Sex differences in appetitive learning of mice

Learning abilities of male and female ddY mice were compared in two appetitive tasks (a lever-press task and an 8-arm radial maze task), and two avoidance tasks (a shuttle box task and a light-dark discrimination T-maze task). In the two types of appetitive learning, male mice were significantly superior to female mice. Sex differences were particularly apparent in the acquisition process. In contrast, there was no significant sex difference in learning of the two avoidance tasks. A sex difference in appetitive learning was not found in juvenile mice prior to sexual maturation, and the mice which had established a lever-press response as juveniles did not show any significant difference in the performance level when tested as adults. Thus, a sex difference appeared only in the acquisition stage of adult mice. These results suggest that there exists a sex difference in motivation level for hunting food but not for feeding, and that it causes a sex difference in appetitive learning.     

Critical periods for the effects of alcohol exposure on learning in rats

Critical periods for alcohol-induced deficits in spatial navigation and passive avoidance learning were investigated with a rat model of fetal alcohol syndrome. Rats were exposed to alcohol prenatally (Gestational Days 1-10 or 11-22) or postnatally (Postnatal Days 2-10) or throughout all 3 periods. Offspring were tested in either a spatial navigation or an avoidance task as juveniles or adults. As juveniles, the combined exposure group took longer to learn the spatial navigation task compared with all other groups. This effect was not seen in adults. Passive avoidance performance was not affected. These results suggest that long-term exposure to alcohol during development has adverse effects on spatial learning. The lack of differences in the short-term exposure groups implies that there may not be 1 critical period of alcohol exposure, but that the adverse effects of alcohol during development may be cumulative on some behaviors.     

The effects of early rearing environments on maternal behavior in adult female rats

The purpose of this study was to determine the effect of presence of siblings and exposure to colony cues during early life on the onset of maternal behavior at 20 and 75 days of life, and on subsequent emotional behavior in juvenile and adult female rats. Different groups of animals were reared either with a large number or a small number of siblings (sibling factor), or in the colony room or in a room apart from other mothers with pups (colony factor). Animals were tested for latency (in days) to show maternal behavior at either 20 or 75 days of age, and for emotional behavior (using the open field apparatus) at either 20-40 or 80-100 days of age. Exposure to colony sensory cues significantly reduced latencies for pup retrieval and nest-building in adults, but not in juveniles. Exposure to a large number of siblings reduced the latencies, in both adults and juveniles, to nest build; in juveniles, to lie over 75% of the litter; and in adults, to adopt a nursing posture. Consistent with prior research, juveniles had longer latencies than adults for a number of pup-directed behaviors including: latency to become maternal, latency to retrieve pups, latency to adopt a lactating posture, latency to lick/genital lick, and latency to nest-build. In the emotionality tests, the young animals scored as less emotional than the adults, an effect which was further exaggerated by early colony exposure. Overall results indicated that manipulation of early rearing environments does have a significant positive effect on later responses to young pups by both juvenile and adult female rats.     

Task-specific deficits in reversal performance following superior colliculus lesions in rats

Rats with lesions of the superior colliculus or control operations were tested in acquisition, extinction and reversal performance of operant visual tasks in four experiments. The tasks used in the experiments were: a simultaneous choice task (Experiment 1), a successive choice task (Experiment 2), a simultaneous go/no-go task (Experiment 3) and a successive go/no-go task (Experiment 4). Acquisition discrimination performance was affected by lesions only in Experiment 3, where in contrast with previous reports animals with lesions performed better than controls. Reversal performance of animals with lesions was impaired in Experiments 1 through 3, but not in Experiment 4. Effects on extinction performance were minimal in all experiments. The data are interpreted to indicate a role of the superior colliculus in the processing of spatial information.     

Recognition of emotional‐prosodic meanings in speech by autistic,schizophrenic, and normal children

The abilities of autistic, schizophrenic, and normal‐control children to label four emotional intonations (the emotional task) in speech were tested, along with a linguistic task. All stimuli were pretested on normal adults. Older (≥ 8 years of age) normal children performed as well as adults on both tasks; younger normal children and both younger and older autistic children performed poorly on the emotional task; children (all older) diagnosed as schizophrenic were not significantly impaired in either task. Mental age was not correlated with performance in autistic children. The relevance of these results to other findings regarding emotional and linguistic behaviors in normal and disabled children is considered.     

