Age and sex differences of controlled force exertion measured by a computer-generated quasi-random target-pursuit system.

OBJECTIVES: This study examined age and sex differences of controlled force exertion measured by a computer-generated quasi-random target-pursuit system in 207 males and 249 females aged 15 to 86 years. METHODS: The participants matched submaximal grip exertion of their dominant hand to changing demand values, appearing as a moving quasi-random waveform on the display of a personal computer. They performed the test three times with 1-min intervals (one trial was 40 sec). The total sum of the percent of differences between the demand value and the grip exertion value for 25 sec was used as an evaluation parameter. RESULTS: The errors in controlled force exertion tended to increase constantly with age in both sexes. Significant linear regressions were identified, but there was no significant difference in the rate of increase in both sexes. Analysis of variance showed nonsignificant sex differences among means, except for those in individuals older than 60 years; significant differences between means in the groups older than the 40 yr.-old age group and the 20-24 yr.-old group were found in both sexes. CONCLUSIONS: Controlled force exertion did not show a significant sex difference and decreased gradually with age in both sexes, but decreased remarkably after 40 years of age.

Disruption of neuromedin B receptor gene results in dysregulation of the pituitary-thyroid axis.

The level of thyrotropin (TSH) secretion is determined by the balance of TSH-releasing hormone (TRH) and thyroid hormones. However, neuromedin B (NB), a bombesin-like peptide, highly concentrated in the pituitary, has been postulated to be a tonic inhibitor of TSH secretion. We studied the pituitary-thyroid axis in adult male mice lacking NB receptor (NBR-KO) and their wild-type (WT) littermates. At basal state, NBR-KO mice presented serum TSH slightly higher than WT (18%, P< 0.05), normal intra-pituitary TSH content, and no significant changes in alpha and beta TSH mRNA levels. Serum thyroxine was normal but serum triiodothyronine (T3) was reduced by 24% (P< 0.01) in NBR-KO mice. Pituitaries of NBR-KO mice exhibited no alteration in prolactin mRNA expression but type I and II deiodinase mRNA levels were reduced by 53 and 42% respectively (P< 0.05), while TRH receptor mRNA levels were importantly increased (78%, P< 0.05). The TSH-releasing effect of TRH was significantly higher in NBR-KO than in WT mice (7.1-and 4.0-fold respectively), but, while WT mice presented a 27% increase in serum T3 (P< 0.05) after TRH, NBR-KO mice showed no change in serum T3 after TRH. NBR-KO mice did not respond to exogenous NB, while WT showed a 30% reduction in serum TSH. No compensatory changes in mRNA expression of NB or other bombesin-related peptides and receptors (gastrin-releasing peptide (GRP), GRP-receptor and bombesin receptor subtype-3) were found in the pituitary of NBR-KO mice. Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH. Therefore, the study highlights the important role of NB as a physiological regulator of pituitary-thyroid axis function and gene expression.

Overexpression of gastrin-releasing peptide receptor induced layer disorganization in brain.

Gastrin-releasing peptide-preferring and neuromedin B-preferring receptors, members of the bombesin-like peptide receptor subfamily, are reported to regulate proliferation, migration and differentiation. Since they are expressed in developing brain, we postulated that the gastrin-releasing peptide-preferring and neuromedin B-preferring receptors might be involved in normal brain development. Here we examined the effects of the overexpressions of the gastrin-releasing peptide-preferring and neuromedin B-preferring receptors on chick brain development in vivo using a retrovirus. In the overexpressed exogenous gastrin-releasing peptide-preferring receptor brain, we found laminar disorganization in the telencephalon, tectum and particularly in the cerebellum with severe atrophy. Processes of the radial glial cells in the telencephalon and optic tectum, as well as the projections of the Bergmann glia in the cerebellum were distorted, which might disturb normal cell migration. Despite the atrophy of the cerebellum, densely-stained proliferating cell nuclear antigen- and phospho-histone H3-positive cells increased in number. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells also increased in the cerebellum, suggesting that the ectopically proliferating cells were subjected to apoptosis. Glial fibrillary acidic protein-positive cells also increased in the hyperpallium accessorium and in the outer layers of the tectum. We also found smaller and spindle-shaped cells which resembled undifferentiated embryonic tumor cells. On the other hand, the layer structures of the neuromedin B-preferring receptors overexpressed brain were well organized and developed, and the size of brain was generally enlarged. These results indicated that although the gastrin-releasing peptide-preferring and neuromedin B-preferring receptors are involved in normal brain development, both receptors contribute and exert their effects differently.

