Smaller Olfactory Bulbs Research Articles

First virtual endocast description of an early Miocene representative of Pan-Octodontoidea (Caviomorpha, Hystricognathi) and considerations on the early encephalic evolution in South American rodents

AbstractThe study of the cranial endocast provides valuable information to understand the behavior of an organism because it coordinates sensory information and motor functions. In this work, we describe for the first time the anatomy of the encephalon of an early Miocene pan-octodontoid caviomorph rodent (Prospaniomys priscus Ameghino, 1902) found in the Argentinean Patagonia, based on a virtual 3D endocast. This fossil rodent has an endocast morphology here considered ancestral for Pan-Octodontoidea and other South American caviomorph lineages, i.e., an encephalon with anteroposteriorly aligned elements, mesencephalon dorsally exposed, well-developed vermis of the cerebellum, and rhombic cerebral hemispheres with well-developed temporal lobes. Prospaniomys Ameghino, 1902 also has relatively small olfactory bulbs, large paraflocculi of the cerebellum, and low endocranial volume and degree of neocorticalization. Its encephalization quotient is low compared with Paleogene North American and European noncaviomorph rodents, but slightly higher than in several late early and late Miocene caviomorphs. Paleoneurological anatomical information supports the hypothesis that Prospaniomys was a generalist caviomorph rodent with terrestrial habits and enhanced low-frequency auditory specializations. The scarce paleoneurological information indicates that several endocast characters in caviomorph rodents could change with ecological pressures. This work sheds light on the anatomy and evolution of several paleoneurological aspects of this particular group of South American rodents.

Pathological consequences of chronic olfactory inflammation on neurite morphology of olfactory bulb projection neurons

Chronic olfactory inflammation (COI) in conditions such as chronic rhinosinusitis significantly impairs the functional and anatomical components of the olfactory system. COI induced by intranasal administration of lipopolysaccharide (LPS) results in atrophy, gliosis, and pro-inflammatory cytokine production in the olfactory bulb (OB). Although chronic rhinosinusitis patients have smaller OBs, the consequences of olfactory inflammation on OB neurons are largely unknown. In this study, we investigated the neurological consequences of COI on OB projection neurons, mitral cells (MCs) and tufted cells (TCs). To induce COI, we performed unilateral intranasal administration of LPS to mice for 4 and 10 weeks. Effects of COI on the OB were examined using RNA-sequencing approaches and immunohistochemical analyses. We found that repeated LPS administration upregulated immune-related biological pathways in the OB after 4 weeks. We also determined that the length of TC lateral dendrites in the OB significantly decreased after 10 weeks of COI. The axon initial segment of TCs decreased in number and in length after 10 weeks of COI. The lateral dendrites and axon initial segments of MCs, however, were largely unaffected. In addition, dendritic arborization and AIS reconstruction both took place following a 10-week recovery period. Our findings suggest that olfactory inflammation specifically affects TCs and their integrated circuitry, whereas MCs are potentially protected from this condition. This data demonstrates unique characteristics of the OBs ability to undergo neuroplastic changes in response to stress.

Role of serotonin in modulating the development and function of adult-born neurons in the olfactory bulb.

Role of serotonin in modulating the development and function of adult-born neurons in the olfactory bulb.

Lizards as models to explore the ecological and neuroanatomical correlates of miniaturization

Abstract Extreme body size reductions bring about unorthodox anatomical arrangements and novel ways in which animals interact with the environment. Drawing from studies of vertebrates and invertebrates, we provide a theoretical framework for miniaturization to inform hypotheses using lizards as a study system. Through this approach, we demonstrate the repeated evolution of miniaturization across 11 families and a tendency for miniaturized species to occupy terrestrial microhabitats, possibly driven by physiological constraints. Differences in gross brain morphology between two gecko species demonstrate a proportionally larger telencephalon and smaller olfactory bulbs in the miniaturized species, though more data are needed to generalize this trend. Our study brings into light the potential contributions of miniaturized lizards to explain patterns of body size evolution and its impact on ecology and neuroanatomy. In addition, our findings reveal the need to study the natural history of miniaturized species, particularly in relation to their sensory and physiological ecology.

Unexplained repeated pregnancy loss is associated with altered perceptual and brain responses to men's body-odor.

