Knockout mice in understanding the mechanism of action of lithium.

Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium-myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, IMPase activity was found to be decreased; however, inositol levels were not found to be altered. Behavioural analysis indicated decreased immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviours robustly induced by lithium. In homozygous Smit1-knockout mice, free inositol levels were decreased in the frontal cortex and hippocampus. These animals behave like lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced-swim test model of depression. In contrast with O'Brien et al. [O'Brien, Harper, Jove, Woodgett, Maretto, Piccolo and Klein (2004) J. Neurosci. 24, 6791-6798], we could not confirm that heterozygous Gsk3b (glycogen synthase kinase 3beta)-knockout mice exhibit decreased immobility in the Porsolt forced-swim test or decreased amphetamine-induced hyperactivity in a manner mimicking lithium's behavioural effects. These data support the role of inositol-related processes rather than GSK3beta in the mechanism of the therapeutic action of lithium.

The reward system and maternal behavior in an animal model of depression: a microdialysis study.

RATIONALE AND OBJECTIVES: Flinders sensitive line (FSL) rats, an animal model of depression, display a different pattern of maternal behavior compared to Sprague-Dawley (SD) controls. In this study, we examined the rewarding value of mother-infant interaction for FSL dams. MATERIALS AND METHODS: In the main study, we measured monoamine levels in the nucleus accumbens (NAc) of early postpartum FSL and SD dams during an interaction with pups, using the microdialysis technique. In addition, we compared the preference patterns of FSL and SD rats using the conditioned place preference paradigm, with pups as the unconditioned stimuli. RESULTS: Dopamine (DA) levels in dialysates from the NAc of SD dams but not FSL dams were elevated while interacting with pups but the metabolism of DA to dihydroxyphenylacetic acid was greater in FSL than in SD dams. While SD dams showed a conditioned preference for a region that was associated with SD pups, FSL dams did not show a preference for regions associated either with SD or FSL pups, but water deprived FSL rats demonstrated a preference to a region associated with water, eliminating an alternative explanation of learning deficit in FSL rats. CONCLUSIONS: Taken together, these results suggest that FSL dams are less rewarded by pups, compared to control dams.

Nucleus Accumbens Dopamine Signaling Regulates Sexual Preference for Females in Male Mice.

Sexual preference for the opposite sex is a fundamental behavior underlying reproductive success, but the neural mechanisms remain unclear. Here, we examined the role of dopamine signaling in the nucleus accumbens core (NAcc) in governing chemosensory-mediated preference for females in TrpC2-/- and wild-type male mice. TrpC2-/- males, deficient in VNO-mediated signaling, do not display mating or olfactory preference toward females. We found that, during social interaction with females, TrpC2-/- males do not show increased NAcc dopamine levels, observed in wild-type males. Optogenetic stimulation of VTA-NAcc dopaminergic neurons in TrpC2-/- males during exposure to a female promoted preference response to female pheromones and elevated copulatory behavior toward females. Additionally, we found that signaling through the D1 receptor in the NAcc is necessary for the olfactory preference for female-soiled bedding. Our study establishes a critical role for the mesolimbic dopaminergic system in governing pheromone-mediated responses and mate choice in male mice.

Weight gain and maternal behavior in CCK1 deficient rats.

The OLETF rat model of obesity has been extensively studied as an adult model of hyperphagia-induced obesity. In order to better understand the early circumstances that make OLETF pups obese, we investigated body weight from postnatal day (PND) 1 and examined diurnal maternal behavior over the first three postpartum weeks by undisturbed observations. Male and female OLETF rats weighed significantly more than LETO controls from PND 1 until adulthood. Differences in nursing behavior were observed only in the third postnatal week: OLETF dams exhibited more frequent nursing. OLETF dams displayed less self-directed behaviors and activity, over the entire postpartum period examined. Taken together, these data demonstrate that OLETF males and females are heavier from birth and suggest that maternal factors may contribute to weight differences between the strains.

Immobility in the swim test and observations of maternal behavior in lactating Flinders sensitive line rats.

In order to elucidate the relationship between maternal behavior and depression, the Flinders sensitive line (FSL) model of depression was studied and compared to Sprague-Dawley (SD) controls. Immobility in the swim test was measured, as an index for depressive-like behavior, and frequencies of maternal and non-maternal behaviors were recorded using short un-intrusive observations in the home cage. Lactating FSL rats displayed higher levels of immobility in the swim test compared to controls, indicating depressive-like behavior. In addition, compared to SD rats, FSL dams showed less frequent pup licking and non-nutritive contact with pups during the first and third weeks of lactation. In the third postpartum week, FSL dams showed less frequent nursing postures and more frequent self-directed behaviors. Thus, lactating FSL dams exhibit both depressed-like behavior and some abnormalities in maternal behavior.

