Temporal trends in equine sperm progressive motility: a systematic review and meta-regression.

In brief: Adverse trends in reproductive function are a concern in humans, companion, livestock, and wildlife species. This study indicates that equine populations are at risk of a comparable decline in sperm progressive motility. Abstract: There is increasing evidence reporting geographically sensitive adverse trends in human semen quality, with parallel trends observed in the dog sentinel. Despite significant economic and welfare complications associated with poor testicular function, trends in current equine populations are undetermined. Given the predictive value of sperm progressive motility (PMOT) in male factor infertility and fertilisation potential, research determining trends in this parameter is warranted. This research analysed trends in stallion sperm PMOT through systematic review and meta-regression. Using a comprehensive search strategy, Scopus, Embase (Ovid), Medline (Ovid), and VetMed (CAB direct) were scoped for eligible data. Using best practices, 230 meta-data points from 229 articles published from 1991 to 2021 were collated for meta-regression analysis. Sperm PMOT declined significantly between 1984 and 2019 (simple linear regression: b -0.340, P = 0.017; meta-regression: b -0.610, P ≤ 0.001). Overall and yearly PMOT declines were predicted at 33.51 and 0.96%, respectively (1984: 63.69 ± 5.07%; 2019: 42.35 ± 3.69%). Trends remained consistent irrespective of sensitivity analyses. Yearly and overall declines were stronger in western (yearly: 0.75%, overall: 26.29%) compared to non-western (yearly: 0.46%, overall: 10.65%) populations. Adverse trends contribute vital data to the debate surrounding declining semen quality, supporting the use of equines as novel comparative models for human reproduction. Results could have significant economic, health, and welfare consequences for equine breeding sectors. A comparable decline in human, dog, and horse sperm quality is indicative of a common environmental aetiology, indicating the need for a holistic One Health approach in determining causes and developing preventative strategies.

Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: results from a randomized study in patients with migraine.

OBJECTIVE: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. METHODS: A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. RESULTS: The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. CONCLUSION: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.

Mecp2 truncation in male mice promotes affiliative social behavior.

Mouse models of Rett syndrome, with targeted mutations in the Mecp2 gene, show a high degree of phenotypic consistency with the clinical syndrome. In addition to severe and age-specific regression in motor and cognitive abilities, a variety of studies have demonstrated that Mecp2 mutant mice display impaired social behavior. Conversely, other studies indicate complex enhancements of social behavior in Mecp2 mutant mice. Since social behavior is a complicated accumulation of constructs, we performed a series of classic and refined social behavior tasks and revealed a relatively consistent pattern of enhanced pro-social behavior in hypomorphic Mecp2 (308/Y) mutant mice. Analyses of repetitive motor acts, and cognitive stereotypy did not reveal any profound differences due to genotype. Taken together, these results suggest that the mutations associated with Rett syndrome are not necessarily associated with autism-relevant social impairment in mice. However, this gene may be a valuable candidate for revealing basic mechanisms of affiliative behavior.

Thermal contrast in the atmosphere of venus: initial appraisal from pioneer venus probe data.

The altitude profiles of temperature and pressure measured during the descent of the four Pioneer Venus probes show small contrast below the clouds but significant differences within the clouds at altitudes from 45 to 61 kilometers. At 60 kilometers, the probe which entered at 59.3 degrees north latitude sensed temperatures 25 K below those of the lower latitude probes, and a sizable difference persisted down to and slightly below the cloud base. It also sensed pressure below those of the other probes by as much as 49 millibars at a mean pressure of 200 millibars. The measured pressure differences are consistent with cyclostrophic balance of zonal winds ranging from 130 +/- 20 meters per second at 60 kilometers to 60 +/- 17 meters per second at 40 kilometers, with evidence in addition of a nonaxisymmetric component of the winds. The clouds were found to be 10 to 20 K warmer than the extended profiles of the lower atmosphere, and the middle cloud is convectively unstable. Both phenomena are attributed to the absorption of thermal radiation from below. Above the clouds, in the lower stratosphere, the lapse rate decreases abruptly to 3.5 K per kilometer, and a superimposed wave is evident. At 100 kilometers, the temperature is minimum, with a mean value of about 170 K.

Structure of the Atmosphere of Venus up to 110 Kilometers: Preliminary Results from the Four Pioneer Venus Entry Probes.

