Visual recognition in monkeys: effects of transection of fornix

Summary An earlier finding from this laboratory of only a mild recognition impairment after hippocampal removal in mature monkeys (Mishkin 1978) contrasts with the severe deficit originally reported by Gaffan (1974) following transection of the fornix in immature monkeys. Investigation of some of the methodological differences between the two studies (lesion site, age of monkeys, and behavioral paradigm) failed to resolve the discrepancy in results, only a small impairment resulting under all conditions examined. While some still unexplored differences must underlie the divergent findings, it appears that only a comparatively mild impairment in recognition memory results from damage to the hippocampal system under a wide variety of conditions.     

Effects of combined and separate removals of rostral dorsal superior temporal sulcus cortex and perirhinal cortex on visual recognition memory in rhesus monkeys

The dorsal bank of the superior temporal sulcus (STSd) bears anatomical relations similar to those of perirhinal cortex, an area critical for visual recognition memory. To examine whether STSd makes a similar contribution to visual recognition memory, performance on visual delayed nonmatching-to-sample (DNMS) was assessed in rhesus monkeys with combined or separate ablations of the perirhinal cortex and STSd as well as in unoperated controls. Consistent with previous findings, ablations of perirhinal cortex produced deficits nearly as severe as that found after rhinal (i.e., entorhinal plus perirhinal) cortex lesions. However, combined lesions of perirhinal cortex and STSd produced a deficit no greater than that produced by perirhinal cortex ablation alone, and lesions of STSd alone were without effect on DNMS. We conclude that STSd is not critically involved in visual recognition memory.     

Effects of fornix transection and cingulate cortical ablation on spatial memory in rhesus monkeys

Summary This study, together with a parallel study in rats (Markowska et al. 1988), attempted to relate the effects of hippocampal-system damage on similar tasks in both rats and monkeys. Not only were monkeys given a task (Experiment 1) which was of the sort usually used with rats, but in the companion study rats were given tasks (Experiment 2) like those usually used with monkeys. Experiment 1 examined the performance of rhesus monkeys with hippocampal-system damage on a spatial working memory task. Monkeys were trained preoperatively on delayed nonmatching-to-sample in a T-maze, placed into groups matched for their preoperative learning scores, and then received one of three treatments: 1) transection of the fornix; 2) ablation of the cingulate cortex; or 3) a sham operation. Monkeys with fornix transection were severely and significantly impaired, but monkeys with cingulate cortical ablations were not significantly impaired, relative to the controls. The results demonstrate that monkeys with fornix transection are severely impaired on a spatial working memory task requiring locomotion and, taken together with earlier work, suggest that the effect of fornix transection in both rodents and nonhuman primates is at least qualitatively similar (see Markowska et al. 1988). Experiment 2 assessed the role of the fornix and cingulate cortex in three conditional tasks in which the monkeys were provided with various spatial cues to indicate which one of two objects was rewarded. Both experimental groups were unimpaired, relative to the control group, on all three tasks, indicating that fornix transection does not produce a general impairment in place learning.     

Dissociated effects of perirhinal cortex ablation,fornix transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe

