Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of Ih current in VTA dopaminergic neurons

Abstract

Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to either stress-related psychiatric disorders, including depression, or to well-adaptation to future adversity and sources of stress, a behavior phenotype termed “resilience”. We have previously shown that interfering with the development of mother-pups bond with the Repeated Cross Fostering (RCF) stress protocol can induce resilience to depression-like phenotype in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both in vivo and ex vivo pharmacology to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and behavioral resilience. We found reduced hyperpolarization-activated (I h ) cation current amplitude and evoked firing in VTA dopaminergic neurons from both young and adult RCF female mice. In vivo , VTA-specific pharmacological manipulation of the I h current reverted the pro-resilient phenotype in adult early-stressed mice or mimicked behavioral resilience in adult control animals. This is the first evidence showing how pro-resilience behavior induced by early events is linked to a long-lasting reduction of I h current and excitability in VTA dopaminergic neurons.

Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

“…Preparation of midbrain slices ( N = 3 mice/group) was performed as described previously [ 22 , 35 ]. Briefly, mice were anesthetized with halothane and decapitated.…”

Interactions Between Experience, Genotype and Sex in the Development of Individual Coping Strategies

“…A complex genotype × sex interaction moderates the long-term effects of RCF on coping with FST. Thus, the early manipulation of the social environment did not influence levels of immobility expressed by adult D2 male mice, it increased levels of immobility expressed by B6 male and D2 females and it decreased immobility levels expressed by B6 females (Di Segni et al, 2016 , 2019 ; D’Addario et al, 2021 ; Lo Iacono et al, 2021 ). This variability does not seem to depend on variable sensitivity to the manipulation of the early environment.…”

“…Early postnatal life represents a particularly relevant time window for individual development, since it is characterized by the extreme sensitivity of neurodevelopment trajectories to environmental influences (Daskalakis et al, 2013 ; Di Segni et al, 2018 ; Luby et al, 2020 ; Nelson and Gabard-Durnam, 2020 ; Babicola et al, 2021 ; D’Addario et al, 2021 ; Lo Iacono et al, 2021 ). Early experiences can shape synaptic plasticity (Aisa et al, 2009 ; Lupien et al, 2009 ; Korosi et al, 2012 ) permanently affecting brain functioning and modulating behavioral response to stimuli in adulthood (Mintz et al, 2005 ; Coccurello et al, 2009 ; Mcclelland et al, 2011 ).…”

“…These experiences can regulate flexibility of stress coping strategies adopted in adult life leading to either adaptive or maladaptive coping styles (Pryce et al, 2005 ; Arborelius and Eklund, 2007 ; Jezierski et al, 2007 ; Lupien et al, 2009 ; Rivarola and Suarez, 2009 ). Thus, several studies have shown that the same negative events experienced in early life can result in higher susceptibility to mental disturbances but also strengthen resilience to adverse experiences in adulthood (Di Segni et al, 2017 , 2018 ; D’Addario et al, 2021 ). Finally, precocious aversive experiences can differently impact physical and mental health depending on genetics (Di Segni et al, 2017 , 2018 ).…”

“…Sex differences in transcriptional signatures of early and adult stress exposure in many brain regions have been reported in both human and animal models (see Brivio et al, 2020 for review; Labonté et al, 2017 ; Barko et al, 2019 ; Peña et al, 2019 ; Parel and Peña, 2020 for review). Data collected in RCF-exposed B6 females indicate a major influence of the early experience on the plasticity of DA neurons located in the ventral tegmental area (VTA; D’Addario et al, 2021 ), in line with the previously described alteration of the mesocorticolimbic DA response to positive/aversive experiences by these mice (Di Segni et al, 2016 , 2017 ), and very recent findings (Lo Iacono et al, 2021 ) revealed the role of interaction between sex and genotype on RCF-induced alteration of transcripts in the VTA of adult mice.…”