The stalk-eyed fly as a model for aggression - is there a conserved role for 5-HT between vertebrates and invertebrates?

Serotonin (5-HT) has largely been accepted to be inhibitory to vertebrate aggression, whereas an opposing stimulatory role has been proposed for invertebrates. Herein, we argue that critical gaps in our understanding of the nuanced role of 5-HT in invertebrate systems drove this conclusion prematurely, and that emerging data suggest a previously unrecognized level of phylogenetic conservation with respect to neurochemical mechanisms regulating the expression of aggressive behaviors. This is especially apparent when considering the interplay among factors governing 5-HT activity, many of which share functional homology across taxa. We discuss recent findings using insect models, with an emphasis on the stalk-eyed fly, to demonstrate how particular 5-HT receptor subtypes mediate the intensity of aggression with respect to discrete stages of the interaction (initiation, escalation and termination), which mirrors the complex behavioral regulation currently recognized in vertebrates. Further similarities emerge when considering the contribution of neuropeptides, which interact with 5-HT to ultimately determine contest progression and outcome. Relative to knowledge in vertebrates, much less is known about the function of 5-HT receptors and neuropeptides in invertebrate aggression, particularly with respect to sex, species and context, prompting the need for further studies. Our Commentary highlights the need to consider multiple factors when determining potential taxonomic differences, and raises the possibility of more similarities than differences between vertebrates and invertebrates with regard to the modulatory effect of 5-HT on aggression.

Saccadic head rotations during walking in the stalk-eyed fly (Cyrtodiopsis dalmanni).

In stalk-eyed flies (Diopsidae), the eyes are positioned at the end of rigid peduncles protruding laterally from the head. Sexual selection for eye span in male Cyrtodiopsis dalmanni results in eye span that exceeds body length and exceeds the eye span of females. We studied whether the twofold higher moment of inertia (MOI) of the male head results in a reduced head rotation velocity during turning. We analysed films of flies performing walking turns and compared the head kinematics between the sexes. The significance of head rotation to turning was evaluated from the turning kinematics of flies with immobilized (glued) heads. Male and female C. dalmanni rotated their heads relative to the surrounding environment 1.55-fold (male) and 1.65-fold (female) faster than the angular velocity of the body by performing rapid head saccades. During the larger turns, flies with immobilized heads were unable to reorient gaze as fast as the control flies. Despite the larger MOI of the head, male C. dalmanni match the head saccade of females suggesting that eye span elongation is coupled by an adaptation of the neck apparatus to rotate the wider head.

Sex differences in aggression: Differential roles of 5-HT2, neuropeptide F and tachykinin.

Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonin's (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2's involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.

Neuromodulation of Nestmate Recognition Decisions by Pavement Ants.

Ant colonies are distributed systems that are regulated in a non-hierarchical manner. Without a central authority, individuals inform their decisions by comparing information in local cues to a set of inherent behavioral rules. Individual behavioral decisions collectively change colony behavior and lead to self-organization capable of solving complex problems such as the decision to engage in aggressive societal conflicts with neighbors. Despite the relevance to colony fitness, the mechanisms that drive individual decisions leading to cooperative behavior are not well understood. Here we show how sensory information, both tactile and chemical, and social context-isolation, nestmate interaction, or fighting non-nestmates-affects brain monoamine levels in pavement ants (Tetramorium caespitum). Our results provide evidence that changes in octopamine and serotonin in the brains of individuals are sufficient to alter the decision by pavement ants to be aggressive towards non-nestmate ants whereas increased brain levels of dopamine correlate to physical fighting. We propose a model in which the changes in brain states of many workers collectively lead to the self-organization of societal aggression between neighboring colonies of pavement ants.

Assessment strategies and fighting patterns in animal contests: a role for serotonin?

