Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Early life adversities shape physiological response of VTA dopaminergic neurons to positive and negative stimuli and behavior in adulthood

Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to stress-related psychiatric disorders, such as depression and addiction or, alternatively, increasing resilience to stress effects. We have previously shown that interfering with the development of mother-pups bond by the Repeated Cross Fostering (RCF) protocol induces resilience to depression-like phenotype, and increases susceptibility to cocaine effects in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both in vivo and ex vivo pharmacology approaches to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and their behavior. We found reduced hyperpolarization-activated (Ih) cation current amplitude and evoked firing in VTA dopaminergic neurons from both young and adult RCF female mice. In vivo pharmacological manipulation of the VTA neurons Ih current reverted the pro-resilient to depression phenotype and reduced sensitivity to cocaine effects in adult early-stressed mice or mimicked behavioral resilience to depression in adult control animals. However, ih current manipulation in control mice was not able to increase the sensitivity to cocaine effects. This is the first evidence showing how pro-resilience to depression behavior and susceptibility to cocaine induced by early events are linked to a long-lasting reduction of Ih current and excitability in VTA dopaminergic neurons.