Michela Bondì

Time course of alterations after olfactory bulbectomy in mice

Olfactory bulbectomy in rodents causes behavioral alterations, which result in a model of depression, validated for pharmacological screening of antidepressant drugs. To unravel the appearance and time course of the major behavioral effects which follow surgery, mice underwent olfactory bulb ablation or sham operation, and were analyzed after 1, 2, or 4 weeks. Bulbectomized (BX) mice were anosmic, and hyperactive when tested under stressful situations in the forced swimming test. Predatory aggression was upregulated in a time-dependent way: only after 4 weeks BX mice were faster than controls in attacking prey. At the same time, they were less aggressive against intruders; they did not differ from controls in open field exploration, but displayed a cognitive impairment in water maze. Behavioral tests thus indicated a marked hyperreactivity, a dissociation among different aggressive behaviors, and also a cognitive impairment induced by bulbectomy. Histological confirmation of the damage revealed that major modifications took place in the rostral pole of frontal lobes, with a significant increase in the width of the rostral migratory stream, 2 weeks after surgery, and in the subventricular zone, 4 weeks after surgery. These results suggest a base for the time-course of appearance of behavioral symptoms in BX mice.

Animal models of depression: olfactory lesions affect amygdala, subventricular zone, and aggression.

Psychiatric or depressed patients show alterations in both olfactory projection areas and mucosa. In rodents, ablation of olfactory bulbs causes a depression-like syndrome, useful to test antidepressant agents. We studied in mice the behavioral symptoms and neuroanatomical correlates after mucosal damage or ablation of the olfactory bulb. Our results are based on a battery of tests exploiting anxious, aggressive, and depressive behavior, on morphological and immunohistochemical analysis. We found similar results in both sensory-damaged and bulbectomized animals, with a behavioral dissociation concerning different forms of aggression. These findings do not support a simple downregulation of social interactions in damaged mice. The most prominent modifications in the brains of sensory damaged and bulbectomized mice are detected in the subventricular zone (SVZ), the source area of neural stem cells, and in the content of cAMP-dependent protein kinase within the amygdala, suggesting a central role of this structure in the functional modulation of behavior.

S1P3 receptor influences key physiological properties of fast-twitch extensor digitorum longus muscle

To examine the role of sphingosine 1-phosphate (S1P) receptor 3 (S1P3) in modulating muscle properties, we utilized transgenic mice depleted of the receptor. Morphological analyses of extensor digitorum longus (EDL) muscle did not show evident differences between wild-type and S1P3-null mice. The body weight of 3-mo-old S1P3-null mice and the mean cross-sectional area of transgenic EDL muscle fibers were similar to those of wild-type. S1P3 deficiency enhanced the expression level of S1P1 and S1P2 receptors mRNA in S1P3-null EDL muscle. The contractile properties of S1P3-null EDL diverge from those of wild-type, largely more fatigable and less able to recover. The absence of S1P3 appears responsible for a lower availability of calcium during fatigue. S1P supplementation, expected to stimulate residual S1P receptors and signaling, reduced fatigue development of S1P3-null muscle. Moreover, in the absence of S1P3, denervated EDL atrophies less than wild-type. The analysis of atrophy-related proteins in S1P3-null EDL evidences high levels of the endogenous regulator of mitochondria biogenesis peroxisome proliferative-activated receptor-γ coactivator 1α (PGC-1α); preserving mitochondria could protect the muscle from disuse atrophy. In conclusion, the absence of S1P3 makes the muscle more sensitive to fatigue and slows down atrophy development after denervation, indicating that S1P3 is involved in the modulation of key physiological properties of the fast-twitch EDL muscle.

Effects of cysteinyl-leukotriene receptors’ antagonism by montelukast on lung mechanics and olfactory system histology in healthy mice

Context: At variance with steroid administration, the possible effects of leukotrienes inhibition on basal respiratory mechanics and olfactory system function are still unclear. Objective: To investigate if interference with the leukotrienes activity may influence basal lung mechanics in healthy mammals, as well as the olfactory system. Materials and methods: We measured lung mechanics by the end-inflation occlusion method in control and in montelukast i.p. treated anaesthetised healthy mice (10 mg/kg/die for a week). A study of olfactory system histology was also conducted. Results: Elastance and resistive properties of the lung were not affected by montelukast, while a significant increment of lung hysteresis was observed. The analysis of olfactory system histology revealed no significant effects of montelukast compared to controls. Discussion and conclusions: Leukotrienes’ antagonism does not affect respiratory mechanics in basal conditions, except for a hysteresis increment, which might counteract the increase in expiratory flow in asthmatic subjects assuming montelukast.

Daily variations of spirometric indexes and maximum expiratory pressure in young healthy adults.

In order to document possible variations in the main spirometric indexes in young healthy adults due to the time of the day, we performed standard and complete spirometric measurements at three different hours of the same day (8 am, 4 pm and 12 am) in 33 healthy, non-smoking young volunteers of both sexes. An index of airway resistance was also calculated. We confirm a general worsening of spirometric indexes at night-time compared to daily hours. This result also includes the main effort-independent indexes which were not previously measured. Maximum expiratory pressure does not show daily variations, while an index of respiratory system resistance exhibits a progressive increase from morning to night.

The olfactory system is affected by steroid aerosol treatment in mice.

