Effects of Posterior Caudatoputamen Indirect Pathway Activity on Auditory Cortical Activation in Female Rats

Abstract

Hallucinations are a part of a complex and disabling psychiatric disorder of schizophrenia. Strong associations with dysregulated dopamine signaling, especially via dopamine D2 receptors, have been made with these symptoms. Despite a huge amount of progress in determining how dopamine works, a mystery still lingers in the mechanisms underlying auditory hallucinations, one of the main symptoms of schizophrenia. Here we investigated the relation of dopamine, sex differences, hormonal states, and activation of cells in female rats caudatoputamen (CPu) and the auditory cortex (Au1). This research looks at the effects of dopamine on Fos expression as a marker of neuronal activity using a combination of intracranial dopamine infusions, immunohistochemistry and immunofluorescence. Dopamine infusion in the auditory striatum leads to increase in Fos expression in the Au1, and the greatest activation occurs during the proestrus phase of the estrous cycle. Elevated levels of both estrogen and progesterone during proestrus are clearly important in enhancing dopaminergic response, suggesting the crucial participation of gonadal hormones in modulating neuronal activation. In addition, a comparison with male subjects reveals significant sex based differences for dopaminergic signaling with female subjects being more sensitive. The effects of haloperidol, a selective D2 receptor antagonist, on dopamine induced auditory cortical activation are also explored by the dissertation. The CPu is densely comprised of D2 receptors, and therefore it is likely that D2 receptors in the CPu play a key role in this linkage between dopamine dysregulation and Au1 activity. Consistent with this idea, haloperidol significantly attenuated Fos expression in the Au1. This attenuation parallels the therapeutic effects of antipsychotic medications reinforcing the significance of this model in studying schizophrenia like symptoms. Taken together, these findings provide compelling evidence for sex, hormonal state, and dopaminergic signaling interactions with modulating auditory cortical activity. These insights also give us an understanding to the neural circuitry underlying auditory hallucinations, and the mechanisms by which antipsychotics mitigate auditory hallucinations. Further, this work also emphasizes the importance of incorporating sex and hormonal factors into preclinical study designs since these variables may define critical pathways to developing more effective and therapeutic interventions for schizophrenia and other dopamine associated disorders. Finally, this work adds to our knowledge of dopaminergic modulation of cortical activity, specifically with respect to sex differences and hormonal regulation. The work lays a foundation for future investigations into the neurobiological substrates of schizophrenia and identifies targets in treatment strategy modifications to meet the unique needs of female patients.