Chronic chemogenetic stimulation of the anterior olfactory nucleus reduces newborn neuron survival in the adult mouse olfactory bulb.

During adult rodent life, newborn neurons are added to the olfactory bulb (OB) in a tightly controlled manner. Upon arrival in the OB, input synapses from the local bulbar network and the higher olfactory cortex precede the formation of functional output synapses, indicating a possible role for these regions in newborn neuron survival. An interplay between the environment and the piriform cortex in the regulation of newborn neuron survival has been suggested. However, the specific network and the neuronal cell types responsible for this effect have not been elucidated. Furthermore, the role of the other olfactory cortical areas in this process is not known. Here we demonstrate that pyramidal neurons in the mouse anterior olfactory nucleus, the first cortical area for odor processing, have a key role in the survival of newborn neurons. Using DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technology, we applied chronic stimulation to the anterior olfactory nucleus and observed a decrease in newborn neurons in the OB through induction of apoptosis. These findings provide further insight into the network regulating neuronal survival in adult neurogenesis and strengthen the importance of the surrounding network for sustained integration of new neurons.

Olfactory ensheathing cells: Unique glial cells promising for treatments of spinal cord injury.

Spinal cord injury (SCI) is generally the consequence of physical damage, which may result in devastating consequences such as paraplegia or paralysis. Some certain candidates for SCI repair are olfactory ensheathing cells (OECs), which are unique glial cells located in the transition region of the peripheral nervous system and central nervous system and perform neuron regeneration in the olfactory system throughout life. Culture studies have clarified many properties of OECs, but their mechanisms of actions are not fully understood. Successful results achieved in animal models showcased that SCI treatment with OEC transplants is suitable for clinical trials. However, clinical trials are limited by difficulties like cell acquisition for autograft transplantation. Despite the improvements in both animal and clinical studies so far, there is still insufficient information about the mechanism of actions, adverse effects, proper application methods, effective subtypes, and sources of cells. This review summarizes pre-clinical and clinical literature focused on the cellular characterization of both OECs in vitro and post-transplantation. We highlight the roles and effects of OECs on (a) the injury-induced glial milieu, (b) neuronal growth/regeneration, and (c) functional recovery after injury. Due to the shown benefits of OECs with in vitro and animal studies and a limited number of clinical trials, where safety and effectivity were shown, it is necessary to conduct more studies on OECs to obtain effective and feasible treatment methods.

Alterations in Piriform and Bulbar Activity/Excitability/Coupling Upon Amyloid-ß Administration in vivo Related to Olfactory Dysfunction.

BACKGROUND: Deficits in odor detection and discrimination are premature symptoms of Alzheimer's disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-ß peptide (Aß), which can be prevented by reducing Aß levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aß accumulation and Aß-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility needs further exploration. OBJECTIVE: To characterize the effects of Aß on OB and PCx excitability/coupling and on olfaction. METHODS: Aß oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in slices. Olfaction was assessed through the habituation/dishabituation test. RESULTS: Aß did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aß. Finally, Aß treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in slices. CONCLUSION: Our results show that Aß-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.

Recurrent circuitry is required to stabilize piriform cortex odor representations across brain states.

Pattern completion, or the ability to retrieve stable neural activity patterns from noisy or partial cues, is a fundamental feature of memory. Theoretical studies indicate that recurrently connected auto-associative or discrete attractor networks can perform this process. Although pattern completion and attractor dynamics have been observed in various recurrent neural circuits, the role recurrent circuitry plays in implementing these processes remains unclear. In recordings from head-fixed mice, we found that odor responses in olfactory bulb degrade under ketamine/xylazine anesthesia while responses immediately downstream, in piriform cortex, remain robust. Recurrent connections are required to stabilize cortical odor representations across states. Moreover, piriform odor representations exhibit attractor dynamics, both within and across trials, and these are also abolished when recurrent circuitry is eliminated. Here, we present converging evidence that recurrently-connected piriform populations stabilize sensory representations in response to degraded inputs, consistent with an auto-associative function for piriform cortex supported by recurrent circuitry.

Excitability of Neural Activity is Enhanced, but Neural Discrimination of Odors is Slightly Decreased, in the Olfactory Bulb of Fasted Mice.

