Examination of the role of adrenergic receptor stimulation in the sensitization of neuroinflammatory-based depressive-like behavior in isolated Guinea pig pups.

Early-life attachment disruption appears to sensitize neuroinflammatory signaling to increase later vulnerability for stress-related mental disorders, including depression. How stress initiates this process is unknown, but studies with adult rats and mice suggest sympathetic nervous system activation and/or cortisol elevations during the early stress are key. Guinea pig pups isolated from their mothers exhibit an initial active behavioral phase characterized by anxiety-like vocalizing. This is followed by inflammatory-dependent depressive-like behavior and fever that sensitize on repeated isolation. Using strategies that have been successful in adult studies, we assessed whether sympathetic nervous system activity and cortisol contributed to the sensitization process in guinea pig pups. In Experiment 1, the adrenergic agonist ephedrine (3 or 10 mg/kg), either alone or with cortisol (2.5 mg/kg), did not increase depressive-like behavior or fever during initial isolation the following day as might have been expected to if this stimulation was sufficient to account for the sensitization process. In Experiment 2, both depressive-like behavior and fever sensitized with repeated isolation, but beta-adrenergic receptor blockade with propranolol (10 or 20 mg/kg) did not affect either of these responses or their sensitization. The high dose of propranolol did, however, reduce vocalizing. These results suggest sympathetic nervous system activation is neither necessary nor sufficient to induce the presumptive neuroinflammatory signaling underlying sensitization of depressive-like behavioral or febrile responses in developing guinea pigs. Thus, processes mediating sensitization of neuroinflammatory-based depressive-like behavior following early-life attachment disruption in this model appear to differ from those previously found to underlie neuroinflammatory priming in adults.

Sensitization of depressive-like behavior is attenuated by disruption of prostaglandin synthesis days following brief early attachment-figure isolation.

Childhood psychological trauma appears to sensitize stress-related neuroinflammatory systems to increase later vulnerability for depression and other stress-related mental disorders. Isolation of guinea pig pups from the maternal attachment figure for 3 h in threatening surroundings leads to a sensitization of inflammatory-mediated, depressive-like behavior and fever during later isolations. A previous study found the non-selective COX inhibitor naproxen administered before the initial isolation moderated depressive-like behavior and its sensitization. Here, we examined effects of naproxen given following early isolation. Male and female guinea pig pups surgically implanted with telemetry devices to measure core temperature were isolated for 3 h on 2 consecutive days near weaning (first isolation Day 20-24). Several days later, they began 4 consecutive days of injection with either saline vehicle or 10 or 20 mg/kg naproxen prior to a third isolation in early adolescence, that is, 10 days after their first isolation. Across the first two isolations, depressive-like behavior and fever sensitized. Both doses of naproxen attenuated depressive-like behavior during the third isolation. Fever was unaffected. Results suggest prostaglandin mediation of sensitization of depressive-like behavioral, but not febrile, responses to subsequent isolation. Findings also support further study of anti-inflammatory treatments to mitigate lasting consequences of early-attachment disruption.

Social buffering of plasma corticosterone and amygdala responses of young rats following exposure to periorbital shock: Implications for eyeblink conditioning development.

The developmental onset of aversive learning processes depends on complex interactions between endocrine, neural, and social influences. Emergence of avoidance conditioning in rat pups is triggered by elevated plasma corticosterone activating the amygdala. Further, the mother's ability to buffer the corticosterone response delays the onset of avoidance in ˜2-week-old pups. Eyeblink conditioning (EBC) also develops during the pre-weaning period. In previous work, little or no conditioning was observed on Day 17 for pups housed in the home cage with mother and littermates between training sessions, whereas pups isolated between training sessions did show some conditioning. This suggests that social buffering may also delay the onset of this form of aversive learning. In the present study with Day-17 pups, one session of periorbital shock, the typical EBC unconditioned stimulus for young rat pups, resulted in lower plasma corticosterone levels and neural activity in the central nucleus of the amygdale (CeA) of pups returned to the mother and homecage following the session as compared to pups isolated following the shock session. These findings demonstrate social buffering of the physiological response to aversive stimulus exposure under conditions of EBC and support the hypothesis that social buffering of early adverse experience may adjust the timing of emergence of EBC in rat pups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Psychological Stress, Its Reduction, and Long-Term Consequences: What Studies with Laboratory Animals Might Teach Us about Life in the Dog Shelter.

