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Radial arm maze performance in rats following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Recently, we reported that in utero and lactational exposure to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a task-specific reduction of errors on the radial arm maze (RAM), without similar improvements on other spatial learning tasks including the Morris water maze. The effect was more pronounced in males than in females. This study further investigated the effects of in utero and lactational exposure to TCDD on RAM performance by testing male and female TCDD-exposed rats on either an eight-arm RAM with all arms baited or a 12-arm RAM with 8 of the 12 arms baited. If the rats have improved spatial learning or memory on the RAM, then they should be improved on both RAM tasks; whereas, if they are using adjacent arm selection or some other response strategy to solve the task, they should not show enhanced performance on the 12-arm RAM where not all the arms are rewarded. Time-mated Sprague-Dawley dams were gavaged with corn oil vehicle or one of two doses of TCDD in vehicle (0.1 or 0.2 microg/kg body weight) on gestational days 10 to 16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and female from each litter was tested on the eight-arm RAM with all arms baited. As in our previous studies, the 0.1-microg/kg TCDD-exposed male rats showed a significant decrease in the number of errors. However, the 0.2-microg/kg males did not differ from the controls. Neither group of TCDD-exposed females differed from the controls. None of the TCDD-exposed rats differed from the controls in adjacent arm selection behavior. An additional male and female from each litter were tested on the 12-arm RAM with only 8 of the 12 arms baited. In this task, neither TCDD group differed from the controls. These results suggest that the reduction of errors on the eight-arm RAM may be due to increased response patterning or use of intramaze cues rather than to improved spatial learning or memory. Also, the reduction in errors was only present at the lower dose of TCDD suggesting that the improvement in performance is only present at very low, nonovertly toxic doses of TCDD.

Animals↗

Morphological, neurochemical, and behavioral studies on serotonergic denervation and graft-induced reinnervation of the rat hippocampus.

A procedure was developed to conduct simultaneously immunocytochemical and neurochemical studies on the serotonergic system in adjacent 300-micron-thick slices of rat hippocampus. This procedure was applied to correlate morphological (innervation pattern and density), neurochemical (5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake and release) and behavioral (spatial learning) effects of neurotoxin-induced denervation and reinnervation by grafting fetal mesencephalic raphe cells. Intracerebroventricular injections of a low dose of 5,7-dihydroxytryptamine caused a discrete serotonergic denervation of the hippocampus. Eleven months after lesioning, 5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake capacity were decreased by 50-60%. By this time, the residual fibers displayed an enhanced vulnerability towards K(+)-induced depolarization. Grafting of a fetal raphe cell suspension resulted in a reinnervation of the host hippocampus. The pattern of reinnervation was comparable to control innervation and the density was supranormal at the level of the graft. As observed semiquantitatively, the innervation density decreased with distance from the core of the graft. Neurochemical studies showed that the fibers were capable of synthesizing, metabolizing and releasing 5-hydroxytryptamine. The turnover of 5-hydroxytryptamine in both the denervated and the reinnervated hippocampus was comparable to that in control tissue. Previous behavioral testing of the denervated and of the denervated and implanted animals did not reveal any effect on spatial learning, either in an individual or in a social test paradigm. The latter data substantiate the notion that interference with the hippocampal serotonergic innervation does not hamper adequate spatial learning.

5,7-Dihydroxytryptamine↗

Serial spatial reversal learning in rats: comparison of instrumental and automaintenance procedures.

