Stephen D Liberles

Harvard Medical School | HMS · Department of Cell Biology

Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues1–4. The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the m...

Objective Glucose dependent insulinotropic polypeptide (GIP) is well established as an incretin hormone, boosting glucose-dependent insulin secretion. However, whilst anorectic actions of its sister-incretin glucagon-like peptide-1 (GLP-1) are well established, a physiological role for GIP in appetite regulation is controversial, despite the superi...

Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function1,2. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall...

Odorants are detected as smell in the nasal epithelium of mammals by two G-protein-coupled receptor families, the odorant receptors and the trace amine-associated receptors1,2 (TAARs). TAARs emerged following the divergence of jawed and jawless fish, and comprise a large monophyletic family of receptors that recognize volatile amine odorants to eli...

Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron su...

Our external senses of sight, smell, sound, touch, and taste enable us to perceive the external world. In addition, our viscerosensory system monitors the physiological state of peripheral organs. This bodily sensory system orchestrates multi-organ physiological responses, regulating feeding, drinking, sickness behaviors, and generating the interna...

Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes1,2. On infection, immune cells release a ‘storm’ of cytokines and other mediators, many of which are detected by neurons3,4; yet, the responding neural circuits and neuro–immune interaction mechanisms that evoke sick...

Enteroendocrine cells are specialized sensory cells of the gut-brain axis that are sparsely distributed along the intestinal epithelium. The functions of enteroendocrine cells have classically been inferred by the gut hormones they release. However, individual enteroendocrine cells typically produce multiple, sometimes apparently opposing, gut horm...

The nervous system uses various coding strategies to process sensory inputs. For example, the olfactory system uses large receptor repertoires and is wired to recognize diverse odours, whereas the visual system provides high acuity of object position, form and movement 1–5 . Compared to external sensory systems, principles that underlie sensory pro...

Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that detects bloodborne factors. Here, we use genetic approaches based on an area postrema cell atlas to reveal inhibitory neurons that counteract nausea-asso...

The vagus nerve is an indispensable body-brain connection that controls vital aspects of autonomic physiology like breathing, heart rate, blood pressure, and gut motility, reflexes like coughing and swallowing, and survival behaviors like feeding, drinking, and sickness responses. Classical physiological studies and recent molecular/genetic approac...

Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find...

The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles—whether or not there are dedicated neurons with restricted targets that act as “labeled lines” to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By perfor...

Nutrient sensors allow animals to identify foods rich in specific nutrients. The Drosophila nutrient sensor, diuretic hormone 44 (DH44) neurons, helps the fly to detect nutritive sugar. This sensor becomes operational during starvation; however, the mechanisms by which DH44 neurons or other nutrient sensors are regulated remain unclear. Here, we id...

Internal state controls olfaction through poorly understood mechanisms. Odours that represent food, mates, competitors and predators activate parallel neural circuits that may be flexibly shaped by physiological need to alter behavioural outcome¹. Here we identify a neuronal mechanism by which hunger selectively promotes attraction to food odours o...

Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses and is anatomically privileged to detect blood-borne signals. To investigate nausea mechanisms, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing a few neuron types. Using m...

Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find...

Across animal species, meals are terminated after ingestion of large food volumes, yet underlying mechanosensory receptors have so far remained elusive. Here, we identify an essential role for Drosophila Piezo in volume-based control of meal size. We discover a rare population of fly neurons that express Piezo, innervate the anterior gut and crop (...

Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (∼100 neurons/mouse) that guard the airways against assault. W...

Mechanosensory neurons across physiological systems sense force using diverse terminal morphologies. Arterial baroreceptors are sensory neurons that monitor blood pressure for real-time stabilization of cardiovascular output. Various aortic sensory terminals have been described, but those that sense blood pressure are unclear because of a lack of s...

Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry...

Mating drive is balanced by a need to safeguard resources for offspring, yet the neural basis for negative regulation of mating remains poorly understood. In rodents, pheromones critically regulate sexual behavior. Here, we observe suppression of adult female sexual behavior in mice by exocrine gland-secreting peptide 22 (ESP22), a lacrimal protein...

