Serotonin 1A receptor knockout (5-HT1AR KO) mice exhibit increased behavioral inhibition in conflict tests. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests. First, we considered whether behavioral inhibition in these knockout mice is a consequence of reduced exploratory motivation. The knockout mice engage in normal exploration during a light-dark test and normal exploration of a novel object in a familiar environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Second, we tested whether these mice exhibit increased behavioral inhibition in response to any aversive cues, or whether this response depends on cue modality. Knockout mice respond normally to discrete aversive cues in the Vogel lick-suppression test, arguing that their phenotype is restricted to conflict tests based on complex or spatial aversive cues. Third, to probe the processing of spatial aversive cues, we assessed fear conditioning to contextual cues. After contextual fear conditioning, knockout and wild-type (WT) mice express freezing responses when exposed to the training environment. However, when placed in an ambiguous environment containing both conditioned and novel cues, the freezing response of knockout mice does not significantly decrease as it does in WT mice, suggesting that the knockout fear response is biased toward threatening cues. We hypothesize that this inappropriate generalization of fearful behavior to a context containing both fearful and neutral stimuli, a phenomenon that occurs in a subset of human anxiety disorders such as panic disorder and post-traumatic stress disorder, underlies the anxiety phenotype of 5-HT1AR KO mice.
Bibliographical noteFunding Information:
This study was supported by NIH Grants F32 MH12364 and K01 MH64948 (CTG), NIMH Grant R01 MH068542, NIH Grant P01 MH48125 and a NARSAD Distinguished Investigator Award (RH), and NIMH Grant K08 MH069823 (JAG). KCK was supported by an NSF Graduate Research Fellowship. JAG is a Pfizer Foundation Postdoctoral Fellow in Biological Psychiatry, and is supported by the Bowman Family Foundation as a NARSAD Young Investigator. We are grateful to Caroline Ling for her help with initial fear conditioning experiments.
- Fear conditioning
- G-protein-coupled receptor