Individual differences in age-related neurocognitive outcomes: within-subject assessment of memory for odors

Cognitive decline is a common feature of aging, particularly in memory domains supported by the medial temporal lobe (MTL). The ability to identify intervention strategies to treat or prevent this decline is challenging due to substantial variability between adults in terms of age of onset, rate and severity of decline, and many factors that could influence cognitive reserve. These factors can be somewhat mitigated by use of within-subject designs. Aged outbred Long-Evans rats have proven useful for identifying translationally relevant substrates contributing to age-related decline in MTL-dependent memory. In this population, some animals show reliable impairment on MTL-dependent tasks while others perform within the range of young adult rats. However, currently there are relatively few within-subject behavior protocols for assessing MTL function over time, and most require extensive training and appetitive motivation for associative learning. In the current study, we aimed to test whether water maze learning impairments in aged Long-Evans rats would be predictive of delayed recognition memory impairments and whether these odor memory impairments would be stable within subjects over multiple rounds of testing

Is Avoiding an Aversive Outcome Rewarding? Neural Substrates of Avoidance Learning in the Human Brain

Avoidance learning poses a challenge for reinforcement-based theories of instrumental conditioning, because once an aversive outcome is successfully avoided an individual may no longer experience extrinsic reinforcement for their behavior. One possible account for this is to propose that avoiding an aversive outcome is in itself a reward, and thus avoidance behavior is positively reinforced on each trial when the aversive outcome is successfully avoided. In the present study we aimed to test this possibility by determining whether avoidance of an aversive outcome recruits the same neural circuitry as that elicited by a reward itself. We scanned 16 human participants with functional MRI while they performed an instrumental choice task, in which on each trial they chose from one of two actions in order to either win money or else avoid losing money. Neural activity in a region previously implicated in encoding stimulus reward value, the medial orbitofrontal cortex, was found to increase, not only following receipt of reward, but also following successful avoidance of an aversive outcome. This neural signal may itself act as an intrinsic reward, thereby serving to reinforce actions during instrumental avoidance

Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze.

The Morris water maze task was originally designed to assess the rat’s ability to learn to navigate to a specific location in a relatively large spatial environment. This article describes new measures that provide information about the spatial distribution of the rat’s search during both training and probe trial performance. The basic new measure optimizes the use of computer tracking to identify the rat’s position with respect to the target location. This proximity measure was found to be highly sensitive to age-related impairment in an assessment of young and aged male Long-Evans rats. Also described is the development of a learning index that provides a continuous, graded measure of the severity of age-related impairment in the task. An index of this type should be useful in correlational analyses with other neurobiological or behavioral measures for the study of individual differences in functional/biological decline in aging

Hippocampal lesions disrupt decrements but not increments in conditioned stimulus processing

Studies recording hippocampal neural activity show widespread registration of events during associative learning. Recent computational models of hippocampal function have stressed its role in attentional processes specified by well-developed modern theories of associative learning. These modeling efforts are largely aimed at accounting for the behavioral outcomes of damage to the hippocampal system in terms of underlying changes in information processing. Two experiments examined the effects of neurotoxic lesions of the hippocampus on changes in attentional processing of a conditioned stimulus (CS) in appetitive Pavlovian conditioning in rats. In Experiment 1, hippocampal lesions eliminated the reduction in associability of a CS usually produced by preexposure to that cue (latent inhibition). In Experiment 2, hippocampal lesions interfered with the loss in associability of a CS normally produced when that CS consistently predicts another event. In contrast, in Experiment 2, hippocampal lesions did not prevent the enhancement of CS associability when a previously consistent predictive relation between two events was made inconsistent. This research supports previous claims that the hippocampus is involved in regulating the processing of CSs in Pavlovian conditioning, and provides new evidence for a hippocampal role in decremental, but not incremental, changes in attention

Removal of Cholinergic Input to Rat Posterior Parietal Cortex Disrupts Incremental Processing of Conditioned Stimuli

Recent research suggests that the basal forebrain cholinergic neurons innervating the cortex play a role in attentional functions in both primates and rodents. Among the cortical targets of these projections in primates is the posterior parietal cortex (PPC), a region shown to be critically involved in the regulation of attention. Recent anatomical studies have defined a cortical region in the rat that may be homologous to the PPC of primates. In the present study, cholinergic innervation of the PPC was depleted by intracortical infusion of the immunotoxin 192 IgG-saporin. Control and lesioned rats were then tested in two associative learning paradigms designed to increase attentional processing of conditioned stimuli (CSs). In one experiment, attention was manipulated by shifting a predictive relation between a light CS and another CS to a less predictive relation. Unlike control rats, lesioned rats failed to increase attention when the predictive relation was modified. In a second experiment, attentional processing of a tone CS was increased when its introduction during training coincided with a change in the value of the unconditioned stimulus, a phenomenon referred to as unblocking. Unlike control rats, lesioned rats failed to exhibit unblocking. In both paradigms, lesioned rats conditioned normally when the training procedures did not encourage increased attentional processing. These findings, across different behavioral paradigms and stimulus modalities, provide converging evidence that intact cholinergic innervation of the PPC is important for changes in attention that can increase the processing of certain cues

