Size and reversal learning in the beagle dog as a measure of executive function and inhibitory control in aging

Several studies converge on the idea that executive processes age earlier than other cognitive processes. As part of a larger effort to investigate age-related changes in executive processes in the dog, inhibitory control was measured in young, middle-aged, old, and senior dogs using size discrimination learning and reversal procedures. Compared to young and middle-aged dogs, old and senior dogs were impaired on both the initial learning of the size task and the reversal of original reward contingencies. Impaired performance in the two aged groups was characterized as a delay in learning the correct stimulus-reward contingencies and, among the senior dogs in particular, an increase in perseverative responding. These separate patterns of reversal impairments in the old and senior dogs may reflect different rates of aging in subregions of the frontal cortex.     

Aging affects acquisition and reversal of reward-based associative learning

Reward-based associative learning is mediated by a distributed network of brain regions that are dependent on the dopaminergic system. Age-related changes in key regions of this system, the striatum and the prefrontal cortex, may adversely affect the ability to use reward information for the guidance of behavior. The present study investigated the effects of healthy aging on different components of reward learning, such as acquisition, reversal, effects of reward magnitude, and transfer of learning. A group of 30 young (mean age = 24.2 yr) and a group of 30 older subjects (mean age = 64.1 yr) completed two probabilistic reward-based stimulus association learning tasks. Older subjects showed poorer overall acquisition and impaired reversal learning, as well as deficits in transfer learning. When only those subjects who showed evidence of significant learning were considered, younger subjects showed equivalently fast learning irrespective of reward magnitude, while learning curves in older subjects were steeper for high compared to low reward magnitudes. Acquired equivalence learning, which requires generalization across stimuli and transfer of learned contingencies to new stimuli, was mildly impaired in older subjects.     

物质成瘾及其戒除:基于反转学习的视角

物质成瘾与反转学习损伤密切相关,成瘾者往往不能灵活地适应变化的刺激—结果的联结,这可能进一步加剧成瘾者的物质使用。近年来研究发现,物质成瘾者的反转学习相关的腹外侧前额和背外侧前额等脑区激活异常,这些异常与成瘾者的冲动性和强迫性有关。此外,个体的反转学习能力对其成瘾行为具有一定预测性。今后应增加对不同类型物质成瘾者的反转学习脑机制及物质相关线索对成瘾者反转学习影响的研究,并且进一步探讨成瘾者的冲动性和强迫性对其反转学习的调节及个体反转学习能力对其成瘾行为的预测。     

Delay-dependent impairment of reversal learning in rats treated with trimethyltin

Recent theories of hippocampal function focus on its role in the formation of associations in the temporal domain. A reversal learning paradigm based on leverpress automaintenance was developed to vary the CS-US relationship along two independent dimensions, one temporal and one not: CS(+)-US delay and the probability of reinforcement [P(RFT)] following the CS+. Eight male hooded Long-Evans rats were trained to reverse these automaintained discriminations repeatedly, until stable performance was achieved. The neurotoxicant trimethyltin (TMT) was used to induce lesions in the CNS, including the CA3-4 region of Ammon's Horn in dorsal hippocampus. Following iv injection of 7 mg/kg TMT to half the rats, reversal learning was assessed under varying conditions of delay and P(RFT). After recovery from the acute effects of TMT (1-2 weeks), treated rats reversed normally when no delay separated the CS+ and US; with delays of 2 to 4 s, they reversed less completely within a session than did controls. Changing P(RFT) did not affect reversal learning in either group, but reduced response rates similarly in both groups. Morphological damage was quantified by measuring the length of the remaining pyramidal cell line in sections of dorsal hippocampus. The degree of behavioral impairment correlated significantly with hippocampal damage only at nonzero CS(+)-US delays. These results indicate that TMT impaired ability of rats to integrate temporal relationships between stimulus events, and are consistent with theories of hippocampal mediation of temporal associations.     

