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Seizure-prone EL/Suz mice exhibit physical and motor delays and heightened locomotor activity in response to novelty during development.

Seizure-prone EL/Suz mice have been studied as a model of multifactorial epilepsy for five decades. In prior behavioral studies, EL/Suz mice were shown to exhibit heightened locomotor activity, which implies a state of underlying hyperexcitability. The aim of the present study was to establish the premorbid behavioral development of basic motor skills and activity levels of EL/Suz mice, as compared with DDY mice, the control strain that is not seizure-prone. EL/Suz and DDY pups were monitored from Postnatal Day (PND) 3 to assess body weight, surface righting, negative geotaxis, forelimb grip strength, eye opening, habituation to a novel environment, and exploratory behavior in a two-compartment task. EL/Suz mice weighed less from PNDs 3 to 21 and exhibited delayed surface righting (PNDs 3, 5, 7) and negative geotaxis (PNDs 5, 7, 9) responses. EL/Suz and DDY mice differed in their habituation to a novel environment, with EL/Suz mice exhibiting higher activity, both within a single 10-minute session and across the 3 days of testing. EL/Suz and DDY mice also differed in the two-compartment task, with EL/Suz mice exhibiting increased locomotor activity and spending a greater amount of time in the light compartment. Thus, the present findings reveal that EL/Suz mice exhibit some developmental delays, altered habituation to a novel environment, and increased exploratory activity. Overall, the present results demonstrate that the behavioral and physiological phenotype of seizure-prone EL/Suz mice is deviant more than 2 months before the onset of seizure susceptibility.

Age Factors↗

Biochemical and behavioral anxiolytic-like effects of R(+)HA-966 at the level of the ventral tegmental area in rats.

RATIONALE: R(+) HA-966, a weak partial agonist at the glycine/NMDA receptor complex, has been shown to have anxiolytic-like actions on restraint stress-induced mesoprefrontal dopamine metabolism. OBJECTIVE: This study investigates the putative anxiolytic, R(+) HA-966, applied locally at the level of the mesocorticolimbic dopamine cell bodies in the ventral tegmental area (VTA), on the acquisition and expression of conditioned fear. METHODS: Ten to 14 days after cannula implantation, rats were subjected to the acquisition session (10x5 s tone paired with 0.5 s, 0.8 mA footshock) followed about 24 h later by the expression session (ten tones only) of a conditioned fear protocol. Rats were treated with R(+) HA-966 (15 microg/VTA) or saline before either the acquisition or expression sessions. Other rats were injected with saline or R(+) HA-966 (10 microg/side), intra-medial prefrontal cortex, on the expression day. RESULTS: R(+)HA-966, intra-VTA, prevented stress-induced changes in mesoprefrontal, but not mesoaccumbal, dopamine metabolism and was associated with a reduction in fearful responses to physical (footshock) and psychological (conditioned fear) stressors. Additionally, rats treated with R(+)HA-966 intra-VTA before the acquisition session were less fearful at the beginning of the expression session. Local injection of R(+)HA-966 into medial prefrontal cortex did not have anxiolytic-like behavioral or biochemical actions but diminished the expression of exploratory behavior in non-stress, control rats. CONCLUSIONS: These studies indicate that the stress-induced activation of the mesoprefrontal dopamine neurons is necessary for the normal expression of fearful behaviors.

Animals↗

Abnormal open field behavior after anterolateral hypothalamic injection of 6-hydroxydopamine.

To investigate the importance of forebrain catecholamine terminals in open field behavior, rats were microinjected bilaterally in the medial forebrain bundle at the level of the anteralteral hypothalamus with 6-hydroxydopamine (6-OHDA), a specific catecholaminergic neurotoxin. These 6-OHDA microinjections produced extensive loss of forebrain catecholamine terminals; identical vehicle microinjections did not. When 6-OHDA rats were given 8 open field (OF) tests in the first or the fifth postinjection week, they had a longer latency to enter the OF, crossed fewer squares and reared less than normal rats or rats microinjected with vehicle. The abnormal OF behavior of 6-OHDA rats was not a generalized loss of locomotor activity because 6-OHDA rats were normally active in the home cage. The abnormal OF behavior of 6-OHDA rats was also not a result of a generalized lack of reactivity because the OF test elicited an increase of plasma corticosterone in 6-OHDA rats. The possibility that 6-OHDA rats were abnormal in the OF because they were hyperractive to it was not consistent with the observations that the OF activity of 6-OHDA rats did not change with repetitive testing, 6-OHDA rats did not defecate more than vehicle rats, and 6-OHDA rats did not display freezing behavior. These results suggest, but do not prove, that the abnormal OF behavior of 6-OHDA rats reflects a deficit of exploratory behavior that is correlated with extensive loss of forebrain catecholamine terminals.

