Think You Know How Smell Works? Sniff Again.

The sense of smell is mediated by GPCRs in the odorant receptor (OR) family. Greer et al. report a new family of odor detectors, MS4As, that have similar cellular localization and chemodetection ability as ORs but are not GPCRs and follow a strikingly different logic of odor coding at the periphery.

Cyclic Regulation of Sensory Perception by a Female Hormone Alters Behavior.

Females may display dramatically different behavior depending on their state of ovulation. This is thought to occur through sex-specific hormones acting on behavioral centers in the brain. Whether incoming sensory activity also differs across the ovulation cycle to alter behavior has not been investigated. Here, we show that female mouse vomeronasal sensory neurons (VSNs) are temporarily and specifically rendered "blind" to a subset of male-emitted pheromone ligands during diestrus yet fully detect and respond to the same ligands during estrus. VSN silencing occurs through the action of the female sex-steroid progesterone. Not all VSNs are targeted for silencing; those detecting cat ligands remain continuously active irrespective of the estrous state. We identify the signaling components that account for the capacity of progesterone to target specific subsets of male-pheromone responsive neurons for inactivation. These findings indicate that internal physiology can selectively and directly modulate sensory input to produce state-specific behavior. PAPERCLIP.

Murine pheromone proteins constitute a context-dependent combinatorial code governing multiple social behaviors.

During social interactions, an individual's behavior is largely governed by the subset of signals emitted by others. Discrimination of "self" from "other" regulates the territorial urine countermarking behavior of mice. To identify the cues for this social discrimination and understand how they are interpreted, we designed an olfactory-dependent countermarking assay. We find major urinary proteins (MUPs) sufficient to elicit countermarking, and unlike other vomeronasal ligands that are detected by specifically tuned sensory neurons, MUPs are detected by a combinatorial strategy. A chemosensory signature of "self" that modulates behavior is developed via experience through exposure to a repertoire of MUPs. In contrast, aggression can be elicited by MUPs in an experience-independent but context-dependent manner. These findings reveal that individually emitted chemical cues can be interpreted based on their combinatorial permutation and relative ratios, and they can transmit both fixed and learned information to promote multiple behaviors.

Flexible scaling and persistence of social vocal communication.

Innate vocal sounds such as laughing, screaming or crying convey one's feelings to others. In many species, including humans, scaling the amplitude and duration of vocalizations is essential for effective social communication1-3. In mice, female scent triggers male mice to emit innate courtship ultrasonic vocalizations (USVs)4,5. However, whether mice flexibly scale their vocalizations and how neural circuits are structured to generate flexibility remain largely unknown. Here we identify mouse neurons from the lateral preoptic area (LPOA) that express oestrogen receptor 1 (LPOAESR1 neurons) and, when activated, elicit the complete repertoire of USV syllables emitted during natural courtship. Neural anatomy and functional data reveal a two-step, di-synaptic circuit motif in which primary long-range inhibitory LPOAESR1 neurons relieve a clamp of local periaqueductal grey (PAG) inhibition, enabling excitatory PAG USV-gating neurons to trigger vocalizations. We find that social context shapes a wide range of USV amplitudes and bout durations. This variability is absent when PAG neurons are stimulated directly; PAG-evoked vocalizations are time-locked to neural activity and stereotypically loud. By contrast, increasing the activity of LPOAESR1 neurons scales the amplitude of vocalizations, and delaying the recovery of the inhibition clamp prolongs USV bouts. Thus, the LPOA disinhibition motif contributes to flexible loudness and the duration and persistence of bouts, which are key aspects of effective vocal social communication.

PIEZO2 in sensory neurons and urothelial cells coordinates urination.

Henry Miller stated that "to relieve a full bladder is one of the great human joys". Urination is critically important in health and ailments of the lower urinary tract cause high pathological burden. Although there have been advances in understanding the central circuitry in the brain that facilitates urination1-3, there is a lack of in-depth mechanistic insight into the process. In addition to central control, micturition reflexes that govern urination are all initiated by peripheral mechanical stimuli such as bladder stretch and urethral flow4. The mechanotransduction molecules and cell types that function as the primary stretch and pressure detectors in the urinary tract mostly remain unknown. Here we identify expression of the mechanosensitive ion channel PIEZO2 in lower urinary tract tissues, where it is required for low-threshold bladder-stretch sensing and urethral micturition reflexes. We show that PIEZO2 acts as a sensor in both the bladder urothelium and innervating sensory neurons. Humans and mice lacking functional PIEZO2 have impaired bladder control, and humans lacking functional PIEZO2 report deficient bladder-filling sensation. This study identifies PIEZO2 as a key mechanosensor in urinary function. These findings set the foundation for future work to identify the interactions between urothelial cells and sensory neurons that control urination.

