Health benefits of a physical exercise program for inpatients with mental health; a pilot study.

The positive effect of exercise on human health and the relationship between physical activity, health, and wellbeing are well studied and extensively documented in the literature. However, considerably less attention is devoted to the impact of exercise on mental health and wellbeing for people experiencing a mental illness, in general, and in particular for inpatients in the mental health care system. Here, we determine the clinical feasibility and effects of short-term (up to three months) vs long-term (up to six months) group-based exercise program for inpatients with chronic mental health. Changes in psychiatric symptoms, well-being, empathy, and physiological fitness factor (e.g., fasting blood glucose, lipid profile, hemoglobin A1C, and BMI) were monitored before, during and following the physical exercise program. Here, we demonstrated that long-term physical activity improved negative symptoms, but not positive symptoms, while improvement in the severity of the illness as measured by the BPRS questionnaire was found to be independent of the training time. We additionally showed that the empathic ability of patients who exercised for more than three months was significantly improved as compared to the other experimental groups. No significant differences were found in wellbeing, mood, satisfaction, and functioning between exercise groups and the control group. Furthermore, physical activity did not improve any of the physiological parameters that were measured in this study. Together, these data indicate that exercise for at least 3 months seems to improve the overall patient mental state, but not his or her physiological parameters, while improvement in negative symptoms and patient's empathy may occur only after a long-term physical exercise activity.

The influence of immune activation at early vs late gestation on fetal NRG1-ErbB4 expression and behavior in juvenile and adult mice offspring.

Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g. schizophrenia and autism) in the offspring. In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alteration of the exposed MIA mice at juvenile and adulthood. We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material in fetal brain. At the behavioral levels, adult late-MIA-exposed female offspring, but not juvenile, display lack preference to a novel object. While working memory alteration observed only in adult male MIA-exposed offspring at late gestation day. In addition, we found that adult females MIA-exposed mice spent more time in the center of the open field than female-saline groups. On the other hand, juvenile male offspring exposed to MIA at early, but not late, gestation day displayed a significant alteration in social interaction. Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes, and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.

Estimating wall guidance and attraction in mouse free locomotor behavior.

In this study, we estimate the influence exerted by the wall of the Open Field on the trajectory of the mouse. The wall exerts two types of influence on the mouse's path: one of guidance and one of attraction. The guiding influence is expressed by the tendency of mice to progress in parallel to the wall. This tendency wanes with increasing distance from the wall but is observed at large distances from it. The more parallel the mouse is to the wall the higher is its speed, even when distant from the wall. This association between heading direction and speed shows that the mouse controls its heading in reference to the wall. It is also observed in some blind strains, revealing that wall-guidance is not based exclusively on vision. The attraction influence is reflected by movement along the wall and by the asymmetry between speed during movement toward, and during movement away from the wall: sighted mice move faster toward the wall, whereas blind mice use similar speeds in both directions. Measures characterizing these influences are presented for five inbred strains, revealing heritable components that are replicable across laboratories. The revealed structure can lead to the identification of distinct groups of genes that mediate the distinct influences of guidance and attraction exerted by the wall. It can also serve as a framework for the decoding of electrophysiological data recorded in free moving rodents in the Open Field.

Wild mouse open field behavior is embedded within the multidimensional data space spanned by laboratory inbred strains.

The vast majority of studies on mouse behavior are performed on laboratory mouse strains (Mus laboratorius), while studies of wild-mouse behavior are relatively rare. An interesting question is the relationship between the phenotypes of M. laboratorius and the phenotypes of their wild ancestors. It is commonly believed, often in the absence of hard evidence, that the behavior of wild mice exceeds by far, in terms of repertoire richness, magnitude of variables and variability of behavioral measures, the behavior of the classical inbred strains. Having phenotyped the open field behavior (OF) of eight of the commonly used laboratory inbred strains, two wild-derived strains and a group of first-generation-in-captivity local wild mice (Mus musculus domesticus), we show that contrary to common belief, wild-mouse OF behavior is moderate, both in terms of end-point values and in terms of their variability, being embedded within the multidimensional data space spanned by laboratory inbred strains. The implication could be that whereas natural selection favors moderate locomotor behavior in wild mice, the inbreeding process tends to generate in mice, in some of the features, extreme and more variable behavior.

