Behaviors Disrupted due to Over-Expression of Tau in the Cholinergic Pedunculopontine Tegmentum
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The pedunculopontine tegmentum (PPTg) is a structure located in the brainstem and has become a main focus of study for neurodegenerative diseases, such as Progressive Supranuclear Palsy (PSP). The PPTg is comprised of three neuronal subtypes: GABAergic, glutamatergic, and cholinergic. PSP pathology includes an extensive degeneration of cholinergic neurons within the PPTg as well as aggregates of a pathogenic microtubule stabilizing protein (tau) throughout the brain. Moreover, PSP symptomology includes a deficit in the acoustic startle reflex (ASR), impairment of motor function and coordination, as well as dysexecutive dementia. Currently, there are no pharmacological treatments available for those diagnosed with PSP, and drug discovery efforts are hindered by the lack of an adequate preclinical animal model. We hypothesize the complete loss of cholinergic neurons within the PPTg, in addition to the deposition of tau in the PPTg via virally mediated overexpression, and the subsequent distribution of tau along PPTg projections, will produce PSP symptomology and mimic disease progression. Using ChAT-Cre rats, that only express cre recombinase in cholinergic neurons, virally mediated (adeno associated virus) human tau in the 1N4R isoform (seen in PSP) was injected into the PPTg and the thalamus in an effort to produce maximum tau expression in the PPTg cholinergic neurons. At 4 weeks, 8 weeks, and 14 weeks post-surgery, rats were tested in a variety of behavioral paradigms: acoustic startle reflex (ASR), marble burying, locomotor activity, horizontal ladder, vertical descent paradigm, hole board, and hindlimb clasping. Operant training and testing was ongoing throughout the 14 weeks. Four weeks post-surgery, rats exhibited significant deficits in ASR, horizontal ladder, vertical descent paradigm, and hindlimb clasping. Additionally, rats displayed significant emotional deficits in marble burying, as well as a trend toward decreased exploratory behavior in the hold board test. Operant testing revealed an intact working memory, but gave insight to other behaviors, such as perseverative lever pressing, or altered salience of reward pellets. Though histology is pending, our results suggest there is significant cholinergic neuron loss in the PPTg, as well as degeneration that has spread to other areas via PPTg pathways. This tau model attempted to induce PSP-like pathology to recreate key clinical symptomology. The motor and emotional deficits observed in our animals, which did not diminish over time, suggests this may be an appropriate preclinical animal model for the disease, and could find utility in drug discovery efforts.