Abstract
Anxiety disorders are amongst the most prevalent mental health disorders. Several lines of evidence have implicated cortical regions such as the medial prefrontal cortex, orbitofrontal cortex, and insular cortex along with the hippocampus in the top–down modulation of anxiety-like behaviour in animal models. Both rodent models of anxiety, as well as treatment with anxiolytic drugs, result in the concomitant activation of multiple forebrain regions. Here, we sought to examine the effects of chemogenetic activation or inhibition of forebrain principal neurons on anxiety and despair-like behaviour. We acutely activated or inhibited Ca2+/calmodulin-dependent protein kinase II α (CamKIIα)-positive forebrain excitatory neurons using the hM3Dq or the hM4Di Designer Receptor Exclusively Activated by Designer Drug (DREADD) respectively. Circuit activation was confirmed via an increase in expression of the immediate early gene, c-Fos, within both the hippocampus and the neocortex. We then examined the influence of DREADD-mediated activation of forebrain excitatory neurons on behavioural tests for anxiety and despair-like behaviour. Our results indicate that acute hM3Dq DREADD activation of forebrain excitatory neurons resulted in a significant decline in anxiety-like behaviour on the open field, light–dark avoidance, and the elevated plus maze test. In contrast, hM3Dq DREADD activation of forebrain excitatory neurons did not alter despair-like behaviour on either the tail suspension or forced swim tests. Acute hM4Di DREADD inhibition of CamKIIα-positive forebrain excitatory neurons did not modify either anxiety or despair-like behaviour. Taken together, our results demonstrate that chemogenetic activation of excitatory neurons in the forebrain decreases anxiety-like behaviour in mice.
Highlights
Multiple cortical circuits including the medial prefrontal cortex (Davidson, 2002; Tovote et al, 2015), orbitofrontal cortex (Milad and Rauch, 2007), anterior insula (Paulus and Stein, 2006), primary motor cortex (Li et al, 2018), somatosensory cortices (Rauch, 1995), and the hippocampal subfields (Shin and Liberzon, 2010; Calhoon and Tye, 2015) are implicated in the modulation of anxiety-like behaviour
Immunohistochemical analysis indicated a significant increase in c-Fos positive cell numbers within the dentate gyrus (DG), CA1, and CA3 hippocampal subfields of CNO treated calmodulin-dependent protein kinase II α (CamKIIα)-tTA:TetO-hM3Dq mice (Figure 1E, p = 0.015 DG, p = 0.009 CA1, p = 0.03 CA3)
We examined the influence of hM4Di Designer Receptor Exclusively Activated by Designer Drug (DREADD)-mediated inhibition of the cortex and hippocampus 2 h following acute CNO (0.5 mg/kg) administration using western blotting for the neuronal activity marker, c-Fos (Figure 1F)
Summary
Multiple cortical circuits including the medial prefrontal cortex (mPFC) (Davidson, 2002; Tovote et al, 2015), orbitofrontal cortex (Milad and Rauch, 2007), anterior insula (Paulus and Stein, 2006), primary motor cortex (Li et al, 2018), somatosensory cortices (Rauch, 1995), and the hippocampal subfields (Shin and Liberzon, 2010; Calhoon and Tye, 2015) are implicated in the modulation of anxiety-like behaviour. While several previous studies using rodent models have dissected the contribution of individual cortical and subcortical circuits in the modulation of specific anxiety-like behavioural responses, it is likely that diverse brain regions, including multiple cortical circuits, would be concomitantly recruited in an ethological context This is supported by studies in diverse rodent models associated with increased anxiety-like behaviour, such as immobilisation stress (Ons et al, 2004), air puff (Duncan et al, 1996), swim stress (Molteni et al, 2008), exposure to novel environments such as an open field (Santini et al, 2011), elevated plus maze (EPM) (Muigg et al, 2009), and exposure to cat odour (Úbeda-Contreras et al, 2018), as well as in response to pharmacological agents that modulate anxiety-like behaviour (Hoehn-Saric et al, 2004; Linden et al, 2004; Wise et al, 2007). These findings indicate that acute chemogenetic activation of forebrain excitatory neurons exerts anxiolytic effects across diverse anxiety-related behavioural tasks
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