Rats and mice share common ethologically relevant parameters of exploratory behavior.

Detailed studies of rat exploratory behavior reveal that it consists of typical behavior patterns having a distinct structure. Recently we have developed interactive software that uses as input the automatically digitized time-series of the animal's location for the visualization, analysis, capturing and quantification of these patterns. We use this software here for the study of BALB/cJtau mouse behavior. The results suggest that a considerable number of rat patterns are also present in the mouse. These ethologically-relevant patterns have a significant potential as a phenotyping tool.

Controlling the false discovery rate in behavior genetics research.

The screening of many endpoints when comparing groups from different strains, searching for some statistically significant difference, raises the multiple comparisons problem in its most severe form. Using the 0.05 level to decide which of the many endpoints' differences are statistically significant, the probability of finding a difference to be significant even though it is not real increases far beyond 0.05. The traditional approach to this problem has been to control the probability of making even one such error--the Bonferroni procedure being the most familiar procedure achieving such control. However, the incurred loss of power stemming from such control led many practitioners to neglect multiplicity control altogether. The False Discovery Rate (FDR), suggested by Benjamini and Hochberg [J Royal Stat Soc Ser B 57 (1995) 289], is a new, different, and compromising point of view regarding the error in multiple comparisons. The FDR is the expected proportion of false discoveries among the discoveries, and controlling the FDR goes a long way towards controlling the increased error from multiplicity while losing less in the ability to discover real differences. In this paper we demonstrate the problem in two studies: the study of exploratory behavior [Behav Brain Res (2001)], and the study of the interaction of strain differences with laboratory environment [Science 284 (1999) 1670]. We explain the FDR criterion, and present two simple procedures that control the FDR. We demonstrate their increased power when used in the above two studies.

SEE: a tool for the visualization and analysis of rodent exploratory behavior.

The complexity of exploratory behavior creates a need for a visualization and analysis tool that will highlight regularities and help generating new hypotheses about the structure of this behavior. The hypotheses can then be formulated as algorithms that capture the patterns and quantify them. SEE is a Mathematica based software developed by us for the exploration of exploratory behavior. The raw data for SEE are a time series of the animal 's coordinates in space sampled at a rate that allows a meaningful computation of speeds. SEE permits: (i) a visualization of the path of the animal and a computation of the dynamics of activity; (ii) a decomposition of the path into several modes of motion (1st gear, 2nd gear, etc.) and a computation of the typical maximal speeds, the spatial spread, and the proportion of each of these modes; and(iii) a visualization of the location in the environment of stopping episodes, along with their dwell time. These visualizations highlight the presence of preferred places, including the animal's so-called home base, and permits a computation of the spatio-temporal diversity in the location of stopping episodes. The software also: (i) decomposes the animal's path into round trips from the home base, called 'excursions', and computes the number of stops per excursion; (ii) generates a visualization of the phase space (path+speed, traced in a three-dimensional graph) of any progression segment or list of such segments; and (iii) produces a visualization of the way places in the animal's operational world are connected to each other. SEE also permits the definition and computation of behavioral endpoints across any section of any database of raw data. The range of applicability of SEE to various experimental set ups, tracking procedures, species, and preparations is addressed in the discussion.

Hormonal regulation of peripheral benzodiazepine receptor binding properties is mediated by subunit interaction.

The peripheral benzodiazepine receptor (PBR) is composed of three subunits with molecular masses of 18, 30, and 32 kDa. Many physiological functions have been attributed to the PBR, including regulation of steroidogenesis. Furthermore, the PBR itself is under hormonal regulation. In the current study, we investigated the role of female gonadal sex hormones in the regulation of PBR expression in steroidogenic and nonsteroidogenic tissues. To accomplish this, adult female rats were pharmacologically castrated using chronic administration of the gonadotropin-releasing hormone agonist decapeptyl (triptorelin-D-Trp(6)-LHRH). Half of these rats received 17beta-estradiol as hormone replacement, while a control group received daily injections of vehicle only. We found that PBR binding capacity dropped by 40 and 48% in ovaries and adrenals, respectively, following decapeptyl administration, as opposed to no change in the kidney. This down-regulation of PBR densities was prevented by estradiol replacement. We did not find evidence for transcriptional, posttranscriptional, and translational mechanisms in this decapeptyl-induced down-regulation. In contrast, immunoprecipitation of the PBR complex, using antibodies against the 18- and 32-kDa subunits of the complex, demonstrated that there were changes in PBR subunit interactions, consistent with the down-regulation of PBR binding capacity. These findings represent a novel hormone-dependent posttranslational regulatory mechanism.

