The Journal of Neuroscience, June 1993, 13(6): 2430-2451 Lesions of the Perirhinal and Parahippocampal Cottices in the Monkey Produce Long-lasting Memory Impairment in the Visual and Tactual Modalities Wendy A. Suzuki, I,* Stuart Zola-Morgan,1~3 Larry R. Squire,lv3 and David G. AmaraP* ‘Group in Neurosciences, University of California at San Diego, La Jolla, California 92093, “The Salk Institute, San Diego, California 92186, and 3Veterans Affairs Medical Center, San Diego, California 92161 and Department of Psychiatry, University of California at San Diego, La Jolla, California 92093 Compared to normal animals, monkeys with bilateral lesions man amnesia,the deficit associatedwith H+A+ lesionsin mon- of the perirhinal and parahippocampal cortices (PRPH lesion) keys is multimodal (Murray and Mishkin, 1984) and long-last- were impaired on both a visual and a tactual version of the ing (Zola-Morgan and Squire, 1985). In addition, animals with delayed nonmatching to sample task. In addition, the mem- H+A+ lesionsexhibit preserved short-term memory (Overman ory deficit was long-lasting, as indicated by the finding of a et al., 1990) intact skill-based memory, and intact habit-like significant deficit when the visual version of the delayed forms of memory (Malamut et al., 1984;Zola-Morgan and Squire, nonmatching to sample task was readministered approxi- 1984) in analogy to the preserved memory abilities of human mately 2 years after surgery. Animals with PRPH lesions amnesicpatients (for reviews, seeSquire and Zola-Morgan, 1991; performed normally on discrimination tasks in the visual and Squire, 1992). tactual modalities. Multimodal and long-lasting memory im- Although the importance of the medial temporal lobe for pairments are defining characteristics of human medial tem- memory function hasbeen known for sometime, a critical issue poral lobe amnesia. Accordingly, these results demonstrate for current research has been to determine the relative contri- important parallels between the memory deficit associated butions of the individual structures within the medial temporal with PRPH lesions and human medial temporal lobe amnesia. lobe. A large body of evidence in both monkeys and humans These data, taken together with previous findings, suggest supports the idea that the hippocampal formation is important that the perirhinal and parahippocampal cortices play an for memory function (Mahut et al., 1982; Zola-Morgan et al., important role in memory function and that these cortical 1986, 1989a; Squire et al., 1990; Victor and Agamanolis, 1990). areas are critical components of the medial temporal lobe The amygdala, however, does not appear to contribute to the memory system. same kind of memory (Zola-Morgan et al., 1989b; Squire and [Key words: memory, hippocampus, amnesia, medial tem- Zola-Morgan, 1991; Murray, 1992).An important recent finding poral lobe, delayed nonmatching to sample task, nonhuman has been that two additional medial temporal lobe structures, primate] the perirhinal and parahippocampal cortices, also contribute to memory function (Horel et al., 1987; Zola-Morgan et al., 1989~; It has been known since the 1950s due initially to the study of Meunier et al., 1990; Gaffan and Murray, 1992). In one study, the famous amnesic patient H.M., that the medial temporal a group of monkeys sustaining bilateral lesions limited to the lobe is essentialfor normal memory function (Scoville and Mil- perirhinal and parahippocampalcortices (referred to in the pres- ner, 1957). In the monkey, bilateral damageto medial temporal ent article as the PRPH I group from Zola-Morgan et al., 1989~) lobe structures including the hippocampal formation (made up exhibited a severe visual memory impairment on three tasks of the dentate gyrus, the hippocampus proper, the subicular sensitive to medial temporal lobe amnesia.In order to examine complex, and the entorhinal cortex), amygdala, and adjacent further how closely the deficit following PRPH lesionsresembles perirhinal and parahippocampal cortices (H+A+ lesion) pro- human medial temporal lobe amnesia, two major issueswere ducesa severe memory impairment (Mishkin, 1978; Zola-Mor- addressed. gan and Squire, 1985) that resembleshuman amnesia in many The first issueconcerns whether the memory deficit exhibited ways (Squire and Zola-Morgan, 1991). For example, as in hu- by animals with PRPH lesionsextends to more then one sensory modality. In the previous study, the PRPH I group was tested only in the visual modality. Yet, an important characteristic of Received June 4, 1992; revised Nov. 23, 1992; accepted Dec. 9, 1992. human amnesiais that it is modality general. The secondissue This work was supported by the Medical Research Service of the Department of Veterans Affairs, NIH Grants 19063 and 16980, the Office of Naval Research, concerns whether or not the memory impairment associated and the M&night Foundation. W.A.S. was supported by the Systems and Inte- with the PRPH lesion is enduring. In the