TY - JOUR
T1 - Behavioral flexibility in a mouse model for obsessive-compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants
T2 - Impaired Pavlovian reversal learning in SAPAP3 mutants
AU - van den Boom, Bastijn J. G.
AU - Mooij, Adriana H.
AU - Misevičiūtė, Ieva
AU - Denys, Damiaan
AU - Willuhn, Ingo
N1 - © 2019 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.
PY - 2019
Y1 - 2019
N2 - Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3 −/− ) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3 −/− display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3 −/− and wild-type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS−), contingencies were reversed (CS+ became CS− and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3 −/− acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3 −/− were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3 −/− are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3 −/− not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3 −/− as a suitable model for the study of OCD. The observation that compulsive-like behavior, anxiety and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for the treatment of OCD.
AB - Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3 −/− ) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3 −/− display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3 −/− and wild-type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS−), contingencies were reversed (CS+ became CS− and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3 −/− acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3 −/− were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3 −/− are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3 −/− not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3 −/− as a suitable model for the study of OCD. The observation that compulsive-like behavior, anxiety and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for the treatment of OCD.
KW - Animals
KW - Conditioning, Classical
KW - Female
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Nerve Tissue Proteins/genetics
KW - Obsessive-Compulsive Disorder/genetics
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85062344283&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30688005
U2 - https://doi.org/10.1111/gbb.12557
DO - https://doi.org/10.1111/gbb.12557
M3 - Article
C2 - 30688005
SN - 1601-1848
VL - 18
SP - e12557
JO - Genes, brain, and behavior
JF - Genes, brain, and behavior
IS - 4
M1 - e12557
ER -