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Lesions of the Hippocampal Formation but Not Lesions of the Fornix Or the Mammillary Nuclei Produce Long-Lasting Memory Impairment in Monkeys

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Lesions of the Hippocampal Formation but Not Lesions of the Fornix Or the Mammillary Nuclei Produce Long-Lasting Memory Impairment in Monkeys The Journal of Neuroscience, March 1989, g(3): 898-913 Lesions of the Hippocampal Formation But Not Lesions of the Fornix or the Mammillary Nuclei Produce Long-Lasting Memory Impairment in Monkeys Stuart Zola-Morgan,’ Larry R. Squire,’ and David G. AmaraF ‘Veterans Administration Medical Center, San Diego, California 92161, and Department of Psychiatry, University of California, San Diego, La Jolla, California 92093, and 2The Salk Institute, San Diego, California 92138 A group of tasks sensitive to human amnesia were used to ported following bilateral fomix damage(Hassler and Reichert, characterize the severity and duration of memory impairment 1957; Sweet et al., 1959; Heilman and Seipert, 1977), the as- in monkeys following bilateral damage to the hippocampal sessmentof memory function in these caseswas often basedon formation, fornix, or mammillary nuclei. Monkeys with hip- anecdotal reports, and in no case has comprehensive neuro- pocampal formation lesions (which included the hippocam- psychological and neuropathological analysis been conducted. pus proper, dentate gyrus, subiculum, posterior entorhinal Several caseshave also been reported in which memory was cortex, and much of the parahippocampal gyrus) exhibited apparently intact following fomix damage(Woolsey and Nelson, a substantial and lasting memory impairment. Monkeys with 1975; seeGarcia-Bengochea and Friedman, 1987, for a review), fornix transection or bilateral damage to the mammillary nu- although these reports also provided insufficient neuropsycho- clei were impaired on the first task administered after sur- logical and/or neuropathological data. gery (delayed nonmatching to sample). However, they per- The mammillary nuclei were initially linked to memory func- formed all the other tasks normally and were unimpaired tion becausethey are consistently damagedin alcoholic Kor- when the delayed nonmatching to sample task was re-ad- sakoff s syndrome (Barbizet, 1970; Brierley, 1977). Yet, in this ministered 18 months after surgery. The findings are con- disorder the mammillary nuclei are not the only site of damage sistent with reports that damage limited to the human hip- (Mair et al., 1979). Damage to the mediodorsal nucleus of the pocampus can produce a clinically significant and permanent thalamus, for example, has been suggestedto be responsiblefor amnesia. Because fornix transection or mammillary lesions the amnesiaof Korsakoff s syndrome, either alone (Victor et al., produced only transient memory impairment, it seems un- 1971) or in combination with damageto the mammillary nuclei likely that similar damage in humans can cause a severe or (Markowitsch, 1982; Butters, 1984). permanent amnesia. One promising approach to understanding the anatomy of amnesia is afforded by the recent development of an animal Bilateral damageto the medial temporal lobe or to the midline model of human amnesiain the monkey (Mishkin, 1982; Squire diencephalic region of the human brain has been known for and Zola-Morgan, 1983; Mahut and Moss, 1984). The model nearly a century to causea profound amnesic syndrome (Gud- has relied especiallyon the delayed nonmatching to sampletask, den, 1896; von Bechterev, 1900). Considerableuncertainty re- an object-recognition memory task that is sensitive to human mains, however, about which specific structures and connec- amnesia(Squire et al., 1988). Monkeys with bilateral lesionsof tions within these regions must be damaged(for reviews, see the hippocampal formation are impaired on this object-recog- Mair et al., 1979; Damasio, 1984; Squire, 1987).One traditional nition task (Mishkin, 1978; Mahut et al., 1982; Murray and idea is that amnesiaresults when damageoccurs within the so- Mishkin, 1984; Zola-Morgan and Squire, 1986). called Papez (1937) circuit, which includes the hippocampal Other studieshave evaluated the performance of monkeys on formation, fomix, and mammillary (seeAppendix) nuclei (Bar- the delayed nonmatching to sample task following lesions of bizet, 1970; Brierley, 1977). either the mammillary nuclei or the fomix. In one study, mon- Recent findings from a carefully studied patient (R.B.) show keys with lesions of the mammillary nuclei were only mildly that amnesia can result from bilateral damage limited to the impaired on the delayed nonmatching to sampletask (Aggleton hippocampus (Zola-Morgan et al., 1986). The effects on human and Mishkin, 1985) and less impaired than monkeys with le- memory of selective damageto the fomix or mammillary nuclei sionsof the anterior mediodorsal nucleus (Aggleton and Mish- are unclear at this time. While impaired