COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters.

Whereas recent investigations have revealed viral, inflammatory, and vascular factors involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung pathogenesis, the pathophysiology of neurological disorders in coronavirus disease 2019 (COVID-19) remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium is a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Last, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.

Assessment of metacognitive monitoring and control in baboons (Papio papio).

Metacognition refers to the ability of an organism to evaluate its states of knowledge (metacognitive monitoring) and engage in appropriate information-seeking behaviors when a lack of knowledge is detected (metacognitive control). This study assessed metacognitive monitoring and control in three Guinea baboons (Papio papio). Monkeys were required to report on a touchscreen the location of two target stimuli that had previously appeared briefly on a grid. They could either respond directly or use a "Repeat" key providing an opportunity to repeat the target stimuli. In Experiment 1, the baboons used the Repeat key more frequently in difficult trials and transferred this use of the key to novel conditions. Two baboons showed higher accuracy when they declined using the key compared to Baseline trials in which the key was not available, suggesting accurate metacognitive monitoring judgments. The same two baboons were consistently faster at reporting the targets' locations after a repetition of the stimulus. In Experiment 2, the baboons had to choose between two Repeat keys, one for each target. Two baboons showed a preference for repeating the presentation of the less visible target, suggesting that they identified what information they lack. Overall, results support the hypothesis of metacognitive monitoring in baboons, and also provide limited evidence for metacognitive control. We propose that tests requiring subjects to choose between several metacognitive responses in computerized tasks provide a suitable new approach for studying targeted information-seeking behaviors in animals.

Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons.

The production of new neurons in the olfactory bulb (OB) through adulthood is a major mechanism of structural and functional plasticity underlying learning-induced circuit remodeling. The recruitment of adult-born OB neurons depends not only on sensory input but also on the context in which the olfactory stimulus is received. Among the multiple steps of adult neurogenesis, the integration and survival of adult-born neurons are both strongly influenced by olfactory learning. Conversely, optogenetic stimulation of adult-born neurons has been shown to specifically improve olfactory learning and long-term memory. However, the nature of the circuit and the synaptic mechanisms underlying this reciprocal influence are not yet known. Here, we showed that olfactory learning increases the spine density in a region-restricted manner along the dendritic tree of adult-born granule cells (GCs). Anatomical and electrophysiological analysis of adult-born GCs showed that olfactory learning promotes a remodeling of both excitatory and inhibitory inputs selectively in the deep dendritic domain. Circuit mapping revealed that the malleable dendritic portion of adult-born neurons receives excitatory inputs mostly from the regions of the olfactory cortex that project back to the OB. Finally, selective optogenetic stimulation of olfactory cortical projections to the OB showed that learning strengthens these inputs onto adult-born GCs. We conclude that learning promotes input-specific synaptic plasticity in adult-born neurons, which reinforces the top-down influence from the olfactory cortex to early stages of olfactory information processing.

Adult neurogenesis in the olfactory system shapes odor memory and perception.

The olfactory system is a dynamic place. In mammals, not only are sensory neurons located in the sensory organ renewed through adult life, but also its first central relay is reconstructed by continuous neuronal recruitment. Despite these numerous morphological and physiological changes, olfaction is a unique sensory modality endowed with a privileged link to memory. This raises a clear conundrum; how does the olfactory system balance its neuronal turnover with its participation in long-term memory? This review concentrates on the functional aspects of adult neurogenesis, addressing how the integration of late-born neurons participates in olfactory perception and memory. After outlining the properties of adult neurogenesis in the olfactory system, and after describing their regulation by internal and environmental factors, we ask how the process of odorant perception can be influenced by constant neuronal turnover. We then explore the possible functional roles that newborn neurons might have for olfactory memory. Throughout this review, and as we concentrate almost exclusively on mammalian models, we stress the idea that adult neurogenesis is yet another form of plasticity used by the brain to copes with a constantly changing olfactory world.

Adult-born neurons in the olfactory bulb: integration and functional consequences.

