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PubMed2003

In search of a better mouse test.

To elucidate pathways from specific genes to complex behaviors, assays of mouse behavior need to be valid, reliable and replicable across laboratories. Behavioral assays are proving to be as complex as the intricate cellular and molecular pathways that are the main interest of many mouse users. There is no perfect behavioral test, but we propose some aphorisms to stimulate discussion that is necessary for continued progress in task development. For maximal utility, a behavioral test should yield valid data for most of the commonly used inbred mouse strains. Tests of simple, ubiquitous behaviors usually yield meaningful data for most mice, especially when based on automated scoring or on simple physical measures that are likely to be replicable across laboratories. Extreme test scores resulting from non-performance on a task can inflate the apparent reliability of a test, and devious adaptations to a task can undermine its validity. The optimal apparatus configuration for certain genetic or pharmacological analyses might depend on the particular laboratory environment. Despite our best efforts, the mice will continue to win some innings.

Animals↗

PubMed2003

Physical and emotional stress have differential effects on preference for saccharine and open field behaviour in rats.

Stress may influence the sensitivity of subjects to rewarding stimuli and stress modality may differentially affect this sensitivity. This relation was investigated in our animal model using chronic physical (repeated mild foot shocks) and emotional (witness) stress. Previous research has established that the two stressors have differential long-term effects on behaviour, where physical stress caused inactivity in a small open field and emotional stress hyperactivity. Rats were stressed on 5 consecutive days and tested for locomotor activity in a small open field (day 10) and saccharine preference (day 11). The preference for graded concentrations of saccharine over water was used as a measure for their sensitivity to reward. Physical stress treatment induced a long-term decrease both in preference for saccharine and open field activity compared to control treatment. Emotional stress animals showed an increase in open field behaviour activity and a slight increase in saccharine preference. Physical stress seems to cause anhedonia, while emotional stress might cause an increased sensitivity to reward. In conclusion, stress can induce differential long-term effects on sensitivity to positive stimuli and the response to novelty depending on stress modality.

Adaptation, Psychological↗

PubMed2003

Behavior of the gray short-tailed opossum (Monodelphis domestica) in the open field and in response to a new object, in comparison with the rat.

We compared the behavior of the gray short-tailed opossums (Monodelphis domestica) and Long-Evans rats during repeated exposures to the open-field (OF) test. Animals were videotaped for 10 min on four consecutive days. A new object was placed in the center of the field on the third day and it was present there again on the fourth day. The rate of locomotor activity in the opossum was always higher than that in the rat. On the first exposure to the open field, both species showed strong thigmotaxy. On the second day, opossums shifted a significant part of their activity to the internal and central parts of the field, while thigmotaxy dominated in the rats' behavior till the end of the experiment. The frequency and time of exploration of a new object placed on the central square was higher in the opossums than in rats. They also showed higher frequency of rearings and lower defecation scores, while the time of grooming was similar to the rats'. These results, that are consistent with those of our earlier experiments in the elevated plus maze (EPM), show that in response to novelty Monodelphis opossums change their behavior from defensive to exploratory faster than rats and then explore it more intensely. These differences may be either a result of different ecologies or evolution of the two species.

Animals↗

PubMed2003

The nucleus accumbens shell is critical for normal expression of pup-retrieval in postpartum female rats.

The nucleus accumbens (NA) plays an important modulatory role in the control of normal expression of maternal behavior (termed maternal performance). The present study investigated the relative functions of two subregions of the NA (the shell and core) in maternal performance. Electrolytic lesions of the shell or core were performed either before parturition or immediately after a varying amount of maternal experience (none, 1 or 24h) during the immediate postpartum period. Maternal performance was tested on Day 1 postpartum and re-tested 9 days later using a pup sensitization technique. Results show that lesions of the shell, but not the core, significantly disrupted pup-retrieval: the shell-lesioned rats took significantly longer to finish retrieving all test pups, but their retrieval latency for the first pup was not affected. Neither lesion affected other components of maternal behavior (pup licking, nest building and nursing). These findings suggest that the shell, but not the core, is critical for the normal expression of pup-retrieval behavior possibly through its role in maintaining maternal motivation or attention.

Animals↗

PubMed2000

Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks.

