Endocannabinoids, Emotional Behavior and Psychiatric IllnessCannabinoid type 1 receptors located on single-minded 1–expressing neurons control emotional behaviors
Highlights
▶CB1 receptors on Sim1-expressing neurons control locomotor reactivity and anxiety. ▶Cued-fear expression is decreased in Sim-CB1−/− mutants. ▶Repeated stress reverses the decreased cued-fear memory observed in Sim-CB1−/− mutants. ▶Stress-induced adrenal hyperplasia is similar in Sim-CB1+/+ and Sim-CB1−/− mice.
Section snippets
Animals
Sim1-Cre expressing mice (The Jackson Laboratory, Bar Harbor, ME, USA) were crossed with homozygous CB1-flox mice (CB1f/f) (Marsicano et al., 2003) to obtain heterozygous Cre-expressing/CB1-flox mice (CB1Sim1-Cre;f/+, step 1). These mice were again crossed with CB1f/f to obtain homozygous CB1Sim1-Cre;f/f mice (step 2). Male mice from step 2 were finally bred with CB1f/f females to generate littermate experimental animals (CB1Sim1-Cre;f/f and CB1f/f, called thereafter Sim1-CB1−/− and Sim1-CB1+/+
Focal excision of the CB1 allele in the CNS of Sim1-CB1−/− mice
The PCR analysis of genomic DNA extracted from brain regions of wild-type and mutant mice revealed an effective deletion of the CB1 allele in the hypothalamus and the amygdala of Sim1-CB1−/− mice (Fig. 2). On the other hand, the CB1 allele was found to be present in the mutant mouse cortex, striatum, thalamus, nucleus accumbens, brainstem, hippocampus, pituitary gland, and spinal cord (Fig. 2). In keeping with the role of the PVN in the regulation of the HPA axis, we also checked whether the
Discussion
A previous study has reported that Sim1-Cre mice effectively express Cre activity in all brain regions/nuclei that express Sim1 (Balthasar et al., 2005). In turn, in situ hybridization experiments aimed at tagging areas expressing Sim1 mRNAs have shown strong expression in the hypothalamus—especially in PVN/SON—and in the nucleus of the lateral olfactory tract (Balthasar et al., 2005). Lower expression levels of Sim1 expression were observed in the MBA, in the LH and PH, in the BNST, and in the
Conclusion
This study reveals that CB1 receptors located on Sim1-expressing neurons exert a tonic inhibitory control over locomotor reactivity and a tonic stimulatory control on anxiety behavior when confronted acutely with novel environments. On the other hand, following acute and repeated stress, these receptors exert an inhibitory control over anxiety and cued-conditioned fear, respectively. In keeping with the high concentration of Sim1-expressing neurons in the PVN and the reduction of CB1 receptor
Acknowledgments
We are grateful to colleagues from the laboratory for fruitful discussions, to Delphine Gonzales and Claire Lordan and the Genotyping Platform of the NeuroCentre Magendie for mouse genotyping, to Magali Billy, Magalie Soares, Fiona Corailler, Hélène Doat, Jean-Pierre Villars, and the Animalerie Centrale of the NeuroCentre Magendie for taking care of the animals. This study was supported by grants from la Délégation Générale à l'Armement (to S.D.), EU-FP7 (Reprobesity, Health-F2-2008-22371 to
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