Serial reversals of a spatial discrimination were trained in rats under automaintenance conditions, in which food reward occurred regardless of responding. This automaintained reversal learning was compared to instrumental reversal learning in other rats trained under a similar procedure which required responding for reward. In the automaintenance (AU) procedure, rats received food after every retraction of a "positive" response lever (S+); retraction of a second, "neutral" lever (So) was not paired with food delivery. Responses to the S+ were elicited at fairly constant rates during daily 100-trial conditioning sessions. Responses to the So occurred early in each session but rapidly diminished across trials. When the valences of the levers were reversed, responding shifted to the new S+ and diminished on the new So. Criterion for reversal was defined as a discrimination ratio (DR) of at least 90% responding to the S+ in two consecutive 10-trial blocks. With repeated reversals, acquisition of criterion performance occurred with increasing rapidity, reaching an asymptote below that required for the original discrimination. A second group of rats was trained on a similar instrumental schedule, in which at least one response to the S+ was required for food delivery. Response rates in this instrumental (IN) group were approximately double those of the AU group. However, ratios of S+ to So response rates were similar to those of the AU group, and the serial reversal curves generated were qualitatively similar. Thus rats can show improvement across serial reversals of a spatial discrimination based entirely on pairings of stimulus events (automaintenance), in a manner similar to that observed in instrumental procedures, in which reward is contingent upon correct responding.

Animals↗

Postnatal phencyclidine-induced deficit in adult water maze performance is associated with N-methyl-D-aspartate receptor upregulation.

The N-methyl-D-aspartate (NMDA) receptor plays an important role in developmental plasticity. Earlier, we have shown that blocking the NMDA receptor with the non-competitive antagonist phencyclidine (PCP), during a brief postnatal period, disrupts the water maze performance in young juvenile rats (starting at 25 days of age). We now show the long-term effects of postnatal phencyclidine exposure on spatial learning and memory. Male and female rats were exposed to PCP (1 and 5mg/kg) or saline, from postnatal days 5-15, and their performance in the Morris water maze (MWM) was tested both as adolescents (starting on postnatal day (PD) 35) and as adults (starting on postnatal day 60). Separate groups of adult male and female postnatal PCP-treated and saline-treated rats were sacrificed and saturation [3H]MK-801 binding experiments were carried out in their hippocampi and frontal cortices; hippocampus and frontal cortex have high densities of NMDA receptors and both regions are important in spatial learning and memory. Postnatal PCP administration disrupted the water maze performance both in adolescent and adult rats of both sexes. Adult male and female rats treated postnatally with PCP had increased maximal [3H]MK-801 binding in the hippocampus and frontal cortex compared to same-sex saline-treated controls. Taken together, repeated postnatal PCP (RPP) administration impaired the acquisition of spatial learning in adolescent and adult male and female rats, and this cognitive deficit was associated with increased [3H]MK-801 labeled NMDA receptor in the hippocampus and frontal cortex. These findings are consistent with the hypothesis that PCP treatment during the postnatal period produces deficits in the water maze performance by disrupting the developing glutamatergic system.

Aging↗

Effects of nitric oxide synthase inhibition on spatial discrimination learning and central DA2 and mACh receptors.

Cholinergic and dopaminergic systems are involved in spatial memory and are modulated by nitric oxide (NO); NO has well documented effects on place learning in rodents. The aim of the present study was to investigate the effect of NOS inhibition on place learning in the water maze and to evaluate the relationships between NOS inhibition, learning performance, dopamine (DA) D2 and muscarinic acetylcholine (mACh) receptors. Male Sprague-Dawley rats received the NOS inhibitor Nomega-Nitro-l-Arginine (l-NA), or saline and were trained in the water maze. Rats that were not trained, but received the same treatments were also included. Following treatments with or without water maze training, [3H]-QNB and [3H]-spiperone binding in cortex, striatum and hippocampus were determined to assess the effects of NOS inhibition and/or learning on DA D2 and mACh receptor regulation. The overall results of the present study showed that: (1) NOS inhibition impairs performance in the MWM; (2) NOS inhibition does not affect specific binding to DA D2 (striatum and hippocampus) and mACh (cortex and hippocampus) receptors; (3) MWM training lowers D2 and mACh receptor binding in cortical regions.

Animals↗

Reversal of prenatal diazepam-induced deficit in a spatial-object learning task by brief, periodic maternal separation in adult rats.

