Several key questions in the lab

• How does a neuron encode experience in forms of gene and protein expression and optimize cellular functions?
• If and how peripheral neurons integrate signals from the outside and inside world?
• How do the main and accessory olfactory systems collaborate to guide social behavior in a context-dependent manner?
• How does adaptation at the periphery impacts the brain circuits and behavior in healthy and disease conditions?

Sensory adaptation

In everyday life, animals constantly encounter diverse stimuli that activate sensory systems. For example, when we are walking in the forest, we perceive a variety of smells like woods, flowers, soil, as well as signals from other modalities like sound, visual scene, and touch. To efficiently interpret sensory information in the dynamic environment and avoid being overwhelmed by the constant barrage of sensory inputs, animals need to ignore background stimuli that exist persistently or appear repeatedly (and thus “predicted”), and highlight novel or salient information. To achieve this goal, neurons and their networks encode the environmental context and modulate their functions, but how?

Previous studies have shown that experience-dependent plasticity in the brain plays key roles in optimizing behaviors. Networks of neurons in the brain change the patterns and strength of synaptic connections based on experience. For example, neurons in the piriform cortex (the primary cortex in the olfactory system) are known to suppress their responses to repetitive stimuli over timescales of minutes. However, relatively little was known about the plasticity in the periphery, except for extremely fast adaptation occurred within milliseconds to seconds. Therefore, traditional models assume that the sensory neurons respond to the same stimuli in the same manner irrespective of animals’ experience, whereas neurons in the brain flexibly modulate their responses based on experience. In addition, previous studies have focused on adaptation to repetitive stimuli and relatively short timescales like minutes, and thus it is unclear how animals adapt to the persistent environmental stimuli over longer timescales like hours to days. We are interested in these timescales, as animals typically stay in one environment for hours – e.g., resting in a nest or exploring outside to search for food and mates – and sensory statistics fluctuate over these timescales as well.

Olfactory system

The sense of smell plays critical roles in detecting chemical cues from the outside world, environment and other animals, and taking appropriate actions. Odors are detected by sensory neurons. Most mammals have two major olfactory subsystems, main and accessory systems, which are responsible for volatile (environmental) and non-volatile (social) odors through odorant receptors (ORs) and vomeronasal receptors (VRs), respectively. Each sensory neuron expresses only one receptor among a huge number of receptors (~1200 ORs and ~300 VRs in mice), and thus serves as a single channel to the chemical world. This feature allows us to unambiguously identify each of the receptor-defined subtypes via single-cell omics across experiments and quantify changes on a receptor-by-receptor basis. In addition, because activity levels of those neurons are determined by interactions between receptors and odors, this uniquely large array of sensory neuron subtypes experience a wide range of activity levels in each environment. Finally, those neurons are not embedded within complex networks (no lateral connections, relatively small influence from the top-down inputs), and thus an ideal model to study the cell-autonomous mechanisms linking neural activity to functions through gene and protein expression.

Olfactory sensory neurons in the nose project directly to the olfactory bulb in the brain and form synapses at the insulated neuropil structure called glomerulus. Each of the glomeruli receives inputs from neurons expressing a single OR, and thus the patterns of neural activity across a large number of ORs are converted into the spatial patterns of neural activity across glomeruli. Each of the projection neurons in the olfactory bulb samples from a single glomerulus, and project to higher olfactory brain areas including the piriform cortex, olfactory tubercle, and cortical amygdala. The accessory system has a similar but distinct circuit architecture; a subset of VRs (type II VRs) do not follow the one-receptor-per-neuron rule and two VRs are expressed in a single neuron, sensory neurons project to the accessory olfactory bulb locating at the posterior-dorsal part of the olfactory bulb, each projection neuron samples from multiple glomeruli and send output to largely non-overlapping brain areas including various domains of amygdala. Interestingly, the cortical amygdala receives inputs from both the main and accessory pathways. We are particularly interested in two brain areas: olfactory bulb and cortical amygdala.

Our recent research discovered long-term transcriptional adaptation in olfactory sensory neurons (Tsukahara*, Brann* et al, 2021). We revealed, by using single-cell transcriptomics and in vivo calcium imaging, olfactory sensory neurons in the olfactory system reconfigure their transcriptomes based on the history of neural activity and flexibly modulate sensory responses. For example, a neuron responds to their ligands strongly if it is inactive in one environment, whereas the response of the same neuron to the same odor is attenuated if it is highly active in another environment. Importantly, changes in the degree of sensory responses can be predicted by the changes in expression of many genes that are involved in generating action potentials, such as GPCR signaling factors, ion channels, and calcium-binding and -signaling proteins. These results indicate that the patterns of neural activity evoked by the same stimuli at the periphery could change across environments over hours to days, and even individual sensory neurons at the periphery can build a predictive model of the environment through gene expression and distinguish background and novel signals.

This novel form of adaptation contrasts with well-known adaptation, which is through synaptic modulation, in the brain, and short timescales (~ minutes), and asks reconsideration about the models of sensory processing, which traditionally expect stable periphery.

• Molecular mechanisms linking neural activity to functions through gene and protein expression in peripheral sensory neurons.
• Integration of sensory stimuli and signals from inside of the body signifying internal states and life stages in peripheral sensory neurons.
• Establishing an in vitro neuronal culture system to examine physiological and molecular changes proportional to activity changes and identify key genes for transcriptional adaptation.
• Molecular basis of social recognition at the periphery and its flexibility across life stages.
• Long-term adaptation in the olfactory bulb (especially the effects of peripheral adaptation).
• Integration of the information from main and accessory olfactory systems in the cortical amygdala.
• Linking behavioral alterations in ASD models to molecular changes in peripheral sensory neurons.