Dissociation of locomotor activation and suppression of food intake induced by CRF in CRFR1-deficient mice.

Corticotropin-releasing factor (CRF) systems are involved in locomotor and feeding behaviors. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the central nervous system. However, the role for each receptor in locomotor activity and feeding remains to be determined. Using CRFR1 null mutant mice, the present study examined the functional significance of this receptor in ambulation and feeding. CRF treatment of wild-type mice resulted in increased levels of locomotion whereas no change was observed in CRFR1-deficient mice as compared to vehicle-treated mutant mice. In contrast, CRF decreased food-water intake in both wild type and CRFR1-deficient mice equally. These results support an important role for CRFR1 in mediating CRF-induced locomotor activation, whereas other receptor subtypes, likely CRFR2, may mediate the appetite-suppressing effects of CRF-like peptides.

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice.

A two-trial memory task, based on a free-choice exploration paradigm in a Y-maze, was previously developed to study recognition processes in Sprague-Dawley rats. Because this paradigm avoids the use of electric shock or deprivation that may have nonspecific effects and does not require learning of a rule, it may be particularly useful for studying memory in mice. Four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57BL/6 x SJL/J), and one outbred strain (CD1) were used to validate this task in mice and to characterize a strain distribution in response to novelty and working memory. Exploration was measured with a short (2 min) intertrial interval (ITI) between acquisition and retrieval, while memory was examined with longer intervals (30 min, 1 h, and 2 h). A study of the time course of the response to novelty revealed varying degrees of preference and/or habituation to novelty among the different strains, with CD1 exhibiting a very high response to novelty and others showing lower (C57 x SJL hybrids) to complete absence (SJL) of exploration of novelty. Memory span, assessed with increasing ITIs, varied widely among strains from 30 min (C57 x SJL hybrids) to at least 2 h (C57 and BALB). Such demonstrated sensitivity to a wide range of behavioral phenotypes supports the use of this spatial memory task as an effective tool for the study of genetic influences on the response to novelty and recognition processes in mice.

Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1.

Corticotropin-releasing factor (CRF) has been hypothesized to be involved in the pathophysiology of anxiety, depression, cognitive and feeding disorders. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the CNS. However, the role for each receptor subtype in animal models of neuropsychiatric disorders remains to be determined. Using CRFR1 deficient mice, the present study investigated the functional significance of this CRF receptor subtype in anxiety-like and memory processes. CRFR1 knockout mice displayed an increased exploratory behavior in both the Elevated Plus-maze (EPM) and the Black and White (B-W) test box models of anxiety, indicating an anxiolytic-like effect of the CRFR1 gene deletion. In contrast, during the retrieval trial of a two-trial spatial memory task wild type mice made more visits to and spent more time in the novel arm as opposed to the two familiar ones of a Y-maze apparatus. No increase in the level of exploration of the novel arm by the CRFR1 deficient mice was observed. This indicates that CRFR1 knockout mice are impaired in spatial recognition memory. These results demonstrate that genetic deletion of the CRFR1 receptor can lead to impairments in anxiety-like and cognitive behaviors, supporting a critical role for this receptor in anxiety and cognitive biological processes.

Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat.

There is growing evidence that stress during prenatal and postnatal periods of life can modify adaptive capacities in adulthood. The hypothalamo-pituitary-adrenal axis may mediate an animal's responses to perinatal stressful events and thus serve as a neurobiological substrate of the behavioural consequences of these early events. However, little is known about the long-term effects of prenatal stressors throughout the entire life of the animals. The focus of the present study was to examine the long-term influences of a prenatal and postnatal stress on glucocorticoid secretion and cognitive performance. Prenatal stress of rat dams during the last week of pregnancy and postnatal daily handling of rat pups during the first 3 weeks of life were used as stressors. The long-term effects of these manipulations were analysed using a longitudinal approach throughout the entire life of the animals, and were repeatedly tested in adulthood (4-7 months), middle age (13-16 months) and in later life (20-24 months). The study demonstrated that prenatal stress and postnatal handling induced opposite effects on both glucocorticoid secretion and cognitive performance. Prenatal stress accelerated the age-related hypothalamo-pituitary-adrenal axis dysfunctions; indeed, circulating glucocorticoids levels of prenatally stressed middle-aged animals are similar to old control ones, and also induced cognitive impairments. In contrast, postnatal handling protected from the age-related neuroendocrine and behavioural alterations. These results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age-related memory deficits.

Cognitive enhancing effects in young and old rats of pBC264, a selective CCK(B) receptor agonist.

