Elsevier

Behavioural Brain Research

Volume 182, Issue 2, 4 September 2007, Pages 193-207
Behavioural Brain Research

Review
Selective breeding for infant rat separation-induced ultrasonic vocalizations: Developmental precursors of passive and active coping styles

https://doi.org/10.1016/j.bbr.2007.04.014Get rights and content

Abstract

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic–pituitary–adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate “anxious”/“depressed” phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an “aggressive” phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting “coping styles” with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation.

Section snippets

Temperament and attachment in children: developmental stability and inheritance

Behavioral inhibition in childhood is a pattern of responding in which the child shows anxiety, distress or caution in response to novelty [17], [78], [79]. Behavioral inhibition has been suggested to be a temperamental trait, defined as biologically-based stability of affect and behavior over the course of childhood through adolescence and into adulthood [133]. Thus, toddlers exhibiting behavioral inhibition continue to show behavioral inhibition as children, and are far more likely to

Selective breeding for high and low rates of infant vocalization responses to maternal separation

As with other infant mammals, infant rodents (pups) cry initially when separated from mothers (dams) and littermates; these cries peak at 45 kHz and are therefore called ultrasonic vocalizations or USV. Rat and mouse pups, like other mammalian species, also experience maternal separation as a stressful event, producing increased autonomic nervous system activity and cardiovascular changes, activation of the hypothalamic–pituitary–adrenal (HPA) axis, and a ramping up of noradrenergic and opioid

Weight differences at birth

An unexpected effect of selection was that Low line birth weights have been significantly lower than both High and Random line weights since the 14th (S14) generation of breeding (Fig. 2A). Line differences in mean litter weights at birth have remained stable and were still highly significantly different through Generation 28 (Fig. 2B). However, by weaning Low line weights are not different from the High and Random lines for either sex, into adulthood [24]. The genetic and/or prenatal

Early differences in monoamine systems

A number of neurotransmitters have been implicated in the modulation of infant rat isolation-induced USV and in adult rat anxiety-related behaviors. Among these, influences of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) systems have been most systematically observed in rat pups [25], [76]. Because High and Low line rat pups show such extraordinary extremes of USV to isolation at P10, changes in at least one of these systems seemed likely. Therefore, we examined line differences in

Social play in the juvenile period

Play is one of the earliest social behaviors that preweanling rats engage in that are not oriented toward the dam. In rats, play begins at about P18, shortly after eye opening and with independent feeding, and peaks during the periadolescent period between 30 and 40 days of age [98], [113], [157], [162]. As in other mammals, play in rats is thought to have paralleled the evolution of the prefrontal cortex [46], [51], [117]. Consistent with this view, rat play is comprised of complex sets of

Developmental continuity in adult affective regulation

If separation-induced USV rates are an indicator of an infant anxiety-like state, does it follow that extremes of infant USV rates predict anxiety-like behavior in adulthood? Human studies examining samples of children expressing childhood inhibition and adult anxiety/depression disorders suggest that this may be the case. On the other hand, expressions of infantile states are not necessarily predictive of lifelong behavioral traits. Infantile isolation-induced USV may, for example, be an

Autonomic nervous system (ANS) regulation of heart rate

Selection for infant USV has also produced distinct modes of cardiac responsiveness to stress. In a study of 18-day-old juveniles we found that compared to the Random line both the High and Low USV lines exhibit enhanced cardiac reactivity to stress [27]. Fig. 9 shows heart rate changes at Baseline (Home cage), Isolation (Novel cage) and Recovery (Home cage), in 2-min epochs, in P18 juveniles that were taken from the home cage and placed individually into a novel environment, then returned to

Low line male–male aggression

As noted above, another potential component of a Low line model suggested by autonomic and behavioral data would be elevated aggressive behavior. To test this hypothesis we paired Low line adult males with novel partners of the same line and compared them to comparably-treated males in the Random line, in a novel but neutral, non-threatening environment (Social Interaction test [55]). Since rats are not generally aggressive in this context, males of both lines were previously socially isolated

Emotional regulation, attachment and coping styles

It appears then, that selective breeding for high and low rates of vocalization in response to maternal separation has produced two distinct temperamental styles that include alterations in behavioral, physiological, and neurochemical characteristics. The integrity of these personal styles are continuous across the life span, and express themselves as adult phenotypes comparable to those seen in human populations. In humans and in the selected lines, the origins of behavioral predispositions

Acknowledgements

This work was supported by NIMH Grant: R01 MH40430, R03 MH54207, National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD).

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