The dopaminergic cell loss in the substantia nigra pars compacta (SNc) that causes Parkinson's disease (PD) creates a complex array of motor and cognitive symptoms. Although alterations in corticostriatal interactions play a major role in PD symptomatology, brainstem abnormalities also contribute significantly to PD symptoms. One circuit that has been especially useful in characterizing these brainstem disturbances is the trigeminal reflex blink. PD patients and animal models of PD exhibit hyperexcitable reflex blinks, a lack of blink habituation, and decreased long term potentiation (LTP) -like plasticity of the blik reflex. The reduced ability to potentiate blink circuits could result from saturation of this hyperexcitable circuit or it could indicate a general impairment of brainstem motor learning that may create many of the brainstem disorders in PD. In order to determine PD's effects on the motor learning capability of trigeminal reflex blink circuit, it is critical to investigate the capcity for long term depression (LTD)-like plasticity. The proposed studies will utilize behavioral and in vivo electrophysiological techniques to characterize the neural mechanisms underlying motor learning in the trigeminal reflex blink circuit in a 6-OHDA lesioned rat model of PD.
Specific Aim 1 investigates the hypothesis that dopamine cell loss in the nigrostriatal pathway disrupts motor learning of trigeminal blink reflex circuit utilizing previously established LTD and LTP inducing protocols involving the presentation of high frequency stimulation to the supraorbital branch of the trigeminal nerve. These data will demonstrate the degree of disruption for short-term plasticity and long term learning of reflex blinking caused by PD.
Specific Aim 2 examines the hypothesis that the deficient brainstem motor learning in PD results from dysfunctional patterns of substantia nigra pars reticulata (SNr) activity using multi-electrode recordings of the SNr in alert, behaving control and 6-OHDA rats during the learning paradigm. If the hypothesis is correct, SNr discharge in 6-OHDA lesioned rats will be much more irregular and synchronized than in control rats.
Specific Aim 3 will test the hypothesis that the disruptions in brainstem motor learning result from an alteration in the pattern of SNr output rather than simply an increase in discharge frequency. Deep brain stimulation of the subthalamic nucleus (STN DBS) utilizing regular (130 Hz) or irregular (mean frequency 130 Hz) stimulation will be applied to 6-OHDA lesioned rats while they undergo the motor learning protocol. The ability of regular, but not irregular STN DBS to attenuate PD blink disturbances would support the hypothesis that DBS achieves its therapeutic effect through regularizing abnormal firing patterns of basal ganglia neurons. Overall, these experiments will elucidate the neural basis of diminished brainstem motor learning in PD and provide insight into the therapeutic mechanism of DBS in the treatment of PD that may lead to more effective use of this important PD treatment.
Parkinson's disease (PD) affects more than 500,000 people in the US with 50,000 new cases reported each year. Although dopamine cell death is well established as the cause of PD, how this loss of neurons produces the devastating symptoms of PD is poorly understood. A disruption of motor learning, a fundamental disturbance in PD, may be responsible for many of these symptoms. The proposed study will identify the neural basis for impaired brainstem motor learning in PD and investigate the mechanisms through which a common treatment for PD, deep brain stimulation, may ameliorate these problems in brainstem motor learning.
|Kaminer, Jaime; Thakur, Pratibha; Evinger, Craig (2015) Effects of subthalamic deep brain stimulation on blink abnormalities of 6-OHDA lesioned rats. J Neurophysiol 113:3038-46|
|Ryan, Michael; Kaminer, Jaime; Enmore, Patricia et al. (2014) Trigeminal high-frequency stimulation produces short- and long-term modification of reflex blink gain. J Neurophysiol 111:888-95|
|Kaminer, Jaime; Thakur, Pratibha; Evinger, Craig (2014) Frequency matters: beta-band subthalamic nucleus deep-brain stimulation induces Parkinsonian-like blink abnormalities in normal rats. Eur J Neurosci 40:3237-42|