Social isolation and oxytocin antagonism increase emotion-related behaviors and heart rate in female prairie voles.

Social isolation influences depression- and anxiety-related disorders and cardiac function. Oxytocin may mediate these conditions through interactions with social behavior, emotion, and cardiovascular function, via central and/or peripheral mechanisms. The present study investigated the influence of oxytocin antagonism using L-368,899, a selective oxytocin receptor antagonist that crosses the blood-brain barrier, on depression- and anxiety-related behaviors and heart rate in prairie voles. This rodent species has translational value for investigating interactions of social stress, behavior, cardiac responses, and oxytocin function. Adult female prairie voles were socially isolated or co-housed with a sibling for 4 weeks. A subset of animals in each housing condition was subjected to 4 sessions of acute L-368,899 (20 mg/kg, ip) or saline administration followed by a depression- or anxiety-related behavioral assessment. A subset of co-housed animals was evaluated for cardiac function following acute administration of L-368,899 (20 mg/kg, ip) and during behavioral assessments. Social isolation (vs. co-housing) increased depression- and anxiety-related behaviors. In isolated animals, L-368,899 (vs. vehicle) did not influence anxiety-related behaviors but exacerbated depression-related behaviors. In co-housed animals, L-368,899 exacerbated depression-related behaviors and increased heart rate at baseline and during behavioral tests. Social isolation produces emotion-related behaviors in prairie voles; central and/or peripheral oxytocin antagonism exacerbates these behavioral signs. Oxytocin antagonism induces depression-relevant behaviors and increases basal and stressor-reactive heart rate in co-housed prairie voles, similar to the consequences of social isolation demonstrated in this model. These results provide translational value for humans who experience behavioral and cardiac consequences of loneliness or social stress.

Behavioral and cardiovascular consequences of disrupted oxytocin communication in cohabitating pairs of male and female prairie voles.

Negative social experiences may influence psychological and physiological health via altered central oxytocin communication. The prairie vole is valuable for investigating the potential influence of oxytocin on responses to social experiences. Prairie voles are socially monogamous, live in pairs or family groups, and respond negatively to changes in the social environment. This study investigated the hypothesis that disruptions of oxytocin in one prairie vole of a cohabitating male-female pair would alter social behavior in that specific animal; and these behavioral changes in turn would influence the untreated partner's behavior and physiology. Pharmacological antagonism of oxytocin with the receptor antagonist L-368,899 in the male prairie vole disrupted social behaviors between the male and his untreated female partner. This manipulation also negatively influenced the behavior and cardiovascular function in the untreated female partner, including increased: (a) depression-relevant behaviors in two behavioral stressors, (b) basal mean arterial pressure and heart rate, and (c) cardiovascular reactivity to the behavioral stressors. These results suggest that disruptions of oxytocin and social behavior in one animal may produce indicators of social stress in an untreated social partner. This preliminary research provides a foundation for future studies to investigate mechanisms underlying responses to social experiences in humans.

Cardiac and behavioral effects of social isolation and experimental manipulation of autonomic balance.

Improved understanding of how depression and social isolation interact to increase cardiac morbidity and mortality will improve public health. This experiment evaluated the effect of pharmacological autonomic blockade on cardiac and behavioral reactivity following social isolation in prairie voles. Experiment 1 validated the dose and time course of pharmacological autonomic antagonism of peripheral ß-adrenergic (atenolol) and muscarinic cholinergic receptors (atropine methyl nitrate), and Experiment 2 used a novel protocol to investigate behavioral responses in the tail suspension test during pharmacological autonomic blockade as a function of social isolation (vs. paired control). Prairie voles isolated for 4 weeks (vs. paired) displayed significantly elevated heart rate and reduced heart rate variability. Autonomic receptor antagonism by atenolol led to exaggerated reductions in heart rate and standard deviation of normal-to-normal intervals, and lower amplitude of respiratory sinus arrhythmia in the isolated group (vs. paired). Administration of atropine led to an attenuated increase in heart rate in the isolated group (vs. paired), and similar near-zero levels of respiratory sinus arrhythmia amplitude in both groups. During the tail suspension test, isolated animals (vs. paired) displayed significantly greater immobility. In paired animals, atenolol administration did not influence immobility; atropine administration increased the duration of immobility (vs. vehicle). In isolated animals, atenolol administration increased the duration of immobility; atropine did not influence immobility duration (vs. vehicle). The current study contributes to our understanding of differential effects of social isolation and autonomic imbalance on cardiac and behavioral reactivity.