Animals↗

Behavioral impairment of APP(V717F) mice in fear conditioning: is it only cognition?

Alzheimer's Disease (AD) is a devastating human neurodegenerative disorder associated with progressive deterioration of cognitive abilities. The APP(V717F) mouse, an animal model of AD showing robust overexpression of the human amyloid precursor protein (APP) carrying the mutation 717 V --> F, was also shown to exhibit learning and memory performance deficits. However, AD patients suffer from other abnormalities including altered emotionality. Emotionality has not been analyzed in AD mouse models. Here, motor and posture patterns exhibited by APP(V717F) mice are described in a detailed manner in fear conditioning, a paradigm that allows one to test both mnemonic and emotional characteristics of mice. Our results revealed a complex set of behavioral alterations in APP(V717F) mice in measures of exploratory behavior and fear suggesting that the effects of APP(V717F) overexpression in this mouse model are not limited to cognition and may need to be thoroughly examined in the future in a broad range of behavioral tests.

Alzheimer Disease↗

[Effects of L-dopa and transcranial magnetic stimulation on behavioral reactions in kindled rats].

In acute experiment in rats, the chronic epileptogenesis was reproduced in the form of pharmacological kindling induced via repeated picrotoxin administrations (1.0-1.2 mg/kg, intraperitoneally). A reduction of exploratory behavior was shown in the early period of kindling (24 h as of the moment of the last epileptogen administration). The marked alleviation of these disturbances was registered in two weeks from the moment of cessation of kindled irritations. L-DOPA (100 mg/kg, intraperitoneally) and transcranial magnetic stimulation (20 impulses with an induction at the height of their development of 1.5 TI) was followed by the net increasing exploratory, sexual and eating behavior. This is in favour of regarding the activation of dopaminergic system as a mechanism of action of transcranial magnetic stimulation upon kindling-induced behavioral deterioration.

Animals↗

Absence of behavioral effects of intrauterine phenobarbital exposure in rats.

Phenobarbital (Ph) exposure in experimental animals has been associated with impaired brain growth and maturation. In order to look for behavioral correlates of these structural changes, rat pups were tested after intrauterine exposure to Ph. Five Sprague-Dawley rat dams were fed powdered chow containing Ph (0.75 mg/g of chow) from day 8 through the remainder of pregnancy, resulting in serum Ph levels of 19 to 36 micrograms/ml. Control (C) dams were fed plain chow. All pups were cross-fostered to control dams at birth. During their first 3 weeks of age, the acquisition of signs of physical maturation and neurologic development (such as incisor eruption, free-fall righting, rope climbing and descending, etc.) and the development of exploratory behavior in an open chamber were assessed. On days 39 to 48, 24 pups were tested in a water-T maze. Litter size and pup size were smaller in Ph-exposed dams than in controls, but acquisition of all signs of development except eye opening, activity in the exploratory chamber, and time and error scores on water-T maze testing did not differ between the two groups. The reasons that behavioral effects were not found in this study compared with previous studies may include the young age of the animals tested, the differences among behavioral parameters examined, the fact that controls were matched by weight with the experimental animals in this study, and different susceptibility to teratogenic effects among different species.

Animals↗

Conspecific exploration in the T-maze: abnormalities in S100 beta transgenic mice.

S100 beta, a calcium binding brain protein expressed by astrocytes, has been shown to be involved in higher neural processes, including hippocampal-dependent behavioral traits and hippocampal neuronal long-term potentiation (LTP) and depression (LTD), neurophysiological phenomena that may be involved in exploring, learning and remembering novel stimuli. In the present study, the exploratory behavior of previously generated transgenic mice overexpressing the protein are compared to that of normal control mice of identical genetic background and age in a T-maze. The test mice encountered a normal control and an S100 beta transgenic mouse (the choice mice) in the goal arms of the T-maze. We show that no test mice exhibited any preference for either genotype of choice mouse. However, there was a significant difference in the spatial and temporal exploratory pattern between control and S100 beta test mice, demonstrating that S100 beta overexpression significantly altered the behavior of the transgenic mice. We suggest that one probable factor underlying the abnormalities observed is impaired short-term memory.

Animals↗

Apolipoprotein E expression and behavioral toxicity of high charge, high energy (HZE) particle radiation.

