Characterization of Dopamine-Responsive Serotonergic Neurons Underlying Aggression Modulation

Abstract

The monoaminergic neuromodulatory systems (including the noraderenergic, serotonergic, and dopaminergic neuronal systems) have long been thought of as the custodians of mental health. Dysfunction amongst these neural populations is associated with psychiatric disease, which is often treated with pharmacotherapeutic agents targeting these monoaminergic systems. Increasingly, such therapies manipulate these neuronal populations in tandem to achieve increased therapeutic efficacy. It has therefore become important to understand the putative interactions amongst these neural systems. In this thesis, I explore the interactions between the serotonergic and dopaminergic neuronal systems, investigating both the effects of dopamine on serotonergic neurons as well as those of serotonin on the midbrain dopaminergic system. Chapter 1 reviews evidence for such interactions, with a focus on the capacity of serotonergic neurons to respond to dopaminergic stimulation. It further introduces two subtypes of serotonergic neurons characterized by expression of dopamine receptor-cre driver lines, Drd1a-cre and Drd2-cre, and demonstrates the necessity of these serotonergic subtypes in the modulation of male aggressive behavior. Chapters 2 through 4 employ intersectional genetic approaches to characterize the anatomical distribution, developmental onset, dopamine responsiveness, patterns of gene expression, and hodology of these two serotonergic neuronal subtypes. These chapters demonstrate that there are subpopulations of serotonergic neurons that express receptors for dopamine and are capable of responding to dopaminergic stimulation. This work achieves an unprecedented resolution in cell subtype specificity coupled with molecular, anatomical, and pharmacological characterization, thus resolving this dopamine-serotonin interplay without the confounding ambiguities and limitations surrounding prior studies in the field. Chapter 5 explores the inverse relationship, investigating the effects of constitutive serotonergic neuron activity on the development of midbrain dopaminergic hodology. Collectively, this body of work lays a foundation upon which to build our understanding of transmonoaminergic interaction at the level of the cell, the circuit, and the organism.