Optogenetic Manipulation of Posterior Caudatoputamen Indirect Pathway Neurons Causes Auditory Cortical Activation in Rats

Abstract

Auditory hallucinations are prevalent in many neuropsychiatric disorders and are also a cardinal symptom of schizophrenia. Most research on the mechanism of auditory hallucinations has focused on functional imaging of the auditory cortex. Recent research has revealed structural and functional interaction between the striatum and the neocortex. Previous studies in our laboratory have shown that dopamine infusion into the posterior caudatoputamen (CPu), the “auditory striatum,” produce activation of the rat auditory cortex. To establish the next projection site from these neurons, we virally infused an anterograde AAV-GFP into this region of the auditory striatum which resulted in expression mainly at the same rostral-caudal level of the lateral globus pallidus (LGP) as the infusion site. Since antipsychotic drugs target D2 dopamine receptors on neurons of the indirect pathway (CPu-LGP) to alleviate psychotic symptoms, we transfected terminals in the LGP with a retrograde AAV-Jaws-GFP to neuroanatomically discriminate the indirect pathway. Inactivation of the striatal indirect pathway neurons with Jaws stimulation resulted in significant activation of the auditory cortex via c-Fos expression. Conversely, activation of these same striatal indirect pathway neurons with stimulation of ChannelRhodopsin-2 (ChR2) showed no significant change in auditory cortex activation. The results of these studies will elucidate a potential alternative neural circuit mechanism underlying the pathophysiology of auditory hallucinations in neuropsychiatric disorders.