The protective effects of social bonding on behavioral and pituitary-adrenal axis reactivity to chronic mild stress in prairie voles.

Positive social interactions may protect against stress. This study investigated the beneficial effects of pairing with a social partner on behaviors and neuroendocrine function in response to chronic mild stress (CMS) in 13 prairie vole pairs. Following 5 days of social bonding, male and female prairie voles were exposed to 10 days of CMS (mild, unpredictable stressors of varying durations, for instance, strobe light, white noise, and damp bedding), housed with either the social partner (paired group) or individually (isolated group). Active and passive behavioral responses to the forced swim test (FST) and tail-suspension test (TST), and plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone, were measured in all prairie voles following the CMS period. Both female and male prairie voles housed with a social partner displayed lower durations of passive behavioral responses (immobility, a maladaptive behavioral response) in the FST (mean ± SEM; females: 17.3 ± 5.4 s; males: 9.3 ± 4.6 s) and TST (females: 56.8 ± 16.4 s; males: 40.2 ± 11.3 s), versus both sexes housed individually (females, FST: 98.6 ± 12.9 s; females, TST: 155.1 ± 19.3 s; males, FST: 92.4 ± 14.1 s; males, TST: 158.9 ± 22.0 s). Female (but not male) prairie voles displayed attenuated plasma stress hormones when housed with a male partner (ACTH: 945 ± 24.7 pg/ml; corticosterone: 624 ± 139.5 ng/ml), versus females housed individually (ACTH: 1100 ± 23.2 pg/ml; corticosterone: 1064 ± 121.7 ng/ml). These results may inform understanding of the benefits of social interactions on stress resilience. Lay Summary: Social stress can lead to depression. The study of social bonding and stress using an animal model will inform understanding of the protective effects of social bonds. This study showed that social bonding in a rodent model can protect against behavioral responses to stress, and may also be protective against the elevation of stress hormones. This study provides evidence that bonding and social support are valuable for protecting against stress in humans.

Urinary volatile compounds differ across reproductive phenotypes and following aggression in male Siberian hamsters.

Chemical communication plays an integral role in social behavior by facilitating social encounters, allowing for the evaluation of social partners, defining territories and advertising information such as species and sex. Odors provide information about the social environment for rodents and other mammals; however, studies identifying chemical compounds and their functions have thus far focused primarily on a few species. In addition, considerably less attention has been focused on how environmental factors and behavioral context alter these compounds during periods of reproductive quiescence. We examined the effects of photoperiod and social context on chemical communication in the seasonally breeding Siberian hamster which displays modest territorial aggression during long "summer-like" days, but increased aggression in short "winter-like" days. We collected urine samples from long- and short-day male hamsters to investigate how photoperiod and subsequent changes in reproductive phenotype alter urinary volatile compound profiles. Next, we identified changes in urinary compounds before and after an aggressive encounter. Male hamsters exhibited a diverse urinary profile across photoperiods; however, long-day reproductive males showed higher levels of individual compounds when compared to short-day non-reproductive males. In addition, individual compounds were altered following an aggressive encounter; some changed only in long days whereas others changed regardless of photoperiod. Further, aggression and circulating levels of testosterone were positively correlated with urinary compounds in long-, but not short-day males. These findings suggest both photoperiod- and aggression-specific physiological regulation of urinary compounds in this species and contribute to a greater understanding of chemical communication more broadly.

Photoperiod and aggression induce changes in ventral gland compounds exclusively in male Siberian hamsters.

