Naltrexone reverses age-induced cognitive deficits in rats

We evaluated young (3-4 months) and aged (22-24 months) male Sprague-Dawley rats in an attentional set-shifting procedure that assessed reversal, intradimensional shift (IDS), and extradimensional shift (EDS) discrimination learning tasks within one test session. These aspects of discrimination learning are sensitive to damage to distinct regions of frontal cortex. Compared to young animals, aged rats were significantly impaired on the EDS task and did not demonstrate significant impairment on the reversal or IDS tasks. The opioid antagonist naltrexone (2mg/kg, ip) was administered to young and aged rats prior to testing to assess possible improvements in aged-related cognitive impairments. Naltrexone (2mg/kg) attenuated the impairments in cognitive function in the EDS task for aged animals, but did not alter any task performance in the younger group. These results suggest that normal aging in rats is associated with impaired medial frontal cortex function as assessed by this attentional set-shifting procedure and opioid mediated mechanisms may represent a therapeutic target for drugs to improve cognitive deficits associated with aging.     

Orbitofrontal dopaminergic dysfunction causes age-related impairment of reversal learning in rats

Reversal learning is a domain that involves cognitive flexibility and is defined as the ability to rapidly alter established patterns of behavior when confronted with changing circumstances. This function depends critically on the orbitofrontal cortex (OFC) in the prefrontal cortical (PFC) structure, which is among the most sensitive to the influences of aging, and impaired reversal learning is a common functional disturbance of aged brain. The present study was designed to clarify the precisely neurochemical basis of this impaired learning in rats. For this purpose, we first examined reversal learning in young (3-month-old) and aged (24-month-old) rats using a T-maze discrimination task. The ability of aged rats to learn initially a reward rule for a T-maze discrimination task was almost equal to that of young rats, suggesting that simple discrimination ability was normal in aged rats. However, the ability to learn a reversed rule in a subsequent task was markedly impaired in aged rats. In addition, aged rats had reduced dopaminergic transmission concomitant with attenuated tyrosine hydroxylase (TH) activity in the OFC. Moreover, age-related impairment of reversal learning was improved by an intra-OFC infusion of 30 ng, but not 10 ng, of the D1 receptor agonist SKF 81297. Increasing dose of SKF 81297 to 100 ng also improved the impairment, but this effect was weaker than that of 30 ng, indicating that the SKF 81297 response was an inverted “U” pattern. The maximum SKF 81297 response (30 ng) was abolished by the D1 receptor antagonist SCH 23390. Thus, age-related impairment of reversal learning was due to a D1 receptor-mediated hypodopaminergic mechanism in the OFC. This finding provides direct evidence showing the involvement of OFC dopaminergic dysfunction in the development of cognitive inflexibility during the normal aging process     

Executive function in Tourette's syndrome and obsessive-compulsive disorder

BACKGROUND: Cognitive performance was compared in the genetically and neurobiologically related disorders of Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD), in three domains of executive function: planning, decision-making and inhibitory response control. METHOD: Twenty TS patients, twenty OCD patients and a group of age- and IQ-matched normal controls completed psychometric and computerized cognitive tests and psychiatric rating scales. The cognitive tests were well-characterized in terms of their sensitivity to other fronto-striatal disorders, and included pattern and spatial recognition memory, attentional set-shifting, and a Go/No-go set-shifting task, planning, and decision-making. RESULTS: Compared to controls, OCD patients showed selective deficits in pattern recognition memory and slower responding in both pattern and spatial recognition, impaired extra-dimensional shifting on the set-shifting test and impaired reversal of response set on the Go/No-go test. In contrast, TS patients were impaired in spatial recognition memory, extra-dimensional set-shifting, and decision-making. Neither group was impaired in planning. Direct comparisons between the TS and OCD groups revealed significantly different greater deficits for recognition memory latency and Go/No-go reversal for the OCD group, and quality of decision-making for the TS group. CONCLUSIONS: TS and OCD show both differences (recognition memory, decision-making) and similarities (set-shifting) in selective profiles of cognitive function. Specific set-shifting deficits in the OCD group contrasted with their intact performance on other tests of executive function, such as planning and decision-making, and suggested only limited involvement of frontal lobe dysfunction, possibly consistent with OCD symptomatology.     

Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability

The authors examined set-shifting abilities in rats injected with antagonists of N-methyl-D-aspartate (NMDA) receptors (MK801) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (LY293558) into the medial prefrontal cortex (mPFC). Set-shifting was assessed with a maze-based task requiring a switch between brightness and texture discrimination strategies. Intra-mPFC injection of MK801 prior to training on the 2nd discrimination impaired discrimination strategy acquisition. The MK801-induced deficit was due to increased perseverative responding. AMPA receptor blockade also impaired acquisition of the 2nd discrimination; these impairments were due to more general cognitive deficits. Results suggest that, within the mPFC, both AMPA and NMDA receptors are necessary for set-shifting, and that NMDA receptor hypofunction impairs the capacity to modify existing knowledge or to inhibit responses that are no longer appropriate.     

Prefrontal cortical mechanisms underlying delayed alternation in mice

The prefrontal cortex (PFC) has been implicated in the maintenance of task-relevant information during goal-directed behavior. Using a combination of lesions, local inactivation, and optogenetics, we investigated the functional role of the medial prefrontal cortex (mPFC) in mice with a novel operant delayed alternation task. Task difficulty was manipulated by changing the duration of the delay between two sequential actions. In experiment 1, we showed that excitotoxic lesions of the mPFC impaired acquisition of delayed alternation with long delays (16 s), whereas lesions of the dorsal hippocampus and ventral striatum, areas connected with the PFC, did not produce any deficits. Lesions of dorsal hippocampus, however, significantly impaired reversal learning when the rule was changed from alternation to repetition. In experiment 2, we showed that local infusions of muscimol (an agonist of the GABA(A) receptor) into mPFC impaired performance even when the animal was well trained, suggesting that the mPFC is critical not only for acquisition but also for successful performance. In experiment 3, to examine the mechanisms underlying the role of GABAergic inhibition, we used Cre-inducible Channelrhodopsin-2 to activate parvalbumin (PV)-expressing GABAergic interneurons in the mPFC of PV-Cre transgenic mice as they performed the task. Using whole cell patch-clamp recording, we demonstrated that activation of PV-expressing interneurons in vitro with blue light in brain slices reliably produced spiking and inhibited nearby pyramidal projection neurons. With similar stimulation parameters, in vivo stimulation significantly impaired delayed alternation performance. Together these results demonstrate a critical role for the mPFC in the acquisition and performance of the delayed alternation task.     

Systemic and prefrontal cortical NMDA receptor blockade differentially affect discrimination learning and set-shift ability in rats

The authors examined discrimination rule learning and extradimensional set-shifting ability in rats given systemic or intracranial injections of the N-methyl-D-aspartate (NMDA) receptor antagonist MK801. Pretraining systemic injections of MK801 impaired both the acquisition of the initial discrimination rule (Set 1) and the shift to the 2nd rule (Set 2). Pretraining intramedial prefrontal cortical (mPFC) administration of MK801 did not impair Set 1 acquisition. Intra-mPFC injection of MK801 was previously found to impair Set 2 acquisition. Impaired Set 2 performance was due to increased cognitive perseveration. The data suggest that discrimination learning in naive subjects requires NMDA receptors outside the mPFC, whereas NMDA receptors within the mPFC are selectively involved in the modification of previous knowledge and/or the inhibition of previously learned responses.     

Early discrimination reversal learning impairment and preserved spatial learning in a longitudinal study of Tg2576 APPsw mice

To understand the relationship between amyloid-beta and cognitive decline in Alzheimer's disease, we evaluated cortical and hippocampal function in a transgenic mouse model of amyloid over-expression in Alzheimer's disease, the Tg2576 mouse. Tg2576 mice and their non-transgenic littermates were assessed at both 6 and 14 months of age in a battery of cognitive tests: attentional set-shifting, water maze spatial reference memory and T-maze working memory. Spatial reference memory was not affected by Tg status at either age. Working memory was only affected by age, with 6-month-old mice performing better than 14-month-old ones. Older mice were also significantly impaired on reversal learning and on the intra- and extra-dimensional shift in attentional set-shifting. A significant transgene effect was apparent in reversal learning, with Tg2576 mice requiring more trials to reach criterion at 6 months old. These data indicate that the effects of normal aging in C57B6xSJL F1 mice are most pronounced on putative frontal cortex-dependent tasks and that increasing Abeta load only affects discrimination reversal learning in our study.     