Distributions of two chicken bombesin receptors, bombesin receptor subtype-3.5 (chBRS-3.5) and gastrin-releasing peptide receptor (chGRP-R) mRNAS in the chicken telencephalon.

Bombesin (BN)-like peptide receptors are known to be essential to the regulation of not only homeostasis, including feeding behavior, but also of emotional systems in mammal. Recently, two novel BN receptors, chicken BN-like peptide receptor subtype-3.5 (chBRS-3.5) and gastrin-releasing peptide receptor (chGRP-R), have been identified. Here, we report the localizations of these receptors' mRNAs in the chick brain through development using in situ hybridization. First, chBRS-3.5 mRNA signals were found in the dorsal ventricular ridge at embryonic day (ED) 9. Strong signals were observed in the hyperpallium accessorium, nidopallium and nucleus basorostralis pallii, and moderate signals were found in the hippocampus, cortex piriformis, hyperpallium intercalatum, area temporo-parieto-occipitalis, nucleus striae terminalis lateralis, nucleus olfactorius anterior and organum septi lateralis at ED16. This wide expression in the pallium persisted during posthatch periods. Abundant expressions in the hyperpallium, nidopallium, considered to be similar to the mammalian cortex, as well as in the hippocampus, indicate participation of these molecules in the processing of sensory information, motor function, learning and memory. Telencephalic areas devoid of chBRS-3.5 signals were the entopallium, arcopallium anterius, globus pallidus, nucleus intrapeduncularis, tuberculum olfactorius, nucleus septalis lateralis, hypothalamic and thalamic areas. In contrast to chBRS-3.5, chGRP-R mRNA signals were found in the pallidum at ED5 and 9. At ED16, chGRP-R mRNA signals were localized in the medial striatum and hypothalamus. GRP-R expression in the hypothalamic region was phylogenically conserved. Thus, chBRS-3.5 mRNA signals were distributed in a broader region and were more intense than chGRP-R mRNA. Taken together, chGRP-R and chBRS-3.5 mRNA occurred in similar regions of mammals that express GRP-R. BN/GRP-immunoreactive neurons and varicosities were found mainly in the pallium, especially in the hyperpallium accessorium and nidopallium, and this distribution coincided with that of chBRS-3.5 mRNA. This result suggests that the endogenous ligands for chBRS-3.5 were likely BN-like peptides produced in the pallium.

Neuromedin B.

Neuromedin B (NMB) is one of the bombesin (BN)-related peptides in mammals. It was originally purified from pig spinal cords, and it has been shown to be present in central nervous system as well as in gastrointestinal tract. BN and its related peptides have various physiological effects. These include regulation of exocrine and endocrine secretions, smooth muscle contraction, feeding, blood pressure, blood glucose, body temperature and cell growth. NMB exerts its effect by binding to the cell surface receptor. A high affinity receptor, NMB receptor (NMB-R) has been identified. This is a G-protein coupled receptor with seven membrane-spanning regions. Upon agonist binding, several intracellular signaling cascades including phospholipase activation, calcium mobilization and protein kinase C (PKC) activation lead to expression of several genes, DNA synthesis or cellular effects such as secretion. Existence of NMB-R has been demonstrated in several brain regions, notably in olfactory and thalamic regions, and in gastrointestinal tracts. Recent analysis using NMB-R-deficient mice, generated by gene-targeting technique, enables to distinguish functional properties of NMB-R from GRP-R. In this review, molecular characterization, anatomical distribution and pharmacological properties of NMB and NMB-R will be presented. Moreover, physiological roles of NMB and its receptor demonstrated by the analysis of NMB-R-deficient mice will be reported. Comparison with GRP/GRP-R system will provide important information about BN-like peptide systems in mammals.

