Estrogens regulate early embryonic development of the olfactory sensory system via estrogen-responsive glia

ABSTRACT Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.

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Estrogen regulates early embryonic development of the olfactory sensory system via estrogen responsive glia

10.1101/2021.06.03.446864 ◽

2021 ◽

Author(s):

Aya Takesono ◽

Paula Schirrmacher ◽

Aaron Scott ◽

Jon M Green ◽

Okhyun Lee ◽

...

Keyword(s):

Embryonic Development ◽

Sex Differentiation ◽

Sensory System ◽

Early Embryonic Development ◽

Sexual Dimorphisms ◽

Cell Ablation ◽

Olfactory Glomeruli ◽

Estrogen Activity ◽

Glomerular Development ◽

The Brain

Estrogen is well-known to regulate development of sexual dimorphisms of the brain, however its role in the brain during early embryonic development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs specifically in a type of glia located within the OB, which we name estrogen-responsive olfactory bulb/EROB cells. With estrogen activity, EROB cells extend their ramified projections that overlay the OB outermost layer and tightly interact with olfactory sensory neurons (OSNs) at the olfactory glomeruli. Pharmacologically inhibiting estrogen activity and/or EROB cell ablation impedes olfactory glomerular development, including OSN pathfinding, topological organisation of olfactory glomeruli and inhibitory neurogenesis in the OB. Furthermore, activation of this estrogen/EROB-dependent mechanism decreases the intrinsic neuronal activity primarily in the OB, and this alteration of estrogen signalling disrupts olfaction-mediated behaviour. We propose that estrogen acts on glia to regulate development of functional OB circuits, thereby modulating the local intrinsic excitability in the OB and olfaction-mediated behaviour. Our data also suggest a possibility that the estrogen/EROB cascade may be an important site of action for environmental estrogens causative of neurodevelopmental impairments in animals and humans.

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COUP-TFI regulates diameter of the axon initial segment in the mammalian neocortex

10.1101/2020.10.07.329284 ◽

2020 ◽

Author(s):

Xuanyuan Wu ◽

Haixiang Li ◽

Jiechang Huang ◽

Cheng Xiao ◽

Shuijin He

Keyword(s):

Action Potential ◽

Initial Segment ◽

Neuronal Excitability ◽

Developmental Stages ◽

Pyramidal Cells ◽

Axon Initial Segment ◽

Action Potential Generation ◽

Potential Generation ◽

Cell Ablation ◽

Specialized Structure

AbstractThe axon initial segment is a specialized structure that controls neuronal excitability by generating action potentials. Currently, AIS plasticity with regard to changes in length and location in response to neural activity has been extensively investigated, but how AIS diameter is regulated remains elusive. Here we report that COUP-TFI is an essential regulator of AIS diameter in both developing and adult mouse neocortex. Embryonic ablation of COUP-TFI prevented expansion of AIS diameter that occurs during postnatal development in layer II/III pyramidal cells of the mouse motor cortex, thereby leading to an impairment of action potential generation. Inactivation of COUP-TFI in adult neurons also led to reduced AIS diameter and impaired action potential generation. In contrast to different developmental stages, single-cell ablation and global ablation produced opposite effects on spontaneous network in COUP-TFI-deficient neurons. Further, mice exhibited less anxiety-like behaviors after postnatal inactivation of COUP-TFI induced by tamoxifen. Our results demonstrate that COUP-TFI is indispensable for both expansion and maintenance of AIS diameter and that a change in AIS diameter fine-tunes synaptic inputs through a metaplasticity mechanism in the adult neocortex.

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Plume Dynamics Structure the Spatiotemporal Activity of Mitral/Tufted Cell Networks in the Mouse Olfactory Bulb

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.633757 ◽

2021 ◽

Vol 15 ◽

Author(s):

Suzanne M. Lewis ◽

Lai Xu ◽

Nicola Rigolli ◽

Mohammad F. Tariq ◽

Lucas M. Suarez ◽

...