Accurate assessment of the probability of success in an aggressive confrontation with a conspecific is critical to the survival and fitness of the individuals. Various game theory models have examined these assessment strategies under the assumption that contests should favor the animal with the greater resource-holding potential (RHP), body size typically being the proxy. Mutual assessment asserts that an individual can assess their own RHP relative to their opponent, allowing the inferior animal the chance to flee before incurring unnecessary costs. The model of self-determined persistence, however, assumes that an individual will fight to a set personal threshold, independent of their opponent's RHP. Both models have been repeatedly tested using size as a proxy for RHP, with neither receiving unambiguous support. Here we present both morphological and neurophysiological data from size-matched and mismatched stalk-eyed fly fights. We discovered differing fighting strategies between winners and losers. Winners readily escalated encounters to higher intensity and physical contact and engaged in less low-intensity, posturing behaviors compared with losers. Although these fighting strategies were largely independent of size, they were associated with elevated levels of 5-HT. Understanding the neurophysiological factors responsible for mediating the motivational state of opponents could help resolve the inconsistencies seen in current game theory models. Therefore, we contend that current studies using only size as a proxy for RHP may be inadequate in determining the intricacies of fighting ability and that future studies investigating assessment strategies and contest outcome should include neurophysiological data.

The organization of societal conflicts by pavement ants Tetramorium caespitum: an agent-based model of amine-mediated decision making.

Ant colonies self-organize to solve complex problems despite the simplicity of an individual ant's brain. Pavement ant Tetramorium caespitum colonies must solve the problem of defending the territory that they patrol in search of energetically rich forage. When members of 2 colonies randomly interact at the territory boundary a decision to fight occurs when: 1) there is a mismatch in nestmate recognition cues and 2) each ant has a recent history of high interaction rates with nestmate ants. Instead of fighting, some ants will decide to recruit more workers from the nest to the fighting location, and in this way a positive feedback mediates the development of colony wide wars. In ants, the monoamines serotonin (5-HT) and octopamine (OA) modulate many behaviors associated with colony organization and in particular behaviors associated with nestmate recognition and aggression. In this article, we develop and explore an agent-based model that conceptualizes how individual changes in brain concentrations of 5-HT and OA, paired with a simple threshold-based decision rule, can lead to the development of colony wide warfare. Model simulations do lead to the development of warfare with 91% of ants fighting at the end of 1 h. When conducting a sensitivity analysis, we determined that uncertainty in monoamine concentration signal decay influences the behavior of the model more than uncertainty in the decision-making rule or density. We conclude that pavement ant behavior is consistent with the detection of interaction rate through a single timed interval rather than integration of multiple interactions.

Rapid evolution of postzygotic reproductive isolation in stalk-eyed flies.

We test the relative rates of evolution of pre- and postzygotic reproductive isolation using eight populations of the sexually dimorphic stalk-eyed flies Cyrtodiopsis dalmanni and C. whitei. Flies from these populations exhibit few morphological differences yet experience strong sexual selection on male eyestalks. To measure reproductive isolation we housed one male and three female flies from within and between these populations in replicate cages and then recorded mating behavior, sperm transfer, progeny production, and hybrid fertility. Using a phylogeny based on partial sequences of two mitochondrial genes, we found that premating isolation, postmating isolation prior to hybrid eclosion, and female hybrid sterility evolve gradually with respect to mitochondrial DNA sequence divergence. In contrast, male hybrid sterility evolves much more rapidly-at least twice as fast as any other form of reproductive isolation. Hybrid sterility, therefore, obeys Haldane's rule. Although some brood sex ratios were female biased, average brood sex ratio did not covary with genetic distance, as would be expected if hybrid inviability obeyed Haldane's rule. The likelihood that forces including sexual selection and intra- and intergenomic conflict may have contributed to these patterns is discussed.

Stress induces rapid changes in central catecholaminergic activity in Anolis carolinensis: restraint and forced physical activity.

