Genetic reduction of noradrenergic function alters social memory and reduces aggression in mice

Abstract

Aberrant social behavior is a hallmark of many cognitive, mood, and neurological disorders, although the specific molecular mechanisms underlying the behavioral deficits are not well understood. The neurotransmitter noradrenaline (NA) has been implicated in some of these disorders, as well as in several aspects of social behavior in humans and animals. We tested dopamine β-hydroxylase knockout (Dbh −/−) mice that lack NA in various social behavior paradigms. Dbh −/− mice have relatively normal performance in the elevated plus maze, light/dark box, and open field test – three measures of anxiety – and a social recognition test. In contrast, Dbh −/− mice displayed a specific deficit in a social discrimination task and had a nearly complete absence of resident-intruder aggression. These results indicate that intact NA signaling is required for some types of social memory and aggression, but that a lack of NA does not greatly affect anxiety in mice. Further exploration of NA deficits in neurological disease may reveal mechanisms of aberrant social behavior.

Introduction

Defects in the noradrenergic system have been implicated in many mood, cognitive, and neurological disorders that manifest abnormal social behavior, including attention deficit and hyperactivity disorder (ADHD), anxiety disorder, psychotic depression, and Alzheimer's disease. In addition, evidence has been mounting in recent years suggesting that noradrenaline (NA) also plays an important role in the regulation of several aspects of social behavior, including social anxiety [1], [2], aggression [3], [4], and social memory [5], [6], [7], [8], [9]. Therefore, an understanding of the contribution of NA to these behaviors may lead to a more detailed comprehension of neurological disease symptomology and treatment.

A strong connection between NA, anxiety, and other stress-related disorders has been previously established [1], [2], [10], [11], [12], [13], [14], although the valance of the interaction is the subject of some controversy. Stress increases the firing of locus coeruleus noradrenergic neurons and induces cortical and subcortical NA release, which is associated with anxiety-like behaviors. Interactions between NA and corticotropin-releasing factor (CRF) are thought to activate the nervous system in response to environmental challenge, and dysfunction of these systems is hypothesized to contribute to anxiety disorders. However, it is important to consider that, depending on neurochemical and environmental influences, activation of the noradrenergic system can be anxiolytic.

The ability to recognize familiar individuals, or social memory, is critical to the formation of social groups, reproductive behavior, and ultimately, species survival, and this type of memory is impaired in Alzheimer's disease. NA appears to be critical for some aspects of social memory. For example, lesions of the noradrenergic projections to the olfactory bulb in female mice before birth increase cannibalism of newborn pups [5], and genetically engineered female mice that lack NA show impaired maternal behavior, with most pups born to those mothers dying within a few days of birth [7]. Pharmacological depletion of central NA impairs the ability of adult rats to recognize a familiar juvenile, whereas pharmacological elevation of NA enhances social recognition [6], [8], [9]. These findings strongly suggest that noradrenaline plays an important role in regulating the formation of social memory.

The noradrenergic system also appears to be involved in aggressive behavior. For example, lesions of the noradrenergic system reduce aggression [15], [16], [17], [18]. In addition, genetically engineered mice that lack α_2C-adrenergic autoreceptors, and consequently have increased NA levels, show enhanced isolation-induced aggression toward an unfamiliar intruder, whereas mice that overexpress these receptors show the opposite trend [19].

Because anxiety, social memory, and aggression all appear dependent on central NA, it is likely that NA is a critical element in the neural pathways that regulate social behavior in general. We hypothesized that mice with genetically reduced noradrenergic function will display abnormal social behavior. Specifically, we predicted that mice lacking NA would display reduced anxiety, impaired social memory, and low levels of aggression. To test these hypotheses, we examined these social behaviors in dopamine β-hydroxylase knockout (Dbh −/−) mice. DBH is the enzyme that converts dopamine to noradrenaline, and Dbh −/− mice lack the ability to synthesize NA and show a complete loss of noradrenergic function [20], [21]. This model of NA depletion is especially relevant for human disorders because DBH activity is controlled by a polymorphism in the human Dbh gene [22].