Differential effects of social isolation upon body weight, food consumption, and responsiveness to novel and social environment in bombesin receptor subtype-3 (BRS-3) deficient mice.

The effects of social isolation on body weight gain, food consumption, and responsiveness to novel and social environment were assessed in an animal model for obesity, bombesin receptor subtype-3 (BRS-3) deficient mice. In Experiment 1, body weight gain and food consumption of group- and isolation-housed wild-type and BRS-3-deficient mice were compared. In wild-type mice, group-housed animals showed greater mean body weight gain and food consumption than did the isolation-housed cohort in the early stage of the experiment, whereas in BRS-3-deficient mice, the isolation-housed mice showed greater body weight gain and food consumption than the group-housed cohort by prolonged isolation housing. In Experiment 2, isolation-housed wild-type mice exhibited increased stereotypic and vertical movements relative to group-housed subjects in a novel environment, but this effect was not observed in BRS-3-deficient mice. In Experiment 3, when social response was assessed in animals housed in isolation, BRS-3-deficient mice exhibited lower social responses than did wild-type mice. We conclude that BRS-3-deficient mice and wild-type mice are differentially affected by social isolation. These results suggest that BRS-3 expression in the CNS may affect the neural mechanisms that regulate isolation effects in wild-type animals.

Hyperresponsiveness to palatable and aversive taste stimuli in genetically obese (bombesin receptor subtype-3-deficient) mice.

Taste preference in obese mice was examined using genetically obese (bombesin receptor subtype-3: BRS-3 deficient) animals. Preference for either sodium saccharin (0.2%). sodium chloride (0.9%), citric acid (0.1%), or quinine sulfate (0.002%) solution was examined using a two-bottle test situation, and BRS-3 deficient mice not only showed a stronger preference for saccharin solution, but also a stronger aversive response to quinine solution, relative to wild-type littermates. Furthermore, a conditioned taste-aversion test measured the consumption of sodium saccharin (0.2%) and sodium chloride (0.9%) solutions after intraperitoneal injection of LiCl (0.3 M, 1 mg/kg), and BRS-3-deficient mice exhibited stronger aversion to both solutions than did control animals. In situ hybridization demonstrated that the BRS-3 gene is expressed in the parabrachial nucleus, the medial and central nuclei of the amygdala, and the hypothalamic nuclei such as paraventricular nucleus, all of which are known to be involved in taste perception. These results suggest that expression of the BRS-3 gene in these nuclei is important for the modulation of taste preference, as well as the development of obesity.

Effect of long-term exercise training on regional myocardial perfusion changes in patients with coronary artery disease.

The cardiac rehabilitation of patients with coronary artery disease (CAD) promotes exercise tolerance, improves left ventricular function, and decreases the heart rate and systolic blood pressure at the same load intensity. Several studies have shown that cardiac rehabilitation improves myocardial perfusion in CAD patients. However, the long-term (> or = 1 year) effect of cardiac rehabilitation on myocardial perfusion is still controversial. The effect of long-term exercise training on myocardial perfusion in CAD patients was assessed using thallium-201 (201Tl) exercise studies at a baseline (4 months after the onset of CAD) and at a 1-year or more follow-up in 58 patients with stable CAD. The subjects had been divided into a training group (n=35) participating in supervised exercise 2 times per week for the follow-up period, and the control group (n=23). There was an improvement in the myocardial perfusion on stress 201Tl scintigraphy in 20 of the 35 (57.1%) trained patients and in 3 of the 23 (13.0%) of the control patients (p<0.001). The number of 201Tl stress myocardial perfusion defect segments was significantly decreased after the cardiac rehabilitation training (231 to 153 segments), but showed no change in the control group (158 to 156 segments) (p<0.01). In spite of no significant differences in the number of involved coronary arteries, it improved (12/17 patients: 70.6%) more in the patients who had trained for more than 2 years compared to the patients who had trained for less than 2 years. The exercise tolerance increased in 25 of the 35 training group patients (71.4%), and in only 3 of the 23 control group patients (13.0%). The peak double products increased from 20,131+/-6,010 to 28,370+/-5,600 (p<0.01) in the training group, and showed no change in the control group (20,567+/-5,112 to 20,964+/-7,728 (NS)). The results indicated that the long-term physical training increased exercise tolerance and the double products of CAD patients. In addition, the training resulted in improved cardiac perfusion as evidenced by 201Tl scintigraphy. The findings suggest that exercise training is an advisable and effective treatment for patients with CAD.