Immobilization stress and physical activity separately influence monoaminergic function. In addition, it appears that stress and locomotion reciprocally modulate neuroendocrine responses, with forced exercise ameliorating stress-induced serotonergic activity in lizards. To investigate the interaction of forced physical activity and restraint stress on central dopamine (DA), norepinephrine (NE), and epinephrine (Epi), we measured these catecholamines and their metabolites in select brain regions of stressed and exercised male Anolis carolinensis lizards. Animals were handled briefly to elicit restraint stress, with some lizards additionally forced to run on a track until exhaustion, or half that time (50% of average time to exhaustion), compared to a control group that experienced no restraint or exercise. Norepinephrine concentrations in the hippocampus and locus ceruleus decreased with restraint stress, but returned to control levels following forced exhaustion. Levels of NE in the raphé nuclei and area postrema, and epinephrine in raphé became elevated following restraint stress, and returned to control levels following forced physical activity to 50% or 100% exhaustion. Striatal DA increased as animals were exercised to 50% of exhaustion, and returned to baseline with exhaustion. At exhaustion, striatal Epi levels were diminished, compared with controls. In the area postrema, exhaustion reversed a decline in epinephrine levels that followed forced physical activity. These results suggest that stress stimulates a rapid influence on central catecholamines. In addition, forced exercise, and even exhaustion, may alleviate the effects of restraint stress on central monoamines.

Different effects of intensity and duration of locomotor activity on circadian period.

An outstanding unresolved issue in chronobiology is how the level of locomotor activity influences length of the free-running, endogenous circadian period (tau). To address this issue, the authors studied a novel model, 4 replicate lines of laboratory house mice (Mus domesticus) that had been selectively bred for high wheel-running activity (S) and their 4 unselected control (C) lines. Previous work indicates that S mice run approximately twice as many revolutions/day and exhibit an altered dopaminergic function as compared with C mice. The authors report that S mice have a tau shorter by about 0.5 h as compared with C mice. The difference in tau was significant both under constant light (control lines: tau = 25.5 h; selected: tau = 24.9 h) and under constant dark (control lines: 23.7 h; selected: 23.4 h). Moreover, the difference remained statistically significant even when the effects of running speed and time spent running were controlled in ANCOVA. Thus, something more fundamental than just intensity or duration of wheel-running activity per se must underlie the difference in tau between the S and C lines. However, despite significant difference in total wheel-running activity between females and males, tau did not differ between the sexes. Similarly, among individuals within lines, tau was not correlated with wheel-running activity measured as total revolutions per day. Instead, tau tended to decrease with average running speed but increase with time spent running. Finally, within individuals, an increase in time spent running resulted in decreased tau in the next few days, but changes in running speed had no statistically significant effect. The distinctions between effects of duration versus intensity of an activity, as well as between the among- versus within-individual correlations, are critical to understanding the relation between locomotor activity and pace of the circadian clock.

David vs. Goliath: Serotonin modulates opponent perception between smaller and larger rivals.

During agonistic encounters, the perception of a larger opponent through morphological signaling typically suppresses aggression in the smaller individual, preventing contest intensity escalation. However, non-morphological factors such as central serotonin (5-HT) activity can influence individual aggression, potentially altering contest intensity despite initial size discrepancies. When male stalk-eyed flies (Teleopsis dalmanni) fight, contest escalation is directly proportional to similarity in body size, with escalation being lower in size-mismatched contests. We have shown that both high-intensity aggression and the probability of winning are increased in males with pharmacologically elevated 5-HT relative to size-matched non-treated opponents. Here, we hypothesized that, in size-mismatched contests, increasing brain 5-HT in the smaller opponent could similarly increase aggression and counteract the low contest intensity normally driven by size discrepancy. Size-mismatched male pairs (greater than 5% difference in eyestalk length) engaged in a forced fight paradigm, with the smaller fly either untreated or with pharmacologically elevated 5-HT levels. The expression of high-intensity aggressive behaviors was significantly increased in smaller treated opponents, but the probability of winning was not altered. This suggests that while elevated serotonergic activity can increase aggression and intensity despite perception of a larger opponent, this is not sufficient to overcome size biases with respect to contest outcome. However, the fact that larger opponents continued to win against smaller treated flies was not simply a function of size. Instead, untreated larger males adjusted their fighting strategy to match the increased aggression of their smaller treated opponent, suggesting contextual flexibility in behavior based on individual opponent assessment.

Evolution of a small-muscle polymorphism in lines of house mice selected for high activity levels.

