possible involvement of peripheral adrenergic systems in memory dysfunctions which accompany aging. © 1985 AcademicPress, Inc.
The ability to retain newly acquired information declines with age. Deficits in memory have been found in studies of retention in aged humans (Botwinick, 1973; Craik, 1977; Drachman, 1978; Kubanis & Zornetzer, 1981; Morley, Haxby, & Lundgren, 1980; Zornetzer, 1984), monkeys (Bartus, 1981; Bartus, Dean, & Beer, 1983; Bartus, Dean, Beer, & Lippa, 1982), rodents (Gold & McGaugh, 1975; Gold, McGaugh, Hankins, Rose, & Vasquez, 1981; Kubanis, Gobbel, & Zornetzer, 1981; Kubanis & Zornetzer, 1981; Zornetzer, 1984), and Aplysia (Bailey, Castelluci, Koester, & Chen, 1983). A substantial amount of research has focused on the hypothesis that deficits in cognitive function seen with aging may be based, at least in part, on degeneration of forebrain cholinergic systems (Bartus et al., 1983; Coyle, Price, & DeLong, 1983; Davies, 1981; Davis & Yamamura, 1978; Perry, 1980). There is extensive evidence that in humans, central cholinergic systems are impaired with aging, particularly in individuals diagnosed as having senile dementia of the Alzheimer's type (Bartus et al., 1983; Coyle et al., 1983; Davies, 1981; Davis & 1 To whom all correspondence and requests for reprints should be addressed. 2 This research was supported by USPHS Postdoctoral Fellowship MH08646 (to D.B.S.), an award from the James McKeen Cattell Foundation and USPHS Research Grants AG01642 and MH31141 (to P.E.G.), and AG00538 and MH12526 and Office of Naval Research Contract N00014-84-K-0391 (to J. L. McG.). 213 0163-1047/85 $3,00 Copyright© 1985by AcademicPress, Inc. All rightsof reproductionin any form reserved.
214
STERNBERG ET AL.
Yamamura, 1978; Drachman & Glosser, 1981; Perry, 1980). Furthermore, memory is impaired in many situations by administration of cholinergic antagonists such as scopolamine (Bartus, 1981; Bartus et al., 1982, 1983). These findings have led to many attempts to ameliorate the memory deficits using pharmacological treatments which enhance cholinergic activity (Bartus, 1981; Bartus et al., 1982, 1983; Christie, Shering, Ferguson, & Glen, 1981; Davis, Mohs, & Tinklenberg, 1979; Kubanis & Zornetzer, 1981; Zornetzer, 1984). These efforts have, as yet, met with limited success. Recently the findings of a number of studies suggest that dysfunctions in adrenergic mechanisms may also contribute to the rapid forgetting observed with old age. For example, the/3-adrenergic antagonist, propranolol, induces amnesia in young humans which resembles the naturally occurring memory impairment in aged humans (Soloman et al., 1983). Additionally, brain noradrenergic function in aged rodents shows decreases in turnover, reuptake, tyrosine hydroxylase activity, receptor binding, cAMP responses, and release in response to acute footshock stimulation (Kubanis & Zornetzer, 1981; Welsh & Gold, 1984; Zornetzer, 1984). The decreased responsiveness of brain norepinephrine seen in aged rats following a footshock is paralleled by a decrease in the release of the adrenomedullary hormone, epinephrine, in response to footshock (McCarty, 1981). This finding is of particular interest in view of extensive evidence that, in young rats and mice, retention is enhanced by moderate doses of epinephrine administered immediately after training (Gold, McCarty, & Sternberg, 1982; McGaugh, 1983). Further, treatments that alter peripheral adrenergic functioning, such as adrenal demedullation, and peripheral administration of epinephrine or adrenergic antagonists, alter the effects on memory of a variety of treatments, including electrical stimulation of the brain (Gold et al., 1982; McGaugh, 1983). These findings suggest that age-related memory deficits may be related to a decline in peripheral epinephrine. We now report that, in aged rats and mice, retention is enhanced by peripheral administration of epinephrine. METHODS
Male CFW mice (4 and 24 months old) and male Fischer 344 rats (3, 12, and 24 months old) were trained in a one-trial inhibitory (passive) avoidance task. The training apparatuses for rats and mice were similar in all respects except size. The apparatus was a trough-shaped alley which had a door separating a well-lit white start compartment and a dimly-lit shock compartment (Sternberg, Gold, & McGaugh, 1982). The walls and floor of the shock compartment consisted of stainless-steel plates through which the footshock (1.0 mA or 600/xA, 2 s, mice; 200 /xA, 0.4 s, rats) was delivered. On the training trial, each animal was placed in the start compartment, the door was lowered to form a hurdle
AGE-RELATED MEMORY DEFICITS
215