Fear conditioning-induced alterations of phospholipase C-beta1a protein level and enzyme activity in rat hippocampal formation and medial frontal cortex

We investigated the effects of one-trial fear conditioning on phospholipase C-beta1a catalytic activity and protein level in hippocampal formation and medial frontal cortex of untreated control rats and rats prenatally exposed to ethanol. One hour following fear conditioning of untreated control rats, phospholipase C-beta1a protein level was increased in the hippocampal cytosolic fraction and decreased in the hippocampal membrane and cortical cytosolic and cortical membrane fractions. Twenty-four hours after fear conditioning, phospholipase C-beta1a protein level was reduced in the hippocampal cytosolic fraction and elevated in the cortical nuclear fraction; in addition, 24 h after conditioning, phospholipase C-beta1a activity in the cortical cytosolic fraction was increased. Rats that were exposed prenatally to ethanol displayed attenuated contextual fear conditioning, whereas conditioning to the acoustic-conditioned stimulus was not different from controls. In behavioral control (unconditioned) rats, fetal ethanol exposure was associated with reduced phospholipase C-beta1a enzyme activity in the hippocampal nuclear, cortical cytosolic, and cortical membrane fractions and increased phospholipase C-beta1a protein level in the hippocampal membrane and cortical cytosolic fractions. In certain cases, prenatal ethanol exposure modified the relationship between fear conditioning and changes in phospholipase C-beta1a protein level and/or activity. The majority of these effects occurred 1 h, rather than 24 h, after fear conditioning. Multivariate analysis of variance revealed interactions between fear conditioning, subcellular fraction, and prenatal ethanol exposure for measures of phospholipase C-beta1a protein level in hippocampal formation and phospholipase C-beta1a enzyme activity in medial frontal cortex. In the majority of cases, fear conditioning-induced changes in hippocampal phospholipase C-beta1a protein level were augmented in rats prenatally exposed to ethanol. In contrast, fear conditioning-induced changes in cortical phospholipase C-beta1a activity were, often, in opposite directions in prenatal ethanol-exposed compared to diet control rats. We speculate that alterations in subcellular phospholipase C-beta1a catalytic activity and protein level contribute to contextual fear conditioning and that learning deficits observed in rats exposed prenatally to ethanol result, in part, from dysfunctions in phospholipase C-beta1a signal transduction.     

The Effects of Selective Cholinergic Basal Forebrain Lesions and Aging upon Expectancy in the Rat

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na⁺/K⁺-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.     

Susceptibility to induction of long-term depression is associated with impaired memory in aged Fischer 344 rats

The current study employed aged and young male Fischer 344 rats to examine the relationship between long-term depression (LTD), age, and memory. Memory performance was measured on two tasks that are sensitive to hippocampal function; inhibitory avoidance and spatial discrimination on the Morris water maze. The slope of the extracellular excitatory postsynaptic field potential was recorded from CA3-CA1 synapses in hippocampal slices. Low frequency stimulation (LFS) induced a modest LTD only in aged animals under standard recording conditions. The decrease in synaptic transmission examined only in aged animals correlated with memory scores on the spatial task and LTD was not observed in aged animals with the highest memory scores. LTD induction was facilitated by increasing the Ca(2+)/Mg(2+) ratio of the recording medium or employing a paired-pulse stimulation paradigm. Age differences disappeared when LFS was delivered under conditions of elevated Ca(2+)/Mg(2+) in the recording medium. Using multiple induction episodes under conditions which facilitate LTD-induction, no age-related difference was observed in the maximum level of LTD. The results indicate that the increased susceptibility to LTD induction is associated with impaired memory and results from a shift in the induction process. The possible relationship between LTD and memory function is discussed.     

