Interaction with stressed mothers affects corticosterone levels in pups after reunion and impairs the response to dexamethasone in adult mice.

BACKGROUND: Early adverse experiences are preeminent factors for the development of affective disorders. In the present study, we analyzed the effects of different postnatal manipulations applied either on the mother or on the offspring in mice. Maternal behavior and adrenocortical activity of both mothers and offspring at the end of postnatal stress and at adulthood were considered. METHODS: From postnatal day (PND) 1 to 14 mice underwent 15min of: (a) brief (15min) pups' exposure to clean bedding (CB: clean bedding), (b) mothers' exposure to the odor of a novel male (SM: stressed mother) or (c) mothers' exposure to a clean cage (CSM: control stressed mother), and (d) standard rearing (N-H: non-handled). The behavior of mouse dams during and after stress sessions was analyzed. Serum corticosterone of mothers and pups at the end of the stress session and 30min after reunion was assessed on PND 14. Moreover, anxiety levels and HPA-axis inhibitory feedback in response to dexamethasone administration were evaluated in adult male offspring. RESULTS: Overall, during the 14 days of treatment CB mothers when reunited with their pups showed higher maternal behavior than other dams. After the last stress (PND 14) SM and CSM maternal corticosterone levels increased as well as those of CB pups. While 30min of mother-infant interaction restored baseline corticosterone levels in SM and CSM mothers and in CB pups, SM and CSM offspring showed a decrease of corticosterone under baseline levels. At adulthood, SM and CSM males did not show the suppressive hormonal response to dexamethasone treatment. Moreover, adult CB and SM male mice displayed decreased anxiety in the open field. CONCLUSIONS: Maternal psychosocial stress during lactation seems to permanently affect the offspring's HPA functioning. These effects may be dissociated from the behavioral response as suggested by the decrease of anxiety in SM and CB adult mice.

Chronic administration of olanzapine affects Behavioral Satiety Sequence and feeding behavior in female mice.

The aim of the study was to assess the effects of chronic olanzapine (Ola) administration on feeding behavior. Although atypical antipsychotics (AAPs) have greatly improved the management of schizophrenia and extrapyramidal symptoms, substantial bodies of literature point out that most of these agents are highly related to a major risk of metabolic drawbacks, leading to dyslipidemia and obesity. Among these compounds, Ola is one of the more weight gain-inducing AAPs. In the present study, we analyzed the Behavioral Satiety Sequence (BSS) in female mice given a palatable diet (wet mash) and chronically administered Ola (0.75, 1.5, 3 mg/kg per os) for 36 days. The results showed that administration of the highest dose of Ola postponed the onset of satiation, as suggested by the rightward shift of the BSS. This effect was confirmed by an increase in the actual food intake by the Ola (3 mg/kg) mice. These results suggest that one of the possible mechanisms involved in AAPinduced weight gain is alteration of the hunger-satiety regulation in female mice. These findings are consistent with the hypothesis that enhanced food intake and diminished central sensitivity to satiation signaling may cooperate in promoting weight gain and metabolic dysregulation in rodents and patients taking antipsychotic medications.

Pain sensitivity in mice lacking the Ca(v)2.1alpha1 subunit of P/Q-type Ca2+ channels.

The role of voltage-gated Ca(2+) (Ca(V)) channels in pain mechanisms has been the object of intense investigation using pharmacological approaches and, more recently, using mutant mouse models lacking the Ca(V)alpha(l) pore-forming subunit of N-, R- and T-type channels. The role of P/Q-type channels in nociception and pain transmission has been investigated by pharmacological approaches but remains to be fully elucidated. To address this issue, we have analyzed pain-related behavioral responses of null mutant mice for the Ca(V)2.1alpha(1) subunit of P/Q-type channels. Homozygous null mutant Ca(V)2.1alpha(1)-/- mice developed dystonia at 10-12 days after birth and did not survive past weaning. Tested at ages where motor deficit was either absent or very mild, Ca(V)2.1alpha(1)-/- mice showed reduced tail withdrawal latencies in the tail-flick test and reduced abdominal writhes in the acetic acid writhing test. Adult heterozygous Ca(V)2.1alpha(1)+/- mice did not show motor deficits in the rotarod and activity cage tests and did not show alterations in pain responses in the tail-flick test and the acetic acid writhing test. Strikingly, they showed a reduced licking response during the second phase of formalin-induced inflammatory pain and a reduced mechanical allodynia in the chronic constriction injury model of neuropathic pain. Our findings show that P/Q-type channels play an antinociceptive role in sensitivity to non-injurious noxious thermal stimuli and a pronociceptive role in inflammatory and neuropathic pain states, pointing to an important role of Ca(V)2.1 channels in central sensitization.

