Impaired odor recognition memory in patients with hippocampal lesions

In humans, impaired recognition memory following lesions thought to be limited to the hippocampal region has been demonstrated for a wide variety of tasks. However, the importance of the human hippocampus for olfactory recognition memory has scarcely been explored. We evaluated the ability of memory-impaired patients with damage thought to be limited to the hippocampal region to recognize a list of odors. The patients were significantly impaired after a retention delay of 1 h. Olfactory sensitivity was intact. This finding is in agreement with earlier reports that rats with hippocampal lesions exhibited memory impairment on an odor delayed nonmatching to sample task (after 30 min and 1 h) and that patients with damage thought to be limited to the hippocampal region were impaired on an odor span memory task. Olfactory recognition memory, similar to recognition memory in other sensory modalities, depends on the integrity of the hippocampal region.     

Cholinergic modulation of visual attention and working memory: dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine

Two experiments examined the effects of reductions in cortical cholinergic function on performance of a novel task that allowed for the simultaneous assessment of attention to a visual stimulus and memory for that stimulus over a variable delay within the same test session. In the first experiment, infusions of the muscarinic receptor antagonist scopolamine into the medial prefrontal cortex (mPFC) produced many omissions but did not impair rats' ability to correctly detect a brief visual stimulus. However, these animals were highly impaired in remembering the location of that stimulus following a delay period, although in a delay-independent manner. In the second experiment, another group of animals with selective 192IgG-saporin lesions of the nucleus basalis magnocellularis (nBM) were not impaired under conditions of low-attentional demand. However, when the stimulus duration was reduced, a significant memory impairment was observed, but similar to the results of the first experiment, the nBM-lesioned animals were not impaired in attentional accuracy, although aspects of attention were compromised (e.g., omissions). These findings demonstrate that (1) cortical cholinergic depletion produces dissociable deficits in attention and memory, depending on the task demands, (2) delay-independent mnemonic deficits produced by scopolamine are probably due to impairments other than simple inattention, and (3) working memory deficits are not simply dependent on attentional difficulties per se. Together, these findings implicate the nBM cortical cholinergic system in both attentional and mnemonic processing.     

Transverse patterning reveals a dissociation of simple and configural association learning abilities in rats with 192 IgG-saporin lesions of the nucleus basalis magnocellularis

This experiment tests the hypothesis that the cholinergic nucleus basalis magnocellularis (NBM) is necessary for complex or configural association learning, but not elemental or simple association learning. Male Long-Evans rats with bilateral 192 IgG-saporin lesions of the NBM (n = 12) and sham-operated controls (n = 8) were tested in the transverse patterning problem, which provides a test of both simple and configural association learning. Rats were trained in phases to concurrently solve first one, then two, and finally three different visual discriminations; Problem 1 (A+ vs B- sign) and Problem 2 (B+ vs C-) could be solved using simple associations, whereas solving Problem 3 (C+ vs A-) required the ability to form configural associations. Consistent with our hypothesis, the NBM lesion group solved the simple discriminations in Problems 1 and 2 but showed impaired configural association learning in Problem 3. Additionally, when Problem 2 was introduced, previously high levels of performance on Problem 1 suffered more in the NBM lesion group than in the control group; this finding suggests an impairment in the ability of animals with NBM lesions to divide attention among multiple stimuli or to shift between strategies for solving different problems. Results support our argument that the NBM is critically involved in the acquisition of associative problems requiring a configural solution but not in problems that can be solved using only simple associations. The observed impairments in configural association learning and the apparent loss of cognitive flexibility or capacity are interpreted as reflecting specific attentional impairments resulting from NBM damage.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.     

Bilateral entorhinal cortex lesions impair acquisition of delayed spatial alternation in rats

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about 3 weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produced a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.     

