title: Beyond Gene Inactivation: Evolution of Tools for Analysis of Serotonergic Circuitry.
abstract: In the brain, serotonin (5-hydroxytryptamine, 5-HT) controls a multitude of physiological and behavioral functions. Serotonergic neurons in the raphe nuclei give rise to a complex and extensive network of axonal projections throughout the whole brain. A major challenge in the analysis of these circuits is to understand how the serotonergic networks are linked to the numerous functions of this neurotransmitter. In the past, many studies employed approaches to inactivate different genes involved in serotonergic neuron formation, 5-HT transmission, or 5-HT metabolism. Although these approaches have contributed significantly to our understanding of serotonergic circuits, they usually result in life-long gene inactivation. As a consequence, compensatory changes in serotonergic and other neurotransmitter systems may occur and complicate the interpretation of the observed phenotypes. To dissect the complexity of the serotonergic system with greater precision, approaches to reversibly manipulate subpopulations of serotonergic neurons are required. In this review, we summarize findings on genetic animal models that enable control of 5-HT neuronal activity or mapping of the serotonergic system. This includes a comparative analysis of several mouse and rat lines expressing Cre or Flp recombinases under Tph2, Sert, or Pet1 promoters with a focus on specificity and recombination efficiency. We further introduce applications for Cre-mediated cell-type specific gene expression to optimize spatial and temporal precision for the manipulation of serotonergic neurons. Finally, we discuss other temporally regulated systems, such as optogenetics and designer receptors exclusively activated by designer drugs (DREADD) approaches to control 5-HT neuron activity.
authors.affiliation: †Max-Delbrück-Center for Molecular Medicine (MDC), Berlin 13125, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hainer
authors.affiliation: ‡University of Bristol, Bristol BS8 1 TD, United Kingdom.
authors.forename: Valentina
authors.initials: V
authors.lastname: Mosienko
authors.affiliation: ‡University of Bristol, Bristol BS8 1 TD, United Kingdom.
authors.forename: Stella
authors.initials: S
authors.lastname: Koutsikou
authors.affiliation: ‡University of Bristol, Bristol BS8 1 TD, United Kingdom.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Crook
authors.affiliation: §National Institute of Environmental Health Science, Durham, North Carolina 27709, United States.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gloss
authors.affiliation: ‡University of Bristol, Bristol BS8 1 TD, United Kingdom.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kasparov
authors.affiliation: ‡University of Bristol, Bristol BS8 1 TD, United Kingdom.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Lumb
authors.affiliation: †Max-Delbrück-Center for Molecular Medicine (MDC), Berlin 13125, Germany.|∥Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
mesh_terms: D000818:Animals; D015870:Gene Expression; D005821:Genetic Techniques; D009434:Neural Pathways / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism*
keywords: Cre recombinase; Pet1; SERT; Serotonergic system; TPH2; optogenetics