Spontaneous alternation and exploration in staggerer mutant mice

Staggerer mutant mice were found to be less active in terms of motor activity in a maze, hole poking and rearing. Staggerer mutant mice also showed a lack of spontaneous alternation in both 2-trial and 4-trial tests. A lack of spontaneous alternation in this mutant may be due to a deficit in response inhibition or in spatial orientation, similar to that of animals with limbic lesions.     

Mice lacking the adenosine A1 receptor are anxious and aggressive,but are normal learners with reduced muscle strength and survival rate

Behavioural assessment of mice lacking adenosine A1 receptors (A1Rs) showed reduced activity in some phases of the light-dark cycle, reduced exploratory behaviour in the open-field and in the hole-board, increased anxiety in the plus maze and dark-light box and increased aggressiveness in the resident-intruder test. No differences were found in spatial reference and working memory in several Morris water maze tasks. Both mutant mice had reduced muscle strength and survival rate. These results confirm the involvement of adenosine in motor activity, exploratory behaviour, anxiety and aggressiveness. A1Rs also appear to play a critical role in ageing-related deterioration.     

Behavior on the water maze platform: relationship to learning and open field exploration in aged and adult rats

In the present study we examined whether age-related deficits in the water maze could be accounted for by changes in the behavior on the platform, and whether platform behavior represents some form of exploration, akin to that seen in the open field. Twenty-seven aged and 8 adult rats (26 and 3 months old Wistar rats, respectively) were tested in an empty open field and spatial object exploration task, followed by 9 days of escape learning in a water maze. The aged as compared to the adults exhibited lower levels of open field activity and were deficient in the object displacement task. Escape deficits in the water maze and reduced activity levels on the platform were also found. In the aged, water maze performance was correlated with behavior on the platform, including quiescence, orienting-like activity and turning behavior, a form of axial rotation. In both age groups, turning behavior was also correlated with exploratory activity in the open field. In conclusion, the results support the hypothesis that age-related impairments in the water maze relate to changes in platform behavior, which, in turn, might reflect exploratory activity.     

Disruption of exploratory and habituation behavior in mice with mutation of DISC1: an ethologically based analysis

Disrupted-in-schizophrenia-1 (DISC1) is a gene that has been functionally linked with neurodevelopmental processes and structural plasticity in the brain. Clinical genetic investigations have implicated DISC1 as a genetic risk factor for schizophrenia and related psychoses. Studies using mutant mouse models of DISC1 gene function have demonstrated schizophrenia-related anatomical and behavioral endophenotypes. In the present study, ethologically based assessment of exploratory and habituation behavior in the open field was conducted in DISC1 (L100P), wild-type (WT), heterozygous (HET), and homozygous (HOM) mutant mice of both sexes. Ethological assessment was conducted in an open-field environment to explore specific topographies of murine exploratory behavior across the extended course of interaction from initial exploration through subsequent habituation (the ethogram). During initial exploration, HET and HOM DISC1 mutants evidenced increased levels of locomotion and rearing to wall compared with WT. A HOM-specific increase in total rearing and a HET-specific increase in sifting behavior and reduction in rearing seated were also observed. Over subsequent habituation, locomotion, sniffing, total rearing, rearing to wall, rearing free, and rearing seated were increased in HET and HOM mutants vs. WT. Overall, grooming was increased in HOM relative to other genotypes. HET mice displayed a selective decrease in habituation of sifting behavior. These data demonstrate impairment in both initial exploratory and habituation of exploration in a novel environment in mice with mutation of DISC1. This is discussed in the context of the functional role of the gene vis à vis a schizophrenia phenotype as well as the value of ethologically based approaches to behavioral phenotyping.     

Reduced hippocampal neurogenesis and skill reaching performance in adult Emx1 mutant mice

