PD is characterized by the degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNc), disturbing the function of a group of interconnected subcortical structures, the BG. A classic hypothesis in PD suggests that following dopaminergic denervation, the discharge of cells in the SNr, an output structure of the BG, increases, thereby intensifying the inhibitory influence that this GABAergic structure exerts on its targets, including for example, the thalamus or the superior colliculus (SC). The main consequence will be the development of the well-known motor symptoms of PD, which are rigidity, akinesia and tremor. It is increasingly recognized, however, that many non-motor symptoms are also strongly associated to the disease. They include autonomic troubles, sleep disturbance, neuropsychiatric manifestations and/or sensory deficits and are often experienced by the patients as more disturbing in their everyday life than the motor symptoms.
Among the sensory symptoms, a lot of visual problems have been reported such as deficits in visual acuity, contrast sensitivity, visual perception as well as in tasks implying deeper visual processing. Occulo-motor reflexes have also been shown to be disturbed in PD. The study of those reflexes is important within the visual system, as they convey a voluntary or reflexive motor response to a visual stimulation. Therefore, their disturbance could result from a sensory and/or motor problem. It has been shown that voluntary saccades are slowed down in PD with difficulties to initiate and then to suppress an ongoing saccade. The literature is more controversial concerning reflexive saccades but several experiments tend to show they are faster in PD patients.
Surprisingly, despite numerous clinical studies characterizing those visual deficits, few experiments have investigated their cause(s) or the functional state of visual structures in PD or in animal models of the disease. The only data available show that the latencies of visual evoked potential from PD visual cortex were longer compared to those from their matching controls. It is widely recognized that motor symptoms in PD are due to the degeneration of dopaminergic neurons from the ventral midbrain, disturbing the normal functioning of the whole basal ganglia network. We know that cortical and sub-cortical visual structures, such as the visual cortex or the SC, are anatomically and functionally connected to the basal ganglia. Therefore, it seems coherent to hypothesize whether, like motor symptoms, the degeneration of dopaminergic neurons from the ventral midbrain could disturb the processing and transmission of visual information that can explain some of the visual deficits seen in PD. The current project is part of this general background aiming to understand the effect of a BG dysfunction, following dopaminergic denervation, on the visual system.
We first tackled this unexplored problematic using a subcortical visual structure, the superior colliculus. We tested the capacity of the SC to respond to the presentation of bright flashes in a rat model of PD using our well-mastered electrophysiological protocols in anesthetized rats. In this condition of anesthesia, the neurons in the intermediate and deep layers of the SC, projecting toward the main input of the BG and receiving a direct projection from the SNr, are unresponsive to visual stimuli. However, sensitivity to visual events can be restored by local injections of a GABAA antagonist, bicuculline, via a canula coupled to the electrode. Our results showed that this injection gives rise to exaggerated light responses in SC following the presentation of the flashes in rats with a partial and total dopaminergic lesion with the neurotoxin 6-hydroxydopamine (6-OHDA) injected in SNc. As illustrated in figure 1, those responses were faster, bigger in amplitude and lasted longer compared to normal control rats with the same injection. We suggest that a neuro adaptation has taken place within the SC after the dopaminergic lesion in SNc, probably to compensate the growing inhibitory influence coming from SNr, characteristic of the disease, and to maintain a normal functioning. The sudden pharmacological reduction of SNr abnormal inhibitory tone with bicuculline contributed to reveal this plasticity in SC expressed by an impressive sensory rebound.
Figure 1: Effect of 6-OHDA lesions on visual responses in the subthalamic nucleus and superior colliculus. Peri-stimulus histrograms (PSTH) and raster displays showing individual examples of visual responses recorded simultaneously in the superior colliculus (top histograms) and the subthalamic nucleus (bottom histograms) following the presentation of a light flash (0 – double lines) in a control rat (left histograms), a rat with a partial lesion (middle histograms) and a rat with a total lesion (right histograms).
Reference: Rolland M, Carcenac C, Overton PG, Savasta M, Coizet V. Enhanced visual responses in the superior colliculus and subthalamic nucleus in an animal model of Parkinson’s disease. Neuroscience. 2013 Jul;252:277-88