The four Pioneer Venus entry probes transmitted data of good quality on the structure of the atmosphere below the clouds. Contrast of the structure below an altitude of 50 kilometers at four widely separated locations was found to be no more than a few degrees Kelvin, with slightly warmer temperatures at 30 degrees south latitude than at 5 degrees or 60 degrees north. The atmosphere was stably stratified above 15 or 20 kilometers, indicating that the near-adiabatic state is maintained by the general circulation. The profiles move from near-adiabatic toward radiative equilibrium at altitudes above 40 kilometers. There appears to be a region of vertical convection above the dense cloud deck, which lies at 47.5 to 49 kilometers and at temperature levels near 360 K. The atmosphere is nearly isothermal around 100 kilometers (175 to 180 K) and appears to exhibit a sizable temperature wave between 60 and 70 kilometers. This is where the 4-day wind is believed to occur. The temperature wave may be related to some of the wavelike phenomena seen in Mariner 10 ultraviolet photographs.

Optimising the biocompatibility of 3D printed photopolymer constructs in vitro and in vivo.

3D printing is a rapid and accessible fabrication technology that engenders creative custom design solutions for cell scaffolds, perfusion systems and cell culture systems for tissue engineering. Critical to its success is the biocompatibility of the materials used, which should allow long-term tissue culture without affecting cell viability or inducing an inflammatory response for in vitro and in vivo applications. Polyjet 3D printers offer arguably the highest resolution with the fewest design constraints of any commercially available 3D printing systems. Although widely used for rapid-prototyping of medical devices and 3D anatomical modelling, polyjet printing has not been adopted by the tissue engineering field, largely due to the cytotoxicity of leachates from the printed parts. Biocompatibility in the context of cell culture is not commonly addressed for polyjet materials, as they tend to be optimised for their ability to fabricate complex structures. In order to study the potential issues surrounding the leaching of toxins, we prepared cell culture substrates using the commercially available MED610 photopolymer. The substrates were cleaned using either the manufacturer-specified 'biocompatible' washing procedures, or a novel protocol incorporating a sonication in isopropanol and water step. We then compared the effectiveness of these both in vitro and in vivo. Using primary mouse myoblast cultures, the manufacturer's protocol led to inconsistent and poorer cell viability when compared to the sonication protocol (p = 0.0002 at 48 h after indirect exposure). Subdermal implantation of MED610 into nude rats demonstrated a significant foreign body response with a greater number of giant cells (p = 0.0161) and foreign bodies (p = 0.0368) when compared to the sonication protocol, which was comparable to the control (sham) groups. These results present an improved, cytocompatible cleaning protocol of printable photopolymers to facilitate creative 3D-printed custom designs for cell culture systems for both in vitro and in vivo tissue engineering applications.

The Application of Pulsed Electromagnetic Fields (PEMFs) for Bone Fracture Repair: Past and Perspective Findings.

Bone fractures are one of the most commonly occurring injuries of the musculoskeletal system. A highly complex physiological process, fracture healing has been studied extensively. Data from in vivo, in vitro and clinical studies, have shown pulsed electromagnetic fields (PEMFs) to be highly influential in the fracture repair process. Whilst the underlying mechanisms acting to either inhibit or advance the physiological processes are yet to be defined conclusively, several non-invasive point of use devices have been developed for the clinical treatment of fractures. With the complexity of the repair process, involving many components acting at different time steps, it has been a challenge to determine which PEMF exposure parameters (i.e., frequency of field, intensity of field and dose) will produce the most optimal repair. In addition, the development of an evidence-backed device comes with challenges of its own, with many elements (including process of exposure, construct materials and tissue densities) being highly influential to the field exposed. The objective of this review is to provide a broad recount of the applications of PEMFs in bone fracture repair and to then demonstrate what is further required for enhanced therapeutic outcomes.

Genetic definition of ras effector elements.

The products of ras genes may function as GTP-binding signal transducers, but the nature of their targets is largely unknown. To define genetically the cellular effector(s) of ras in rat fibroblast transformation, somatic variants that suppress the nontransforming phenotype of v-H-ras effector domain mutations were sought. Variant cell lines perturbed in the ras effector pathway were recovered, and the properties of one suggest that the primary target of ras action may be altered. In this cell variant, no single residue in the ras protein effector domain must be wild type to bring about transformation. In parental rat cells, conservative substitutions are tolerated in six of nine residues. Functional interaction with the target may not require a high degree of structural specificity in the ras protein effector domain.

A ras effector domain mutant which is temperature sensitive for cellular transformation: interactions with GTPase-activating protein and NF-1.

