Mice display learning and behavioral deficits after a 30-day spaceflight on Bion-M1 satellite.

Profound effects of spaceflight on the physiology of humans and non-human animals are well-documented but incompletely explored. Current goals to undertake interplanetary missions increase the urgency to learn more about adaptation to prolonged spaceflight and readaptation to Earth-normal conditions, especially with the inclusion of radiation exposures greater than those confronted in traditional, orbital flights. The 30-day-long Bion M-1 biosatellite flight was conducted at a relatively high orbit, exposing the mice to greater doses of radiation in addition to microgravity, a combination of factors relevant to Mars missions. Results of the present studies with mice provide insights into the consequences on brain function of long-duration spaceflight. After landing, mice showed profound deficits in vestibular responses during aerial drop tests. Spaceflown mice displayed reduced grip strength, rotarod performance, and voluntary wheel running, each, which improved gradually but incompletely over the 7-days of post-flight testing. Continuous monitoring in the animals' home cage activity, in combination with open-field and other tests of motor performance, revealed indices of altered affect, expressed as hyperactivity, potentiated thigmotaxis, and avoidance of open areas which, together, presented a syndrome of persistent anxiety-like behavior. A learned, operant response acquired before spaceflight was retained, whereas the acquisition of a new task was impaired after the flight. We integrate these observations with other results from Bion-M1's program, identifying deficits in musculoskeletal and cardiovascular systems, as well as in the brain and spinal cord, including altered gene expression patterns and the accompanying neurochemical changes that could underlie our behavioral findings.

Fluid shift versus body size: changes of hematological parameters and body fluid volume in hindlimb-unloaded mice, rats and rabbits.

The cardiovascular system is adapted to gravity, and reactions to the loss of gravity in space are presumably dependent on body size. The dependence of hematological parameters and body fluid volume on simulated microgravity have never been studied as an allometric function before. Thus, we estimated red blood cell (RBC), blood and extracellular fluid volume in hindlimb-unloaded (HLU) or control (attached) mice, rats and rabbits. RBC decrease was found to be size independent, and the allometric dependency for RBC loss in HLU and control animals shared a common power (-0.054±0.008) but a different Y0 coefficient (8.66±0.40 and 10.73±0.49, respectively, P<0.05). Blood volume in HLU animals was unchanged compared with that of controls, disregarding body size. The allometric dependency of interstitial fluid volume in HLU and control mice shared Y0 (1.02±0.09) but had different powers N (0.708±0.017 and 0.648±0.016, respectively, P<0.05), indicating that the interstitial fluid volume increase during hindlimb unloading is more pronounced in larger animals. Our data underscore the importance of size-independent mechanisms of cardiovascular adaptation to weightlessness. Despite the fact that the use of mice hampers application of a straightforward translational approach, this species is useful for gravitational biology as a tool to investigate size-independent mechanisms of mammalian adaptation to microgravity.

Reflex erection in the rat: reciprocal interplay between hemodynamic and somatic events.

BACKGROUND: Penile erection is a complex reflex under spinal control and modulated by the brain. The hemodynamic events under autonomic control and the perineal muscles somatic activity are interconnected during the reflex erection at the spinal level, however if the afferent feedback on the corpus cavernosum pressure during an erection affects the somatic activity (perineal muscles contractions) and vice versa is not known. This study was aimed to test this hypothesis using a rat model. METHODS: Intracavernous pressure (ICP) and bulbocavernosus (BC) muscle EMG were recorded during reflex erections elicited with dorsal penile nerve (DNP) electrical stimulation in anaesthetized acutely spinalized SD rats with surgically (bilateral cavernous nerve section, CnX, n = 8) and pharmacologically (trimetaphan infusion, TMPh, n = 8) abolished pressor response, or with surgically (bilateral section of the motor branch of the pudendal nerve, PnX, n = 7) and pharmacologically (1 mg/kg d-tubocurarine, n = 8) blocked perineal muscles contractions, or with interrupted afferent input from the penis (bilateral crush of the dorsal penile nerve, DPnX, n = 7). Control rats (n = 8) received no intervention. RESULTS: Moderate positive correlations were found between net parameters of pressor and somatic activity during DNP-stimulation induced reflex erection in spinal rats, particularly the speed of pressor response development was positively correlated to EMG parameters. No changes of EMG activity were found in CnX rats, while the decrease of BC EMG in TMPh-treated males can be attributed to direct inhibitory action of TMPh on neuromuscular transmission. Pressor response latency was increased and ICP front slope decreased in dTK and PnX rats, indicating that perineal muscles contraction augment pressor response. DPN crush had little effect on ICP and EMG. CONCLUSION: Afferent input on the level of intracavernous pressure and the perineal muscles activity has minimal impact on, correspondingly, the somatic and the autonomic components of the reflex erection in spinal males, once the reflex has been initiated.

Pharmacological analysis of Poecilotheria spider venoms in mice provides clues for human treatment.