Mammalian homeobox gene Emx family is involved in the development of the rostral brain. Loss-of-function studies suggest that, despite the agenesis of corpus callosum, the Emx1 mutants display relatively modest defects compared to the Emx2 mutants. However, the role of the Emx1 in neurogenesis and brain function has never been explored. We used unbiased stereology to determine the number of proliferating progenitors and immature neurons in the adult neurogenic zones. Although previous studies have established that the formation of the dentate gyrus (DG) requires Emx2, we found that the adult Emx1 mutants also exhibited a smaller DG, reduced number of proliferating progenitor cells and immature neurons in the DG, in contrast to the indistinguishable level of neurogenesis in the subventricular zone when compared to the wild type mice. In view of the involvement of callosal projection neurons in mediating interhemispheric crosstalk and spatial coupling between the limbs, and the importance of DG in hippocampus-dependent function in learning and memory, we assessed motor and cognitive functions. Emx1 deletion impaired performance on a forelimb skill reaching task and attenuated training induced hippocampal neurogenesis, but it did not affect motor activity or basic motor function as evaluated in the open field, wire hanging and rotor rod tests. Unexpectedly, the adult Emx1 mutant mice did not exhibit impairment in spatial learning and memory in the Barnes maze test. Our data suggest that deletion of the Emx1 gene reduces hippocampal neurogenesis and affects higher motor function that requires extensive learning.     

Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1

Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a(-/-)) are characterized by deficient short- and long-term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a(-/-) mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic-like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of explorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O-maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a(-/-) mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a-dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavioral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a(-/-) mice bore no relation to the behavioral changes as observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed.     

Effects of subchronic methylphenidate hydrochloride administration on the locomotor and exploratory behavior of prepubertal mice

The increasing use of methylphenidate hydrochloride (MPH) in children led us to examine the effects of MPH administration in developing mice. Male CD-1 mice were administered MPH (40 mg/kg, subcutaneously) or saline daily from postnatal days 26-32. The mice were then tested from postnatal days 33-37 for locomotion and exploration in the open field, anxiety in the elevated plus maze, and learning in the Morris water maze. The results indicate that MPH-pretreated mice were more exploratory and less fearful in the open field, entering more center squares than saline controls. MPH-pretreated mice also exhibited less anxiety, spending more time in the open arm and exhibiting more head dips in the elevated plus maze than controls. There was no significant difference between MPH and saline-treated mice in the time taken to find the visible or hidden platform in the water maze task. The results indicate that treatment with MPH has significant effects on later behavior, reducing fear and anxiety, and increasing exploration, but no effect on performance in a spatial learning task.     

High and low rearing subgroups of rats selected in the open field differ in the activity of K+-stimulated p-nitrophenylphosphatase in the hippocampus

Na(+)/K(+)-adenosinetriphosphatase (Na(+)/K(+)-ATPase) is of paramount importance for the proper functioning of the organism. The enzyme is involved in several aspects of brain function, such as the repolarization of the neuronal membranes and neurotransmitters uptake/release. Therefore, individual differences in the activity of brain Na(+)/K(+)-ATPase may result in differences in the functioning of the brain, which, in consequence, could lead to behavioral divergences. Individual differences in rearing, an exploratory behavior, have been shown to be genetically determined. In rats, the inhibition of the activity of Na(+)/K(+)-ATPase was reported to induce changes in the exploratory behavior. The aim of this work was to verify if subgroups of rats selected according to the number of rearings (high and low rearing subgroups) in the open field test differ in the activity of Na(+)/K(+)-ATPase in brain regions. Adult, male outbred Wistar rats were selected in the open field test according to the number of rearings in subgroups of high (HR) and low (LR) rearing responders. After a rest of about 20 days after the open field session, HR and LR rats were sacrificed. In the first experiment, frontal cortex, striatum, brainstem, hippocampus and the amygdala (including the overlying limbic cortex) were dissected. The reaction of dephosphorylation of Na(+)/K(+)-ATPase (K(+) stimulated p-nitrophenylphosphatase) was assayed in homogenates rich in synaptosomes. The results obtained showed a statistically significant higher activity of K(+)p-nitrophenylphosphatase only in the hippocampus of HR subgroup of rats. This result was replicated in two other subsequent experiments with different HR and LR subgroups of rats selected at different times of the year. Our data suggest that the difference in the activity of Na(+)/K(+)-ATPase in the hippocampus is innate and is involved in the expression of the rearing behavior.     

Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice

After we could recently demonstrate a beneficial effect of environmental enrichment on AD-like brain pathology in female TgCRND8 mice [Ambrée O, Leimer U, Herring A, G?rtz N, Sachser N, Heneka MT, et al. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 2006;169:544-52] the present study focuses on the behavioural effects of environmental enrichment with special emphasis on learning and memory performance in this AD model. In the first experiment spontaneous exploration, locomotor activity and anxiety-related behaviour were assessed as the performance in learning tasks can be biased substantially by exploratory behavioural traits. In the second experiment spatial memory in the Barnes maze test and object recognition memory were examined. Regarding exploratory behaviour transgenic mice from standard housing condition were statistically indistinguishable from wild-type controls. Enrichment had comparable effects in both genotypes indicated by higher levels of exploration and locomotor activity. In transgenic mice the elevated plus-maze revealed less anxiety-related behaviour due to enrichment in contrast to wild-type mice that statistically did not differ in anxiety-related behaviour. Concerning learning and memory performance, cognitive deficits of standard housed transgenic mice could be demonstrated in both learning tasks. Surprisingly, in both housing conditions a significantly higher number of transgenic mice refused to explore any objects compared to wild-type mice. Furthermore, the Barnes maze test revealed deficits of the transgenic mice in spatial memory compared to wild-type mice whereas no effect of environmental enrichment was detectable. Thus environmental enrichment increased exploratory behaviour and decreased anxiety-related behaviour but could not clearly ameliorate deficits in learning and memory performance of TgCRND8 mice.     

Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation

Alpha-synuclein was implicated in Parkinson's disease when missense mutations in the alpha-synuclein gene were found in autosomal dominant Parkinson's disease and alpha-synuclein was shown to be a major constituent of protein aggregates in sporadic Parkinson's disease and other synucleinopathies. We have generated transgenic mice expressing A53T mutant and wild-type human alpha-synuclein. The mutant transgenic protein was distributed abnormally to the axons, perikarya, and dendrites of neurons in many brain areas. In electron microscopic immunogold studies, no aggregation of alpha-synuclein was found in these mice. However, behavior analysis showed a progressive reduction of spontaneous vertical motor activity in both mutant lines correlating with the dosage of overexpression. In addition, deficits of grip strength, rotarod performance, and gait were observed in homozygous PrPmtB mice. Transgenic animals expressing mutant alpha-synuclein may be a valuable model to assess specific aspects of the pathogenesis of synucleinopathies.     

Proestrous compared to diestrous wildtype, but not estrogen receptor beta knockout, mice have better performance in the spontaneous alternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus and mirror maze

17beta-Estradiol (E(2)) may influence cognitive and/or affective behavior in part via the beta isoform of the estrogen receptor (ERbeta). Endocrine status and behavior in cognitive (object recognition, T-maze), anxiety (open field, elevated plus maze, mirror maze, emergence), and motor/coordination (rotarod, activity chamber) tasks of proestrous and diestrous wildtype (WT) and ERbeta knockout (betaERKO) mice was examined. Proestrous (WT or betaERKO), versus diestrous, mice had higher E(2) and progestin levels in plasma, hippocampus, and cortex. The only effect of genotype on hormone levels was for corticosterone, such that betaERKO mice had higher concentrations of corticosterone than did WT mice. Proestrous WT, but not betaERKO, mice had improved performance in the object recognition (greater percentage of time with novel object) and T-maze tasks (greater percentage of spontaneous alternations) and less anxiety-like behavior in the plus maze (increased duration on open arms) and mirror chamber task (increased duration in mirror) than did diestrous mice. This pattern was not seen in the rotarod, open field, or activity monitor, suggesting effects may be specific to affective and cognitive behavior, rather than motor behavior/coordination. Thus, enhanced performance in cognitive tasks and anti-anxiety-like behavior of proestrous mice may require actions of ERbeta in the hippocampus and/or cortex.     

Early social enrichment augments adult hippocampal BDNF levels and survival of BrdU-positive cells while increasing anxiety- and "depression"-like behavior

Early experiences affect brain function and behavior at adulthood. Being reared in a communal nest (CN), consisting of a single nest where three mothers keep their pups together and share care-giving behavior from birth to weaning (postnatal day [PND] 25), provides an highly socially stimulating environment to the developing pup. Communal nest characterizes the natural ecologic niche of many rodent species including the mouse. At adulthood, CN reared mice, compared to mice reared in standard nesting laboratory condition (SN), show an increase in BDNF protein levels and longer survival of BrdU-positive cells in the hippocampus. Open field and elevated plus maze results indicate that CN mice, although showing levels of exploratory and locomotor activity similar to those of SN mice, displayed increased anxiety-like behavior, performing more thigmotaxis in the open field and spending less time in the open arms of the plus maze. Furthermore, CN mice displayed higher levels of immobility behavior in the forced swim test. Overall, these findings show that CN, an highly stimulating early social environment, increases adult neuronal plasticity, as suggested by high BDNF levels and augmented number of newly generated cells in the hippocampus, which is associated to an increased anxiety- and "depression"-like behavior. These findings are discussed in the framework of the neurotrophin hypothesis of depression.     

