Research reportAge and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein (APP) mice
Research highlights
▶ Construction of nests is an affiliative behavior influenced by numerous factors. Mice overexpressing mutant amyloid precursor protein (APP) fail to construct nests. ▶ Nest building in APP mice becomes progressively worse from 2 to 20 months of age. ▶ These results suggest that APP expression modulates nest construction.
Introduction
Understanding the biological basis of affiliative behaviors poses a unique problem in neuroscience since these behaviors often involve interactions between conspecifics and other changing environmental stimuli. Adding to this difficulty, affiliative behaviors can be modulated by an assortment of variables including age, neurochemical levels, hormonal status, genetics, and disease. Understanding the neural basis for affiliative behaviors not only contributes to our understanding of normal behavior, but also may elucidate therapeutic methods to enhance motivation and drive in psychiatric conditions and other diseases.
Nesting behavior, one type of affiliative behavior, is displayed by males and females in both parental and non-parental contexts [1], [2], [3], [4], [5], [6], [7], [8]. Nesting behavior can be considered a goal-directed behavior which involves stereotyped sensorimotor actions [9] (chewing, forelimb movements) and is fundamentally controlled by levels of arousal and motivation (the drive for warmth, safety, or rearing young). Given this array of factors which may drive nesting responses, it is not surprising that there are a variety of known modulators of nesting behavior [2], [10], [11], [12], [13], [14]. On the most basic level, the material available for nest construction will determine nest construction abilities and tendencies [5], [15], [16]. Social context can also modulate nest building [17]. A powerful example of this comes from studies of nest building in birds wherein the time required to gather nest materials and construct the nest (sometimes exceeding 300 h) is reduced in species which build nests together as a pair [5]. In another example, female Norway rats with pups decrease their frequency of nest-directed behaviors in the presence of male conspecifics [17]. Thus, environmental context can modulate nesting behavior.
Several brain regions are implicated in mammalian nesting behavior. These regions include the caudate putamen [18], ventral tegmental area [19], hippocampus [20], septum [21] and medial preoptic area of the hypothalamus [22]. Specific neurotransmitter systems including dopamine, norepinephrine, and serotonin [18], [23], [24], and neuroendocrine factors (e.g., prolactin [25]) have been identified as important for nesting behavior. For example, restoration of dopamine (i.e., stimulation of D1 receptors) in the caudate putamen can rescue nesting behavior in dopamine deficient mice [18]. Further, nesting behavior is disrupted in serotonin depleted rodent mothers [26]. Thus, multiple brain regions and neurochemical factors contribute to nesting behavior.
This study stems from an observation in our colony that Alzheimer's disease (AD) model mice overexpressing human mutations of the amyloid-β precursor protein (APP), in particular the Tg2576 mouse model [27], fail to construct nests when provided bedding material for enrichment. This observation is supported by literature showing similar results [28], [29] in APP mice. However, our initial observations suggested, unlike earlier results in a study limited to female mice [28], that this deficit is age-dependent and sex independent. Therefore, here we explored nest construction in mixed sex cohorts of APP and non-transgenic litter-mate (WT) mice throughout aging (2–20 months) to test whether nest construction is indeed modulated by age in APP mice. Such results may be important when considering analogies between nest construction as a stereotyped behavior and the progressive loss of executive function clinically observed in AD [30]. Further, these findings may contribute to understanding the various biological influences on this fundamental behavior.
Section snippets
Subjects
Mice bred and maintained within the Nathan S. Kline Institute for Psychiatric Research animal facility were used. Tg2576 (APP, on the B6SJLF1/J background) mice were generated previously by overexpressing the 695-amino acid isoform of human APP containing the KM670/671NL mutation, as described [27]. Age-matched non-transgenic litter-mate mice (WT) were used as controls. Three age-groups of mixed sex mice were used: 2–3 months, n = 7 WT (4 male, 3 female), n = 8 APP (4 male, 4 female); 10–12 months, n = 6
Nest building with paper towel material
To assess the influence and/or possible interactions of age and APP gene overexpression on nesting behavior, we first explored nest construction with paper towel material using a three point scaling system (see Section 2) in APP and WT mice. Examples of nests when supplied paper towel material from APP and WT mice are shown in Fig. 1(A). In contrast to the relatively immediate chewing and tearing behavior towards the paper towels observed in WT mice, APP mice investigated but did not destruct
Discussion
Nesting behavior is one of many behaviors which is important for the survival of an animal and its offspring. Here we explored the involvement of APP gene overexpression and aging on nest construction in the Tg2576 transgenic mouse model [27]. Both male and female Tg2576 mice showed reduced or absent nest construction when supplied with either paper towels or commercially available cotton nesting material in their home cages. Furthermore, this genotype effect was progressively modulated by age
Conclusion
As previously discussed, affiliative behaviors such as the behavior of nest building observed in the present study, are influenced by a wide array of factors. The results of this study in part reinforce the notion of genetic factors as important contributors to affiliative behaviors. Mutant APP gene overexpression dramatically disrupts nest building in mice of both sexes. Also though, we found that APP gene expression interacts with age (perhaps in accordance with progressive Aβ deposition
Acknowledgments
This work was supported by grant DC003906 to D.A.W. We thank Regina Sullivan for helpful discussions regarding this work and Anne Borkowski for assistance with mouse breeding and genotyping.
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