Apolipoprotein E (apoE) is a lipid binding protein that plays an important role in tissue repair following brain injury. In the present studies, we have investigated whether apoE affects the behavioral toxicity of high charge, high energy (HZE) particle radiation. METHODS: Sixteen male apoE knockout (KO) mice and sixteen genetically matched wild-type (WT) C57BL mice were used in this experiment. Half of the KO and half of the WT animals were irradiated with 600 MeV/amu iron particles (2 Gy whole body). The effect of irradiation on motor coordination and stamina (Rotarod test), exploratory behavior (open field test), and spatial working and reference memory (Morris water maze) was assessed. ROTAROD TEST: Performance was adversely affected by radiation exposure in both KO and WT groups at 30 d after irradiation. By 60 d after radiation, the radiation effect was lost in WT, but still apparent in irradiated KO mice. OPEN FIELD TEST: Radiation reduced open field exploratory activity 14, 28, 56, 84, and 168 d after irradiation of KO mice, but had no effect on WT mice. MORRIS WATER MAZE: Radiation adversely affected spatial working memory in the KO mice, but had no discernible effect in the WT mice as assessed 180 d after irradiation. In contrast, irradiated WT mice showed marked impairment of spatial reference memory in comparison to non-irradiated mice, while no effect of radiation was observed in KO mice. CONCLUSIONS: These studies show that apoE expression influences the behavioral toxicity of HZE particle radiation and suggest that apoE plays a role in the repair/recovery from radiation injury of the CNS. ApoE deficiency may exacerbate the previously reported effects of HZE particle radiation in accelerating the brain aging process.

Animals↗

Suppression of active sleep by chronic treatment with chlorimipramine during early postnatal development: effects upon adult sleep and behavior in the rat.

In an attempt to study the possible role of active sleep in brain development, male rats were injected twice daily with chlorimipramine, a potent monoamine reuptake blocker, from 1 week to 3 weeks of postnatal age. AS was reduced to less than 10% of total sleep time, the level found in mature rats. Most of the AS reduction was compensated for by quiet sleep but a slight increase in wakefulness also occurred, owing to brief interruptions of sleep at times when AS was expected. In adulthood, the AS-deprived rats showed a higher percentage of AS than did the controls, due to an increase in frequency and duration of AS epochs. Moreover, many of the epochs contained abnormally frequent and strong jerky body movements and rapid-eye-movements, reminiscent of neonatal AS patterns. In addition, the amplitude of hippocampal theta waves during AS was greater than in control rats. The chlorimipramine-treated rats also showed behavioral abnormalities in later life. On the open field test exploratory behavior was much reduced, while increased rearing and defecation occurred. Masculine sexual performance was severely deficient, primarily due to the low level of intromissions and ejaculations. Experimental animals performed less efficiently than controls on a temporal learning task (differential reinforcement of low response rate) and responded more rapidly on a spatial task (left-right alternation learning). These results demonstrate that early interference with the functioning of monoaminergic systems can have long-lasting physiological and behavioral consequences. Furthermore, they are consistent with the hypothesis that AS is an important factor in normal brain development.

Aggression↗

Effects of mu and delta opioid receptor agonists and antagonists on absence epilepsy in WAG/Rij rats.

The effects of various types of opioid receptor agonists and antagonists were determined in a genetic rat model for generalized absence epilepsy. Rats of the WAG/Rij strain spontaneously showed several hundred spike-wave discharges per day. Intracerebroventricular (i.c.v.) injections of the selective mu agonist DAMGO (0.2, 0.7 microgram) resulted in a dose-related increase in the number of spike-wave discharges, while the selective delta agonist DPDPE (20, 60 micrograms) was without effect. DAMGO reduced the duration of automatic behavior, enhanced the immobile behavior (after the low dose) and had no effect on exploratory behavior. On the other hand, DPDPE significantly enhanced the total time spent on exploration, but did not influence other behavioral parameters. There was no correlation between the ability to the drug to modulate the epileptic activity and behavioral changes. The nonselective antagonist naloxone, administered either i.p. (0.4, 2.0, 10 mg/kg) or i.c.v. (10, 50 micrograms), increased the number of spike-wave discharges in a dose-dependent way. The specific delta receptor antagonist naltrindole (0.3, 1 mg/kg) was without effect, as was the irreversible mu receptor antagonist beta-funaltrexamine (beta-FNA). Pretreatment with beta-FNA diminished the action of DAMGO. These results clearly indicate that activation of the mu opioid receptor increases the number of spike-wave discharges, and that modulation of delta receptors is not effective. On the other hand, the naloxone-induced enhancement of spike-wave discharges, suggests a tonic control of the epileptic activity by another opioid system. These results point to an important role of the mu-, but not delta-, receptor in facilitation of the epileptic activity in WAG/Rij rats.