Chemical communication is a critical component of social behavior as it facilitates social encounters, allows for evaluation of the social partner, defines territories and resources, and advertises information such as sex and physiological state of an animal. Odors provide a key source of information about the social environment to rodents; however, studies identifying chemical compounds have thus far focused primarily on few species, particularly the house mouse. Moreover, considerably less attention has been focused on how environmental factors, reproductive phenotype, and behavioral context alter these compounds outside of reproduction. We examined the effects of photoperiod, sex, and social context on chemical communication in the seasonally breeding Siberian hamster. We sampled ventral gland secretions in both male and female hamsters before and after an aggressive encounter and identified changes in a range of volatile compounds. Next, we investigated how photoperiod, reproductive phenotype, and aggression altered ventral gland volatile compound composition across the sexes. Males exhibited a more diverse chemical composition, more sex-specific volatiles, and showed higher levels of excretion compared to females. Individual volatiles were also differentially excreted across photoperiod and reproductive phenotype, as well as differentially altered in response to an aggressive encounter. Female volatile compound composition, in contrast, did not differ across photoperiods or in response to aggression. Collectively, these data contribute to a greater understanding of context-dependent changes in chemical communication in a seasonally breeding rodent.

Short-day aggression is independent of changes in cortisol or glucocorticoid receptors in male Siberian hamsters (Phodopus sungorus).

Testosterone mediates aggression in many vertebrates. In some species, aggression remains high during the non-breeding season (e.g., winter), when testosterone levels are low. In Siberian hamsters (Phodopus sungorus), we have demonstrated photoperiodic changes in aggression with hamsters housed in short, "winter-like" days displaying significantly more territorial aggression than long-day animals, despite low levels of testosterone. The mechanisms by which photoperiod regulates aggression, however, remain largely unknown. Adrenocortical hormones (e.g., glucocorticoids) have been implicated in mediating seasonal aggression; circulating concentrations of these hormones have been correlated with aggression in some species. The goal of this study was to examine the role of cortisol and glucocorticoid receptors in mediating photoperiodic changes in aggression in male Siberian hamsters. Males were housed in long or short days and treated with either exogenous cortisol or vehicle. Circulating levels of cortisol, adrenal cortisol content, and aggression were quantified. Lastly, photoperiodic effects on glucocorticoid receptor (GR) protein levels were quantified in limbic brain regions associated with aggression, including medial prefrontal cortex, amygdala, and hippocampus. Short-day hamsters were more aggressive than long-day hamsters, however cortisol treatment did not affect aggression. Photoperiod had no effect on serum or adrenal cortisol or GR levels in the brain regions examined. Taken together, these data suggest that increases in cortisol levels do not cause increases associated with short-day aggression, and further that GR protein levels are not associated with photoperiodic changes in aggression. The results of this study contribute to our understanding of the role of adrenocortical steroids in mediating seasonal aggression.

Social isolation disrupts innate immune responses in both male and female prairie voles and enhances agonistic behavior in female prairie voles (Microtus ochrogaster).

Psychosocial stress, specifically social isolation, is an important risk factor for the development of a variety of psychological and physiological disorders. Changes in immune function have been hypothesized to mediate this relationship. The current study used the prairie vole (Microtus ochrogaster) model of isolation-induced depressive-like behavior to test whether social isolation led to changes in innate immune function. Specifically, we used hemolytic complement (CH50) and bacteria killing assays to assess innate immunity, in paired or singly housed male and female prairie voles. Further, in a second experiment we tested whether females exposed to an additional short-term social stressor, a resident-intruder trial, would show changes in immune function as well as enhanced hypothalamic pituitary axis (HPA) activity as indicated by elevated plasma corticosterone levels. Socially isolated animals, regardless of sex, had significantly reduced CH50s and bacteria killing ability. Socially isolated females exposed to a resident-intruder stressor also showed reduced CH50s and bacteria killing ability as well as significant increases in aggressive behavior, however, they did not show elevated circulating corticosterone levels. Collectively, these data will help inform our understanding of the relationship between social isolation and physiological and psychological health.

Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole.

Exposure to social and environmental stressors may influence behavior as well as autonomic and cardiovascular regulation, potentially leading to depressive disorders and cardiac dysfunction including elevated sympathetic drive, reduced parasympathetic function, and ventricular arrhythmias. The cellular mechanisms that underlie these interactions are not well understood. One mechanism may involve alterations in the expression of Connexin43 (Cx43) and Connexin45 (Cx45), gap junction proteins in the heart that play an important role in ensuring efficient cell-to-cell coupling and the maintenance of cardiac rhythmicity. The present study investigated the hypothesis that long-term social isolation, combined with mild environmental stressors, would produce both depressive behaviors and altered Cx43 and Cx45 expression in the left ventricle of prairie voles - a socially monogamous rodent model. Adult, female prairie voles were exposed to either social isolation (n = 22) or control (paired, n = 23) conditions (4 weeks), alone or in combination with chronic mild stress (CMS) (1 week). Social isolation, versus paired control conditions, produced significantly (p < 0.05) increased depressive behaviors in a 5-min forced swim test, and CMS exacerbated (p < 0.05) these behaviors. Social isolation (alone) reduced (p < 0.05) total Cx43 expression in the left ventricle; whereas CMS (but not isolation) increased (p < 0.05) total Cx45 expression and reduced (p < 0.05) the Cx43/Cx45 ratio, measured via Western blot analysis. The present findings provide insight into potential cellular mechanisms underlying altered cardiac rhythmicity associated with social and environmental stress in the prairie vole.

The effects of environmental enrichment on depressive and anxiety-relevant behaviors in socially isolated prairie voles.

OBJECTIVES: Social isolation is associated with depression, anxiety, and negative health outcomes. Environmental enrichment, including environmental and cognitive stimulation with inanimate objects and opportunities for physical exercise, may be an effective strategy to include in treatment paradigms for affective disorders as a function of social isolation. In a rodent model-the socially monogamous prairie vole-we investigated the hypothesis that depression- and anxiety-related behaviors after social isolation would be prevented and remediated with environmental enrichment. METHODS: Experiment 1 investigated the preventive effects of environmental enrichment on negative affective behaviors when administered concurrently with social isolation. Experiment 2 investigated the remediating effects of enrichment on negative affective behaviors when administered after a period of isolation. Behaviors were measured in three operational tests: open field, forced swim test (FST), and elevated plus maze. RESULTS: In isolated prairie voles, enrichment prevented depression-relevant (immobility in FST, group × housing interaction, p = .049) and anxiety-relevant behaviors (exploration in open field, group × housing interaction, p = .036; exploration in elevated plus maze, group × housing interaction, p = .049). Delayed enrichment also remediated these behaviors in isolated animals (immobility in FST, main effect of housing, p = .001; exploration in open field, main effect of housing, p = .047; exploration in elevated plus maze, main effect of housing, p = .001) and was slightly more effective than physical exercise alone in remediating anxiety-relevant behaviors. CONCLUSIONS: These findings provide insight into the beneficial effects of an enriched environment on depression- and anxiety-relevant behaviors using a translational rodent model of social isolation.

Disruption of social bonds induces behavioral and physiological dysregulation in male and female prairie voles.

The social disruption of losing a partner may have particularly strong adverse effects on psychological and physiological functioning. More specifically, social stressors may play a mediating role in the association between mood disorders and cardiovascular dysfunction. This study investigated the hypothesis that the disruption of established social bonds between male and female prairie voles would produce depressive behaviors and cardiac dysregulation, coupled with endocrine and autonomic nervous system dysfunction. In Experiment 1, behaviors related to depression, cardiac function, and autonomic nervous system regulation were monitored in male prairie voles during social bonding with a female partner, social isolation from the bonded partner, and a behavioral stressor. Social isolation produced depressive behaviors, increased heart rate, heart rhythm dysregulation, and autonomic imbalance characterized by increased sympathetic and decreased parasympathetic drive to the heart. In Experiment 2, behaviors related to depression and endocrine function were measured following social bonding and social isolation in both male and female prairie voles. Social isolation produced similar levels of depressive behaviors in both sexes, as well as significant elevations of adrenocorticotropic hormone and corticosterone. These alterations in behavioral and physiological functioning provide insight into the mechanisms by which social stressors negatively influence emotional and cardiovascular health in humans.

