Objective/Rationale:
Cholinergic systems decline early in PD and are hypothesized to contribute to cognitive impairments as well as to impairments in performing complex movements and postural instability. The main objectives of this project are (1) to determine the impact of interactions between decline in cholinergic and dopaminergic brain systems on cognitive and motor functions; (2) to demonstrate that the attentional deficits which result from cholinergic system decline contribute to movement control deficits; and (3) to determine whether new cholinergic treatments benefit both attention and the ability to perform complex movements.
Project Description:
We will assess attentional and movement control capacities in a pre-clinical model with (a) selective loss of forebrain cholinergic neurons, (b) loss of dopaminergic input to the striatum, and (c) with combined disruption of cortical cholinergic and striatal dopaminergic systems.
Attentional capacity will be determined using a sustained attention task, including manipulations that tax the cognitive control of attentional performance. To assess complex movement and gait deficits, we will use beam traversal tests and other tests of complex movement control. Distractors will be used in order to determine the role of demands on attention on complex movement control.
We will assess the therapeutic potential of drugs that stimulate a group of subtypes of nicotinic acetylcholine receptors (nAChRs), alpha4beta* nAChRs, administered alone and as an adjunct to L-dopa treatment. We expect that the combined administration of both compounds benefits the attentional performance as well as complex movement control of models experiencing the decline in both cholinergic and dopaminergic brain systems.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Conventional dopaminergic treatments of Parkinson’s disease do not robustly improve deficits in complex movement and postural control, including error-prone walking, stepping or stair climbing deficits and falls. Our research will assess the usefulness of combined cholinergic and dopaminergic treatment to alleviate these more complex symptoms of the disease. In addition, the cholinergic component of this treatment approach is expected to improve the cognitive status of patients with Parkinson’s disease.
Anticipated Outcome:
We expect that the results from this research will support a more comprehensive understanding of the neuronal mechanisms responsible for the complex cognitive-motor symptoms of Parkinson’s disease. Furthermore, we expect that our findings will show that impairments in the control of complex movements are associated with impairments in attention. Treatments that improve attentional abilities will also benefit the ability of the animal model, and eventually of patients, to perform complex movements and maintain postural control.
Progress Report
We developed a new behavioral test system for the assessment of gait and complex movement control and fall propensity in pre-clinical models. The models were trained to traverse stationary and rotating rods, placed horizontally or at inclines, and while exposed to distractors. The models also performed a sustained attention task. We then generated models of an early disease state by producing limited loss to the forebrain cholinergic system as well as the striatal dopaminergic projection system. These models fell more frequently than control animals and falls were associated with incomplete rebalancing after slips and low traversal speed. Their attentional performance was also impaired and this was correlated with fall rates.
Furthermore, the placement and size of dopaminergic lesion correlated significantly with fall rates. The results support the hypothesis that after dual cholinergic-dopaminergic lesions, attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement, thereby “unmasking” impaired striatal control of complex movements and yielding falls. Additional evidence indicates that the treatment with an agonist at alpha4beta2* nicotinic receptor subtypes reduces the number of falls in these models, consistent with the pro-attentional efficacy of such drugs. Taken together, this research has generated a test system for the assessment of levodopa-insensitive PD symptoms and suggests a new treatment for these symptoms.
Presentations & Publications
Kucinski, A., Paolone, G., Bradshaw, M., Albin, R.L., & Sarter, M. (2013). Modeling fall propensity in Parkinson’s disease: Deficits in the attentional control of complex movements in rats with cortical-cholinergic and striataldopaminergic deafferentation. Journal of Neuroscience, resubmission under review.
Spuz, C.A., Paolone, G., Briscoe, S., Bradshaw, M., Albin, R.L., & Sarter, M. (2011). Deficits in attentional control of balance, mobility, and complex movements in a rat model of early state, multisystem Parkinson disease. Society for Neuroscience Annual Meeting. Washington, D.C.
Kucinski, A.J., Paolone, G., Peterson, C., Ronani, E., Albin, R.L., & Sarter , M. (2012). Deficits in the attentional control of posture and complex movements in a rat model of early state, multisystem Parkinson’s disease. Society for Neuroscience Annual Meeting. New Orleans, LA.
Final Outcome
Cognitive symptoms, complex movement deficits and increased propensity for falls are interrelated,levodopa-unresponsive symptoms in patients with Parkinson’s Disease (PD). Evidence from human studies suggests that damage to forebrain cholinergic systems contribute to falls in PD, perhaps as a result of deficits in the attentional control of complex movements. We developed a new behavioral test system for the assessment of gait and complex movement control and fall propensity in rats. Pre-clinical models were trained to traverse stationary and rotating rods, placed horizontally or at inclines, and while exposed to distractors. Pre-clinical models also performed an operant Sustained Attention Task.
We then generated pre-clinical models that model an early disease state by producing limited loss to the forebrain cholinergic system as well as the striatal dopaminergic projection system. These pre-clinical models fell more frequently than controls and falls were associated with incomplete rebalancing after slips and low traversal speed. Their attentional performance was also impaired and this was correlated with fall rates. Furthermore, the placement and size of dopaminergic lesion correlated significantly with fall rates. The results support the hypothesis that after dual cholinergic-dopaminergic lesions, attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement, thereby “unmasking” impaired striatal control of complex movements and yielding falls. Additional evidence indicates that the treatment with an agonist at alpha4beta2* nicotinic receptor subtypes reduces the number of falls in these pre-clinical models, consistent with the pro-attentional efficacy of such drugs. Taken together, this research has generated a test system for the assessment of levodopa-insensitive PD symptoms and suggests a new treatment for these symptoms.