Genetic redundancy is a problem in gene targeting studies because functionally relevant sister proteins can compensate for the lack of protein product of a targeted gene. A molecular system is chosen in which it is hoped to demonstrate both the lack and presence of compensation after disruption of particular single genes. Mammals may not be able to compensate for the lack of heregulin, a single ligand for multiple ErbB receptors, however, compensation is expected when a single ErbB receptor is knocked out. To investigate this the heregulin-1, ErbB2, or ErbB3 locus was disrupted in a targeted manner and mice heterozygous for the mutation were analyzed. Heregulin and its receptors were shown to be involved in embryonic brain development and, more recently, in plastic changes associated with adult brain function in rodents. Although they have never been shown to play roles in mammalian behavior, it was decided to characterize the mice behaviorally using a battery of simple tests. Heregulin mutant mice exhibited elevated activity levels in the open field, showed improved rotorod performance, and finished T-maze spontaneous alternation task faster compared to control wild type littermates, findings that suggest a consistent hyperactivity across tests. ErbB2 and ErbB3 mutant mice, whose strain origin was identical to that of heregulin mutants, showed no sign of the behavioral alterations. It is suggested that the abnormalities seen in heregulin mutant mice are due to mutation at that locus and the lack of alterations seen in ErbB2 and ErbB3 mutant mice is the result of compensation by unaltered sister receptors.

Animals↗

PubMed1981

Effects of beta-(Tyr9)melanotropin-(9-18) decapeptide on passive and active avoidance behavior and on open-field activity of rats.

The effects of the administration of beta-(Tyr9)melanotropin-(9-18) into the lateral ventricle in a dose of 1.0 micrograms in 2 microliters were studied on passive avoidance behavior, extinction of active avoidance behavior, and open-field activity in rats. beta-(Tyr9) melanotropin-(9-18) given 30 min pretrial facilitated the acquisition of passive avoidance behavior; however, it was ineffective on retention when the material was given immediately posttrial or 30 min before retention testing. The extinction of active behavior was delayed. In open-field activity, the ambulation rate and rearing activity were increased 30 min following administration. The data suggest that beta-(Tyr9)melanotropin-(9-18) has distinct neurotropic properties, and is able to modify behavioral reactions.

Animals↗

PubMed1997

Effects of Tyr-D-Arg-Phe-beta-Ala-NH2, a novel dermorphin analog, on elevated plus-maze learning and spontaneous alternation performance in mice.

1. The effects of intracerebroventricular administration of Tyr-D-Arg-Phe-beta-Ala-NH2 (TAPA), a novel dermorphin analog, on plus-maze learning and spontaneous alternation performance were investigated in mice. 2. The pre- or posttraining or preretention administration of TAPA (0.3-3.0 ng) alone failed to affect transfer latency of plus-maze learning, whereas TAPA (3 ng) produced a significant decrease in percent alternation without affecting total arm entries. 3. beta-Funaltrexamine (5 micrograms) almost completely reversed the TAPA (3 ng)-induced decrease in percentage of alternation. 4. These results suggest that stimulation of mu-opioid receptors disrupts spontaneous alternation performance associated with spatial working memory.

Analgesics, Opioid↗

PubMed2002

Comparisons between C57BL/6J and A/J mice in motor activity and coordination, hole-poking, and spatial learning.

The C57BL/6J (B6) inbred mouse strain was compared to the A/J inbred strain for motor activity in an open-field, exploration of a hole-board, motor coordination in the coat-hanger test, and spatial learning in the Morris water maze. B6 mice displayed a higher number of segment crossings in the open-field and of hole-poking responses than A/J mice. The performance of B6 mice was superior to that of A/J mice not only in the submerged but also in the visible platform version of the Morris water maze. By contrast to their hypoactivity, the A/J strain had shorter movement times in the coat-hanger test, indicating faster motor speed, although the groups did not differ in latencies before falling. These results indicate that recombinant inbred or congenic strains derived from B6 and A/J mice offer considerable potential for discerning the genetic basis of several behavioral phenotypes.

Animals↗

PubMedDate not supplied

Prenatal exposure to anti-HIV drugs. long-term neurobehavioral effects of lamivudine (3TC) in CD-1 mice.

The present study was aimed at investigating the long-term effects of prenatal exposure to lamivudine (3TC), an antiretroviral drug used in clinical practice alone or in combination with zidovudine (AZT) to prevent mother-to-child transmission of the HIV virus. Pregnant CD-1 mice were given per os twice daily either 3TC at different doses (125, 250, or 500 mg/kg) or vehicle solution (NaCl 0. 9%) from pregnancy day 10 to delivery. Offspring behavior was examined on postnatal day 35 in a 20-min social interaction test. At adulthood different behavioral endpoints were analyzed, including locomotor activity and exploration in an open field following administration of the muscarinic antagonist scopolamine (2 mg/kg), spatial learning in either radial arm or Morris water maze, virgin female behavior in a maternal induction test, and pain sensitivity in a hot-plate test (52 +/- 0.1 degrees C). Our findings confirm the low neurotoxicity of 3TC in comparison to AZT. However some significant behavioral alterations were found, namely (1) a decrease in immobility in the open field test, (2) an increase in the responsiveness to scopolamine shown by the 500-mg/kg 3TC mice (sniffing behavior) in the open field, and (3) a longer escape latency in the first day of the reversal phase in the Morris task (particularly marked in the 250-mg/kg treatment group). No significant changes in either pain sensitivity, social/affiliative, or maternal behavior were found, although a higher occurrence of aggressive behavior toward foster pups was noted in both 125- and 500-mg/kg 3TC females.