Olfaction and satiety status influence each other: cues from the olfactory system modulate eating behavior, and satiety affects olfactory abilities. However, the neural mechanisms governing the interactions between olfaction and satiety are unknown. Here, we investigate how an animal's nutritional state modulates neural activity and odor representation in the mitral/tufted cells of the olfactory bulb, a key olfactory center that plays important roles in odor processing and representation. At the single-cell level, we found that the spontaneous firing rate of mitral/tufted cells and the number of cells showing an excitatory response both increased when mice were in a fasted state. However, the neural discrimination of odors slightly decreased. Although ongoing baseline and odor-evoked beta oscillations in the local field potential in the olfactory bulb were unchanged with fasting, the amplitude of odor-evoked gamma oscillations significantly decreased in a fasted state. These neural changes in the olfactory bulb were independent of the sniffing pattern, since both sniffing frequency and mean inhalation duration did not change with fasting. These results provide new information toward understanding the neural circuit mechanisms by which olfaction is modulated by nutritional status.

Similarity and Strength of Glomerular Odor Representations Define a Neural Metric of Sniff-Invariant Discrimination Time.

The olfactory environment is first represented by glomerular activity patterns in the olfactory bulb. It remains unclear how these representations intersect with sampling behavior to account for the time required to discriminate odors. Using different chemical classes, we investigate glomerular representations and sniffing behavior during olfactory decision-making. Mice rapidly discriminate odorants and learn to increase sniffing frequency at a fixed latency after trial initiation, independent of odor identity. Relative to the increase in sniffing frequency, monomolecular odorants are discriminated within 10-40 ms, while binary mixtures require an additional 60-70 ms. Intrinsic imaging of glomerular activity in anesthetized and awake mice reveals that Euclidean distance between activity patterns and the time needed for discriminations are anti-correlated. Therefore, the similarity of glomerular patterns and their activation strengths, rather than sampling behavior, define the extent of neuronal processing required for odor discrimination, establishing a neural metric to predict olfactory discrimination time.

Photoactivation of olfactory sensory neurons does not affect action potential conduction in individual trigeminal sensory axons innervating the rodent nasal cavity.

Olfactory and trigeminal chemosensory systems reside in parallel within the mammalian nose. Psychophysical studies in people indicate that these two systems interact at a perceptual level. Trigeminal sensations of pungency mask odour perception, while olfactory stimuli can influence trigeminal signal processing tasks such as odour localization. While imaging studies indicate overlap in limbic and cortical somatosensory areas activated by nasal trigeminal and olfactory stimuli, there is also potential cross-talk at the level of the olfactory epithelium, the olfactory bulb and trigeminal brainstem. Here we explored the influence of olfactory and trigeminal signaling in the nasal cavity. A forced choice water consumption paradigm was used to ascertain whether trigeminal and olfactory stimuli could influence behaviour in mice. Mice avoided water sources surrounded by both volatile TRPV1 (cyclohexanone) and TRPA1 (allyl isothiocyanate) irritants and the aversion to cyclohexanone was mitigated when combined with a pure odorant (rose fragrance, phenylethyl alcohol, PEA). To determine whether olfactory-trigeminal interactions within the nose could potentially account for this behavioural effect we recorded from single trigeminal sensory axons innervating the nasal respiratory and olfactory epithelium using an isolated in vitro preparation. To circumvent non-specific effects of chemical stimuli, optical stimulation was used to excite olfactory sensory neurons in mice expressing channel-rhodopsin (ChR2) under the olfactory marker protein (OMP) promoter. Photoactivation of olfactory sensory neurons produced no modulation of axonal action potential conduction in individual trigeminal axons. Similarly, no evidence was found for collateral branching of trigeminal axon that might serve as a conduit for cross-talk between the olfactory and respiratory epithelium and olfactory dura mater. Using direct assessment of action potential activity in trigeminal axons we observed neither paracrine nor axon reflex mediated cross-talk between olfactory and trigeminal sensory systems in the rodent nasal cavity. Our current results suggest that olfactory sensory neurons exert minimal influence on trigeminal signals within the nasal cavity.

Odorant features differentially modulate beta/gamma oscillatory patterns in anterior versus posterior piriform cortex.