The generation of new neurons is sustained throughout life in the olfactory system. In recent years, tremendous progress has been made toward understanding the proliferation, differentiation, migration, and integration of newborn neurons in the olfactory bulb. Here, we discuss recent findings that shed light on different aspects of the integration of adult-born neurons into olfactory circuitry and its significance for behavior.

Bone marrow cell transplantation restores olfaction in the degenerated olfactory bulb.

Bone marrow contains heterogeneous cell types including end-lineage cells, committed tissue progenitors, and multipotent stem/progenitor cells. The immense plasticity of bone marrow cells allows them to populate diverse tissues such as the encephalon, and give rise to a variety of cell types. This unique plasticity makes bone marrow-derived cells good candidates for cell therapy aiming at restoring impaired brain circuits. In the present study, bone marrow cells were transplanted into P20 mice that exhibit selective olfactory degeneration in adulthood between P60 and P150. These animals, the so-called Purkinje Cell Degeneration (PCD) mutant mice, suffer from a progressive and specific loss of a subpopulation of principal neurons of the olfactory bulb, the mitral cells (MCs), sparing the other principal neurons, the tufted cells. As such, PCD mice constitute an interesting model to evaluate the specific role of MCs in olfaction and to test the restorative function of transplanted bone marrow-derived cells. Using precision olfactometry, we revealed that mutant mice lacking MCs exhibited a deficit in odorant detection and discrimination. Remarkably, the transplantation of wild-type bone marrow-derived cells into irradiated PCD mutant mice generated a large population of microglial cells in the olfactory bulb and reduced the degenerative process. The alleviation of MC loss in transplanted mice was accompanied by functional recovery witnessed by significantly improved olfactory detection and enhanced odor discrimination. Together, these data suggest that: (1) bone marrow-derived cells represent an effective neuroprotective tool to restore degenerative brain circuits, and (2) MCs are necessary to encode odor concentration and odor identity in the mouse olfactory bulb.

Disruption of Adult Neurogenesis in the Olfactory Bulb Affects Social Interaction but not Maternal Behavior.

Adult-born neurons arrive to the olfactory bulb (OB) and integrate into the existing circuit throughout life. Despite the prevalence of this phenomenon, its functional impact is still poorly understood. Recent studies point to the importance of newly generated neurons to olfactory learning and memory. Adult neurogenesis is regulated by a variety of factors, notably by instances related to reproductive behavior, such as exposure to mating partners, pregnancy and lactation, and exposure to offspring. To study the contribution of olfactory neurogenesis to maternal behavior and social recognition, here we selectively disrupted OB neurogenesis using focal irradiation of the subventricular zone in adult female mice. We show that reduction of olfactory neurogenesis results in an abnormal social interaction pattern with male, but not female, conspecifics; we suggest that this effect could result from the inability to detect or discriminate male odors and could therefore have implications for the recognition of potential mating partners. Disruption of OB neurogenesis, however, neither impaired maternal-related behaviors, nor did it affect the ability of mothers to discriminate their own progeny from others.

Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice.

BACKGROUND: In mammals, new neurons are added to the olfactory bulb (OB) throughout life. Most of these new neurons, granule and periglomerular cells originate from the subventricular zone (SVZ) lining the lateral ventricles and migrate via the rostral migratory stream toward the OB. Thousands of new neurons appear each day, but the function of this ongoing neurogenesis remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we irradiated adult mice to impair constitutive OB neurogenesis, and explored the functional impacts of this irradiation on the sense of smell. We found that focal irradiation of the SVZ greatly decreased the rate of production of new OB neurons, leaving other brain areas intact. This effect persisted for up to seven months after exposure to 15 Gray. Despite this robust impairment, the thresholds for detecting pure odorant molecules and short-term olfactory memory were not affected by irradiation. Similarly, the ability to distinguish between odorant molecules and the odorant-guided social behavior of irradiated mice were not affected by the decrease in the number of new neurons. Only long-term olfactory memory was found to be sensitive to SVZ irradiation. CONCLUSION/SIGNIFICANCE: These findings suggest that the continuous production of adult-generated neurons is involved in consolidating or restituting long-lasting olfactory traces.