Encoding changes in orbitofrontal cortex in reversal-impaired aged rats

Previous work in rats and primates has shown that normal aging can be associated with a decline in cognitive flexibility mediated by prefrontal circuits. For example, aged rats are impaired in rapid reversal learning, which in young rats depends critically on the orbitofrontal cortex. To assess whether aging-related reversal impairments reflect orbitofrontal dysfunction, we identified aged rats with reversal learning deficits and then recorded single units as these rats, along with unimpaired aged cohorts and young control rats, learned and reversed a series of odor discrimination problems. We found that the flexibility of neural correlates in orbitofrontal cortex was markedly diminished in aged rats characterized as reversal-impaired in initial training. In particular, although many cue-selective neurons in young and aged-unimpaired rats reversed odor preference when the odor-outcome associations were reversed, cue-selective neurons in reversal-impaired aged rats did not. In addition, outcome-expectant neurons in aged-impaired rats failed to become active during cue sampling after learning. These altered features of neural encoding could provide a basis for cognitive inflexibility associated with normal aging.     

Complexin II is essential for normal neurological function in mice

Complexins (CPLXs) are modulators of synaptic vesicle release. At 1 year of age, CPLXII knockout (KO) mice appear normal. However, behavioral testing reveals underlying deficits of motor and cognitive function in these mice. We found motor deficits on the rotarod, and learning deficits in the Morris water maze (both acquisition and reversal) and the two-choice swim tank (reversal). The reversal learning deficits are particularly noticeable, being present from the earliest time of testing, when most other behaviors are normal. CPLXII KO mice also fail to develop adult patterns of exploratory behavior in the open field and show deficits in interactive grooming behaviors. The behavioral deficits worsen with age. For example, while rotarod performance is normal until 10 weeks, it is impaired from 24 weeks onwards. Similarly, deficits in spatial learning in the Morris water maze are mild at 8 weeks, but pronounced by 1 year of age. The deficits seen in CPLXII KO mice are not due to physical weakness, since their ability to run, swim and grip is unimpaired. Rather, the mice appear to have deficits of higher function. The deficits seen in CPLXII KO mice are strikingly similar to those seen in the R6/2 model of Huntington's disease (HD) where a progressive depletion of CPLXII is seen. This suggests that depletion of CPLXII contributes to cognitive abnormalities in R6/2 mice. Given that decreased expression of CPLXII is seen in HD and schizophrenic patients, a role for CPLXII depletion should be considered in other diseases where motor, cognitive and psychiatric symptoms co-exist.     

Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning

Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging-related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging.     

Specific Neuropsychological Deficits in Schizophrenic Patients with Preserved Intellectual Function

Although a wide range of cognitive deficits have been demonstrated in schizophrenia, it is not clear whether specific deficits stand out from general intellectual decline. Separate cases have been made for selective impairments in mnemonic and in executive function but these remain unconfirmed. A common problem in studies of schizophrenia is heterogeneity of deficits and Shallice, Burgess, and Frith (1991) have addressed this by using a single case study approach. The present study used the CANTAB battery of neuropsychological tests to examine cognitive performance in a small group of schizophrenic patients with preserved intellectual function. This test battery allows a componential analysis of performance, and its neurological validation may enable specific neurobiological hypotheses to be addressed. Twelve schizophrenic patients with current IQ greater than 90 and within 10 points of premorbid IQ were assessed on tests of visuospatial memory, spatial working memory, planning, and attentional set-shifting. Their performance was compared to that of 12 matched controls. The patient group, as a whole, was impaired on all tasks but the pattern of impairment varied across individuals. Consistently, severe deficits were seen on tests of delayed matching to sample and attentional set-shifting. These deficits are compared to those seen in patients with unipolar depression, who showed similar deficits in delayed matching to sample but not set-shifting, and are considered in terms of common cognitive mechanisms and possible neural substrates.     