Extensive lesions of cholinergic basal forebrain neurons do not impair spatial working memory

A recent studysuggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that mayhave damaged cerebellar Purkinje cells. The present studytested rats with highlyselective lesions of cholinergic neurons in all major areas of the basal forebrain on a spatial working memorytask in the radial arm maze. In postoperative testing, there were no significant differences between lesion and control groups in working memory, even with a delayperiod of 8 h, with the exception of a transient impairment during the first 2 d of postoperative testing at shorter delays (0 or 2 h). This finding corroborates other results that indicate that the cholinergic basal forebrain does not playa significant role in spatial working memory. Furthermore, it underscores the presence of intact memoryfunctions after cholinergic basal forebrain damage, despite attentional impairments that follow these lesions, demonstrated in other task paradigms.     

Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy

192IgG-saporin (SAP) was used to selectively destroy cholinergic neurons in the rostral basal forebrain (e.g., medial septum (MS) and vertical limb of the diagonal band of Broca (VDB)) and/or the caudal basal forebrain (e.g., nucleus basalis magnocellularis (NBM)) of ovariectomized Sprague-Dawley rats. The effects of these lesions on two different cognitive tasks, a delayed matching to position (DMP) T-maze task, and a configural association (CA) operant conditioning task, were evaluated and compared. Injecting SAP into either the MS or NBM significantly impaired acquisition of the DMP task. Analysis showed that the effects were due largely to an affect on response patterns adopted by the rats during training, as opposed to an effect on working memory performance. Notably, the impairment in DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. Despite the deficit, most animals eventually learned the task and reached criterion; however by the end of training, controls and animals that received SAP into either the MS or NBM appeared more likely to use an allocentric place strategy to solve the task, whereas animals that received SAP into both the MS and NBM were more likely to use an egocentric response strategy. Cholinergic lesions also produced a small but significant affect on acquisition of the CA task, but only with respect to response time, and only in the SAP-NBM-treated animals. SAP-NBM lesions also produced small but significant impairments in both the number of responses and response time during the acquisition of simple associations, possibly reflecting an effect on alertness or attention. Notably, the effects on CA acquisition were small, and like the effects on DMP acquisition did not correlate with the degree of cholinergic denervation of the hippocampus. We conclude that selective basal forebrain cholinergic lesions produce learning deficits that are task specific, and that cholinergic denervation of either the frontal cortex or hippocampus can affect response patterns and strategy in ways that affect learning, without necessarily reflecting deficits in working memory performance.     

The role of the dorsal and ventral hippocampus in olfactory working memory

Olfactory working memory and pattern separation for odor information was assessed in male rats using a matching-to-sample for odors paradigm. The odor set consisted of a five aliphatic acids with unbranched carbon chains that varied from two- to six-carbons in length. Each trial consisted of a sample phase followed by a choice phase. During the sample phase, rats would receive one of five different odors. Fifteen seconds later during the choice phase one of the previous odors was presented simultaneously side by side with a different odor that was based on the number of aliphatic acids that varied in the carbon chains from two- to six-carbons in length and rats were allowed to choose between the two odors. The rule to be learned in order to receive a food reward was to always choose the odor that occurred during the study phase. Odor separations of 1, 2, 3 or 4 were selected for each choice phase and represented the carbon chain difference between the study phase odor and the test phase odor. Once an animal reached a criterion of 80–90% correct across all temporal separations based on 40 trials, rats received a control, dorsal hippocampal, or ventral hippocampal lesion and were retested on the task. On postoperative trials, only the ventral hippocampal lesion group was impaired relative to both control and dorsal hippocampal groups groups. There were no effects on odor pattern separation. All groups of rats could discriminate between the odors. The data suggest that the ventral hippocampus, but not dorsal hippocampus, supports working memory for odor information.     