Mammalian olfaction and reproduction are tightly linked, a link less explored in humans. Here, we asked whether human unexplained repeated pregnancy loss (uRPL) is associated with altered olfaction, and particularly altered olfactory responses to body-odor. We found that whereas most women with uRPL could identify the body-odor of their spouse, most control women could not. Moreover, women with uRPL rated the perceptual attributes of men's body-odor differently from controls. These pronounced differences were accompanied by an only modest albeit significant advantage in ordinary, non-body-odor-related olfaction in uRPL. Next, using structural and functional brain imaging, we found that in comparison to controls, most women with uRPL had smaller olfactory bulbs, yet increased hypothalamic response in association with men's body-odor. These findings combine to suggest altered olfactory perceptual and brain responses in women experiencing uRPL, particularly in relation to men's body-odor. Whether this link has any causal aspects to it remains to be explored.

Expression patterns of activating transcription factor 5 (atf5a and atf5b) in zebrafish

The Activating Transcription Factor 5 (ATF5) is a basic leucine-zipper (bZIP) transcription factor (TF) with proposed stress-protective, anti-apoptotic and oncogenic roles which were all established in cell systems. In whole animals, Atf5 function seems highly context dependent. Atf5 is strongly expressed in the rodent nose and mice knockout (KO) pups have defective olfactory sensory neurons (OSNs), smaller olfactory bulbs (OB), while adults are smell deficient. It was therefore proposed that Atf5 plays an important role in maturation and maintenance of OSNs. Atf5 expression was also described in murine liver and bones where it appears to promote differentiation of progenitor cells. By contrast in the rodent brain, Atf5 was first described as uniquely expressed in neuroprogenitors and thus, proposed to drive their proliferation and inhibit their differentiation. However, it was later also found in mature neurons stressing the need for additional work in whole animals. ATF5 is well conserved with two paralogs, atf5a and atf5b in zebrafish. Here, we present the expression patterns for both from 6 h (hpf) to 5day post-fertilization (dpf). We found early expression for both genes, and from 1dpf onwards overlapping expression patterns in the inner ear and the developing liver. In the brain, at 24hpf both atf5a and atf5b were expressed in the forebrain, midbrain, and hindbrain. However, from 2dpf and onwards we only detected atf5a expression namely in the olfactory bulbs, the mesencephalon, and the metencephalon. We further evidenced additional differential expression for atf5a in the sensory neurons of the olfactory organs, and for atf5b in the neuromasts, that form the superficial sensory organ called the lateral line (LL). Our results establish the basis for future functional analyses in this lower vertebrate.

A smaller olfactory bulb in a mouse model of Down syndrome

Persons with trisomy 21 (Down syndrome) present different phenotypes, including early neurodegeneration, which is prominent in the brain olfactory areas, and olfactory deficit. The use of in vivo techniques in animal models allows to characterize and follow up these slowly developing phenomena. We explored by means of magnetic resonance imaging the olfactory bulb of the Ts65Dn mouse, an established model of Down syndrome, searching for possible syndrome‑related changes. In vivo imaging provided a first glimpse of the trisomic olfactory bulb as compared to euploid one. The olfactory bulb volume was smaller in trisomic mice, suggesting that changes in olfactory bulb may be apparent already in the young adult (2‑ to 8‑month‑old) mice, which are amenable to follow‑up in vivo. These findings lead the way to future work aimed at characterizing the Down syndrome‑related development of morphological alterations in the olfactory bulb and relating them to changes in olfactory performance, which were detected in this mouse model.

Olfactory bulb surroundings can help to distinguish Parkinson’s disease from non-parkinsonian olfactory dysfunction

BackgroundThe olfactory bulb is one of the first regions of insult in Parkinson’s disease (PD), consistent with the early onset of olfactory dysfunction. Investigations of the olfactory bulb may, therefore, help early pre-motor diagnosis. We aimed to investigate olfactory bulb and its surrounding regions in PD-related olfactory dysfunction when specifically compared to other forms of non-parkinsonian olfactory dysfunction (NPOD) and healthy controls. MethodsWe carried out MRI-based olfactory bulb volume measurements from T2-weighted imaging in scans from 15 patients diagnosed with PD, 15 patients with either post-viral or sinonasal NPOD and 15 control participants. Further, we applied a deep learning model (convolutional neural network; CNN) to scans of the olfactory bulb and its surrounding area to classify PD-related scans from NPOD-related scans. ResultsCompared to controls, both PD and NPOD patients had smaller olfactory bulbs, when measured manually (both p < .001) whereas no difference was found between PD and NPOD patients. In contrast, when a CNN was used to differentiate between PD patients and NPOD patients, an accuracy of 88.3% was achieved. The cortical area above the olfactory bulb which stretches around and into the olfactory sulcus appears to be a region of interest in the differentiation between PD and NPOD patients. ConclusionMeasures from and around the olfactory bulb in combination with the use of a deep learning model may help differentiate PD patients from patients with NPOD, which may be used to develop early diagnostic tools based on olfactory dysfunction.