RATIONALE: The implication of CCK(B) receptors in cognitive processes is far from fully understood. OBJECTIVE: The present study investigated the effect of propionyl-BC264, a selective agonist of CCK(B) receptors, in young and old rats. METHODS: Cognitive functions were studied in a two-trial recognition memory task developed in our laboratory. RESULTS: It was shown that propionyl-BC264 enhanced information processing in young as well as in old rats when injected (10 microg/kg; IP) immediately after the acquisition phase and before the retrieval trial but not before the acquisition trial. This cognitive enhancing effect was blocked by prior administration of L 365,260, a selective CCK(B) receptor antagonist. CONCLUSIONS: In view of the fact that BC264 is devoid of anxiogenic effects, it could be of value in the treatment of cognitive impairments associated with both normal and pathological ageing.

Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development.

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.

Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion.

It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.

Extension of a new two-trial memory task in the rat: influence of environmental context on recognition processes.

A two-trial memory task, based on place or object exploration in a Y-maze, was developed to study recognition processes in young and aged Sprague-Dawley rats (Dellu et al., 1992). This paradigm avoids the use of electric shocks or deprivations that may have nonspecific effects, and the task does not require learning of a rule, i.e., involves essentially working memory. A number of behavioral parameters in several animals could be recorded automatically, thus allowing a detailed analysis of behavior and a simultaneous testing of several animals. We extended this task in order to evaluate the role of contextual information in recognition memory. When the contextual environment during acquisition and retrieval trials was unchanged, place recognition remained intact despite interpolated explorations. When the contextual environment during acquisition and retrieval trials was changed, object recognition was impaired. It was clearly shown that the correct choice between two discrete cues (e.g., small objects) is conditional on more diffuse environmental cues. Thus, it can be hypothesized that at least two kinds of recognition processes can be assessed in animals: an automatic process, based on a discrimination between familiarity and novelty, and a second process, more cognitively based and more effortful. In conclusion, the two-trial task in the Y-maze is sensitive, specific, and fast. It allows the study of both spatial and nonspatial memory, allows the study of different levels (automatic vs controlled) of cognitive processes and their neuroanatomical substrates, and may be profitably employed in aging studies and neuropharmacological research in general.

Facilitation of cognitive performance in aged rats by past experience depends on the type of information processing involved: a combined cross-sectional and longitudinal study.

The impact of past history on behavior across the life span is largely unknown. This is why the role of previous experience in subsequent memory performances has been studied in a combined longitudinal (animals repeatedly tested) and cross-sectional (animals tested once at various ages) study, in male Sprague-Dawley rats. Different types of memory (reference and working memory) and/or information processing (route or place learning) were assessed in three different tasks (T-maze, Morris water maze, and eight-arm radial maze). Our results indicate that experience prevents age-related impairments in the learning phase of the T-maze and the Morris water maze, in both middle-aged and old rats. Nonexperienced animals of the same age were found to present age-related memory deficits. However, previous experience did not have any effect on the learning of the radial maze or on the reversal performance. It is suggested that controlled processes (intentional and attentional) are impaired by aging and cannot be improved by training, whereas automated processes appear to benefit from it. These data underline the heterogeneity of cognitive aging and indicate that aging is not inevitably accompanied by a decline in performance.

Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly--a life-span study in rats.

Inter- and intra-individual differences in hypothalamo-pituitary adrenal (HPA) axis activity and behavioral reactivity to novelty between young and old rats were evidenced in this longitudinal life-span study. Higher responders to novelty (HR) had a higher corticosterone secretion which showed a quicker increase with age than did the others (LR); the differences in response to novelty observed in youth were no longer apparent in the old rats. Response to novelty in youth is a predictive factor of accelerated aging of the HPA axis. These early changes, which precede the appearance of the memory deficits, may be a causal factor. Disappearance of behavioral and endocrinological inter-individual differences at 21 months highlights the importance of not restricting aging studies to old subjects.

Novelty-seeking in rats--biobehavioral characteristics and possible relationship with the sensation-seeking trait in man.

A behavioral trait in rats which resembles some of the features of high-sensation seekers in man has been characterized. Given that the response to novelty is the basis of the definition of sensation-seeking, individual differences in reactivity to novelty have been studied on behavioral and biological levels. Certain individuals labeled as high responders (HR) as opposed to low responders (LR) have been shown to be highly reactive when exposed to a novel environment. These groups were investigated for free-choice responses to novel environments differing in complexity and aversiveness, and to other kinds of reinforcement, i.e. food and a drug. The HR rats appeared to seek novelty, variety and emotional stimulation. Only HR individuals have been found to be predisposed to drug-taking: they develop amphetamine self-administration whereas LR individuals do not. They also exhibit a higher sensitivity to the reinforcing properties of food. On a biological level, compared to LR rats, HR animals have an enhanced level of dopaminergic activity in the nucleus accumbens both under basal conditions or following a tail-pinch stress. HR and LR rats differ in reactivity of the corticotropic axis: HR rats exposed to a novel environment have a prolonged secretion of corticosterone compared to LR rats. The association of novelty, drug and food seeking in the same individual suggests that these characteristics share common processes. Differences in dopaminergic activity between HR and LR rats are consistent with results implicating these dopaminergic neurons in response to novelty and in drug-taking behavior. Given that rats self-administer corticosterone and that HR rats are more sensitive to the reinforcing properties of corticosteroids, it could be speculated that HR rats seek novelty for the reinforcing action of corticosterone. These characteristics may be analogous to some for the features found in human high-sensation seekers and this animal model may be useful in determinating the biological basis of this human trait.