Oscillatory activity is a prominent characteristic of the olfactory system. We previously demonstrated that beta and gamma oscillations occurrence in the olfactory bulb (OB) is modulated by the physical properties of the odorant. However, it remains unknown whether such odor-related modulation of oscillatory patterns is maintained in the piriform cortex (PC) and whether those patterns are similar between the anterior PC (aPC) and posterior PC (pPC). The present study was designed to analyze how different odorant molecular features can affect the local field potential (LFP) oscillatory signals in both the aPC and the pPC in anesthetized rats. As reported in the OB, three oscillatory patterns were observed: standard pattern (gamma + beta), gamma-only and beta-only patterns. These patterns occurred with significantly different probabilities in the two PC areas. We observed that odor identity has a strong influence on the probability of occurrence of LFP beta and gamma oscillatory activity in the aPC. Thus, some odor coding mechanisms observed in the OB are retained in the aPC. By contrast, probability of occurrence of different oscillatory patterns is homogeneous in the pPC with beta-only pattern being the most prevalent one for all the different odor families. Overall, our results confirmed the functional heterogeneity of the PC with its anterior part tightly coupled with the OB and mainly encoding odorant features whereas its posterior part activity is not correlated with odorant features but probably more involved in associative and multi-sensory encoding functions.

FMRI correlates of olfactory processing in typically-developing school-aged children.

Human olfactory processing is understudied relative to other sensory modalities, despite its links to neurodevelopmental and neurodegenerative disorders. To address this limitation, we developed a fast, robust fMRI odor paradigm that is appropriate for all ages and levels of cognitive functioning. To test this approach, thirty-four typically developing children aged 7-12 underwent fMRI during brief, repeated exposure to phenylethyl alcohol, a flower-scented odor. Prior to fMRI scanning, olfactory testing (odor detection and identification) was conducted. During fMRI stimulus presentation, odorant release was synchronized to each participant's inspiratory phase to ensure participants were inhaling during the odorant exposure. Between group differences and correlations between activation and odor detection threshold scores were tested using the FMRIB Software Library. Results demonstrated that our 2-min paradigm significantly activated primary and secondary olfactory regions. In addition, a significant relationship between odor detection threshold and higher activation in the right amygdala and lower activation in the left frontal, insular, occipital, and cerebellar regions was observed, suggesting that this approach is sensitive to individual differences in olfactory processing. These findings demonstrate the feasibility of studying olfactory function in children using brain imaging techniques.

NMDA spikes mediate amplification of inputs in the rat piriform cortex.

The piriform cortex (PCx) receives direct input from the olfactory bulb (OB) and is the brain's main station for odor recognition and memory. The transformation of the odor code from OB to PCx is profound: mitral and tufted cells in olfactory glomeruli respond to individual odorant molecules, whereas pyramidal neurons (PNs) in the PCx responds to multiple, apparently random combinations of activated glomeruli. How these 'discontinuous' receptive fields are formed from OB inputs remains unknown. Counter to the prevailing view that olfactory PNs sum their inputs passively, we show for the first time that NMDA spikes within individual dendrites can both amplify OB inputs and impose combination selectivity upon them, while their ability to compartmentalize voltage signals allows different dendrites to represent different odorant combinations. Thus, the 2-layer integrative behavior of olfactory PN dendrites provides a parsimonious account for the nonlinear remapping of the odor code from bulb to cortex.

Temporally specific engagement of distinct neuronal circuits regulating olfactory habituation in Drosophila.

Habituation is the process that enables salience filtering, precipitating perceptual changes that alter the value of environmental stimuli. To discern the neuronal circuits underlying habituation to brief inconsequential stimuli, we developed a novel olfactory habituation paradigm, identifying two distinct phases of the response that engage distinct neuronal circuits. Responsiveness to the continuous odor stimulus is maintained initially, a phase we term habituation latency and requires Rutabaga Adenylyl-Cyclase-depended neurotransmission from GABAergic Antennal Lobe Interneurons and activation of excitatory Projection Neurons (PNs) and the Mushroom Bodies. In contrast, habituation depends on the inhibitory PNs of the middle Antenno-Cerebral Track, requires inner Antenno-Cerebral Track PN activation and defines a temporally distinct phase. Collectively, our data support the involvement of Lateral Horn excitatory and inhibitory stimulation in habituation. These results provide essential cellular substrates for future analyses of the molecular mechanisms that govern the duration and transition between these distinct temporal habituation phases. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Precise Synaptic Balance in the Zebrafish Homolog of Olfactory Cortex.