Functional properties of two bombesin-like peptide receptors revealed by the analysis of mice lacking neuromedin B receptor.

The neuromedin B-preferring receptor (NMB-R) is one of the members of the bombesin (BN)-like peptide receptor subfamily in mammals. Previously, we have generated and characterized mice with targeted disruption of the two other BN-like peptide receptors, bombesin receptor subtype-3 (BRS-3) and gastrin-releasing peptide-preferring receptor (GRP-R). Here we describe the generation and analysis of NMB-R-deficient mice to investigate how NMB-R differs from BRS-3 and GRP-R. Compensation for NMB-R deficiency by overexpression of GRP-R and/or BRS-3 was not detected. Although the hypothermic effect of NMB was reduced by 50% in NMB-R-deficient mice, the effect of GRP infusion was comparable to the wild-type mice. In contrast, fundic smooth muscle contraction on stimulation with NMB or GRP was normal in NMB-R-deficient mice. Administration of GRP but not NMB suppressed glucose intake in both normal and NMB-R-deficient mice. These results suggest that the NMB-R has an essential role in thermoregulation, but not for smooth muscle contraction of the fundus or for the suppression of feeding behavior. In addition, the behavioral phenotypes of GRP-R-deficient mice were not observed in NMB-R-deficient mice. These data show that the functions of NMB-R and GRP-R are distinct, with only partial overlap.

Carboxy-terminal truncation of long-tailed amyloid beta-peptide is inhibited by serine protease inhibitor and peptide aldehyde.

The 42/43-residue amyloid beta-peptide (Abeta) is widely believed to play a major role in Alzheimer's disease. The present study shows that the rat brain contains a carboxypeptidase that efficiently deletes three amino acids from Abeta1-43. The carboxypeptidase activity in the brain was completely inhibited by 1 mM phenylmethylsulfonyl fluoride, suggesting the protease is a serine carboxypeptidase. The carboxy-terminal truncation of Abeta1-43 was moderately inhibited by carbobenzoxy-Leu-leucinal, carbobenzoxy-Leu-Leu-leucinal, and carbobenzoxy-Leu-Leu-norvalinal, and weakly by antipain. The present data suggest that the serine carboxypeptidase contributes to the generation of short-tailed Abeta peptides and is important in the intracellular clearance of Abeta1-42/43 in brains.

Generation and characterization of mice lacking gastrin-releasing peptide receptor.

Gastrin-releasing peptide (GRP) is a mammalian bombesin-like peptide which is widely distributed in the central nervous system as well as in the gastrointestinal tract. GRP binds to its high affinity receptor (GRPR) to elicit a wide spectrum of biological effects on behavior, digestion, and metabolism. To define the in vivo function of GRPR, we generated GRPR null mutant mice by gene targeting. The intracerebroventricular administration of GRP caused hypothermia in wild-type mice, but not in mutant mice. The GRPR deficient mice showed significantly increased locomotor activity during the dark period, and social responses scored by sniffing, mounting, and approaching behaviors against an intruder. Aggressive scores such as fighting and biting were not altered in the mutant mice. These phenotypes were observed in mice generated from two independent ES cell clones and backcrossed to a C57BL/6J background. The GRPR deficient mice should be useful for studying the bombesin system in vivo.

Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity.

Mammalian bombesin-like peptides are widely distributed in the central nervous system as well as in the gastrointestinal tract, where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism and behaviour. They bind to G-protein-coupled receptors on the cell surface to elicit their effects. Bombesin-like peptide receptors cloned so far include, gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype-3 (BRS-3). However, despite the molecular characterization of BRS-3, determination of its function has been difficult as a result of its low affinity for bombesin and its lack of an identified natural ligand. We have generated BRS-3-deficient mice in an attempt to determine the in vivo function of the receptor. Mice lacking functional BRS-3 developed a mild obesity, associated with hypertension and impairment of glucose metabolism. They also exhibited reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia. Our data suggest that BRS-3 is required for the regulation of endocrine processes and metabolism responsible for energy balance and adiposity. BRS-3-deficient mice provide a useful new model for the investigation of human obesity and associated diseases.