There is a long history of laboratory studies of the physiological and behavioral effects of stress, its reduction, and the later psychological and behavioral consequences of unmitigated stress responses. Many of the stressors employed in these studies approximate the experience of dogs confined in an animal shelter. We review how the laboratory literature has guided our own work in describing the reactions of dogs to shelter housing and in helping formulate means of reducing their stress responses. Consistent with the social buffering literature in other species, human interaction has emerged as a key ingredient in moderating glucocorticoid stress responses of shelter dogs. We discuss variables that appear critical for effective use of human interaction procedures in the shelter as well as potential neural mechanisms underlying the glucocorticoid-reducing effect. We also describe recent studies in which enrichment centered on human interaction has been found to reduce aggressive responses in a temperament test used to determine suitability for adoption. Finally, we suggest that a critical aspect of the laboratory stress literature that has been underappreciated in studying shelter dogs is evidence for long-term behavioral consequences-often mediated by glucocorticoids-that may not become apparent until well after initial stress exposure.

Presence of mother prompts dissociation of sickness behavior, fever, and hypothalamic gene expression in lipopolysaccharide-injected guinea pig pups.

During infection, sickness behaviors, such as a hunched stance with piloerection, can facilitate host resistance by supporting the generation and maintenance of fever. Fever, in turn, is mediated by hypothalamic neuroimmune signaling. Sickness behaviors, however, can also be influenced by social stimuli. In this study, guinea pig pups were injected with lipopolysaccharide to simulate a bacterial infection and then exposed to a novel, threatening environment while either with their mother or alone. We found that the presence of the mother suppressed sickness behavior, but enhanced fever, and had no measureable effect on gene expression of hypothalamic mediators of fever. This 3-way dissociation induced by the mother's presence is interpreted in terms of the differential adaptive consequences of behavioral and febrile responses for pups in this situation. The results contribute to a growing literature linking immunological and social processes.

Sensitive phases in the development of rodent social behavior.

Here, we summarize recent advances on how environmental influences during sensitive phases alter the social behavioral phenotype of rodents later in life. Current studies support the view that the prenatal, early postnatal and adolescent periods of life can be regarded as sensitive phases. Environmental cues acting on the organism during these phases have a wide variety of effects on adult social behavior. One pattern that emerges across species and sensitive phases is that adversity tends to reduce social interactions and particularly affiliative social behavior. Concerning underlying mechanisms, various hormones can be involved; however, glucocorticoids frequently serve as the signal instigating plasticity. There is also increasing appreciation of non-endocrine mechanisms, specifically epigenetics and the microbiome. Concerning function, some evidence exists that sensitive phase outcomes adjust the individual's social phenotype to the nature of the social environment to be present during adulthood and breeding, though additional empirical support is still needed.

Central oxytocin alters cortisol and behavioral responses of guinea pig pups during isolation in a novel environment.

The neuropeptide oxytocin plays key roles in social bonding and stress reduction, and thus appears to be a likely mediator of maternal buffering of infant stress responses. In the guinea pig, the presence of the mother in a threatening environment buffers cortisol elevations as well as active (vocalizing) and passive (e.g. crouching) responses typical of isolation in this species; yet, effects of OT in guinea pig pups under any conditions have not been reported. Here, we examined the ability of intracerebroventricular (ICV) OT to moderate plasma cortisol levels and behavior in guinea pig pups isolated in a brightly lit, novel environment, and the ability of a highly selective OT antagonist (OTA) to reduce buffering by the mother. We found that ICV OT moderated cortisol levels and vocalizations, but increased time spent in the crouched stance, particularly in females. In addition, OT modulated other ongoing behaviors in a sex-dependent fashion. In females, OT reduced duration of walking and rearing, and increased time spent quiet, while in males OT increased duration of rearing. OTA, however, was without effect on cortisol levels or behavior. These findings, including sex differences in response, extend results from other species to the guinea pig. Further, while demonstrating that exogenous OT is sufficient to reduce biobehavioral stress responses typical of isolated guinea pig infants, the results suggest that endogenous OT is not necessary for maternal buffering of infant responses in this species.

Central neuroimmune activity and depressive-like behavior in response to repeated maternal separation and injection of LPS.