In the rat, prenatal exposure to diazepam (DZ) induces a permanent reduction in GABA/BZ receptor (R) function and behavioural abnormalities. Environmental modifications during early stages of life can influence brain development and induce neurobiological and behavioural changes throughout adulthood. Indeed, a subtle, periodic, postnatal manipulation increases GABA/BZ R activity and produces facilitatory effects on neuroendocrine and behavioural responses. We here investigated the impact of prenatal treatment with DZ on learning performance in adult 3- and 8-month-old male rats and the influence of a brief, periodic maternal separation on the effects exerted by prenatal DZ exposure. Learning performance was examined employing a non-aversive spatial, visual and/or tactile task, the "Can test". Behavioural reactivity, emotional state and fear/anxiety-driven behaviour were also examined using open field (OF), acoustic startle reflex (ASR) and elevated plus-maze (EPM) tests. A single daily injection of DZ (1.5mg/kg, s.c.), over gestational days (GD) 14-20, induced, in an age-independent manner, a severe deficit in learning performance, a decrease in locomotor and explorative activity and an increase in peak amplitude in the ASR. Furthermore, anxiety-driven behaviour in EPM was disrupted. Daily maternal separation for 15 min over postnatal days 2-21 exerted opposite effects in all the paradigms examined. Prenatally DZ-exposed maternal separated rats, in contrast to respective non-separated rats, showed an improvement in learning performance, a decrease in emotionality and a normalization of the exploratory behaviour in EPM. These results suggest that a greater maternal care, induced by separation, can serve as a source for the developing brain to enhance neuronal plasticity and to prevent the behavioural abnormalities induced by prenatal DZ exposure.

Acoustic Stimulation↗

Spatial acquisition in the Morris water maze and hippocampal long-term potentiation in the adult guinea pig following brain growth spurt--prenatal ethanol exposure.

Previous work has demonstrated that in the guinea pig, chronic prenatal ethanol exposure throughout gestation can result in deficits in spatial learning in the Morris water maze and impaired hippocampal long-term potentiation (LTP). The behavioural effects are known to be dose dependent because water maze deficits occur at a dose of 4 g ethanol/kg maternal body weight/day, but not at a dose of 3 g/kg/day, administered throughout gestation. It is possible that the gradual, progressive development of tolerance to ethanol throughout gestation limits ethanol toxicity, especially for lower doses of ethanol. The present study examined whether neurobehavioural deficits are produced by prenatal ethanol exposure at a dose of 3 g/kg/day, administered only during the brain growth spurt (BGS), a regimen designed to limit the development of ethanol tolerance. Pregnant guinea pigs [term, about gestational day (GD) 68] received oral administration of ethanol (1.5 g/kg maternal body weight/day on GD 43 and 44 and then 3 g/kg maternal body weight/day from GD 45 to 62), isocaloric-sucrose/pair-feeding, or water. Offsprings were studied between postnatal days (PD) 40 and 80. The maternal blood ethanol concentration (BEC) on GD 57 or 58, at 1 h after the daily dose, was 245+/-19 mg/dl (n=7). This BGS--prenatal ethanol exposure regimen did not affect spatial learning performance in the Morris water maze over a 7-day test period or in the LTP recorded in the CA1 region of the hippocampus. Thus, even when limiting the development of ethanol tolerance seen with chronic ethanol treatment throughout gestation, ethanol exposure during the BGS does not result in deficits in the behavioural and electrophysiological measures of hippocampal integrity assessed in the present study. These data indicate that in the guinea pig, the BGS may not constitute a critical period of vulnerability for ethanol-induced deficits in spatial learning or hippocampal synaptic plasticity in young adult offspring.

Animals↗

[Comparison of the effects of thyroliberin and ACTH4-7 PGP on the learning of rats during the solving of spatial orientation tasks].

The influence of TRH (100 micrograms/kg) and ACTH4-7 Pro-Gly-Pro (15 micrograms/kg and 25 micrograms/kg) involved an acceleration of the spatial learning on the 12-arm radial maze and on T-maze in rats; an increase in the number of correct choice after short (5-10 min) retention interval; and affected the working and reference spatial memory in the test of reinforced place performance. The effects of the TRH and ACTH4-7 Pro-Gly-Pro did not interfere with one another.

Adrenocorticotropic Hormone↗

Spatial reversal learning in preclinical scrapie-inoculated mice.

Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.

Animals↗

The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison.

RATIONALE: Antagonists at the metabotropic glutamate 5 (mGlu5) receptor produce robust anxiolytic effects in a number of rat tests. However, there is evidence that mGlu5 receptor antagonists may also impair working memory and spatial learning following intracerebroventricular administration. OBJECTIVES: The aim of this study is to compare the effect of the potent and selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-piperidine (MPEP), administered systemically on rodent tests of cognition and anxiety. METHODS: MPEP was assessed in the following rodent tests, 60 min following oral administration: Geller--Seifter conflict, conditioned emotional response (CER), Vogel conflict, delayed match to position (DMTP) and Morris water maze. Diazepam was also tested as a comparator. RESULTS: MPEP had a significant anxiolytic effect, comparable in magnitude to diazepam, at 10--30 mg/kg in the two conflict and CER tasks. There was no effect of MPEP up to 30 mg/kg on working memory in the DMTP task, but at 100 mg/kg, there was a significant reduction in choice accuracy at the longest delay interval (24 s). MPEP (3--30 mg/kg) did not significantly impair spatial learning in the Morris water maze, although during the last probe trial, 30-mg/kg-treated rats were significantly less accurate than controls. In contrast, diazepam significantly impaired performance in both the DMTP and Morris water maze tests. Assessment of plasma and brain concentration of MPEP approximately 75 min following oral administration showed a dose linearity from 3 to 30 mg/kg and good brain penetration, i.e. a brain/plasma ratio of 3.1. CONCLUSIONS: Oral administration of the selective mGlu5 receptor antagonist MPEP induces a robust anxiolytic-like effect in rat conflict tests comparable to that seen with diazepam, but in contrast to diazepam, MPEP does not impair working memory or spatial learning at anxiolytic doses.

Animals↗

The sectored foraging field: a novel design to quantify spatial strategies, learning, memory, and emotion.

Although Norway rats are naturally gregarious, males typically live alone at some point during adulthood. Different social ecologies often require different learning strategies and also modulate response to stressors and gonadal development. To measure effects of the social environment on the interaction between cognition and emotion during aging, we focused on a natural learning context and devised the sectored foraging field, a progressively difficult spatial navigation task. Here, we describe how this apparatus and protocol permits multiple learning strategies in a minimally stressful environment, enabling finely graded analyses of cognition and emotionality. Male Sprague-Dawley rats living alone throughout adulthood adopted a sex-typic discernible spatial strategy. In contrast, males housed in group contexts utilized an algorithmic kinesthetic strategy, repeating the same motor action until they found food. Removal of food and distal, but not local cues, elicited anxious alertness, particularly in group-housed males. Cognitive performance of group-housed rats subsequent to food and cue removal was significantly impaired, yet enhanced in isolates.

Animals↗

Unpacking the cognitive map: the parallel map theory of hippocampal function.

In the parallel map theory, the hippocampus encodes space with 2 mapping systems. The bearing map is constructed primarily in the dentate gyrus from directional cues such as stimulus gradients. The sketch map is constructed within the hippocampus proper from positional cues. The integrated map emerges when data from the bearing and sketch maps are combined. Because the component maps work in parallel, the impairment of one can reveal residual learning by the other. Such parallel function may explain paradoxes of spatial learning, such as learning after partial hippocampal lesions, taxonomic and sex differences in spatial learning, and the function of hippocampal neurogenesis. By integrating evidence from physiology to phylogeny, the parallel map theory offers a unified explanation for hippocampal function.

Animals↗

Neurotoxicological outcomes of perinatal heptachlor exposure in the rat.

