Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein (APP) mice

Abstract

Elucidating the modulators of social behavioral is important in understanding the neural basis of behavior and in developing methods to enhance behavior in cases of disorder. The work here stems from the observation that the Alzheimer's disease mouse model Tg2576, overexpressing human mutations of the amyloid-β precursor protein (APP), fails to construct nests when supplied paper towels in their home cages. Experiments using commercially available cotton nesting material found similar results. Additional experiments revealed that the genotype effect is progressively modulated by age in APP mice but not their WT counterparts. There was no effect of sex on nesting behavior in any group. Finally, this effect was independent of ambient temperature – even when subjected to a cold environment, APP mice fail to build nests whereas WT mice do. These results suggest that the APP gene plays a role in affiliative behaviors and are discussed in relation to disorders characteristic of mutations in the APP gene and in affective dysfunction, including Alzheimer's disease.

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.