Natural segmentation of the locomotor behavior of drug-induced rats in a photobeam cage.

Recently, Drai et al. (J Neurosci Methods 96 (2000) 119) have introduced an algorithm that segments rodent locomotor behavior into natural units of 'staying in place' (lingering) behavior versus going between places (progression segments). This categorization, based on the maximum speed attained within the segment, was shown to be intrinsic to the data, using the statistical method of Gaussian Mixture Model. These results were obtained in normal rats and mice using very large (650 or 320 cm) circular arenas and a video tracking system. In the present study, we reproduce these results with amphetamine, phencyclidine and saline injected rats, using data measured by a standard photobeam tracking system in square 45 cm cages. An intrinsic distinction between two or three 'gears' could be shown in all animals. The spatial distribution of these gears indicates that, as in the large arena behavior, they correspond to the difference between 'staying in place' behavior and 'going between places'. The robustness of this segmentation over arena size, different measurement system and dose of two psychostimulant drugs indicates that this is an intrinsic, natural segmentation of rodent locomotor behavior. Analysis of photobeam data that is based on this segmentation has thus a potential use in psychopharmacology research.

Statistical discrimination of natural modes of motion in rat exploratory behavior.

We analyze the locomotor behavior of the rat during exploration, and show that digitally collected data (time series of positions) provide a sufficient basis for establishing that the rat uses several distinct modes of motion (first, second, third, and sometimes fourth gear). The distinction between these modes is obtained by first segmenting the time series into sequences of data points occurring between arrests (as ascertained within the resolution of the data acquisition system). The statistical distribution of the maximal amount of motion occurring within each of these episodes is then analyzed and shown to be multi modal. This enables us to decompose motion into distinct modes. In one application of this decomposition we show that the ethological ad hoc notion of stopping behavior corresponds to progression without leaving first gear. We do so by showing that the spatial spread of such progressions is confined to a small 20-50 cm range in a 6.5 m diameter arena. This provides a justification for a construct of 'staying in place'. This construct is not defined in terms of position in objective space, but purely in terms of the rat's own behavior. We test the generality of our method by applying it to mouse exploratory behavior.

The dynamics of long-term exploration in the rat. Part I. A phase-plane analysis of the relationship between location and velocity.

Rat exploratory behavior consists of regular excursions into the environment from a preferred place termed a home base. A phase plane representation of excursions reveals a geometrical pattern that changes during exploration in both shape and size. We first show that with time and repeated exposures to the same large environment there is a gradual increase in the length of excursions; each rat has its own characteristic length of excursions; but all rats share a similar rate of excursion growth. As in our experimental setup the rats perform increasingly longer paths from one location, while locomoting back and forth along the walls of the arena, exposure is more extensive at the proximal part of the route, and less at the distal part. We consequently show that the rat's velocity pattern changes concurrently with the increase in excursion length, and in correlation with the level of exposure (familiarity) to places. The primitive velocity pattern consists of slow progression while moving away from base and fast progression while returning to it. During exposure the asymmetry in velocity is inverted. The inversion spreads across successive excursions from the home base outwards. The rate of spread of this inversion is higher than the rate of increase in excursion length, and is similar across rats. Because it spreads more rapidly than the increase in excursion length, the global shape of the excursion trajectory changes. The dynamics of excursion shape share similar properties with the dynamics of excursion length. Both might reflect the same intrinsic constraints on the amount of novelty that a rat can handle per excursion.

A traveling wave of lateral movement coordinates both turning and forward walking in the ferret.