Reduced locomotion in the serum and glucocorticoid inducible kinase 3 knock out mouse

The serum and glucocorticoid inducible kinase isoform SGK3 is expressed in the brain including hippocampal neurons. It is activated by phosphoinositide-3 (PI3) kinase and thus a putative target of neurotrophic factors. In vitro experiments pointed to the ability of SGK3 to regulate several transporters and ion channels including the AMPA receptor GluR1. In order to explore the in vivo functional significance of SGK3 in the regulation of spatial learning and exploratory behavior, we assessed the performance of SGK3 knockout mice (SGK3-/-) and their wild type littermates (SGK3+/+) in a place navigation task in the water-maze, radial maze in a battery of forced and free exploration tests, acoustic startle and a test for motoric coordination. According to water-maze and radial maze testing reference and working memory was intact in SGK3-/- mice. However, detailed analysis of swimming patterns of SGK3-/- mice in the water-maze revealed a deficit in precision and goal-directed navigation in space. SGK3-/- mice showed reduced exploratory activity, which was observed in several environments and increased centre field avoidance in the open-field. SGK3-/- mice further showed reduced darting behavior on open surfaces, indicating that the knock out may modify basic patterns of locomotion. In conclusion, lack of SGK3 leads to subtle behavioral defects which may result from deranged neuronal regulation of transporters and ion channels.     

Inhibition of fatty acid amide hydrolase by chlorpyrifos in juvenile rats results in altered exploratory and social behavior as adolescents

The organophosphorus insecticide chlorpyrifos (CPF) is suspected to cause developmental neurotoxicity in children leading to long term effects. Developmental exposure of rat pups to CPF at low levels disrupts degradation of the brain endocannabinoids through the inhibition of fatty acid amide hydrolase (FAAH) and decreases the reactivity of juvenile rats in an emergence test. In this study, we further investigated the effects of developmental CPF exposure on behavior but also included exposure to PF-04457845, a specific inhibitor of FAAH, for comparison of behavior altered by FAAH inhibition with behavior altered by CPF. Ten day old rat pups were exposed orally either to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 daily for 7 days. In an open field (day 23), the high CPF and PF-04457845 groups exhibited increased motor activity but no differences in the time spent in the field’s center. In an elevated plus maze (day 29), all treatment groups had increased open arm activity but ethological behaviors associated with anxiety were not altered. Behaviors in the maze associated with increased general activity and exploratory drive were increased. Social interactions (day 36) were measured and all treatment groups exhibited increased levels of play behavior. The similarities in behavior between PF-04457845 and CPF suggest that enhanced endocannabinoid signaling during the exposure period plays a role in the persistent alteration of behavior observed following developmental CPF exposure.     

Repeated imipramine enhances sensitivity of the brain dopaminergic system related to exploratory behavior

Summary The influence of imipramine treatment on apomorphine-induced behavior was studied. Imipramine was administered twice a day for 14 days at 10 mg/kg. The control group received a single dose of imipramine. Both groups were tested at 48 hours after imipramine administration, using open field; the number of line crossings and episodes of rearing and looking into holes were counted as part of the exploratory behavior. Repeated, but not single, administration of imipramine increased the exploratory activity induced by apomorphine injection an effect which was blocked by haloperidol pretreatment. The results indicate that repeated imipramine administration enhances the sensitivity of brain dopamine receptors related to exploratory behavior.     

Role of lateral habenula in the regulation of exploratory behavior and its relationship to stress in rats

The lateral habenula is a major station conveying information between the limbic forebrain and midbrain. Bilateral lesions of the lateral habenula were found to increase exploratory behavior, including locomotor activity, rearing and hole-poke responses in rats. These effects were not due to an augmentation of general motor function, since the animal's performance on the Rota-rod treadmill was not significantly changed by the same manipulation. Lateral habenular lesion was also found to potentiate the effects of footshock stress on exploratory behavior in an open field. It is suggested that the lateral habenula probably plays an inhibitory role in the expression of certain emotion-related behaviors under normal and stressful situations.     

Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat protein gp120

Transgenic mice expressing HIV-1 coat glycoprotein gp120 in brain glial cells were previously shown to display AIDS dementia-like neuropathological changes and reduced hippocampal long-term potentiation. In this report, neuromotor and cognitive performance in 3- and 12-month-old gp120-expressing mice was compared with wildtype controls. Rotarod and cage activity measures showed no significant differences between transgenic animals and controls of either age. Open field activity was slightly altered in 12-month-old gp120 animals (reduced corner crossings and dwell in centre), but not in the 3-month-olds. Cognitive assessment using the Morris water maze showed unimpaired performance in 3-month-old mice during acquisition and (no-platform) probe trials. In 12-month-old gp120 animals, escape latency and swimming velocity during the acquisition trials were significantly reduced, but performance improved at roughly the same rate as in control animals. However, the probe trials revealed a highly significant reduction in spatial retention in transgenic mice of this age. This demonstration of age-dependent impairments in open field activity and spatial reference memory may relate to cognitive and neuromotor deficits seen in a proportion of HIV-1-infected individuals.     

Effects of systemic injections of dopaminergic agents on the habituation of rats submitted to an open field test

Many studies have reported that systemic injections of dopaminergic drugs result in profound changes in the behavior of animals in the open field. At the same time, it is hypothesized that increased brain dopaminergic activity prevents animals from habituating to a novel environment, and this effect would be responsible for the conditioned hyperactivity observed when rats are tested later in a drug-free state. However, little is known on the concurrent effects of these drugs, on learning processes and motor activity. To examine this issue, in the present study we assessed the effects of injections of the dopamine (DA) agonists amphetamine and apomorphine, the receptor antagonist chlorpromazine and the atypical neuroleptic clozapine on exploratory activity and habituation in rats exposed to the open field test. The observer scored the occurrence of animal behavior during three postinjection observation periods (0-5, 5-10 and 10-15 min). The results confirmed that amphetamine and apomorphine lead to a dose-dependent behavioral activation, while chlorpromazine produces an opposite effect, extending previous accounts of behavior of systemic-injected rats with these drugs. Independent of the level of motor activity, higher or lower than the control groups, habituation still occurs following DA agonists (amphetamine and apomorphine) and antagonist (chlorpromazine) injections in rats submitted to the open field test. Furthermore, the reduction of the exploratory activity over time in the open field after clozapine was less pronounced than in controls, in contrast to classical DA agents. The present results suggest that activation of DA mechanisms is involved in species-typical behaviors associated with exploratory behavior, but does not seem to be involved in non-associative learning processes, such as habituation. These effects could not be attributed to the decline in brain levels of the drugs during the session, as the behavioral activation remained high in rats previously habituated and injected with dopaminergic agonists within the same protocol. On the other hand, the atypical DA blocker clozapine reduced the expression of habituation, opening the possibility of involvement of alternative mechanisms, such as 5-HT mechanisms, in this non-associative learning process.     

Emotional behavior and expression patterns of tyrosine hydroxylase and tryptophan hydroxylase in senescence-accelerated mouse (SAM) P6 mice

Senescence-accelerated prone mouse 6 (SAMP6) is a model for senile osteoporosis. It was recently reported that SAMP6 has a memory deficit in the water maze test. Because emotion and cognition are thought to interact, in the present study to examine emotional behavior in SAMP6, we employed a battery of tasks (open field, elevated plus maze, light-dark exploration, marble-burying behavior, tail suspension), using three age groups (1, 4, and 8 months of age) of SAMP6 mice and age-matched control SAMR1 (senescence-accelerated resistant mouse 1) mice. All three age groups of SAMP6 showed higher activity than SAMR1 in the open field test and reduced anxiety as measured in terms of time spent on the open arms in the elevated plus maze, time spent in the light box in the light-dark exploration, and time spent in marble-burying behavior in the marble-burying test. All three age groups of SAMP6 showed reduced immobility time compared with SAMR1 in the tail suspension test. Western blot analyses showed increased expression levels of tyrosine hydroxylase phosphorylated at serine-40 in striatum and nucleus accumbens and of tryptophan hydroxylase phosphorylated at serine-58 in brain stem of 1-month-old SAMP6. These results suggest that one possible reason for the alterations of motor activity and emotional behavior of SAMP6, at least after 1 month of age, is increased dopamine and serotonin levels.