The developing nervous system has been identified as a potential target of pesticide exposure. Heptachlor is a cyclodiene pesticide that was widely used for many years, and for which inadvertent exposure to children and fetuses took place in the early 1980s; yet little is known regarding the developmental neurotoxicity of it and other cyclodienes. The aim of this study was to determine whether perinatal heptachlor exposure results in persistent alterations in nervous system function. Pregnant Sprague-Dawley dams were dosed from gestational day (GD) 12 to postnatal day (PND) 7, whereupon the rat pups were dosed directly until PND 21 (group A) or PND 42 (group B). Dose levels were 0, 0.03, 0.3, or 3 mg/kg/day, po. There were no dose-related effects on maternal weight, litter size, or pup growth. GABA(A) receptor binding (using [(35)S] tert-butylbicyclophosphorothionate; TBPS) and GABA-stimulated Cl- flux were evaluated in control and high-dose brain tissues taken on PND 7, 21, and 43. The B(max) values for [(35)S]-TBPS binding in brainstem, but not cortex, were decreased in female rats across all ages tested. There were no such changes in male rats, nor were K(D) values altered in either tissue or gender. GABA-stimulated Cl- flux was decreased in female cortex synaptoneurosomes only on PND 21. The ontogeny of the righting response (PND 2-5) was delayed in the high-dose females. All subsequent testing took place a week to months after dosing ceased. The functional observational battery (FOB) showed treatment-related, but not necessarily dose-related, changes in different aspects of the rat's reactivity and activity levels. Group-A rats also showed altered within-session habituation of motor activity. There were no heptachlor-related differences in motor activity following challenge with a range of chlordiazepoxide doses. Cognitive assessments were conducted in both groups of rats. There were no statistically significant differences among treatment groups in a one-trial passive avoidance test, although there was a trend toward less learning. In group B, rats (both sexes), heptachlor altered spatial learning in the Morris water maze during two weeks of daily training (2 trials/day). On probe trials, heptachlor-treated rats did not show significant preference for the correct quadrant (all dose groups in males, high dose in females). These rats did not show alterations on subsequent working-memory training (where the platform position was relearned each day). Thus, perinatal exposure to heptachlor produced neurochemical and persistent neurobehavioral changes, including alterations in spatial learning and memory.

Animals↗

Importance of forebrain cholinergic and GABAergic systems to the age-related deficits in water maze performance of rats.

The present study investigated the performance of rats at 3-4 months and 21 months of age in the Morris water maze and correlated age-related cognitive deficits with changes in both cholinergic and GABAergic systems in the frontal cortex. The older rats were divided into two groups, unimpaired old and impaired old according to their ability to find a hidden submerged platform in the water maze, for electrophysiological, neurochemical, and morphological studies. The firing rate of frontal cortical neurones was recorded from the motor area of the frontal cortex under urethane anaesthesia and was found to be significantly slower in the two aged groups of rats compared to the young rats, but there were no differences between the two aged groups. The sensitivity of frontal cortex neurones of the impaired and unimpaired old age groups to ACh and to carbachol was significantly lower than that of the young group, but there were no differences between the two old age groups. In contrast, sensitivity of frontal cortex neurones to bicuculline was significantly higher in the aged rats compared with the young rats and was significantly greater in the impaired old rats than in the unimpaired old rats. The sensitivity of cortical neurones to glutamate was unaffected by age. There were also significant correlations between the percentages of cortical neurones responding to ACh and bicuculline and different parameters of water maze acquisition during days 7-8, but not during days 2-3, when spatial learning had not begun, and days 13-14, when spatial learning was complete. Biochemical and morphological analyses did not show any significant differences in ChAT activity and AChE-positive fibre density in the frontoparietal cortices of the three groups of rats. The results demonstrate that the learning deficit observed in old age rats cannot be adequately explained solely by a reduction in cholinergic receptor sensitivity and that an age-related increase in GABAergic tone may be a more important determinant of cognitive impairment.

Acetylcholine↗

Chronic inhibition of nitric oxide synthesis enhances both subventricular zone neurogenesis and olfactory learning in adult mice.