Analysis of Variance↗

Neither acute nor chronic exposure to a naturalistic (predator) stressor influences the interleukin-1beta system, tumor necrosis factor-alpha, transforming growth factor-beta1, and neuropeptide mRNAs in specific brain regions.

Physical (neurogenic) stressors may influence immune functioning and interleukin-1beta (IL-1beta) mRNA levels within several brain regions. The present study assessed the effects of an acute or repeated naturalistic, psychogenic stressor (predator exposure) on brain cytokine and neuropeptide mRNAs. Acute predator (ferret) exposure induced stress-like behavioral effects, including elicitation of a startle response and reduced exploratory behaviors; these responses diminished after 30 sessions. Moreover, acute and repeated predator exposure, like acute restraint stress, increased plasma corticosterone levels measured 5 min later, but not 2 h after stressor exposure. In contrast, none of the stressors used influenced IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory proteins I and II, or tumor necrosis factor-alpha mRNA levels in the prefrontal cortex, amygdala, hippocampus, or hypothalamus. Likewise, there were no stressor effects on transforming growth factor-beta1, neuropeptide Y, glycoprotein 130, or leptin receptor mRNAs in brain regions. Thus, the naturalistic/psychogenic stressor used does not affect any of the brain cytokine component mRNAs studied. It is suggested that this type of stressor activates homeostatic mechanisms (e.g., glucocorticoid release), which act to preclude brain cytokine alterations that would otherwise favor neuroinflammatory/neuroimmunological responses and the consequent increase of brain sensitivity to neurotoxic and neurodegenerative processes.

Analysis of Variance↗

5-HT1A receptor activation before acute stress counteracted the induced long-term behavioral effects.

The long-term behavioral consequences of acute immobilization (IMMO) in rats and the effects of 5-HT(1A) receptor activation (8-OH-DPAT: 0.3 mg/kg, sc) were studied. Corticosterone levels after IMMO with previous 8-OH-DPAT treatment were also studied. Twenty-four hours after IMMO (3 h), rats performed conditioned (passive avoidance) and unconditioned (escape behavior) anxiety tests in the elevated T maze. Pre-exposure to IMMO induces long-term behavioral changes in contrast with control rats. These behavioral alterations include an increase of anxiogenic responses, such as exploratory behavior and passive avoidance response. This effect was counteracted by 8-OH-DPAT pretreatment and reversed by WAY-100635 when administered before 8-OH-DPAT. Serum corticosterone levels increased during the first hour of stress and after 8-OH-DPAT administration. Our results support the hypothesis that involvement of acute stress is crucial in the anxiety-like behaviors and in the potentiation of fear. The activation of 5-HT(1A) receptors counteracted the long-term effects induced by IMMO.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Models of infantile malnutrition in rats: effects on maternal behavior.

The effects of 6 commonly used methods for producing malnutrition in suckling rats upon the behavior of their dams were examined. In these methods, (1) large litters were fostered on the dams; (2) dams were fed low-protein diets; (3) dams were fed an inadequate amount of a good quality diet; (4) pups were removed from the dams and kept with a nonlactating female for half of the day; (5) pups were removed from the dams and kept in an incubator for half of the day; or (6) some of th dams' teats were destroyed. Dams that were themselves food deprived showed a shift from resting to exploratory behaviors with some indication of increased attention to the pups compared to controls. Dams whose pups were starved but that were well fed themselves showed lower levels of resting and higher levels of attention to pups but no elevation in exploratory activity. Although the long-term significance of the behavioral changes of the dams is not known, the immediate effect was to minimize the impact of the experimenter's manipulations on the metabolic energy available to the pups for growth and development.

Animals↗

[Selection vector and ontogenetic development of behavior under domestication of wild Norway rats].

Hereditary variation in rates of ontogenetic formation of exploratory behavior, glucocorticoid functions, and neurotransmitter systems in wild Norway rats during selection for absence of defensive response towards humans (domestication) is demonstrated. Interrelated shifts in the development of behavior and neurohormonal systems are shown. A comparison of the data obtained with the results of domestication of another species-silver fox-suggests that equally vectorized selection of animals belonging to different taxa produces equally directed changes of their regulatory systems.

Aggression↗

Inbred Roman high- and low-avoidance rats: differences in anxiety, novelty-seeking, and shuttlebox behaviors.

