Animals subjected to an inescapable stress environment typically exhibit two different behaviors—active activity (swimming and climbing) and passive activity (immobility) (Lucki, 1997). Passive activity can thus be an indicator of behavioral despair in this paradigm (Porsolt et al., 1977). This passive activity can be reduced by acute or chronic treatment with clinical antidepressant drugs (Liu et al., 2010; Lu et al., 2006). We replicated this finding in rats treated with either a sub-anesthetic dose of ketamine (15 mg/kg i.p.) or fluoxetine (10 mg/kg i.p.). Fluoxetine and ketamine treated rats displayed

significantly reduced duration of passive activity in the forced swim test (Figure 6A) compared to saline-treated rats, confirming antidepressant-like Selleck Epigenetic inhibitor effects of these compounds in this behavioral paradigm. Additionally, diazepam did not have antidepressant-like effects in forced swim test (Figure 6B) even though it showed hyperexploration in OFT, suggesting specificity of this behavioral

test (Figure S6). To determine whether knockdown of HCN1 in the dorsal CA1 region can produce antidepressant-like effects, rats were microinjected bilaterally with lentivirus learn more expressing either shRNA-control or shRNA-HCN1. Similar to fluoxetine or ketamine treatment, knockdown of HCN1 was associated with an antidepressant-like effect compared with shRNA-control-infected animals (Figure 6C). Because shRNA-HCN1-infected rats displayed higher exploration activity

(Figures 5B and 5F) in the open field test, we further analyzed whether there was a relationship between exploration activity and duration of passive activity. We found, however, that there was no correlation between passive activity in FST and exploration activity in OFT (Figure 6D), suggesting specificity of antidepressant-like effects by knockdown of HCN1 in the dorsal hippocampal CA1 aminophylline region. Patients with treatment-resistant depression have pathologically altered activity in the limbic-cortical area (Mayberg et al., 2005). Animal models of depression induced by chronic mild stress display an increase in the ventral CA1 activity. This could be reversed by fluoxetine, highlighting the significance of hippocampal activity in the treatment of depression (Airan et al., 2007). Because genetic silencing of HCN1 gene in a small region of the dorsal hippocampal CA1 region produced anxiolytic- and antidepressant-like effects, it is possible that chronic knockdown of HCN1 could cause changes in hippocampal activity. We used voltage-sensitive dye (VSD) imaging to determine whether a localized, chronic knockdown of HCN1 can change hippocampal activity. We placed a stimulating electrode in the stratum radiatum (SR), near the border between the CA1 and CA2 regions to activate the Schaffer collaterals ( Chang et al., 2007). Both VSD optical signals and extracellular field potentials were recorded in the SR of the CA1 region ( Figures 7B and 7C).