A niche for adult neurogenesis in social behavior.

The structural and functional changes occurring into the brain is the hallmark of its tremendous capacity for dealing with the complexity that we are facing throughout life. It is also the hallmark of what neuroscientists refer as neuroplasticity. The continuous generation of cohorts of new neurons in some discrete regions of the adult brain, including the olfactory system, is a newly recognized form of neuroplasticity that has been recently the focus of neuroscience studies. Several lines of evidence indicate that this recruitment of newly-generated neurons is extremely sensitive to the overall neuronal activity of the host circuits. Therefore, adult neurogenesis represents, not only a constitutive replacement mechanism for lost neurons, but also a process supporting a capacity of neural plasticity in response to specific experience throughout life. The remarkable complexity of the social life offers a host of daily challenges that require a diversity of brain mechanism to make sense of the ever-changing social world. This review describes some recent findings which have begun to define reciprocal relationships between the production and integration of newborn neurons in the adult brain and social behavior. These studies demonstrate how this domain of research has the potential to address issues in the functional contribution of adult neurogenesis in the expression of some social traits as well in the role of some social contexts to finely regulate the production, survival and integration of adult newborn neurons.

Learning and survival of newly generated neurons: when time matters.

New interneurons are continually added to the olfactory bulb (OB), the first central relay for processing olfactory information, throughout life. It remains unknown how these adult-generated interneurons integrate into preexisting networks or die. We used immunohistochemical approaches to quantify adult neurogenesis in mice subjected to olfactory training. We identified a critical period in the life of an adult-generated OB interneuron, during which learning triggers distinct consequences. Using a discrimination learning task performed at various times after the birth of new interneurons, we found that olfactory training could increase, decrease, or have no effect on the number of surviving newly generated neurons. Cell survival and elimination depend on both the age of the cell and its location within the granule cell layer. This study provides new insight into the contribution of the newly generated interneurons to OB function. It demonstrates that neuronal elimination is an active process, rather than a simple consequence of nonuse.

Changes in social exploration of a lipopolysaccharides-treated conspecific in mice: role of environmental cues.

Despite the many advantages offered by sociality in animals, one of its main drawbacks is the increased propensity to be exposed to parasites and pathogens. In infection (bacteria and viruses), one of the common symptoms used to describe an animal experiencing an acute inflammation is a "social disinterest". According to the literature, this reduction in social behaviors would be an adaptive feature preventing further contamination. However, if the case of parasitic infection has been extensively studied, concerning inflammatory processes, no direct evidence of a proper isolation of sick animals by healthy conspecifics has been provided. The present study aimed to investigate the effects of endotoxin-induced inflammation (LPS, lipopolysaccharides) on the behavior of healthy conspecifics to verify a possible active social isolation of the immune-challenged animal. In addition, we applied variations to the functional significance of the situation by pre-exposing healthy subjects to unsanitary olfactory cues (i.e., 1,5-diaminopentane, odor of decaying flesh). Observations revealed several results: (1) no agonistic behavior was observed during dyadic encounter, whatever the immune status of the conspecifics or the olfactory stimulation; (2) endotoxin-induced inflammation triggered several behavioral changes in healthy conspecifics: increased inter-individual distance, decreased physical contacts, and changes in the modalities of social exploration (increased proportion of muzzle sniffing and decreased proportion of ano-genital sniffing); (3) these effects were more salient after olfactory priming with 1-,5-diaminopentane. Our data reveal that mice are able to discriminate the "state of sickness" in conspecifics use this information to support pertinent behavioral changes. Moreover, these results support the idea that mice would switch from a "controlled exposure" strategy under standard condition to a "pathogen avoidance" strategy under a specific unsanitary context.

Control of early events in olfactory processing by adult neurogenesis.