Four experiments were performed with macaque monkeys (rhesus, Macaca mulatta, and cynomolgus, M.fascicularis). In experiment 1 six rhesus monkeys learned pre-operatively to perform delayed matching-to-sample, with complex naturalistic scenes as the stimulus material. Three of these monkeys then received bilateral ablations of the perirhinal cortex, while the other three received fornix transection. Both groups showed an impairment postoperatively, but the effect of perirhinal cortex ablation was significantly more severe than the effect of fornix transection. In experiment 2 the same animals, together with three normal, control rhesus monkeys,which had a similar training history, performed simple, spatial discrimination learning in a Wisconsin General Test Apparatus. The animals with fornix transection were impaired, but the animals with ablations of perirhinal cortex were not. In experiment 3 the nine animals from experiment 2 were tested for the acquisition of systematic preferences among four novel foods (apple, lemon, olive, meat). Their results were compared with those from a previously published experiment with normal and amygdalectomized cynomolgus monkeys which had been given the same food preference test. Amygdalectomy produced a significant disruption of food preference learning but the other two lesions (fornix transection and perirhinal cortex ablation) did not. In experiment 4, 16 rhesus monkeys (9 normal controls, 4 with perirhinal cortex ablation, and 3 with fornix transection) learned to discriminate among complex naturalistic scenes, in a task in which each scene was presented only once per day in the main part of the experiment. The two operated groups were impaired, and there was no significant difference between the severity of the impairments. Thus, the effects of perirhinal cortex ablation can be doubly dissociated from the effects of fornix transection (experiments 1 and 2) and both can be dissociated from the effects of amygdalectomy (experiment 3). Furthermore, the results of experiment 4 show that the effects of perirhinal cortex ablation are not limited to tasks of memory over short retention intervals. On the basis of the presently reported data and other known effects of perirhinal cortex ablation, it is suggested that this ablation produces an impairment in knowledge (semantic memory) about objects.     

Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques

Summary To assess the contributions of the basal forebrain cholinergic nuclei to visual recognition memory in macaques, we compared the effects of lesions of (a) the nucleus basalis of Meynert, (b) the medial septal and diagonal band nuclei, and (c) all nuclei combined on performance of delayed nonmatching-to-sample with trial-unique stimuli. Whereas monkeys with the separate lesions did not differ from each other or from normal control animals, those with combined lesions showed a significant impairment. With time and extended practice, however, the performance of the animals with combined lesions recovered to normal levels. During the recovery period, these monkeys showed an initially increased sensitivity to scopolamine that later dissipated, at which time they also failed to show the improvement that follows physostigmine administration in normal animals. Postmortem assessment of cortical choline acetyltransferase activity revealed that only the group with combined lesions had significant depletion of this enzyme. The results suggest that (1) the basal forebrain cholinergic system participates in mnemonic processes in primates and that (2) extensive damage to this system is necessary before impairments in recognition memory, even transient ones, can be observed.     

Cognitive function in aged ovariectomized female rhesus monkeys

To determine whether ovariectomy exacerbates age-related cognitive decline, the performance of 6 aged monkeys that had been ovariectomized early in life (OVX-Aged) was compared to that of 8 age-matched controls with intact ovaries (INT-Aged) and that of 5 young controls with intact ovaries (INT-Young) in tasks of visual recognition memory, object and spatial memory, and executive function. The OVX-Aged monkeys were marginally more impaired than the INT-Aged monkeys on the delayed nonmatching-to-sample with a 600-s delay. In contrast, they performed significantly better than the INT-Aged controls on the spatial condition of the delayed recognition span test. The hypothesis that prolonged estrogenic deprivation may exaggerate the age-related decline in visual recognition memory will require additional support. However, the findings suggest that long-term ovariectomy may protect against the development with aging of spatial memory deficits.     

Analysis of alpha-2 adrenergic agonist effects on the delayed nonmatch-to-sample performance of aged rhesus monkeys