Brain Aging: Changes in the Nature of Information Coding by the Hippocampus

Advanced age in rats is associated with a decline in spatial memory capacities dependent on hippocampal processing. As yet, however, little is known about the nature of age-related alterations in the information encoded by the hippocampus. Young rats and aged rats identified as intact or impaired in spatial learning capacity were trained on a radial arm maze task, and then multiple parameters of the environmental cues were manipulated to characterize the changes in firing patterns of hippocampal neurons corresponding to the presence of particular cues or the spatial relationships among them. The scope of information encoded by the hippocampus was reduced in memory-impaired aged subjects, even though the number of neurons responsive to salient environmental cues was not different from that in young rats. Furthermore, after repeated manipulations of the cues, memory-intact aged rats, like young rats, altered their spatial representations, whereas memory-impaired aged rats showed reduced plasticity of their representation throughout testing. Thus changes in hippocampal memory representation associated with aging and memory loss can be characterized as a rigid encoding of only part of the available information

Disruption of Decrements in Conditioned Stimulus Processing by Selective Removal of Hippocampal Cholinergic Input

The attention directed to environmental stimuli can be modified by experience. For example, preexposure of a conditioned stimulus (CS) in the absence of reinforcement can retard subsequent conditioning of that stimulus when it is paired directly with an unconditioned stimulus, a phenomenon referred to as latent inhibition. Similarly, consistent pairings of a CS with another event can slow the acquisition of new information about that CS. Such phenomena suggest that reductions in the processing of CSs occur when they are made behaviorally irrelevant or consistent predictors of other events. On the basis of the observation that hippocampal lesions prevented such reductions in CS processing, we hypothesized that damage to basal forebrain cholinergic neurons that project to the hippocampus, using microinjections of the selective immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB), also would disrupt normal reductions in CS processing. Lesions of hippocampal cholinergic input disrupted decreases in CS processing, manifested in both an absence of latent inhibition and a lack of reduced processing of a CS that had been a consistent predictor of another CS. These results indicate that cholinergic neurons in the MS/VDB play a role in the regulation of CS processing. Furthermore, these findings (in conjunction with previous findings) implicat

The Role of an Amygdalo-Nigrostriatal Pathway in Associative Learning

The present study examined the role of an amygdalo-nigrostriatal pathway in associative learning. An asymmetrical lesion model was used to test whether a circuit from the amygdala central nucleus to the dorsolateral striatum, via the substantia nigra, is critical for mediating conditioned orienting responses. Rats with an asymmetrical lesion, consisting of neurotoxic removal of central nucleus neurons in one hemisphere and depletion of the dopamine innervation of the dorsolateral striatum in the contralateral hemisphere, failed to acquire conditioned orienting responses. In contrast, the asymmetrical lesion had no effect on spontaneous orienting or learning another response directed to the source of the food unconditioned stimulus in the same task. A second experiment tested the effect of reversible inactivation of the dorsolateral striatum contralateral to a neurotoxic central nucleus lesion on acquisition of the conditioned orienting response. Although inactivation did not affect spontaneous orienting, rats failed to acquire the conditioned orienting response during sessions in which inactivation occurred. Immediately after the inactivation procedure was terminated, however, a significant increase in orienting to the conditioned stimulus was evident. These data support the interpretation that the dorsolateral striatum provides a route for the expression of the conditioned orienting response but is not essential for acquisition of this learned behavior

Basal forebrain cholinergic lesions disrupt increments but not decrements in conditioned stimulus processing

Magnocellular neurons in the basal forebrain provide the major cholinergic innervation of cortex. Recent research suggests that this cholinergic system plays an important role in the regulation of attentional processes. The present study examined the ability of rats with selective immunotoxic lesions of these neurons (made with 192 IgG- saporin) to modulate attention within an associative learning framework. Each rat was exposed to conditioned stimuli (CS) that were either consistent or inconsistent predictors of subsequent cues. Intact control rats showed increased CS associability when that cue was an inconsistent predictor of a subsequent cue, whereas lesioned rats were impaired in increasing attention to the CS when its established relation to another cue was modified. In a separate experiment designed to test latent inhibition, it was shown that removal of the corticopetal cholinergic neurons spared a decrement in associability that occurs when rats are extensively preexposed to a CS prior to conditioning. These data indicate that the cholinergic innervation of cortex is critical for incrementing, but not for decrementing attentional processing. The specific behavioral tests used to assess the role of the basal forebrain cholinergic system in the present study were previously used to identify a role for the amygdala central nucleus in attention (Holland and Gallagher, 1993b). Those studies, together with the results in this report, indicate that regulation of attentional processes during associative learning may be mediated by projections from the amygdala to the basal forebrain cholinergic system