Student Theses and Dissertations

Date of Award

2015

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Friedman Laboratory

Abstract

Eat. Sleep. Breathe. Move. These functions, critical to an individual’s survival, are controlled by highly conserved neurotransmitter and neuromodulatory systems, which are principally located in the brainstem. These different brainstem neural populations, while performing apparently simple life sustaining functions, are remarkably complex. For proper function, survival circuits need to receive information from brain regions responsible for sensing survival needs, and rapidly exert broad control over the brain to generate adaptive behavior like foraging during energy deficit and escape from predation. How can survival circuits generate such autocratic control? Survival circuits principally affect global brain function in two ways: diffuse projection patterns and transmitter co-release. Through these two mechanisms, cell types small in number can have an enormous impact on neural processing and behavioral output through combinatorial complexity. However, the properties that allow these systems to address critical survival needs also make them exceptionally difficult to study; and current technology is no match to the complexity of the circuit. To understand the role that these neural circuits play in the functioning animal, it is necessary to develop technologies that can identify molecular markers, which will provide an access point for the study and manipulation of different cell types. The current work presents studies that I’ve performed over the past three and a half years, where I have sought to functionally dissect neural circuits of the brainstem. Through the development and application of a number of novel molecular technologies, we have gained critical insight into the molecular and neural basis of behavior. The first part of this work describes the functional dissection of dorsal raphe cell types to elucidate their role in modulating survival functions. The second part outlines the development of a novel technology, Retro-TRAP, which we developed to address a critical, unmet need in neuroscience: molecular profiling of neurons based on their connectivity. In these studies, a particular emphasis was placed on the dopaminergic and serotonergic nuclei of the midbrain (the ventral tegmental area/substantia nigra pars compacta and dorsal raphe, respectively), as they are essential for key survival behaviors, such as feeding and locomotion. These populations of neurons are therefore ideal for studying the generation of purposive behaviors in the context of survival circuitry.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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