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The cerebral cortex is widely accepted to be involved in the control of cognition and the processing of learned information. However, data suggest that it may also have a role in the regulation of innate responses because rodents, cats or primates with surgical removal of cortical regions show excessive aggression and rage elicited by threatening stimuli. Nevertheless, the imprecision and chronic nature of these lesions leave open the possibility that compensatory processes may underlie some of these phenotypes. In the present study we applied a precise, rapid and reversible inhibition approach to examine the contribution of the cerebral cortex to defensive behaviours elicited by a variety of innately aversive stimuli in laboratory mice. Pharmacological treatment of mice carrying the pharmacogenetic inhibitory receptor hM4D selectively in neocortex, archicortex and related dorsal telencephalon‐derived structures resulted in the rapid inhibition of cerebral cortex neural activity. Cortical inhibition was associated with a selective increase in defensive behaviours elicited by an aggressive conspecific, a novel prey and a physically stressful stimulus. These findings are consistent with a role for cortex in the acute inhibition of innate defensive behaviours. [ABSTRACT FROM AUTHOR]