Neonatal maternal separation in male rats increases intestinal permeability and affects behavior after chronic social stress

Prolonged maternal separation in rats has several effects on health and behavior. Here we investigated how maternal separation might interact with social stress in adulthood on behavior and gastrointenstinal permeability. The effects of either daily 180 min long term pup-dam separation (LMS) during the stress hyporesponsive period or daily 10 min brief maternal separation (BMS) on behavior, corticosterone and intestinal permeability were investigated, compared to a non-handling (NH) condition in male offspring. The animals from each separation condition were then randomly assigned to adult stress and control conditions, where the stress condition was exposure to 14 days of social instability (CSI). Sucrose preference, elevated plus maze behavior and corticosterone were measured. Colitis was experimentally induced by dextran sulfate sodium for 7 days, followed by measurement of intestinal permeability using the (51)CrEDTA method. Granulocyte marker protein was measured in feces and colons were examined histologically for inflammation. Prior to the social stress, the LMS offspring showed elevated corticosterone levels, lower elevated plus maze activity and less fluid consumption. After social stress, corticosterone levels were suppressed in LMS animals and again they showed less fluid consumption. LMS animals had significantly higher intestinal permeability, but only when also exposed to the social stress in adulthood. The current results support a two-hit model, whereby early life events interact with adult life events in altering animals' vulnerability.     

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus–pituitary–adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.     

Neonatal social isolation alters both maternal and pup behaviors in rats

The development of emotional behavior is dependent on the early experiences of the infant and the quality of maternal care. In these experiments, the effects of social isolation during the preweaning period on both pup behavior and maternal responsivity were examined. In the first study, the number of ultrasonic vocalizations (USVs) emitted after brief maternal separation was measured in neonatal rats with differing histories of social isolation. The social isolation procedure consisted of 5 days of daily separation from the dam and littermates for either 3 or 6 hr. At both ages tested, socially isolated pups vocalized significantly less than control pups. In the second study, the effects of prior isolation either daily for 5 previous days (Chronic Isolation) or for 4 hr prior to testing (Acute Isolation) were examined in a T-maze choice test. Pup vocalizations in the presence of the dam and dams' maternal behavior were assessed. When the dam was confined to the start box or during the maternal free access period, both Chronic and Acute Isolates vocalized less than pups that had never left the home nest. Dams spent more time with and licked and groomed more frequently and for a longer time both Chronic and Acute Isolates compared to pups that had always been with dams in the home nest. These results suggest that early isolation experience can alter subsequent responses to separation stress in neonatal rats and that maternal behavior is sensitive to the prior experiences of offspring.     

Wheel-running activity increases with social stress in male DBA mice

Social affiliation-avoidance behaviors are essential indices of sociality. We examined changes in social affiliation-avoidance behaviors in an open-field apparatus while simultaneously measuring wheel-running activity. Recent studies suggest that mice increase wheel-running activity in stressful situations; thus, we hypothesized that wheel-running activity would reflect a state of social stress and avoidance. Mean duration of wheel-running increased significantly when mice were confronted with unfamiliar mice compared to cage mates. There were negative correlations between the amount of wheel-running and social affiliation indices. We also examined the effect of social defeat on wheel-running activity. Mice that had experienced social defeat significantly increased their wheel-running when an aggressor mouse was present. This social defeat-induced wheel-running activity was ameliorated by the administration of diazepam. Our results indicate that wheel-running activity is relevant to social affiliation-avoidance behaviors and may be a reliable index of anxiety induced by social stress.     

Prenatal stress and prepuberal social rearing conditions interact to determine sexual behavior in male rats

The two major categories of factors known to influence adult sexual behavior potentials are the relative amounts of androgen present during specific stages of perinatal ontogeny and adequate social stimulation during prepuberal development. The possible interaction between these two was evaluated by characterizing the ejaculatory and lordotic behavior potentials of prenatally stressed and control male rats that had been weaned at 16 days of age and raised either in total social isolation or with a same-age female, a control male, or a prenatally stressed male. The decrement in male sexual behavior produced by prenatal stress was attenuated by raising the male with either a female or a control male. Social isolation alone or in combination with stress resulted in severely deficient male behavior. Peripheral skin shock promoted ejaculatory behavior in many previously noncopulating prenatally stressed males raised with other stressed males, but it was ineffective in most isolated animals. The high lordosis potential characteristic of prenatally stressed male rats was slightly lower in the group with a female cagemate and was markedly decreased by social isolation. These results support and extend the finding by Dunlap, Zadina, and Gougis (1978) that prenatal hormonal events and prepuberal rearing conditions can interact to attenuate or accentuate the effects that either treatment alone has on the development of adult sexual behavior potentials.     