In the version of this article initially published, the line graph showing TNF-α levels in Fig. 2d was inadvertently duplicated. A graph of IL-6 levels should be shown in place of the duplication. These results were also incorrectly described in the main text, which originally stated: “At an early time point of infection (6 h), RTX-treated mice sho...

Many internal organs change volume periodically. For example, the stomach accommodates ingested food and drink, the bladder stores urine, the heart fills with blood, and the lungs expand with every breath. Specialized peripheral sensory neurons function as mechanoreceptors that detect tissue stretch to infer changes in organ volume and then relay t...

Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and body weight are still not fully understood. Here, we determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the acute...

Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1⁺ nociceptors suppressed protective immunity against lethal Staphylococcus aureus p...

The airways contain a myriad of sensory cells that mediate olfaction, control breathing, and protect the respiratory system from damage and disease. The vagus nerve is a major conduit between lung and brain required for normal respiration, and some vagal sensory neurons detect airway expansion that occurs with every breath. Mechanical inflation of...

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals re...

A single sensory cue can evoke different behaviors that vary by recipient. Responses may be influenced by sex, internal state, experience, genotype, and coincident environmental stimuli. Pheromones are powerful inducers of mouse behavior, yet pheromone responses are not always stereotyped. For example, male and female mice respond differently to se...

Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal...

Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine-associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classica...

Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve...

Breathing is essential for survival and under precise neural control. The vagus nerve is a major conduit between lung and brain required for normal respiration. Here, we identify two populations of mouse vagus nerve afferents (P2ry1, Npy2r), each a few hundred neurons, that exert powerful and opposing effects on breathing. Genetically guided anatom...

Sensory cues that predict reward or punishment are fundamental drivers of animal behavior. For example, attractive odors of palatable food or a potential mate predict reward, while aversive odors of pathogen-laced food or a predator predict punishment. Aversive and attractive odors can be detected by intermingled sensory neurons that express highly...

Comparison of SNS-Cre/TdT vs Parv-Cre/TdT neuron expression profiles. Differential expression analysis of microarray data from SNS-Cre/TdTomato+ neurons (n = 4) vs Parv-Cre/TdTomato+ neurons (n = 4). Transcripts are ranked by fold-change, with the following information given: Affymetrix ID, genebank accession number, gene symbol, description, avera...

Comparison of IB4 positive vs IB4 negative SNS-Cre/TdT neuron profiles. Differential expression analysis of microarray data from IB4+SNS-Cre/TdTomato+ neurons (n = 3) vs IB4−SNS-Cre/TdTomato+ neurons (n = 3). These cells were sorted from the same animals. Transcripts are ranked by fold-change, with the following information given: Affymetrix ID, ge...

Sensory systems define an animal's capacity for perception and can evolve to promote survival in new environmental niches. We have uncovered a noncanonical mechanism for sweet taste perception that evolved in hummingbirds since their divergence from insectivorous swifts, their closest relatives. We observed the widespread absence in birds of an ess...

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Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequ...

Significance Cadaverine and putrescine, two diamines emanating from decaying flesh, are strongly repulsive odors to humans but serve as innate attractive or social cues in other species. Here we show that zebrafish, a vertebrate model system, exhibit powerful and innate avoidance behavior to both diamines, and identify a high-affinity olfactory rec...

Animals display a repertoire of different social behaviours. Appropriate behavioural responses depend on sensory input received during social interactions. In mice, social behaviour is driven by pheromones, chemical signals that encode information related to age, sex and physiological state. However, although mice show different social behaviours t...

Extended Data Figure 4. ESP22-derived tryptic peptides identified by MS. (a) The amino acid sequence of immature ESP22 is depicted, along with a predicted signal peptide and the epitope used for antibody generation. Four tryptic peptides were identified by MS (highlighted in red), including one peptide containing the first amino acid after the pred...