To study the correlated evolution of locomotor behavior and exercise physiology, we conducted an artificial selection experiment. From the outbred Hsd:ICR strain of Mus domesticus, we began eight separate lines, each consisting of 10 breeding pairs. In four of the lines, we used within-family selection to increase voluntary wheel running. The remaining four lines were random-bred (within lines) to serve as controls. Various traits have been monitored to test for correlated responses. Here, we report on organ masses, with emphasis on the triceps surae muscle complex, an important extensor of the ankle. Mice from the selected lines exhibit reduced total body mass, increased relative (mass-corrected) kidney mass, and reduced relative triceps surae mass. In addition, a discrete muscle-mass polymorphism was observed: some individuals had triceps surae that were almost 50% lighter than normal for their body mass. This small-muscle phenotype was observed in only three of the eight lines: in one control line, it has fluctuated in frequency between zero and 10%, whereas in two of the selected lines it has increased in frequency to approximately 50% by generation 22. Data from a set of parents and offspring (generations 23 and 24) are consistent with inheritance as a single autosomal recessive allele. Evidence for the adaptive significance of the small-muscle allele was obtained by fitting multiple-generation data to hierarchical models that include effects of genetic drift and/or selection. The small-muscle allele is estimated to have been present at low frequency (approximately 7%) in the base population, and analysis indicates that strong selection favors the allele in the selected but not control lines. We hypothesize that the small muscles possess functional characteristics and/or that the underlying allele causes pleiotropic effects (e.g., reduced total body mass; increased relative heart, liver, and kidney mass) that facilitate high levels of wheel running. Nevertheless, at generation 22, wheel running of affected individuals did not differ significantly from those with normal-sized muscles, and the magnitude of response to selection has been similar in all four selected lines, indicating that multiple genetic "solutions" are possible in response to selection for high activity levels.

Dominance, plasma testosterone levels, and testis size in house mice artificially selected for high activity levels.

Male house mice (Mus domesticus) from four replicate lines selectively bred for high voluntary wheel-running behavior were compared with four random-bred control lines with respect to dominance, testis size, and plasma testosterone level. Behavior was measured with a tube apparatus in which focal mice encountered a standard opponent from an inbred strain, and positions of mice were scored over a 10-min period; the test was replicated the following day. Blood samples were taken from undisturbed mice 1 week prior to testing (baseline condition) and immediately after the first tube test; plasma testosterone was measured by enzyme immunoassay with chromatography. As compared with control lines, mice from selected lines tended to be smaller in body mass, to have larger testes, and were significantly less likely to advance towards their opponent during the second tube-test encounter. However, no significant differences in either baseline or post-encounter testosterone levels were detected. Significant differences in body mass, relative testis size, position during the first tube-test encounter, and baseline testosterone were found among the replicate lines within linetype, which indicates founder effects, random genetic drift, unique mutations, and/or multiple responses to selection. At the level of individual variation (residuals from nested analysis of covariance models), an inverse relationship between baseline testosterone and advancing in the tube test was observed, and the relationship was stronger during the second test day. This unexpected result may reflect an alternate coping strategy.

Food wasting by house mice: variation among individuals, families, and genetic lines.

Under ad libitum conditions, laboratory house mice (Mus domesticus) fragment considerable amounts of pelleted food and leave it scattered in their cages. The proportion of food thus wasted (in relation to food eaten) varies remarkably among individuals, from 2% to 40%, but is highly consistent in consecutive trials, even when the mice were moved from 22 to -10 degrees C and food consumption doubled. Food wasting did not differ either between the sexes or between genetic lines that had been selected (10 generations) for high voluntary wheel-running behavior (n=4) and their unselected control lines (n=4). However, it varied significantly among replicate lines within the selection groups and among families within the lines (coefficient of intraclass correlation for full sibs, rhof=0.41 in room temperature trials and rhof=0.34 in cold trials). Moreover, the percent of food wasted was negatively correlated with food consumption in the cold trials (males: r=-.36, females: r=-.20) and with total litter mass at weaning (the litters into which they were born; r=-.24), two traits that may affect Darwinian fitness. We conclude that food wastage should not be ignored without justification in calculations of food consumption. In addition, "table manners" can convey reliable information about family origin of an individual and its quality, and therefore could potentially play a role in establishment of social status.

Heightened serotonin influences contest outcome and enhances expression of high-intensity aggressive behaviors.