The mature brain needs to have flexible control over behavior in the face of ever-changing needs. It achieves this control through morphological and physiological changes at the level of molecules, spines, dendrites, and axons and through processes of adult neurogenesis, entire cells. The functional maturation of newly generated cells in the adult forebrain involves the expression of neurotransmitter receptors before synaptic activity and excitatory gamma-aminobutyric acid (GABAergic) influences prior to glutamatergic input. The production of new cells for incorporation into neural circuits that are already up and running gives rise to a unique situation that may require epigenetic regulation. However, once mature, new neurons must carve out a niche among more established cells to be useful. How do they survive and what are they used for? Recent studies have revealed that adult neurogenesis alters the olfactory bulb at all levels, from single cells to the network and system levels. It has also been suggested that cell turnover may be particularly beneficial for the processing of new information in dynamic networks. However, elucidating the functional meaning of adult neurogenesis must wait for the development of new paradigms to eliminate the pool of newly generated neurons but sparing the preexisting ones. Nevertheless, there is already considerable correlative evidence to indicate that adult neurogenesis is a plastic mechanism by which the performance of the brain can be optimized in a given environment.

Chronic inhibition of nitric oxide synthesis enhances both subventricular zone neurogenesis and olfactory learning in adult mice.

The ability to generate new neurons during the course of adult life is preserved in the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus in the mammalian brain. These two regions constitute specifically regulated neurogenic niches, and provide newborn neurons involved in olfactory and spatial learning, respectively. Nitric oxide (NO) is a negative regulator of neurogenesis in the subventricular zone, whereas its role in the dentate gyrus remains controversial. Using systemic administration of NO synthase (NOS) inhibitors to chronically inhibit NO production, we increased neural precursor proliferation in the subventricular zone as well as neurogenesis in the olfactory bulb, without modifying the number of mitotic cells or the granular cell layer thickness in the dentate gyrus. The same treatment specifically improved olfactory learning performance, whereas spatial learning and memory was unchanged, thus demonstrating that olfactory memory is closely associated with the level of ongoing neurogenesis in the subventricular zone-olfactory bulb. The anatomical specificity of the NOS inhibitor actions was not due to differences in the availability of NO, as demonstrated by immunohistochemical detection of neuronal NOS and S-nitrosylated proteins in both regions. Remarkably, the distinct NO sensitivity might result from a differential expression of epidermal growth factor receptor in precursor cells in both regions, as the proliferative effect of NOS inhibitors in the subventricular zone was restricted to the cells that expressed this receptor.

[Adult neurogenesis: from basic research to clinical applications]. / Neurogenèse adulte: aspects fondamentaux et potentiels thérapeutiques.

Neural stem cells have recently been found in the central nervous system of adult rodents and humans. In defined conditions, these multipotent cells can generate the three major cell types of the nervous system (neurons, oligodendrocytes and astrocytes). These findings raise questions on the functional role of neural stem cells in the adult brain, and point to the possibility of novel therapeutic approaches. We have been investigating the functional consequences of neural stem cells for the adult circuits of the olfactory system. We are currently investigating this unexpected juvenile characteristic for cognitive functions. For instance, we are exploring the potential of brain adaptation brought into play by adult neurogenesis. Our most recent studies show that neurogenesis contributes to long-term adjustment of the mature brain. Many questions remain to be answered, however. To what extent can we distinguish and compare neuronal production during embryogenesis and adulthood? How does a newborn cell migrate and find its target? How is cellular fate decided? By showing correlations between the regenerative capacities and cognitive functions of the adult brain, our results have interesting implications for the use of endogenous neuronal stem cells for brain repair in patients with neurodegenerative diseases or brain injury due to stroke or trauma.

Information processing in the mammalian olfactory system.