Psychosocial stress affects energy balance in mice: modulation by social status.

Stress has been associated with changes in eating behaviour and food preferences. Moreover, psychosocial and socio-economical challenges have been related with neuroendocrine-autonomic dysregulation followed by visceral obesity and associated risk factors for disease. In the current study, we provide a model of body weight development, food intake, energy expenditure of subordinate and dominant mice under psychosocial stress either in the presence of a standard diet or of a high palatable diet. When only standard chow was available stressed animals consumed more food in comparison to the control counterpart. Moreover, subordinate mice, at the end of the stress period were heavier in comparison to dominant animals. This last result was due to a decrease in the caloric efficiency of dominant animals in comparison to subordinates. Confirming this, the results of the experiment 2 showed that dominant mice significantly increase their energy expenditure at the end of the chronic psychosocial stress procedure in comparison to subordinate mice, as measured by indirect calorimetry. When a palatable high fat diet was available subordinate animals became heavier in comparison with both dominant and control animals. No differences in the caloric intake were found between groups. Subordinate mice ingested more calories from fat than controls, while dominant animals ingested more calories from carbohydrates. These results suggest that psychosocial stress can be a risk factor for overeating and weight gain in mice. However, social status influences the extent to which an individual keeps up with adverse environment, influencing the vulnerability toward stress related disorders.

Paw preference and brain dopamine asymmetries.

The hemispheric content of dopamine and its metabolites in the frontal cortex, caudatus putamen and nucleus accumbens septi was evaluated in relation to behavioral lateralization assessed by paw preference. Three groups of C3H/He mice were selected on the basis of their performance in the paw preference test (left-handed, ambidextrous and right-handed) and levels of dopamine and its metabolites were measured in the two hemispheres of each group. Mice showed significant differences in hemispheric content of dopamine and 3-4 dihydroxyphenylacetic acid in the nucleus accumbens septi depending on the behavioral lateralization as expressed by paw preference. The hemispheric dominance (right hemisphere/right hemisphere + left hemisphere content of dopamine and metabolites x 100) was also calculated for each mouse. Significant differences in hemispheric dominance for dopamine, 3-4 dihydroxyphenylacetic acid and 3-methoxytyramine in the nucleus accumbens were found between right-handed and left-handed mice. This dominance was ipsilateral to the preferred paw: % right hemisphere/total content of dopamine and its metabolites were lowest in left-handed, highest in right-handed and intermediate in ambidextrous mice. Finally, individual % right hemisphere/total content for dopamine, 3-4 dihydroxyphenylacetic acid and 3-methoxytyramine in the nucleus accumbens positively correlated with individual paw preference scores. The analysis of the other brain areas did not reveal any significant effect. These results suggest a strong relationship between mesoaccumbens dopamine asymmetries and both the direction and the intensity of behavioral lateralization as expressed by paw preference in mice.

Ultrasonic vocalizations as an index of social memory in female mice.

Ultrasonic vocalization (UV) as a measure of social memory was investigated in female mice. UVs emitted by a resident female in the presence of a same-sex partner were measured during a 3-min, pretest social interaction. In a second 3-min test session, mice were reexposed to the familiar partner or presented with a novel partner. In the first case, there was a decline in UVs emitted by resident mice when the intervals between the 2 sessions were 15, 30, or 60 min. After 24 hr, this effect disappeared. In contrast, with a novel female partner, the number of UVs remained unchanged. Scopolamine (0.05 mg/kg ip) disrupted this memory process: Drug-treated females did not show the expected decrease in UVs when reexposed to the familiar female after 30 min. This study provides behavioral and pharmacological evidence that ultrasonic calls can be used as a measure of social memory in female mice.

Male olfactory cues affect mothers' behavior in mice: effects of benzodiazepines.

RATIONALE: Threatening social stimuli were used in this study as aversive conditions to test anxiety in lactating female mice. The odors of potential infanticidal males or the "stress odor" left by restrained mice represented two aversive conditions that have been suggested to modulate the time spent by the mothers to reach their pups after 30 min of separation. OBJECTIVES: The effects of drugs acting at the benzodiazepine receptors were evaluated on the behavior of mothers exposed to different threatening social cues. METHODS: Lactating mice of the NMRI outbred strain with 8-day old pups were treated with (1) chlordiazepoxide (CDP) 2.5, 5.0 and 10 mg/kg i.p.; (2) flumazenil 10 mg/kg i.p. and (3) methyl beta-carboline-3-carboxylate (beta-CCM) 3.0 mg/kg i.p. RESULTS: The odors left by stressed females changed the mothers' exploratory behavior, but not the latency to reach pups. The latency was higher in the presence of cues from potentially infanticidal males. CDP (5.0 mg/kg) reduced the time spent to contact pups, whereas the other CDP doses did not modify the dam's behavior. Flumazenil, given in combination with CDP (5.0 mg/kg) antagonized the latter anxiolytic effect. In addition, in the presence of cues from potentially infanticidal males beta-CCM had anxiogenic activity, increasing latency to reach pups. The same CDP and beta-CCM doses were ineffective in the presence of cues from stressed females and in the absence of olfactory cues from conspecifics. CONCLUSIONS: This study provides behavioral and pharmacological validation of a new model of anxiety specifically designed for lactating females.