Disruption of attachment relations in early life is linked to greater vulnerability to depressive illness at later ages. Evidence suggests this process involves stress-induced activation of central inflammatory factors, though the specific mediators and processes involved are not known. We used a guinea pig model in which effects of maternal separation appear more clearly due to absence of the attachment figure than is the case for other laboratory rodents. Separation in a novel environment on two consecutive days evoked a depressive-like behavioral response that sensitized during a final test 9 days later. At this time, prior separation blunted the response of prostaglandin synthesizing enzymes (COX-2 and mPGES) and chemokines (CXCL-1 and MCP-1) 120 min following injection with lipopolysaccharide and isolation in a novel cage. The blunted response was not associated with a greater plasma cortisol elevation. In addition, injection of saline just prior to isolation at the oldest age elicited small, but significant, elevations in several signaling molecules, particularly at 30 min. These results demonstrate lasting central inflammatory consequences of our separation procedure. However, contrary to expectations, sensitization of depressive-like behavior was not associated with an increase in expression of neuroimmune mediators to inflammatory challenge. Together with earlier findings, the results suggest a multi-step process in which inflammatory response to an initial separation affects downstream mediators to sensitize depressive-like behavior.

The adaptive shaping of social behavioural phenotypes during adolescence.

Developmental behavioural plasticity is a process by which organisms can alter development of their behavioural phenotype to be better adapted to the environment encountered later in life. This 'shaping' process depends on the presence of reliable cues by which predictions can be made. It is now established that cues detected by the mother can be used (primarily via hormones prenatally and maternal behaviour in the early postnatal stage) to shape the behavioural phenotype of her offspring. However, it is becoming increasingly clear that adolescence is another period in which conditions are well-suited for such shaping to occur. We review here how mammalian social behaviour may be shaped in adolescence. We identify limited extant examples, briefly discuss underlying mechanisms, and provide evidence that observed changes are indeed adaptive. We contend that while plasticity diminishes with age, the shaping of the behavioural phenotype in adolescence offers several advantages, including that adolescence is closer to the onset of mating than are earlier phases of life; that unlike earlier phases, information is obtained directly from the environment rather than mediated by the mother; and unlike later in adulthood, there is substantial underlying neural plasticity associated with development to support behavioural change. We also consider conditions that favour the occurrence of social behaviour plasticity during adolescence, including a high degree of sociality and a prolonged developmental period and the implication of these conditions for the occurrence of sex differences in the shaping process.

Adult males buffer the cortisol response of young guinea pigs: Changes with age, mediation by behavior, and comparison with prefrontal activity.

In the guinea pig, the presence of the mother buffers hypothalamic-pituitary-adrenal (HPA) responses of her young during exposure to a novel environment, and can do so even if she is anesthetized. In contrast, under comparable conditions other conspecifics (siblings, other adult females) are less effective or ineffective in doing so. However, we recently observed that an unfamiliar adult male reduced plasma cortisol elevations and increased Fos in the prefrontal cortex of preweaning pups exposed to a novel enclosure for 120min. Here we found adult males buffered the adrenocortical response of preweaning pups at 60 as well as 120min and of periadolescent guinea pigs if exposure was of 120min. Further, because males vigorously engaged in social interactions with the young during exposure, we examined the effect of behavior by comparing the impact of conscious and unconscious (anesthetized) adult males. When tested with a conscious but not unconscious male, pups exhibited reduced plasma cortisol elevations. Pups, particularly females, had greater Fos induction in the prefrontal cortex when with a conscious versus unconscious adult male. Overall, we found that an unfamiliar adult male can buffer the cortisol response of guinea pigs both before and after weaning, though more-prolonged exposure appears necessary in the older animals. Further, unlike buffering by the biological mother, the effect of the male is mediated by behavioral interactions. Thus, the buffering of the infant guinea pig's cortisol response by the mother and an unfamiliar adult male involve different underlying mechanisms.

Early Attachment Disruption, Inflammation, and Vulnerability for Depression in Rodent and Primate Models.

Early experiments in nonhuman primates established the relation between disruption of filial attachment and depressive-like outcomes. Subsequent studies in rats and mice have been instrumental in linking depressive-like outcomes to disturbances in maternal behavior. Another aspect of attachment disruption, absence of the attachment object per se, may be studied more effectively in a different laboratory rodent-the guinea pig. Here, we discuss the rationale for using guinea pigs for this work. We then review guinea pig studies providing evidence for inflammatory mechanisms mediating both depressive-like behavior during separation as well as sensitization of stress responsiveness such as is thought to lead to increased vulnerability to depression at later ages. Finally, we discuss recent complementary work in adult monkeys that suggests cross-species generalizability of broad principles derived from the guinea pig experiments. Overall, the findings provide experimental support for human research implicating inflammatory mechanisms in the development of increased stress responsiveness and vulnerability to depression following attachment disruption and other forms of early-life stress. Specifically, the findings suggest inflammatory mechanisms may set in motion a cascade of underlying processes that mediate later increased stress responsiveness and, therefore, depression susceptibility.