Neuronal computations critically depend on the connectivity rules that govern the convergence of excitatory and inhibitory synaptic signals onto individual neurons. To examine the functional synaptic organization of a distributed memory network, we performed voltage clamp recordings in telencephalic area Dp of adult zebrafish, the homolog of olfactory cortex. In neurons of posterior Dp, odor stimulation evoked large, recurrent excitatory and inhibitory inputs that established a transient state of high conductance and synaptic balance. Excitation and inhibition in individual neurons were co-tuned to different odors and correlated on slow and fast timescales. This precise synaptic balance implies specific connectivity among Dp neurons, despite the absence of an obvious topography. Precise synaptic balance stabilizes activity patterns in different directions of coding space and in time while preserving high bandwidth. The coordinated connectivity of excitatory and inhibitory subnetworks in Dp therefore supports fast recurrent memory operations.

Neuronal Response Latencies Encode First Odor Identity Information across Subjects.

Odorants are coded in the primary olfactory processing centers by spatially and temporally distributed patterns of glomerular activity. Whereas the spatial distribution of odorant-induced responses is known to be conserved across individuals, the universality of its temporal structure is still debated. Via fast two-photon calcium imaging, we analyzed the early phase of neuronal responses in the form of the activity onset latencies in the antennal lobe projection neurons of honeybee foragers. We show that each odorant evokes a stimulus-specific response latency pattern across the glomerular coding space. Moreover, we investigate these early response features for the first time across animals, revealing that the order of glomerular firing onsets is conserved across individuals and allows them to reliably predict odorant identity, but not concentration. These results suggest that the neuronal response latencies provide the first available code for fast odor identification.SIGNIFICANCE STATEMENT Here, we studied early temporal coding in the primary olfactory processing centers of the honeybee brain by fast imaging of glomerular responses to different odorants across glomeruli and across individuals. Regarding the elusive role of rapid response dynamics in olfactory coding, we were able to clarify the following aspects: (1) the rank of glomerular activation is conserved across individuals, (2) its stimulus prediction accuracy is equal to that of the response amplitude code, and (3) it contains complementary information. Our findings suggest a substantial role of response latencies in odor identification, anticipating the static response amplitude code.

Prenatal bisphenol A exposure is associated with medial amygdala neuron hyperresponsiveness to predator odor in rats.

Perinatal exposure to bisphenol A (BPA) causes several alterations in brain function and behavior. In previous studies, we showed that prenatal treatment with low-level BPA impaired gender-specific behavior, enhanced depression-like behavior, and augmented behavioral responses to predator odor in rats. On this premise, we hypothesized that BPA-treated rats were more susceptible to predator odor stress. To test the potential neural mechanism underlying this effect, we conducted an electrophysiological study of neurons in the medial amygdala-a regional component of the olfactory pathway with high estrogen and androgen receptor expression, and thus a potential target of BPA-in rats exposed to BPA. Extracellular recordings were obtained during the presentation of 3 plant odors and 3 predator odorants. Odor-responsive neurons in BPA-exposed rats showed greater activity in response to fox odor than did those in control rats. This finding complements the results of our previous behavioral study in which BPA-exposed rats exhibited enhanced avoidance behavior in response to fox odor. Given the close relationship between olfactory signaling and the stress response system, we suspect that BPA modifies the olfactory pathway at the level of the medial amygdala and thus modulates the corresponding stress response.

Hippocampal projections to the anterior olfactory nucleus differentially convey spatiotemporal information during episodic odour memory.

The hippocampus is essential for representing spatiotemporal context and establishing its association with the sensory details of daily life to form episodic memories. The olfactory cortex in particular shares exclusive anatomical connections with the hippocampus as a result of their common evolutionary history. Here we selectively inhibit hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually cued odour recall. We find that spatial odour memory and temporal odour memory are independently impaired following inhibition of distinct, topographically organized hippocampal-AON pathways. Our results not only reveal a longstanding unknown function for the AON but offer new mechanistic insights regarding the representation of odours in episodic memory.

Flight motor networks modulate primary olfactory processing in the moth Manduca sexta.

