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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.

Food restriction is a robust nongenic, nonsurgical and nonpharmacologic intervention known to improve health and extend lifespan in various species. Food is considered the most essential and frequently consumed natural reward, and current observations have demonstrated homeostatic responses and neuroadaptations to sustained intermittent or chronic deprivation. Results obtained to date indicate that food deprivation affects glutamatergic synapses, favoring the insertion of GluA2-lacking α-Ammino-3-idrossi-5-Metil-4-idrossazol-Propionic Acid receptors (AMPARs) in postsynaptic membranes. Despite an increasing number of studies pointing towards specific changes in response to dietary restrictions in brain regions, such as the nucleus accumbens and hippocampus, none have investigated the long-term effects of such practice in the dorsal striatum. This basal ganglia nucleus is involved in habit formation and in eating behavior, especially that based on dopaminergic control of motivation for food in both humans and animals. Here, we explored whether we could retrieve long-term signs of changes in AMPARs subunit composition in dorsal striatal neurons of mice acutely deprived for 12 hours/day for two consecutive days by analyzing glutamatergic neurotransmission and the principal forms of dopamine and glutamate-dependent synaptic plasticity. Overall, our data show that a moderate food deprivation in experimental animals is a salient event mirrored by a series of neuroadaptations and suggest that dietary restriction may be determinant in shaping striatal synaptic plasticity in the physiological state.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of different systems of spatial coordinate integration. The high expression of cannabinoid type 1 (CB 1 ) receptors in structures related to spatial learning-such as the hippocampus, dorsal striatum and amygdala-renders the endocannabinoid system a critical target to study the balance between landmark- and cognitive map-based navigational strategies. In the present study, mice treated with the CB 1 -inverse agonist/antagonist AM251 or vehicle were trained on a Circular Hole Board, a task that could be solved through either navigational strategy. At the end of the behavioral testing, c-Fos immunoreactivity was evaluated in specific nuclei of the hippocampus, dorsal striatum and amygdala. AM251 treatment impaired spatial learning and modified the pattern of the performed navigational strategies as well as the c-Fos immunoreactivity in the hippocampus, dorsal striatum and amygdala. The present findings shed light on the involvement of CB 1 receptors as part of the selection system of the navigational strategies implemented to efficiently solve the spatial problem.