Stress and neuroinflammation.

It has been well established that there is bidirectional communication between the immune and central nervous systems. One context in which this interaction has been extensively studied is that of the stress response. Stress, whether physical or psychological, induces alterations in immune function. Often exposure to a stressor results in pro-inflammatory responses in the brain and periphery. These responses are mediated by a variety of inflammatory molecules including neuropeptides, cytokines, and stress hormones among others. Here, we will discuss several of the more comprehensively studied of these inflammatory mediators and their role(s) in stress-induced neurogenic inflammation.

Chronic social isolation in the prairie vole induces endothelial dysfunction: implications for depression and cardiovascular disease.

Humans with depression show impaired endothelium-dependent vasodilation; one recent demonstration of which was in the form of a reduced acetylcholine (ACh)-induced relaxation of adrenergically-precontracted small arteries biopsied from older depressed patients. Results from such uses of ACh in general have been validated as the most predictive marker of endothelium-related cardiovascular diseases. Accordingly, we examined vascular reactivity to ACh in the socially isolated prairie vole, a new animal model relevant to human depression and cardiovascular disease. Thoracic aortas were carefully dissected from female prairie voles after one month of social isolation (versus pairing with a sibling). Only aortas that contracted to the adrenergic agent phenylephrine (PE) and then relaxed to ACh were evaluated. Among those, ACh-induced relaxations were significantly reduced by social isolation (p<0.05), with maximum relaxation reaching only 30% (of PE-induced precontraction) compared to 47% in aortas from paired (control) animals. Experimental removal of the endothelium from an additional set of aortic tissues abolished all ACh relaxations including that difference. In these same tissues, maximally-effective concentrations of the nitric oxide-donor nitroprusside still completely relaxed all PE-induced precontraction of the endothelial-free smooth muscle, and to the same degree in tissues from isolated versus paired animals. Finally, in the absence of PE-induced precontraction ACh did not relax but rather contracted aortic tissues, and to a significantly greater extent in tissues from socially isolated animals if the endothelium was intact (p<0.05). Thus, social isolation in the prairie vole may (1) impair normal release of protective anti-atherosclerotic factors like nitric oxide from the vascular endothelium (without altering the inherent responsiveness of the vascular smooth muscle to such factors) and (2) cause the endothelium to release contracting factors. To our knowledge this is the first demonstration of this phenomenon in an animal model of depression induced solely by social isolation. These findings have implications for understanding mechanisms involved in depression and cardiovascular disease.

Neurotensin induced Egr-1 activity is altered in the postpartum period in mice.

Neurotensin (NT) is a 13 amino acid neuropeptide that is identical in mice and humans and is released from and acts upon a number of social brain regions. Recent work indicates NT neurotransmission may be altered in postpartum females and support the onset of some maternal behaviors. In a recent study, we highlighted how virgin and postpartum brains from mice selected for high offspring protection differ in response to injected NT (0.1 µg) relative to vehicle when examining c-Fos profiles across the CNS. In this companion study we use a second marker for brain activity, Egr-1, and evaluate multiple brain regions. Common significant increased Egr-1 responses to NT (relative to vehicle) were found in both female groups only in ventromedial hypothalamus. In lateral periaqueductal gray, virgin mice showed a significant Egr-1 increase with NT (relative to vehicle), but maternal mice did not. When comparing NT injections, virgin (relative to maternal) mice had significantly higher activity in five regions, including anterior hypothalamus, lateral hypothalamus, somatosensory cortex, paraventricular nucleus, and zona incerta; no regions were higher in maternal mice. A Principal Components Analysis was also used for data mining and in virgin mice, greater changes in activity hubs were found with NT (relative to vehicle) than for maternal mice. Overall, a lower sensitivity to NT in terms of Egr-1 reactivity in the maternal state was highlighted and this is consistent with previous c-Fos results. These findings provide additional insight into the mechanisms by which NT functions in the CNS.

