The relationship existing between stress and development of psychopathologies is widely studied as psychiatric disorders, including depression, affect large numbers of people worldwide. Luckily, not all individuals are equally affected by exposure to aversive events, indicating a role for the interplay between genetic and environmental factors in determining the behavioural outcome. We have previously shown that the RCF manipulation (a stressing disruption of the newborn-mother relationship) of C57 females induces pro-resilience behavior in adults via a long-lasting reduction of both hyperpolarization-activated (Ih) current and evoked cell excitability in identified DAergic neurons of the intermediate VTA (D'Addario et al., 2021). Here, we aim to expand our research and show that, in a mirrored way, the susceptibility to depression shown by adult DBA RCF females is paralleled by a potentiation of both Ih current and cell excitability in those neurons. We also predict that DBA males will lack such alterations, as they are unaffected by RCF. Last, we want to investigate whether the long-lasting modulation of DAergic neurons equally affects all VTA neurons, or, rather, is induced in a cell/area-selective manner. To do so, we will adopt a multidisciplinary approach based on the use of behavioral tests, slice patch-clamp recording, in vivo intraVTA infusion of drugs and retrograde labelling / mapping of VTA neurons. We hope that our studies will help demonstrating that the long-term (epigenetic) modulation of the electrophysiological profile of TH+ neurons of the intermediate VTA represents the `crosslink between post-natal stressing experience and development of resilience/depression in adulthood of individuals with different genetic background.
To the best of our knowledge, no one had shown insofar how pro-resilience behavior induced by early events is linked to a long-lasting reduction of Ih current and excitability in VTA DAergic neurons. We demonstrated such link using C57 females challenged with the RCF protocol (35). Here we intend to expand our study to investigate possible roles for genetic differences across mouse strains (DBA vs C57) and for gender differences within the same genetic background in relation to functional properties of VTA neurons. In fact, provided the same early-life experience (RCF protocol), adult DBA RCF females develop susceptibility to depression at odd with both C57 RCF females (showing resilience) and DBA RCF males (appearing unaltered). Such different sensitivity on individual basis is intriguingly similar to what happens in humans and prompted us to a deep investigation of its neuronal bases. We expect a long-lasting increase of Ih current and excitability in VTA DAergic neurons from pro-depression DBA RCF females and lack of electrophysiological alterations in neurons from DBA RCF males.
Notably, considered that different sub-regions of the VTA project to brain areas distinct as per control of higher functions (e.g. mood; reward; motor control), here we also intend to identify exactly which VTA sub-region is mostly involved with the RCF / resilience-depression outcome link.
If our working hypotheses will be experimentally verified, the new insights potentially brought onto the scientific community by our project would describe how the (epi)genetic modulation of DAergic neurons belonging to specific areas of the VTA may play a role in entering, during adult life, resilience or vulnerability to the depression-like phenotype following exposure to stressing experiences during early-life.
This multidisciplinary, interdepartmental study performed at the behavioral, network and cellular level on acquired animal models of post-natal stress will hopefully provide robust evidences helping clarifying mechanisms which might be, at least in part, also occurring in humans, thus indicating potential targets for cell/molecule specific therapeutic interventions in depression-related psychopathology.
Our preliminary results from DBA RCF females show (Fig.2) that indeed depression-like behavior induced by RCF in DBA adult females correlates with a long-lasting potentiation of Ih current and excitability in TH+ DAergic neurons of the intermediate, but not lateral VTA, thus proving our working hypotheses insofar valid.