Neonatal maternal separation and neuroendocrine programming of the respiratory control system in rats

Neonatal maternal separation (NMS) disrupts central nervous system (CNS) development. Although the consequences of NMS are typically linked with abnormal psychological and behavioural development, there is growing evidence indicating that NMS affects maturation of the respiratory control system. This review discusses results from animal studies in which ventilatory responses to chemical stimuli were measured either in unrestrained rats or in an anesthetised preparation. Data show that NMS interferes with development of ventilatory chemoreflexes in a persistent, sex-specific fashion by affecting both the central and peripheral components of the respiratory control system. NMS likely disrupts the balance between inhibitory (GABAergic) and excitatory modulation within key integrative structures involved in respiratory regulation. Because enhancement of ventilatory chemoreflexes is a hallmark of several cardio-respiratory disorders in humans these results raise important questions concerning the impact of the neonatal of environment on the emergence of respiratory disease related to neural control dysfunction later in life.     

Neonatal organization of adult partner preference behavior in male rats

Male rats were castrated or sham castrated shortly after birth. Castrated males were then injected every other day on days 0-10 with testosterone propionate (TP, 0.5 mg), dihydrotestosterone propionate (DHTP, 0.5 mg) or the oil vehicle (0.05 ml); sham-castrated males received oil injections. In adulthood, when substituted with DHT, DHT + E2, or T (silastic implants), sexual partner preference was measured in an automated open field (AOF), in which wire mesh prevented sexual interaction with incentives, and in a 3-compartment box (3-CB), in which sexual interaction with tethered incentives was possible. Choices were an estrous female and a nonestrous female or an estrous female and a sexually active male. In adulthood, following long-term treatment with DHT or DHT + E2, the males did not show any partner preference when sexual interaction with incentives was prevented. Following sexual experience with an estrous female these males preferred the estrous over the nonestrous female, although this change could also be due to long-term hormone treatment. In the 3-CB, a clearcut preference emerged for the estrous female over the nonestrous conspecific, although the neonatally DHTP- or oil-treated males scored lower than the neonatally TP-treated or control males. Six weeks after removal of the hormone implants, when tested in the 3-CB (estrous female vs. active male), the males showed no partner preference. Unexpectedly the control males showed a low preference for the active male. Three weeks T-treatment made all males show a preference for the estrous female (in 3-CB).(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal chronic stress induces subsensitivity to chronic stress in adult rats. I. Effects on forced swim behavior and endocrine responses

An influence of early stimulation on sensitivity to acute stress in adulthood has been reported. The purpose of the present work was to determine the effect of exposure of male and female rats to three models of chronic stress (unpredictable stress, cold stress and handling) from day 2 to day 15 of life on behavioral and endocrine sensitivity to chronic stresses in adulthood. The chronic stresses applied in adulthood were a model of intermittent cold stress (daily 30-min sessions at -20 degrees C for 15 days) and the Katz's model of unpredictable chronic stress (15 days). Forced swim behavior and serum concentration of the stress-sensitive hormones, corticosterone and prolactin, were chosen to investigate stress sensitivity. It was found that all neonatal treatments stimulated body weight gain, did not cause infant mortality and did not affect forced swim behavior as adult. The repetitive exposure to cold stress in adulthood did not cause major impairment of forced swim behavior and did not affect basal levels of serum corticosterone and prolactin in either control or experimental rats. These findings support the view that repeated stressors can induce behavioral and endocrine adaptation in rats. The neonatal treatments did not affect this characteristic. The exposure of control rats to the unpredictable stress model severely impaired forced swim behavior and increased basal levels of serum corticosterone and prolactin. This observation conforms to the view that standard laboratory rats cannot adapt to unpredictable chronic stress. This has been reported to cause a behavioral depression syndrome comprising forced swim deficit and endocrine alterations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal bonadal hormones: effect on maternal and sexual behavior in the male rat

