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Co-authors Akari Hagiwara & Venkatesh N Murthy

A moment’s introspection reveals that our perceptions and actions are strongly affected by our behavioral states.  Whether you are sleepy, awake, distracted or vigilant will affect how you perceive the world. Of course, perceptions are also altered by neurological disorders or drug use.  What are the brain mechanisms that underlie this dependence of perception on behavioral states? Although there is no simple answer to this question, part of the state-dependence is thought to arise from a set of chemical messengers called neuromodulators that are released selectively under the right circumstances to alter the function of brain circuits. One such neuromodulator is serotonin, a chemical that has been linked to many complex mental functions including aggression and appetite, as well as to neurological diseases. Serotonin is released by a set of neurons in the brainstem called the raphe nuclei, whose axons fan out to reach virtually all regions of the brain. In this study, we asked how release of serotonin alters odor processing in mice.

Odorants stimulate neurons in the nose, which then convey information about the identity and intensity of odors to the olfactory bulb. The axons from the receptor neurons in the nose make synaptic connections with neurons in the olfactory bulb. This raw information coming from the nose is processed in yet unclear ways by circuits in the bulb before it is sent on to higher brain areas. It has long been suspected that processing within bulbar circuits is altered by behavioral states. In this study, we were surprised to find that even the input to the olfactory bulb is mutable. We found that synapses made by sensory neurons, which are responsible for conveying all the information from the nose to the brain, can be altered by serotonin.

Synapses made by olfactory sensory neurons release the neurotransmitter glutamate to activate postsynaptic targets.  The release of this transmitter is modulated by G-protein coupled receptors (GPCRs) located near the release sites through intracellular signaling pathways.  Activation of one type of presynaptic GPCR called GABAB receptor reduces transmitter release in olfactory sensory neurons. We discovered in our study that serotonin dials down release more indirectly. It does so by activating neighboring neurons (the so-called periglomerular neurons), causing them to release more of the inhibitory transmitter GABA, which in turn activates presynaptic GABAB receptors to turn down the strength of odor input to the brain. In addition to revealing the central role of periglomerular interneurons, we also pinpoint the specific subtype of serotonin receptor (5-HT2c receptor) involved in this effect.

What does the effect of serotonin on odor inputs mean for perception and behavior? Since neurons that release serotonin change their firing depending on behavioral states, our results suggest that behavioral states may alter how smells are conveyed to the brain. During wakefulness or intense arousal, increased serotonergic activity could reduce the sensory gain to prevent input saturation associated with fast breathing. Conversely, decreased serotonergic activity could turn up the gain during sleep or reduced arousal. Finally, since many psychiatric disorders in humans involve altered serotonin signaling, it is tempting to speculate that these patients may have altered smell perception.

Read more in Nature Neuroscience

See also: News and Views by Dugué & Mainen

View Venkatesh Murthy’s Faculty Profile