Keyword(s):

Olfactory Bulb ◽

Olfactory System ◽

Large Scale ◽

Early Stage ◽

Wide Field ◽

Flow Conditions ◽

Population Activity ◽

Plume Dynamics ◽

Olfactory Glomeruli ◽

Odor Plumes

Although mice locate resources using turbulent airborne odor plumes, the stochasticity and intermittency of fluctuating plumes create challenges for interpreting odor cues in natural environments. Population activity within the olfactory bulb (OB) is thought to process this complex spatial and temporal information, but how plume dynamics impact odor representation in this early stage of the mouse olfactory system is unknown. Limitations in odor detection technology have made it difficult to measure plume fluctuations while simultaneously recording from the mouse's brain. Thus, previous studies have measured OB activity following controlled odor pulses of varying profiles or frequencies, but this approach only captures a subset of features found within olfactory plumes. Adequately sampling this feature space is difficult given a lack of knowledge regarding which features the brain extracts during exposure to natural olfactory scenes. Here we measured OB responses to naturally fluctuating odor plumes using a miniature, adapted odor sensor combined with wide-field GCaMP6f signaling from the dendrites of mitral and tufted (MT) cells imaged in olfactory glomeruli of head-fixed mice. We precisely tracked plume dynamics and imaged glomerular responses to this fluctuating input, while varying flow conditions across a range of ethologically-relevant values. We found that a consistent portion of MT activity in glomeruli follows odor concentration dynamics, and the strongest responding glomeruli are the best at following fluctuations within odor plumes. Further, the reliability and average response magnitude of glomerular populations of MT cells are affected by the flow condition in which the animal samples the plume, with the fidelity of plume following by MT cells increasing in conditions of higher flow velocity where odor dynamics result in intermittent whiffs of stronger concentration. Thus, the flow environment in which an animal encounters an odor has a large-scale impact on the temporal representation of an odor plume in the OB. Additionally, across flow conditions odor dynamics are a major driver of activity in many glomerular networks. Taken together, these data demonstrate that plume dynamics structure olfactory representations in the first stage of odor processing in the mouse olfactory system.

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Olfactory Development, Part 1: Function, From Fetal Perception to Adult Wine-Tasting

Journal of Child Neurology ◽

10.1177/0883073817690867 ◽

2017 ◽

Vol 32 (6) ◽

pp. 566-578 ◽

Cited By ~ 10

Author(s):

Harvey B. Sarnat ◽

Laura Flores-Sarnat ◽

Xing-Chang Wei

Keyword(s):

Olfactory Bulb ◽

Amniotic Fluid ◽

Neuronal Differentiation ◽

Cranial Nerve ◽

Metabolic Diseases ◽

Maternal Diet ◽

Sensory System ◽

Olfactory Bulbs ◽

Olfactory Development ◽

Brain Malformations

Discrimination of odorous molecules in amniotic fluid occur after 30 weeks’ gestation; fetuses exhibit differential responses to maternal diet. Olfactory reflexes enable reliable neonatal testing. Olfactory bulbs can be demonstrated reliably by MRI after 30 weeks’ gestation, and their hypoplasia or aplasia also documented by late prenatal and postnatal MRI. Olfactory axons project from nasal epithelium to telencephalon before olfactory bulbs form. Fetal olfactory maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the transitory fetal ventricular recess. Immaturity does not signify nonfunction. Olfaction is the only sensory system without thalamic projection because of its own intrinsic thalamic equivalent. Diverse malformations of the olfactory bulb can be diagnosed by clinical examination, imaging, and neuropathology. Some epileptic auras might be primarily generated in the olfactory bulb. Cranial nerve 1 should be tested in all neonates and especially in patients with brain malformations, endocrinopathies, chromosomopathies, and genetic/metabolic diseases.