and the animal was allowed to cross over the hurdle into the compartment where footshock was delivered. Immediately following training, each animal received a subcutaneous injection of saline or epinephrine (0.01 or 0.1 mg/kg). Retention tests for saline-injected animals were administered 2 h, 24 h, 1 week, or 2 weeks after training, while the epinephrineinjected animals only received retention tests 24 h after training. The latency to enter the shock compartment was used as the measure of retention (300-s cut-off latency). Statistics used were two-tailed MannWhitney U-tests, p < .05 unless otherwise noted. In addition, other groups of male CFW mice (4 and 24 months old) were trained in a Y maze visual discrimination appetitive task. They were water deprived and maintained at 85-90% of their original weights. Each animal was placed in the Y maze for 3 min of familiarization every day for 3 days prior to training, and was given 3 min of water in its home cage after each familiarization trial. On the training day, the animal was placed in the start compartment, the door was opened, and the animal was allowed to explore the maze until it found water in the lighted arm of the maze (either right or left; varied randomly). The animal remained in the maze and was allowed to drink for an additional 3 rain. Immediately following training, the mouse received a subcutaneous injection of saline or epinephrine (0.1 mg/kg). Twenty-four hours later, the animal received a retention trial. The testing procedures were identical to those used in training. The animal's choice of arms (correct = lighted arm) was used as a measure of retention.
RESULTS In the first experiment, 4- and 24-month-old mice were trained with a 600-~A footshock (2-s duration). Different groups were tested for retention 1, 7, or 14 days later (N = 12 and 5-7 per group for young and old mice, respectively). Only the 4-month-old mice tested at 1 day showed significant retention of the learned response (Day 1 vs Day 2, sign test, p < .05). To better evaluate forgetting in these animals, additional mice were trained with the higher footshock level (1.0 mA; 2s) and tested at 2 h or 1, 7, or 14 days later (N = 12 and 4-7 per group for young and old mice, respectively). With this footshock intensity, young animals exhibited good retention performance at all intervals. At 2 h following training, the older mice had retention scores somewhat, but insignificantly, lower than those of the younger animals. At all longer retention intervals, the aged mice had median latencies below 30 s. At each of these trainingtesting intervals (1-14 days), retention latencies of the 24-month-old mice were significantly lower than those of the comparable group of 4-monthold mice. These findings are consistent with others reported in mice and with our previous results in rats (Bartus et al., 1982; Craik, 1977; Gold et al., 1981; Kubanis et al., 1981; Kubanis & Zornetzer, 1981; Zornetzer,
216
STERNBERG ET AL.
1984). The results do not appear to be a consequence of age-related changes in footshock sensitivity: The young and old mice did not differ in flinch thresholds (50%: young = 0.18 /xA, old = 0.13 /zA) or jump thresholds (0.45 /xA for both ages). The effects of immediate post-trial epinephrine on 24-h retention performance are shown in Fig. 1. At both doses, epinephrine significantly enhanced retention performance of both young and old mice. Of particular interest is the finding that the retention of old mice given post-training epinephrine was comparable to or better than that of the young controls. The results obtained with appetitive training are shown in Table 1. Once again, epinephrine enhanced retention performance of both 4- and 24-month-old mice (p < .05, Fisher exact probability tests, one-tailed; pooled p < .05 two-tailed). Thus, in both young and old mice, epinephrine enhanced memory in appetitive as well as aversive learning tasks. As Fig. 2 shows, the retention performance of old rats was significantly poorer than that of young rats when the animals were tested 1 week after training on the inhibitory avoidance task. Epinephrine administered immediately after training significantly enhanced 1-week retention performance of both 1- and 2-year-old rats. The performance of the epinephrine-treated groups was comparable to that of the young animals. DISCUSSION These findings provide further support for the view that peripheral adrenergic mechanisms may play an important role in memory modulation in normal adult animals. Our findings that memory is enhanced by post300
- •
Old
~'~ Young z LLI
200 I-I--" laJ
100
SAL 0.01 0.1 EPINEPHRINE (rng/kg) (600ffA,2.0secfs, 1day retention test) FI~. 1. An age comparison of epinephrine modulation of memory in mice. Epinephrine facilitates retention performance in both young and old mice in a one-trial inhibitory avoidance task. Retention is expressed as latency to reenter the shock compartment 24 h after aversive training (600/zA fs; 2 s). N = 25-38 and 6-14 per group for young and old mice, respectively.