Cloning and expression of the neuromedin B receptor and the third subtype of bombesin receptor genes in the mouse.

We cloned the genes for the mouse homologue of the neuromedin B receptor (NMB-R) and the bombesin receptor subtype 3 (BRS-3). Both receptor genes consist of three exons with well-conserved intron-exon borders. Although the NMB-R gene spans more than 10 kb, the BRS-3 gene spans only about 4 kb. Comparison of the mouse and human receptor sequences indicates 90% (NMB-R) and 85% (BRS-3) sequence homology at the amino-acid level. In the adult mouse, the NMB-R mRNA is expressed in the brain, testis, esophagus, intestine and uterus, whereas the BRS-3 mRNA is expressed predominantly in the brain. In the brain, the NMB-R gene expression is prominent in the thalamic and olfactory regions, and the BRS-3 gene is expressed particularly in the hypothalamic region. In mouse testis, the NMB-R gene expression is prominent, and the expression of BRS-3 mRNA is barely detected. In contrast, BRS-3 has been shown to be expressed in rat testis and guinea-pig uterus, therefore it is possible that a different subtype of the bombesin receptor mediates the same response in different species. Together with the mouse GRP-R gene cloned previously, cloning of the mouse NMB-R and BRS-3 genes permits comparison of function and structure of the three bombesin receptor subtypes in the mouse.

[Application of tuberculosis medical examination radiographs to scoliosis screening in high schools].

The purpose of this study was to assess the utilization of tuberculosis examination radiographs for scoliosis screening in high schools, for early diagnosis and early treatment of adolescent idiopathic scoliosis in the health management of students. We examined 2,068 first year high school students (1,058 males and 1,010 females) in Wakayama Prefecture, who had chest X-ray photographs taken between 1994 to 1996, and 24 cases (3 males and 21 females) were identified with scoliosis of more than 10 degrees Cobb angle. Fifteen of the cases received further examinations in the hospital, and were diagnosed with definite adolescent idiopathic scoliosis, while 6 cases who did not receive hospital examinations had their abnormality of the spine noted in past periodic health examinations. In the remaining 3 students scoliosis could not be confirmed. The correlation coefficient between the Cobb angle measured in the tuberculosis examination radiographs and in the total spinal radiographs taken by the hospital was 0.815 (p < 0.001). These results suggest that the tuberculosis examination radiographs may be useful for scoliosis screening in high schools.

[Clinical evaluation of cefpirome sulfate for severe infections in patients with hematological disorders. Hanshin Study Group of Hematopoietic Disorders and Infections].

We investigated the therapeutic efficacy and safety of cefpirome sulfate (CPR) in treatment of hematopoietic disorder-associated infections. A total of 219 patients were admitted to 12 hospitals of Hanshin Study Group of hematopoietic disorders and infections between April 1994 and March 1996 and were enrolled in this study. Most patients received intravenously infused CPR at a dose of 1 or 2 g twice a day for 3 days or more. Twenty nine patients dropped out or were excluded and remaining 190 patients were adopted for the evaluation. A overall response rate was 58.4% (111/190). Among neutropenic patients, the response rate was 50% (8/16) in patients whose peripheral neutrophil counts (PNC) remained less than 100/microliter throughout the observation period and was 53.7% (22/41) in patients with PNC remained less than 500/microliter. In contrast, in patient whose PNC was below 500 before the treatment but exceeded 501/microliter during of at the end of the treatment, the response rate was as high as 78.4% (29/37). When G-CSF was combined, the response rate became significantly (P < 0.05) higher, 68.5% (50/73), as compared with that, 52.1% (61/117), in patients without it. In cases in which the causative organisms could be identified, the organisms were eliminated in 81.8% (9/11) of the patients infected with Gram-positive bacteria, whereas in 100% (12/12) in those infected with Gram-negative bacteria. Skin eruption developed in 6 patients during the treatment with CPR, and vascular pain and parosmia in one each other. These symptoms subsided soon after discontinuation or even without discontinuation of CPR. Abnormal laboratory findings, mainly liver dysfunction, i.e. elevation of slight degree of serum transaminase levels, were observed. The values, however, turned to normal immediately after the cessation or completion of the treatment. In conclusion, CPR is considered to be an antibiotic of value with high efficacy and safety in treatment of hematopoietic disorder-associated infections.

