Neurons that synthesize and release 5-hydroxytryptamine (5-HT; serotonin) express a core set of genes that establish and maintain this neurotransmitter phenotype and distinguish these neurons from other brain cells. Beyond a shared 5-HTergic phenotype, these neurons display divergent cellular properties in relation to anatomy, morphology, hodology, electrophysiology and gene expression, including differential expression of molecules supporting co-transmission of additional neurotransmitters. This diversity suggests that functionally heterogeneous subtypes of 5-HT neurons exist, but linking subsets of these neurons to particular functions has been technically challenging. We discuss recent data from molecular genetic, genomic and functional methods that, when coupled with classical findings, yield a reframing of the 5-HT neuronal system as a conglomeration of diverse subsystems with potential to inspire novel, more targeted therapies for clinically distinct 5-HT-related disorders.
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The authors are grateful to the peer reviewers for their thoughtful input and to members of the Dymecki laboratory for discussions related to this article. The work of the authors is supported by US National Institutes of Health grants (P01 HD036379 to B.W.O., K.G.C. and S.M.D.; R01 DA034022 to B.W.O. and S.M.D.; R21 DA036056 to S.M.D.; and R01 DA 021801 to K.G.C.), the Blavatnik Biomedical Accelerator (grant to B.W.O. and S.M.D.) and the GVR Khodadad Family Foundation (grant to S.M.D.).
Nature Reviews Neuroscience thanks P. Gaspar, C. Lowry and T. Sharp for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Transiently appearing segmented divisions of the developing embryonic hindbrain of vertebrates that are distinguishable morphologically. Rhombomeres function as molecularly discrete, transverse progenitor domains, each giving rise to cell populations with some restriction in fates.
The most rostral transverse segment of the developing embryonic hindbrain. It abuts the midbrain at its rostral border and rhombomere 1 at its caudal border and thus is often referred to as the midbrain–hindbrain junction. The isthmus gives rise to select neurons.
- Fate mapping
Indelibly marking a regionally or temporally restricted cohort of cells so as to be able to link labelled mature cells to their developmental origin. Genetic fate mapping involves the use of gene-enhancer-driven Cre or Flp recombinase expression to ‘capture’ cells for constitutive reporter expression. Reporter expression results from Cre-mediated or Flp-mediated recombination of an otherwise ‘silent’ transgene.
- Intersectional genetics
Here refers specifically to the use of gene-enhancer-driven Cre and Flp recombinase expression in conjunction with expression of a dual-recombinase-responsive reporter or effector transgene to afford precise labelling or manipulation of cells defined by a history of both Cre and Flp expression.
- Transcriptomic technologies
High-throughput approaches, such as microarray gene chip and next-generation RNA sequencing, that allow measurement of the relative abundances of all transcripts (including mRNAs, non-coding RNAs and microRNAs) expressed by a tissue, a pool of cells or a single cell or contained in an isolated cellular compartment, such as the nucleus or synaptosome.
Release of more than one neurotransmitter from a single neuron, either from the same or segregated release sites.
The use of photoactivable ion channel proteins cloned from algae to acutely excite or inhibit transfected cells using light.
- Intrinsic electrical properties
The set of electrical characteristics a neuron possesses by virtue of its membrane permeability and capacitance, morphology and its intracellular ionic content and the ionic driving forces acting upon on it. Typically, intrinsic properties are divided into passive and active properties.
- Fibre photometry
The use of a brain-implanted optical fibre to visualize and record local Ca2+ fluctuations, a proxy for neuroelectrical activity, as revealed by a genetically encoded calcium indicator, such as GCaMP6. Typically, this method does not provide single-neuron activity resolution but reflects aggregate Ca2+ fluxes coming from populations of cells.
- Volume transmission
Neuronal release of neurotransmitter in a diffuse manner, either in the absence of a closely apposed postsynaptic site or in the absence of an efficient local reuptake mechanism, such that cells and synapses distal to the locus of release may ultimately bind the released transmitter.
- Selective serotonin reuptake inhibitors
(SSRIs). SSRIs are a class of pharmacological compounds that block the reuptake of extracellular 5-HT by the serotonin transporter, frequently prescribed to treat major depressive disorder and increasingly prescribed to treat other affective disorders such as anxiety and obsessive–compulsive disorder.
- Prepulse inhibition
(PPI). The tendency for an organism to display an attenuated response to a given sensory stimulus if it is preceded by a (typically weaker) prestimulus; for example, as observed in the blunting of the acoustic startle reflex to a sudden unexpected loud noise by a preceding quieter tone.
An acronym that stands for designer receptors exclusively activated by designer drugs, an approach that deploys metabotropic receptors that have been re-engineered to respond preferentially to designer compounds (which are otherwise biologically inert) in order to manipulate the activity of transfected cells.
- Clozapine N-oxide
An engineered ligand, derived from the antipsychotic psychoactive drug clozapine, that activates DREADD (designer receptors exclusively activated by designer drugs) receptors but is otherwise inert (in its unmetabolized form).
The use of DREADD (designer receptors exclusively activated by designer drugs) technology to acutely manipulate the activity of a population of cells, typically to investigate its in vivo functions.
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Okaty, B.W., Commons, K.G. & Dymecki, S.M. Embracing diversity in the 5-HT neuronal system. Nat Rev Neurosci 20, 397–424 (2019). https://doi.org/10.1038/s41583-019-0151-3
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