Cognitive development in macaques: Attentional set-shifting in juvenile and adult rhesus monkeys

In humans and nonhuman primates, the structure and function of frontal cortical regions of the brain are not completely developed until early adulthood. How this cortical development affects cognitive function continues to be elucidated. To that end, this experiment tested the ability of juvenile and adult rhesus monkeys to perform a cognitive task that is dependent upon intact frontal cortical function for optimal performance. Twenty-four juvenile (mean age 2.3 years) and 16 adult (mean age 10.3 years) rhesus monkeys were tested on the Cambridge Neuropsychological Test Automated Battery intradimensional/extradimensional set-shifting (ID/ED) task. Performance on the ID/ED task has been shown to be dependent upon frontal cortical function in both humans and nonhuman primates. Compared with adults, juveniles were impaired on the reversal of simple discrimination, intradimensional shift, reversal of intradimensional shift, and the extradimensional shift stages of the task. These results indicate juveniles committed more perseverative errors and more errors on the set-formation and set-shifting components of the ID/ED task. The developmental stage of the juvenile monkeys corresponds to roughly 5 to 6-year-old children, and these results are consistent with performance of human children and adults on similar ID/ED tests and on several other tests of attentional set-shifting or attentional flexibility. Furthermore, these results are consistent with the ongoing development of frontal cortical structures relating to ongoing cognitive development in nonhuman primates.     

Effects of rat medial prefrontal cortex lesions on olfactory serial reversal and delayed alternation tasks

When reward reinforcement in a two-choice discrimination task is regularly changed from one stimulus to another immediately after one learning acquisition session, the learning efficiency of a rat increases as if the rat has come to recognize this regularity of reversal. To investigate how the rat medial prefrontal cortex (mPFC) is involved in such improvement, we examined the performance of mPFC-lesioned rats in a serial reversal task of olfactory discrimination. The performance of other mPFC-lesioned rats in a delayed alternation task was also analyzed using the same apparatus to evaluate the contribution of the mPFC to working memory. The mPFC-lesioned rats demonstrated selective difficulty in the second reversal session in the serial reversal task and also showed performance impairment in the delayed alternation task. These results suggest that the rat mPFC mediating working memory is involved in early progress in learning efficiency during experiences of multiple reversals, which may be relevant to cognitive operations in reversal learning beyond a one-time reversal of stimulus response associations.     

A deficit in attentional set-shifting of violent offenders

BACKGROUND: Recent brain imaging studies suggest that proneness to violence and antisocial behaviour may be associated with dysfunction of the prefrontal cortex. The present study. therefore, examined aspects of prefrontally guided executive functions in a group of criminal violent men. METHODS: Violent offenders undergoing forensic psychiatric examination by court order undertook computerized tasks for planning, visual working memory and attentional set-shifting from the Cambridge Neuropsychological Test Automated Battery. Their performance was compared to that of subjects with marginal mental retardation and normal controls. RESULTS: Violent offenders performed well on tasks for spatial and figurative working memory, as well as on a test for planning. A marked impairment was observed in the attentional set-shifting task: offenders made significantly more errors than the other groups when required to shift attention from one perceptual dimension to another. Reversal learning was also deficient. Correlational analyses within the offender group revealed that poor performance on the perceptual shift problem was associated with fewer errors in tasks for working memory and planning. CONCLUSIONS: The present results suggest that violent offenders show dual impairments in inhibitory cognitive control. First, they are deficient in shifting attention from one category to another. Secondly, the ability to alter behaviour in response to fluctuations in the emotional significance of stimuli is compromised. These deficits might constitute cognitive reflections of the biological prefrontal alterations observed in this group of people.     