Recently, modern neuroscience has made considerable progress in understanding how the brain perceives, discriminates, and recognizes odorant molecules. This growing knowledge took over when the sense of smell was no longer considered only as a matter for poetry or the perfume industry. Over the last decades, chemical senses captured the attention of scientists who started to investigate the different stages of olfactory pathways. Distinct fields such as genetic, biochemistry, cellular biology, neurophysiology, and behavior have contributed to provide a picture of how odor information is processed in the olfactory system as it moves from the periphery to higher areas of the brain. So far, the combination of these approaches has been most effective at the cellular level, but there are already signs, and even greater hope, that the same is gradually happening at the systems level. This review summarizes the current ideas concerning the cellular mechanisms and organizational strategies used by the olfactory system to process olfactory information. We present findings that exemplified the high degree of olfactory plasticity, with special emphasis on the first central relay of the olfactory system. Recent observations supporting the necessity of such plasticity for adult brain functions are also discussed. Due to space constraints, this review focuses mainly on the olfactory systems of vertebrates, and primarily those of mammals.

Nicotinic receptors regulate the survival of newborn neurons in the adult olfactory bulb.

Cholinergic axons and nicotinic receptors are abundant in all layers of the olfactory bulb (OB), the main region of newborn neuron integration in the adult brain. Here, we report that the OB granule cell layer in mice lacking the predominant form of brain high-affinity nicotinic acetylcholine receptors (beta(2)(-/-) mice) displayed nearly 50% more newborn neurons and significantly fewer apoptotic cells than did beta(2)(+/+) mice. Conversely, in vivo chronic nicotine exposure significantly decreased the number of newborn granule cells in beta(2)(+/+) but not beta(2)(-/-) adult mice, confirming that the survival of newborn neurons can be controlled by the activation of beta(2)-containing nicotinic acetylcholine receptors. Unexpectedly, investigating the behavioral consequence of an increased number of granule cells in beta(2)(-/-) mice revealed that these animals have a less robust short-term olfactory memory than their wild-type counterparts. Taken together, these results provide evidence that high-affinity nicotinic receptors are involved in the maturation of adult OB local circuits. They also indicate that an increase in the number of granule cells does not necessarily correlate with better olfactory performance and further highlight the importance of cholinergic afferents for olfactory processing.

Olfactory processing in a changing brain.

The perception of odorant molecules provides the essential information that allows animals to explore their surrounding. We describe here how the external world of scents may sculpt the activity of the first central relay of the olfactory system, i.e., the olfactory bulb. This structure is one of the few brain areas to continuously replace one of its neuronal populations: the local GABAergic interneurons. How the newly generated neurons integrate into a pre-existing neural network and how basic olfactory functions are maintained when a large percentage of neurons are subjected to continuous renewal, are important questions that have recently received new insights. Furthermore, we shall see how the adult neurogenesis is specifically subjected to experience-dependent modulation. In particular, we shall describe the sensitivity of the bulbar neurogenesis to the activity level of sensory inputs from the olfactory epithelium and, in turn, how this neurogenesis may adjust the neural network functioning to optimize odor information processing. Finally, we shall discuss the behavioral consequences of the bulbar neurogenesis and how it may be appropriate for the sense of smell. By maintaining a constitutive turnover of bulbar interneurons subjected to modulation by environmental cues, we propose that adult ongoing neurogenesis in the olfactory bulb is associated with improved olfactory memory. These recent findings not only provide new fuel for the molecular and cellular bases of sensory perception but should also shed light onto cellular bases of learning and memory.

Social regulation of reproduction in the female mound-builder mouse (Mus spicilegus).

Social environment influences the reproductive physiology and sexual behaviour of the female house mouse Mus musculus. An all-female environment tends to suppress the oestrous cycles, whereas the presence of a male induces and synchronises sexual receptivity. However, reproductive responses to social environment may differ among the various species of rodents. In mound-builder female mice, Mus spicilegus, periods of sexual receptivity are interrupted by periods where adult females display a vaginal closure. We investigated the influence of different social environments on the vaginal opening and oestrous state of adult female M. spicilegus. Result showed that when females were grouped their vaginas were generally closed but that vaginal opening occurred when they were isolated or housed with a sexual partner. Females became sexually receptive when housed with a male, but when isolated their cervical smears did not reach characteristics of the oestrus. In female M. spicilegus, male presence thus has a stimulating effect on oestrous induction. Furthermore, cohabitation with females has an inhibiting effect on vaginal opening.