Comparative studies of social buffering: A consideration of approaches, terminology, and pitfalls.

KIYOKAWA, Y. and HENNESSY, M.B. Comparative studies of social buffering: A consideration of approaches, terminology, and pitfalls…NEUROSCI BIOBEHAV REV XXX-XXX, .- Over the past decades, there has been an increasing number of investigations of the impact of social variables on neural, endocrine, and immune outcomes. Among these are studies of "social buffering"-or the phenomenon by which affiliative social partners mitigate the response to stressors. Yet, as social buffering studies have become more commonplace, the variety of approaches taken, definitions employed, and divergent results obtained in different species can lead to confusion and miscommunication. The aim of the present paper, therefore, is to address terminology and approaches and to highlight potential pitfalls to the study of social buffering across nonhuman species. We review and categorize variables currently being employed in social buffering studies and provide an overview of responses measured, mediating sensory modalities and underlying mechanisms. It is our hope that the paper will be useful to those contemplating examination of social buffering in the context of their own research.

A multispecies approach for understanding neuroimmune mechanisms of stress.

The relationship between stress challenges and adverse health outcomes, particularly for the development of affective disorders, is now well established. The highly conserved neuroimmune mechanisms through which responses to stressors are transcribed into effects on males and females have recently garnered much attention from researchers and clinicians alike. The use of animal models, from mice to guinea pigs to primates, has greatly increased our understanding of these mechanisms on the molecular, cellular, and behavioral levels, and research in humans has identified particular brain regions and connections of interest, as well as associations between stress-induced inflammation and psychiatric disorders. This review brings together findings from multiple species in order to better understand how the mechanisms of the neuroimmune response to stress contribute to stress-related psychopathologies, such as major depressive disorder, schizophrenia, and bipolar disorder.

Actualmente está bien establecida la relación entre los efectos del estrés y los resultados adversos sobre la salud, especialmente para el desarrollo de los trastornos afectivos. Los mecanismos neuroinmunes, muy bien conservados entre las especies, y a través de los cuales las respuestas a los estresores se traducen en efectos sobre hombres y mujeres, han generado recientemente gran atención tanto para los investigadores como para los clínicos. El empleo de modelos animales, desde ratones y cobayos, hasta primates, ha mejorado enormemente nuestra comprensión acerca de estos mecanismos a nivel molecular, celular y conductual. La investigación en humanos ha identificado regiones y conexiones cerebrales de interés, como también asociaciones entre la inflamación producida por el estrés y los trastornos psiquíatricos. Esta revisión reúne hallazgos en múltiples especies para una mejor comprensión de cómo contribuyen los mecanismos de la respuesta neuroinmune a las psicopatologías relacionadas con el estrés como el trastorno depresivo mayor, la esquizofrenia y el trastorno bipolar.

Les effets nocifs du stress sur la santé sont maintenant bien connus, en particulier en ce qui concerne le développement des troubles affectifs. Les mécanismes neuro-immunitaires très bien conservés parmi les espèces et par lesquels les réponses aux facteurs de stress se répercutent sur les hommes et les femmes ont récemment suscité une attention particulière des chercheurs et des cliniciens. L'utilisation de modelès animaux, de la souris au cobaye et jusqu'aux primates, a considérablement amélioré notre compréhension de ces mécanismes aux niveaux moléculaire, cellulaire et comportemental. La recherche chez l'homme a permis d'identifier des régions cérébrales particulières et des connexions intéressantes, ainsi que des associations entre l'inflammation induite par le stress et les troubles psychiatriques. Cet article fait la synthèse des données de nombreuses espèces afin de mieux comprendre comment les mécanismes de la réponse neuro-immunitaire au stress contribuent aux psychopathologies liées au stress, comme les troubles dépressifs caractérisés, la schizophrénie et les troubles bipolaires.

Influence of postnatal glucocorticoids on hippocampal-dependent learning varies with elevation patterns and administration methods.

