The development of compulsive coping behaviour is associated with a downregulation of Arc in a Locus Coeruleus neuronal ensemble.

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Velazquez-Sanchez, Clara 
Muresan, Leila 
Marti-Prats, Lucia 

Some compulsive disorders have been considered to stem from the loss of control over coping strategies, such as displacement. However, the cellular mechanisms involved in the acquisition of coping behaviours and their subsequent compulsive manifestation in vulnerable individuals have not been elucidated. Considering the role of the locus coeruleus (LC) noradrenaline-dependent system in stress and related excessive behaviours, we hypothesised that neuroplastic changes in the LC may be associated with the acquisition of an adjunctive polydipsic water drinking, a prototypical displacement behaviour, and the ensuing development of compulsion in vulnerable individuals. Thus, male Sprague Dawley rats were characterised for their tendency, or not, to develop compulsive polydipsic drinking in a schedule-induced polydipsia (SIP) procedure before their fresh brains were harvested. A new quantification tool for RNAscope assays revealed that the development of compulsive adjunctive behaviour was associated with a low mRNA copy number of the plasticity marker Arc in the LC which appeared to be driven by specific adaptations in an ensemble of tyrosine hydroxylase (TH)+, zif268- neurons. This ensemble was specifically engaged by the expression of compulsive adjunctive behaviour, not by stress, because its functional recruitment was not observed in individuals that no longer had access to the water bottle before sacrifice, while it consistently correlated with the levels of polydipsic water drinking only when it had become compulsive. Together these findings suggest that downregulation of Arc mRNA levels in a population of a TH+/zif268- LC neurons represents a signature of the tendency to develop compulsive coping behaviours.

Animals, Male, Rats, Adaptation, Psychological, Compulsive Behavior, Down-Regulation, Locus Coeruleus, Neurons, Rats, Sprague-Dawley, RNA, Messenger, Tyrosine 3-Monooxygenase
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Springer Science and Business Media LLC
Wellcome Trust (109738/Z/15/Z)
Medical Research Council (MR/N02530X/1)
Engineering and Physical Sciences Research Council (EP/R025398/1)
This work, carried at the department of Psychology of the University of Cambridge, was funded by a UKRI grant (MR/N02530X/1) to Barry Everitt, Trevor Robbins, Amy Milton, Jeff Dalley and David Belin and a Wellcome Trust Seed Award (109738/Z/15/Z) to DB. Leila Muresan was supported by a EPSRC grant (EP/R025398/1). Lucia Marti-Prats was supported by a Leverhulme Trust Early Career Fellowship (ECF-2018-713) and Isaac Newton Trust fellowship (18.08(g)).