Trace amine-associated receptors: ligands, neural circuits, and behaviors

Abstract

Trace amine-associated receptors (TAARs) are G Protein-Coupled Receptors that function as vertebrate olfactory receptors. Like odorant receptors, TAARs constitute an ever-evolving sensory subsystem, with individual TAARs recognizing particular chemicals and some evoking stereotyped behaviors. Several TAARs mediate aversion or attraction towards volatile amines that include the mouse odor trimethylamine, the predator odor 2-phenylethylamine, and the death-associated odor cadaverine. TAAR-expressing sensory neurons achieve monoallelic receptor expression, use canonical olfactory signaling molecules, and target a dedicated olfactory bulb region. In mouse, TAAR4 and TAAR5 are encoded by adjacent genes and localize to adjacent glomeruli, yet mediate opposing behaviors. Future studies are needed to understand how TAAR-expressing sensory neurons engage higher-order neural circuits to encode odor valence.

Figure 1. TAAR expression in the olfactory system

(A) Anatomy of the mouse nose in sagittal view, with major chemosensory structures displayed (VNO- vomeronasal organ; MOE-main olfactory epithelium. (B) A sagittal section of olfactory tissue with TAAR-expressing neurons genetically labeled. Images are derived from TAAR5 knockout mice, in which β-galactosidase is expressed from the endogenous Taar5 locus. Labeled neurons include a subset of all TAAR neuron types (see discussion of receptor re-selection following Taar pseudogene expression), and are visualized by wholemount X-gal staining. The imaged region is indicated in panel A by the blue dashed box. Multiple TAAR-innervating glomeruli are observed in the olfactory bulb, as shown in Figure 4A. Image in panel A is adapted from [50].

Figure 2. TAAR ligands, expression patterns, and behavioral roles

Human (h), mouse (m), rat (r), and/or zebrafish (z) genomes contain genes from indicated TAAR subfamilies. Mice and rats have multiple TAAR7s and TAAR8s, as indicated in parenthesis. All mammalian subfamilies, but not all teleost subfamilies, are depicted. All TAARs except TAAR1 are expressed in olfactory epithelium (OE), and in mouse, all TAARs are located dorsally except TAAR6, TAAR7a, and TAAR7b. The identities, ecological sources, and evoked behavioral responses of TAAR ligands are shown (*behavioral response lost in TAAR knockout mice, EC₅₀ determined in HEK-293 cells).

Figure 3. Mapping odor preferences on the mammalian TAAR phylogeny

Two branches of the TAAR phylogenetic tree prefer primary amines (TAARs 1–4) and tertiary amines (TAARs 5–9). zTAAR13c is not depicted but clusters with primary amine detectors. A third major TAAR clade evolved in teleosts (not shown), with almost all losing the canonical Asp^3.32 amine recognition site. Image adapted from [18].

Figure 4. Projections of TAAR neurons in the brain

(A) Wholemount view of TAAR inputs in the olfactory bulb. Subsets of all TAAR-expressing neuron types were simultaneously visualized using genetic approaches, as described for Figure 1B. (B) Two-color immunohistochemistry for TAAR4 (green) and TAAR5 (red) labels adjacent glomeruli in the olfactory bulb. Image adapted from [14].