AGE-RELATED MEMORY DEFICITS
217
TABLE 1
Epinephrine Modulation of M e m o r y in Mice Young
Old
Sal
Epi
Sal
Epi
4 8
9 3
2 6
8 2
33
75
25
80
Correct Errors
Percentage animals making correct choice
training administration of epinephrine suggest that the hormone affects retention by influencing memory storage processes. The possibility that epinephrine might affect attentional or motivational processes was not addressed in these experiments. Furthermore, when viewed in relation to other findings indicating diminished responsiveness of adrenergic systems to stress (McCarty, 1981; Ritter & Pelzer, 1978; Welsh & Gold, 1984), the findings suggest that the memory deficits in aged rats may result in part from decreased function of adrenal medullary catecholamines. Depressed function of central noradrenergic mechanisms (Kubanis & Zornetzer, 1981; Welsh & Gold, 1984; Zornetzer, 1984) may also be important in age-related memory deficits. Recent findings indicate that, in humans Sal [7//Epi (03 mg/kg) •
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"U, z LIJ I--
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"/// ....
y//A
<, 200 z
o I-z txl
ILl
°° ! TOday
1year
2 year
[200 #A, 0.4 sec fs, I week retention test )
Retention performance of rats in a one-trial inhibitory avoidance task. Retention is expressed as latency to reenter the shock compartment 1 week following training. There is a significant decrease in retention performance in old rats. A post-training injection of epinephrine enhanced retention performance of both 1- and 2-year-old rats. N = 12 per group for 70-day-old rats, and N = 7-12 per group for 1- and 2-year-old rats. FIo. 2.
218
STERNBERG ET AL,
as well as mice, the number of cell bodies in locus coeruleus, a brain stem nucleus which contributes most of the forebrain norepinephrine, decreases greatly with age (Bondareff, Mountjoy, & Roth, 1982; Vijayashankar & Brody, 1979; McGeer, McGeer, & Suzuki, 1977). In mice, the extent of the cell loss appears to be correlated with a decline in memory capacity (Leslie, Loughlin, McGaugh, Sternberg, & Zornetzer, 1983; Leslie, Loughlin, McGaugh, Sternberg, Young, & Zornetzer, 1985; Zornetzer, McGaugh, Gold, & Sternberg, 1983). When viewed in the context of epinephrine effects on brain function, including release of brain norepinephrine (Gold & Van Buskirk, 1978a, b), and electrographic arousal (Baust, Niemczyk, & Vieth, 1963), it seems likely that disruption of central as well as peripheral adrenergic mechanisms may contribute to age-related memory impairments. Thus, the findings reported here suggest that debilitation of adrenergic mechanisms may be a major contributor to memory deficits which accompany aging. However, it should be noted that the present results do not diminish the possible role of central or peripheral cholinergic contributions to age-related memory failures. For example, in the peripheral nervous system, it may well be the case that dysfunction of cholinergic neurons, e.g., afferents to the adrenal medulla via the splanchnic nerve, represents the primary cause of diminished adrenergic function. Thus, a full understanding of the roles of neurohumoral systems in age-related deficits will require examination of the interactions of these systems, as well as, more generally, interactions between a wide class of neurobiological changes observed with aging. REFERENCES Bailey, C. H., Castellucci, V. F., Koester, J., & Chen, M. (1983). Behavioral changes in aging aplysia: A model system for studying the cellular basis of age-impaired learning, memory, and arousal. Behavioral and Neural Biology, 38, 70-81. Bartus, R. T. (1981). Age-related memory loss and cholinergic dysfunction: Possible directions based on animal models. In T. Crook & K. S. Gershon (Eds.), Strategies for the development of an effective treatment for senile dementia. (pp. 71-92). New Canaan: Mark Powley Associates, Inc. Bartus, R. T., Dean, R. L., & Beer, B. (1983). An evaluation of drugs for improving memory in aged monkeys: Implications for clinical trials in humans. Psychobiology Bulletin, 19, 168-184. Bartus, R. T., Dean, R. L., Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction: A critical view. Science (Washington, DC) 217, 408417. Baust, W., Niemczyk, H., & Vieth, K. (1963). The action of blood pressure on the ascending reticular activating system with special reference to adrenalin-induced EEG arousal. Electroencephalography and Clinical Neurophysiology, 63, 63-72. Bondareff, W., Mountjoy, C. Q., & Roth, M. (1982). Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia. Neurology, 32, 164-168. Botwinick, J. (1973). Aging and behavior. New York: Springer.
