RESUMEN
Gut bacteria influence brain functions and metabolism. We investigated whether this influence can be mediated by direct sensing of bacterial cell wall components by brain neurons. In mice, we found that bacterial peptidoglycan plays a major role in mediating gut-brain communication via the Nod2 receptor. Peptidoglycan-derived muropeptides reach the brain and alter the activity of a subset of brain neurons that express Nod2. Activation of Nod2 in hypothalamic inhibitory neurons is essential for proper appetite and body temperature control, primarily in females. This study identifies a microbe-sensing mechanism that regulates feeding behavior and host metabolism.
Asunto(s)
Proteína Adaptadora de Señalización NOD2 , Peptidoglicano , Animales , Apetito , Bacterias/genética , Bacterias/metabolismo , Temperatura Corporal , Ratones , Neuronas/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Proteína Adaptadora de Señalización NOD2/metabolismo , Peptidoglicano/metabolismoRESUMEN
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.
Asunto(s)
Anosmia/virología , Encéfalo/virología , COVID-19 , Mucosa Olfatoria/patología , Animales , COVID-19/patología , Cricetinae , Humanos , Inflamación , Mucosa Olfatoria/virología , ARN Viral , SARS-CoV-2RESUMEN
Olfaction is the first sensory modality to develop during fetal life in mammals, and plays a key role in the various behaviors of neonates such as feeding and social interaction. Odorant cues (i.e., mother or predator scents) can trigger potentiation or inhibition of ultrasonic vocalizations (USV) emitted by pups following their isolation. Here, we report how USV are inhibited by olfactory cues using a sono-olfactometer that has been designed to quantify precisely olfaction in pups congenitally infected by cytomegalovirus. This olfactory-driven behavioral test assesses the USV emitted in presence of unfamiliar odorants such as citral scent or adult male mouse scent. We measure the number of USV emitted as an index of odorant detection during the three periods of the 5-min isolation time of the pup into the sono-olfactometer: first period without any odorant, second period with odorant exposure and last period with exhaust odorant. This protocol can be easily used to reveal olfactory deficits in pups with altered olfactory system due to toxic lesions or infectious diseases.
RESUMEN
In developed countries, cytomegalovirus (CMV)-infected newborns are at high risk of developing sensorineural handicaps such as hearing loss, requiring extensive follow-up. However, early prognostic tools for auditory damage in children are not yet available. In the fetus, CMV infection leads to early olfactory bulb (OB) damage, suggesting that olfaction might represent a valuable prognosis for neurological outcome of this viral infection. Here, we demonstrate that in utero CMV inoculation causes fetal infection and growth retardation in mice of both sexes. It disrupts OB normal development, leading to disproportionate OB cell layers and rapid major olfactory deficits. Olfaction is impaired as early as day 6 after birth in both sexes, long before the emergence of auditory deficits. Olfactometry in males reveals a long-lasting alteration in olfactory perception and discrimination, particularly in binary mixtures of monomolecular odorants. Although sensory inputs to the OB remain unchanged, hallmarks of autophagy are increased in the OB of 3-postnatal week-old mice, leading to local neuroinflammation and loss of neurons expressing tyrosine hydroxylase and calbindin. At the cellular level, we found CMV-infected cells and an increased number of apoptotic cells scattered throughout the OB layers, whereas cell proliferation in the neurogenic subventricular zone was decreased. These cellular observations were long-lasting, persisting up to 16 weeks after birth in both males and females and thus providing a mechanism supporting olfactory loss. Despite obvious differences in neurogenesis between human and mouse, these findings offer new strategies aimed at early detection of neurological dysfunctions caused by congenital infections.SIGNIFICANCE STATEMENT In developed countries, congenital cytomegalovirus (CMV)-infected newborns are at high risk of developing sensory handicaps such as hearing loss, thus requiring prolonged follow-up. In this study, we describe for the first time the functional impact of congenital CMV infection on the olfactory system and its associated sense of smell. We demonstrate that a mouse model of congenital CMV infection shows defects in olfactory bulb (OB) normal development and pronounced olfactory deficits affecting acuity and discrimination of odorants. These major olfactory deficits occur long before the emergence of auditory deficits through the upregulation of OB autophagy inducing local neuroinflammation and altered neuron content. Our findings provide new opportunities for designing olfactory means to monitor the possible neurological outcome during congenital CMV infection.
Asunto(s)
Infecciones por Citomegalovirus/fisiopatología , Trastornos de la Audición/fisiopatología , Trastornos del Olfato/fisiopatología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Olfato/fisiología , Animales , Animales Recién Nacidos , Anomalías Congénitas/etiología , Anomalías Congénitas/patología , Anomalías Congénitas/fisiopatología , Infecciones por Citomegalovirus/complicaciones , Femenino , Trastornos de la Audición/etiología , Trastornos de la Audición/virología , Masculino , Ratones , Trastornos del Olfato/etiología , Trastornos del Olfato/virología , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/virologíaRESUMEN
Olfaction is an important sensory modality driving fundamental behaviors. During odor-dependent learning, a positive value is commonly assigned to an odorant, and multiple forms of plasticity are involved when such odor-reward associations are formed. In rodents, one of the mechanisms underlying plasticity in the olfactory bulb consists in recruiting new neurons daily throughout life. However, it is still unknown whether adult-born neurons might participate in encoding odor value. Here, we demonstrate that exposure to reward-associated odors specifically increases activity of adult-born neurons but not preexisting neurons. Remarkably, adult-born neuron activation during rewarded odor presentation heightens discrimination learning and enhances the ability to update the odor value during reversal association. Moreover, in some cases, activation of this interneuron population can trigger olfactory learning without sensory stimulation. Taken together, our results show a specific involvement of adult-born neurons in facilitating odor-reward association during adaptive learning.
Asunto(s)
Aprendizaje Discriminativo/fisiología , Bulbo Olfatorio , Neuronas Receptoras Olfatorias/fisiología , Recompensa , Olfato/fisiología , Animales , Femenino , Masculino , Modelos Neurológicos , Odorantes , Bulbo Olfatorio/citología , Bulbo Olfatorio/fisiología , RatasRESUMEN
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.