AutonoMouse: High throughput operant conditioning reveals progressive impairment with graded olfactory bulb lesions.

Operant conditioning is a crucial tool in neuroscience research for probing brain function. While molecular, anatomical and even physiological techniques have seen radical increases in throughput, efficiency, and reproducibility in recent years, behavioural tools have somewhat lagged behind. Here we present a fully automated, high-throughput system for self-initiated conditioning of up to 25 group-housed, radio-frequency identification (RFID) tagged mice over periods of several months and >106 trials. We validate this “AutonoMouse” system in a series of olfactory behavioural tasks and show that acquired data is comparable to previous semi-manual approaches. Furthermore, we use AutonoMouse to systematically probe the impact of graded olfactory bulb lesions on olfactory behaviour, demonstrating that while odour discrimination in general is robust to even most extensive disruptions, small olfactory bulb lesions already impair odour detection. Discrimination learning of similar mixtures as well as learning speed are in turn reliably impacted by medium lesion sizes. The modular nature and open-source design of AutonoMouse should allow for similar robust and systematic assessments across neuroscience research areas.

Neuroplastic changes in the olfactory bulb associated with nasal inflammation in mice

Rhinitis and rhinosinusitis are olfactory disorders caused by inflammation of the nasal passage and paranasal sinuses. Although patients with chronic rhinosinusitis have smaller olfactory bulbs (OBs), there is limited knowledge regarding the influence of chronic nasal inflammation on OB neurons. Repeated intranasal administration of LPS that induced persistent nasal inflammation in mice caused a loss of olfactory sensory neurons (OSNs) and gliosis and synaptic loss in the OBs within 3weeks. The present study aimed to clarify the effects of long-term LPS treatment on the OB neurocircuit. LPS was repeatedly administered into a mouse nostril for up to 24weeks. For the recovery analyses, the mice received LPS for 10weeks and were subsequently maintained without additional treatment for another 10weeks. The effects of these treatments on the OBs were examined histologically. Three or more mice were analyzed per group. Long-term repeated LPS administration caused OB atrophy, particularly in the layers along which OSN axons travel and in the superficial external plexiform layer, in which tufted cells form synapses with interneurons. Interestingly, the OBs recovered from atrophy after cessation of LPS administration: OB volume and superficial external plexiform layer thickness returned to pretreatment levels after the nontreatment period. In contrast, OSN regeneration was incomplete. These results suggest that chronic nasal inflammation induces structural changes in a specific OB circuit related to tufted cells, whereas tufted cells retain a high degree of plasticity that enables recovery from structural damages after inflammation subsides.

DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors.

Specification of dorsoventral regional identity in progenitors of the developing telencephalon is a first pivotal step in the development of the cerebral cortex and basal ganglia. Previously, we demonstrated that the two zinc finger doublesex and mab-3 related (Dmrt) genes, Dmrt5 (Dmrta2) and Dmrt3, which are coexpressed in high caudomedial to low rostrolateral gradients in the cerebral cortical primordium, are separately needed for normal formation of the cortical hem, hippocampus, and caudomedial neocortex. We have now addressed the role of Dmrt3 and Dmrt5 in controlling dorsoventral division of the telencephalon in mice of either sex by comparing the phenotypes of single knock-out (KO) with double KO embryos and by misexpressing Dmrt5 in the ventral telencephalon. We find that DMRT3 and DMRT5 act as critical regulators of progenitor cell dorsoventral identity by repressing ventralizing regulators. Early ventral fate transcriptional regulators expressed in the dorsal lateral ganglionic eminence, such as Gsx2, are upregulated in the dorsal telencephalon of Dmrt3;Dmrt5 double KO embryos and downregulated when ventral telencephalic progenitors express ectopic Dmrt5 Conditional overexpression of Dmrt5 throughout the telencephalon produces gene expression and structural defects that are highly consistent with reduced GSX2 activity. Further, Emx2;Dmrt5 double KO embryos show a phenotype similar to Dmrt3;Dmrt5 double KO embryos, and both DMRT3, DMRT5 and the homeobox transcription factor EMX2 bind to a ventral telencephalon-specific enhancer in the Gsx2 locus. Together, our findings uncover cooperative functions of DMRT3, DMRT5, and EMX2 in dividing dorsal from ventral in the telencephalon.SIGNIFICANCE STATEMENT We identified the DMRT3 and DMRT5 zinc finger transcription factors as novel regulators of dorsoventral patterning in the telencephalon. Our data indicate that they have overlapping functions and compensate for one another. The double, but not the single, knock-out produces a dorsal telencephalon that is ventralized, and olfactory bulb tissue takes over most remaining cortex. Conversely, overexpressing Dmrt5 throughout the telencephalon causes expanded expression of dorsal gene determinants and smaller olfactory bulbs. Furthermore, we show that the homeobox transcription factor EMX2 that is coexpressed with DMRT3 and DMRT5 in cortical progenitors cooperates with them to maintain dorsoventral patterning in the telencephalon. Our study suggests that DMRT3/5 function with EMX2 in positioning the pallial-subpallial boundary by antagonizing the ventral homeobox transcription factor GSX2.

