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Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease.

Abada YS, Nguyen HP, Ellenbroek B, Schreiber R - PLoS ONE (2013)

Bottom Line: The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test.Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task.The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients.

View Article: PubMed Central - PubMed

Affiliation: Neuropharmacology, EVOTEC AG, Hamburg, Germany ; Brain Research Institute Dept. of Neuropharmacology, University of Bremen - FB 2, Bremen, Germany.

ABSTRACT
Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the Huntingtin (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in 'pain' sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery.

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Related in: MedlinePlus

Strategy shifting.Number of rats that exhibited Place (P) or Response (R) learning strategy during each Probe trial P1, P2 and P3 (days 8, 16 and 23 respectively) are represented for WT and TG cohorts of 2 and 6 months of age. The size corresponds to animals that made (1) correct arm choices with a learning index greater than 0.5 during each training session, and (2) were successful for the two last trials prior to the probe trials in the cross maze.
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pone-0071633-g002: Strategy shifting.Number of rats that exhibited Place (P) or Response (R) learning strategy during each Probe trial P1, P2 and P3 (days 8, 16 and 23 respectively) are represented for WT and TG cohorts of 2 and 6 months of age. The size corresponds to animals that made (1) correct arm choices with a learning index greater than 0.5 during each training session, and (2) were successful for the two last trials prior to the probe trials in the cross maze.

Mentions: On trial days 8, 16, and 23 a probe trial was done to assess which strategy rats used to solve the task (Fig. 2). The north arm (N) was now the new start arm. Rats entering the same arm as during training sessions were designated place learners (allocentric learning) and rats entering the opposite arm were designated response learners (egocentric learning). Data were only analyzed for animals that made (1) correct arm choices with a learning index greater than 0.5 during each training session, and (2) were successful for the two last trials prior to the probe trial. Two months old rats exhibited a preference for response learning on P1 (response: WT = 73% and TG  = 77%) and P2 (response: WT  = 67% and TG  = 57%). This preference for response learning was maintained on P3 (response: WT  = 64% and TG  = 67%). Six months old WT rats again exhibited a clear response learning during P1 (WT  = 73%) while only half of TG rats were response learners. However, during P2 and P3, WT rats have adopted a place learning strategy (WT, place: P2 = 66% and P3 = 57%), whereas TG rats showed a response learning strategy (TG, response: P2 = 50% and P3 = 60%). Although WT rats results between both probe sessions (P1→P3) would suggest a shifting towards a place learning (Δ = 30%), this was not statistically significant (χ2 = 1.606, P>0.05).


Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease.

Abada YS, Nguyen HP, Ellenbroek B, Schreiber R - PLoS ONE (2013)

Strategy shifting.Number of rats that exhibited Place (P) or Response (R) learning strategy during each Probe trial P1, P2 and P3 (days 8, 16 and 23 respectively) are represented for WT and TG cohorts of 2 and 6 months of age. The size corresponds to animals that made (1) correct arm choices with a learning index greater than 0.5 during each training session, and (2) were successful for the two last trials prior to the probe trials in the cross maze.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3815226&req=5

pone-0071633-g002: Strategy shifting.Number of rats that exhibited Place (P) or Response (R) learning strategy during each Probe trial P1, P2 and P3 (days 8, 16 and 23 respectively) are represented for WT and TG cohorts of 2 and 6 months of age. The size corresponds to animals that made (1) correct arm choices with a learning index greater than 0.5 during each training session, and (2) were successful for the two last trials prior to the probe trials in the cross maze.
Mentions: On trial days 8, 16, and 23 a probe trial was done to assess which strategy rats used to solve the task (Fig. 2). The north arm (N) was now the new start arm. Rats entering the same arm as during training sessions were designated place learners (allocentric learning) and rats entering the opposite arm were designated response learners (egocentric learning). Data were only analyzed for animals that made (1) correct arm choices with a learning index greater than 0.5 during each training session, and (2) were successful for the two last trials prior to the probe trial. Two months old rats exhibited a preference for response learning on P1 (response: WT = 73% and TG  = 77%) and P2 (response: WT  = 67% and TG  = 57%). This preference for response learning was maintained on P3 (response: WT  = 64% and TG  = 67%). Six months old WT rats again exhibited a clear response learning during P1 (WT  = 73%) while only half of TG rats were response learners. However, during P2 and P3, WT rats have adopted a place learning strategy (WT, place: P2 = 66% and P3 = 57%), whereas TG rats showed a response learning strategy (TG, response: P2 = 50% and P3 = 60%). Although WT rats results between both probe sessions (P1→P3) would suggest a shifting towards a place learning (Δ = 30%), this was not statistically significant (χ2 = 1.606, P>0.05).

Bottom Line: The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test.Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task.The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients.

View Article: PubMed Central - PubMed

Affiliation: Neuropharmacology, EVOTEC AG, Hamburg, Germany ; Brain Research Institute Dept. of Neuropharmacology, University of Bremen - FB 2, Bremen, Germany.

ABSTRACT
Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the Huntingtin (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in 'pain' sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery.

Show MeSH
Related in: MedlinePlus