memory has been re- kin, 1983a, b). In 2 other studies, monkeys with fomix tran- sectionperformed aswell ascontrols on the delayed nonmatching Received May 23, 1988; revised July 20, 1988; accepted July 22, 1988. to sampletask (Mahut et al., 1982)or were only mildly impaired Supported by the Medical Research Service of the Veterans Administration, (Bachevalier et al., 1985). In the first study, the monkeys were NIH Grants NS19063, NS16980, and MH41479, NSFGrant BSN85-12349, and tested 5 years after surgery, while in the secondstudy, monkeys The Office of Naval Research. We thank Drs. Kasden, Jacobsen, and Holmes for instruction in the surgical approach to the mammillary nuclei; Ellen Bulder, Carol were trained preoperatively and then tested after surgery. Micheletti, Jasmine Allen, and Jerri Milana for behavioral testing; and Cecelia Several issuesremain to be clarified concerning the role of LeClair, Michael Mesches, and Janet Weber for histological assistance. Correspondence should be addressed to Stuart Zola-Morgan, Veterans Admin- the fomix and mammillary nuclei in memory function. The first istration Medical Center, 33 50 La Jolla Village Drive, San Diego, CA 92 16 1. issueconcerns the severity of memory impairment that results Copyright 0 1989 Society for Neuroscience 0270-6474/89/030898-16$02.00/O from lesionsof each structure. In 2 previous studies, monkeys The Journal of Neuroscience, March 1989, 9(3) 899 with fornix transection (Bachevalier et al., 1985) or mammillary 2: Zola-Morgan and Squire, 1986). Six monkeys (3 males and 3 females) nuclei lesions (Aggleton and Mishkin, 1985) exhibited at most received bilateral lesions of the fomix (FX). A seventh monkey intended for this operated group did not sustain bilateral damage to the fomix. a mild memory impairment. Monkeys in these studies were Histological evaluation revealed unilateral damage to the fomix and a trained preoperatively and then tested postoperatively. In other small unilateral lesion of the septum. This animal performed normally studies of monkeys with hippocampal lesions, performance on all the tasks and was not included in the data analysis. Histological was also mildly impaired when preoperative training was given material from this animal is presented in Figures 2 and 3 to show the (Mishkin, 1978; Murray and Mishkin, 1984). Based on these normal appearance of the fomix in thionin and AChE preparations. Two male monkeys received bilateral lesions of the mammillary nu- findings, one might suppose that similar effects on memory clei (MN). A third monkey, intended for this operated group, sustained should be produced by damage to the hippocampal formation, only a small unilateral lesion to the mammillary nuclei. A fourth monkey fornix, or mammillary nuclei. However, performance was sub- sustained unilateral hypothalamic damage anterior to the mammillary stantially impaired following hippocampal formation lesions nuclei, which transected the fomix. While there was no direct damage to the mammillary nuclei, there was substantial unilateral shrinkage of when training beganpostoperatively (Mahut et al., 1982; Mahut the medial mammillary nucleus. A photomicrograph of the normal and and Moss, 1984; Zola-Morgan and Squire, 1986; see Ringo, shrunken medial mammillary nuclei from this animal is shown in Figure 1988, for further discussion).It remains unclear how monkeys 4. The scores for these 2 animals were not included in the data analysis. with fornix transection or mammillary nuclei lesionswould per- The 3 remaining monkeys (2 males and 1 female) comprised an un- form on memory tasks if training began postoperatively and operated, normal control group (N). Behavioral data for these monkeys were reported previously (tests 1 and 2: Zola-Morgan et al., 1982; tests how these 2 groups would perform in comparison to monkeys 3-6: Zola-Morgan and Squire, 1985; test 7: Zola-Morgan and Squire, with hippocampal lesions. 1984). Monkeys were maintained on a daily ration of Purina Monkey A secondissue concerns the nature of the memory impairment Chow, supplemented with fruit and chewable vitamin C tablets (250 exhibited by operated monkeys. Whereas the development of a m3). nonhuman primate model of human amnesia has depended Although the groups were not all tested contemporaneously, animals were given the same sequence of tests (see below). In addition, all an- heavily on the delayed nonmatching to sample task, human imals were tested in the same facility, using the same apparatus and amnesiaaffects performance on a variety of different tasks. Re- test protocols. A research protocol describing all aspects of the present cently, monkeys with large bilateral medial temporal lobe le- study that related to the use of animals (care and maintenance, surgery, sionswere found to be impaired on several different tasks that behavioral testing, and euthanasia) was approved by the Animal Re- search Committees of the V.A. Medical
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