Behavioral and mesocorticolimbic dopamine responses to non aggressive social interactions depend on previous social experiences and on the opponent's sex.

In these experiments we evaluated the relationship between behavioral and brain dopamine (DA) responses to social interactions. Subjects were group housed male mice confronted with a non aggressive male or female conspecific following either repeated defeat (defeated) or repeated non aggressive experiences (social). Defeated mice showed more defensive/submissive reactions then mice of the social group regardless of the opponent sex. However, mice defeated by females showed reduced social exploration without significant differences in non social exploration whilst the opposite was true for mice defeated by male opponents. Non aggressive social interactions enhanced dopamine metabolism in the prefrontal cortex (pFC) of DEFEATED mice regardless of opponent sex. However, only mice defeated by females showed enhanced dopamine metabolism and release in the nucleus accumbens septi (NAS) and olfactory tubercle (OT) following interaction with the non aggressive opponent. Finally, correlation between central and behavioral responses evidenced that 3,4-dihydroxiphenilacetic acid levels in the pFC were positively correlated with defensive behaviors and negatively correlated with non social exploration in mice confronted with male opponents but not in those confronted with females. The latter, showed a significant positive correlation between 3-methoxytyramine (3-MT) levels in the OT and defensive responses and significant negative correlation between social investigation and 3-MT levels in the OT and in the NAS. These results indicate a strict relationship between mesocorticolimbic dopamine transmission and behavior responses to social cues. Moreover, they strongly support the view that mesocorticolimbic DA modulates social behavior by affecting perceptive processing.

Effects of postnatal stress on dopamine mesolimbic system responses to aversive experiences in adult life.

The effects of postnatal stress on mesolimbic dopamine (DA) functioning in 90-day-old mice were investigated. Postnatal stress consisted of 15 min daily exposure to clean bedding (CB) in the absence of the mother for the first two weeks of life. Controls were daily exposed to home cage bedding (HCB) in the absence of the mother. A single brief (5-10 min) exposure to restraint produced a clear-cut increase in DA metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT)) in the nucleus accumbens septi (NAS) of adult HCB but not CB mice. Moreover, when tested in an elevated plus maze, CB mice showed more exploration and reduced fearfulness in comparison with HCB mice. Taken together, these results indicate reduced emotional reactivity in adult mice repeatedly stressed during postnatal development. Moreover, HCB mice but not CB mice showed altered behavioral responsiveness to apomorphine following repeated restraint stress (10 daily 120 min) in adult life, although no difference in the behavioral response to either a low or a high dose of apomorphine was observed in adult unstressed mice of the CB and HCB groups. These results indicate that the effects of early experiences on brain DA functioning may not be evident in basal conditions and be revealed only under environmental pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-related effects of stress on cholinergic sensitivity.

The effect of the administration of the muscarinic cholinergic agonist oxotremorine on locomotor activity was investigated in DBA/2 mice subjected to chronic restraint stress of different durations (120 min daily for 10, 14 or 18 days). Oxotremorine induced a depressant effect on locomotion, which was reduced after 10 and 14 days of restraint, but not after a 18-day restraint stress. Acetylcholine (ACh) content was significantly reduced in prefrontal cortex after 10 and 14 days of stress but returned to control values after 18 days of restraint. No changes in ACh content were observed in nucleus accumbens and striatum. These results are discussed in terms of possible changes in muscarinic receptor sensitivity.

Effects of postnatal manipulation on nociception and morphine sensitivity in adult mice.

