Inflammation is a body’s response to pathogens and cell death, characterized by recruitment of immune cells and release of cytokines, which can affect the nervous system functions. Cytokines can cause beneficial (sickness behavior) or detrimental (neurodegeneration) effects via neuronal plasticity, and thus inflammation is considered as a key trigger for neurodegenerative diseases such as Alzheimer’s disease. Coincidentally, the impaired sense of smell is also an early marker of many neurogenerative diseases (typically years earlier than cognitive decline). Furthermore, persistent inflammation in the olfactory epithelium in the nose where odorant molecules are detected is a major hallmark of long-COVID patients with olfactory impairment.

Based on these circumstances, our lab aims to understand how inflammation impacts the olfactory system (especially olfactory sensory neurons in the nose), and how inflammation-induced plasticity in the nose contributes to the subsequent neurodegeneration in the brain. We use mouse models that mimic bacterial or viral infection and characterize the patterns of cytokine expression in the nose and their impacts in plasticity at neuronal (odor responses) and tissue level (neuronal survival and neurogenesis) levels, as well as odor-driven behaviors.

We plan to expand our research to other conditions associated with inflammation and olfactory dysfunctions such as neurodegenerative diseases and obesity. In collaboration with Dr Diane Haakonsen at LTRI, we also study how mitochondria stress and cellular response to it reconfigure the neuronal states and lead to neurodegeneration by focusing on a mouse model of an accelerated neurodegenerative disease Deafness-Dystonia-Optic Neuropathy (DDON) caused by mutations in a key gene in mitochondrial protein transport pathway.

Social behavior towards other individuals is central for our well-being and survival. Although social behavior is a type of innate behavior that can be executed without learning, its patterns can be drastically changed by going through life stages. For example, in mice, sexual experience transforms the behavior towards pups from aggression to indifference to parenting in males, and indifference to parenting in females, at least partly through circulating sex hormones. Although prior studies have shown critical roles of a brain structure, the hypothalamus, in hormonal regulation of social behavior, how these hormones (and other signals) modulate the sensory system is understudied. Nevertheless, growing evidence has shown that responses to social odors, even in peripheral sensory neurons, are modulated by life stages, which suggests an intriguing possibility that the nose is a unique organ to sense and integrate signals from the inside and outside of our body.

Our lab studies how sexual experience, pregnancy, and parenthood modulate the peripheral olfaction via gene expression and how peripheral plasticity contributes to changes in social behavior. In collaboration with Dr Andrea Jurisicova, we also study how ovarian failure (menopause) reconfigure the peripheral olfaction by using mouse models of premature ovarian failure.

Impaired social behavior, such as difficulty in social communication and avoidance of eye contact, is commonly observed in people with autism spectrum disorders (ASD). An emerging target for alleviating social impairment in ASD is Arginine vasopressin (AVP), a peptide that control water homeostasis via systemic circulation and social behavior as a neurotransmitter in the brain; AVP levels in blood and cerebrospinal fluid correlate with degree of social behavior in humans and rodents (lower AVP results in less social behavior), and intranasal delivery of AVP is shown to improve social behavior in children with ASD. These results suggest that boosting AVP signaling may help alleviate behavioral alterations in ASD, even though AVP itself is not identified as an ASD risk gene and underlying mechanisms are still unknown.

We recently discovered a rare population of olfactory sensory neurons in the mouse and human nose expressing AVP, which is among the first evidence of AVP-producing neurons outside of the brain to our knowledge. As olfactory sensory neurons detect odors and send the outputs directly to the olfactory bulb in the brain, it is possible that nasally-produce AVP plays pivotal roles in social behavior and intranasal AVP augments this endogenous nose-to-brain pathway. To understand roles of these AVP-expressing neurons in social behavior, our lab studies the downstream circuits in the brain and phenotypes of sensory neuron-specific knock-out mice in social behavior, with a focus on the interaction between parents and neonatal or juvenile mice.

Our research on the plasticity in olfactory sensory neurons pose an important question in neuroscience: How does the brain deal with experience- or internal state-dependent modulation of inputs from the periphery?

By using models we are building in research projects 1-4, we are aiming to ask if the brain (especially in the olfactory bulb and cortical amygdala) exploit plastic changes in sensory inputs to adjust sensory perception or normalize out peripheral changes to prioritize stability.

We are currently focusing on the peripheral neurons, but aiming to address this in the future.

1. Identifying mechanisms linking odor-driven activation of olfactory sensory neurons to neurogenesis (stem cells)
2. Activity-dependent reconfiguration of the presynaptic terminals in olfactory sensory neurons using spatial transcriptomics and proteomics.
3. Characterizing long-term adaptation in the olfactory bulb (integration of sensory inputs, local circuitry, and feedback projection
4. Characterizing atypical olfactory sensory neurons projecting glomeruli with heavy feedback projection from the basal forebrain cholinergic neurons
5. Establishing an in vitro neuronal culture system to examine physiological and molecular changes proportional to activity changes and identify key genes for transcriptional adaptation.
6. Integration of the information from main and accessory olfactory systems in the cortical amygdala.

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.

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.