A series of v-rasH effector domain mutants were analyzed for their ability to transform rat 2 cells at either low or high temperatures. Three mutants were found to be significantly temperature sensitive: Ile-36 changed to Leu, Ser-39 changed to Cys (S39C), and Arg-41 changed to Leu. Of these, the codon 39 mutant (S39C) showed the greatest degree of temperature sensitivity. When the same mutation was analyzed in the proto-oncogene form of ras(c-rasH), this gene was also found to be temperature sensitive for transformation. Biochemical analysis of the proteins encoded by v-rasH(S39C) and c-rasH(S39C) demonstrated that the encoded p21ras proteins were stable and bound guanine nucleotides in vivo at permissive and nonpermissive temperatures. On the basis of these findings, it is likely that the temperature-sensitive phenotype results from an inability of the mutant (S39C) p21ras to interact properly with the ras target effector molecule(s) at the nonpermissive temperature. We therefore analyzed the interaction between the c-rasH(S39C) protein and the potential target molecules GTPase-activating protein (GAP) and the GAP-related domain of NF-1, on the basis of stimulation of the mutant p21ras GTPase activity by these molecules in vitro. Assays conducted across a range of temperatures revealed no temperature sensitivity for stimulation of the mutant protein, compared with that of authentic c-rasH protein. We conclude that for this mutant, there is a dissociation between the stimulation of p21ras GTPase activity by GAP and the GAP-related domain NF-1 and their potential target function. Our results are also consistent with the existence of a distinct, as-yet-unidentified effector for mammalian ras proteins.

Estimation of anisotropic permeability in trabecular bone based on microCT imaging and pore-scale fluid dynamics simulations.

In this paper, a comprehensive framework is proposed to estimate the anisotropic permeability matrix in trabecular bone specimens based on micro-computed tomography (microCT) imaging combined with pore-scale fluid dynamics simulations. Two essential steps in the proposed methodology are the selection of (i) a representative volume element (RVE) for calculation of trabecular bone permeability and (ii) a converged mesh for accurate calculation of pore fluid flow properties. Accurate estimates of trabecular bone porosities are obtained using a microCT image resolution of approximately 10 µm. We show that a trabecular bone RVE in the order of 2 × 2 × 2 mm3 is most suitable. Mesh convergence studies show that accurate fluid flow properties are obtained for a mesh size above 125,000 elements. Volume averaging of the pore-scale fluid flow properties allows calculation of the apparent permeability matrix of trabecular bone specimens. For the four specimens chosen, our numerical results show that the so obtained permeability coefficients are in excellent agreement with previously reported experimental data for both human and bovine trabecular bone samples. We also identified that bone samples taken from long bones generally exhibit a larger permeability in the longitudinal direction. The fact that all coefficients of the permeability matrix were different from zero indicates that bone samples are generally not harvested in the principal flow directions. The full permeability matrix was diagonalized by calculating the eigenvalues, while the eigenvectors showed how strongly the bone sample's orientations deviated from the principal flow directions. Porosity values of the four bone specimens range from 0.83 to 0.86, with a low standard deviation of ± 0.016, principal permeability values range from 0.22 to 1.45 ⋅ 10 -8 m2, with a high standard deviation of ± 0.33. Also, the anisotropic ratio ranged from 0.27 to 0.83, with high standard deviation. These results indicate that while the four specimens are quite similar in terms of average porosity, large variability exists with respect to permeability and specimen anisotropy. The utilized computational approach compares well with semi-analytical models based on homogenization theory. This methodology can be applied in bone tissue engineering applications for generating accurate pore morphologies of bone replacement materials and to consistently select similar bone specimens in bone bioreactor studies.

Physical environment modulates the behavioral responses induced by chemical stimulation of dorsal periaqueductal gray in mice.

In order to investigate the relationship between behaviors elicited by chemical stimulation of the dorsal periaqueductal gray (dorsal PAG) and spontaneous defensive behaviors to a predator, the excitatory amino acid D,L-homocysteic acid (5 nmol in 0.1 micro l), was infused into the dorsal PAG and behavioral responses of mice were evaluated in two different situations, a rectangular novel chamber or the Mouse Defense Test Battery (MDTB) apparatus. During a 1-min period following drug infusion, more jumps were made in the chamber than in the MDTB runway but running time and distance traveled were significantly higher in the runway. Animals were subsequently tested using the standard MDTB procedure (anti-predator avoidance, chase and defensive threat/attack). No drug effects on these measures were significant. In a further test in the MDTB apparatus, the pathway of the mouse during peak locomotion response was blocked 3 times by the predator stimulus (anesthetized rat) to determine if the mouse would avoid contact. Ninety percent of D,L-homocysteic treated animals made direct contact with the stimulus (rat), indicating that D,L-homocysteic-induced running is not guided by relevant (here, threat) stimuli. These results indicate that running as opposed to jumping is the primary response in mice injected with D,L-homocysteic into the dorsal PAG when the environment enables flight. However, the lack of responsivity to the predator during peak locomotion suggests that D,L-homocysteic-stimulation into the dorsal PAG does not induce normal antipredator flight.