The long-term effects of postnatal manipulation on nociception were studied in NMRI albino male mice. During the first two weeks of life, pups were removed from their cage and deprived of maternal/nest odour for 15 min/day. To evaluate pain sensitivity, adult mice exposed to this postnatal manipulation (CB group) were tail flick and formalin tested for acute and tonic pain, respectively. CB mice showed a reduced pain sensitivity both in tail-flick and in formalin tests in comparison with control animals. Moreover, responsiveness to morphine (MO 1.0, 2.5, and 5.0 mg/kg, i.p.) in young (35 days old) and adult (90 days old) postnatally manipulated animals was evaluated with the tail-flick test: a decrease of the antinociceptive effects induced by morphine both in young and adult males was observed in postnatally manipulated animals. Morphine induced significant analgesic effects in control mice at doses lower than those affecting nociceptive thresholds both in young and adult CB mice. In addition, young animals showed a higher sensitivity to morphine than adults, independently of postnatal manipulation. The long-term effects of postnatal manipulation on nociception are discussed in terms of involvement of the opioid system and of the characteristics of pup manipulation.

Neurobiological and behavioral aspects of recognition in female mice.

Female mice were tested for their capability to recognize female littermates in adulthood. Sibling females did not show any of the behavioral indices of recognition reported in the literature for sibling males during a 2-h social interaction. Conversely, adult females that experienced 7 days of separation from unrelated cagemates were able to recognize each other: during reunion, they showed reduced olfactory exploration, higher levels of affiliative behavior, and changes in nociception that were opioid dependent. Familiar females treated with naloxone (5.0 mg/kg, i.p.) did not show the increase in tail-flick latency that characterized saline-treated familiar pairs. Unfamiliar females did not show any behavioral modifications during social interaction. These data stress the role of familiarity in female-female social interaction and suggest that more recent experiences conceal earlier information gained before weaning. The importance of familiarity in females was found to be in contrast with the relevance of genetic recognition in male mice, but was well adapted to male and female roles within the social structure of mouse populations.

A model of social stress in dominant mice: effects on sociosexual behaviour.

The possibility of socially stressing the dominant/aggressive member of a pair of male mice is tested. Male mice (NMRI outbreed strain) were housed in pairs to assess dominant and subordinate roles by agonistic interactions and urine-marking test. Social stress for dominant males consisted in 30 min/day of exposure to their subordinate partner interacting with a female in the adjacent compartment of the cage, for 9 days. Results showed that dominance status was maintained. Behavioural observations indicated that neither the subordinates nor the dominant males habituated to this experimental procedure. At the end of the chronic stress, dominant animals were given the opportunity to interact for 30 min with a female in their compartment. Results indicated that stressed dominants showed impairment in their sexual behaviour and were more oriented towards the physical environment in comparison with control dominants. The behavioural response to apomorphine (0.25 mg/kg) indicated an alteration of the dopaminergic functioning in socially stressed dominant mice. This study suggests that the characteristics of the stressor and the effects of the chronic social stress could be different, according to male social status.

Enhancement of radial maze performances in CD1 mice after prenatal exposure to oxiracetam: possible role of sustained investigative responses developed during ontogeny.

A longitudinal study aimed at analyzing the behavioral effects of prenatal exposure to the nootropic compound oxiracetam was carried out in CD1 mice. Two groups of females were injected either with oxiracetam or saline from the beginning of pregnancy until parturition. Examination of pups from birth until the first month of age revealed no-influence of the treatment on litter size, body weights, sensory motor reflexes and motility. When placed in the open field at one month of age, mice born by mothers exposed to oxiracetam displayed more self grooming and spent less time in freezing than control mice. Prenatally treated mice were then found more interactive with their environment since the introduction of a novel object in the open field was followed by increased ambulation and higher sniffing object and rearing object scores. At three months of age, mice from both groups were tested in a radial six-arm maze task. Choice accuracy was significantly higher in prenatally treated mice which also tended to optimize their exploratory sequences by frequently running the maze in a clock-wise fashion. These results suggest that the better learning performances observed in the experimental group could be viewed as a consequence of an enhanced cognitive development based upon the higher rate of interactions with the environment shown by prenatally treated mice during ontogeny.

Anxiety and maternal aggression in house mice (Mus musculus): a look at interindividual variability.

The hypotheses were tested that mouse motherhood is accompanied by decreased reactivity to aversive stimuli and that female anxiety is inversely related to the probability of displaying intense forms of postpartum aggression. Outbred Swiss female mice were tested for anxiety in a light/dark choice test when virgin, pregnant, or lactating, and then tested for maternal aggression (5-min exposure to a male intruder) on postpartum Day 7. Anxiety declined in pregnant and lactating females when compared with virgin animals. Furthermore, females who displayed higher scores of postpartum fighting were less anxious in the previous test regardless of reproductive stage. Part of interindividual variability in postpartum aggression might thus be related to differences in the extent to which individuals perceive and react to anxiogenic situations. In addition, the higher emotionality characterizing the C57BL/6 and DBA/2 inbred strains may be responsible for the lack of a clear-cut exhibition of maternal aggression in these two strains.