The outcome of behavioral interactions between organisms can have significant fitness implications. Therefore, it is of great theoretical and practical importance to understand the mechanisms that modify different agonistic behaviors. Changes in central monoamines, such as serotonin (5-HT), contribute to modifying the expression of aggressive encounters in both vertebrates and invertebrates. In several invertebrate groups, neural 5-HT has been linked to heightened aggression and conflict escalation. The male stalk-eyed fly (Teleopsis dalmanni) competes with conspecifics daily over access to resources such as food and mates. Because encounters escalate in a stereotypical manner, stalk-eyed flies provide an excellent model system to study behavioral syndromes. We hypothesized that noninvasive, pharmacological augmentation of brain 5-HT by administration of the precursor, 5-hydroxytryptophan (5-HTP), would increase stereotypic behavioral escalation and the probability of winning a conflict over food. Size-matched male 5-HTP-treated and untreated flies were placed in a forced-fight paradigm and their aggressive behaviors scored. Individuals with higher brain 5-HT levels had a markedly higher probability of winning the contests, displayed greater levels of high-intensity aggressive behaviors and fewer retreats. Pretreatment with 5-HTP did not significantly alter octopamine or tyramine, suggesting that central 5-HT may modulate aggression in these organisms and play a role in determining reproductive success and resource attainment.

Whole brain monoamine detection and manipulation in a stalk-eyed fly.

Understanding the physiological mechanisms that influence conflict resolution is of great importance because the outcome of contests over limited resources such as mates, territories, and food has significant fitness consequences. Male stalk-eyed flies (Teleopsis dalmanni) compete over territory and mates and provide an excellent model system to study aggression. To investigate potential effects of serotonin (5-HT) on aggressive behavior in these flies, we developed a dissection and sample preparation method sufficiently sensitive to measure monoamine concentrations from whole brain samples of small insects. This new method allows the detection of monoamines from a single fly brain using high performance liquid chromatography with electrochemical detection. The method allows for the detection and quantification of octopamine (OA), 5-hydroxytryptophan (5-HTP), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), tyramine (TA), and serotonin (5-HT) and provides a means for assessing changes in stalk-eyed fly brain monoamine concentrations in response to drug administration in food media. We successfully elevated 5-HT levels approximately 8-fold that of control levels in stalk-eyed fly brains by oral administration of the 5-HT precursor 5-HTP. Furthermore, in size-matched competitions for a food resource, flies that had elevated 5-HT in response to 5-HTP pretreatment exhibited a high probability of winning the contests. These results suggest that 5-HT enhances aggression in the stalk-eyed fly and highlight the potential of our method for testing putative roles of monoamines in modulating self and rival assessment in conflict resolution.

Drag-based 'hovering' in ducks: the hydrodynamics and energetic cost of bottom feeding.

Diving ducks use their webbed feet to provide the propulsive force that moves them underwater. To hold position near the bottom while feeding, ducks paddle constantly to resist the buoyant force of the body. Using video sequences from two orthogonal cameras we reconstructed the 3-dimensional motion of the feet through water and estimated the forces involved with a quasi-steady blade-element model. We found that during station holding, near the bottom, ducks use drag based propulsion with the webbed area of the foot moving perpendicular to the trajectory of the foot. The body was pitched at 76+/-3.47 degrees below the horizon and the propulsive force was directed 26+/-1.9 degrees ventral to the body so that 98% of the propulsive force in the sagittal plane of the duck worked to oppose buoyancy. The mechanical work done by moving both feet through a paddling cycle was 1.1+/-0.2 J which was equivalent to an energy expenditure of 3.7+/-0.5 W to hold position while feeding at 1.5 m depth. We conclude that in shallow water the high energetic cost of feeding in ducks is due to the need to paddle constantly against buoyancy even after reaching the bottom. The mechanical energy spent on holding position near the bottom, while feeding, is approximately 2 fold higher than previous estimates that were made for similar bottom depths but based on the presumed motion of the body instead of motion of the feet.

Selection for intrinsic endurance modifies endocrine stress responsiveness.