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Christie, J. E., Shering, A., Ferguson, J., & Glen, A. I. M. (1981). Physostigmine and arecoline: Effects of intravenous infusions in Alzheimer presenile dementia. British Journal of Psychiatry, 138, 46-50. Coyle, J. T., Price, D. L., & DeLong, M. R. (1983). Alzheimer's disease: A disorder of cortical cholinergic innervation. Science (Washington, D.C.) 219, 1184-1190. Craik, F. J. M. (1977). Age differences in human memory. In J. E. Birren & K. W. Schaie (Eds.), Handbook of the psychology of aging (pp. 384-420). New York: Van NostrandReinhold. Davies, P. (1981). Theoretical treatment possibilities for dementia of the Alzheimer type: The cholinergic hypothesis. In T. Crook & K. S. Gershon (Eds.), Strategies for the development of an effective treatment for senile dementia (pp. 19-34). New Canaan: Mark Powley Associates, Inc. Davis, K. I., Mohs, R. C., & Tinklenberg, J. R. (1979). Enhancement of memory by pfiysostigmine. New England Journal of Medicine, 301, 946. Davis, K. L., & Yamamura, H. I. (1978). Cholinergic underactivity in human memory disorders. Life Sciences, 23, 1729-1734. Drachman, D. (1978). Central cholinergic system and memory. In M. Lipton, A. DiMascio, & K. Killam (Eds.), Psychopharmacology: A generation of progress (pp. 651-662). New York: Raven Press. Drachman, D. A., & Glosser G. (1981). Pharmacologic strategies in aging and dementia: The cholinergic hypothesis. In T. Crook & K. S. Gershon (Eds.), Strategies for the development of an effective treatment for senile dementia (pp. 35-52). New Canaan: Mark Powley Associates, Inc. Gold, P. E., McCarty, R., & Sternberg, D. B. (1982). Peripheral catecholamines and memory modulation. In C. A. Marsan & H. Mathies (Eds.), Neuronal plasticity and memory formation (pp. 327-338). New York: Raven Press. Gold, P. E., & McGaugh, J. L. (1975). Changes in learning and memory during aging. In J. M. Ordy and K. R. Brizzee (Eds.), Neurobiology of aging (pp. 145-158). New York: Plenum. Gold, P. E., McGaugh, J. L., Hankins, L. L., Rose, R. P., & Vasquez, B. J. (1981). Age dependent changes in retention in rats. Experimental Aging Research, 8, 53-58. Gold, P. E., & Van Buskirk, R. (1978a). Posttraining brain norepinephrine concentrations: Correlation with retention performance of avoidance training and with peripheral epinephrine modulation of memory processing. Behavioral Biology, 23, 509-520. Gold, P. E., & Van Buskirk, R. (1978b). Effects of alpha- and beta-adrenergic receptor antagonists on posttrial epinephrine modulation of memory: Relationship to postttraining brain norepinephrine concentrations. Behavioral Biology, 24, 168-184. Kubanis, P., Gobbel, J., & Zornetzer, S. F. (1981). Age-related memory deficits in Swiss mice. Behavioral and Neural Biology, 32, 241-247. Kubanis, P., & Zornetzer, S. F. (1981). Age-related behavioral and neurobiological change s: A review with emphasis on memory. Behavioral and Neural Biology, 31, 115-172. Leslie, F. M., Loughlin, S. E., McGaugh, J. L., Sternberg, D. B., & Zornetzer, S. F. (1983). Noradrenergic changes in senescent memory loss. Abstracts Society for Neuroscience, 9, 98. Leslie, F. M., Loughlin, S. E., McGaugh, J. L., Sternerg, D. B., Young, L. E., & Zornetzer, S. F. (1985). Noradrenergic changes memory loss in aged mice. Brain Research, in press. McCarty, R. (1981). Aged rats: Diminished sympathetic adrenal medullary response to acute stress. Behavioral and Neural Biology, 33, 204-212. McGaugh, J. L. (1983). Hormonal influences on memory. Annual Review of Psychology, 34, 297-323. McGeer, P. L., McGeer, E. G., & Suzuki, J. S. (1977). Aging and extrapyramidal function. Archives of Neurology, 34, 33-35.