5-methoxy-N,N-di(iso)propyltryptamine hydrochloride (Foxy)-induced cognitive deficits in rat after exposure in adolescence

Foxy or Methoxy Foxy (5-methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO-DIPT) is rapidly gaining popularity among recreational users as a hallucinogenic “designer drug.”Unfortunately, much remain unknown about the consequences of its use on neuropsychological development or behavior. During one of two adolescent periods, the rats were given repeated injections of 5 mg/kg or 20 mg/kg of 5-MeO-DIPT or a corresponding volume of isotonic saline. After the animals reached adulthood, they were trained and tested on a number of tasks designed to assess the impact of 5-MeO-DIPT, if any, on spatial memory, presumably involving declarative memory systems as well as a nonspatial task that is considered sensitive to disruptions in nondeclarative memory. Both the 5-MeO-DIPT- and saline-treated rats were able to master spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Regardless of exposure level during adolescence, the performance of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. Detected reductions in serotonin activity in the forebrain similar to the effects of extensively investigated compounds such as methylenedioxymethamphetamine (MDMA), suggest that 5-MeO-DIPT may produce its adverse effects by compromising serotonergic systems in the brain.     

Consequences of serial cortical, hippocampal, and thalamic lesions and of different lengths of overtraining on the acquisition and retention of learning tasks

The ability of the rat brain to acquire or to retain specific learning tasks was tested under conditions of multiple lesions and widely different amounts of practice. Lesion targets were (a) the medial prefrontal and cingulate cortex, (b) the anterior and mediodorsal thalamus, and (c) the dorsal and ventral hippocampus. Rats were divided into seven groups. The first group received lesions of all three structural complexes prior to training in a delayed alternation and an active avoidance task. Groups 2-4 received lesions in different combinations of two of the three structural complexes prior to task acquisition. Group 5 first learned both tasks and then received the medial cortical lesion; thereafter it was retrained to criterion. Then, the thalamic lesion was made, and relearning was tested a second time. Finally, the hippocampal region was damaged, and a last relearning test was given. Groups 6 and 7 also first acquired both tasks; however, after that, they received 240 (Group 6) or 1,280 (Group 7) trials of overtraining. Following this, all three structural complexes were given lesions serially before relearning of the two tasks was tested. Nine of the ten animals of Group 1 failed to acquire the alternation task, but all learned the avoidance task. In Groups 2-4, all rats acquired both tasks. Postoperatively, rats of Group 5 were inferior to those of Group 6 in both tasks, and rats of Group 7 were the most successful animals of the last three groups. These results question the assumption that serial lesions with intermittent training between lesions have beneficial effects, and they also stress the importance of task practice, that is, of behavioral experience. It is argued that prolonged training will lead to a widely distributed storage of information within the brain. The process of wide diffusion of information will, however, be disturbed (or at least retarded) by lesions made shortly after task acquisition or task reacquisition (as was the case for animals of Group 5).     

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.     

DSP4 treatment worsens hippocampal pyramidal cell damage after transient ischemia.

Recent studies in the rat have suggested that hippocampal norepinephrine can regulate the amount of damage seen after transient forebrain ischemia. We used the gerbil to study the role of norepinephrine in ischemic damage. Using tyrosine hydroxylase immunocytochemistry and chemical measurements of norepinephrine, we determined that the gerbil hippocampus has a similar but topographically different norepinephrine innervation than the rat. Brains from gerbils treated with 100 mg/kg of N-(2-chloroethyl)-N-methyl-2-bromobenzylamine (DSP4) had 60% less norepinephrine than saline-treated controls, similar to the effect of the drug in rats. We administered DSP4 to gerbils two weeks before exposing them to 5 min of bilateral carotid artery occlusion. Animals treated with DSP4 and subjected to ischemia had worse pyramidal cell loss in the CA3 and CA4 regions than saline-treated ischemic controls. CA1 pyramidal cell loss (about 90%) was severe in both the saline- and DSP4-treated animals. These data provide further evidence that norepinephrine can regulate the neuronal death in the hippocampal formation after transient forebrain ischemia. Furthermore, this is the first demonstration of that regulation in the gerbil and suggests that noradrenergic input to the hippocampus may be important in ischemia in other species besides the rat.     

A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat

Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha₁-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in α₂-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a loss of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.     

The toxicity of tumor necrosis factor-alpha upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer's disease

Inflammation and reduced forebrain norepinephrine are features of Alzheimer's disease that may interact to contribute to the degeneration of specific neural systems. We reproduced these conditions within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease. Tumor necrosis factor-alpha was infused into the basal forebrain of young mice pretreated with a norepinephrine neuronal toxin, N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4), with the expectation that the loss of noradrenergic input would enhance the loss of cholinergic neurons. The results indicate that chronic infusion of tumor necrosis factor-alpha alone significantly decreased cortical choline acetyltransferase activity and increased the number of activated microglia and astrocytes within the basal forebrain. The loss of forebrain norepinephrine following systemic treatment with DSP4 did not alter the level of cortical choline acetyltransferase activity or activate microglia but significantly activated astrocytes within the basal forebrain. Infusion of tumor necrosis factor-alpha into DSP4-pretreated mice also reduced cortical choline acetyltransferase activity on the side of the infusion; however, the decline was not significantly greater than that produced by the infusion of tumor necrosis factor-alpha alone. The neurodegeneration seen may be indirect since a double-immunofluorescence investigation did not find evidence for the co-existence of tumor necrosis factor-alpha type I receptors on choline acetyltransferase-positive cells in the basal forebrain. The results suggest that noradrenergic cell loss in Alzheimer's disease does not augment the consequences of the chronic neuroinflammation and does not enhance neurodegeneration of forebrain cholinergic neurons.     