The BEACH Protein LRBA Promotes the Localization of the Heterotrimeric G-protein Golf to Olfactory Cilia

BEACH domain proteins are involved in membrane protein traffic and human diseases, but their molecular mechanisms are not understood. The BEACH protein LRBA has been implicated in immune response and cell proliferation, and human LRBA mutations cause severe immune deficiency. Here, we report a first functional and molecular phenotype outside the immune system of LRBA-knockout mice: compromised olfaction, manifesting in reduced electro-olfactogram response amplitude, impaired food-finding efficiency, and smaller olfactory bulbs. LRBA is prominently expressed in olfactory and vomeronasal chemosensory neurons of wild-type mice. Olfactory impairment in the LRBA-KO is explained by markedly reduced concentrations (20–40% of wild-type levels) of all three subunits αolf, β1 and γ13 of the olfactory heterotrimeric G-protein, Golf, in the sensory cilia of olfactory neurons. In contrast, cilia morphology and the concentrations of many other proteins of olfactory cilia are not or only slightly affected. LRBA is also highly expressed in photoreceptor cells, another cell type with a specialized sensory cilium and heterotrimeric G-protein-based signalling; however, visual function appeared unimpaired by the LRBA-KO. To our knowledge, this is the first observation that a BEACH protein is required for the efficient subcellular localization of a lipid-anchored protein, and of a ciliary protein.

PP07. A PML/POLYCOMB/SLIT AXIS REGULATES MIGRATION OF BOTH NORMAL AND NEOPLASTIC CELLS IN THE CNS

INTRODUCTION: The control of SVZ neural progenitor/stem cells (NPCs) migration through the rostral migratory stream (RMS) is essential for normal neurogenesis and serve as the fundamental basis of production/replacement of neurons in the adult brain. Alterations of these processes can lead to neoplastic transformation and glioblastoma multiforme (GBM). The ability of GBM cells to migrate through the brain parenchyma represents a key factor underlying GBM aggressiveness. GBM cells use the same routes used by neuroblasts/immature neurons and neural stem cells upon injury, such as vessels and myelin tracts, suggesting that GBM migration may lay its roots in essential cellular processes controlling migration of immature neurons/neuroblasts and neural stem cells (1). However, our understanding of mechanisms regulating cell migration/invasion during brain tumourigenesis remains limited. METHODS: We combined in vivo and in vitro approaches, including the use of genetically modified mice, primary HGG tissues/NPCs (in collaboration with S Brandner, UCL, C Jones, ICR, S Pollard, Edinburgh, and others). RESULTS: Here we report that the stem cell factor and RAS effector Promyelocytic Leukaemia protein (PML) (2,3) regulates cell migration through the epigenetic control of Slit axon guidance genes in normal and neoplastic cells in the central nervous system. Loss of PML leads to impaired NSC and neuroblast migration and a smaller olfactory bulb in the adult mouse brain. PML controls cell migration via Polycomb Repressive 2-dependent regulation of the Slit axon guidance genes. A similar epigenetically controlled PML/Slit axis is functional also upon RAS-driven neoplastic transformation of NSCs and in primary GBM cells. PML expression inversely correlates with Slit1 expression and patient prognosis in GBM and is enriched in the mesenchymal subtype, which is characterized by activation of the RAS/MAPK pathway. Finally, PML loss impairs tumor growth in an orthotopic animal model. CONCLUSIONS: Taken together, these findings disclose a novel molecular axis at the root of cell migration during normal neurogenesis and brain tumourigenesis. Reference 1. Cuddapah VA et al. Nat Rev Neurosci 15: 455–465. 2. Regad T. et al. Nature neuroscience 12: 132–140. 3. Salomoni P. et al. Cell Res 18: 622–640.