The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs.

Potential predators emit uncharacterized chemosignals that warn receiving species of danger. Neurons that sense these stimuli remain unknown. Here we show that detection and processing of fear-evoking odors emitted from cat, rat, and snake require the function of sensory neurons in the vomeronasal organ. To investigate the molecular nature of the sensory cues emitted by predators, we isolated the salient ligands from two species using a combination of innate behavioral assays in naive receiving animals, calcium imaging, and c-Fos induction. Surprisingly, the defensive behavior-promoting activity released by other animals is encoded by species-specific ligands belonging to the major urinary protein (Mup) family, homologs of aggression-promoting mouse pheromones. We show that recombinant Mup proteins are sufficient to activate sensory neurons and initiate defensive behavior similarly to native odors. This co-option of existing sensory mechanisms provides a molecular solution to the difficult problem of evolving a variety of species-specific molecular detectors.

LUSH shapes up for a starring role in olfaction.

In the fruit fly Drosophila, odorant-binding proteins are secreted into the fluid that bathes olfactory neurons. Laughlin et al. (2008) now challenge the assumption that the odorant-binding protein LUSH passively transports its pheromone to a specific olfactory receptor. Instead, LUSH undergoes a conformational change upon pheromone binding that is sufficient for neuronal activation.

Sensory neurobiology: Muscles power pheromone sensation.

While we understand how the five main sensory organs enable and facilitate stimulus detection, little is known about how the vomeronasal organ enables pheromone sensation. A new study finds specialized muscles poised to coordinate stimulus delivery, dynamics, and arousal.

Identification of protein pheromones that promote aggressive behaviour.

Mice use pheromones, compounds emitted and detected by members of the same species, as cues to regulate social behaviours such as pup suckling, aggression and mating. Neurons that detect pheromones are thought to reside in at least two separate organs within the nasal cavity: the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). Each pheromone ligand is thought to activate a dedicated subset of these sensory neurons. However, the nature of the pheromone cues and the identity of the responding neurons that regulate specific social behaviours are largely unknown. Here we show, by direct activation of sensory neurons and analysis of behaviour, that at least two chemically distinct ligands are sufficient to promote male-male aggression and stimulate VNO neurons. We have purified and analysed one of these classes of ligand and found its specific aggression-promoting activity to be dependent on the presence of the protein component of the major urinary protein (MUP) complex, which is known to comprise specialized lipocalin proteins bound to small organic molecules. Using calcium imaging of dissociated vomeronasal neurons (VNs), we have determined that the MUP protein activates a sensory neuron subfamily characterized by the expression of the G-protein Galpha(o) subunit (also known as Gnao) and Vmn2r putative pheromone receptors (V2Rs). Genomic analysis indicates species-specific co-expansions of MUPs and V2Rs, as would be expected among pheromone-signalling components. Finally, we show that the aggressive behaviour induced by the MUPs occurs exclusively through VNO neuronal circuits. Our results substantiate the idea of MUP proteins as pheromone ligands that mediate male-male aggression through the accessory olfactory neural pathway.

Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system.

Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice.

Less is more: Hormonal-induced decrease in brain activity is required for associative learning.

Memory develops during early life, yet the corresponding molecular mechanisms are largely unknown. Leinwand and Scott (2021) reveal a link between juvenile hormone, neural activity, and memory-evoked behavior during a critical period that promotes associative learning in the adult fly.

Bespoke behavior: mechanisms that modulate pheromone-triggered behavior.

What is good for others, may not be in my best interest. Individuals should not, and do not, respond identically in the same environment. Personalized social behavior is particularly important to ultimately ensure reproductive fitness. How and where neural activity is modulated to customize behavior has remained largely unknown. The robust response to pheromones provides a platform to identify the logic of how the brain initiates social behavior. Mouse pheromones engage innate motor actions that underlie social behavior yet are plastic to suit individual needs. Recent study of mouse pheromone behavior, neurocircuit activity, and functional manipulations is beginning to paint a complex, dynamic, and diverse picture of the mechanisms that enable flexible modulation of social behavior.

