Thibaut SESIA, Rob HAMELEERS, Rinske VLAMINGS, Eva WOLBERT, Süleyman KAPLAN, Arjan BLOKLAND, Yasin TEMEL

Continuous reversal using internal or external cues: A novel test measuring set shifting in Parkinsonian rats

Parkinson’s disease (PD) is a predominant movement disorder, but profound cognitive deficits (e.g. bradyphrenia, memory, and set shifting) also occur. To model the deficits in set shifting using internal and external cues in rats we developed a continuous reversal task in which the active lever, left or right lever, alternated after a variable number of lever presses. In one task the active lever was signaled by a light (external cue condition, EC) whereas in the other task the active lever was not signaled (internal cue condition, IC). In this study we evaluated the effects of a partial bilateral striatal 6-OHDA lesion as model for PD on the performance in both tasks. Following behavioral testing the lesions were verified using tyrosine hydroxylase (TH) immunohistochemistry. The 6-OHDA lesioned animals were specifically impaired in the IC condition and not in the EC task. In other words, the lesioned animals kept pressing a lever longer although it was not longer active. The present response switching task is sensitive to 6-OHDA lesions and may mimic set-shifting deficits in PD.

Keywords:

Set-shifting, Continuous reversal, 6-OHDA lesion, Parkinson’s disease,

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Alexander, G.E., Crutcher, M.D., DeLong, M.R., 1990. Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog. Brain Res. 85, 119-146.
Ayyildiz, M., Kozan, R., Agar, E., Kaplan, S., 2008. Sexual dimorphism in the medial vestibular nucleus of adult rats: Stereological study. Anat. Sci. Int. 83, 131-139.
Birrell, J.M., Brown, V.J., 2000. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J. Neurosci. 20, 4320-4324.
Brown, R.G., Marsden, C.D., 1988. Internal versus external cues and the control of attention in Parkinson’s disease. Brain. 111, 323-345.
Brown, R.G., Marsden, C.D., 1991. Dual task performance and processing ressources in normal subjects and patients with Parkinson disease. Brain. 114, 215-231.
Cools, R., Barker, R.A., Sahakian, B.J., Robbins, T.W., 2001. Mechanisms of cognitive set flexibility in Parkinson’s disease. Brain. 124, 25032512.
Deumens, R., Blokland, A., Prickaerts, J., 2002. Modeling Parkinson’s disease in rats: An evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp. Neurol. 175, 303-317.
Fahn, S., 2003. Description of Parkinson’s disease as a clinical syndrome. Ann. NY Acad. Sci. 991, 1-14.
Floresco, S.B., Ghods-Sharifi, S., Vexelman, C., Magyar, O., 2006. Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. J. Neurosci. 26, 2449-2457.
Hayes, A.E., Davidson, M.C., Keele, S.W., Rafal, R.D., 1998. Toward a functional analysis of the basal ganglia. J. Cogn. Neurosci. 10, 178198.
Kirik, D., Rosenblad, C., Björklund, A., 1998. Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp. Neurol. 152, 259-277.
Ling, Z.D., Collier, T.J., Sortwell, C.E., Lipton, J.W., Vu, T.Q., Robie, H.C., Carvey, P.M., 2000. Striatal trophic activity is reduced in the aged rat brain. Brain Res. 856, 301-309.
Moustafa, A.A., Sherman, S.J., Frank, M.J., 2008. A dopaminergic basis for working memory, learning and attentional shifting in Parkinsonism. Neuropsychologia. 46, 3144-3156.
Nagano-Saito, A., Leyton, M., Monchi, O., Goldberg, Y.K., He, Y., Dagher, A., 2008. Dopamine depletion impairs frontostriatal functional connectivity during a set-shifting task. J. Neurosci. 28, 3697-3706.
Owen, A.M., 2004. Cognitive dysfunction in Parkinson’s disease: The role of frontostriatal circuitry. Neuroscientist. 10, 525-537.
Owen, A.M., Roberts, A.C., Hodges, J.R., Summers, B.A., Polkey, C.E., Robbins, T.W., 1993. Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson’s disease. Brain. 116, 1159-1175.
Polito, C., Ramat, S., 2007. 3.116 Set-shifting deficit and fronto-temporal hypometabolism in early Parkinson’s disease. Parkinsonism Relat. D. 13, 157-157.
Ragozzino, M.E., Detrick, S., Kesner, R.P., 1999. Involvement of the prelimbic-infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning. J. Neurosci. 19, 4585-4594.
Ragozzino, M.E., Jih, J., Tzavos, A., 2002. Involvement of the dorsomedial striatum in behavioral flexibility: Role of muscarinic cholinergic receptors. Brain Res. 953, 205-214.
Temel, Y., Visser-Vandewalle, V., Kaplan, S., Kozan, R., Daemen, M.A., Blokland, A., Schmitz, C., Steinbusch, H.W., 2006. Protection of nigral cell death by bilateral subthalamic nucleus stimulation. Brain Res. 1120, 100-105.
Witt, K., Daniels, C., Schmitt-Eliassen, J., Kernbichler, J., Rehm, S., Volkmann, J., Deuschl, G., 2006. The impact of normal aging and Parkinson’s disease on response preparation in task-switching behavior. Brain Res. 1114, 173-182.