Recent interest in the lasting effects of early-life stress has expanded to include effects on cognitive performance. An increase in circulating glucocorticoids is induced by stress exposure and glucocorticoid effects on the hippocampus likely underlie many of the cognitive consequences. Here we review studies showing that corticosterone administered to young rats at the conclusion of the stress-hyporesponsiveness period affects later performance in hippocampally-mediated trace eyeblink conditioning. The nature and even direction of these effects varies with the elevation patterns (level, duration, temporal fluctuation) achieved by different administration methods. We present new time course data indicating that constant glucocorticoid elevations generally corresponded with hippocampus-mediated learning deficits, whereas acute, cyclical elevations corresponded with improved initial acquisition. Sensitivity was greater for males than for females. Further, changes in hippocampal neurogenesis paralleled some but not all effects. The findings demonstrate that specific patterns of glucocorticoid elevation produced by different drug administration procedures can have markedly different, sex-specific consequences on basic cognitive performance and underlying hippocampal physiology. Implications of these findings for glucocorticoid medications prescribed in childhood are discussed.

Adaptive shaping of the behavioural and neuroendocrine phenotype during adolescence.

Environmental conditions during early life can adaptively shape the phenotype for the prevailing environment. Recently, it has been suggested that adolescence represents an additional temporal window for adaptive developmental plasticity, though supporting evidence is scarce. Previous work has shown that male guinea pigs living in large mixed-sex colonies develop a low-aggressive phenotype as part of a queuing strategy that is adaptive for integrating into large unfamiliar colonies. By contrast, males living in pairs during adolescence become highly aggressive towards strangers. Here, we tested whether the high-aggressive phenotype is adaptive under conditions of low population density, namely when directly competing with a single opponent for access to females. For that purpose, we established groups of one pair-housed male (PM), one colony-housed male (CM) and two females. PMs directed more aggression towards the male competitor and more courtship and mating towards females than did CMs. In consequence, PMs attained the dominant position in most cases and sired significantly more offspring. Moreover, they showed distinctly higher testosterone concentrations and elevated cortisol levels, which probably promoted enhanced aggressiveness while mobilizing necessary energy. Taken together, our results provide the clearest evidence to date for adaptive shaping of the phenotype by environmental influences during adolescence.

Depressive-like behavior, its sensitization, social buffering, and altered cytokine responses in rhesus macaques moved from outdoor social groups to indoor housing.

Psychosocial stressors appear to promote the onset of depressive illness through activation and sensitization of inflammatory mechanisms. Here, adult male rhesus monkeys brought from large outdoor social groups to indoor housing for 8 days reliably exhibited a hunched, depressive-like posture. When rehoused indoors a second 8 days about 2 weeks later, monkeys housed alone, but not those with an affiliative partner, showed sensitization of the depressive-like hunched posture. Housing indoors also affected circulating pro-inflammatory cytokines: IL-1ß showed increased responsiveness to immune challenge, and IL-1ß and TNF-α showed reduced suppression by dexamethasone. Sensitivity of the anti-inflammatory cytokine IL-10 to immune challenge exhibited a relative increase from the first to the second round of indoor housing in animals housed in pairs, and a relative decrease in animals housed alone. Cytokine levels during indoor housing were positively correlated with duration of depressive-like behavior. Plasma cortisol levels increased but did not differentiate housing conditions or rounds. Results demonstrate a rapid induction and sensitization of depressive-like behavior to indoor individual housing, social buffering of sensitization, and associated inflammatory responses. This paradigm may provide a practical nonhuman primate model for examining inflammatory-mediated consequences of psychosocial stressors on depression and possible social buffering of these effects.

Maternal separation increases later immobility during forced swim in guinea pig pups: evidence for sensitization of a depressive-like state.

Early-life stress is thought to increase later vulnerability for developing depressive illness by sensitizing underlying stress-responsive systems. Guinea pig pups separated from their mother and isolated in a novel cage for 3 hr exhibit a sensitized depressive-like behavioral response when separated again the following day as well as weeks later. The behavioral response and its sensitization appear to be mediated by inflammatory factors. To determine if this sensitization is specific to the separation response or if it reflects a broader underlying depressive-like state, guinea pig pups that had either been separated for 3 hr or remained with their mothers were observed in the forced swim test the following 3 days. Earlier separation was found to increase the duration of immobility, a measure sensitive to antidepressant treatment. These results support the use of the guinea pig as a model for examining mechanisms of inflammatory-mediated sensitization of depression following stress in early life.