Orbital prefrontal cortex and guidance of instrumental behavior of rats by visuospatial stimuli predicting reward magnitude

The orbital prefrontal cortex (OPFC) is part of a circuitry mediating the perception of reward and the initiation of adaptive behavioral responses. We investigated whether the OPFC is involved in guidance of the speed of instrumental behavior by visuospatial stimuli predictive of different reward magnitudes. Unoperated rats, sham-lesioned rats, and rats with bilateral lesions of the OPFC by N-methyl-D-aspartate (NMDA) were trained in a visuospatial discrimination task. The task required a lever press on the illuminated lever of two available to obtain a food reward. Different reward magnitudes were permanently assigned to lever presses to respective sides of the operant chamber; that is, responses to one lever (e.g., the left one) were always rewarded with one pellet and responses to the other lever with five pellets. On each trial, the position of the illuminated lever was pseudorandomly determined in advance. Results revealed that OPFC lesions did not impair acquisition of the task, as the speed of conditioned responses was significantly shorter with expectancy of a high reward magnitude. In addition, during reversal, shift and reshift of lever position–reward magnitude contingencies and under extinction conditions, performance of the OPFC-lesioned and control groups did not differ. It is concluded that the OPFC in rats might not be critical for adapting behavioral responses to changes of stimulus–reward magnitude contingencies signaled by visuospatial cues.     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

Structural Imaging Measures of Brain Aging

During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily “normal” or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer’s disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age-related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer’s disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between “Normal” and “Healthy” brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society.     

The roles of orbital frontal cortex in the modulation of antisocial behavior

This article considers potential roles of orbital frontal cortex in the modulation of antisocial behavior. Two forms of aggression are distinguished: reactive aggression elicited in response to frustration/threat and goal directed, instrumental aggression. It is suggested that orbital frontal cortex is directly involved in the modulation of reactive aggression. It is argued that orbital frontal cortex does not "inhibit" reactive aggression but rather may both increase or decrease its probability as a function of social cues present in the environment. Early dysfunction in this function of orbital frontal cortex may be linked to the development of Borderline Personality Disorder. Instrumental aggression is linked to a fundamental failure in moral socialization. However, the available data suggest that the amygdala, but not orbital frontal cortex, is required for functions such as aversive conditioning and passive avoidance learning that are necessary for moral socialization. Psychopathic individuals who present with significant instrumental aggression, are impaired in aversive conditioning and passive avoidance learning and show evidence of amygdala dysfunction. Orbital frontal cortex and the amygdala are involved in response reversal where instrumental responses must be reversed following contingency change. Impairments in response reversal are also seen in psychopathic individuals. However, it remains unclear whether impairment in response reversal per se is associated with antisocial behavior.     

Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats

Exposures to uncontrollable stress have been shown to alter ensuing synaptic plasticity in the hippocampus and interfere with hippocampal-dependent spatial memory in rats. The present study examined whether stress, which impairs hippocampal long-term potentiation (LTP), also affects (nonspatial) hippocampal-dependent object-recognition memory, as tested on the visual paired comparison task (VPC) in rats. After undergoing an inescapable restraint–tailshock stress experience, rats exhibited markedly impaired recognition memory at the 3-h (long) familiarization-to-test phase delay but not at the 5-min (short) delay. In contrast, unstressed control animals showed robust recognition memory (i.e., they exhibited reliable preferences for novel over familiar objects) at both short- and long-delay periods. The impairing effect of stress on long-delay recognition memory was transient because 48 h after undergoing stress experience, animals performed normally at the long delay. Similar to stress, microinfusions of DL-2-amino-5-phosphonovaleric acid (APV), a competitive N-methyl-D-aspartate receptor (NMDAR) antagonist that blocks LTP, into the dorsal hippocampus selectively impaired object-recognition memory at the long-delay period. Together, these results suggest that stress and intrahippocampal administration of APV affect recognition memory by influencing synaptic plasticity in the hippocampus.

[The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper H. Blair.]

     

Memory for Duration: Role of Hippocampus and Medial Prefrontal Cortex

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).     

The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.     