Extended Data Figure 5. Electrophysiological responses to ESP22 in VNO sensory neurons (a) Single-unit extracellular loose-seal recording from a single VNO sensory neuron repeatedly exposed to different stimuli indicates reproducibility of responses. (b) The percentage of basal VNO sensory neurons responsive to 20 pM (n=383) and 2 nM (n=749) ESP22.

Extended Data Figure 10. ESP22 (10 µg) inhibits sexual behavior of C3H males. (a) Raster plots of sexual behavior displayed by C3H males towards C3H juvenile females (postnatal day 17) painted with indicated stimuli (30 min social interaction). Each tick indicates onset of one mount. (b) Quantitative analysis of parameters associated with sexual be...

Extended Data Figure 7. Trpc2−/− males display increased sexual behavior towards wild type juveniles. a–b, Histograms of mounts by minute of social interaction and intermount intervals displayed towards juveniles by Trpc2+/+ and Trpc2−/− males (sum, n=12). Inset depicts average intermount intervals. (mean ± s.e.m., *p<0.05, **p<0.01, Mann-Whitney U...

Extended Data Figure 1. RNA in situ hybridization to characterize expression of Esp genes in the lacrimal gland. Colorimetric analysis was performed in tissue from animals indicated using cRNA riboprobes for (a) Esp15 and (b) Esp22, and two-color fluorescence analysis was performed (c) in juvenile lacrimal gland with cRNA riboprobes for Esp22 (red)...

Extended Data Figure 8. Trpc2−/− males display sexual behavior towards juvenile males. (a) Raster plots depicting individual mounting displays of adult Trpc2+/+ and Trpc2−/− males towards juvenile males (C57BL/6, postnatal day 17) during social interaction (30 min). Each tick indicates onset of one mount. (b) Quantitative analysis of parameters ass...

Extended Data Figure 2. qPCR analysis of gene expression. (a) Esp22 qPCR primers specifically detect a plasmid containing cloned Esp22, but not plasmids containing other Esps with >60% identity to Esp22. cDNA was derived from lacrimal gland (b, c, d, e), submaxillary gland (e), or other tissues (f) of animals indicated. In (f), abundance is calcula...

Extended Data Figure 3. Quantification of protein levels in tear fluid by Western Blot analysis using an anti-ESP22 antibody. A standard curve based on signal intensity was generated using different concentrations of recombinant ESP22 (a, left panel; b). The arrow indicates the intensity level of the band in the juvenile tear sample (a, right panel...

Extended Data Figure 6. cFos responses to ESP22 in the amygdala (a) ESP22 and juvenile tear fluid, but not MBP, induce cFos expression in the postero-ventral MeA. Dashed lines and arrows indicate boundaries of MeA regions. (b) Similar responses were not observed in other amygdala nuclei that receive olfactory input, including the postero medial cor...

Extended Data Figure 9. ESP22 did not decrease social investigation time. Wild type C57BL/6 males were introduced to C3H juvenile females painted with stimuli indicated. Social investigation time of the male was recorded as time spent with the nose in direct contact with the female. These data were extracted from the same experiments reported in Fi...

Mammalian pheromones control a myriad of innate social behaviors and acutely regulate hormone levels. Responses to pheromones are highly robust, reproducible, and stereotyped and likely involve developmentally predetermined neural circuits. Here, I review several facets of pheromone transduction in mammals, including (a) chemosensory receptors and...

Male and female mice behave differently when encountering a male. A recent study identifies progesterone receptor-expressing neurons in the hypothalamus that are required for sexual behavior and male aggression. These findings provide insight into how neural circuits control sexually dimorphic behaviors.

Background: Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species, but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown. Results: Here, we identify a mouse chemosign...

Some chemoreceptors of the trace amine-associated receptor (TAAR) family detect innately aversive odors and are proposed to activate hardwired olfactory circuits. However, the wiring of TAAR neurons, the regulatory mechanisms of Taar gene choice, and the subcellular localization of TAAR proteins remain unknown. Here, we reveal similarities between...