[Association of polymorphisms in SULT1A1 and UGT1A1 Genes with breast cancer risk and phenotypes in Russian women].

Estrogens are critical for breast cancer initiation and development. Sulfotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 1A1 (UGT1A1) conjugate and inactivate both estrogens and their metabolites, thus preventing estrogen-mediated mitosis and mutagenesis. SULT1A1 and UGT1A1 genes are both polymorphic, and different alleles encode functionally different allozymes. We hypothesize that low activity alleles SULT1A1*2 and UGT1A1*28 are associated with the higher risk for breast cancer and more severe breast tumor phenotypes. We performed a case-control study, which included 119 women of Russian ancestry with breast cancer and 121 age-matched Russian female controls. We used PCR, followed by pyrosequencing to determine SULT1A1 and UGT1A1 genotypes. Our data showed that UGT1A1*28 allele was presented at a higher frequency than the wild type UGT1A1*1 allele in breast cancer patients as compared to controls (p = 0.002, OR = 1.79, CI 1.23-2.63). Consistently, the frequency of genotypes that contain the UGT1A1*28 allele in the homozygous or heterozygous state was greater than the frequency of the wild type UGT1A1*1/*1 genotype in breast cancer patients as compared to controls (p = 0.003, OR = 4.00, CI 1.49-11.11 and p = 0.014, OR = 2.04, CI 1.14-3.57, respectively). The group of individuals, carrying the UGT1A1*28 allele in the homo- or heterozygous state also presented larger breast tumors (>2 cm) as compared to the group with high enzymatic activity genotypes p = 0.011, OR = 3.44, CI 1.42-8.36). No association was observed between any of the SULT1A1 genotypes and breast cancer risk or phenotypes. Our data suggest that UGT1A1 but not SULT1A1 genotype might be important for breast cancer risk and phenotype in Russian women.

Structural characterization of the isoenzymatic forms of human myeloperoxidase.

Myeloperoxidase from human neutrophils was isolated by ion-exchange and gel-filtration chromatography and shown by SDS-polyacrylamide gel electrophoresis to be comprised of alpha and beta subunits with apparent Mr values of 58,000 and 15,000, respectively. The apparent Mr of the native protein was 130,000-140,000, indicating that the holoenzyme has the quaternary structure alpha 2 beta 2. Automated Edman degradation of the separated alpha and beta subunits showed that the amino-terminal sequences were different from one another and demonstrated no sequence microheterogeneity. Comparison of these sequences with those in the National Biomedical Research Foundation data bank of protein sequences revealed that the subunits of human myeloperoxidase were not homologous to any known protein. Myeloperoxidase purified from HL-60 cells grown in culture demonstrated the same alpha 2 beta 2 subunit structure. Three isoenzymes of myeloperoxidase, prepared by gradient elution from a CM-Sepharose column, underwent quantitative analysis. No structural basis for the different elution pattern of the myeloperoxidase isoenzymes was discerned by amino-acid analysis, N-terminal sequence, polyacrylamide gel electrophoresis, or digestion with neuraminidase or enzymes known to cleave N-linked heterosaccharides. The structural basis for the myeloperoxidase isoenzymes of human neutrophils, each possessing equivalent activity, is not apparent from these studies.

An alternative experimental procedure for studying predator-related defensive responses.