Physical exercise dampens an individual's stress response and decreases symptoms of anxiety and depression disorders. While the extrinsic relationship of exercise and psychological state is established, their intrinsic relationship is unresolved. We investigated the potential intrinsic relationship of exercise with stress responsiveness using NIH rats bidirectionally selected for intrinsic endurance capacity. Selection resulted in two populations, one with high intrinsic endurance (high capacity runners; HCR) and one with low intrinsic endurance (low capacity runners; LCR). Animals from these populations were subjected to the elevated plus maze (EPM) and novel environment to assess levels of anxiety-like behavior, and to restraint stress to determine stress responsiveness. Pre-test plasma corticosterone levels and the response of plasma corticosterone to exposure to the EPM and restraint were analyzed using ELISA. A dexamethasone suppression test was performed to assess negative feedback tone of corticosterone release. Pre-test plasma corticosterone levels were similar between LCR and HCR, and these populations had similar behavioral and corticosterone responses to the EPM. Following restraint, HCR animals exhibited more anxiotypic behavior than LCR animals on the EPM, and exhibited an increase in plasma corticosterone following EPM and restraint that was not observed in LCR animals. HCR animals also exhibited more anxiotypic behavior in the novel environment compared to LCR animals. Plasma corticosterone levels were equally reduced in both populations following dexamethasone administration. Overall, our data suggest a positive genetic relationship between exercise endurance and stress responsiveness, which is at odds with the established extrinsic relationship of these traits.

Free flight maneuvers of stalk-eyed flies: do eye-stalks affect aerial turning behavior?

The eyes of stalk-eyed flies (Diopsidae) are positioned at the end of rigid peduncles projected laterally from the head. In dimorphic species the eye-stalks of males exceed the eye-stalks of females and can exceed body length. Eye-stalk length is sexually selected in males improving male reproductive success. We tested whether the long eye-stalks have a negative effect on free-flight and aerial turning behavior by analyzing the morphology and free-flight trajectories of male and female Cyrtodiopsis dalmanni. At flight posture the mass-moment-of-inertia for rotation about a vertical axis was 1.49-fold higher in males. Males also showed a 5% increase in wing length compared to females. During free-flight females made larger turns than males (54 +/- 31.4 vs. 49 +/- 36.2 degrees , t test, P < 0.033) and flew faster while turning (9.4 +/- 5.45 vs. 8.4 +/- 6.17 cm s(-1), ANOVA, P < 0.021). However, turning performance of both sexes overlapped, and turn rate in males even marginally exceeded turn rate in females (733 +/- 235.3 vs. 685 +/- 282.6 deg s(-1), ANCOVA, P < 0.047). We suggest that the increase in eye-span does result in an increase in the mechanical requirements for aerial turning but that male C. dalmanni are capable of compensating for the constraint of longer eye-stalks during the range of turns observed through wingbeat kinematics and increased wing size.

Effects of excessive long-term exercise on cardiac function and myocyte remodeling in hypertensive heart failure rats.

The long-term effects of exercise on cardiac function and myocyte remodeling in hypertension/progression of heart failure are poorly understood. We investigated whether exercise can attenuate pathological remodeling under hypertensive conditions. Fifteen female Spontaneously Hypertensive Heart Failure rats and 10 control rats were housed with running wheels beginning at 6 months of age. At 22 months of age, heart function of the trained rats was compared with heart function of age-matched sedentary hypertensive and control rats. Heart function was measured using echocardiography and left ventricular catheterization. Cardiac myocytes were isolated to measure cellular dimensions. Fetal gene expression was determined using Western blots. Exercise did not significantly impact myocyte remodeling or ventricular function in control animals. Sedentary hypertensive rats had significant chamber dilatation and cardiac hypertrophy. In exercised hypertensive rats, however, exercise time was excessive and resulted in a 21% increase in left ventricular diastolic dimension (P<0.001), a 24% increase in heart to body weight ratio (P<0.05), a 27% increase in left ventricular myocyte volume (P<0.01), a 13% reduction in ejection fraction (P<0.001), and a 22% reduction in fractional shortening (P<0.01) compared with sedentary hypertensive rats. Exercise resulted in greater fibrosis and did not prevent activation of the fetal gene program in hypertensive rats. We conclude that excessive exercise, in the untreated hypertensive state can have deleterious effects on cardiac remodeling and may actually accelerate the progression to heart failure.