Short-term, high-dose administration of corticosterone by injection facilitates trace eyeblink conditioning in young male rats.

Glucocorticoids released as part of the physiological response to stress are known to affect cognitive function, presumably via effects on the hippocampus. Trace classical eyeblink conditioning is an associative learning task which depends on the hippocampus and has been used to examine the development of learning processes in young mammals. Previously, we demonstrated deficits in trace eyeblink conditioning associated with postnatal administration of the glucocorticoid corticosterone by creating a sustained elevation with methods such as subcutaneous timed-release pellets and osmotic mini-pumps which were active over several days. In the present study, we examined the effects of an oscillating pattern of corticosterone elevation on subsequent trace eyeblink conditioning. Twice daily corticosterone injections (high, low, or vehicle) were administered over a 3-day period, starting at postnatal day 15. Then, on postnatal day 28, animals underwent trace classical eyeblink conditioning to examine the possible influence of earlier corticosterone elevations on the development of learning and memory. Eyeblink conditioning was affected by corticosterone treatments, but only for males, and only very early in acquisition; Males receiving the high dose of corticosterone exhibited facilitation of learning relative to controls. These data demonstrate that oscillating corticosterone elevations produce opposite effects on this associative learning task than do sustained elevations.

Effects of repeated petting sessions on leukocyte counts, intestinal parasite prevalence, and plasma cortisol concentration of dogs housed in a county animal shelter.

OBJECTIVE: To describe changes in WBC counts, plasma cortisol concentration, and fecal parasite shedding of dogs housed in an animal shelter and determine the effects of daily petting sessions on these variables. DESIGN: Hybrid prospective observational and experimental study. ANIMALS: 92 healthy dogs newly arrived to an animal shelter and 15 healthy privately owned dogs (control group). PROCEDURES: Blood and fecal samples were collected from shelter dogs 1, 3, and 10 days after arrival and from control dogs once. A subset of shelter dogs (n = 15) was assigned to receive 30 minutes of petting daily. Plasma cortisol concentration was measured, CBCs were performed, and fecal samples were evaluated for parasite ova. RESULTS: For shelter dogs, total leukocyte, neutrophil, and lymphocyte counts increased significantly between days 1 and 10, with less consistent increases in monocyte count and neutrophil-to-lymphocyte count ratio. Parasite shedding was unaffected by duration of shelter stay but was greater for shelter versus control dogs. For shelter dogs, plasma cortisol concentration decreased with time and was higher than that of control dogs on each day. Total leukocyte, neutrophil, and monocyte counts and neutrophil-to-lymphocyte count ratios were also higher for shelter versus control dogs. Petting sessions resulted in a decrease in plasma cortisol concentration but in no other variables. CONCLUSIONS AND CLINICAL RELEVANCE: Large increasing immunologic responses, heavy parasite shedding, and high but decreasing plasma cortisol concentration were identified in shelter dogs. Daily 30-minute petting sessions affected only cortisol values, so the clinical importance of petting for immunologic and other health outcomes remains unclear.

Selective social buffering of behavioral and endocrine responses and Fos induction in the prelimbic cortex of infants exposed to a novel environment.

In mammals, the presence of the mother can reduce or "buffer" stress responses of her young in threatening conditions. We compared the effect of the mother, a familiar littermate, and an unfamiliar adult male on three classes of response shown by guinea pig pups in a novel environment: short latency active behaviors, particularly vocalizing; slower developing passive behaviors that appear mediated by inflammatory mechanisms; and hypothalamic-pituitary-adrenal activity. We also examined Fos induction in the prelimbic cortex, a region hypothesized to mediate buffering effects. Only the mother significantly suppressed all classes of behavior. The greatest selectivity was observed for passive behavioral responses. Contrary to expectations, the adult male reduced plasma cortisol levels of pups as effectively as did the mother. The presence of the male also resulted in increased Fos induction in the prelimbic cortex and high levels of social interaction. Maternal buffering was not associated with prelimbic activity. These results confirm the ability of the mother to reduce active behavioral and HPA responses and suggest a specific maternal buffering effect on the later developing passive behavioral responses. The findings also demonstrate an unexpected ability of adult males to reduce HPA responses and raise the possibility that different social partners buffer HPA activity through different underlying processes.