Penguins reduced olfactory receptor genes common to other waterbirds.

The sense of smell, or olfaction, is fundamental in the life of animals. However, penguins (Aves: Sphenisciformes) possess relatively small olfactory bulbs compared with most other waterbirds such as Procellariiformes and Gaviiformes. To test whether penguins have a reduced reliance on olfaction, we analyzed the draft genome sequences of the two penguins, which diverged at the origin of the order Sphenisciformes; we also examined six closely related species with available genomes, and identified 29 one-to-one orthologous olfactory receptor genes (i.e. ORs) that are putatively functionally conserved and important across the eight birds. To survey the 29 one-to-one orthologous ORs in penguins and their relatives, we newly generated 34 sequences that are missing from the draft genomes. Through the analysis of totaling 378 OR sequences, we found that, of these functionally important ORs common to other waterbirds, penguins have a significantly greater percentage of OR pseudogenes than other waterbirds, suggesting a reduction of olfactory capability. The penguin-specific reduction of olfactory capability arose in the common ancestor of penguins between 23 and 60 Ma, which may have resulted from the aquatic specializations for underwater vision. Our study provides genetic evidence for a possible reduction of reliance on olfaction in penguins.

Endocranial morphology of Microchoerus erinaceus (Euprimates, Tarsiiformes) and early evolution of the Euprimates brain.

Innovations in brain structure and increase in brain size relative to body mass are key features of Primates evolutionary history. Surprisingly, the endocranial morphology of early Euprimates is still rather poorly known, and our understanding of early euprimate brain evolution (Eocene epoch) relies on a handful of specimens. In this article, we describe the endocranial cast of the tarsiiform Microchoerus erinaceus from the late Early Eocene of Perrière (Quercy fissure filling, France) based on a virtual reconstruction extracted from CT scan data of the endocranial cavity of the complete, undeformed specimen UM-PRR1771. The endocast of M. erinaceus shows the derived features observed in other Euprimates (e.g. sylvian fissure and temporal lobe), with limited neocortical folding, and a telencephalic flexure comparable to that of extant primates. Comparison with the endocasts of other available late Eocene primates shows that they already exhibited a variety of brain morphologies, highlighting the complex history of the external features of the primate brain, as early as the Eocene. M. erinaceus was a fruit and gum eater considered as nocturnal based on its orbit size. However, its brain showed small olfactory bulbs--smaller than in the coeval diurnal taxa Adapis parisiensis--and a neocorticalization similar to folivorous taxa. These observations contrast with patterns observed in primates today where nocturnal taxa have larger olfactory bulbs than diurnal taxa, and call into question a direct correlation between frugivory and neocorticalization increase in primates.

Shh-proteoglycan interactions regulate maturation of olfactory glomerular circuitry.

The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (Shh(Ala/Ala)), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature Shh(Ala/Ala) mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry.

Clinical observation of isolated congenital anosmia

To introduce 8 patients with isolated congenital anosmia and to discuss the clinical manifestations, imaging characteristics and family characteristics of this rarely seen disorder. Eight patients with isolated congenital anosmia treated between April 2007 and April 2012 were reviewed retrospectively. There were 4 males and 4 females. A detailed medical history collection, physical examination, nasal endoscopy, T&T and Sniffin'Sticks subjective olfactory function tests, olfactory event-related potentials sinonasal computed tomography scan and sex hormones level monitoring were performed in all patients. Seven cases underwent magnetic resonance image of olfactory pathway examination. All patients were anosmia without evidence of other defects. ENT physical examination, nasal endoscopy and computed tomography scan were normal except 4 cases with obvious nasal septum deviation, 2 cases with concha bullosa. Subjective olfactory test indicated all of them were anosmia. Olfactory event-related potentials were obtained in only 1 patient. Magnetic resonance imaging revealed the smaller or atrophy olfactory bulb and olfactory tract in five cases, the absence of olfactory bulbs and tracts in two case. A female patient did not have MRI examination because of wearing IUDs. Detection of 8 patients of sex hormones were normal. Family characteristics: 3 patients showed family inheritance pattern. The diagnosis of isolated congenital anosmia should be based on chief complaint, medical history, physical examination, olfactory test, nasal endoscopy, olfactory testing, olfactory imaging and olfactory event-related potentials. Magnetic resonance image of olfactory pathway and olfactory event-related potentials have important value for the diagnosis. More attention should be paid to the genetic susceptibility of the family.