Changes in CNS response to neurotensin accompany the postpartum period in mice.

Neurotensin (NT) is a highly conserved neuropeptide in mammals. Recent studies suggest that altered NT neurotransmission in postpartum females could promote the emergence of some maternal behaviors, including offspring protection. Here we evaluated how virgin and postpartum brains from mice selected for high maternal defense differ in response to NT. Virgin and postpartum mice were injected with either vehicle or 0.1 µg NT icv and brains were evaluated for c-Fos immunoreactivity, an indirect marker of neuronal activity. Using ANOVA analysis, common significant responses to NT were found in both female groups in four brain regions, including supraoptic nucleus, ventromedial nucleus, bed nucleus of stria terminalis dorsal, and a subregion of lateral septum (LS). For postpartum mice, only one additional region showed a significant response to NT relative to vehicle, whereas for virgin mice seven unique brain regions showed a significant c-Fos response: nucleus accumbens shell, paraventricular nucleus, central amygdala, and substantia nigra. Using a principal components analysis of c-Fos, we identified regions within each group with highly correlated activity. As expected, virgin and postpartum mice (vehicle conditions) showed different activity hubs and in the postpartum group the hubs matched regions linked to maternal care. The response to injected NT was different in the maternal and virgin groups with maternal mice showing a stronger coordinated activity in periaqueductal gray whereas virgin mice showed a stronger septal and amygdala linking of activity. Together, these results indicate neuronal responses of virgin and postpartum mice to NT and highlight pathways by which NT can alter maternal responses.

Maternal defense is modulated by beta adrenergic receptors in lateral septum in mice.

Maternal defense (offspring protection) is a critical and highly conserved component of maternal care in mammalian systems that involves dramatic shifts in a female's behavioral response to social cues. Numerous changes occur in neuronal signaling and connectivity in the postpartum female, including decreases in norepinephrine (NE) signaling in subregions of the CNS. In this study using a strain of mice selected for maternal defense, we examined whether possible changes in NE signaling in the lateral septum (LS) could facilitate expression of maternal aggression. In separate studies that utilized a repeated measures design, mice were tested for maternal defense following intra-LS injections of either the ß-adrenergic receptor agonist isoproterenol (10 µg or 30 µg) or vehicle (Experiment 1), the ß-adrenergic receptor antagonist propranolol (2 µg) or vehicle (Experiment 2), or the ß1-receptor antagonist, atenolol (Experiment 3). Mice were also evaluated for light-dark performance and pup retrieval. Thirty micrograms of the agonist isoproterenol significantly decreased number of attacks and time aggressive relative to vehicle without affecting pup retrieval or light-dark box performance. In contrast, the antagonist propranolol significantly increased maternal aggression (lowered latency to attack and increased total attack time) without altering light-dark box test. The ß1-specific antagonist, atenolol, significantly decreased latency to attack (1 µg vs. vehicle) without altering other measures. Although the findings were identified in a unique strain of mice, the results of these studies support the hypothesis that changes in NE signaling in LS during the postpartum period contribute to the expression of offspring protection.

Behavioral and pharmacological assessment of a potential new mouse model for mania.

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

Aggressive encounters differentially affect serum dehydroepiandrosterone and testosterone concentrations in male Siberian hamsters (Phodopus sungorus).

