Transcriptomic and Network Analyses Reveal Immune Modulation by Endocannabinoids in Approach/Avoidance Traits

Andrea Termine, Carlo Fabrizio, Juliette Gimenez, Anna Panuccio, Francesca Balsamo, Noemi Passarello, Silvia Caioli, Luana Saba, Marco De Bardi, Francesco Della Valle, Valerio Orlando, Laura Petrosini, Daniela Laricchiuta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Approach and avoidance (A/A) tendencies are stable behavioral traits in responding to rewarding and fearful stimuli. They represent the superordinate division of emotion, and individual differences in such traits are associated with disease susceptibility. The neural circuitry underlying A/A traits is retained to be the cortico-limbic pathway including the amygdala, the central hub for the emotional processing. Furthermore, A/A-specific individual differences are associated with the activity of the endocannabinoid system (ECS) and especially of CB1 receptors whose density and functionality in amygdala differ according to A/A traits. ECS markedly interacts with the immune system (IS). However, how the interplay between ECS and IS is associated with A/A individual differences is still ill-defined. To fill this gap, here we analyzed the interaction between the gene expression of ECS and immune system (IS) in relation to individual differences. To unveil the deep architecture of ECS-IS interaction, we performed cell-specific transcriptomics analysis. Differential gene expression profiling, functional enrichment, and protein–protein interaction network analyses were performed in amygdala pyramidal neurons of mice showing different A/A behavioral tendencies. Several altered pro-inflammatory pathways were identified as associated with individual differences in A/A traits, indicating the chronic activation of the adaptive immune response sustained by the interplay between endocannabinoids and the IS. Furthermore, results showed that the interaction between the two systems modulates synaptic plasticity and neuronal metabolism in individual difference-specific manner. Deepening our knowledge about ECS/IS interaction may provide useful targets for treatment and prevention of psychopathology associated with A/A traits.

Original languageEnglish (US)
Article number2538
JournalInternational journal of molecular sciences
Issue number5
StatePublished - Mar 1 2022

Bibliographical note

Funding Information:
Funding: This work was supported by the Italian Ministry of Health (Grant number GR-2018-12365733 to D.L.), Ricerca Corrente of IRCCS Fondazione Santa Lucia, Rome, Italy (to L.P.), and KAUST BAS 01/01 (to V.O.).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • Endocannabinoid system
  • Endocannabinoids
  • Immune system
  • Network analysis
  • RNA-Seq
  • Transcriptomics

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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