Serotonergic Modulation of the Olfactory Bulb

Abstract

Serotonin is a neuromodulator whose actions are thought to modulate mood and brain states. Growing evidence correlates perturbations in the serotonergic system with neuropsychiatric diseases ranging from depression to schizophrenia. The dorsal raphe nucleus (DRN), a serotonergic cluster of neurons in the brainstem, projects widely throughout anterior brain regions, including the olfactory bulb. Electrophysiological recordings from the DRN show that its activity fluctuates with behavior over hundreds of milliseconds. Study of serotonergic modulation of the olfactory bulb has focused on modulation on the timescale of brain states (minutes to hours). This dissertation describes our work to understand how serotonergic inputs affect olfactory bulb codes on the time scale of behavior. Here we show that the serotonergic system plays a role in olfactory bulb coding on fast time scales (hundreds of milliseconds to seconds). Mitral and tufted cells, the two primary types of olfactory bulb output neurons, send olfactory information to distinct downstream targets. Brief stimulation of the DRN led to excitation of tufted cells at rest and potentiation of their odor responses. While mitral cells at rest were also excited by DRN activation, their odor responses could be suppressed or potentiated. This bidirectional modulation led to improved pattern separation of mitral cell odor responses. In vitro whole-cell recordings revealed that specific optogenetic activation of raphe axons affected bulbar neurons through dual release of serotonin and glutamate. Our data indicate that the raphe nuclei, in addition to their role in neuromodulation of brain states, are also involved in fast sub-second top-down modulation, similar to cortical feedback. Notably, this modulation can differentially sensitize or decorrelate distinct output channels. This work sheds light on the function of the serotonergic system in healthy brains, and future work will explore how this modulatory signature in olfactory outputs may be altered in diseased states.