Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Oxytocinergic system alteration induced by attachment bond disruption mediates altered reward sensitivity in adulthood

Early life experiences have the potential role to alter both brain development and adult behavior. Particularly, the formation of the attachment bond is crucial for well-being and mental health, and its disruption is related to expression of several psychopathologies, such as drug addiction. Interestingly, oxytocin (Oxt) plays an important role in the formation of the attachment bond and dopaminergic (DA) circuits development, and alterations of both Oxt and DA systems are involved in drug addiction. We have recently showed that an early life manipulation (Repeated Cross Fostering, RCF) able to alter the mother-pups bond induces in C57 female mice a behavioral phenotype characterized by increased vulnerability to cocaine effects in adulthood affecting DA mesocorticolimbic system. Here, we first replicate behavioral data of RCF female mice, also showing new specific social deficit induced by the RCF manipulation. Then, we hypothesize that RCF manipulation impacts Oxt system development altering the sensitivity to rewarding stimuli (cocaine, social novelty, saccharine) in adult life. To test this hypothesis, we investigated the main targets of the Oxt system: Oxt levels, Oxt receptor (OxtR) within the mesocorticolimbic system and the Receptors for Advanced Glycation End-Products (RAGE) (a recently identified Oxt transporter), across different cellular subtypes in pFC. We found that RCF manipulation induced in C57 female at postnatal day (PND) 5, a reduction in Oxt brain levels and and increase in OXT plasma levels, that persist into adulthood. Moreover, in adult RCF compared to Control females, altered OxtR and OXT levels in the nucleus accumbens (NAc) were also observed. Finally, we also reported reduced RAGE expression in specific cellular subtypes in pFC. Restoring brain oxytocin levels through subcutaneous injection of oxytocin (20ul, 0.2 ng/ul) from PND1 to PND4, was sufficient to reduce increased sensitivity to cocaine effects in adult RCF females (as evaluated by cocaine-induced Conditioned Place Preference) as well as social novelty, without affecting saccharine preference. Importantly, the early OXT pharmacological treatment also induced opposite effects compared to the RCF manipulation on brain and plasma OXT levels, NAc OxtR expression and RAGE expression in pFC. Altogether, our results demonstrate the critical role for Oxt system in RCF-induced vulnerability to cocaine effects and social novelty reported in adult C57 females.