A within-modality test of semantic knowledge: The Size/Weight Attribute Test

Individuals with semantic dementia (SD; n=12) or Alzheimer's disease (AD; n=20) and healthy volunteers (n=40) were tested on tasks probing attribute rather than associative knowledge of animals and objects in the visual and verbal domains. The tasks were within modality, in that they probed knowledge in a single presentation modality (pictures or written words) and did not require cross-modal matching. Participants were required to make the same simple judgment about triads of animal stimuli ("Which is the largest and smallest?") and object stimuli ("Which is the heaviest and lightest?"). Control participants scored at ceiling on this simple task. Overall, the SD patients were significantly more impaired on this task than were the AD patients, who in turn were significantly more impaired than the controls. There was a strong trend for SD but not AD patients to show worse performance with verbal than visual material. However, no significant effects of category were found in either patient group. The Size/Weight Attribute Test has the potential to assess modality-specific deficits of semantic knowledge.     

Development of attentional allocation in the dual task paradigm.

Top-down control over attention was investigated on a dual task in 10-year-olds (N=15) and adults (N=21). The tasks were an auditory digit span (DS) and a simple visual response time (RT) task. In four conditions, participants performed neither (no-task), one (DS or RT only) or both tasks (dual). Dependent variables were DS accuracy, RT and pupillary dilation to digits as an estimate of mental effort. Children's behavioral and psychophysiological responses as a function of sequence length and stimulus position were generally similar to those of adults. Slopes of the functions relating pupillary dilation to memory load were linear and increasing in both groups, shallower in dual than that in DS only and shallower in children than that in adults. Children's behavioral results on the DS task began to diverge from those of adults as task demands shifted from passive retention to active rehearsal, but the children did not appear to try harder to compensate for a lower level of behavioral performance. Taken together, the findings suggest that although children allocated their attention in a similar manner as adults, their top-down control over attention in accordance with task difficulty was not yet fully mature.     

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.     

The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes

The effect of life-long 60% ad lib food restriction on performance in two tasks involving spatial memory, the eight-arm radial maze and the Morris water maze, was studied in young and aged Fischer 344 rats. Restricted (R) and ad lib (AL) feeding groups were compared at 8, 16, and 24 months of age on both tasks. A 30-month-old R group was also tested in the Morris water maze. In the eight-arm maze, although 24-month-old animals performed more poorly than 8- and 16-month-old animals during the first week of testing, overall accuracy of performance did not vary significantly as a function of age. Twenty-four-month-old animals took longer to make 10 choices than did younger animals, and there was a significant interaction between feeding regimen and age, reflecting the fact that at the two younger ages, R groups performed more quickly than the AL groups. In the Morris water maze, both distance swum and time to find the platform increased with age. Life-long food restriction led to small but significant improvements in performance in the water maze in aged rats. R groups showed evidence for better retention over 24-hour intervals than did AL groups. By 30 months of age, however, R animals showed impaired performance relative to younger R groups. These differential findings on the two tasks, as they were used here, suggest that there was greater impairment with age on the spatial memory task requiring retention of information over long intervals than there was on the task primarily involving working memory within a trial. Life-long food restriction would appear to delay the impairments of age, but not prevent them.     

Executive functioning and speed of processing in phenylketonuria

Treated phenylketonuria (PKU) has been linked to dopaminergic depletion in the dorsolateral prefrontal cortex, potentially leading to selective executive impairment. White matter abnormalities may lead to generalized slowing of information processing. These 2 hypotheses were evaluated in adults with PKU on a lifelong diet. Those with PKU were significantly slower than the control group regardless of working memory load on an n-back task and marginally slower regardless of trial type (inhibitory or noninhibitory) on a flanker task. There were no significant differences in speed on object alternation learning or perceptual judgment tasks. There were no group differences in accuracy on any task. These findings do not appear consistent with the selective executive hypothesis. A cognitive slowing account may prove more informative in adults with PKU, but more evidence is needed. The findings suggest that continuous dietary management is a fairly successful strategy in terms of cognitive outcome for adults.     

