Behavioral and neuroendocrine reactivity to stress in the WKHA/WKY inbred rat strains: a multifactorial and genetic analysis

Abstract

Genetic factors have been shown to influence the nature and the intensity of the stress responses. In order to understand better the genetic mechanisms involved, we have studied the behavioral and neuroendocrine responses to novel environments in the WKHA/WKY inbred strains and we have investigated the genetic relationships between these traits in a segregating F2 intercross. The animals were submitted to behavioral tests known to provide both indices of activity and fear (activity cages, open field and elevated plus-maze). The plasma levels of prolactin, ACTH, corticosterone, glucose and renin activity were determined after a 10-min exposure to novelty. Our results showed that WKHA rats, compared to WKYs, were more active in a familiar as well as in novel environments. They exhibited also less anxiety-related behaviors and lower neuroendocrine responses. A principal component analysis performed on the behavioral F2 results defined three independent factors: general activity, anxiety and defecation, none of them being correlated with the neuroendocrine measures. Thus this study suggests that these different responses to stress are independent components that may have distinct molecular bases.

Introduction

To cope with environmental challenges, the organism sets off an adaptative response involving both behavioral and neuroendocrine adjustments. With regard to the nature and/or intensity of these two types of responses, a wide range of interindividual variability has been described in humans 18, 19, in rodents 15, 17, 22and in domestic species [23].

Even if environmental factors (especially early influences and previous experiences) play a key role in the interindividual variability of the stress responses, several studies have underlined the implication of genetic factors in humans 37, 43. In animals, considerable differences in the nature and/or intensity of the stress responses have been described among strains of mice 39, 44and of rats 3, 36, 40. Furthermore, it has been possible to carry out divergent genetic selections on the basis of a differential behavioral and/or neuroendocrine response to environmental stimulations (see for review [12]). Despite those numerous studies demonstrating the role of genetic factors in stress reactivity little is known about their molecular bases. New molecular tools, such as QTL mapping (i.e. Quantitative Trait Loci), allow now the investigation of the molecular bases of psychobiological traits such as morphine-preference [5]and emotionality [21].

Among all the indices of stress reactivity that can be measured in animals, locomotor response to a novel environment has often been of particular interest (see 2, 27, 34). Indeed, locomotor activity is a basic component of the response to environmental challenges. In humans, hyperactivity has been involved in several psychiatric disorders, such as Attention Deficit Hyperactivity Disorder (ADHD) [32]. Studying the genetic bases of hyperactivity and its behavioral and/or neuroendocrine correlates should help to clarify the biological mechanisms involved in stress responses and related pathologies.

The WKHA (Wistar-Kyoto-Hyperactive) inbred strain derives from an initial cross between SHR (Spontaneously Hypertensive Rat) and WKY (Wistar-Kyoto) rats. The animals were genetically selected for the parental SHR's high locomotor reactivity to a novel environment in activity cages and the normotensive blood pressure of the parental WKY, and have been inbred for over twenty generations 29, 30. WKHA rats have kept the hyperactivity of the SHR strain but are normotensive. Later studies indicated that the WKHA rats, compared to the WKY control strain, were also more active in a free exploration test [42]and displayed lower neuroendocrine responses to novelty [11].

In the present study we first characterized the WKHA and WKY strains according to their spontaneous activity and to their behavioral and neuroendocrine reactivity in novel environments, by the use of tests thought to assess activity and fear-related behaviors. Then we investigated the genetic relationships between these traits in a segregating intercross.