Asthma needs continuous treatment often for years. In humans, some drugs are administered via aerosol, therefore they come in contact with both respiratory and olfactory mucosa. We explored the possibility that antiasthma corticosteroid treatment could influence the olfactory function by passage through the nose. A group of mice was exposed twice daily for 42 days to fluticasone propionate aerosol and was compared with a control group. Olfactory behavior, respiratory mechanics, histology, and immunoreactivity in the olfactory system were assessed. Fluticasone-treated mice were slower in retrieving a piece of hidden food, but both groups were similarly fast when the food was visible. When a clearly detectable odor was present in the environment, all mice behaved in a similar way. Respiratory mechanics indices were similar in all mice except for the viscose resistance, which was reduced in fluticasone-treated mice. Olfactory mucosa of fluticasone-treated mice was thicker than that of controls. Slight but consistent differences in staining were present for Olfactory Marker Protein but not for other proteins. A mild impairment of olfactory function is present in mice chronically treated with fluticasone aerosol, apparently accompanied by slight modifications of the olfactory receptor cells, and suggests monitoring of olfactory function modifications in long-term steroid users.

Variations of respiratory mechanics in the rat during the day

We applied the end-inflation occlusion method to measure resistive and elastic properties of the rats respiratory system at two different hours of the day, 8.00 a.m. and 4.00 p.m. Contextually lung hysteresis surface areas were also measured. We found a significant reduction of resistive pressure necessary for the movement of air in the airways and for the movement of lung and chest wall tissue, hence of respiratory and lung resistances, in the afternoon with respect to morning hours (Rrs, min 0.037 vs 0.117 cm H2O/ml sec−1, p = 0.008, Rl, min 0.021 vs 0.068 cm H2O/ml sec−1, p = 0.001). The areas of hysteresis were significantly higher in the afternoon compared to the morning (3.71 vs 2.51 cm H2Oml, p = 0.039). No other significant differences in respiratory mechanical parameters were found. Thus we show in the rat that airways and lung and chest wall resistances exhibit variations during the day, confirming previously reported data describing a circadian rhythm of resistance in other animal species. Hysteretic behaviour of the lungs also changes during the day, suggesting diurnal variations of alveolar surfactant activity.

Daily variations in lung volume measurements in young healthy adults

Lung volume measurements were performed on 30 healthy young volunteers of both genders at three different times of the day (8 am, 4 pm, and 12 am). They included total lung capacity, functional residual capacity (FRC), vital capacity, residual volume (RV), inspiratory and expiratory reserve volumes, and inspiratory capacity, and were technically performed according to well-known, recently stated, international standards.We found statistical increments of the mean values of total lung capacity, FRC, and RV at 4 pm with respect to both 8 am and 12 am The possible mechanisms explaining these findings are addressed, including daily variations of respiratory system compliance, alveolar surfactant activity, and abdominal wall and diaphragmatic muscle tonic activity.

The ablation of S1P3 receptor protects mouse soleus from age-related drop of muscle mass, force and regenerative capacity

We investigated the effects of S1P3 deficiency on the age-related atrophy, decline in force, and regenerative capacity of soleus muscle from 23-mo-old male (old) mice. Compared with muscle from 5-mo-old (adult) mice, soleus mass and muscle fiber cross-sectional area (CSA) in old wild-type mice were reduced by ~26% and 24%, respectively. By contrast, the mass and fiber CSA of soleus muscle in old S1P3-null mice were comparable to those of adult muscle. Moreover, in soleus muscle of wild-type mice, twitch and tetanic tensions diminished from adulthood to old age. A slowing of contractile properties was also observed in soleus from old wild-type mice. In S1P3-null mice, neither force nor the contractile properties of soleus changed during aging. We also evaluated the regenerative capacity of soleus in old S1P3-null mice by stimulating muscle regeneration through myotoxic injury. After 10 days of regeneration, the mean fiber CSA of soleus in old wild-type mice was significantly smaller (-28%) compared with that of regenerated muscle in adult mice. On the contrary, the mean fiber CSA of regenerated soleus in old S1P3-null mice was similar to that of muscle in adult mice. We conclude that in the absence of S1P3, soleus muscle is protected from the decrease in muscle mass and force, and the attenuation of regenerative capacity, all of which are typical characteristics of aging.

Pressure-Flow Relationship in Swine Ureter: Effect of Nitric Oxide Synthase Inhibition by L-NAME

Introduction: The purpose of this report is to elucidate the possible role of nitric oxide (NO) in modulating smooth muscle tone of swine ureteral wall and its hydraulic resistance to urinary flow. Materials and Methods: We performed direct monitoring of perfusion pressure for different flows in isolated fresh swine ureter. Fluid used for perfusions was saline or L-NAME 200 μmol saline added, and relative pressure-flow relationships were obtained. Results: The general shape of pressure-flow relationships indicates a decrease of ureteral hydraulic resistance with increasing flow. NO synthase inhibition by L-NAME caused a statistically significant increase of perfusion pressures for every tested flow, hence of ureteral hydraulic resistance. Conclusions: Our data show an effective role of NO in modulating ureteral flow resistance, and suggest possible pharmacological implications. A simple mathematical approach to define hydraulic ureteral flow resistance for low and high urinary flows is also suggested.