Strain-specific cognitive deficits in adult mice exposed to early life stress

Early life stress is a prominent risk factor for the development of adult psychopathology. Numerous studies have shown that early life stress leads to persistent changes in behavioral and endocrine responses to stress. However, despite recent findings of gene expression changes and structural abnormalities in neurons of the forebrain neocortex, little is known about specific cognitive deficits that can result from early life stress. Here we examined five cognitive functions in two inbred strains of mice, the stress-resilient strain C57Bl/6 and the stress-susceptible strain Balb/c, which were exposed to an infant maternal separation paradigm and raised to adulthood. Between postnatal ages P60 to P90, mice underwent a series of tests examining five cognitive functions: Recognition memory, spatial working memory, associative learning, shifts of attentional sets, and reversal learning. None of these functions were impaired in IMS C57Bl/6 mice. In contrast, IMS Balb/c mice exhibited deficits in spatial working memory and extradimensional shifts of attention, that is, functions governed primarily by the medial prefrontal cortex. Thus, like recently discovered changes in frontocortical gene expression, the emergence of specific cognitive deficits associated with the medial prefrontal cortex is also strain-specific. These findings illustrate that early life stress can indeed affect specific cognitive functions in adulthood, and they support the hypothesis that the genetic background and environmental factors are critical determinants in the development of adult cognitive deficits in subjects with a history of early life stress.     

Executive functions in the heterozygous reeler mouse model of schizophrenia

Deficits in working memory and executive functions are now considered among the most reliable endophenotypes for schizophrenia. To determine whether cognitive deficits exist in mouse models of the disease, the authors trained heterozygous reeler (+/rl) mice on a series of visual discriminations similar to those used to test executive abilities in primates. These mice resemble schizophrenia patients in that both have reduced levels of reelin protein and altered gamma aminobutyric acid neurotransmission in the prefrontal cortex. The +/rl mice showed a selective deficit in reversal learning, with a pattern of errors that suggested impaired visual attention rather than a deficiency in perseveration and inhibitory control. These results show that cognitive dysfunction may serve as a useful biomarker in mouse models of neuropsychiatric disease.     

Executive functions in young males with fragile X syndrome in comparison to mental age-matched controls: baseline findings from a longitudinal study

The performance of 54 boys with fragile X syndrome (FXS), ages 7 to 13 years, was compared to that of a group of typically developing boys who were matched on mental age (MA) and ethnicity across multiple measures of executive function (EF). Boys with FXS varied in their ability to complete EF measures, with only 25.9% being able to complete a set-shifting task and 94.4% being able to complete a memory for word span task. When compared to the control group, and controlling for MA and maternal education, boys with FXS showed significant deficits in inhibition, working memory, cognitive flexibility/set-shifting, and planning. No group differences were observed in processing speed. Mental age significantly impacted performance on working memory, set-shifting, planning, and processing speed tasks for both groups. In boys with FXS, MA significantly predicted performance on working memory and set-shifting tasks. Our findings suggest that deficits in EF in boys with FXS are not solely attributable to developmental delays but, rather, present as a true array of neurocognitive deficits.     

Guidance of instrumental behavior under reversal conditions requires dopamine D1 and D2 receptor activation in the orbitofrontal cortex

The orbitofrontal cortex (OFC) plays a critical role in learning a reversal of stimulus-reward contingencies. Dopamine (DA) neurons probably support reversal learning by emitting prediction error signals that indicate the discrepancy between the actually received reward and its prediction. However, the role of DA receptor-mediated signaling in the OFC to adapt behavior to changing stimulus-reward contingencies is largely unknown. Here we examined the effects of a selective D1 or D2 receptor blockade in the OFC on learning a reversal of previously acquired stimulus-reward magnitude contingencies. Rats were trained on a reaction time (RT) task demanding conditioned lever release with discriminative visual stimuli signaling in advance the upcoming reward magnitude (one or five food pellets). After acquisition, RTs were guided by stimulus-associated reward magnitudes, i.e. RTs of responses were significantly shorter for expected high versus low reward. Thereafter, stimulus-reward magnitude contingencies were reversed and learning was tested under reversal conditions for three blocks after pre-trial infusions of the selective D1 or D2 receptor antagonists R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinhydrochloride (SCH23390), eticlopride, or vehicle. For comparisons, we included intra-OFC infusions of the selective N-methyl-d-aspartate receptor antagonist AP5. Results revealed that in animals subjected to intra-OFC infusions of SCH23390 or eticlopride learning a reversal of previously acquired stimulus reward-magnitude contingencies was impaired. Thus, in a visual discrimination task as used here, D1 and D2 receptor-mediated signaling in the OFC seems to be necessary to update the reward-predictive significance of stimuli.