Abstract
The circadian clock regulates many biochemical and physiological pathways, and lack of clock genes, such as Period (Per) 2, affects not only circadian activity rhythms, but can also modulate feeding and mood-related behaviors. However, it is not known how cell-type specific expression of Per2 contributes to these behaviors. In this study, we find that Per2 in glial cells is important for balancing mood-related behaviors, without affecting circadian activity parameters. Genetic and adeno-associated virus-mediated deletion of Per2 in glial cells of mice leads to reduced despair and anxiety. This is paralleled by an increase of the GABA transporter 2 (Gat2/Slc6a13) and Dopamine receptor D3 (Drd3) mRNA, and a reduction of glutamate levels in the nucleus accumbens (NAc). Interestingly, neuronal Per2 knock-out also reduces despair, but does not influence anxiety. The change in mood-related behavior is not a result of a defective molecular clock, as glial Bmal1 deletion has no effect on neither despair nor anxiety. Exclusive deletion of Per2 in glia of the NAc reduced despair, but had no influence on anxiety. Our data provide strong evidence for an important role of glial Per2 in regulating mood-related behavior.
Highlights
Most organisms from cyanobacteria to humans have time-keeping mechanisms, termed circadian clocks, which allow adaptation to the 24-h day[42]
The PER2 and glial fibrillary acidic protein (GFAP) signal did not overlap in the GPer[2] animals and no yellow color was observed (Fig. 1A, right panel), strongly suggesting that PER2 was absent in glial cells
The activity in the second half of the dark phase (ZT16-22) was for both genotypes higher in the wheel-running assessment compared to the general activity pattern. These results show that the reduced immobility time of GPer[2] animals in the forced swim test (FST) was not due to a higher activity level compared to controls and, the higher activity in the FST is related to despair rather than to general activity
Summary
Most organisms from cyanobacteria to humans have time-keeping mechanisms, termed circadian clocks, which allow adaptation to the 24-h day[42]. A whole-body mutation of the clock gene Per[2] revealed a manic phenotype in the Porsolt’s forced swim test (FST), which was associated with reduced dopamine degradation, leading to increased dopamine levels in the nucleus accumbens (NAc)[23] This is consistent with the view that the pharmacological manipulation of the monoaminergic system regulates mood, explaining in part the pathophysiology of d epression[36]. We deleted Per[2] in GFAP positive cells of adult animals by delivering Cre with an adeno-associated virus to exclude developmental contributions to our experiments Both models lacking Per[2] in Gfap-expressing cells (termed GPer[2] and vGPer2) were assessed for despair- and anxiety-related behavior using the FST and O-maze test, respectively. We observed changes in the glutamatergic and GABAergic systems, as well as upregulation of the dopamine receptor D3
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