Proof-of-principle of ed-DBS (experience-driven deep brain stimulation) in the hemiparkinson rat model

Parkinson's Disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra (SN). The loss of DA leads to debilitating motor symptoms, such as tremors, rigidity, and bradykinesia. Deep brain stimulation (DBS) is considered state-of-the-art in the treatment of motor symptoms in advanced PD. The standard practice is to stimulate the subthalamic nucleus (STN) or internal globus pallidus (GPi) continuously via surgically implanted electrodes. However, continuous administration of DBS conflicts with the firing patterns of nigrostriatal DA neurons because these neurons generate rapid phasic DAergic signals in response to specific experiences, such as the presentation of a reward-predicting stimulus (S) or an unexpected reward (S*). This conflict may be one of the reasons for only moderate treatment efficacy of DBS. In our Boğaziçi University Scientific Research Projects (BAP) project, we hypothesize that treatment outcomes are enhanced if DBS is given acutely, in an experience dependent (ed) fashion that is tailored to specific experiences of the subject, involving S-S* contingencies (Experience-driven (ed)-DBS to improve motor symptoms in the hemiparkinson rat model under grant number 15981). Towards a test of this hypothesis, we will a) integrate DBS with operant conditioning in which experiences can be completely controlled, and b) determine the value of ed-DBS for the brain. In this thesis, we took initial steps towards achieving these aims. Specifically, we integrated the operant setup with DBS and tested the viability of our methods with two rats, one hemiparkinson rat and one control. In this thesis work, we report data which show support for the success of our behavioral training procedures, surgical approach, and integration of a conditioned inhibition procedure with ed-DBS. Keywords: Variable Interval Schedule, Discrimination Learning, Hemiparkinson Rat, 6-Hydroxydopamine, Apomorphine-Induced Rotation