A major challenge in treating Parkinson's disease (PD) is the presence of postural instability and gait
disorders, such as freezing of gait (FOG). FOG are disruptive involuntary pauses that lead to a decreased
quality of life in PD patients. In early stages of PD, dopaminergic medications produce partial improvement in
gait, but overtime, most patients develop gait problems resistant to current pharmacological medications and
deep brain stimulation. To date, the neural mechanism underlying this debilitating symptom is poorly
understood. Thus, this proposal combines cell-specific neurophysiology, optogenetics, and video-tracking to
explore the mechanisms involved. Prior work demonstrates that PD patients with FOG exhibit degeneration of
cholinergic neurons in the pedunculopontine nucleus (PPN) and that non-human primate models of PD with
PPN-cholinergic lesions also show postural deficits and FOG. In the proposed study, we will address the
involvement of the PPN in gait disorders by first determining how the physiology of the PPN changes in
response to dopamine depletion (Aim 1), then determining if glutamatergic neurons have aberrant activity
following dopamine depletion and PPN-cholinergic lesions (Aim 2), and finally determining if stimulation of
glutamatergic neurons in the PPN can rescue gait disorders in a mouse model of PD (Aim 3).
To identify the general involvement of the PPN in PD gait disorders, we will combine neuronal
ensemble recordings with optogenetic tagging to record from distinct neuronal populations in the PPN in
bilaterally depleted transgenic mice. PPN activity (neuronal firing rate, firing pattern, and local field potential)
will be paired with a corridor crossing task in awake-behaving animals. Next, we propose to investigate the
pathological changes in the glutamatergic neuronal population of the PPN in PD gait disorders.
To study the involvement of the glutamatergic neurons in the PPN during gait disorders, such as FOG,
we first combine dopamine depletion and PPN-cholinergic lesion. PPN activity (glutamatergic and GABAergic
neurons) will be paired with behavior as above. Secondly, we measure gait and FOG while optogenetically
stimulating glutamatergic neurons in the PPN. Elucidating the mechanism of FOG may lead to the
development of therapies that will ameliorate gait disorders, avoid the need for more invasive surgical
treatment, and significantly increase the quality of life in these patients.