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8. Maturation of the Fetal Olfactory Bulb

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2015.256 ◽

2015 ◽

Vol 42 (S2) ◽

pp. S4-S4

Author(s):

Harvey B. Sarnat

Keyword(s):

Olfactory Bulb ◽

Progenitor Cells ◽

Granular Layer ◽

Genetic Diseases ◽

Autologous Transplantation ◽

Sensory System ◽

Granule Cell Layer ◽

Paraffin Sections ◽

Mature Brain ◽

Brain Malformations

The olfactory bulb exhibits architecture unique amongst laminar cortices, lacking molecular and subplate zones and having superficial synaptic glomeruli. Its ontogenesis also is unique because neuroblasts do not migrate radially but stream in from the rostral telencephalon; an ependymal-lined olfactory ventricle is transitory. The olfactory is the only sensory system to not project to the thalamus but incorporates a thalamic equivalent. It is a repository of progenitor cells in the mature brain. The aim was to define olfactory bulb development in the human foetus: synaptogenesis and cellular maturation.Immunoreactivity in paraffin sections of synaptophysin, NeuN, calretinin, vimentin and nestin was examined at autopsy in olfactory bulb in 20 foetuses, 9-40wks gestation. Synaptophysin reactivity was seen around the somata of mitral and tufted neurons at 9wks, synaptic glomeruli at 13wks. The granule cell layer in the core exhibited NeuN-reactive nuclei in cells of the outer half at 20wks; 60% of granular neurons reacted by term. Synaptophysin reactivity in the granular layer initiates at 15wk. GABAergic calretinin-reactive neurons and neurites and synaptic glomeruli appeared at 13wks. Nestin- and vimentin-reactive bipolar progenitor cells were shown at all gestational ages, mainly in the granular layer, the ratio to other cells remaining constant. Synapses form in the small accessory olfactory bulb of the nervus terminalis earlier than in the main bulb. Development of synaptic vesicles in the human fetal olfactory bulb is precise both spatially and temporally, but not yet fully mature at term.In brain malformations and congenital metabolic and genetic diseases, the olfactory bulb may be affected and provide additional neuropathological data. Therapeutic autologous transplantation of olfactory progenitor cells focus renewed interest in the olfactory bulb.

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A TAP1 null mutation leads to an enlarged olfactory bulb and supernumerary, ectopic olfactory glomeruli

Open Biology ◽

10.1098/rsob.130044 ◽

2013 ◽

Vol 3 (5) ◽

pp. 130044 ◽

Cited By ~ 1

Author(s):

Ernesto Salcedo ◽

Nicole M. Cruz ◽

Xuan Ly ◽

Beth A. Welander ◽

Kyle Hanson ◽

...

Keyword(s):

Olfactory Bulb ◽

Graft Rejection ◽

Class I ◽

Null Mutation ◽

Major Histocompatibility ◽

Main Olfactory Bulb ◽

Major Histocompatibility Class ◽

Tissue Graft ◽

Olfactory Glomeruli ◽

Major Histocompatibility Class I

Major histocompatibility class I (MHCI) molecules are well known for their immunological role in mediating tissue graft rejection. Recently, these molecules were discovered to be expressed in distinct neuronal subclasses, dispelling the long-held tenet that the uninjured brain is immune-privileged. Here, we show that MHCI molecules are expressed in the main olfactory bulb (MOB) of adult animals. Furthermore, we find that mice with diminished levels of MHCI expression have enlarged MOBs containing an increased number of small, morphologically abnormal and ectopically located P2 glomeruli. These findings suggest that MHCI molecules may play an important role in the proper formation of glomeruli in the bulb.

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Presynaptic NMDARs cooperate with local spikes toward GABA release from the reciprocal olfactory bulb granule cell spine

eLife ◽

10.7554/elife.63737 ◽

2020 ◽

Vol 9 ◽

Author(s):

Vanessa Lage-Rupprecht ◽

Li Zhou ◽

Gaia Bianchini ◽

S Sara Aghvami ◽

Max Mueller ◽

...