Reactivity to novelty during youth as a predictive factor of cognitive impairment in the elderly: a longitudinal study in rats.

A life-span study of certain behavioral traits was conducted in rats. Animals were repeatedly tested in a circular corridor for reactivity to novelty and in a recognition memory task for cognitive abilities. These measures revealed important inter-individual differences in young as well as in old subjects. Some of these differences appear with aging (memory deficits) and others disappear (high reactivity to novelty). Moreover, a relationship between high reactivity to novelty in youth and deficits in memory recognition in elderly was found. Rats that are high-responders to novelty had age-related memory impairments whereas the low-responder rats did not. While the biological mechanism linking these two behavioral traits remains to be demonstrated, this study shows that age-related impairments can be predicted by factors detectable early in life.

Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processes in the rat.

The neurosteroids, pregnenolone sulfate (PREG-S) and tetrahydroprogesterone (TH-PROG), act on the GABAA receptor with antagonist or agonist-like properties, respectively. In this study the effect of the infusion of PREG-S and TH-PROG into the nucleus basalis magnocellularis (NBM) of the rat was examined in a two-trial memory task. The results show that PREG-S (5 ng in 0.5 microliter) enhances memory performance when injected after an acquisition trial; conversely TH-PROG (2 ng in 0.5 microliter) disrupts performance when injected before an acquisition trial. A role for neurosteroids in memory processes subserved by the nucleus basalis magnocellularis is of interest in view of the implication of this structure and these substances in neurodegenerative processes.

A two-trial memory task with automated recording: study in young and aged rats.

A two-trial recognition task, based on place or object exploration in a Y-maze, was developed to study memory in adult and aged rats. This paradigm avoids the use of electric shocks or deprivation that may have non-specific influences on the responses, and the task does not require learning of a rule. A number of behavioral parameters in several animals could be recorded automatically. These behavioral parameters were found to be differently influenced both by the type of recognition (place vs. object) and by the inter-trial interval (recognition retention time). Impaired recognition was also detected in 18-months-old rats. This recognition task which combines simplicity, sensitivity and high specificity may thus be a useful adjunct to our current battery of memory tasks.

Cognitive enhancing properties of beta-CCM infused into the nucleus basalis magnocellularis of the rat.

Peripheral administration of various benzodiazepine derivatives or beta-carbolines (inverse agonists at benzodiazepine receptors), has been shown to affect memory. In this study, the effect of local infusion of a beta-carboline-methyl beta carboline-3-carboxylate (beta-CCM) into the nucleus basalis magnocellularis (NBM) of rats was examined in a two-trial recognition task. The results show that beta-CMM (3 micrograms/0.5 microliter) enhances recognition performance when injected both before or immediately after the acquisition trial. These effects appear to be mediated by a benzodiazepine (BZD) receptor since they were blocked by pretreatment with Ro 15-1788, a BZD receptor antagonist. This study supports the involvement of the NBM in cognitive processes, and demonstrates that these processes can be influenced by alteration of GABAergic neurotransmission.

Learning disturbances following excitotoxic lesion of cholinergic pedunculo-pontine nucleus in the rat.

Compared to brain anterior cholinergic systems such as the septo-hippocampal and nucleus basalis-cortical pathways, posterior cholinergic groups have received little attention with respect to their involvement in learning and memory. In this study, the effect of lesion of the cholinergic pedunculo-pontine cell bodies (PPN) by the excitotoxin quisqualic acid was investigated on spontaneous locomotor activity and learning in rats. Behavioral tasks designed to test both reference memory (cross maze and water maze) or working memory (radial maze) were used. PPN lesion had no effect on initial nor on nocturnal locomotor activity in a circular corridor. The lesion disrupted learning in the water and radial mazes, but was without influence on acquisition in the cross maze. The difference in results obtained in the two tasks designed to test reference memory (cross maze and water maze) indicated that the disturbance depended on task difficulty rather than on a particular memory component. It is suggested that the PPN is involved in the sustained attention required to perform correctly in water and radial mazes. The PPN cannot therefore be considered as a uniquely extrapyramidal structure. In addition to its descending outputs, the PPN has ascending connections to the neocortex, either directly or indirectly via the thalamus, and so pathological changes in this region may be partly responsible for the cognitive disorders of aging or those observed in various neurodegenerative conditions.