The effects of hippocampal lesions on learning, memory, and reward expectancies

The hippocampus appears to be critical for the formation of certain types of memories. Hippocampal-lesioned animals fail to exhibit some spatial, contextual, and relational associations. After aspiration lesions of the hippocampus and/or cortex, male rats were allowed to recover for three weeks before being trained on a matching-to-position task. The matching-to-position task was altered to influence the type of cognitive strategies a subject would use to solve the task. The main behavioral manipulation was the reinforcement contingency assignment: Use of a differential outcomes procedure (DOP) or a nondifferential outcomes procedure (NOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition via Pavlovian trace conditioning, whereas the NOP results in random reward contingency. We found that hippocampal lesions did retard learning the matching rule, regardless of the reinforcement contingency assignment. However, when delay intervals were added to the task memory performance of subjects with hippocampal lesions was dramatically impaired--if subjects were not trained with the DOP. When subjects were trained with the DOP, the hippocampal lesion had a marginal effect on delayed memory performance. These findings demonstrate two important points regarding lesions of the hippocampus: (1) hippocampal lesions have a minimal effect on the on the ability of rats to use reward information to solve a delayed discrimination task; (2) rats with hippocampal lesions have the ability to learn about reward information using Pavlovian trace conditioning procedures.     

Rats depend on habit memory for discrimination learning and retention

We explored the circumstances in which rats engage either declarative memory (and the hippocampus) or habit memory (and the dorsal striatum). Rats with damage to the hippocampus or dorsal striatum were given three different two-choice discrimination tasks (odor, object, and pattern). These tasks differed in the number of trials required for learning (~10, 60, and 220 trials). Dorsal striatum lesions impaired discrimination performance to a greater extent than hippocampal lesions. Strikingly, performance on the task learned most rapidly (the odor discrimination) was severely impaired by dorsal striatum lesions and entirely spared by hippocampal lesions. These findings suggest that discrimination learning in the rat is primarily supported by the dorsal striatum (and habit memory) and that rats engage a habit-based memory system even for a task that takes only a few trials to acquire. Considered together with related studies of humans and nonhuman primates, the findings suggest that different species will approach the same task in different ways.     

Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts

The cholinergic hypothesis of geriatric memory dysfunction suggests (a) that basal forebrain lesions in animals should mimic cognitive and mnemonic impairments of human dementia and (b) that cholinergic grafts in the cortex and hippocampus may alleviate such impairments, whether induced by basal forebrain lesions or due to the intrinsic processes of ageing. Our own studies addressing these issues are reviewed. Although aged rats manifest impairments in short-term memory that are reversed by cholinergic grafts in the cortex and hippocampus, basal forebrain lesions have produced ambiguous results, which in part are attributable to nonspecific effects of the lesions. Acetylcholinesterase histochemistry and the topography of NBM-cortical connections indicate that basal forebrain lesions that include the NBM in general spare the cholinergic innervation of the prefrontal cortex, but can damage prefrontal cortical outflows via the globus pallidus. Two experiments are presented to indicate that the medial prefrontal cortex and its ventral striatal outputs provide a critical substrate for normal short-term memory performance in delayed matching and nonmatching tasks. These observations can resolve many of the discrepancies in previous lesion and graft studies.     

Basolateral amygdala noradrenergic activity is involved in the acquisition of conditioned odor aversion in the rat

Conditioned odor aversion (COA) is the avoidance of an odorized-tasteless solution (the conditioned stimulus, CS), the ingestion of which precedes toxicosis. Previous works have shown that the basolateral nucleus of the amygdala (BLA) is involved in the acquisition, and more precisely, the control of the CS memory trace, of COA. Since catecholamine depletion of the amygdala induced a deficit in the potentiated version of COA, this study investigated the role of the adrenergic system in the BLA during COA. Male Wistar rats bilaterally implanted with cannulae aimed at the BLA were microinjected with the beta-adrenergic antagonist propranolol (1 microg/0.2 microl) during the acquisition (5 min before the CS presentation, pre-CS, or immediately after, post-CS) or during the retrieval test (5 min before test, pre-test). Results showed that pre-CS, but neither post-CS nor pre-test, infusions of propranolol impaired COA, suggesting that beta-adrenergic system activity in the BLA is involved in the acquisition but not the expression of COA. Moreover, the fact that pre-CS, but not post-CS, treatment disrupted COA suggests that beta-adrenergic system in the BLA is involved in the initiation but not the maintenance of the CS memory trace during COA acquisition.     

