Patients with myotonic dystrophy have numerous physical symptoms, including musclular, skeletal, cardiac and vision difficulties. It has been long realized that they experience cognitive impairment, with a lower IQ overall and specific deficits in attention, visuo-spatial function, perception, executive function and autism spectrum disorder symptoms     
. Apathy, hypersomnia and anxiety have been more recently associated with myotonic dystrophy and are dissociable from the physical disabilities. They appear to be explicit symptoms of the disease, and like the physical symptoms, there is a correlation with the severity of disease and cognitive deficits in which less severely affected patients generally have milder cognitive deficits.
The pleiotropy of this disease is reflected in symptoms, their severity and the molecular alterations that occurs. The disease is caused by a trinucleotide repeat expansion situated in the 3′UTR of the DMPK
gene, located immediately 5′ of the SIX5
gene but the core of the biochemical defect is sequestration of MBNL1 by the expanded trinucleotide repeat RNA in nuclear foci. RNA processing is disrupted, in part due to inactivation of the alternative splice regulator, MBNL1 which normally regulates splicing of several transcripts including Cncl1
, a chloride channel associated with myotonia  
. This RNA-dominant disease consequently has many possible molecular alterations that lead to individual symptoms. Therefore, it is important to ascertain which molecular alteration leads to the cognitive and emotional deficits seen in DM1 patients.
Neither Six5−/− nor Dmpk−/− mice appear to affect cognitive function in mouse models of DM1. In DM1, a trinucleotide repeat is expanded and disrupts normal RNA processing in the nucleus, and sequestering Mbnl1 protein in specific foci. Since in both Six5−/− and Dmpk−/− mice, there is no trinucleotide repeat, these mutants can be used to differentiate between the direct effect of a gene and the effect of impairing the function of other proteins with which they interact. Supporting the hypothesis that RNA metabolic disruption is key to the development of DM1 symptoms, we found deficits only in the Mbnl1−/− mice. Mbnl1−/− mice have normal spatial learning and memory but show severe alterations in motivated behavior. Specifically, Mbnl1−/− mice showed signs of motivation and apathy in a physically demanding task (Morris water maze) or a simple task (sucrose consumption).
Due to their physical symptoms, the cognitive and emotional phenotype of the Mbnl1−/−
mice is difficult to assess. However, Mbnl1−/−
mice show unmotivated behavior in the water maze, failing to switch from passive strategies to a spatially selective search as exhibited by increased floating in the watermaze task 
. Interestingly, this increased floating only manifested after probe trials were performed. Combining this observation with normal performance in the visual watermaze suggests a complex interaction between the difficulty of the task and a substantial motivational component that underlie their lack of spatial acquisition, with the possibility that muscular weakness also contributes to apathy. Thus, Mbnl1−/−
mice may become unmotivated if they fail to learn the platform location expediently. A number of Mbnl1−/−
mice also exhibited such pronounced thigmotaxis that they were excluded from final analysis. The remaining Mbnl1−/−
mice showed normal spatial learning and memory when tested without the platform present, however, the Mbnl1−/−
mice that demonstrated pronounced thigmotaxis did not show any spatial learning and memory. This demonstrates that Mbnl1 deficit in these mice results in a range of severity of the observed phenotypes.
To substantiate a phenotype of decreased motivation, we tested Mbnl1−/−
mice for apathy towards sucrose. The mice were tested in their home cage with the sucrose and water bottles presented in their normal location. Therefore, physical complications of this task are minimal as the physical demands are the same as drinking water in their home cage: these mutants do not experience dehydration from an inability to reach the water bottle. In this test for anhedonia, Mbnl1−/−
mice show preference for sucrose over water at a much reduced rate than their wild-type counterparts. The Mbnl1−/−
mice appear to require a higher reward as a 16% solution was equally appealing to the Mbnl1−/−
mice as a 4% solution was to the wild-type mice. This suggests that the mutant mice do not have an innate aversion to sucrose but instead that they have a decreased interest in seeking a sweet reward. This finding may be particularly relevant as apathy is a striking feature in myotonic dystrophy patients and has been shown to be independent of both clinical depression and peripheral muscular weakness 
In addition to lack of motivation, myotonic dystrophy patients have increased anxiety. We tested all three mutant mouse strains for alterations in anxiety levels and only Mbnl1−/− mice exhibited high levels of thigmotaxis, a behavior indicative of anxiety. Although Dmpk−/− and Six5−/− showed no overt anxiety phenotype in the open field, we performed only one test of anxiety and thus subtle phenotypes may exist that can be detected using other tests. In a second test of anxiety, the elevated plus maze, the Mbnl1−/− mice showed conflicting signs of increased and decreased anxiety. Given these ambiguous results, it is difficult to determine if these mice are good models of anxiety observed in myotonic dystrophy patients. Furthermore, it would be difficult to determine the basis for their altered performance in either the open field and elevated plus maze tasks. The underlying cause of altered performance could be decreased motivation to explore, increased anxiety or musculoskeletal effect, or a combination of all three factors, all three of which are consistent with the human disease.
Finally, contextual associative learning was normal in the Mbnl1−/−
mice. Since DM patients do not show remote memory deficits, we did not test memory at later times. Specifical alterations in 24-hour memory consolidated and remote memory were not tested however, based on a normal memory phenotype at seven days, which is it is indicative of protein-synthesis dependent memory and the transition to a remote memory 
, we speculate that all three mutant strains will show relatively normal memory at these times as well. Taken together, these data suggest a normal spatial learning, with a complex motivational alteration that may result in part through an interaction of muscular effects with emotional state in Mbnl1−/−
Important questions to address in the future will be to assess motivational drive in Mbnl1−/−
mice with normal musculoskeletal function. Since these are separable in patients with DM1, it is likely that the transcripts controlled by Mbnl1 processing may play a specific role in apathy and motivation. The specific transcripts that undergo altered splicing due to Mbnl1 are not all known. Deep sequencing of the different mutant models of DM1 will be very useful in generating and further refining genotype/phenotype relationships. Mbnl1 belongs to a three-member family, and the role of specific Mbnl family members may further refine our understanding of the transcriptional misregulation that leads to specific symptoms 
. The lack of these specific phenotypes in the Dmpk−/−
mice suggests that these genes do not play a role in motivation when they are specifically deleted but their dysfunction, as caused by the DM1 trinucleotide repeat expansion, may still participate in generating cognitive effects in patients. Defining the specific regions of the brain that show functional impairment in Mbln1 knockout mice and identification of Mbnl1 target RNAs in these areas will be critical to understanding this complex phenotype. These lines of inquiry should allow key insights into the molecular targets and circuits that regulate motivation, and spatial learning and memory in humans.