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Morely, G. K., Haxby, J. V., & Lundgren, S. L. (1980). Memory, aging and dementia. In G. J. Maletta and Pirozzolo (Eds.), The aging nervous system (pp. 110-125). New York: Praeger. Perry, E. K. (1980). The cholinergic system in old age and Alzheimer's disease. Age and Aging, 9, 1-8. Ritter, S., & Pelzer, N. (1978). Magnitude of stress-induced brain norepinephrine depletion varies with age. Brain Research, 152, 170-175. Solomon, S., Hotchkiss, E., Saravay, S. M., Bayer, C., Ramsey, P., & Blum, R. S. (1983). Impariment of memory function by antihypertensive medication. Archives of General Psychiatry, 40, 1109-1112. Sternberg, D. B., Gold, P. E., & McGaugh, J. L. (1982). Noradrenergic sympathetic blockade: Lack of effect on memory or retrograde amnesia. European Journal of Pharmacology, 81, 133-136. Vijayashankar, N., & Brody, H. (1979). A quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging. Journal of Neuropathology and Experimental Neurology, 38, 490-497. Welsh, K. A., & Gold, P. E. (1984). Age-related changes in brain catecholamine responses to a single footshock. Neurobiology of Aging, 5, 55-59. Zornetzer, S. F. (1984). Brain substrates of senescent memory decline. In L. R. Squire and N. Butters (Eds.), The neuropsychology of memory (pp. 588-600). New York: Guilford Press. Zornetzer, S. F., McGaugh, J. L., Gold, P. E., & Sternberg, D. B. (1983). Adrenergic influences in age-related changes in memory. Presented at 36th Annual Scientific Meeting of the Gerontological Society of America, San Francisco.
Age-Related Memory Deficits in Rats and Mice: Enhancement with Peripheral Injections of Epinephrine DEBRA B . STERNBERG, *'1 JOE L . MARTINEZ, JR.,~: PAUL E . GOLD,:~ AND JAMES L . MCGAUGH *'2
*Center for the Neurobiology of Learning and Memory and Department of Psychobiology, University of California, Irvine, California 92717; ?Department of Psychology, University of California, Berkeley, California 94720; and CDepartment of Psychology, University of Virginia, Charlottesville, Virginia 22901 Epinephrine peripherally administered to rats and mice immediately following avoidance and/or appetitive training enhances later memory retention in both young and old animals. These findings suggest a possible involvement of peripheral adrenergic systems in memory dysfunctions which accompany aging. © 1985 AcademicPress, Inc.