The gonadal hormone testosterone (T) regulates aggression across a wide range of vertebrate species. Recent evidence suggests that the adrenal prohormone dehydroepiandrosterone (DHEA) may also play an important role in regulating aggression. DHEA can be converted into active sex steroids, such as T and estradiol (E(2)), within the brain. Previous studies show that circulating DHEA levels display diurnal rhythms and that melatonin increases adrenal DHEA secretion in vitro. Here we examined serum DHEA and T levels in long-day housed Siberian hamsters (Phodopus sungorus), a nocturnal species in which melatonin treatment increases aggression. In Experiment 1, serum DHEA and T levels were measured in adult male hamsters during the day (1200 h, noon) and night (2400 h, midnight). In Experiment 2, aggression was elicited using 5-min resident-intruder trials during the day (1800 h) and night (2000 h) (lights-off at 2000 h). Serum DHEA and T levels were measured 24 h before and immediately after aggressive encounters. In Experiment 1, there was no significant difference in serum DHEA or T levels between noon and midnight, although DHEA levels showed a trend to be lower at midnight. In Experiment 2, territorial aggression was greater during the night than the day. Moreover, at night, aggressive interactions rapidly decreased serum DHEA levels but increased serum T levels. In contrast, aggressive interactions during the day did not affect serum DHEA or T levels. These data suggest that nocturnal aggressive encounters rapidly increase conversion of DHEA to T and that melatonin may play a permissive role in this process.

The role of androgens in the mediation of seasonal territorial aggression in male Siberian hamsters (Phodopus sungorus).

Testosterone (T) mediates aggression in a wide range of species. In some species, however, aggressive behavior persists or increases during the non-breeding season when T levels are relatively low. Animals that do not display a positive correlation between aggression and gonadal steroids suggest the need for further investigation of alternative neuroendocrine mechanisms mediating seasonal aggression. Siberian hamsters (Phodopus sungorus) are an ideal study system because they display increased territorial aggression during the non-breeding season which may be independent of circulating T levels. The goals of the present study were to: 1) explore the role of T in the aggression of reproductive males, and 2) test the hypothesis that the adrenal steroid dehydroepiandrosterone (DHEA) acts as an endocrine regulator of seasonal aggression. In Experiment 1, individuals were housed in long day (breeding) photoperiod and received castrations, exogenous T capsules or both manipulations. In Experiment 2, animals were housed in either long or short days (non-breeding) photoperiod and received DHEA or empty capsules. In both experiments, serum hormone levels and aggressive behavior were assessed. In Experiment 1, castration did not reduce aggression whereas exogenous T actually inhibited aggressive behavior. In Experiment 2, short-day individuals were more aggressive than long-day animals but DHEA treatment did not affect aggressive behavior, regardless of photoperiod. The present study supports the hypothesis that circulating gonadal steroids are not necessary to activate aggressive behavior in adult male hamsters. Further, seasonal changes in territorial aggression appear independent of circulating levels of DHEA in Siberian hamsters.

Novel mechanisms for neuroendocrine regulation of aggression.

In 1849, Berthold demonstrated that testicular secretions are necessary for aggressive behavior in roosters. Since then, research on the neuroendocrinology of aggression has been dominated by the paradigm that the brain receives gonadal hormones, primarily testosterone, which modulate relevant neural circuits. While this paradigm has been extremely useful, recent studies reveal important alternatives. For example, most vertebrate species are seasonal breeders, and many species show aggression outside of the breeding season, when gonads are regressed and circulating testosterone levels are typically low. Studies in birds and mammals suggest that an adrenal androgen precursor-dehydroepiandrosterone (DHEA)-may be important for the expression of aggression when gonadal testosterone synthesis is low. Circulating DHEA can be metabolized into active sex steroids within the brain. Another possibility is that the brain can autonomously synthesize sex steroids de novo from cholesterol, thereby uncoupling brain steroid levels from circulating steroid levels. These alternative neuroendocrine mechanisms to provide sex steroids to specific neural circuits may have evolved to avoid the "costs" of high circulating testosterone during particular seasons. Physiological indicators of season (e.g., melatonin) may allow animals to switch from one neuroendocrine mechanism to another across the year. Such mechanisms may be important for the control of aggression in many vertebrate species, including humans.