Recognition memory for social and non-social odors: differential effects of neurotoxic lesions to the hippocampus and perirhinal cortex

The contributions of the hippocampus (HC) and perirhinal cortex (PER) to recognition memory are currently topics of debate in neuroscience. Here we used a rapidly-learned (seconds) spontaneous novel odor recognition paradigm to assess the effects of pre-training N-methyl-D-aspartate lesions to the HC or PER on odor recognition memory. We tested memory for both social and non-social odor stimuli. Social odors were acquired from conspecifics, while non-social odors were household spices. Conspecific odor stimuli are ethologically-relevant and have a high degree of overlapping features compared to non-social household spices. Various retention intervals (5 min, 20 min, 1h, 24h, or 48 h) were used between study and test phases, each with a unique odor pair, to assess changes in novelty preference over time. Consistent with findings in other paradigms, modalities, and species, we found that HC lesions yielded no significant recognition memory deficits. In contrast, PER lesions caused significant deficits for social odor recognition memory at long retention intervals, demonstrating a critical role for PER in long-term memory for social odors. PER lesions had no effect on memory for non-social odors. The results are consistent with a general role for PER in long-term recognition memory for stimuli that have a high degree of overlapping features, which must be distinguished by conjunctive representations.     

Neurotoxic dorsal CA1 lesions versus 4 VO ischaemic lesions: behavioural comparisons

Anterograde amnesia, a common consequence of transient cerebral ischaemia, has been attributed to cell loss in the hippocampal CA1 subfield. However, variable, widespread damage outside hippocampal CA1 can also occur following ischaemia. We compared the functional consequences of ischaemia and ibotenate acid CA1 lesions on 2 spatial memory tasks (water maze 'place' and 'matching-to-position') to address the possibility that extra-CA1 loss contributes to ischaemia-induced memory deficits in the rat. During place task acquisition, ischaemic rats showed deficits on more measures than ibotenic rats, and during a 1 min probe trial, only ischaemic rats were impaired. On the matching-to-position task, ibotenic rats showed greater impairment than ischaemic rats in terms of one-trial learning, whereas ischaemic rats were more impaired after Trial 2. Ischaemia and ibotenic acid lesions resulted in equivalent CA1 loss, but silver impregnation revealed additional extra-CA1 cell loss in ischaemic rats. Together with the greater behavioural deficits of ischaemic rats, these data indicate a role for extra-CA1 cell loss in ischaemia-induced memory impairments in both animals and humans.     

Effects of post-operative environment on recovery from dorsal hippocampal lesions in young rats: Tests of spatial memory and motor transfer

Young rats (30 days old) were given dorsal hippocampal lesions and then housed in different conditions to assess the contribution of the environment to recovery from the effects of the lesion. They were subsequently tested on a spatial memory task and on a task requiring complex motor movements and transfer ability. Animals with lesions were inferior to sham-operates on both these tasks. Social housing and environmental enrichment improved performance on both tests, but there was no evidence for an interaction between lesion and environmental effects. The validity of using the term “recovery” in these circumstances is discussed, and called into question.     

The effects of pretraining and reminder treatments on retrograde amnesia in rats: comparison of lesions to the fornix or perirhinal and entorhinal cortices

The present experiment examined the effects of pretraining and reminder treatments on the retention of a nonrelational odor-guided digging task following lesions to the hippocampal formation (i.e., fornix) or parahippocampal region (i.e., perirhinal and entorhinal cortices). The results showed that fornix-lesioned rats and control rats had good retention of the task and did not differ from each other; however, perirhinal- and entorhinal-lesioned rats were severely impaired and differed from fornix and control rats. The present experiment found no attenuation of amnesia following pretraining, which may be due to the lesion technique employed and the size of the resulting lesions. However, the experiment found a significant difference in performance following a reminder treatment, even in the severely impaired perirhinal- and entorhinal-lesioned group.     

