Maria C. Alvarado

The Hippocampal/Parahippocampal Regions and Recognition Memory: Insights from Visual Paired Comparison versus Object-Delayed Nonmatching in Monkeys

Recognition memory was assessed by submitting the same adult monkeys to visual paired comparison (VPC) with mixed delays (10-120 sec), followed by three consecutive versions of object-delayed nonmatching-to-sample (DNMS): increasing delays (10-600 sec), lengthened lists (3-10 objects), and intervening distractors in the delays (light at 10 sec, motor task at 30-600 sec, or context change at 600 sec). Four groups were tested: normal controls, monkeys with ibotenic acid lesions of the hippocampal formation (H), and monkeys with aspiration lesions of either the perirhinal (PRh) or parahippocampal (areas TH/TF) cortex. Group H was impaired on VPC at delays ≥60 sec but had difficulty on DNMS only at 600 sec delays with distraction. In group TH/TF, the VPC impairment emerged earlier (30 sec); yet, once the nonmatching rule was mastered, no significant change occurred on any DNMS condition. Only group PRh behaved congruently on VPC and DNMS, exhibiting a deficit at the easiest condition that worsened with increasing delays as well as in DNMS lengthened list and distraction conditions. These results led us to postulate that VPC and DNMS, as previously administered to monkeys, were not equivalent visual recognition memory probes. Specifically, we propose that, for VPC, because of passive (incidental) encoding, the animals performance rests on both item familiarity and event recollection, whereas, for DNMS, because of active (purposeful) encoding, performance relies more on item familiarity. This proposal converges with current models postulating distinct, but interactive, mnemonic roles for the hippocampal and adjacent TH/TF regions.

Reversible inactivation of the medial septum differentially affects two forms of learning in rats

The contribution of the medial septum to different aspects of spatial information processing was assessed by examining the effects of reversible septal inactivation on radial maze performance of rats. In addition, the selectivity with which the medial septum affects learning was studied by testing the effects of septal inactivation on the acquisition of non-spatial information. Rats were first trained according to a spatial working memory procedure that included a 30-min delay between the first 4 (forced) choices and subsequent test (free) choices. The forced choices comprised the sample phase of the experiment while the free choices comprised the test phase. Saline or tetracaine (a local anesthetic) was injected into the medial septal area either before the sample phase, after the sample phase (i.e. at the beginning of the delay period), or just before the test phase. In contrast to the saline injections, tetracaine injected just before the sample or test phases produced a significant increase in errors at test. Tetracaine injection at the beginning of the delay period did not affect test choice accuracy. EEG records showed that septal inactivation drastically, yet temporarily, reduced the hippocampal theta rhythm. Thus, when septal inactivation occurred either before the sample phase or at the beginning of the delay period, hippocampal theta recovered by the time of the test phase. Septal inactivation also produced a significant retardation of learning on a non-spatial reference memory task, although clear improvement over trials did occur. Moreover, the results of subsequent saline injections suggest that at least some of the performance deficit was due to variables other than learning per se.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats with damage to the hippocampal-formation are impaired on the transverse-patterning problem but not on elemental discriminations

We assessed the effects of hippocampal-formation (HF) damage on the rats ability to learn two sets of concurrent visual discriminations. Each set included three problems. One set, called the transverse-patterning problem, was constructed so that each choice stimulus was ambiguous; sometimes it was the correct (+) and sometimes it was the incorrect (-) choice as follows: A+ vs. B-, B+ vs. C-, and C+ vs. A-. It could not be solved unless rats used configural associations. The stimuli were not ambiguous in the second, elemental problem set, A+ vs. B-, C+ vs. D-, and E+ vs. F-. Rats could solve this set without the use of configural associations. Rats with HF damage solved the set of elemental problems, but their performance on the transverse-patterning problem was impaired. These results support Sutherland and Rudys (1989) theory that the hippocampal formation is critical for the acquisition of configural associations.

Some properties of configural learning: an investigation of the transverse-patterning problem.