The administration of alpha-2 adrenergic agonists to aged monkeys has been shown to ameliorate their cognitive deficits on the delayed response (DR) task, a test of spatial working memory (3,5). The present experiment tested whether the alpha-2 agonists, clonidine and guanfacine, would also improve working memory for object feature recognition, as tested by the delayed nonmatch-to-sample (DNMS) task. Five aged monkeys were trained on DNMS and were found to have mild performance deficits comparable to those reported previously for monkeys of similar age (32). However, during the subsequent two years of drug testing, the animals' baseline performance steadily improved, and conditions had to be made progressively more difficult to produce errors in performance. Clonidine and guanfacine significantly altered the DNMS performance of the aged monkeys, but drug-induced improvement was not as robust for DNMS as it was for DR. Clonidine produced a triphasic dose/response curve: Impairment was observed at both very low and high doses, while modest improvement was seen in the middle dose range (average maximal improvement of 21 ± 2.4%). Although improvement could occasionally be replicated for some doses, the clonidine dose/response curves were remarkably inconsistent in the middle dose range. Similarly, doses of guanfacine which had previously produced optimal improvement on the DR task, produced only small but significant improvement in DNMS performance (average improvement of 11 ± 3% for the 0.00011–0.000011 mg/kg dose range). By the end of the drug study, three monkeys were performing well (70–75% correct) with lists of 20 objects and over 400 sec delays, and one monkey performed better than 85% correct with lists of 40 objects and over 800 sec delays. Given the high level of performance of the aged monkeys on the DNMS task, it is unclear whether the weak improvement produced by alpha-2 agonists on the DNMS as compared to the DR task is due to ceiling effects, or rather results from alpha-2 adrenergic mechanisms being more important for spatial working memory than memory for object features. Future experiments utilizing a more difficult object working memory task will be necessary to resolve this issue.     

Place memory and scene memory: effects of fornix transection in the monkey

Summary Five experiments examined the effects of fornix transection upon some spatial and visual learning tasks in monkeys (Macaca fascicularis). For each trial of each task, the monkey was brought to a test tray and allowed to choose between 2 objects on the tray. In different tasks, different cues were provided by the experimenter to guide the monkey's choices. In total 5 different tasks were run (Experiments 1 to 5) and the results showed that the effects of fornix transection varied markedly between tasks: the animals with fornix transection were severely impaired in experiments 1, 3 and 5 but learned normally in experiments 2 and 4. It is concluded that the results cannot be explained by the simple hypothesis of a deficit in place learning, since some forms of place learning are unimpaired by fornix transection. A better general hypothesis is that the memory disrupted by fornix transection is like a snapshot memory, which stores the spatial arrangement of items in a witnessed scene.     

Recognition memory deficits in a subpopulation of aged monkeys resemble the effects of medial temporal lobe damage.

The present study examined individual differences in recognition memory function in a group of Old World monkeys (Macaca mulatta). Four young (9-11 years) and 10 aged (22-33 years) monkeys were tested in the same delayed-nonmatching-to-sample (DNMS) recognition memory procedure that has been widely used to study the effects of experimental hippocampal lesions in young subjects. Animals were first trained to a 90% correct learning criterion in the DNMS task using a 10-second delay between the sample and recognition phase of each trial. The memory demands of the task were then increased by gradually extending the retention interval from 15 seconds to 10 minutes. Three of the aged monkeys performed as accurately as young subjects at all delays. The remaining aged monkeys performed well at the shortest delays (15 and 30 seconds), but progressively greater impairments emerged across delays of 60 seconds, 2 minutes, and 10 minutes. These results suggest that recognition memory is only compromised in a subpopulation of aged monkeys. Moreover, aged monkeys that are impaired in the DNMS task exhibit the same delay-dependent pattern of deficits that is the hallmark of memory dysfunction resulting from medial temporal lobe damage.     

Selective neurotoxic amygdala lesions in monkeys disrupt reactivity to food and object stimuli and have limited effects on memory

Monkeys with bilateral neurotoxic amygdala lesions and normal monkeys were administered tests of emotional reactivity, recognition memory, and reward association memory. There were 3 main findings. First, monkeys with amygdala lesions performed differently than normal monkeys on initial administrations of the emotional reactivity tests and on retests that were given 21-23 months after surgery. Second, they performed like normal monkeys on tests of recognition memory. Third, they were initially impaired on a test of reward association memory, but they were not impaired on a retest that was given 16 months after surgery. These findings underscore the role of the amygdala in aspects of emotional reactivity and reward association memory, but not in recognition memory. In addition, at least some of the behavioral effects of amygdala damage can be long lasting.     

Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys

Aged rhesus monkeys exhibit deficits in hippocampus-dependent memory, similar to aging humans. Here we explored the basis of cognitive decline by first testing young adult and aged monkeys on a standard recognition memory test (delayed nonmatching-to-sample test; DNMS). Next we quantified synaptic density and morphology in the hippocampal dentate gyrus (DG) outer (OML) and inner molecular layer (IML). Consistent with previous findings, aged monkeys were slow to learn DNMS initially, and they performed significantly worse than young subjects when challenged with longer retention intervals. Although OML and IML synaptic parameters failed to differ across the young and aged groups, the density of perforated synapses in the OML was coupled with recognition memory accuracy. Independent of chronological age, monkeys classified on the basis of menses data as peri- or post-menopausal scored worse on DNMS, and displayed lower OML perforated synapse density, than premenopausal monkeys. These results suggest that naturally occurring reproductive senescence potently influences synaptic connectivity in the DG OML, contributing to individual differences in the course of normal cognitive aging.     

Effects of selective neonatal hippocampal lesions on tests of object and spatial recognition memory in monkeys

Earlier studies in monkeys have reported mild impairment in recognition memory after nonselective neonatal hippocampal lesions. To assess whether the memory impairment could have resulted from damage to cortical areas adjacent to the hippocampus, we tested adult monkeys with neonatal focal hippocampal lesions and sham-operated controls in three recognition tasks: delayed nonmatching-to-sample, object memory span, and spatial memory span. Further, to rule out that normal performance on these tasks may relate to functional sparing following neonatal hippocampal lesions, we tested adult monkeys that had received the same focal hippocampal lesions in adulthood and their controls in the same three memory tasks. Both early and late onset focal hippocampal damage did not alter performance on any of the three tasks, suggesting that damage to cortical areas adjacent to the hippocampus was likely responsible for the recognition impairment reported by the earlier studies. In addition, given that animals with early and late onset hippocampal lesions showed object and spatial recognition impairment when tested in a visual paired comparison task, the data suggest that not all object and spatial recognition tasks are solved by hippocampal-dependent memory processes. The current data may not only help explain the neural substrate for the partial recognition memory impairment reported in cases of developmental amnesia, but they are also clinically relevant given that the object and spatial memory tasks used in monkeys are often translated to investigate memory functions in several populations of human infants and children in which dysfunction of the hippocampus is suspected.     

Scopolamine impairs auditory delayed matching-to-sample performance in monkeys

Information concerning the major neurotransmitters critical for auditory memory is sparse. One possibility is the cholinergic system, important for performance in some tasks requiring visual short-term memory and attention [T.G. Aigner, M. Mishkin, The effects of physostigmine and scopolamine on recognition memory in monkeys, Behav. Neural. Biol. 45 (1986) 81-87; N. Hironaka, K. Ando, Effects of cholinergic drugs on scopolamine-induced memory impairment in rhesus monkeys, Jpn. J. Psychopharmacol. 16 (1996) 103-108; T.M. Myers, G. Galbicka, M.L. Sipos, S. Varadi, J.L. Oubre, M.G. Clark, Effects of anticholinergics on serial-probe recognition accuracy of rhesus macaques (Macaca mulatta), Pharmacol. Biochem. Behav. 73 (2002) 829-834; H. Ogura, T.G. Aigner, MK-801 Impairs recognition memory in rhesus monkeys: comparison with cholinergic drugs, J. Pharmacol. Exp. Ther. 266 (1993) 60-64; D.M. Penetar, J.H. McDonough Jr., Effects of cholinergic drugs on delayed match-to-sample performance of rhesus monkeys, Pharmacol. Biochem. Behav. 19 (1983) 963-967; M.A. Taffe, M.R. Weed, L.H. Gold, Scopolamine alters rhesus monkey performance on a novel neuropsychological test battery, Cogn. Brain Res. 8 (1999) 203-212]. Five rhesus monkeys were trained to perform an auditory go/no-go delayed matching-to-sample (DMTS) task wherein two acoustic stimuli (500ms), separated by variable memory delays (500ms, 2500ms, or 5000ms), were either identical sound presentations, i.e., match trials, or two different sound presentations, i.e., nonmatch trials. Sound stimuli were chosen semi-randomly from a large set sound set ( approximately 900). After reaching a criterion of 80% correct on the behavioral task, monkeys were injected with saline or doses of scopolamine hydrochloride mixed in saline (3 microg, 5 microg, and 10 microg per 1kg of weight), 30 min before training. Scopolamine impaired performance accuracy on match trials in a dose-dependent manner. Blocking muscarinic receptors with scopolamine did not significantly impair motor responses, food motivation, or responses to rewarded sound. These findings support the hypothesis that the cholinergic system is important for auditory short-term memory.     

