Brain Research Bulletin 79 (2009) 310–315 Contents lists available at ScienceDirect Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull Research report Subtle but progressive cognitive deficits in the female tgHD hemizygote rat as demonstrated by operant SILT performance Simon Brooks a,∗ , Steven Fielding a , Màtè Döbrössy b , Stephan von Hörsten c , Stephen Dunnett a a Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, Wales, UK b Stereotactic Neurosurgery, Universitaets-Klinikum Freiburg, Breisacher Str. 64, 79106 Freiburg, Germany c Experimental Therapy, Franz-Penzoldt-Center, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany article info Article history: Received 8 January 2009 Received in revised form 5 March 2009 Accepted 16 March 2009 Available online 28 March 2009 Keywords: Operant SILT Implicit learning tgHD rat Huntington’s disease abstract In accordance with the genetic nature of Huntington’s disease (HD), transgenic and knock-in mouse mod- els have been developed that have sought to recapitulate the key features of the human condition. To date, only a single rat model has been developed, the tgHD rat that carries 51 CAG repeats. The tgHD rat has many of the anatomical and behavioural characteristics of HD, including cognitive, emotional and motor abnormalities. To characterize this model further, hemizygous tgHD rats were tested on an operant serial implicit learning task (SILT), to determine whether these animals have an implicit learning deficit as reported in HD patients. The SILT utilises a predictable two-stage sequence of responding to two consec- utive stimuli (S1 and S2) as a probe of implicit learning, embedded amongst many randomly presented two-stage sequences. The results suggest that the hemizygous tgHD rats have a mild but progressive cog- nitive deficit that is attentional in nature. Longitudinal responding to the S1 stimuli demonstrated deficits that progressed over time for both accuracy and reaction time measures, whereas responses to S2 stim- uli were mild and stable over time. Whilst a significant effect of predictability over time was identified, analyses of the final time point alone, failed to demonstrate between group differences in their ability to utilise the predictable information at this time point, when differences between the groups should be at their most pronounced. The results suggest that the hemizygous tgHD rats have mild cognitive deficits that are attentional in nature, but no implicit learning deficit. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Huntington’s disease (HD) is characterized primarily by a func- tional choreic movement which ultimately dissipates as the disease progresses. In addition, HD also induces an array of progressive cognitive deficits [19,23–25,44] that quite often precede the more overt motor symptoms [12,21]. HD is caused by a single mutation in the huntingtin gene on chromosome 4, coding for the huntingtin protein, and results in a version of the protein that carries exces- sive (>36) CAG repeats [17]. Through unknown mechanisms, the mutation causes the abnormal deposition of cytoplasmic and intra- nuclear N-terminal protein fragments that aggregate together to create dense protein inclusions [9,11]. Intra-nuclear inclusions are one of the characteristic features of HD pathology, but the most salient feature of HD in post mortem studies is the massive striatal cell loss and general brain atrophy [8,13,43], which is believed to be primarily responsible for the functional abnormalities. In order to study the disease, many mouse models have been created that use either transgenic (for example [28,35]) or knock-in ∗ Corresponding author. Tel.: +44 2920 874115. E-mail address: BrooksSP@cardiff.ac.uk (S. Brooks). (for example [26,36,45]) technology to integrate HD genetic mate- rial into the mouse genome. The identification of deficits in these animals permits the attempts at subsequent modification of those deficits through the application of novel therapeutic strategies. To date, none of the mouse models faithfully capture the essence of the disease, despite being genetically similar to the disorder. However each of the mouse models displays one or more aspects of the HD phenotype, whether that is striatal and/or cortically specific inclu- sion formation or cell loss [26,29,37,41,45], motor [6,26,28,29] or cognitive [3,27,39,40] impairment, or emotional abnormality [15]. In 2003, the first transgenic rat model, the tgHD rat, was reported [42], which expressed cognitive, emotional and motor disturbances, with spatially specific inclusion depositions and striatal cell loss [20,42]. In addition, the rat model only carried 51 CAG repeats, well within the common pathological range in humans, in contrast to the mouse models, that generally are required to carry between 80 and 150 repeats (depending on the model) to demonstrate behavioural abnormalities. A further benefit from using a rat model is that the rat is much better suited to cognitive testing than the mouse. People with HD exhibit an implicit learning deficit, believed to be caused by the loss of striatal neurons [14,21,22]. In order to probe for implicit learning deficits in experimental rodents, we developed an operant serial implicit learning task (SILT) [18]. This task uses 0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2009.03.003