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

Sebastian Luca D'Addario; Matteo Di Segni; Ada Ledonne; Rosamaria Piscitelli; Lucy Babicola; Alessandro Martini; Elena Spoleti; Camilla Mancini; Donald Ielpo; Francesca R D'Amato; Diego Andolina; Davide Ragozzino; Nicola B Mercuri; Carlo Cifani; Massimiliano Renzi; Ezia Guatteo; Rossella Ventura

doi:10.1016/j.ynstr.2021.100324

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

Neurobiol Stress. 2021 Apr 15:14:100324. doi: 10.1016/j.ynstr.2021.100324. eCollection 2021 May.

Authors

Sebastian Luca D'Addario^{1

2

3}, Matteo Di Segni², Ada Ledonne², Rosamaria Piscitelli^{2

4}, Lucy Babicola^{1

2}, Alessandro Martini², Elena Spoleti⁵, Camilla Mancini⁶, Donald Ielpo^{1

2

3}, Francesca R D'Amato⁷, Diego Andolina^{1

2}, Davide Ragozzino^{2

5}, Nicola B Mercuri^{2

8}, Carlo Cifani⁶, Massimiliano Renzi⁵, Ezia Guatteo^{2

4}, Rossella Ventura^{1

2}

Affiliations

¹ Dept. of Psychology and Center "Daniel Bovet", Sapienza University, Rome, Italy.
² IRCCS Fondazione Santa Lucia, Roma, Italy.
³ Behavioral Neuroscience PhD Programme, Sapienza University, Piazzale Aldo Moro, 5 00184, Rome, Italy.
⁴ Dept. of Motor Science and Wellness, 'Parthenope' University, Via Medina 40, 80133 Naples, Italy.
⁵ Department of Physiology and Pharmacology, Sapienza University, Rome, 00185, Italy.
⁶ University of Camerino School of Pharmaceutical Sciences and Health Products, Camerino, Italy.
⁷ Biochemistry and Cell Biology Institute, National Research Council, Via E Ramarini 32, 00015, Monterotondo Scalo, Roma, Italy.
⁸ Dept. of Systems Medicine, Tor Vergata University, 00133, Rome, Italy.

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.

Keywords: Early stress; Ih current; In vivo pharmacology; Resilience; VTA.