An early and a late developing system for learning and retention in infant monkeys

On the evidence that memory formation and habit formation represent two qualitatively different learning processes based on separate neural mechanisms, the functional development of these two processes was followed ontogenetically. Separate groups of rhesus monkeys of different ages were tested in delayed nonmatching-to-sample and 24-hr concurrent discrimination learning, considered to be measures of recognition memory and discrimination habit formation, respectively. The youngest group of infant monkeys failed to learn the nonmatching task until they were approximately 4 months old. With further maturation, learning ability on this task gradually improved, yet it did not reach adult levels of proficiency even at 1 year of age. Postlearning evaluation with long delays and lists confirmed this slow ontogenetic development of recognition memory to adult levels of function. By contrast, infant monkeys 3-4 months old learned to discriminate long lists of object-pairs about as quickly as adult monkeys despite the use of 24-hr intertrial intervals. This striking dissociation in the ability of infants on the two tasks closely resembles the dissociation first found in adult monkeys rendered amnesic by limbic lesions. The results suggest that whereas the nonlimbic habit system matures early in infancy, the limbic-dependent memory system develops only slowly.     

Age differences in recognition memory of the rhesus monkey (Macaca mulatta)

Aging is accompanied by a gradual decline in memory in both humans and nonhuman primates. To determine whether the impairment in nonhuman primates extends to recognition memory, which is a sensitive index of the integrity of the limbic system, we trained rhesus monkeys of four different age groups (3-6, 14-17, 20-24, and 25-29 years of age) on a delayed nonmatching-to-sample task with trial-unique objects. After the animals had learned the task, which required recognition of single objects presented ten seconds earlier, memory demands were increased by gradually lengthening delay intervals (to 120 seconds) and list lengths (to ten objects). With increasing age, only marginal impairments in learning the basic task were observed. However, clear age-related differences did emerge when either delays or list lengths were increased, with the oldest group of monkeys demonstrating the greatest impairments. The decline in visual recognition ability in aging monkeys parallels the decline in memory observed with advancing age in humans.     

Differential effects on visual and spatial recognition memory of a novel hormone therapy regimen of estrogen alone or combined with progesterone in older surgically menopausal monkeys

Building upon our initial studies in young adult surgically menopausal monkeys, this study examined the effects of a novel schedule of administration of estradiol therapy alone, or in combination with progesterone, on visual and spatial recognition memory in older monkeys. Monkeys were preoperatively trained on a delayed matching-to-sample task and a delayed response task. At the time of ovariectomy, monkeys began their hormonal treatments and were cognitively assessed at 2, 12 and 24 weeks following treatment initiation. A schedule of hormone administration was used that closely modeled the normal fluctuations of hormones during the course of a normal primate menstrual cycle. Monkeys receiving placebo had lower levels of accuracy than monkeys receiving estrogen therapies on the delayed matching-to-sample task that were not apparent until 12 weeks following initiation of therapy and were no longer detected at the 24-week assessment. There was no effect of hormone therapy on accuracy in the delayed response task at any of the postoperative assessments. In both tasks, monkeys treated with estrogen plus progesterone had longer choice response latencies, especially on trials in which they made errors; however these effects did not influence accuracy measures in these animals. Our findings indicate that visual recognition ability may be more sensitive than spatial recognition memory to this novel hormone therapy regimen, that treatment with estradiol plus progesterone was equivalent to that of estradiol alone, and that neither therapy had significant negative impact on memory profiles.     

