SELECTIVE BREEDING FOR DEFICIENT SENSORIMOTOR GATING IS ACCOMPANIED BY INCREASED PERSEVERATION IN RATS F. FREUDENBERG, 1 M. DIECKMANN, 1 S. WINTER, 1 M. KOCH AND K. SCHWABE 1 * Brain Research Institute, Department of Neuropharmacology, Univer- sity of Bremen, P.O. Box 33 04 40, 28334 Bremen, Germany Abstract—Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating that is defi- cient in some neuropsychiatric disorders, such as schizo- phrenia and Tourette’s syndrome. Experimentally induced PPI deficits in rats are regarded as endophenotype to study the biological mechanisms and therapeutic strategies of these disorders. We have recently shown that selectively breeding rats for high and low PPI levels, respectively, leads to groups with different PPI performance that remains stable from the second generation on. We here tested whether the low PPI is accompanied by other behavioral deficits. Different spatial and operant learning paradigms were used to assess rats’ learning and memory abilities as well as their behavioral flexibility. In the delayed alternation T-maze task the two groups did not differ in task acquisition and working memory. Rats with low PPI showed enhanced per- severation during switching between an egocentric and allo- centric radial maze task. Enhanced perseveration was also found in an operant behavioral task, where different de- mands, i.e. a different number of lever presses for a pellet- reward, were assigned to and switched between two levers of a Skinner box. Rats with low PPI stayed longer at the ineffec- tive lever before switching, thus being less able to adjust their behavior to changing reward values. Additionally, PPI low rats had a higher breakpoint value during a progressive ratio-schedule of reinforcement. Rats selectively bred for low PPI showed some cognitive deficits that are apparent in a number of psychiatric disor- ders with deficient information processing. Specifically in both, spatial and operant behavioral paradigms, PPI low rats are deteriorated in their ability to modulate behavior based upon new changing information. They may thus provide a non-pharmacological model that can be used to evaluate new therapeutic strategies ranging from pharmacological treat- ment to functional neurosurgery. © 2007 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: prepulse inhibition, schizophrenia, Tourette’s syndrome, animal model, endophenotype, learning and memory. The concept of the endophenotype or intermediate pheno- type (Gould and Gottesman, 2006; Meyer-Lindenberg and Weinberger, 2006) proposes a biological basis for complex neuropsychiatric diseases that can be studied by using phenotypes that are related to both the clinical symptoms but also to more basic biological mechanisms. Deficits in early information processing or sensorimotor gating are considered core features of schizophrenia and have been linked to psychotic symptom formation and disturbed cog- nitive function in these patients (Cadenhead et al., 2002; Light and Braff, 2005). Deficient sensorimotor gating can be operationalized by reduced prepulse inhibition (PPI) of the startle reaction, which can be measured in humans and animals by using virtually the same approaches. Deficit in PPI is therefore used as an endophenotype marker to study the etiology and pathophysiology underlying the psy- chotic state at the level of animal neurobiology (Braff et al., 2001b). In addition to these sensorimotor gating deficits, disturbed working memory and executive function are con- sidered core features of schizophrenia and thus serve as endophenotypes for this disorder (Hutton et al., 1998; We- ickert et al., 2000; Badcock et al., 2005). Interestingly, in healthy humans, PPI performance has been found to be associated with cognitive functions (Bitsios and Giakou- maki, 2005). We have recently shown that selective breeding in Wistar rats for high and low PPI levels leads to a segre- gation of two rat lines with significantly different PPI al- ready in the first two generations. The PPI deficit in these rats was ameliorated with antipsychotic compounds mak- ing these rats an interesting model with possible predictive validity for the screening of antipsychotic drugs (Hadam- itzky et al., 2007). We here addressed the question, whether these rats show other comorbid features or cog- nitive deficits related to psychiatric disorders with disturbed information processing. For this purpose rats were tested in different spatial and operant paradigms to assess their learning and memory abilities as well as their behavioral flexibility. First, rats were tested in the four-arm baited eight-arm radial maze task, which provides measures of both reference and working memory (Olton, 1979; Olton and Papas, 1979). Thereafter, they were trained in an egocentric strategy, where they had to navigate relative to 1 Present address: Department of Neurosurgery, Medical University, MHH, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany (S. Winter, K. Schwabe); Department of Molecular Neurobiology, Max-Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany (F. Freudenberg); Department of Molecular Neurodegenera- tion, Institute for Physiological Chemistry and Pathobiochemistry, Jo- hannes Gutenberg-University, 55099 Mainz, Germany (M. Dieck- mann). *Correspondence to: K. Schwabe, Department of Neurosurgery, Medical University, MHH, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. E-mail address: schwabe.kerstin@mh-hannover.de (K. Schwabe). Abbreviations: ANOVA, analysis of variance; ASR, acoustic startle response; FR, fixed ratio; ITI, intertrial interval; PE, perseveration error; PLE, perseveration-like error; PPI, prepulse inhibition; RE, re- maining error; RME, reference memory error; SPL, sound pressure level; WCST, Wisconsin Card Sorting Test; WME, working memory error. Neuroscience 148 (2007) 612– 622 0306-4522/07$30.00+0.00 © 2007 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2007.06.034 612