acute pharmacogenetic activation of medial prefrontal cortex excitatory neurons regulates anxiety-like behaviour

The medial prefrontal cortex (mpfc) is implicated in anxiety-like behaviour. in rodent models, perturbations of mpfc neuronal activity through pharmacological manipulations, optogenetic activation of mpfc neurons or cell-type specific pharmacogenetic inhibition of somatostatin interneurons indicate conflicting effects on anxiety-like behaviour. in the present study we examined the effects of pharmacogenetic activation of ca2+/calmodulin-dependent protein kinase α (camkiiα)-positive excitatory neurons on anxiety-like behaviour. we used clozapine-n-oxide (cno) to pharmacogenetically activate virally delivered camkiiα-hm3dq-dreadd in mpfc excitatory neurons. the effects of acute cno or vehicle treatment on anxiety-like behaviour in the open field and elevated plus maze tests were examined in rats virally infected with either camkiiα-hm3dq-dreadd or camkiiα-gfp. in addition, the effects of acute cno treatment on the expression of the neuronal activity marker c-fos were examined in the mpfc as well as downstream target neuronal circuits using immunohistochemistry. acute pharmacogenetic activation of mpfc excitatory neurons evoked a significant decrease in anxiety-like behaviour selectively on the elevated plus maze task, but not the open field test. acute cno treatment resulted in enhanced c-fos-immunopositive cell number in the infralimbic, prelimbic and cingulate subdivisions of the mpfc. this was also accompanied by enhanced c-fos-immunopositive cell number in multiple downstream circuits of the mpfc in cno-treated hm3dq animals. acute pharmacogenetic activation of mpfc excitatory neurons reduces anxiety-like behaviour in a task-specific fashion accompanied by enhanced c-fos expression in the mpfc and multiple target circuits implicated in the regulation of anxiety-like behaviour.