Enhanced Bidirectional Connectivity of the Subthalamo-pallidal Pathway in 6-OHDA-mouse Model of Parkinson's Disease Revealed by Probabilistic Tractography of Diffusion-weighted MRI at 9.4T

Abstract

Parkinson' s disease (PD) is a common neurodegenerative disease of the central nervous system that primarily affects the motor system [1]. The most distinct motor symptoms of PD are gait impairments, tremor, muscular rigidity, slowness of movement as well as non-motor dysfunctions such as behavioral and cognitive impairments [2]. These symptoms of PD are caused by progres-sive loss of dopamine-producing cells in the substantia nigra pars compacta (SNc), one of five nuclei in the basal ganglia that plays a key role in voluntary movement [2,3]. As a result, dopamine levels are lowered, inhibiting innervation of basal ganglia output and dysfunction within the cortico-basal ganglia thalamic pathway [4].The basal ganglia is a network of subcortical nuclei, consisting of the striatum, internal and external globus pallidus (GPi/GPe), subthalamic nucleus (STN), substantia nigra compacta (SNc) and substantia nigra reticulata (SNr) [5]. Neural projections of the striatum involved in the motor system are segregated into direct and indirect pathways. It is believed that dopamine secreted from SNc activates striatal D1 neurons in the direct pathway and inhibits the striatal D2 neurons in the indirect pathway. In PD, dopamine depletion leads to diminished inhibitory direct pathway output An important challenge in Parkinson' s disease (PD) based neuroscience and neuroimaging is mapping the neuronal connectivity of the basal ganglia to understand how the disease affects brain circuitry. However, a majority of diffusion tractography studies have shown difficulties in revealing connections between distant anatomic brain regions and visualizing basal ganglia connectome. In this current study, we investigated the differences in basal ganglia connectivity between 6-OHDA induced ex-vivo PD mouse model and normal ex-vivo mouse model by using diffusion tensor imaging tractography from diffusion-weighted images obtained with a high resolution 9.4 T MR scanner. Connectivity pattern of the basal ganglia were compared between five 6-OHDA and five control ex-vivo mouse brains using results of probabilistic tractography generated with PROBTRACKX. When compared with control mouse, 6-OHDA mouse showed significant enhancements to motor territory-related subthalamopallidal and pallido-subthalamic connectivity. Multi-fiber tractography combined with diffusion MRI data has the potential to help recognize the abnormalities found in connectivity of psychiatric and neurologic disease models.