The ability to retain newly acquired information declines with age. Deficits in memory have been found in studies of retention in aged humans (Botwinick, 1973; Craik, 1977; Drachman, 1978; Kubanis & Zornetzer, 1981; Morley, Haxby, & Lundgren, 1980; Zornetzer, 1984), monkeys (Bartus, 1981; Bartus, Dean, & Beer, 1983; Bartus, Dean, Beer, & Lippa, 1982), rodents (Gold & McGaugh, 1975; Gold, McGaugh, Hankins, Rose, & Vasquez, 1981; Kubanis, Gobbel, & Zornetzer, 1981; Kubanis & Zornetzer, 1981; Zornetzer, 1984), and Aplysia (Bailey, Castelluci, Koester, & Chen, 1983). A substantial amount of research has focused on the hypothesis that deficits in cognitive function seen with aging may be based, at least in part, on degeneration of forebrain cholinergic systems (Bartus et al., 1983; Coyle, Price, & DeLong, 1983; Davies, 1981; Davis & Yamamura, 1978; Perry, 1980). There is extensive evidence that in humans, central cholinergic systems are impaired with aging, particularly in individuals diagnosed as having senile dementia of the Alzheimer's type (Bartus et al., 1983; Coyle et al., 1983; Davies, 1981; Davis & 1 To whom all correspondence and requests for reprints should be addressed. 2 This research was supported by USPHS Postdoctoral Fellowship MH08646 (to D.B.S.), an award from the James McKeen Cattell Foundation and USPHS Research Grants AG01642 and MH31141 (to P.E.G.), and AG00538 and MH12526 and Office of Naval Research Contract N00014-84-K-0391 (to J. L. McG.). 213 0163-1047/85 $3,00 Copyright© 1985by AcademicPress, Inc. All rightsof reproductionin any form reserved.
214
STERNBERG ET AL.
Yamamura, 1978; Drachman & Glosser, 1981; Perry, 1980). Furthermore, memory is impaired in many situations by administration of cholinergic antagonists such as scopolamine (Bartus, 1981; Bartus et al., 1982, 1983). These findings have led to many attempts to ameliorate the memory deficits using pharmacological treatments which enhance cholinergic activity (Bartus, 1981; Bartus et al., 1982, 1983; Christie, Shering, Ferguson, & Glen, 1981; Davis, Mohs, & Tinklenberg, 1979; Kubanis & Zornetzer, 1981; Zornetzer, 1984). These efforts have, as yet, met with limited success. Recently the findings of a number of studies suggest that dysfunctions in adrenergic mechanisms may also contribute to the rapid forgetting observed with old age. For example, the/3-adrenergic antagonist, propranolol, induces amnesia in young humans which resembles the naturally occurring memory impairment in aged humans (Soloman et al., 1983). Additionally, brain noradrenergic function in aged rodents shows decreases in turnover, reuptake, tyrosine hydroxylase activity, receptor binding, cAMP responses, and release in response to acute footshock stimulation (Kubanis & Zornetzer, 1981; Welsh & Gold, 1984; Zornetzer, 1984). The decreased responsiveness of brain norepinephrine seen in aged rats following a footshock is paralleled by a decrease in the release of the adrenomedullary hormone, epinephrine, in response to footshock (McCarty, 1981). This finding is of particular interest in view of extensive evidence that, in young rats and mice, retention is enhanced by moderate doses of epinephrine administered immediately after training (Gold, McCarty, & Sternberg, 1982; McGaugh, 1983). Further, treatments that alter peripheral adrenergic functioning, such as adrenal demedullation, and peripheral administration of epinephrine or adrenergic antagonists, alter the effects on memory of a variety of treatments, including electrical stimulation of the brain (Gold et al., 1982; McGaugh, 1983). These findings suggest that age-related memory deficits may be related to a decline in peripheral epinephrine. We now report that, in aged rats and mice, retention is enhanced by peripheral administration of epinephrine. METHODS
Male CFW mice (4 and 24 months old) and male Fischer 344 rats (3, 12, and 24 months old) were trained in a one-trial inhibitory (passive) avoidance task. The training apparatuses for rats and mice were similar in all respects except size. The apparatus was a trough-shaped alley which had a door separating a well-lit white start compartment and a dimly-lit shock compartment (Sternberg, Gold, & McGaugh, 1982). The walls and floor of the shock compartment consisted of stainless-steel plates through which the footshock (1.0 mA or 600/xA, 2 s, mice; 200 /xA, 0.4 s, rats) was delivered. On the training trial, each animal was placed in the start compartment, the door was lowered to form a hurdle
AGE-RELATED MEMORY DEFICITS
215
and the animal was allowed to cross over the hurdle into the compartment where footshock was delivered. Immediately following training, each animal received a subcutaneous injection of saline or epinephrine (0.01 or 0.1 mg/kg). Retention tests for saline-injected animals were administered 2 h, 24 h, 1 week, or 2 weeks after training, while the epinephrineinjected animals only received retention tests 24 h after training. The latency to enter the shock compartment was used as the measure of retention (300-s cut-off latency). Statistics used were two-tailed MannWhitney U-tests, p < .05 unless otherwise noted. In addition, other groups of male CFW mice (4 and 24 months old) were trained in a Y maze visual discrimination appetitive task. They were water deprived and maintained at 85-90% of their original weights. Each animal was placed in the Y maze for 3 min of familiarization every day for 3 days prior to training, and was given 3 min of water in its home cage after each familiarization trial. On the training day, the animal was placed in the start compartment, the door was opened, and the animal was allowed to explore the maze until it found water in the lighted arm of the maze (either right or left; varied randomly). The animal remained in the maze and was allowed to drink for an additional 3 rain. Immediately following training, the mouse received a subcutaneous injection of saline or epinephrine (0.1 mg/kg). Twenty-four hours later, the animal received a retention trial. The testing procedures were identical to those used in training. The animal's choice of arms (correct = lighted arm) was used as a measure of retention.