Nervous systems must distinguish sensory signals derived from an animal's own movements (reafference) from environmentally derived sources (exafference). To accomplish this, motor networks producing reafference transmit motor information, via a corollary discharge circuit (CDC), to affected sensory networks, modulating sensory function during behavior. While CDCs have been described in most sensory modalities, none have been observed projecting to an olfactory pathway. In moths, two mesothoracic to deutocerebral histaminergic neurons (MDHns) project from flight sensorimotor centers in the mesothoracic neuromere to the antennal lobe (AL), where they provide the sole source of histamine (HA), but whether they represent a CDC is unknown. We demonstrate that MDHn spiking activity is positively correlated with wing-motor output and increased before bouts of motor activity, suggesting that MDHns communicate global locomotor state, rather than providing a precisely timed motor copy. Within the AL, HA application sharpened entrainment of projection neuron responses to odor stimuli embedded within simulated wing-beat-induced flows, whereas MDHn axotomy or AL HA receptor (HA-r) blockade reduced entrainment. This finding is consistent with higher-order CDCs, as the MDHns enhanced rather than filtered entrainment of AL projection neurons. Finally, HA-r blockade increased odor detection and discrimination thresholds in behavior assays. These results establish MDHns as a CDC that modulates AL temporal resolution, enhancing odor-guided behavior. MDHns thus appear to represent a higher-order CDC to an insect olfactory pathway; this CDC's unique nature highlights the importance of motor-to-sensory signaling as a context-specific mechanism that fine-tunes sensory function.

Olfactory Adaptation is Dependent on Route of Delivery.

Odorants are perceived orthonasally (nostrils) or retronasally (oral cavity). Prior research indicates route of delivery impacts odorant perception, pleasantness, and directed behaviors thus suggesting differential processing of olfactory information. Adaptation is a form of neural processing resulting in decreased perceived intensity of a stimulus following prolonged and continuous exposure. The present study objective was to determine whether route of delivery differentially impacts olfactory adaptation and whether cross-adaptation occurs between orthonasal and retronasal pathways. Linalool (12%) or vanillin (25%) were delivered orthonasally [6 L/min (LPM)] and retronasally (8 LPM) in air phase through a custom-built olfactometer. Perceived odorant intensity was collected every 5 min over 10-min exposure. Immediately following the exposure period, cross-adaptation was assessed by shunting the delivery of the odorant from the nostrils to the oral cavity, or vice versa. A control study was also completed in which subjects underwent the orthonasal adaptation protocol using stimulus concentrations matched to the intensity of restronasal stimuli (e.g., 1.5% linalool and 6.25% vanillin). Following orthonasal delivery of both high and low vanillin concentrations, results showed perceived intensity decreased significantly at 5 and 10 min. High concentrations of orthonasal linalool similarly decreased significantly whereas lower concentrations decreased but did not reach statistical significance. Linalool and vanillin delivered retronasally did not adapt as perceived intensity actually increased significantly following a 10-min exposure. In addition, evidence of cross-adaptation was not obvious following extended odorant exposure from either delivery pathway. This study suggests that olfactory processing may be affected by the route of odorant delivery.

History-Dependent Odor Processing in the Mouse Olfactory Bulb.

In nature, animals normally perceive sensory information on top of backgrounds. Thus, the neural substrate to perceive under background conditions is inherent in all sensory systems. Where and how sensory systems process backgrounds is not fully understood. In olfaction, just a few studies have addressed the issue of odor coding on top of continuous odorous backgrounds. Here, we tested how background odors are encoded by mitral cells (MCs) in the olfactory bulb (OB) of male mice. Using in vivo two-photon calcium imaging, we studied how MCs responded to odors in isolation versus their responses to the same odors on top of continuous backgrounds. We show that MCs adapt to continuous odor presentation and that mixture responses are different when preceded by background. In a subset of odor combinations, this history-dependent processing was useful in helping to identify target odors over background. Other odorous backgrounds were highly dominant such that target odors were completely masked by their presence. Our data are consistent in both low and high odor concentrations and in anesthetized and awake mice. Thus, odor processing in the OB is strongly influenced by the recent history of activity, which could have a powerful impact on how odors are perceived.SIGNIFICANCE STATEMENT We examined a basic feature of sensory processing in the olfactory bulb. Specifically, we measured how mitral cells adapt to continuous background odors and how target odors are encoded on top of such background. Our results show clear differences in odor coding based on the immediate history of the stimulus. Our results support the argument that odor coding in the olfactory bulb depends on the recent history of the sensory environment.