Relative phase was recently suggested as a key variable for the dynamical modeling of coordination in both quadruped locomotion and undulation swimming in fish. Relative phase analysis has not yet been applied, however, to the behavior of intact, freely moving animals, but only to simplified situations involving restrained animals and humans. In order to investigate relative phase under free movement conditions, we filmed free locomotion of ferrets (Mustella putorius) from below (through a glass floor) and measured the lateral bending along the head, torso, and tail, and the location of the four paws. We introduced an algorithm which extracts the phase (and thus also the relative phase) even when the movements were neither periodic nor symmetric. Our results show that relative phases between segments have preferred values, which are relatively independent of the amplitude, duration, and asymmetry of the movement. In particular, both walking and turning can be explained as modulations of a single pattern: a cephalo-caudal, traveling wave of lateral movement with a wavelength of approximately one length of the body. The relative phase between movements of adjacent segments is similar when the body is in S shape (i.e., when walking forward), or C shape (i.e., when turning). The movements of the paws in the horizontal plane can also be considered as part of this traveling wave. Our findings suggest that the concept of traveling waves of lateral bending, as found in the locomotion of undulating fish, can be generalized in two ways: (i) by considering the axis around which the movement is centered, it applies not only to forward locomotion, but also to turning: (ii) by incorporating the position of the paws, it applies also to the movement of quadrupeds. Our findings suggest that the relative phase, once it is generalized to asymmetric and quasi-periodic movement, is suitable for modeling coordination patterns under free movement conditions.

Keeping the Body Straight in the Unconstrained Locomotion of Normal and Dopamine-Stimulant-Treated Rats.

During unconstrained locomotor behavior, rats move in and out of a straight posture of the body (including the head). In the present study, the stability of maintaining a straight body was examined in untreated rats and in rats treated with saline (SAL) or with 1 of 3 dopamine stimulants (n = 4 rats per group). The stability of maintaining a straight body can range from very high (with 0.5 mg/kg quinpirole [QUIN]), to high (first half-session with 5 mg/kg (+)-amphetamine [AMPH]), to very low (second half-session with 5 mg/kg AMPH), or can be maintained at a level similar to that observed in untreated rats (with 1.25mg/kg apomorphine [APO]). Stability was assessed by videotaping the rats and, then, by using frame-by-frame analysis, scoring the cumulative proportion of time spent in a straight posture, the frequency of transitions from one hemisphere to the other without being trapped in the midline plane, and the degree of lateral bending during turning and during walking on a curved path. The present study is one in a series identifying key variables that constrain as many degrees of freedom as possible in rat locomotor behavior. The uncovering of such variables is an indispensible step that precedes dynamic systems stability analysis and provides candidates for key variables for the modeling of motor coordination.

Coordination of side-to-side head movements and walking in amphetamine-treated rats: a stereotyped motor pattern as a stable equilibrium in a dynamical system.

Rats injected with 5.0 mg/kg (+)-amphetamine perform, at one stage of the drug's influence, rhythmic side-to-side head movements while walking. This makes them an interesting preparation for investigating how stereotyped motor patterns emerge from the coordination of periodic movements. We report here such a pattern we have isolated: the left foreleg and the right hindleg land on the ground as the head reaches the peak of its movement to the right, and vice versa (contra-lateral pattern). We show that this pattern can be explained as a stable equilibrium in a simple, nonlinear dynamical model, similar to models developed for tapping with both hands in human subjects. The model also accounts for sequences of behavior that are not in the contra-lateral pattern, explaining them as a flow of the system back towards the stable equilibrium after a disturbance. Motor patterns that constitute the building blocks of unconstrained behavior are often defined as fixed phase relations between movements of the parts of the body. This study applies the paradigm of Dynamic Pattern Generation to free (unconstrained) behavior: motor patterns are defined as stable equilibria in dynamical systems, assembled by mutual influence of concurrent movements. Our findings suggest that this definition is more powerful for the description of free behavior. The amphetamine-treated rat is a useful preparation for investigating this notion in an unconstrained animal whose behavior is still not as complex and variable as that of the normal animal.

A phase plane representation of rat exploratory behavior.

