Genetic Manipulations

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Major depression is a heritable disorder that likely involves multiple genes, each with small effects (Wong and Licinio 2001). Targeted gene deletions and gene transfers in animal models are beginning to elucidate the functional significance of potentially relevant genes (Insel 2007). Consider, for example, dysregulation of the HPA axis evinced in depression by an increase in cortisol levels (see Chapter 45, "Neurobiology of Mood Disorders"). Receptors for cortisol are densely expressed in the prefrontal cortex (Webster et al. 2002), where they function as transcription factors that regulate gene expression (Chrousos and Kino 2005). Hundreds of genes in prefrontal cortex appear to be differentially expressed in humans with a history of major depression based on postmortem analysis of whole-genome microarray data (Choudary et al. 2005; Evans et al. 2004; Iwamoto et al. 2004; Sequeira et al. 2006). Genetic manipulations of receptors for Cortisol are not yet feasible in human patients but have recently been studied in various animal models (Boyle et al. 2005; Kaufer et al. 2004; Ridder et al. 2005; Wei et al. 2004). These studies suggest that high-throughput technologies designed to identify candidate genes regulated by receptors for cortisol may yield novel targets for the development of new antidepressants.

Another promising genetic approach involves selective breeding of rodents and subsequent genomewide scans to identify predisposing candidate genes. An intriguing example is the swim-test-susceptible rat, which is bred for extreme passivity in response to uncontrollable stress (Weiss and Kilts 1998). In the swim-test-susceptible rat, eight different antidepressants restore normal swim-test activity after exposure to uncontrollable stress. Four drugs that produce false-positive results in swim tests administered to normal rats (Porsolt et al. 1991) all fail to restore normal swim-test activity in swim-test-susceptible rats. None of the eight tested antidepressants have any effect on a selectively bred line of swim-test-resistant rats, indicating that the detection of antidepressants is best achieved with genetically susceptible rats (Weiss and Kilts 1998). This model is well suited to identify genes involved in a common mechanism of action of diverse antidepressants.

A related strategy combining genetic and developmental approaches to investigate gene-environment interactions is exemplified by studies of BALB/cByJ mice, which typically are more reactive to stress than C57BL/6ByJ mice (Anisman et al. 1998). When stress-susceptible BALB/cByJ mouse pups are raised by stress-resistant C57BL/6ByJ dams, the development of excessive reactivity to stress is diminished in the cross-fostered pups. However, when stress-resistant C57BL/6ByJ pups are raised by stress-susceptible BALB/cByJ dams, the development of subsequent stress reactivity is not affected in the cross-fostered pups. This model demonstrates that genetic factors affect mother-infant interactive styles, which in turn influence the subsequent development of stress susceptibility in mice.

A complementary approach involves targeted disruptions of gene expression in specific brain regions only during critical periods of postnatal brain development. An example is provided by mice engineered to lack the serotonin1A receptor (5-HT1AR) protein. These mice exhibit increased anxiety-like behavior on a variety of tests. Selective expression of 5-HT1AR in the hippocampus and cortex, but not the raphe nuclei, restores to normal the behavior of 5-HT1AR knockout mice (Gross et al. 2002). Additional evidence suggests that tissue-specific 5-HT1AR expression during postnatal development, but not in adulthood, is necessary to achieve the behavioral rescue effect. This model indicates that developmental changes in 5-HT1AR gene expression within specific brain regions are involved in the emergence of anxiety-like behavior in adulthood.

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Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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