In the present study, we introduce an experimental procedure to study, in rats, a wide range of natural defensive reactions. Animals were tested in an experimental apparatus that consisted of a home cage (25 x 25 x 25 cm) connected to another chamber (25 x 25 x 25 cm-the food compartment) by a hallway (12.5 cm wide and 100 cm long, with 25-cm high walls). During 10 days before the testing procedures, each animal was isolated in the home cage, and, at the beginning of the dark phase, allowed to explore the rest of the apparatus and obtain food pellets stored in the food compartment. The testing consisted of three phases: exploring a familiar and safe environment (phase 1, on the 10th day), cat exposure (phase 2, on the 11th day), and, on the following day, exposure to the environment where the predator had been previously encountered (phase 3). These three conditions thus provided a low-defense baseline; a high level of freezing during cat exposure; and a high level of risk assessment to the hostile environment condition. An important feature of the present experimental procedure was that the behavioral responses were very stable among the animals tested within each individual phase of the testing schedule. In each phase of the testing schedule, we have also examined the Fos immunoreactivity in pontine periventricular sites related to controlling behavioral activation (i.e. the nucleus incertus) or attentional status (i.e. the locus coeruleus). Animals actively exploring a safe and familiar environment presented an increased activation of the nucleus incertus; the locus coeruleus, in turn, was particularly activated during cat exposure, and also, to lesser degree, during exposure to the hostile environment. These results give further support to the view that the animals present quite distinct behavioral states during each one of the testing situations. Taken together, the evidence suggests the present experimental procedure as particularly suitable for analyzing the neural basis of a number of specific defensive responses.

Abnormal suppressor cell function in atopic dermatitis.

A status of suppressor cells in patients with atopic dermatitis was studied. As a group, they showed absent concanavalin A-inducible suppressor cell function as measured by proliferative responses to pokeweed mitogen and decreased function as measured by responses to phytohemagglutinin or concanavalin A. Similarly, preincubation in medium enhanced proliferative responses in normal donors but not in atopic dermatitis patients, suggesting an absence of a short-lived suppressor cell population in the latter group. Suppressor cell function correlated negatively with log10 of serum IgE concentrations. Theophylline-sensitive suppressor cell numbers were significantly decreased in atopic dermatitis patients (p less than 0.01). In vitro preincubation of normal lymphocytes with aminophylline or isoproterenol (10 microgram/ml) enhanced subsequent proliferative responses to pokeweed mitogen. In contrast, actual depression was seen with cells from atopic dermatitis patients, suggesting abnormal immunomodulatory effects of these drugs in the disease.

Behavioral correlates of chronic dominance-subordination relationships of male rats in a seminatural situation.

Detailed characterization and analysis of intraspecific aggressive and defensive behaviors of rats in mixed sex groups is beginning to provide an understanding of the complex pattern of behavioral and physiological change associated with variation in dominance status. These findings indicate that male subordination dramatically reduces longevity and produces a pattern of behavior changes very similar to the defenses elicited by predatory exposure. In addition, many of these changes are, in detail, isomorphic to important behavioral features of clinical depression.

Cocaine potentiates defensive behaviors related to fear and anxiety.

Cocaine use has been associated with a number of psychiatric disturbances, and an emerging literature attests to its ability to enhance anxiety-like behaviors in animal models. Ethoexperimental analyses of defensive behaviors, and tests designed specifically to provide individual measures of these behaviors, have been shown to respond very selectively and appropriately to anxiolytic and panicogenic or panicolytic drugs, suggesting that these tests, and this approach, might provide a more detailed and comprehensive description of the emotionality effects of cocaine than is currently available. In a Mouse Defense Test Battery (MDTB) using mouse subjects and an anesthetized rat as the threat stimulus, cocaine consistently enhanced flight and escape, with effects seen at 10-30 mg/kg (i.p.) dose levels. The effect was so potent that a lack of cocaine effect on other behaviors may have been due to response competition, or to early distancing of cocaine-dosed subjects from the threat stimulus. In a Rat Runway Test (RRT) similar to the MDTB but with rat subjects, 4 mg/kg cocaine, i.v. produced an explosive, but well directed, flight response. Flight was still elevated, although of lesser magnitude than originally, 30 min. after the i.v. cocaine, and defensive threat/attack to the oncoming threat stimulus were also reliably increased. Cocaine enhancement of defense was also seen in tests of sniffing "stereotypy" in rats. Sniffing after 30 mg/kg cocaine, i.p. was found to be appropriately oriented toward the direction of incoming air flow, suggesting that it may be part of a defensive risk assessment pattern. In undosed rats, risk assessment is suppressed by the presence of high-magnitude threat stimuli such as a cat, and the same, durable, phenomenon was obtained after 30 mg/kg (i.p.) cocaine. Toy cat exposure initially suppressed sniffing in cocaine-dosed rats, but this suppression was removed and sniffing increased, over repeated dose/toy cat exposures. Crouching in the same animals over these testing regimes supported a "sniffing-suppression" interpretation of these changes and also provided data suggesting that cocaine may enhance crouching. These data, indicating that cocaine enhances a number of defensive behaviors--some more strikingly than others--have implications for the involvement of cocaine in defense-linked psychopathologies; and for the involvement of defense in both conditioning and "sensitization" phenomena associated with cocaine. These effects raise the issue of the relationship between the defense-enhancing and the reinforcing consequences of cocaine.

Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic.

The natural defensive behaviors of laboratory mice have been evaluated in both seminatural and highly structured situations; and characterized in terms of eliciting stimuli, response to pharmacological agents, behavior patterns, and outcome or effect on the social and physical environment. The defense patterns of laboratory mice and rats are generally similar, but mice show risk assessment on initial exposure to highly threatening stimuli while rats do not, while rats display alarm vocalizations, missing in mice. Quantitative differences in freezing and flight for laboratory mice and rats appear to largely reflect domestication effects, with wild mice and rats more similar to each other. This nexus of detailed within-species and comparative data on defense patterns makes it possible to reliably elicit specific defenses in mice or rats in an experimental context, providing well-validated assays of the natural defensive behaviors themselves, as opposed to 'models' of defense. The mouse--rat comparisons indicate considerable cross-species generality for these defense patterns, as does a scattered but considerable literature on other mammalian species, generally involving field studies and typically focusing on those aspects of defensive behavior that are visible at a distance, such as vigilance, or flight. Although potential homologies between normal mouse and human defense systems should ideally involve all four pattern components (stimulus, organismic factors, response characteristics, outcome), predictive validity in terms of response to drugs active against specific defensive psychopathology is the most extensively investigated of these. Flight, as measured in the Mouse Defense Test Battery shows a consistently appropriate response to panicolytic, panicogenic, and panic-neutral drugs, while some other predictive 'panic models' (dPAG-stimulation; DMH-inhibition; possibly conditioned suppression of drinking paradigms) also elicit and (indirectly) measure behaviors potentially related to flight. Models unrelated to flight (e.g. ultrasonic vocalization to conditioned stimuli); or for which flight elements may a relatively minor contributor to the behavior measured (Elevated T-maze) are less predictive of panicolytic or panicogenic action. These findings indicate that natural defensive behaviors provide a well-characterized pattern for analysis of effects of genetic or other physiological manipulations in the mouse, and may also serve as a model for analysis of defense-related human psychopathology.

The characterization and modelling of antipredator defensive behavior.

The mammalian behavioral antipredator defense systems have been characterized in terms of reactions to present, localizable, threat stimuli: Analysis of the relationship between features of the predator and the environment, and specific defensive behaviors indicates that the latter can be predicted with a high degree of accuracy. A different set of defensive behaviors are seen when rats living in burrow systems are confronted by a predator outside the burrow. Flight to the burrow and immobility inside the burrow are followed by active investigation of the surface where the cat was seen (risk assessment), with all of these accompanied by inhibition of nondefensive behaviors such as eating, drinking, sexual behavior and aggression. Two additional behaviors are described in this context, ultrasonic cries made at a high initial rate (50% time) by animals inside the burrow systems, and declining over 1-2 hours following predator exposure, and, a specific modification of eating patterns when the subjects return to the surface and begin to eat. Eating bouts are shortened, with fewer episodes of continuous eating, interspersed with intervals of scanning of the environment, a vigilance activity previously reported in field research. This analysis of a broad spectrum of defensive behaviors is being used to develop test batteries providing simplified models of these phenomena.

Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries.

The use of ethoexperimental techniques to elicit and maximize the full range of defensive behaviors of rats and mice enables a very precise analysis of the effects of drugs on these behavior patterns. Two rat defense test batteries (the fear/defense test battery or F/DTB and the anxiety/defense test battery or A/DTB) have provided evidence that anxiolytic drugs, even from different classes, produce a common pattern of changes in specific behaviors. A recently developed mouse defense test battery (MDTB) has enabled description of mouse defensive behaviors to a predator, for comparison to those of rats, and a series of studies of drug effects on the behaviors measured in the MDTB provides evidence of cross-species generality of anxiolytic drug effects, or lack of effect, on specific defensive behaviors. In addition, tests with panicogenic and panicolytic drugs in the MDTB indicate that these enhance and reduce, respectively, flight reactions, which generally are not altered by anxiolytic compounds. Thus, results from the MDTB, taken in conjunction with those of the two rat test batteries and other defense analyses in rats and mice, provide evidence that many defensive behaviors are similar across rodent species, while the differences obtained provide a consistent pattern across situations. Moreover, the defense test batteries may be used to differentiate the effects of drugs effective against generalized anxiety as opposed to panic, through effects on specific defensive behaviors.