Behavioral and Physiological Consequences of Adult Brain 5-HT Depletion in Mice

Abstract

Review of Whitney et al.Serotonergic neurons from the dorsal raphe innervate the amygdala, the mPFC, and the hippocampus, suggesting they have a substantial role in the modulation of emotional states (Lowry et al., 2005). Consistent with this hypothesis, serotonin (5-HT) dysfunction is a key feature of several psychiatric disorders. Therefore, expanding our understanding of the serotonergic system may provide insight into the mechanisms underlying these diseases.Animal models are useful in revealing how circuits, physiology, and behavior are affected by 5-HT depletion. Several of these models involve pharmacological or genetic manipulation of two rate-limiting enzymes involved in 5-HT biosynthesis: tryptophan hydroxylase (Tph) and aromatic amino acid decarboxylase (AADC). Tph converts the amino acid tryptophan to 5-HT, which is then converted to 5-HT by AADC. Although such models have provided valuable insight into 5-HT functions, most of the methods used to date have been difficult to interpret because 5-HT was depleted in the periphery, as well as in the brain tissue, because other monoamine signaling pathways were also affected or because 5-HT was depleted throughout development rather than selectively in adult neurons.To avoid these problems, Whitney et al. (2016) developed a new strategy for depleting 5-HT selectively in the serotonergic ascending pathway of adult mice. Briefly, they injected adeno-associated virus-expressing Cre recombinase (AAV-Cre) into the serotonergic anterior raphe nuclei of mice in which the brain-specific Tph isoform, Tph2, was flanked by loxP sites (Tph2 fl/fl and Tph2 fl/Ϫ). This allowed deletion of Tph2 selectively in the serotonergic nuclei. This method almost completely eliminated Tph2 and 5-HT immunoreactivity in the dorsal raphe nucleus. Importantly, AADC, norepinephrine, and dopamine levels were unaffected, at least at 2 weeks after injection.The disruption of the 5-HT machinery selectively in serotonergic neurons not only confirmed previous findings regarding its role in sleep-wake cycles and locomotor activity (Alenina et al., 2009), but also revealed novel physiological and behavioral consequences. Although classical measures of anxiety-like behavior (i.e., time spent in bright/unprotected vs dark/ protected areas) were not affected by 5-HT depletion, a marked increase in locomotor activity in the open field was found. Moreover, compared with control, 5-HT-depleted mice spent less time in inactive behaviors in the home cage and more time in active behaviors during both the active (dark) and inactive (light) phase of the day. These data rule out the noveltyinduced hyperlocomotion and indicate a hyperactive phenotype. Furthermore, 5-HT-depleted mice showed also an advanced onset and a delayed offset of their daily activity, suggesting alteration in their circadian activity pattern. Average activity time across the day showed that, although overall activity of 5-HT-depleted mice was increased, it was significantly higher only at specific times, confirming that the increase i...