Dissertation

Cell-Type-Specific Dopamine Signaling in Ventral Hippocampus – Anatomical, Circuit and Behavioral Studies

Godino, Arthur

2022

Overview

Background: Anxiety is an emotional response that, under normal conditions, promotes adaptive safety and survival behaviors through appropriate resolution of approach/avoidance conflicts, but, when inappropriate to the level of threat, contributes to several psychiatric disorders. Despite accumulating evidence for both the ventral hippocampus (vHipp) and the mesocorticolimbic dopamine system in encoding anxiety-relevant information and motivating exploratory behaviors, surprisingly little is known about how dopamine signaling selectively affects vHipp representations of emotionally-salient stimuli to guide approach/avoidance arbitration. To address these shortcomings, we here study dopaminoceptive neurons in mouse vHipp – which can be segregated based on their expression of either the dopamine D1 or D2 receptor – to delineate a model for dopamine neuromodulation within vHipp in coordinating decision-making processes and appropriate behavioral selection.Methods: We capitalized on D1-Cre and D2-Cre transgenic mice to visualize, record and manipulate vHipp D1 and D2 cells. These reporter lines were used for anatomy, single-nuclei RNA-sequencing, ex vivo slice electrophysiology, and cell-type-specific in vivo calcium imaging, chemogenetics and optogenetics. Genetically-encoded fluorescent dopamine sensors were used to record dopamine release in vHipp.Results: At the histological level, D1- and D2-expressing cells exhibit a precise topographical organization across vHipp subfields, which we further dissected using RNA-sequencing of single, sorted nuclei from D1 and D2 cells to identify separate sub-types of dopaminoceptive interneurons and principal cells in this region, which appear especially enriched in the caudo-ventral tip of the ventral CA1 and subiculum. Functionally, we found that anxiogenic environments and approach/avoidance conflicts trigger largely similar patterns of calcium activity in D1 versus D2 vHipp neurons in concert with dopamine release in in this region, which can in turn pharmacologically modulate the electrophysiological properties of these cell types. Bidirectional chemogenetic and optogenetic manipulation of D1 or D2 vHipp neurons’ activity however causally demonstrated their opposite roles in mediating approach/avoidance behaviors in both innate and learned anxiety-inducing situations. Intriguingly, vHipp dopaminoceptive mechanisms also contribute to cocaine-related behaviors, suggesting drug-induced plasticity in this circuit as well.Conclusions: Together, we propose that dopamine dynamics in vHipp operate as a feedback loop that bidirectionally tracks anxiety levels to gate exploratory behaviors through differential recruitment of vHipp D1 and D2 neurons, which in turn arbitrate opposite approach/avoidance and anxiety-like responses. This work paves the way for further studies of dopamine signal processing in limbic regions, and underscores the complexity of the circuit and neuromodulatory mechanisms that govern affective states.

• Publisher: ProQuest Dissertations & Theses
• Subject: Behavioral Sciences / Molecular biology / Neurosciences
• ISBN: 9798379414252