The Accessory Olfactory System Facilitates the Recovery of the Attraction to Familiar Volatile Female Odors in Male Mice.

Odors in female mice induce sexual arousal in male mice. Repeated exposure to female odors attenuates male attraction, which recovers when the odors are removed. The neuronal mechanisms for the recovery of male attraction have not been clarified. In this study, we examined how olfactory systems are involved in the recovery of male attraction to female odors following habituation in mice. Presentation with volatile female odors for 5 min induced habituation in males. To evaluate male attraction to familiar volatile female odors, we measured the duration for investigating volatile female odors from the same female mouse, which was presented twice for 5 min with 1-, 3-, or 5-min interval. Intranasal irrigation with ZnSO4 solution almost completely suppressed investigating behavior, indicating that the main olfactory system is indispensable for inducing the attraction to volatile female odors. In contrast, removal of the vomeronasal organ, bilateral lesions of the accessory olfactory bulb (AOB), or pharmacological blockage of neurotransmission in the AOB did not affect the investigation time at the first odor presentation. However, each one of the treatments decreased the investigation time in the second presentation, compared to that in the first presentation, at longer intervals than control treatment, indicating that the disturbance of neurotransmission in the accessory olfactory system delayed the recovery of the attraction attenuated by the first presentation. These results suggest that the accessory olfactory system facilitates the recovery of the attraction to familiar volatile female odors in male mice.

Multiple Signaling Pathways Coordinately Regulate Forgetting of Olfactory Adaptation through Control of Sensory Responses in Caenorhabditis elegans.

Forgetting memories is important for animals to properly respond to continuously changing environments. To elucidate the mechanisms of forgetting, we used one of the behavioral plasticities of Caenorhabditis elegans hermaphrodite, olfactory adaptation to an attractive odorant, diacetyl, as a simple model of learning. In C. elegans, the TIR-1/JNK-1 pathway accelerates forgetting of olfactory adaptation by facilitating neural secretion from AWC sensory neurons. In this study, to identify the downstream effectors of the TIR-1/JNK-1 pathway, we conducted a genetic screen for suppressors of the gain-of-function mutant of tir-1 (ok1052), which shows excessive forgetting. Our screening showed that three proteins-a membrane protein, MACO-1; a receptor tyrosine kinase, SCD-2; and its putative ligand, HEN-1-regulated forgetting downstream of the TIR-1/JNK-1 pathway. We further demonstrated that MACO-1 and SCD-2/HEN-1 functioned in parallel genetic pathways, and only MACO-1 regulated forgetting of olfactory adaptation to isoamyl alcohol, which is an attractive odorant sensed by different types of sensory neurons. In olfactory adaptation, odor-evoked Ca2+ responses in olfactory neurons are attenuated by conditioning and recovered thereafter. A Ca2+ imaging study revealed that this attenuation is sustained longer in maco-1 and scd-2 mutant animals than in wild-type animals like the TIR-1/JNK-1 pathway mutants. Furthermore, temporal silencing by histamine-gated chloride channels revealed that the neuronal activity of AWC neurons after conditioning is important for proper forgetting. We propose that distinct signaling pathways, each of which has a specific function, may coordinately and temporally regulate forgetting by controlling sensory responses.SIGNIFICANCE STATEMENT Active forgetting is an important process to understand the whole mechanisms of memories. Recent papers have reported that the noncell autonomous regulations are required for proper forgetting in invertebrates. We found that in Caenorhabditis elegans hermaphrodite, the noncell autonomous regulations of forgetting of olfactory adaptation is regulated by three conserved proteins: a membrane protein, MACO-1; a receptor tyrosine kinase, SCD-2: and its ligand, HEN-1. MACO-1 and SCD-2/HEN-1, working in coordination, accelerate forgetting by controlling sensory responses in parallel. Furthermore, temporal regulation of neuronal activity is important for proper forgetting. We suggest that multiple pathways may coordinately and temporally regulate forgetting through control of sensory responses. This study should lead to a better understanding of forgetting in higher organisms.