Abnormal patterns of maternal behavior in a genetic animal model of depression.

The Flinders Sensitive Line (FSL) model is considered a genetic animal model of depression. Among other characteristics, FSL rats express stress-induced anhedonia and an abnormal dopaminergic system. Our hypothesis was that FSL rats would show abnormal maternal behaviors, especially reduced motivation to reach and care for pups and reduced licking and non-nutritive contact, based on their anhedonic characteristics. Mother-infant interactions were assessed by time limited observations in FSL and Sprague-Dawley (SD) controls. In study 1, differences were found in consummatory behaviors: FSL dams compared to SD dams showed less licking and significant decrease in non-nutritive contact from the first to the third postpartum weeks. In addition, shorter duration of nursing postures was seen in FSL compared to SD dams in the first week postpartum, and this difference was significantly increased by the third week postpartum. In study 2, after exposure to acute swim stress, differences emerged in appetitive behaviors: latencies to reach and care for pups were longer in FSL dams compared to controls, suggesting a stress-induced motivational deficit in FSL dams. Possible explanations, especially regarding the FSL dams' reward system are discussed.

Mother-Infant Interactions in Rats Lacking CCK(A) Receptors.

Mediation of mother-infant interactions by the brain-gut peptide cholecystokinin (CCK) was examined by observing behavior of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which lack functional CCKA receptors because of a genetic abnormality. OLETF (n = 10) and control (Long-Evans Tokushima Otsuka [LETO] n = 10) dams interacted with 1 pup of each line on Postpartum Days 6-9. OLETF pups received more body and anogenital licking and emitted substantially more ultrasonic vocalizations than LETO pups. OLETF dams carried pups less frequently and showed a nursing position more frequently than LETO dams. No significant Pup X Dam Line interactions or line differences in dams' activity were detected. The results provide convergent validity to previous pharmacological studies implicating CCK mediation of both infant and maternal behavior.

Diurnal and nocturnal nursing behavior in the OLETF rat.

The Otsuka Long Evans Tokushima Fatty (OLETF) rat model of obesity has been recently found to develop hyperphagia and obesity early in life. Our goal was to investigate the dams' nursing behavior during the day and the night in order to elucidate their contribution to the pre-obesity of the pups. We examined nursing bout number, length, posture, initiative, nursing total time and frequency of other maternal behaviors over the three postpartum (PP) weeks. In the first week, OLETF dams nursed more during the day and presented more self-directed activities during the night. In the third PP week, OLETF dams displayed increased nursing time, bout number, nursing frequency, and supine postures at the beginning of the nursing episodes and less active self-directed behaviors, both day and night, while OLETF pups displayed more initiative in starting nursing bouts. The results suggest a circadian difference in nursing behavior and self-directed activities between the strains on PP week 1 and a strong influence of the OLETF pups on the nursing behavior of the dam on PP week 3, which contributes to their obese features.

Preobesity in the infant OLETF rat: the role of suckling.

The Otsuka Long Evans Tokushima Fatty (OLETF) rat model of obesity, which lacks CCK(1) receptors, has been extensively investigated over the last decade. We have recently focused on the early developmental stages of this strain, finding that OLETF pups are heavier than controls from birth and hyperphagic already from postnatal (PN) Day 2. OLETF mothers present differential maternal behavior patterns and increased nursing time and frequency, which might contribute to the preobese characteristics of the pups. The present investigation examined the pups' ability to gain weight from the nursing episodes. First, we measured the pups' weight gain from one nursing bout from their own dam. Next we examined the pups' weight gain after a feeding competition test with control pups from foster dams of both strains. OLETF pups gained more weight than controls from their own dams on PN Week 1 due to a higher suckling rate (and/or efficacy) and on PN Week 3 due to increased nursing time. When competing with control pups, OLETF pups gained significantly more weight after the same nursing bout, regardless of the strain of the mother. Body mass index (BMI) was significantly higher in OLETF pups compared to controls. The maternal parameters assessed from the experiment were latencies to pup retrieval and to nursing, and nursing duration; differences were only observed in nursing time. OLETF dams increased their average nursing time over the PN weeks, while control dams decreased their nursing time toward weaning. The results suggest an important contribution of OLETF pups toward their own preobese development.