Choosing to urinate. Circuits and mechanisms underlying voluntary urination.

The decision to urinate is a social behavior that is calculated multiple times a day. Many animals perform urine scent-marking which broadcasts their pheromones to regulate the behavior of others and humans are trained at an early age to urinate only at a socially acceptable time and place. The inability to control when and where to void, that is incontinence, causes extreme social discomfort yet targeted therapeutics are lacking because little is known about the underlying circuits and mechanisms. The use of animal models, neurocircuit analysis, and functional manipulation is beginning to reveal basic logic of the circuit that modulates the decision of when and where to void.

Representation of Olfactory Information in Organized Active Neural Ensembles in the Hypothalamus.

The internal representation of sensory information via coherent activation of specific pathways in the nervous system is key to appropriate behavioral responses. Little is known about how chemical stimuli that elicit instinctive behaviors lead to organized patterns of activity in the hypothalamus. Here, we study how a wide range of chemosignals form a discernible map of olfactory information in the ventromedial nucleus of the hypothalamus (VMH) and show that different stimuli entail distinct active neural ensembles. Importantly, we demonstrate that this map depends on functional inputs from the vomeronasal organ. We present evidence that the spatial locations of active VMH ensembles are correlated with activation of distinct vomeronasal receptors and that disjunct VMH ensembles exhibit differential projection patterns. Moreover, active ensembles with distinct spatial locations are not necessarily associated with different behavior categories, such as defensive or social, calling for a revision of the currently accepted model of VMH organization.

What is a pheromone? Mammalian pheromones reconsidered.

Pheromone communication is a two-component system: signaling pheromones and receiving sensory neurons. Currently, pheromones remain enigmatic bioactive compounds, as only a few have been identified, but classical bioassays have suggested that they are nonvolatile, activate vomeronasal sensory neurons, and regulate innate social behaviors and neuroendocrine release. Recent discoveries of potential pheromones reveal that they may be more structurally and functionally diverse than previously defined.

Animal Behavior: Honesty Can Kill.

Virgin male mice naturally kill another male's pups so they can sire their own offspring. New research shows that pups are identified using a combination of generic and 'honest' cues, revealing an unexpected logic underlying pup recognition and ensuing infanticide.

Social Behavior: How the Brain Thinks like a Mom.

Becoming a parent changes our choices and actions. Identifying the underlying neural circuits is necessary to understand the transformation of an animal's behavior post-parenthood. Multiple nodes of the 'parenting circuit' have now been identified to reveal the workings of a single brain region key to the orchestration of parent-specific behaviors.

Voluntary urination control by brainstem neurons that relax the urethral sphincter.

Voluntary urination ensures that waste is eliminated when safe and socially appropriate, even without a pressing urge. Uncontrolled urination, or incontinence, is a common problem with few treatment options. Normal urine release requires a small region in the brainstem known as Barrington's nucleus (Bar), but specific neurons that relax the urethral sphincter and enable urine flow are unknown. Here we identify a small subset of Bar neurons that control the urethral sphincter in mice. These excitatory neurons express estrogen receptor 1 (BarESR1), project to sphincter-relaxing interneurons in the spinal cord and are active during natural urination. Optogenetic stimulation of BarESR1 neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of urination and its dysfunction.

Neuronal development: specifying a hard-wired circuit.

The formation of neuronal circuits that relay distinct olfactory information is thought to depend on cues provided by pre-synaptic receptor neurons. But direct visualization of second order neurons in Drosophila now suggests that dendritic targeting occurs independently of interactions with incoming sensory neurons.

State-dependent responses to sex pheromones in mouse.

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 sex pheromones while mothers and virgin females respond differently to pup cues. Here, we review the origins of variability in responses to reproductive pheromones. Recent advances have indicated how response variability may arise through modulation at different levels of pheromone-processing circuitry, from sensory neurons in the periphery to central neurons in the vomeronasal amygdala. Understanding mechanisms underlying conditional pheromone responses should reveal how neural circuits can be flexibly sculpted to alter behavior.