Affiliative Behavior, Ultrasonic Communication and Social Reward Are Influenced by Genetic Variation in Adolescent Mice

Social approach is crucial for establishing relationships among individuals. In rodents, social approach has been studied primarily within the context of behavioral phenomena related to sexual reproduction, such as mating, territory defense and parental care. However, many forms of social interaction occur before the onset of reproductive maturity, which suggests that some processes underlying social approach among juvenile animals are probably distinct from those in adults. We conducted a longitudinal study of social investigation (SI) in mice from two inbred strains to assess the extent to which genetic factors influence the motivation for young mice to approach one another. Early-adolescent C57BL/6J (B6) mice, tested 4–6 days after weaning, investigated former cage mates to a greater degree than BALB/cJ (BALB) mice, irrespective of the sex composition within an interacting pair. This strain difference was not due to variation in maternal care, the phenotypic characteristics of stimulus mice or sensitivity to the length of isolation prior to testing, nor was it attributable to a general difference in appetitive motivation. Ultrasonic vocalization (USV) production was positively correlated with the SI responses of mice from both strains. Interestingly, several USV characteristics segregated with the genetic background of young mice, including a higher average frequency and shorter duration for the USVs emitted by B6 mice. An assessment of conditioned place preference responses indicated that there was a strain-dependent difference in the rewarding nature of social contact. As adolescent mice aged, SI responses gradually became less sensitive to genetic background and more responsive to the particular sex of individuals within an interacting pair. We have thus identified a specific, genetic influence on the motivation of early-adolescent mice to approach one another. Consistent with classical theories of motivation, which propose a functional relationship between behavioral approach and reward, our findings indicate that reward is a proximal mechanism through which genetic factors affect social motivation during early adolescence

Stimulation of Lateral Septum CRF2 Receptors Promotes Anorexia and Stress-Like Behaviors: Functional Homology to CRF1 Receptors in Basolateral Amygdala

The corticotropin-releasing factor (CRF) system is the primary central mediator of stress-like states, coordinating behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well documented effect of CRF receptor agonist administration, the central sites and behavioral processes underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating decreases in feeding produced by the CR

Figure 3

<p><u>Strain-dependent differences in social investigation as a function of maternal care, stimulus mouse characteristics and length of social isolation</u>. (a) Following 24 hours of social isolation, on PD 30/31, male B6 mice investigated a familiar female stimulus mouse for a greater duration then age-matched BALB males. This strain-dependent pattern was also expressed by (b) male mice that had been raised by a mother of the alternate strain, (c) male mice approaching a female from the alternate strain and (d) male mice approaching a same-strain female after 8–10 days of social isolation. All data are presented as the mean±SEM (** P<0.01, *** P<0.001).</p

Figure 4

<p><u>Approach behaviors of adolescent mice towards a novel olfactory stimulus and a food source</u>. After 24 hrs of social isolation, (a) BALB and B6 mice investigated a lemon-scented cotton ball for a similar amount of time. Following complete food deprivation during a 24-hr social isolation period, (b) BALB males consumed more food (standard lab chow) than mice from the other groups during a 10-min period. All data are presented as the mean±SEM (* P<0.05 compared to BALB females and B6 mice of both sexes).</p

Figure 6

<p><u>Classification of ultrasonic vocalizations into distinct categories</u>. Representative sonograms and descriptive statistics for different types of USV that were emitted by (a–d) BALB and (a′–d′) B6 mice (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000351#s3" target="_blank">Results</a> for classification criteria). Descriptive statistics (mean±std. dev.) are given for the duration of each call type, as well as the beginning and ending dominant frequency. The USV traces are arbitrarily aligned to the 100-msec demarcation on the abscissa of each sonogram. Intensity changes within each representative vocalization are color-coded. (a″–d″) The production of each USV subtype was strain-dependent (* P<0.05, *** P<0.001 for BALB vs. B6 mice).</p

Figure 1

<p><u>Social approach among adolescent mice</u>. (a) The SI responses of test mice were quantified during 5-min tests throughout adolescent development. Weaning age and the average age of reproductive maturity in females is illustrated for mice from both strains. (b) Photograph of a B6 mouse investigating a former cage mate after 24 hrs of social isolation.</p

Pearson's correlation coefficients relating SI responses of test mice to variables associated with USV emission (* P<0.05, ** P<0.01, *** P<0.001).

<p>Pearson's correlation coefficients relating SI responses of test mice to variables associated with USV emission (* P<0.05, ** P<0.01, *** P<0.001).</p

Figure 8

<p><u>Strain-dependent variation in the social conditioned place preference responses of early-adolescent mice</u>. Unconditioned mice from both strains expressed a preference for the paper bedding (control bars) and this natural bias obscured any conditioning effect that might have resulted from pairing social interaction with paper bedding (social <i>plus</i> paper bars). However, there was a robust, strain-dependent SCPP response for B6 mice when the less-preferred aspen bedding was paired with social enrichment (social <i>plus</i> aspen bars). Preference scores were calculated as the time each mouse spent in the aspen bedding-lined environment <i>minus</i> the duration in the paper bedding-lined compartment of the place-preference arena. All data are presented as the mean±SEM (*** P<0.001 for BALB vs. B6 mice).</p

Figure 2

<p><u>Differences in social investigation between adolescent mice as a function of genetic background, age and sex</u>. SI responses of BALB and B6 test mice during adolescent development for (a) males approaching females, (b) females approaching males, (c) males approaching males and (d) females approaching females. All data are presented as the mean±SEM (* P<0.05, ** P<0.01, *** P<0.001 for BALB vs. B6 mice; ^# P<0.05, ^## P<0.01 for PD 25/26 vs. PD 45/46 mice).</p