Beyond Gene Inactivation: Evolution of Tools for Analysis of Serotonergic Circuitry

Cornelia Hainer, Valentina Mosienko*, Stella Koutsikou, Jonathan J. Crook, Bernd Gloss, Sergey Kasparov, Bridget M. Lumb, Natalia Alenina

*Corresponding author for this work

Research output: Contribution to journalSpecial issue (Academic Journal)peer-review

11 Citations (Scopus)
869 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)1116-1129
Number of pages14
JournalACS Chemical Neuroscience
Issue number7
Early online date1 Jul 2015
Publication statusPublished - 15 Jul 2015


  • Cre recombinase
  • optogenetics
  • Pet1
  • Serotonergic system
  • SERT
  • TPH2


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