Model Of Agerelated Frontal Corticalstriatal Impairment

Although the existence of a prefrontal cortex in rats analogous to the primate prefrontal cortex is a matter of controversy, it is generally accepted that the rat medial frontal cortex (infralimbic and prelimbic sub-regions) performs functions that are typically referred to as executive function in primates (Uylings et al., 2003). Birrell and Brown (2000) adapted an attentional set shifting task used in monkeys and humans (Owen et al., 1991; Dias et al., 1996) for use in rats. This task was subsequently used to investigate the effects of aging on prefrontal function in the same study population as that used for the investigation of medial temporal lobe function described above (Barenese et al., 2002).

The rat version of the attentional set shifting task involves digging in a pot for a food reward (see Figure 32.7).

Two perceptual dimensions vary: the odor of the pot (e.g., lemon vs. cinnamon) and the digging medium that is contained within the pot (e.g., confetti vs. gravel). By manipulating the combinations of the dimensions, several types of discriminations can be evaluated, including simple discriminations, compound discriminations, reversals of both simple and compound discriminations, and intra- and extradimensional shifts. The simple

Figure 32.7 This photograph shows a Long-Evans rat sitting on a pot used for digging in the attentional set-shifting task. This task that is detailed in the text has been shown to be sensitive to cortical regions believed to be analogous to human dorsolateral prefrontal cortex. Individual differences in cognitive abilities that are supported by this system have been observed among aged male Long-Evans rats. As shown in this figure, rats are trained to dig in pots containing different types of media (such as the beads shown here) and different odors (e.g., lemon) for a food reward. Throughout the course of training, the rule required to successfully find the food is altered, and the ability of the rats to switch to the new rule is evaluated. Photo credit: Steve Kim, laboratory of Dr. Mark Baxter.

Figure 32.7 This photograph shows a Long-Evans rat sitting on a pot used for digging in the attentional set-shifting task. This task that is detailed in the text has been shown to be sensitive to cortical regions believed to be analogous to human dorsolateral prefrontal cortex. Individual differences in cognitive abilities that are supported by this system have been observed among aged male Long-Evans rats. As shown in this figure, rats are trained to dig in pots containing different types of media (such as the beads shown here) and different odors (e.g., lemon) for a food reward. Throughout the course of training, the rule required to successfully find the food is altered, and the ability of the rats to switch to the new rule is evaluated. Photo credit: Steve Kim, laboratory of Dr. Mark Baxter.

discriminations (SD) require identifying the rewarded pot that contains only a single relevant perceptual dimension (e.g., odors are relevant, and the digging medium is the same in both pots). The compound discriminations (CD) present combinations of both perceptual dimensions (the pots contain both a unique odor and a unique digging medium; either the odor or medium can be the relevant, rewarded stimulus). The reversal discriminations change the valence of the previously rewarded stimulus; e.g., the previously unrewarded pot (—) becomes rewarded (+). Discrimination reversals can occur with both compound (CD-Rev) and simple (SD-Rev) discriminations. An intradimensional (IDS) shift is a new discrimination using the same perceptual dimension as what was previously relevant; for example, if the previous discrimination consisted of a relevant odor stimulus (e.g., lemon and cinnamon), the IDS would be a comparison between two new odors (e.g., peppermint and sage). The extradimensional (EDS) shift requires changing the rule that was used previously and shifting attention to the previously irrelevant stimulus. For example, if the previous comparison was between a lemon/sawdust pot and a cinnamon/confetti pot and the subject had learned that the odor, in this case lemon, was the positive exemplar, then EDS would require inhibiting the "odor" rule and creating the ''digging medium'' rule, e.g., the subject now needs to pay attention to the digging medium in order to accurately identify the pot containing the reward.