Animals↗

PubMed2002

Dual effect of central injection of recombinant rat interleukin-4 on lipopolysaccharide-induced sickness behavior in rats.

Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF), in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-4 on LPS-induced sickness behavior, rats injected intra-peritoneally (i.p.) with LPS were administered intracerebroventricularly (i.c.v.) with IL-4. IL-4 (30 and 300 ng) potentiated the behavioral effects of LPS (175 microg/1000 g) when both molecules were co-injected. However, when IL-4 (30 ng) was injected 12 h prior to LPS, it blocked the depressing effects of LPS on social exploration. These results indicate that the regulation of cytokine-induced sickness behavior by IL-4 can be either inhibitory or stimulatory depending on the sequencing of IL-4 and LPS treatments.

Animals↗

PubMed2002

Hippocampal neurons responding to first-time dislocation of a target object.

To examine how hippocampal neurons respond to a mismatch between retrieved and actual experience, we trained rats to find a hidden platform at a particular location in an annular watermaze and then moved the platform. Several cells that were silent at the new platform location before the move fired vigorously when the rat found the goal. The new activity was paralleled by reduced discharge in a subset of simultaneously recorded interneurons. The pattern of activity returned toward its original configuration as the rat learned the new location. The activation of specific hippocampal neurons following dislocation of a target object may be essential for synaptic plasticity and adaptive modification of the animal's representation of the environment.

Action Potentials↗

PubMed2003

Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin.

Neuroserpin is a neural serpin that inhibits the extracellular protease tissue-type plasminogen activator (tPA). We have generated neuroserpin-deficient mice which are viable and healthy. Zymographic analysis of neuroserpin-deficient brain showed unaltered tPA activity, suggesting that other inhibitors contribute to the regulation of tPA and may compensate for the defect. Analysis of explorative behavior revealed selective reduction of locomotor activity in novel environments, an anxiety-like response on the O-maze, and a neophobic response to novel objects. Mice overexpressing neuroserpin under the control of the Thy1.2 promoter are known to have a reduced brain tPA activity. They showed reduced center exploration in the open-field test and, like neuroserpin-deficient mice, a neophobic phenotype in the novel object test. Our results implicate neuroserpin in the regulation of emotional behavior through a mechanism that is at least in part independent of tPA activity. They are the first evidence for a role of protease inhibitors in mood regulation.

Affect↗

PubMed2003

Exposure to novelty enhances retrieval of very remote memory in rats.

Rats were trained in a one-trial step-down inhibitory avoidance task at the age of 3 months and tested for retention 1 day later, or 3, 6, 9, 12, 15, and 19 months later, i.e., when the animals were 3, 6, 9, 12, 15, 18, or 22 months of age. Retrieval performance declined with time and was undetectable in the last two age groups. Exposure to an unrelated novel environment (a square box lined with black plastic) 1 h before retention testing enhanced retrieval at all ages, regardless of the decline in the level of test session performance. The effect cannot be explained by an anxiogenic effect of the novelty box, or by an influence of novelty on locomotion or exploration, or by a nonspecific influence of exposure to novelty on step-down latency in the inhibitory avoidance apparatus.

Animals↗

PubMedDate not supplied

In vivo development of retinal ON-bipolar cell axonal terminals visualized in nyx::MYFP transgenic zebrafish.

Axonal differentiation of retinal bipolar cells has largely been studied by comparing the morphology of these interneurons in fixed tissue at different ages. To better understand how bipolar axonal terminals develop in vivo, we imaged fluorescently labeled cells in the zebrafish retina using time-lapse confocal and two photon microscopy. Using the upstream regulatory sequences from the nyx gene that encodes nyctalopin, we constructed a transgenic fish in which a subset of retinal bipolar cells express membrane targeted yellow fluorescent protein (MYFP). Axonal terminals of these YFP-labeled bipolar cells laminated primarily in the inner half of the inner plexiform layer, suggesting that they are likely to be ON-bipolar cells. Transient expression of MYFP in isolated bipolar cells indicates that two or more subsets of bipolar cells, with one or two terminal boutons, are labeled. Live imaging of YFP-expressing bipolar cells in the nyx::MYFP transgenic fish at different ages showed that initially, filopodial-like structures extend and retract from their primary axonal process throughout the inner plexiform layer (IPL). Over time, filopodial exploration becomes concentrated at discrete foci prior to the establishment of large terminal boutons, characteristic of the mature form. This sequence of axonal differentiation suggests that synaptic targeting by bipolar cell axons may involve an early process of trial and error, rather than a process of directed outgrowth and contact. Our observations represent the first in vivo visualization of axonal development of bipolar cells in a vertebrate retina.

