Affect represents a major domain of human consciousness, consisting of a complex group of psychophysiological processes to drive human behavior. Many genetic and environmental factors may cause dysregulation of affective states, resulting in disorders that severely disrupt normal cognitive function and diminish the quality of life. Transitions among affective states may naturally happen in affective disorders, or they can be induced by external manipulations including behavioral or pharmacological interventions. Understanding the neural mechanisms underlying affective state transitions will create a basis for clinical management of affective disorders. In this dissertation, I discover and describe new forms of dopaminergic modulation of affective state transitions, evoked by pharmacological and behavioral approaches in mice. I have used comprehensive methodologies combining pharmacological, genetic, optogenetic, and chemogenetic manipulations with behavioral and neuronal readouts to causally interrogate the functions of dopaminergic systems in the regulation of affective states and behaviors. I have revealed that the activity of dopaminergic neurons is regulated by many factors including stress, antidepressants, and sleep disruption, mediating multiple forms of affective state transitions. Using two-photon imaging and glutamate uncaging, I found that dendritic spine plasticity changes in the medial prefrontal cortex during behavioral state transitions require dopamine signaling. In addition to these findings, I have developed next-generation wireless optogenetic and optofluidic platforms collaboratively and demonstrated their functionalities in behavioral experiments that have not been previously achieved. Altogether, the findings and innovations described in this work deepen our mechanistic insights into the regulation of affective states, providing new conceptual and experimental approaches to understand the pathogenesis of affective disorders and develop novel therapeutics.

Creator

• Wu, Mingzheng

DOI

• https://doi.org/10.21985/n2-hr3b-pq41

Subject

• Neurosciences

Language

• en

Alternate Identifier

• etdadmin_upload_925290
• http://dissertations.umi.com/northwestern:16201

Keyword

• Dopamine
• Optogenetics
• Affective disorders

Date created

• 2022-01-01

Resource type

• Dissertation

Rights statement

• In Copyright