Keyword(s):

Olfactory Bulb ◽

Efficient Solution ◽

Granule Cells ◽

Specific Activity ◽

Sensory System ◽

Gaba Release ◽

Cooperative Action ◽

Two Photon ◽

Activity Dependent ◽

Dendrodendritic Synapses

In the rodent olfactory bulb the smooth dendrites of the principal glutamatergic mitral cells (MCs) form reciprocal dendrodendritic synapses with large spines on GABAergic granule cells (GC), where unitary release of glutamate can trigger postsynaptic local activation of voltage-gated Na+-channels (Navs), that is a spine spike. Can such single MC input evoke reciprocal release? We find that unitary-like activation via two-photon uncaging of glutamate causes GC spines to release GABA both synchronously and asynchronously onto MC dendrites. This release indeed requires activation of Navs and high-voltage-activated Ca2+-channels (HVACCs), but also of NMDA receptors (NMDAR). Simulations show temporally overlapping HVACC- and NMDAR-mediated Ca2+-currents during the spine spike, and ultrastructural data prove NMDAR presence within the GABAergic presynapse. This cooperative action of presynaptic NMDARs allows to implement synapse-specific, activity-dependent lateral inhibition, and thus could provide an efficient solution to combinatorial percept synthesis in a sensory system with many receptor channels.

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Comparison of necklace olfactory glomeruli with atypical glomeruli in the rat olfactory bulb

Neuroscience Research Supplements ◽

10.1016/s0921-8696(06)80065-4 ◽

1991 ◽

Vol 14 ◽

pp. S26

Author(s):

Tsukasa Ohtsuki ◽

Koh Shinoda ◽

Shiro Mori ◽

Yahe Shiotani

Keyword(s):

Olfactory Bulb ◽

Olfactory Glomeruli

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Intrinsic neuronal activity during migration controls the recruitment of specific interneuron subtypes in the postnatal mouse olfactory bulb

10.1101/2020.07.28.224568 ◽

2020 ◽

Author(s):

Bugeon Stéphane ◽

Haubold Clara ◽

Ryzynski Alexandre ◽

Cremer Harold ◽

Platel Jean-Claude

Keyword(s):

Olfactory Bulb ◽

Neuronal Activity ◽

Granule Cell ◽

Neuronal Excitability ◽

Critical Factor ◽

Calcium Activity ◽

Radial Migration ◽

Striking Increase ◽

The Impact ◽

Granule Cell Precursors

AbstractNeuronal activity has been identified as a key regulator of neuronal network development, but the impact of activity on migration and terminal positioning of interneuron subtypes is poorly understood. The absence of early subpopulation markers and the presence of intermingled migratory and post-migratory neurons makes the developing cerebral cortex a difficult model to answer these questions. Postnatal neurogenesis in the subventricular zone offers a more accessible and compartmentalized model. Neural stem cells regionalized along the border of the lateral ventricle produce two main subtypes of neural progenitors, granule cells and periglomerular neurons that migrate tangentially in the rostral migratory stream before migrating radially in the OB layers. Here we take advantage of targeted postnatal electroporation to compare the migration of these two population. We do not observe any obvious differences regarding the mode of tangential or radial migration between these two subtypes. However, we find a very striking increase of intrinsic calcium activity only in granule cell precursors when they switch from tangential to radial migration. By decreasing neuronal excitability in granule cell precursors, we find that neuronal activity is critical for normal migratory speed at the end of tangential migration. Importantly, we also find that activity is required for normal positioning and survival of granule cell precursors in the OB layers. Strikingly, decreasing activity of periglomerular neuron precursors did not impact their positioning or survival. Altogether these findings suggest that neuronal excitability plays a subtype specific role during the late stage of migration of postnatally born olfactory bulb interneurons.Significance StatementWhile neuronal activity is a critical factor regulating different aspects of neurogenesis, it has been challenging to study its role during the migration of different neuronal subpopulations. Here, we use postnatal targeted electroporation to label and manipulate the two main olfactory bulb interneuron subpopulations during their migration: granule cell and periglomerular neuron precursors. We find a very striking increase of calcium activity only in granule cell precursors when they switch from tangential to radial migration. Interestingly, blocking activity in granule cell precursors affected their migration, positioning and survival while periglomerular neuron precursors are not affected. These results suggest that neuronal activity is required specifically for the recruitment of granule cell precursors in the olfactory bulb layers.

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