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Updated: Oct 19, 2026
HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice
Published on: July 9, 2016
Serotonin 1B receptors expressed on forebrain excitatory neurons mediate the post-acute anxiolytic response to
Sixtine Fleury1, Yian Shang1, Katherine M Nautiyal2
1Department of Psychological and Brain Sciences, Dartmouth College, 3 Maynard Street, Hanover, NH, 03755, USA.
Introduction:
Psilocybin can produce rapid and sustained antidepressant-like and anxiolytic effects, yet the receptor and circuit mechanisms underlying these behavioral changes remain unclear. While the serotonin 2A receptor mediates psilocybin's acute psychedelic effects, psilocin (the active metabolite of psilocybin) binds many serotonin receptor subtypes. Our prior work has identified the serotonin 1B receptor (5-HT1BR) as being necessary for the post-acute pro-hedonic and anxiolytic effects of psilocybin in mice. 5-HT1BRs are widely expressed throughout the brain on many different neuron subtypes.
Methods:
In order to assess the role of 5-HT1BR expression on terminals of forebrain excitatory neurons in the response to psilocybin, we used a conditional genetic approach to selectively eliminate expression of htr1b in forebrain excitatory neurons using the Emx1 promoter. We examined acute behavioral responses, post-acute anxiolytic effects, and brain-wide neural activation to a single high dose of psilocybin in male and female mice.
Results:
The absence of 5-HT1BR expression on Emx1+ neurons did not alter psilocybin's acute behavioral effects, including head twitch responding and hyperlocomotion. However, psilocybin's post-acute anxiolytic effects in the elevated plus maze (EPM) and novelty suppressed feeding (NSF) assays were strongly attenuated in mice lacking these receptors. Whole-brain c-Fos mapping across 190 regions revealed that psilocybin produced robust activation across the brain in both genotypes, including prefrontal cortices, corticolimbic structures, and sensory cortices. Network-level analyses revealed that psilocybin drove broad inter-regional decorrelation in control mice but increased synchronization in knockouts, with thalamic, prefrontal, and amygdala circuits most strongly affected.
Conclusions:
These findings implicate 5-HT1BRs expressed on terminals of forebrain excitatory neurons as a potential circuit-level excitatory gating mechanism. Overall, these receptors may be important for a coordinated network reorganization following psilocybin that contributes to the anxiolytic behavioral effects.