Bites of tiger spiders belonging to Poecilotheria genus cause moderate to severe pain and long-lasting local or generalized muscle cramps in humans. Bites occur in regions of the spiders' natural habitat, India and Sri Lanka, but the popularity of these colorful tarantulas as pets leads to reports of envenomation cases worldwide. Treatment is predominantly symptomatic and often inadequate since there is almost no clinical or toxicology research data available, and physicians outside India or Sri Lanka typically have no experience in treating such cases. We report toxicity studies of venom from nine Poecilotheria species in laboratory mice (Mus musculus Balb/C males). LD50 values are 5-14 mg of lyophilized crude venom per 1 kg (i.v.). The major symptoms of envenomation include tonic-clonic seizures, jerks, characteristic motor stereotypy, and hyperalgesia and point to voltage-gated sodium channels as a potential target of the venom components. Poecilotheria fasciata venom effects were studied in detail at a sub-lethal dose of 5 mg/kg (LD50 = 12 mg/kg). 13 widely used pharmacological agents (atropine, chloropyramine, chlorpromazine, diazepam, ethanol, flupirtine, haloperidol, ketotifen, lamotrigine, oxcarbazepine, tolperisone, xylazine, and CaCl2) were checked for ability to suppress the envenomation symptoms. Chlorpromazine (10 mg/kg, i.p.), oxcarbazepine (60 mg/kg, p.o.), tolperisone (50 mg/kg, s.c.) and xylazine (2.5 mg/kg, i.p.) were found effective as a pretreatment to mitigate muscle cramps and motor stereotypy. When administered after envenomation chlorpromazine (5 mg/kg, i.v.) effectively reduced the cramps, while oxcarbazepine (30 mg/kg, i.v.) and xylazine (1 mg/kg, i.v.) suppressed the stereotypy.

Adaptation to a blood pressure telemetry system revealed by measures of activity, agility and operant learning in mice.

INTRODUCTION: Implantable telemetry enables continuous monitoring of physiological functions in freely moving animals and can greatly complement pharmacological research. Despite its miniaturization, a sensor/transmitter constitutes 5% or more of a mouse's bodyweight. The aim of the present study was to evaluate whether factors related to the presence of a probe/transmitter influence the ambulatory activity, strength, agility, or operant, motivated behaviors of this small rodent. METHODS: Adult male mice (C57BL/6N, 22-25g, 9-10weeks; implanted n=26, intact n=45) were evaluated during week-long tests, conducted three and eight weeks after surgical implantation of the PA-C10 blood pressure probe. An open field test, grip force measurement, Rotarod test were performed, followed by 7-day continuous monitoring of spontaneous wheel running activity and positively reinforced operant conditioning in an automated data collection system. RESULTS: An implanted blood pressure transmitter did not affect behavior of mice in the open field test, on the Rotarod or their grip force, compared to unoperated controls. Voluntary wheel running distance was reduced three, but not eight weeks after implantation. Three weeks after the surgery, performance in the positively reinforced operant conditioning in operated mice was slightly decreased compared to intact animals, while retention and acquisition of a 2nd, reversal-learning task eight weeks after the surgery were unaffected. DISCUSSION: We conclude that an implantable transmitter may have detectable effects in the first few weeks following implantation on some elements of mouse behavior. With sufficient recovery, mice perform comparably to unoperated controls in tests of strength, endurance, agility and learned operant behavior.

BP101 Peptide Promotes Female Sexual Receptivity in the Rat.

INTRODUCTION: Low sexual desire is a frequent sexual problem in women, with only one drug for the condition approved by the Food and Drug Administration. AIM: To evaluate the ability of a novel synthetic peptide, BP101, to facilitate sexual behavior after intranasal administration or infusion into certain brain areas in female rats. METHODS: Bilaterally ovariectomized female rats, primed with a suboptimal combination of estradiol benzoate (EB) and progesterone, were used as a model of low sexual motivation. Sexual behavior was tested with stud male rats after acute (experiment 1) or long-term (experiment 2) intranasal administration of BP101 or peptide infusion into the olfactory bulb, medial preoptic area, ventromedial hypothalamic nucleus, or ventral tegmental area (experiment 3). MAIN OUTCOME MEASURES: Frequency of solicitations (SF), as an indicator of sexual motivation in female rats, and lordosis frequency and ratio, as measurements of female consummatory sexual behavior. RESULTS: Acute intranasal BP101 administration moderately increased SF, with the highest tested dose of 300 µg/kg causing an 80% increase. Female rats receiving BP101 75 or 300 µg/kg daily on days 6 to 16 of the peptide administration displayed twofold higher SF compared with the placebo-treated animals, an increase comparable to optimally hormone-primed female rats. Infusion of BP101 1 and 5 µg per rat into the medial preoptic area, but not into the olfactory bulb, ventromedial hypothalamic nucleus, or ventral tegmental area, increased SF in female rats supplemented with EB 10 or 20 µg. The effect was relatively more pronounced in female rats receiving EB 10 µg (≈300%) compared with EB 20 µg (≈50%) with direct brain infusions. CONCLUSION: BP101 displays a potent stimulatory effect on sexual motivation in the female rat, and the medial preoptic area seems to be the site of its action. BP101 is effective in female rats receiving different hormone supplementations, making the present data generalizable to pre- and postmenopausal women with hypoactive sexual desire. Andreev-Andrievskiy A, Lomonosov M, Popova A, et al. BP101 Peptide Promotes Female Sexual Receptivity in the Rat. J Sex Med 2017;14:336-346.