Animals↗

PubMed2004

Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat.

To examine the effects of exposure to post-weaning pre-puberty (juvenile) stress on the emotional and cognitive abilities in response to exposure to stress in adulthood, we first exposed rats to a platform stress at the age of 28 d. Two months later the rats were exposed to acute swim stress. Rats exposed to both stressors showed a higher level of anxiety (as measured both in open-field and startle response tests) than controls or rats exposed to either the juvenile or the adulthood stressor. In the Morris water-maze, rats that were exposed to both juvenile and adulthood stress performed better than the other groups. In a second experiment we verified that the effect of the juvenile stress was indeed age-dependent. One group was exposed at the age of 26-28 d and again at the age of 60 d (juvenile + adulthood stress); the other group was exposed to the first stressor at the age of 60-62 d and to the second at the age of 90 d [adulthood (60) + adulthood (90) stress]. Juvenile + adulthood stress had a significantly greater effect than exposure to stress twice in adulthood, on anxiety level and on the performance in the water-maze. Finally, in a third experiment we found that the juvenile+adulthood stress group swam faster and tended to explore the central area more than the other groups--a finding that could explain their better performance on the first trial of the spatial task. These results indicate that an exposure to a relatively brief juvenile stressful experience has profound and long-lasting effects on the ability to cope with stress in adulthood.

Aging↗

PubMed2001

Attack cone avoidance during predator inspection visits by wild finescale dace (Phoxinus neogaeus): the effects of predator diet.

When confronted by potential predators, many prey fishes engage in predator inspection behavior. Previous authors have argued that by selectively avoiding the predator's head during an inspection visit (attack cone avoidance), individual inspectors may reduce their local risk of predation. In field trials, we investigated the effects of predator diet cues on the presence of 'attack cone avoidance' during predator inspection visits. Wild, free-ranging finescale dace (Phoxinus neogaeus) were exposed to the combined cues of a model predator and a distilled water control or the odor of a yellow perch (Perca flavescens) fed dace (with alarm pheromone), swordtail (Xiphophorus helleri) (lacking Ostariophysan alarm pheromone), or perch that were food deprived for four days. Finescale dace modified their predator inspection behavior following exposure to the odor of a perch fed dace (fewer dace present, reduced frequency of inspections, and an increased per capita inspection rate) compared to those exposed to the odor of a perch fed swordtails, perch that were food deprived, or a distilled water control. In addition, dace inspected the tail region more often only when the model predator was paired with the odor of a perch fed dace. In all other treatments, dace inspected the head region of the model predator more often. These data suggest that attack cone avoidance of inspecting prey fishes may be more likely to occur in high-risk situations, such as in the presence of conspecific alarm pheromones in the diet of potential predators.

Animals↗

PubMed2004

Active and passive behavior of animals during the postresuscitation period.

Behavioral reactions (open-field test, elevated plus-maze, pain stress, and feeding behavior) were studied in various periods after clinical death caused by circulatory arrest for 10 or 15 min. We revealed two different phases of behavioral changes: active behavior directed at attaining a specific goal and passive behavior directed towards isolation of the organism from external signals and functional minimization. Active behavior determined by pathological excitation in the central nervous system increased the severity of structural damage to hippocampal CA1 neurons during the postresuscitation period. By contrast, passive behavior and minimization of functions preserved structural integrity in these neurons.

Animals↗

PubMed1997

Developmental changes in manipulation in tufted capuchins (Cebus apella) from birth through 2 years and their relation to foraging and weaning.

This study examined the contributions of physical and sensorimotor development to manipulation in capuchins (Cebus apella) from birth to 2 years. Between months 1-6 and 7-12, manipulation increased significantly in frequency, in the proportion that was vigorous or required fine motor control, and in the proportion directed at portable objects. Fine motor control, moving objects in relation to the body, and stamina are largely in place by 12 months, after which little changed. All elements of the manipulative repertoire have appeared, and vigorous and dexterous activities have peaked before fully independent foraging. Emergence of permanent dentition and achievement of approximately half of adult body size accompany the attainment of fully independent foraging at 15 months. Thereafter, increasing strength and specific knowledge probably contribute more to changing foraging competence in young capuchins than do stamina and sensorimotor development.

Aging↗