The set shifting task described above has advantages in that it contains within-subject measurements that can be used for control data. The ability of the animal to perform simple discriminations to an equal degree across dimensions (e.g., for odors and for digging media) is crucial, and pilot studies must be performed to assure comparable trials to criterion using different odor or medium pairs and/or to eliminate stimuli that cause a natural aversion. Performance on the simple discrimination must be at a baseline level prior to beginning the subsequent phases of the task, and this may vary depending on species (rat or mouse) and even strain.

Because of the neuropsychological and neurobiological evidence that the prefrontal cortex is vulnerable to the effects of normal aging, Dr. Mark Baxter's group (Oxford, UK) examined attentional set shifting using the Birrell and Brown task in young and aged Long-Evans rats (Barense et al., 2002). Performance of the aged rats on the EDS phase was significantly impaired compared to the young rats: the aged rats required significantly more trials to criterion to learn this discrimination (Figure 32.8).

The individual differences in EDS ability in the aged rats were not correlated with impaired spatial learning ability in the Morris water maze. These results indicate that the effects of age may be different in individuals not only within a specific brain region but also across brain regions that subserve different functions. The rat data obtained by Barense et al. (2002) parallels

^m Aged

^m Aged

SD CD IDS Rev EDS Task Phase

Figure 32.8 This graph shows the performance of both young and aged animals on the attentional set-shifting task. The aged rats require more trials than young rats to be proficient at the extradimensional phase (EDS) of the task (p < 0.05), while performing comparably to young on other discriminations in this task (SD = simple discrimination, CD = compound discrimination, IDS = intradimensional shift, REV = reversal). Extradimensional shifts are those that are most directly related to performance on human tasks that identify subjects with cognitive deficits and damage to the prefrontal cortex.

SD CD IDS Rev EDS Task Phase

Figure 32.8 This graph shows the performance of both young and aged animals on the attentional set-shifting task. The aged rats require more trials than young rats to be proficient at the extradimensional phase (EDS) of the task (p < 0.05), while performing comparably to young on other discriminations in this task (SD = simple discrimination, CD = compound discrimination, IDS = intradimensional shift, REV = reversal). Extradimensional shifts are those that are most directly related to performance on human tasks that identify subjects with cognitive deficits and damage to the prefrontal cortex.

a neuropsychological study in healthy aged humans that also demonstrated a lack of correlation between deficits on tests traditionally associated with prefrontal function (including the WCST) and deficits on tasks traditionally associated with hippocampal/medial temporal lobe dysfunction (delayed cued recall) (Glisky et al., 1995).

FRONTAL CORTICAL-STRIATAL-BASED COGNITION: CORRELATING AGE-RELATED DIFFERENCES

Attentional set shifting appears to be sensitive to the effects of aging on the prefrontal cortex, analogous to the sensitivity of spatial learning in the water maze to medial temporal lobe dysfunction in aging. Investigations of the neurobiological basis of age-related deficits in attentional set shifting are just beginning but have proven informative. For example, an analysis of ionotropic glutamate receptor binding in the aged Long-Evans rats assessed for attentional set shifting and spatial learning (described above) revealed that a decrease in binding to a glutamate-receptor subtype (kainate receptors) in the cingulate region of the prefrontal cortex was significantly correlated with poor performance in the EDS phase (Figure 32.9, top panel) but not spatial learning (Figure 32.9, bottom panel) (Nicolle and Baxter, 2003).

In that same study, decreases in NMDA receptor binding in the dorsomedial striatum of the aged group were shown to correlate with preserved memory (R = +.79, p < .05), perhaps indicating a neurobiological response that is compensatory in nature (Nicolle and Baxter, 2003). We hope that this model of age-related

Figure 32.9 This graph shows the correlation between high-affinity [3H]kainate binding in the cingulate cortex and trials to criterion on the extradimensional shift (EDS) phase of the attentional set-shifting task (top panel) or the spatial Learning Index (bottom panel) in young and aged Long-Evans rats. Lower levels of [3H]kainate binding significantly correlated with more trials to criterion (poorer learning) in the cingulate cortex of the aged rats, R = —.83, p < .05. There was no correlation between [3H]kainate binding in cingulate cortex with spatial learning index.