Hippocampal volume is preserved and fails to predict recognition memory impairment in aged rhesus monkeys (Macaca mulatta)

Aged monkeys exhibit deficits in memory mediated by the medial temporal lobe system, similar to the effects of normal aging in humans. The contribution of structural deterioration to age-associated memory loss was explored using magnetic resonance imaging techniques. We quantified hippocampal, cerebral and ventricular volumes in young (n = 6, 9-12 years) and aged (n = 6, 24-29 years) rhesus monkeys. Eleven subjects were tested on a recognition memory task, delayed non-matching-to-sample (DNMS). Compared to young animals, aged monkeys exhibited robust learning deficits and significant memory impairments when challenged with longer retention intervals. Hippocampal volume was statistically equivalent across age groups, differing by less than 6%, and there was no correlation between this measure and DNMS performance. Variability in cerebral volume was greater in the aged compared to young monkeys and this parameter was marginally correlated with DNMS performance with a 10-min delay. These findings confirm and extend the conclusion of recent post-mortem histological analyses demonstrating that normal cognitive aging occurs independently of gross structural deterioration in the primate hippocampus.     

Involvement of single unit activity in inferotemporal and perirhinal cortices in recognition memory of visual objects in the macaque

Recognizing objects from the past is a vitally important ability for everyday live. The studies of brain mechanisms responsible for visual recognition memory suggest that the modulation of single unit activity in the inferotemporal and perirhinal cortices could be an important part of the neuronal substrate of recognition memory. In this review, I will describe Stimulus Specific Adaptation (SSA)--the reduction in neuronal response to previously viewed objects. The experimental tasks in which SSA is observed will be presented, along with the possibility that SSA may be enhanced by saccadic exploration of visual scene. Next, I will demonstrate that under special circumstances (partially split-brain preparation) monkeys could recognize the re-presentation of visual images without the concomitant appearance of SSA. The most promising alternative candidate for neuronal mechanism involved in recognition memory is delay activity--an increased frequency of cell firing in the time between the initial presentation of an image and its subsequent re-presentation. In order to determine if delay activity is important for recognition we have started to investigate the effects on recognition memory of disrupting delay activity by electrical stimulation. Preliminary results indicate a positive correlation between a reduction in delay activity and a decrease in recognition performance.     

Fornix transection impairs visuospatial memory acquisition more than retrieval

It has been hypothesized that some fornical fibres may instantiate a neuromodulatory reinforcement signal supporting memory acquisition in medial temporal cortical regions. This suggests that fornix transection should impair postoperative new learning more severely than the recall of preoperatively acquired information. Here, postoperative recall of 288 concurrent visuo-spatial discrimination problems acquired preoperatively was unaffected after fornix transection in the macaque, whereas new postoperative learning of 72 problems was impaired. This and other recent evidence supports the idea that the main function of the fornix in macaque monkeys is to support new learning about spatio-temporal context.     

Memory traces in spinal cord produced by H-reflex conditioning: effects of post-tetanic potentiation

Operant conditioning of the wholly spinal, largely monosynaptic triceps surae H-reflex in monkeys causes changes in lumbosacral spinal cord that persist after removal of supraspinal influence. We evaluated the interaction between post-tetanic potentiation and these memory traces. Animals in which the triceps surae H-reflex in one leg had been increased or decreased by conditioning were deeply anesthetized, and monosynaptic reflexes to L6-S1 dorsal root stimulation were recorded before and after tetanization from both legs for 3 days after thoracic cord transection. Animals remained anesthetized throughout and were sacrificed by overdose. Reflex asymmetries consistent with the effect of H-reflex conditioning were present after transection and persisted through the 3 days of study. Tetanization affected conditioned leg and control leg reflexes similarly. This finding suggests that, while post-tetanic potentiation and probably H-reflex conditioning alter Ia synaptic transmission, the two phenomena have different mechanisms.