RESULTS In the first experiment, 4- and 24-month-old mice were trained with a 600-~A footshock (2-s duration). Different groups were tested for retention 1, 7, or 14 days later (N = 12 and 5-7 per group for young and old mice, respectively). Only the 4-month-old mice tested at 1 day showed significant retention of the learned response (Day 1 vs Day 2, sign test, p < .05). To better evaluate forgetting in these animals, additional mice were trained with the higher footshock level (1.0 mA; 2s) and tested at 2 h or 1, 7, or 14 days later (N = 12 and 4-7 per group for young and old mice, respectively). With this footshock intensity, young animals exhibited good retention performance at all intervals. At 2 h following training, the older mice had retention scores somewhat, but insignificantly, lower than those of the younger animals. At all longer retention intervals, the aged mice had median latencies below 30 s. At each of these trainingtesting intervals (1-14 days), retention latencies of the 24-month-old mice were significantly lower than those of the comparable group of 4-monthold mice. These findings are consistent with others reported in mice and with our previous results in rats (Bartus et al., 1982; Craik, 1977; Gold et al., 1981; Kubanis et al., 1981; Kubanis & Zornetzer, 1981; Zornetzer,
216
STERNBERG ET AL.
1984). The results do not appear to be a consequence of age-related changes in footshock sensitivity: The young and old mice did not differ in flinch thresholds (50%: young = 0.18 /xA, old = 0.13 /zA) or jump thresholds (0.45 /xA for both ages). The effects of immediate post-trial epinephrine on 24-h retention performance are shown in Fig. 1. At both doses, epinephrine significantly enhanced retention performance of both young and old mice. Of particular interest is the finding that the retention of old mice given post-training epinephrine was comparable to or better than that of the young controls. The results obtained with appetitive training are shown in Table 1. Once again, epinephrine enhanced retention performance of both 4- and 24-month-old mice (p < .05, Fisher exact probability tests, one-tailed; pooled p < .05 two-tailed). Thus, in both young and old mice, epinephrine enhanced memory in appetitive as well as aversive learning tasks. As Fig. 2 shows, the retention performance of old rats was significantly poorer than that of young rats when the animals were tested 1 week after training on the inhibitory avoidance task. Epinephrine administered immediately after training significantly enhanced 1-week retention performance of both 1- and 2-year-old rats. The performance of the epinephrine-treated groups was comparable to that of the young animals. DISCUSSION These findings provide further support for the view that peripheral adrenergic mechanisms may play an important role in memory modulation in normal adult animals. Our findings that memory is enhanced by post300
- •
Old
~'~ Young z LLI
200 I-I--" laJ
100
SAL 0.01 0.1 EPINEPHRINE (rng/kg) (600ffA,2.0secfs, 1day retention test) FI~. 1. An age comparison of epinephrine modulation of memory in mice. Epinephrine facilitates retention performance in both young and old mice in a one-trial inhibitory avoidance task. Retention is expressed as latency to reenter the shock compartment 24 h after aversive training (600/zA fs; 2 s). N = 25-38 and 6-14 per group for young and old mice, respectively.
