The neurobiology of mood disorder Vulnerability to mood disorder


Positional mapping of the genetic loci associated with mood disorder has not yet yielded important clues in searching for fundamental neurobiological causes (see Chapter However, neurobiology informs the genetic search for candidate genes such as the human serotonin transporter ( SERT) gene.(89) Cerebrospinal fluid monoamine levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol ( MHPG) appear to vary in relation to the two SERT polymorphisms.(!0) This is the sort of finding that, if replicated, will start to illuminate abnormal function in the affected phenotype.

An alternative approach to looking for the heritability of mood disorder itself is to examine the heritability of traits that predispose to its development. Such quantitative trait loci can be sought relatively simply in a normal population (see ChapteĀ£.2.4.1). High-trait neuroticism (N) accounts for approximately half of the genetic liability to major depression in women.'l1) Most importantly, N is itself highly heritable and stable in normal populations. Accordingly, individual differences in learning, stress hormone secretion, and a variety of other behaviours lend themselves to genetic studies in animals and ultimately in humans also. The first such successful study showed that 'emotionality' in mice was associated with at least three loci on the mouse genome.(12) These loci may be resolvable to the level of individual genes whose function could represent conserved mechanisms also contributing to human neuroticism. By analogy with other genes linked to common diseases like diabetes, this may lead to the development of novel models of vulnerability to mood disorder which have genuine neurobiological validity.

When animals are selected for differences in emotional behaviour they also show different hypothalamic-pituitary-adrenal (HPA) axis function. Specifically, Roman high- and low-avoidance rats differentially acquire a two-way active avoidance response in a shuttle box. High-avoidance animals show greater prolactin and HPA axis responsivity to stress compared with low-avoidance animals. However, young Roman strain rats show identical HPA axis reactivity, although prolactin responses and behaviour are different/13 In other words, reactivity to the environment may share a measure of common genetic control across physiological and behavioural domains, but HPA abnormality per se develops secondary to emotional experience, or at least is magnified by it. However, the key point is that important differences in stress reactivity may reflect a genetic predisposition and have a biological basis.

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