Figure 32.9 This graph shows the correlation between high-affinity [3H]kainate binding in the cingulate cortex and trials to criterion on the extradimensional shift (EDS) phase of the attentional set-shifting task (top panel) or the spatial Learning Index (bottom panel) in young and aged Long-Evans rats. Lower levels of [3H]kainate binding significantly correlated with more trials to criterion (poorer learning) in the cingulate cortex of the aged rats, R = —.83, p < .05. There was no correlation between [3H]kainate binding in cingulate cortex with spatial learning index.

cognitive impairment will provide a rich source of neurobiological data that will be revealing as to the nature of frontal-cortical cognitive deficits in aging.

Conclusion

Overall, these studies demonstrate that rodent models of cognitive aging can provide a rich resource for uncovering neurobiological alterations associated with age-related cognitive deficits. Findings that some aged rat populations naturally differ in their maintenance of cognitive function with age affords the opportunity to model individual differences in cognitive abilities in the human population. Importantly, rat models are convenient and can be easily manipulated, and the results from such models have broadly paralleled findings observed in humans and nonhuman primates.

As described, there is now an extensive literature using spatial learning ability as a functional measure of the output of the hippocampus/medial temporal system in aged rats. This individual variability in spatial learning in the aged population has been capitalized upon by using subsequent neurobiological assessments to identify the cellular and molecular contributors to age-related impairments. Neurobiological alterations continue to be identified in this model, and it remains a challenge to integrate the current and future findings so that they can provide a comprehensive picture of the range and complexity of alterations that occur during aging. The complexity of normal aging is illustrated by consideration of two different neural systems, the medial temporal lobe and the frontal cortical-striatal system, and how these each relate overall to cognitive function in aging. Individual vulnerability may exist (and probably does) that predisposes some subjects to frontal dysfunction and others to medial temporal lobe dysfunction. There may also be a subpopulation of aged individuals that are vulnerable to deficits in cognitive decline associated with both brain systems. How to identify and how to push these findings to the next level will depend upon sensitive behavioral assessment of these neural systems that are vulnerable to the effects of aging.

The newly devised attentional set shifting task developed for rats shows real promise as a behavioral measure of the integrity of the frontal cortical system, a brain system that is adversely affected by normal age and in numerous pathological age-related diseases. As this model is further developed and refined, the hope is to yield data regarding both molecular and cellular contributors to cognitive impairments associated with frontal cortical-striatal circuitry. In this latter case, the specific circuitry responsible for ''executive functions'' is not yet fully elucidated, and we are just beginning to uncover the neurobiological underpinnings of the widely reported age-related deficits associated with this brain system in the human population. Over the next several years, refinement of this protocol along with a gained understanding of the neural and molecular circuitry should garnish important new data in this arena. This approach will be necessary to identify the neurobiological etiology of individual differences in cognitive deficits in the aged population and will be necessary when trying to reverse age-related cognitive deficits in the human population.

The general approach described here in terms of relating neurobiological changes to individual differences in cognitive abilities among aged rodents should help uncover the underlying brain mechanisms responsible for age-related deficits. Ultimately, this combination of behavioral and neurobiological assessment in the same animals will help direct future therapeutic approaches to combating cognitive decline in the human aged population.

Recommended Resources

Barense M.D., Fox M.T., and Baxter M.G. (2002). Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn. Mem. 9, 191-201. Birrell J.M. and Brown V.J. (2000). Medial frontal cortex mediates perceptual attentional set shifting in the rat. J. Neurosci. 20, 4320-324. Gallagher M. (1993). Severity of spatial learning impairments in aging: development of a learning index for performance in the Morris water maze. Behavioral Neurosci. 107(4), 618-626. Morris R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47-60. http://www.hvsimage.com/

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