Trace amine-associated receptors (TAARs) are vertebrate olfactory receptors. However, ligand recognition properties of TAARs remain poorly understood, as most are "orphan receptors" without known agonists. Here, we identify the first ligands for many rodent TAARs and classify these receptors into two subfamilies based on the phylogeny and binding p...

Predator-prey relationships provide a classic paradigm for the study of innate animal behavior. Odors from carnivores elicit stereotyped fear and avoidance responses in rodents, although sensory mechanisms involved are largely unknown. Here, we identified a chemical produced by predators that activates a mouse olfactory receptor and produces an inn...

The scents of mammals are complex blends of natural products that reveal a wealth of individual information. Many mammals can decipher these scent codes to discern the gender, age, endocrine status, social status, and genotype of conspecifics using dedicated sensory receptors in their olfactory system. Among these social odors are pheromones, chemi...

The mammalian nose is a powerful chemosensor, capable of detecting and distinguishing a myriad of chemicals. Sensory neurons in the olfactory epithelium contain two types of chemosensory G protein-coupled receptors (GPCRs): odorant receptors (ORs), which are encoded by the largest gene family in mammals, and trace amine-associated receptors (TAARs)...

The identification of receptors that detect environmental stimuli lays a foundation for exploring the mechanisms and neural circuits underlying sensation. The mouse vomeronasal organ (VNO), which detects pheromones and other semiochemicals, has 2 known families of chemoreceptors, V1Rs and V2Rs. Here, we report a third family of mouse VNO receptors...

The mammalian olfactory system detects chemicals sensed as odours as well as social cues that stimulate innate responses. Odorants are detected in the nasal olfactory epithelium by the odorant receptor family, whose approximately 1,000 members allow the discrimination of a myriad of odorants. Here we report the discovery of a second family of recep...

The mechanisms underlying sweet taste in mammals have been elusive. Although numerous studies have implicated G proteins in sweet taste detection, the expected G protein-coupled receptors have not been found. Here we describe a candidate taste receptor gene, T1r3, that is located at or near the mouse Sac locus, a genetic locus that controls the det...

Hormones, lipids, vitamins and other biologically active small molecules can be removed from animal tissues by extraction with organic solvents. These compounds can have dramatic effects on cultured cells and the characterization of such compounds can lead to the discovery of new functions for known molecules, or even to the discovery of previously...

Understanding the cellular role of a protein often requires a means of altering its function, most commonly by mutating the gene encoding the protein. Alternatively, protein function can be altered directly using a small molecule that binds to the protein, but no general method exists for the systematic discovery of small molecule ligands. Split-po...

The natural product rapamycin has been used to provide temporal and quantitative control of gene expression in animals through its ability to interact with two proteins simultaneously. A shortcoming of this approach is that rapamycin is an inhibitor of cell proliferation, the result of binding to FKBP12-rapamycin-associated protein (FRAP). To overc...

MS based methodology employing electrospray ionization (ESI) is described for the detection of ternary complexes in which SCH 54292 or SCH 54341 and GDP are noncovalently bound to oncogenic ras protein. The observed molecular weights of 19,816 and 19,570 Da confirmed the presence of noncovalent complexes of ras-GDP-SCH 54292 and ras-GDP-SCH 54341,...

The nucleotide exchange process is one of the key activation steps regulating the ras protein. This report describes the development of potent, non-nucleotide, small organic inhibitors of the ras nucleotide exchange process. These inhibitors bind to the ras protein in a previously unidentified binding pocket, without displacing bound nucleotide. Th...

A novel MS based methodology utilizing electrospray ionization is described for the detection of the noncovalent interaction between a host protein (ras) and its guest ligands (GDP and GTP). The ras proteins are regulatory guanine nucleotide binding proteins which serve as signal transducers controlling cell proliferation or differentiation. They c...

Thesis (Ph. D.)--Harvard University, 1999. Includes bibliographical references.