Pharmacosynthetic modulation of serotonin networks Public Deposited

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  • March 22, 2019
  • Urban, Daniel J.
    • Affiliation: School of Medicine, Department of Pharmacology
  • Dr. Francis Crick described the brain as an exceedingly cunning combination of precision wiring and associative nets (Crick, 1979). While this explanation is over 30 years old, it accurately describes the complexity of the central nervous system modern neuroscientists are challenged with unraveling. The serotonergic network is an example of this intricate design. It originates from a small number of neurons relatively clustered together, but distributes its projections extensively throughout the entire CNS such that virtually every cell in the brain is in close proximity to a serotonin fiber. Advances using small molecules that augment serotonin concentrations such as serotonin selective reuptake inhibitors (SSRIs) have contributed immensely in constructing the frame work of the serotonin network and characterizing its influence on mammalian physiology and behaviors. Even so, these small molecule approaches are limited due to the global impact they have on serotonergic neurotransmission, making the neuronal mechanisms responsible for their effects difficult to discern. One approach to unraveling the complexity of the serotonin network is to dissect the system into its parts by selectively and reversibly controlling specific serotonin nuclei. In fact, Dr. Crick predicted the need for this approach stating that, to understand a complex biological system one must be able to interfere with it both precisely and delicately at all levels, but especially at the cellular and molecular levels (Crick, 1999). The recently developed chemogenetic technique termed Designer receptors exclusively activated by designer drugs (DREADDs) is ideal for selectively stimulating and inhibiting subpopulations of neurons, thereby demonstrating this delicate and precise approach for elucidating neuronal function at the cellular and molecular levels. In this work, we take advantage of this technique to selectively and remotely control the largest of the serotonergic nuclei, the dorsal raphe, and examined its effects on feeding, anxiety and antidepressant-like behaviors and in turn reveal how this nucleus contributes to the wide ranging effects of the serotonergic system.
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  • In Copyright
  • Roth, Bryan
  • Doctor of Philosophy
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  • 2013

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