Control of the limb bud outgrowth in quail-chick chimera.

It is well known that the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) play a major role in growth and patterning of the limb. But a mechanism underlying species-specific growth of the limb has not yet been fully elucidated. To investigate the role of AER and ZPA in limb size control, we constructed quail-chick limb chimeras. When we grafted a whole forelimb bud from one species to another, the size of the developed grafted limb was comparable to the limb of the donor species. Moreover, we demonstrated that neither the interspecific substitution of the posterior half region of the limb bud containing the ZPA nor the exchange of the ectodermal component of the limb involving the AER could alter the species-specific size of the limb. These results indicate that the factors affecting the size of the limb are already involved in the mesodermal component of the limb bud at stage 20 of chick embryo. Thus, the mesoderm dictates limb specificity including size.

Cathepsin D is involved in the clearance of Alzheimer's beta-amyloid protein.

The cerebral deposition of 39-42 residue amyloid beta-protein (Abeta) is a histopathological characteristic of Alzheimer's disease. The present study is aimed at finding proteinases responsible for the intracellular clearance of Abeta. The Abeta-degrading proteinase was purified from rat brain. Amino-terminal sequence analysis indicated the Abeta-degrading proteinase was cathepsin D. Purified cathepsin D hydrolyzed Abeta between Phe19 and Phe20. Cathepsin D is likely to be involved in the intracellular clearance of aggregatable Abeta, since Abeta fragments with Phe20 at the amino-terminus have been reported to be secreted from several lines of cultured cells.

A beta-amyloid peptide variant related with familial Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis is poorly eliminated by cathepsin D.

The cerebral deposition of 40-42 residue amyloid beta-protein (Abeta) is a characteristic of Alzheimer's disease. Cathepsin D is possibly involved in the intracellular clearance of Abeta (Hamazaki, H. (1996) FEBS Lett., in press). The present work shows that cathepsin D hydrolyzes wild-type Abeta 20 times faster than a variant Abeta with a substitution at residue 21 from Ala to Gly. Since the substitution has been linked to familial Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Hendriks et al. (1992) Nature Genet. 1, 218-221), the present observations suggest that the inefficient elimination of Abeta by cathepsin D is capable of being one of causes of the amyloid fibril formation.

Migration of GnRH-immunoreactive neurons from the olfactory placode to the brain: a study using avian embryonic chimeras.

Previous studies suggest that gonadotropin-releasing hormone (GnRH) neurons appear in the olfactory placode and subsequently migrate into the brain during embryonic development. The aim of the present study was to obtain direct evidence for migration of GnRH neurons from the olfactory placode into the brain. Olfactory placodes from quail embryos were transplanted isotopically and isochronically, to replace the unilaterally ablated olfactory placodes of chick embryos. The chimeric embryos were allowed to develop for several days until they reached the embryonic stages when GnRH neurons are seen in the brain in normal embryos. Quail olfactory epithelia were formed in the host chick embryos. Quail olfactory nerves were also formed and reached the olfactory bulb or primordial olfactory bulb. GnRH-immunoreactive cells of quail origin revealed by a triple staining method were observed in the quail olfactory epithelium, quail olfactory nerve, chick olfactory bulb, and septo-preoptic area. These results indicate that GnRH neurons originate in the olfactory placode and migrate into the telencephalon including the septo-preoptic area. A migratory route of GnRH neurons was well documented by the use of a quail neuron-specific antibody, QN. The migratory route in the brain is discussed with special reference to the terminal nerve. A GnRH-immunoreactive neuronal group of chick origin appeared in the diencephalon of chimeric embryos. These diencephalic neurons may be of non-placodal origin. FMRFamide-immunoreactive neurons of quail origin were also found in the quail olfactory nerve and the host olfactory bulb, suggesting that FMRFamide neurons also originate in the olfactory placode and migrate into the brain.