previous study, because grative Neurobiology Training Grant GM08107-06, and by NIMH Predoctoml Fellowship MH10033-02. We thank Pablo Alvarez-Royo, Cecelia Leclair, and the PRPH I group was never retested on the earlier tasks, no Melodee Strukelj for behavioral testing, Robert P. Clower and Janet Weber for estimate of the stability of the impairment was obtained. If the surgical assistance, Mary Ann Lawrence for histological assistance, and Kris Tru- memory deficit exhibited by the PRPH group is similar to the lock for photographic processing. Correspondence should be addressed to Dr. Stuart &la-Morgan, Department human amnesicsyndrome, it should be long-lasting. In the pres- of Psychiatry, M-003, U.C.S.D. School of Medicine, La Jolla, CA 92093. ent study, we evaluated the memory impairment in a group of Copyright 0 1993 Society for Neuroscience 0270-6474/93/132430-22$05.00/O monkeys that received conjoint bilateral lesionslimited to the The Journal of Neuroscience, June 1993, U(6) 2431 perirhinal and parahippocampal cortices (PRPH II group). To Behavioral testing determine if the memory deficit extended to more than one A total of seven tasks were administered, five in the visual modality modality, the PRPH II group and a normal control group were and two in the tactual modality as described below. Detailed descrip- tested on several tasks in both the visual and tactual modalities. tions of the five visual tasks have been published previously (Zola- To determine if the memory deficit was long-lasting, the PRPH Morgan and Squire, 1984, 1985; Zola-Morgan et al., 1989b). Admin- istration of the first visual task was preceded by pretraining procedures II group and the normal control group were tested on the visual for the visual tasks, and the two tactual tasks were directly preceded by version of the delayed nonmatching to sample (DNMS) task tactual pretraining procedures. The pretraining sessions and behavioral shortly after surgery and then again approximately 2 years later. tasks were administered in the order given below. In addition, the PRPH II group and the normal group were tested on two additional amnesia-sensitive tasks. Also, in order Pretraining procedure for the visual tasks to examine discrimination learning in the visual and tactual Monkeys were allowed 6-8 weeks of recovery after surgery before the modalities, the two groups were tested on a visual pattern dis- start of pretraining for the visual tasks. Pretraining for the visual tasks crimination task and a tactual discrimination task. consisted of four to six daily sessions in the WGTA where monkeys learned to obtain raisin rewards by displacing objects that covered any of three food wells located on a stimulus tray in front of the testing Materials and Methods chamber. When the monkeys readily displaced objects presented over any of the three wells, testing began on the visual version of the delayed Subjects nonmatching to sample (DNMS) task. Seven male cynomolgus monkeys (Mucucu fascicu/aris) were used, all weighing between 3.7 and 4.5 kg. Four monkeys received bilateral le- sions of the perirhinal and parahippocampal cortices (PRPH II group). Visual trial-unique delayed nonmatching to sample with The remainingthree monkeyscomprised an unoperatedcontrol group double-sample presentation (N group)and weretested concurrently with the PRPH II group. For purposesof clarity, the four monkeysin the previousstudy of the effects The DNMS task is known to be sensitive to human amnesia (Squire et of PRPH lesions (Zola-Morgan et al., 1989~) will be referred to as the al., 1988) and to medial temporal lobe damage in the monkey (Zola- PRPH I group and the animals will be designated as animals PRPH 1, Morgan and Squire, 1986). The task was administered as described in 2, 3, and 4. In the present study, the four monkeys in the PRPH II Zola-Morgan and Squire (1984), with the following modifications. In- group will be designated as animals PRPH 5, 6, 7, and 8. stead of receiving a single presentation of the sample object over the central well, which is the standard way of administering the task, both Surgery the PRPH II group and the N group received two successive presen- tations of the sample object (double-sample presentation procedure; The surgical procedures used for the PRPH lesion have been described Aggleton and Mishkin, 1983). One of the two sample presentations was in detail elsewhere (Zola-Morgan et al., 1989~). Histological examina- rewarded according to a pseudorandom schedule (Gellerman, 1933). tion of the animals in the PRPH I group (Zola-Morgan et al., 1989~) This modification of the testing procedure was adopted in response to revealed that the most anterior part of the perirhinal cortex at the level difficulties encountered in an earlier study of the effects of PRPH lesions of the temporal pole (area 36pm of Insausti et al., 1987) was spared in (PRPH I group; Zola-Morgan et al., 1989~). In that study, only one of all four animals (Fig. 3 of Zola-Morgan et al., 1989~).