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 i

Is adult neurogenesis essential for olfaction?

International audienceIn mammals, new neurons are recruited into restricted brain areas throughout life. Adult-born neurons produced in the subventricular zone of the lateral ventricle migrate rostrally towards the olfactory bulb. Although thousands of neurons reach this central structure every day, the functional impact of their integration into mature circuits remains a matter of debate. Recent investigations have revealed no striking sensory deficits per se when adult bulbar neurogenesis is challenged. However , some cognitive functions, such as perceptual learning and olfactory memory, are clearly impaired. In this review we highlight the role of network activity in shaping ongoing neurogenesis and, in turn, how the integration of adult-born neurons refines pre-existing network function, and consequently olfactory behavior. Introduction New neurons are continuously generated in two discrete areas of the adult brain: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the hippocampus [1]. The latter gives rise to new granule neurons, which mature locally in the dentate gyrus, whereas the former produces neuroblasts that migrate along the rostral migratory stream (RMS) en route to the olfactory bulb (OB), the first olfactory relay in the CNS. Neural progenitors finish rostral migration in the core of the OB where they begin radial migration and mature into inter-neurons [2]. Despite extensive cellular characterization of individual adult-born neurons, the impact of adult neuro-genesis on OB circuit function and olfactory behavior is still unclear. It has been argued that ongoing adult neu-rogenesis is essential for structural maintenance of the OB circuit because blocking adult neurogenesis depletes the bulb of interneurons [3]. This review focuses on new insights indicating that the function of adult bulbar neu-rogenesis goes beyond the mere maintenance of neuronal circuits. In particular, we detail the functional characteristics of new neurons and how they shape mitral cell function and olfactory behavior. Functions for old and new neurons In rodents, olfaction is a key chemosensory modality that enables diverse essential functions such as food selection, danger detection and conspecific interactions. To fulfill this repertoire of functions the olfactory system has to detect and discriminate between odorants from a rich and varied olfactory environment, and then preserve this informatio

Assessing Olfaction Using Ultrasonic Vocalization Recordings in Mouse Pups with a Sono-olfactometer

International audience[Abstract] 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

High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses

To clarify the mechanisms leading to the development of Creutzfeldt-Jakob disease in some recipients of pituitary-derived human growth hormone (hGH), we investigated the effects of repeated injections of low prion doses in mice. The injections were performed, as in hGH-treated children, by a peripheral route at short intervals and for an extended period. Twelve groups of 24 mice were intraperitoneally inoculated one, two, or five times per week for 200 days with 2 × 10(−5) to 2 × 10(−8) dilutions of brain homogenate containing the mouse-adapted C506M3 scrapie strain. Sixteen control mice were injected once a week for 200 days with a 2 × 10(−4) dilution of normal brain homogenate. Of mice injected in a single challenge with a scrapie inoculum of a 2 × 10(−4), 2 × 10(−5), or 2 × 10(−6) dilution, 2/10, 1/10, and 0/10 animals developed scrapie, respectively. Control mice remained healthy. One hundred thirty-five of 135 mice injected with repeated prion doses of a 2 × 10(−5) or 2 × 10(−6) dilution succumbed to scrapie. Of mice injected with repeated scrapie doses of a 2 × 10(−7) or 2 × 10(−8) dilution, 52/59 and 38/67 animals died of scrapie, respectively. A high incidence of scrapie was observed in mice receiving repeated doses at low infectivity, whereas there was no disease in mice that were injected once with the same doses. Repeated injections of low prion doses thus constitute a risk for development of prion disease even if the same total dose inoculated in a single challenge does not induce the disease

The microbiome–nose–brain axis in health and disease

International audienceGrowing evidence implicates the bacterial populations in the nose as an important factor for personal and global health. Here, we provide a brief overview of the nasal microbiome and speculate on its potential roles in olfactory processing and neurodegeneration, with a particular focus on Parkinson's disease (PD)

Congenital cytomegalovirus infection alters olfaction prior to hearing deterioration in mice

The odorant mixtures are the subject of a patent application (EP3245944 published on November 22, 2017) by Institut Pasteur, Centre National de la Recherche Scientifique, and Assistance Publique–Hôpitaux de Paris on which F.L., P.-M.L., N.T., and S.L. are named as inventors. The remaining authors declare no competing financial interests.International audienceIn 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

Sensory deprivation increases phagocytosis of adult-born neurons by activated microglia in the olfactory bulb.

International audienceThe olfactory bulb (OB) is a highly plastic structure that can change organizational networks depending on environmental inputs in adult mammals. Particularly, in rodents, adult neurogenesis underlies plastic changes in the OB circuitry by continuously adding new interneurons to the network. We addressed the question of whether microglia, the immune cells of the brain, were involved in pruning OB neurons. Using lentiviral labeling of neurons in neonatal or adult mice and confocal analysis, we showed that microglia engulfed parts of neonatal-born and adult-born neurons in the healthy OB. We demonstrated that OB deafferentation by Dichlobenil administration induced sensory deprivation. It also increased phagocytosis of adultborn, but not neonatalborn neurons, by activated microglia. Conversely, intranasal lipopolysaccharide administration induced activation of microglia but changed neither adult neurogenesis nor olfaction. Our data reveal that steady-state microglia eliminate adult-born neurons and their synapses in both healthy and sensory deprived OBs, thereby adapting neuronal connections to the sensory experience

Central nervous system infections in a tropical area: Influence of emerging and rare infections

International audienceBackground and purpose: The frequency of infectious encephalitis and the distribution of causative pathogens in the tropical areas are poorly known and may be influenced by emerging and rare infections. The aim was to characterize a large series of acute infectious encephalitis and myelitis in immunocompetent patients from the Caribbean island of Guadeloupe identifying clinical, biological and radiological features according to pathogens.Methods: Using a hospital database, we retrospectively collected detailed information on a comprehensive series of immunocompetent patients with acute infectious myelitis and encephalitis over the 2012-2018 period.Results: From 259 suspected cases with acute central nervous system (CNS) infection, we included 171 cases for analysis, comprising 141 encephalitis, 22 myelitis, and eight encephalomyelitis. The annual incidence peaked at 15.0/100 000 during the Zika 2016 outbreak. Children accounted for 22.2% of cases. Eight adults died during hospital stay, all encephalitis. Seventeen infectious agents, two of which had never been described in Guadeloupe so far, were identified in 101 cases (59.1%), including 35 confirmed cases (34.7%), 48 probable cases (47.5%), 15 possible cases (14.9%) and three clinical cases (3.0%). The most frequent etiologic agents were zika virus in 23 cases (13.5%), herpes simplex in 12 (7.0%), varicella-zoster virus in 11 (6.4%), dengue virus in 11 (6.4%) and leptospirosis in 11 (6.4%).Conclusions: Zika outbreak had a major influence on the annual incidence of acute CNS infection. Acute neuroleptospirosis is over-represented in our series. Further efforts are mandatory to develop new diagnostic tools for pathogen profiling