CD146 Deletion in the Nervous System Impairs Appetite, Locomotor Activity and Spatial Learning in Mice

Cell adhesion molecules (CAMs) are crucial effectors for the development and maintenance of the nervous system. Mutations in human CAM genes are linked to brain disorders and psychological diseases, and CAM knockout mice always exhibit similar behavioral abnormalities. CD146 is a CAM of the immunoglobulin superfamily that interacts with Neurite Outgrowth Factor and involved in neurite extension in vitro. However, little is known about its in vivo function in the nervous system. In this study, we used a murine CD146 nervous system knockout (CD146ns-ko) model. We found that the brains of some CD146ns-ko mice were malformed with small olfactory bulbs. CD146ns-ko mice exhibited lower body weights and smaller food intake when compared with wild type littermates. Importantly, behavior tests revealed that CD146ns-ko mice exhibited significant decreased locomotor activity and impaired capacity for spatial learning and memory. Our results demonstrate that CD146 is important for mammalian nervous system development and proper behavior patterns.

Fascin Regulates the Migration of Subventricular Zone-Derived Neuroblasts in the Postnatal Brain

After birth, stem cells in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) to become interneurons in the olfactory bulb (OB). This migration is a fundamental event controlling the proper integration of new neurons in a pre-existing synaptic network. Many regulators of neuroblast migration have been identified; however, still very little is known about the intracellular molecular mechanisms controlling this process. Here, we show that the actin-bundling protein fascin is highly upregulated in mouse SVZ-derived migratory neuroblasts. Fascin-1ko mice display an abnormal RMS and a smaller OB. Bromodeoxyuridine labeling experiments show that lack of fascin significantly impairs neuroblast migration, but does not appear to affect cell proliferation. Moreover, fascin depletion substantially alters the polarized morphology of rat neuroblasts. Protein kinase C (PKC)-dependent phosphorylation of fascin on Ser39 regulates its actin-bundling activity. In vivo postnatal electroporation of phosphomimetic (S39D) or nonphosphorylatable (S39A) fascin variants followed by time-lapse imaging of brain slices demonstrates that the phospho-dependent modulation of fascin activity ensures efficient neuroblast migration. Finally, fluorescence lifetime imaging microscopy studies in rat neuroblasts reveal that the interaction between fascin and PKC can be modulated by cannabinoid signaling, which controls neuroblast migration in vivo. We conclude that fascin, whose upregulation appears to mark the transition to the migratory neuroblast stage, is a crucial regulator of neuroblast motility. We propose that a tightly regulated phospho/dephospho-fascin cycle modulated by extracellular signals is required for the polarized morphology and migration in neuroblasts, thus contributing to efficient neurogenesis.

Interspecific Variations of Inner Ear Structure in the Deep‐Sea Fish Family Melamphaidae

Inner ear structures are compared among three major genera of the deep-sea fish family Melamphaidae (bigscales and ridgeheads). Substantial interspecific variation is found in the saccular otoliths, including the presence of a unique otolithic "spur" in the genera Melamphaes and Poromitra. The variation in the saccular otolith is correlated with an increase in the number of hair bundle orientation groups on the sensory epithelia from the genera Scopelogadus to Poromitra to Melamphaes. The diverse structural variations found in the saccule may reflect the evolutionary history of these species. The sensory hair cell bundles in this family have the most variable shapes yet encountered in fish ears. In the saccule, most of the hair bundles are 15-20 μm high, an exceptional height for fish otolithic end organs. These bundles have large numbers of stereovilli, including some that reach the length of the kinocilium. In the utricle, the striolar region separates into two unusually shaped areas that have not been described in any other vertebrates. The brains in all species have a relatively small olfactory bulb and optic tectum, as well as an enlarged posterior cerebellar region that is likely to be involved in inner ear and lateral line (octavolateral) functions. Data from melamphaids support the hypothesis that specialized anatomical structures are found in the ears of some (if not most) deep-sea fishes, presumably enhancing their hearing sensitivity.