AGE-RELATED MEMORY DEFICITS
217
TABLE 1
Epinephrine Modulation of M e m o r y in Mice Young
Old
Sal
Epi
Sal
Epi
4 8
9 3
2 6
8 2
33
75
25
80
Correct Errors
Percentage animals making correct choice
training administration of epinephrine suggest that the hormone affects retention by influencing memory storage processes. The possibility that epinephrine might affect attentional or motivational processes was not addressed in these experiments. Furthermore, when viewed in relation to other findings indicating diminished responsiveness of adrenergic systems to stress (McCarty, 1981; Ritter & Pelzer, 1978; Welsh & Gold, 1984), the findings suggest that the memory deficits in aged rats may result in part from decreased function of adrenal medullary catecholamines. Depressed function of central noradrenergic mechanisms (Kubanis & Zornetzer, 1981; Welsh & Gold, 1984; Zornetzer, 1984) may also be important in age-related memory deficits. Recent findings indicate that, in humans Sal [7//Epi (03 mg/kg) •
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Retention performance of rats in a one-trial inhibitory avoidance task. Retention is expressed as latency to reenter the shock compartment 1 week following training. There is a significant decrease in retention performance in old rats. A post-training injection of epinephrine enhanced retention performance of both 1- and 2-year-old rats. N = 12 per group for 70-day-old rats, and N = 7-12 per group for 1- and 2-year-old rats. FIo. 2.
218
STERNBERG ET AL,
as well as mice, the number of cell bodies in locus coeruleus, a brain stem nucleus which contributes most of the forebrain norepinephrine, decreases greatly with age (Bondareff, Mountjoy, & Roth, 1982; Vijayashankar & Brody, 1979; McGeer, McGeer, & Suzuki, 1977). In mice, the extent of the cell loss appears to be correlated with a decline in memory capacity (Leslie, Loughlin, McGaugh, Sternberg, & Zornetzer, 1983; Leslie, Loughlin, McGaugh, Sternberg, Young, & Zornetzer, 1985; Zornetzer, McGaugh, Gold, & Sternberg, 1983). When viewed in the context of epinephrine effects on brain function, including release of brain norepinephrine (Gold & Van Buskirk, 1978a, b), and electrographic arousal (Baust, Niemczyk, & Vieth, 1963), it seems likely that disruption of central as well as peripheral adrenergic mechanisms may contribute to age-related memory impairments. Thus, the findings reported here suggest that debilitation of adrenergic mechanisms may be a major contributor to memory deficits which accompany aging. However, it should be noted that the present results do not diminish the possible role of central or peripheral cholinergic contributions to age-related memory failures. For example, in the peripheral nervous system, it may well be the case that dysfunction of cholinergic neurons, e.g., afferents to the adrenal medulla via the splanchnic nerve, represents the primary cause of diminished adrenergic function. Thus, a full understanding of the roles of neurohumoral systems in age-related deficits will require examination of the interactions of these systems, as well as, more generally, interactions between a wide class of neurobiological changes observed with aging. REFERENCES Bailey, C. H., Castellucci, V. F., Koester, J., & Chen, M. (1983). Behavioral changes in aging aplysia: A model system for studying the cellular basis of age-impaired learning, memory, and arousal. Behavioral and Neural Biology, 38, 70-81. Bartus, R. T. (1981). Age-related memory loss and cholinergic dysfunction: Possible directions based on animal models. In T. Crook & K. S. Gershon (Eds.), Strategies for the development of an effective treatment for senile dementia. (pp. 71-92). New Canaan: Mark Powley Associates, Inc. Bartus, R. T., Dean, R. L., & Beer, B. (1983). An evaluation of drugs for improving memory in aged monkeys: Implications for clinical trials in humans. Psychobiology Bulletin, 19, 168-184. Bartus, R. T., Dean, R. L., Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction: A critical view. Science (Washington, DC) 217, 408417. Baust, W., Niemczyk, H., & Vieth, K. (1963). The action of blood pressure on the ascending reticular activating system with special reference to adrenalin-induced EEG arousal. Electroencephalography and Clinical Neurophysiology, 63, 63-72. Bondareff, W., Mountjoy, C. Q., & Roth, M. (1982). Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia. Neurology, 32, 164-168. Botwinick, J. (1973). Aging and behavior. New York: Springer.
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