Researchers identify previously unknown subtypes of 5HT neurons.


The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems.  These long-range neurons have cell bodies distributed across nine brainstem nuclei, referred to as the raphe system, and axonal projections that collectively innervate most regions of the brain and spinal cord.  These brain cells make the neurotransmitter serotonin, which helps regulate mood, appetite, breathing rate, body temperature and more.

Though often viewed as a single neuron type based on chemically-based 5HT class, phenotypic diversity within the 5HT neuron system has been observed at various levels, suggesting the existence of specialized subtypes of 5HT neurons that regulate specific biological functions.  However the full extent of molecular, cellular, and functional variation present across the entirety of the 5HT neuronal system, as well as its organizing principles, are currently unknown.  Now, a study from researchers at Harvard Medical School shows that serotonergic neurons come in at least six major molecular subtypes defined by distinct expression patterns of hundreds of genes. The team state that in many cases, the subtypes have been shown to modulate different behaviours in the body.  The opensource study is published in the journal Neuron.

Earlier studies from the lab defined a subgroup of serotonergic neurons in mice by showing that those cells specifically, among all serotonergic neurons, were responsible for increasing the breathing rate when too much carbon dioxide builds up in the body.  Results had shown that the relationship between a mature neuronal system and the different developmental lineages that gave rise to it could be explored.  Therefore, the researchers wanted to learn how utilise this information in a clinical sense.  The current study shows that the molecular phenotypes of these neurons track quite tightly to their developmental origin, with anatomy making some interesting contributions as well.

The current study combined intersectional genetic fate mapping, manual cell  sorting, and genome-wide RNA sequencing to comprehensively deconstruct the mature mouse 5HT system at multiple levels of granularity.  5HT neurons were separately sampled from each raphe nucleus and from each genetically defined 5HT neuron sublineage co-populating and intermingling within each nucleus, down to a single-cell basis. Data findings show salient principles of 5HT neuron organization and reveal thousands of genes significantly differentially expressed across identified 5HT neuron subtypes.  Results show that a serotonergic neuron’s gene expression and function depend not on its location in the adult brain stem and its cellular ancestor in the developing brain.

Results show that subtypes vary in their developmental lineage, anatomical distribution, combinations of receptors on the cell surface and electrical firing properties.  The researchers state that this shows how diverse serotonin neurons are at the molecular level, which may help to explain how they are able to perform so many distinct functions.  They go on to add that global medical community can look for the same molecular signatures in human tissue and begin to tease apart whether particular subtypes of serotonergic neurons are involved in conditions such as sudden infant death syndrome (SIDS) or autism.

The lab explain that having the list of molecular players that make each of these subtypes different from one another gives researchers an important handle on learning more about what that cell type does and how to manipulate only that subtype. The go on to conclude that such research could ultimately reveal previously unknown contributions of the serotonergic neuronal system to disease, inform the development of biomarkers or lead to more targeted therapies; as well as driving the development of different subtypes in stem cell research.

The team surmise that their study provides an understanding of brain function at multiple scales, linking genes and gene networks to the properties of single neurons and populations of neuron subtypical networks, all the way up to the corresponding animal behaviours.  For the future, the researchers state that while the work was done in mice they plan to replicate it in humans as the serotonergic neuronal system is in a highly conserved region of the brain, meaning it tends to remain consistent across vertebrate species.

Source: Harvard Medical School

Anatomical Distribution of Genetically Fate-Mapped 5HT Neuron Sublineages and Unsupervised Clustering of Lineage- and Anatomy-Defined Transcriptomes. (A) Schematic of mouse embryonic hindbrain (left) with serotonergic primordium marked in dark blue; (center) rhombomeric domains from which 5HT neurons arise (R1, R2, R3, R5, and R6P) shaded in different colors (note these same colors are used throughout all figures); (right) their mature anatomical distribution presented in a sagittal brainstem schematic with labeled B1–B9 nuclei. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System. Okaty et al 2015.

Anatomical Distribution of Genetically Fate-Mapped 5HT Neuron Sublineages and Unsupervised Clustering of Lineage- and Anatomy-Defined Transcriptomes. (A) Schematic of mouse embryonic hindbrain (left) with serotonergic primordium marked in dark blue; (center) rhombomeric domains from which 5HT neurons arise (R1, R2, R3, R5, and R6P) shaded in different colors (note these same colors are used throughout all figures); (right) their mature anatomical distribution presented in a sagittal brainstem schematic with labeled B1–B9 nuclei. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System. Okaty et al 2015.

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