Little is known about the conditions that encourage animals to learn to use configural associations to guide their behavior or the consequences of such learning for transfer. This study provided some information about these issues by examining how rats solve the transverse-patterning problem, which requires a configural solution (Spence, 1952). Animals had to concurrently solve 3 simultaneous visual discriminations, represented abstractly as A+ versus B-, B+ versus C-, and C+ versus A-. Experiment 1 indicated that rats use a configural solution even when the problems have an elemental solution, provided that the significance of 1 element (e.g., B) shared by 2 problems is ambiguous (e.g., A+/B-; and B+/C-). Experiments 2 and 3 suggested that, when stimulated to use a configural solution by solving the A+/B- and B+/C- problems, rats transfer the configural solution to problems that have no ambiguous elements.

Memory stages and brain asymmetry in chick learning

Stages of formation of memory and the roles of different forebrain structures in memory formation were investigated by injecting various agents into the brains of chicks close to the time of peck-avoidance training. With L-glutamate injected bilaterally into the hyperstriatum 5 min pretraining, retention was good 1 min posttraining but significantly impaired at 5 min and each subsequent time point from 10 min to 24 hr. With ouabain, retention declined more slowly, showing significant impairment at 15 min and thereafter. With any of three protein synthesis inhibitors (anisomycin, cycloheximide, or emetine), retention was still good 60 min posttraining but significantly impaired at 90 min. The three time courses of decline of retention are consistent with hypotheses of three sequentially dependent stages of memory formation. Glutamate, ouabain, and emetine were found to affect only a restricted volume of tissue. Any of these three agents induced amnesia when injected into the left (but not the right) medial hyperstriatum ventrale or into the right (but not the left) lateral neostriatum; so it appears that both structures are required for formation of memory. Agents that are specific for a presumed stage of memory formation and whose action is restricted spatially should help reveal the roles of different brain structures in different stages of memory formation.

Comparison of the Effects of Damage to the Perirhinal and Parahippocampal Cortex on Transverse Patterning and Location Memory in Rhesus Macaques

Monkeys with damage to the parahippocampal (TH/TF) or perirhinal (PRh) cortex were tested on two sets of the transverse patterning (TP) problem (A+/B-, B+/C-, C+/A- and D+/E-, E+/F-, F+/D-) and delayed nonmatching-to-location paradigm (DNML), with delays ranging from 10 to 600 s. Damage to either area impaired acquisition and performance of TP but not of linear discriminations (e.g., A>B>C>X). Damage to areas TH/TF impaired performance of the DNML at all delays but only affected memory for objects at the longest delay, as measured by a delayed nonmatching-to-sample task (DNMS) (Nemanic et al., 2004). Damage to the PRh impaired performance of the DNMS but not of the DNML. The results present a dissociation in object and place memory for these two cortical regions and suggest a role for each in the cortical circuitry supporting configural/relational memory.

Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood

The present study reviews the long-term effects of neonatal hippocampal damage in monkeys on the development of memory functions and socioemotional behavior. The results showed that neonatal damage to the hippocampal formation impairs specific memory processes, such as those subserving automatic (as opposed to effortful) recognition memory and relational learning, while sparing the abilities to acquire skills, such as object discriminations. Furthermore, the neonatal hippocampectomy led to a progressive loss of social affiliation and a protracted emergence of locomotor stereotypies. While the memory losses following neonatal hippocampal lesions resemble those found after similar lesions acquired in adulthood, only the neonatal lesions resulted in a protracted emergence of abnormal behaviors. These later findings suggested that, presumably, the neonatal lesions impacted on neural systems remote from the site of damage. This was confirmed by our more recent neurobiological studies, demonstrating that neonatal, but not late, lesions of the medial temporal lobe region, disrupt the normal behavioral and cognitive processes subserved by the prefrontal cortex and the caudate nucleus. All together the data support the neurodevelopmental hypothesis viewing early insult to the medial temporal region as the origin of developmental psychosis in humans, such as schizophrenia.