Behavioral effects of morphine in mice: role of experimental housing.

Behavioral effects of morphine were assessed in isolated-timid Swiss mice, and were compared with those observed following morphine administration in nonaggressive-grouped subjects. For this purpose saline- and morphine- (0.5, 1.0, 2.5, and 5.0 mg/kg, IP) injected isolated-timid and nonaggressive-grouped mice interacting with a social partner were observed during a 4-min test. Three main points emerged from the results: a) in basal conditions, compared with social mice, in timid mice the offensive ambivalent behaviors were significantly less pronounced, while the defensive ambivalent behaviors (and all flight behaviors) were significantly more evident; b) 2.5 mg/kg of morphine increased offensive and decreased defensive ambivalent behaviors in timid mice; c) in social mice morphine (2.5 mg/kg) treatment increased defensive ambivalent behaviors and time spent in crouch. The results, which show that the behavioral effects of morphine depend on the state of the individual, are interpreted on the basis of the antiemotional properties of this opiate.

Role of anxiety in subordinate male mice sexual behavior.

Dominant and subordinate male mice behave differently when exposed to a female, with subordinates showing impairment of their sexual performance in the presence of the male antagonist. In the present study, we investigate whether these rank-related behavioral differences can be modified by an anxiolytic treatment. In a first experiment, diazepam (0.25 mg/kg) improves the performance of subordinate mice toward the female, as shown by the increase of proxemic behavior, anogenital sniffing, and social grooming of the female. Social grooming of the female is the only behavior modified by a higher dose of the anxiolytic drug (0.5 mg/kg). A second experiment, in which dominant and isolated mice are subjected to the same experimental procedure, demonstrates that social behavior of these two classes of males is not affected by the pharmacological treatment. The results are discussed in terms of the advantages of using subordinate males in such a sexual context as a model for the study of anxiolytic drugs.

Brief report: Newborn adoption in a confined group of Japanese macaques.

In a group of Japanese macaques, a multiparous high-ranking female gave birth to an infant and, two days later, adopted a neonate abandoned right after birth by a primiparous low-ranking female. Both infants were reared successfully. Whereas the "selfish" explanation does not accord with the evidence from the present case, the "altruistic" explanation cannot be discarded definitively. However, the context and the consequences of the adoption suggest reproductive error on the part of the adoptive mother as the most likely explanation.

Time budgets and behavioural synchronization in aggregated and isolated male and female mice.

Albino mice (Mus musculus ), initially housed in single sex groups and, subsequently, in social isolation, were used in this study to analyze the influence of social companions on the amount and on the distribution throughout the day of several behaviours. An observational recording technique was employed to record behaviour during the dark phase of the day. Behavioural sex differences in grouped mice were observed in four out of six behavioural categories. Females generally proved to be more active than males. Furthermore, prolonged social housing conditions resulted in an increase in male social interactions, in concomitance with changes in their time budgets. Conversely, females showed a decrease over time in social interactions with only slight effects on their time budget. Isolation seemed to increase slightly both male and female activity levels. Subjects housed together generally showed significantly similar Rest, Feed and General Activity patterns throughout the dark phase of the day. By contrast, the averaged patterns of different groups generally proved to be dissimilar in grouped females, but not in grouped males. When isolated, mice showed a distribution of their activities throughout the day different from what they had displayed under social conditions. These data indicate that social environment has an effect on the individual activity profiles which results in a definite synchronization within female groups and in a tendency towards desynchronization within male groups.

Monogenic mouse models of social dysfunction: implications for autism.

Autism is a pervasive disorder characterized by a complex symptomatology, based principally on social dysfunction. The disorder has a highly complex, largely genetic etiology, involving an impressive variety of genes, the precise contributions of which still remain to be determined. For this reason, a reductionist approach to the study of autism has been proposed, employing monogenic animal models of social dysfunction, either by targeting a candidate gene, or by mimicking a single-gene disorder characterized by autistic symptoms. In the present review, we discuss this monogenic approach by comparing examples of each strategy: the mu opioid receptor knock-out (KO) mouse line, which targets the opioid system (known to be involved in the control of social behaviors); and the Fmr1-KO mouse, a model for Fragile X syndrome (a neurodevelopmental syndrome that includes autistic symptoms). The autistic-relevant behavioral phenotypes of the mu-opioid and Fmr1-KO mouse lines are described here, summarizing previous work by our research group and others, but also providing novel experimental evidence. Relevant factors influencing the validity of the two models, such as sex differences and age at testing, are also addressed, permitting an extensive evaluation of the advantages and limits of monogenic mouse models for autism.