The ability to generate new neurons during the course of adult life is preserved in the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus in the mammalian brain. These two regions constitute specifically regulated neurogenic niches, and provide newborn neurons involved in olfactory and spatial learning, respectively. Nitric oxide (NO) is a negative regulator of neurogenesis in the subventricular zone, whereas its role in the dentate gyrus remains controversial. Using systemic administration of NO synthase (NOS) inhibitors to chronically inhibit NO production, we increased neural precursor proliferation in the subventricular zone as well as neurogenesis in the olfactory bulb, without modifying the number of mitotic cells or the granular cell layer thickness in the dentate gyrus. The same treatment specifically improved olfactory learning performance, whereas spatial learning and memory was unchanged, thus demonstrating that olfactory memory is closely associated with the level of ongoing neurogenesis in the subventricular zone-olfactory bulb. The anatomical specificity of the NOS inhibitor actions was not due to differences in the availability of NO, as demonstrated by immunohistochemical detection of neuronal NOS and S-nitrosylated proteins in both regions. Remarkably, the distinct NO sensitivity might result from a differential expression of epidermal growth factor receptor in precursor cells in both regions, as the proliferative effect of NOS inhibitors in the subventricular zone was restricted to the cells that expressed this receptor.

Animals↗

Impaired spatial and sequential learning in rats treated neonatally with D-fenfluramine.

D-Fenfluramine, a serotonin releaser, was administered to neonatal rats on postnatal days 11-20 (a stage of hippocampal development analogous to third trimester human ontogeny). As adults, the D-fenfluramine-treated offspring exhibited dose-related impairments of sequential and spatial learning and reference memory in the absence of sensorimotor impairments. Procedures to minimize stress and to control for other performance effects prior to testing for spatial learning demonstrated that nonspecific factors did not account for the selective effects of D-fenfluramine on learning and memory. Developmental D-fenfluramine-induced spatial and sequential learning deficits are similar to previous findings with developmental MDMA treatment. By contrast, recent findings with developmental D-methamphetamine treatment showed spatial learning deficits while sparing sequential learning. The spatial learning effects common to all three drugs suggest that they may share a common mechanism of action, however, the effects are not related to long-lasting changes in hippocampal 5-HT levels as no differences were found in adulthood. Whether the cognitive deficits are related to the effects of substituted amphetamines on corticosteroids, other aspects of the 5-HT system, or some unidentified neuronal substrates is not known, but the data demonstrate that these drugs are all capable of inducing long-term adverse effects on learning.

Animals↗

Decreased NGFI-A gene expression in the hippocampus of cognitively impaired aged rats.

Hippocampal NGFI-A gene expression is increased following the induction of long-term potentiation, a form of activity-dependent synaptic plasticity that has been implicated in learning. In this study, we show a positive correlation between spatial learning and the constitutive expression of NGFI-A mRNA, selectively in CA1 pyramidal neurons. NGFI-A mRNA expression decreased with age in CA1, CA2 and neocortex. Long-term amitriptyline treatment, which improved spatial learning in young rats, had no significant effects on NGFI-A mRNA levels. Whether hippocampal NGFI-A plays a direct role in the mechanism of learning and memory remains to be determined.

Aging↗

A comparison of wild-caught wood mice and bank voles in the Intellicage: assessing exploration, daily activity patterns and place learning paradigms.

Our previous work has revealed very high baseline neurogenesis in the dentate gyrus of wood mice as compared particularly to bank voles; a difference which may be related to learning capacity. This study explored whether the newly-developed Intellicage system could be used to compare these species in simple spatial learning paradigms. The Intellicage is essentially a group-housing cage that also allows continuous automatic recording of each individual's behaviour. Seven wild-caught bank voles (Clethrionomys glareolus) were compared with seven wild-caught long-tailed wood mice (Apodemus sylvaticus) in the Intellicage system over 9 days. During the first 90 min after entering the cage, the wood mice were substantially more exploratory than the bank voles (P = 0.003). Over subsequent days, both species showed nocturnal activity increases with voles being 3.7 times more active overall. In the spatial learning paradigms, there were significant species-by-time interactions with wood mice outperforming bank voles on both place learning (P = 0.027) and subsequent reversal (P = 0.006). Conclusions are firstly that the wood mice show superior learning abilities in this paradigm, and secondly that the Intellicage serves as a valuable cognitive testing arena for small wild rodents, or for circumstances where cognition must be compared independent of different responses to handling or novel environments.

Activity Cycles↗