A comparison of kainic acid plus colchicine and ibotenic acid-induced hippocampal formation damage on four configural tasks in rats.

J.W. Rudy and R.J. Sutherland (1989) suggested that the hippocampal formation (HF) is necessary for performance of configural tasks and that rats with kainic acid + colchicine (K-C) damage to the HF were impaired on the negative patterning problem (A+, B+, AB-). However, M. Gallagher and P.C. Holland (1992) found spared performance on a similar task (AC+, B+, AB-, C-) when ibotenic acid (IBO) was used. This study compared the effects of K-C- and IBO-induced HF damage on 4 configural tasks: (a) negative patterning, (b) the Gallagher-Holland task, (c) transverse patterning, and (d) place learning. Rats with IBO lesions performed like controls on the Gallagher-Holland task (replicating M. Gallagher & P.C. Holland) but were impaired on negative patterning, transverse patterning, and place learning. In contrast, rats with K-C lesions were impaired on all 4 tasks. The implications of these results for theories of HF function are discussed.

Assessment of locus and extent of neurotoxic lesions in monkeys using neuroimaging techniques: a replication

In a recent study, [Hippocampus 11 (2001) 361] demonstrated that in vivo neuroimaging techniques could be used to accurately quantify the extent of neuronal damage after ibotenic acid injections in non-human primates. The present study was undertaken to replicate these findings and to further estimate whether the concentration of ibotenic acid used (10-15 mg/ml) to produce the neuronal loss did not affect the fibers coursing within or around the targeted brain area. Magnetic resonance (MR) images (T1-weighted and FLAIR) were acquired in three monkeys before and after they received neurotoxic lesions of the hippocampal formation. The postsurgical FLAIR images were taken 7-10 days after surgery to visualize the hyperintense signals produced by increased edema at the injection sites. One year post-surgically, T1-weighted images were acquired and compared with T1-weighted images obtained pre-surgery to estimate reduction in hippocampal volume resulting from neuronal loss. Estimated neuronal loss was then compared with actual cell loss found during histological evaluation of brain tissue. Both neuroimaging techniques accurately estimated the extent of hippocampal damage and damage to surrounding structures. In addition, the concentration of ibotenic acid (10 mg/ml) used in the present study did not appear to have significantly damaged or de-myelinated fibers coursing through or around the hippocampal formation. Together with the previous results of [Hippocampus 11 (2001) 361], the present data strongly demonstrate that in vivo neuroimaging techniques provide powerful tools to estimate reliably and rapidly the extent and localization of brain lesions in non-human primates.

Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor

Background: Retrospective studies in humans have shown a higher prevalence of learning disabilities in children that received multiple exposures to general anesthesia before the age of 4 yr. Animal studies, primarily in rodents, have found that postnatal anesthetic exposure causes neurotoxicity and neurocognitive deficits in adulthood. The authors addressed the question of whether repeated postnatal anesthetic exposure was sufficient to cause long-term behavioral changes in a highly translationally relevant rhesus monkey model, allowing study of these variables against a background of protracted nervous system and behavioral development. Methods: Rhesus monkeys of both sexes underwent either three 4-h exposures to sevoflurane anesthesia (anesthesia group n = 10) or brief maternal separations (control group n = 10) on postnatal day 6 to 10 that were repeated 14 and 28 days later. Monkeys remained with their mothers in large social groups at all times except for overnight observation after each anesthetic/control procedure. At 6 months of age, each monkey was tested on the human intruder paradigm, a common test for emotional reactivity in nonhuman primates. Results: The frequency of anxiety-related behaviors was significantly higher in monkeys that were exposed to anesthesia as neonates as compared with controls: anesthesia 11.04 ± 1.68, controls 4.79 ± 0.77, mean ± SEM across all stimulus conditions. Conclusion: Increased emotional behavior in monkeys after anesthesia exposure in infancy may reflect long-term adverse effects of anesthesia.