Different effects of posttrial driving or blocking of the theta rhythm on avoidance learning in rats

Animals with and without septal electrodes were trained in two simple avoidance tasks, three weeks apart. Following the training trials, some implanted animals received 20 min of either low (LF) or high frequency (HF) septal stimulation, which drove or blocked, respectively, the hippocampal theta rhythm. Animals receiving the theta-driving stimulation subsequently exhibited improved retention performance in the 1-way active avoidance task in comparison to animals receiving HF stimulation or to implanted controls. In the 1-trial passive inhibitory task, LF animals subsequently performed better than did HF animals, but the LF animals' performance was not quite significantly higher than performance of implanted controls. Low frequency stimulation during testing also improved performance in the active avoidance task. Unoperated controls performed at a higher level than implanted controls and HF animals in both tasks, suggesting a lesion effect of the bilaterally-implanted septal electrodes. Nevertheless, the design of these experiments, in which posttrial treatment administration and two tasks requiring opposite responses were employed, appears to provide reasonably direct evidence that the activation of theta rhythms is not simply correlated with learning situations, but also apparently improves the retention of information that has recently been acquired. Thus, these rhythms could be associated with memory storage processes.     

Neuropsychological Attention Skills and Related Behaviours in Adults with Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic disorder associated with mTOR over-activation and disruption of MAPK, PI3K and AMPK signalling. Children with TSC have significant deficits on neuropsychological attention tasks, particularly dual tasking. Here we investigated attentional skills and related behaviours in daily life in normally intelligent adults with TSC and matched controls using the Test of Everyday Attention for Children (TEA-Ch) and the Attention-Deficit Scales for Adults (ADSA). No group differences were demonstrated on selective or sustained attention tasks carried out alone. However, adults with TSC performed significantly worse when these tasks were combined in a cross-modal dual task condition. On the ADSA the TSC group had significantly worse scores on several subscales (attention/concentration, behaviour/disorganization, academic and emotional behaviours) compared to controls and these correlated with dual task performance, indicating a clear impact of dual task deficits on attention-related behaviours in daily life. The presence or absence of epilepsy did not influence dual task performance or attention-deficits in daily life. Taken together with similar findings in children, results suggest that dual task difficulties are a core feature of the neuropsychological phenotype of TSC.     

Relief of carotid stenosis improves impaired cognition in a rat model of chronic cerebral hypoperfusion

To investigate how cognitive impairment is affected by the relief of bilateral carotid stenosis, chronic cerebral hypoperfusion was established through stenosis of the bilateral carotid common artery in adult Sprague-Dawley rats. Subsequently, the model rats received the intragastric placebo, donepezil (5 mg per kg), or surgery to relieve carotid stenosis after bilateral carotid common artery stenosis. After carotid stenosis was relieved, the cerebral blood flow values significantly increased, and P300 latency and escape latency in the Morris water-maze were significantly shortened. The concentrations of acetylcholine and norepinephrine in the dorsal hippocampus increased after carotid stenosis was relieved. Furthermore, P300 latency and escape latency were shortened in the relief-treated group compared to the drug-treated group, and acetylcholine levels in the relief-treated group were higher than the drug-treated group. No significant difference was found for the norepinephrine levels in the dorsal hippocampus between the relief-treated and drug-treated groups. Cognitive impairment can be significantly reduced by bilateral carotid stenosis relief, and the effect of relieving stenosis on cognitive dysfunction is superior to the effect of administering an acetylcholinesterase inhibitor.     

Combined lesions of septum,amygdala, hippocampus,anterior thalamus,mamillary bodies and cingulate and subicular cortex fail to impair the acquisition of complex learning tasks

Summary Previous investigations (Irle and Markowitsch 1982a, 1983, 1984) demonstrated that triple or fourfold lesions within the cat's limbic system fail to produce learning impairments, as opposed to lesions of single or double loci, when tasks of visual reversal, delayed alternation, and active two-way avoidance were used. On the basis of these results, limbic regions of the cat's brain might be considered unessential for intact learning and mnemonic functions. Therefore, in order to obtain indisputable information on the importance of the limbic system for learning and memory, lesions of nearly all limbic core regions of the cat were performed. Ten cats received lesions of seven limbic core regions: the septum, amygdala, anterior thalamus, mamillary bodies, cingulate cortex, subicular cortex, and the hippocampus proper. Nine of these animals were tested postoperatively in the acquisition of a visual reversal task, a spatial alternation and delayed alternation task, and an active two-way avoidance task, and were then compared to the performance levels of ten control animals. The experimental animals turned out to be unimpaired in all tasks tested; the performance scores in the visual reversal and delayed alternation task and — for some experimental animals in the active two-way avoidance task even indicate a slight, though statistically insignificant, facilitation in the learning behavior of these animals. It is assumed that the learning functions underlying the tasks used were taken over by other brain regions, which, prior to massive limbic lesions, may be suppressed or otherwise inhibited. Alternatively, utilization of spared tissue in the damaged limbic regions must be considered as the possible explanation.