In the present study, male inbred animals (from the 10th generation of an inbreeding program that has been carried out in parallel to that of the outbred Roman high- and low-avoidance rat lines), were compared for emotionality in different testing situations, exploratory behavior in the holeboard and two-way, active-avoidance acquisition. Compared to the inbred Roman high-avoidance (RHA-I/Verh) rats, inbred Roman low-avoidance (RLA-I-Verh) rats showed higher emotionality in the open field (reduced distance travelled and number of rearings, and increased self-grooming behavior), in the elevated plus-maze test (increased number of total and open-arm entries, reduced distance travelled in the open arms, and increased self-grooming behavior), and during the habituation period in the shuttle box (decreased number of crossings, increased self-grooming behavior and defecations). Results from the hyponeophagia test were not conclusive, probably due to the test-dependent hyperactivity shown by RHA-I/Verh rats. In the holeboard apparatus, RHA-I/Verh rats explored more than RLA-I/Verh rats, especially when novel objects were located beneath the holes. Finally, RHA-I/Verh animals rapidly acquired active, two-way (shuttlebox) avoidance, whereas RLA-I/Verh animals required four 50-trial sessions to achieve an assymptotic level of 30-40% avoidance. Thus, the behavioral patterns of the Roman inbred strains were very similar to those previously reported for the RHA/Verh outbred lines. Differences in locomotor activity, exploratory, and self-grooming behavior were actually greater between the inbred strains than between the outbred lines. Differences in defecation, however, although still significant, were not so pronounced as those noted previously at this laboratory with the outbred lines.

Animals↗

Chronic exposure to low doses bisphenol A interferes with pair-bonding and exploration in female Mongolian gerbils.

Estrogenic endocrine disruptors, synthetic or naturally occurring substances found in the environment, can interfere with the vertebrate endocrine system and, mimicking estrogens, interact with the neuroendocrine substrates of behavior. Since species vary in their sensitivity to steroids, it is of great interest to widen the range of species included in the researches on neurobehavioral effects of estrogenic endocrine disruptors. We examined socio-sexual and exploratory behavior of Mongolian gerbil females (Meriones unguiculatus), a monogamous rodent, in response to chronic exposure to the estrogenic endocrine disruptor bisphenol A. Paired females were daily administered with one of the following treatments: bisphenol A (2 or 20 microg/kg body weight/day); 17alpha-ethynil estradiol (0.04 microg/kg body weight/day 17alphaE); oil (vehicle). Females were treated for 3 weeks after pairing. Starting on day of pairing, social interactions within pairs were daily recorded. Three weeks after pairing, females were individually tested in a free exploratory paradigm. Bisphenol A and 17alphaE affected male-female social interactions by increasing social investigation. Bisphenol A reduced several exploratory parameters, indicating a decreased exploratory propensity of females. These results highlight the sensitivity of adult female gerbils to bisphenol A during the hormonally sensitive period of pair formation, also considering that the bisphenol A doses tested are well below the suggested human tolerable daily intake.

Analysis of Variance↗

delta 1-Tetrahydrocannabinol but not cannabidiol reduces contact and aggressive behavior of rats tested in dyadic encounters.

A low and a high dose of delta 1-tetrahydrocannabinol (delta 1-THC) and of cannabidiol (CBD) were IP injected in rats that had been isolated for 7 days. Forty-five minutes after injection, the rats were tested for social interactions with non-isolated, untreated test partners in dyadic encounters under standardized conditions. Different aspects of social behavior were analyzed. The high dose of delta 1-THC (10 mg/kg) prevented nearly all social interactions. The low dose of delta 1-THC (1 mg/kg) exerted selective and specific effects on social interactions. Social contact behavior, including crawl over/mounting, and social grooming, and aggressive behavior, including fighting, kicking, and biting, were markedly decreased, whereas social exploratory behavior (exploration of the partner and anogenital investigation) and the behavioral item, approach/follow, were hardly affected by delta 1-THC treatment. Both doses of CBD (2 and 20 mg/kg) failed to change the various aspects of social interaction. It is postulated that the effects of delta 1-THC on close and intimate contact behavior of rats may contribute to the understanding of marihuana taking in humans.

Aggression↗

Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice.

Dopamine-deficient (DD) mice cannot synthesize dopamine (DA) in dopaminergic neurons due to selective inactivation of the tyrosine hydroxylase gene in those neurons. These mice become hypoactive and hypophagic and die of starvation by 4 weeks of age. We used gene therapy to ascertain where DA replacement in the brain restores feeding and other behaviors in DD mice. Restoration of DA production within the caudate putamen restores feeding on regular chow and nest-building behavior, whereas restoration of DA production in the nucleus accumbens restores exploratory behavior. Replacement of DA to either region restores preference for sucrose or a palatable diet without fully rescuing coordination or initiation of movement. These data suggest that a fundamental difference exists between feeding for sustenance and the ability to prefer rewarding substances.

Adenoviridae↗