Prefrontal cortex and hippocampus subserve different components of working memory in rats

Both the medial prefrontal cortex (mPFC) and hippocampus are implicated in working memory tasks in rodents. Specifically, it has been hypothesized that the mPFC is primarily engaged in the temporary storage and processing of information lasting from a subsecond to several seconds, while the hippocampal function becomes more critical as the working memory demand extends into longer temporal scales. Although these structures may be engaged in a temporally separable manner, the extent of their contributions in the "informational content" of working memory remains unclear. To investigate this issue, the mPFC and dorsal hippocampus (dHPC) were temporarily inactivated via targeted infusions of the GABA(A) receptor agonist muscimol in rats prior to their performance on a delayed alternation task (DAT), employing an automated figure-eight maze that required the animals to make alternating arm choice responses after 3-, 30-, and 60-sec delays for water reward. We report that inactivation of either the mPFC or dHPC significantly reduced DAT at all delay intervals tested. However, there were key qualitative differences in the behavioral effects. Specifically, mPFC inactivation selectively impaired working memory (i.e., arm choice accuracy) without altering reference memory (i.e., the maze task rule) and arm choice response latencies. In contrast, dHPC inactivation increased both reference memory errors and arm choice response latencies. Moreover, dHPC, but not mPFC, inactivation increased the incidence of successive working memory errors. These results suggest that while both the mPFC and hippocampus are necessarily involved in DAT, they seem to process different informational components associated with the memory task.     

Glucose attenuation of paradoxical sleep deficits in old rats.

Glucose administration enhances memory in several amnestic populations, including old humans and rodents. The present experiment demonstrates that glucose also enhances measures of sleep in old rats. Three-hour day-time sleep EEGs were assessed in 3- and 24-month-old rats. The animals received injections of saline or glucose (100, 500, and 1000 mg/kg) on different days in a counter-balanced order. At doses of 100 and 500 mg/kg, glucose augmented the duration of paradoxical sleep bouts and total paradoxical sleep time in old, but not young, rats. Within 2 weeks after the sleep tests, measures of several brain neurotransmitter functions were obtained. Glucose was more effective in enhancing paradoxical sleep in those individual aged rats with high levels of hippocampal choline acetyltransferase and occipital cortex serotonin concentrations than in aged rats with lower levels on these neurochemical measures. The findings suggest that glucose attenuates selective age-related sleep deficits in old rats. More generally, these results add to a growing body of evidence indicating that moderate doses of peripheral glucose can influence a variety of CNS measures.     

Age-Related Changes in Neural Activation During Working Memory Performance

Changes in frontal lobe functions are a typical part of aging of the brain. There are age-related declines in working memory performance, a skill requiring frontal lobe activation. This study examined neural activation, using [15 O] water positron emission tomography (PET) methodology, during performance on two verbal working memory tasks in younger and older participants. The results demonstrated the typical areas of activation associated with working memory performance (e.g., dorsolateral prefrontal cortex and inferior parietal cortex) in both groups. However, the younger participants utilized the right dorsolateral prefrontal cortex and anterior cingulate gyrus significantly more than the older participants. In turn, the older participants used the left dorsolateral prefrontal cortex significantly more than the younger participants and maintained material-specific lateralization in their pattern of activation. These findings are consistent with a previous report of different age-related patterns of frontal activation during working memory.     

Age-related differences in the brain areas outside the classical language areas among adults using category decision task

Older adults perform much like younger adults on language. This similar level of performance, however, may come about through different underlying brain processes. In the present study, we evaluated age-related differences in the brain areas outside the typical language areas among adults using a category decision task. Our results showed that similar activation patterns were found in classical language processing areas across the three age groups although regional lateralization indices in Broca’s and Wernicke’s areas decreased with age. The greatest differences, however, among the three groups were found primarily in the brain areas not associated with core language functioning including the hippocampus, middle frontal gyrus, ventromedial frontal cortex, medial superior parietal cortex and posterior cingulate cortex. Therefore, the non-classical language areas may exhibit an age-related difference between three age groups while the subjects show a similar activation pattern in the core, primary language processing during a semantic decision task.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.