Effects of excitotoxic brain lesions on taste-mediated odor learning in the rat

The association learning between taste and odor is important in ingestive behavior. For a better understanding of this learning, we have developed a convenient and useful paradigm to assess the taste-mediated odor learning. In the training session, Wistar male rats drank water from two bottles in their home cages and from eight small glass dishes. In the learning session they were exposed in their home cages and also in a circular open-field apparatus to 0.005 M Na-saccharin and 0.02 M quinine hydrochloride which contained either banana or almond odors. One learning trial consisted of this pair of exposures. The preceding behavioral experiment has shown that these two odors are not aversive and are differentially perceived by rats. In the test session, the animals were put in the open-field apparatus equipped with eight dishes: four contained water with banana, and another four, with almond. Normal control rats preferred to drink water with the odor previously associated with saccharin. Stronger and more persistent preference was attained after two or three learning trials. To elucidate the brain sites responsible for this taste-mediated odor learning, the same procedure was assessed on brain-lesioned rats. Rats with lesions in the amygdala showed rapid extinction of preference to the saccharin-associated odor, whereas control rats did not. However, rats with lesions in the insular cortex showed retention of learning similar to that of the control rats. Rats with lesions in the sulcal prefrontal or cingulate cortices showed moderate disruptive effects on preference to the saccharin-associated odor. In conclusion, the odor learning established in our experimental paradigm is based on the association between the quality of odor and hedonics of taste. The amygdala may play a role in the formation, at least in the retention process, of this taste-odor association learning.     

Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum

The retrograde effects of hippocampal lesions on spatial memory were studied. Rats were given a series of 48 place-navigation trials in an open-field water-maze followed, either 3 days or 14 weeks later, by ibotenic acid lesions of the hippocampus (HPC) or subiculum (SUB), or by sham-surgery (SHAM). Two weeks after surgery they were given a retention test without a hidden escape platform. There was a significant decline in performance with time in the SHAM group, but with the 14-week SHAM group performing significantly better than chance levels, whereas both lesioned groups performed at chance at both retention intervals. All rats were then retrained for 24 trials. SHAM rats escaped rapidly within 2 trials, suggesting a reactivation of memory rather than relearning. The HPC groups were severely impaired during retraining, with a developing trend towards better performance in the 3-day group. After 24 trials of training with the escape platform placed in the opposite quadrant of the pool, this new location was learned successfully by SHAM and SUB rats, but not by HPC rats. These results indicate that selective hippocampal formation lesions can cause deficits in retrieval but do not reveal a time-dependent gradient of memory consolidation.     

Effects of Early Hippocampal Lesions on Trace, Delay, and Long-Delay Eyeblink Conditioning in Developing Rats

The effects of bilateral hippocampal aspiration lesions on later acquisition of eyeblink conditioning were examined in developing Long-Evans rat pups. Lesions on postnatal day (PND) 10 were followed by evaluation of trace eyeblink conditioning (Experiment 1) and delay eyeblink conditioning (Experiment 2) on PND 25. Pairings of a tone conditioned stimulus (CS) and periocular shock unconditioned stimulus (US, 100 ms) were presented in one of three conditioning paradigms: trace (380 ms CS, 500 ms trace interval, 880 ms interstimulus interval [ISI]), standard delay (380 ms CS, 280 ms ISI), or long delay (980 ms CS, 880 ms ISI). The results of two experiments indicated that hippocampal lesions impaired trace eyeblink conditioning more than either type of delay conditioning. In light of our previous work on the ontogeny of trace, delay, and long-delay eyeblink conditioning (Ivkovich, Paczkowski, & Stanton, 2000) showing that trace and long-delay eyeblink conditioning had similar ontogenetic profiles, the current data suggest that during ontogeny hippocampal maturation may be more important for the short-term memory component than for the long-ISI component of trace eyeblink conditioning. The late development of conditioning over long ISIs may depend on a separate process such as protracted development of cerebellar cortex.