Rat spontaneous spatial behavior is considered to be stochastic and is therefore commonly analyzed in terms of cumulative measures. Here, we suggest a method which generates a moment-to-moment representation of this behavior. It has been proposed earlier that rat spatial behavior can be partitioned into natural units termed excursions (round trips) performed from a reference place termed the rat's home base. We offer a phase plane representation of excursions (plotting the rat's momentary location against its momentary velocity). The results reveal a geometrical pattern, typical of young age and early exposure. It consists of low velocity and intermittent progression while moving away from the home base (upstream segment), and high velocity while moving back to it (downstream segment). The asymmetry between the two segments defines a field of significance in the rat's operational world. This field undergoes regular transformations, revealing thereby the rat's strategy of occupancy of the environment. The presented dynamics could provide a framework for the interpretation of concurrent neural events associated with navigation and spatial memory.

Oscillators in the human body and circular-muscle gymnastics.

There is a growing body of literature about the role of oscillators in the living body, and about the interactions between different oscillators. Considering the importance of endogenous oscillators in regulating the body's functions, and the existence of 'dynamical diseases', diseases of control systems which involve oscillators in the body, a way to mend dysfunctioning oscillators seems to be needed. Circular-muscle gymnastics, a method of physical activity which has been developed in Israel, reveals some phenomena which may point in a promising direction. Some of these phenomena call to mind known facts and theories about oscillators and their effects.

Stopping behavior: constraints on exploration in rats (Rattus norvegicus).

In the absence of an obvious reference place, rat locomotor behavior in a novel environment appears haphazard. In previous work, one or two places termed home bases, were shown to stand out from all the other places in the environment in terms of the behaviors performed in them and in terms of their behavioral stability. We use home base location as a reference place for rat movement in locale space, by defining an excursion as a trip starting at a home base and ending at the next stop at a home base. We then establish the uniform distribution as an appropriate model for the number of stops per excursion. This way we show that there is an intrinsic upper bound on the number of times a rat stops during an excursion. As a rat leaves the home base, home base attraction increases with every additional stop performed by it, first slowly and then fast. This cumulative process of attraction may be concluded after each stop, as long as the number of stops does not exceed an intrinsic upper bound; once the upper bound is reached, the rat concludes that excursion and returns to base. The session's upper bound does not increase with the size of the explored area.

The description of rat drug-induced behavior: kinematics versus response categories.

The study of rat drug-induced locomotor behavior is largely based on the assumption that behavior consists of a sequence of response categories performed by the whole animal one at a time. By analysing this behavior under (+)-amphetamine (5 mg/kg), we illustrate how even a precise definition of such categories may not be sufficient for the establishment of behavioral variables that have a "physiological reality." We describe the changes of relation between the parts of the rat's body in reference to selected coordinate systems, and show that a great variety of locomotor patterns observed under amphetamine can be reduced to as few as 3 descriptive component-variables. These continuous and relatively independent variables, which behave predictably in the course of drug action, operate simultaneously. Variations in their relative timing of onset and termination account for the apparent variability in observed behavior. The economy and generality of a description based on these variables suggest the existence of corresponding central mechanisms of control.

Home base behavior in amphetamine-treated tame wild rats (Rattus norvegicus).

When a rat treated with amphetamine (0.5-5 mg/kg) locomotes in an unfamiliar environment, there are one or two places which it visits most often. In these one or two places the mean duration of a visit (stop) is the longest, and, compared to other places, the incidence of grooming and rearing are the highest. Since in intact rats these features of place characterize it as a 'home base', it is concluded that under amphetamine rats also establish one or two home bases. One home base was generally established by rats treated with low doses of amphetamine, while two bases were most evident in those treated with high doses. Since the paths of locomotion in amphetamine-treated rats were previously described to be stereotyped, it is suggested that home base location under this drug may be used as a reference point in the assessment of the organization of stereotyped locomotor behavior.

Home base behavior of rats (Rattus norvegicus) exploring a novel environment.

When rats are placed in a novel environment, they alternate between progression and stopping: in the course of a session they stop briefly in many places, but in one or two places they also stop for very long periods. The place in which they stay for the longest cumulative time is defined as the rat's home base. In this place the incidences of grooming and of rearing are high and often the highest. In addition, the number of visits to the home base is typically the highest. Some rats establish a secondary base with similar properties to those of the main home base. The location of the base influences the mode of progression throughout the environment: progression away from base is slower and includes more stops than progression back. It is suggested that this paradigm may be used for the analysis of the spatial organization of locomotor behavior in neuroscience research.