Neonatal exposure of rats to androgen results in alteration of adult sex behavior and gonadotropin release. Other sexually dimorphic adult behaviors have also been shown to be dependent, either in part or in full, upon exposure to androgen neonatally. The present study was conducted to determine the effect of neonatal androgens in organizing the brain of the male rat (Long-Evans strain) with regard to maternal behavior. The results indicate that males neonatally exposed to androgen exhibit poor maternal behavior as adults when compared to males castrated at birth and males receiving gonadotropin antiserum in infancy. The males castrated at birth and males receiving gonadotropin antiserum in infancy, when primed with estrogen and progesterone, showed high levels of female sexual behavior when compared to controls. In terms of male sex behavior, the control groups performed slightly better than the males castrated at birth and males receiving antisera in infancy. The results suggest that the neonatal pituitary gland has an indirect role in the process of sexual differentiation.     

Exposure to PCB 77 affects the maternal behavior of rats

Polychlorinated biphenyls are environmental contaminants known to affect neurobehavioral development in many laboratory studies using different animal models. Because of their bioaccumulation and long half-life they are a serious concern for our own species. The dioxin-like PCB congener 3,4,3',4'-tetrachlorobiphenyl (PCB 77) has estrogenic and anti-estrogenic properties, and has been shown to affect brain chemistry and behavior of developing rats when administered during gestation. Since many developmental outcomes in mammals depend upon the type of maternal care provided by the dams, we investigated the effects of two doses of PCB 77 (2 and 4 mg/kg administered during gestational days 6-18) on the maternal behavior of the treated dams. Both doses of PCB 77 reduced the amount of nursing time in which the dams displayed the high-crouch posture over postnatal days 1-6. In addition, the high dose increased the amount of maternal licking and grooming of the litters and the amount of time the dams spent on the nest. The high dose also increased pup mortality, and both doses reduced the weight gain of the litters during the first 6 days of life. These results document effects of PCB 77 on maternal behavior and serve to raise questions about the importance of maternal contributions to the developmental effects of this and similar contaminants.     

Solitary and social behavior of male rats in the open-field

The short-term effects of anxiolytic drugs have been assessed with tests of social affiliative behavior in rats. These tests must be completed in a brief time span, yet must include measures both of solitary activity and social behavior to dissociate affiliative from sedative and hypermotive drug effects. This study demonstrates that a paradigm of observation of alternating periods of solitary and social behavior of male rats yields data in accord with facts known about rats tested in separate, uninterrupted periods of solitary and social behavior. Agreement was obtained on the reliability of group and intersession behavior, on the levels of behavior, on the changes in behavior over trials and on the correlations between behaviors characteristic of rats tested separately in the two situations.     

Neonatal maternal separation and early life programming of the hypoxic ventilatory response in rats

The neonatal period is critical for central nervous system (CNS) development. Recent studies have shown that this basic neurobiological principle also applies to the neural circuits regulating respiratory activity as exposure to excessive or insufficient chemosensory stimuli during early life can have long-lasting consequences on the performance of this vital system. Although the tactile, olfactory, and auditory stimuli that the mother provides to her offspring during the neonatal period are not directly relevant to respiratory homeostasis, they likely contribute to respiratory control development. This review outlines the rationale for the link between maternal stimuli and programming of the hypoxic ventilatory response during early life, and presents recent results obtained in rats indicating that experimental disruption of mother-pup interaction during this critical period elicits significant phenotypic plasticity of the hypoxic ventilatory response.     

Within-litter variation in maternal care received by individual pups correlates with adolescent social play behavior in male rats

Maternal care represents an essential environmental factor during the first post-natal week(s) of rodents and is known to have lasting consequences for neuronal structure, brain function as well as behavioral outcome later in life, including social functions and reward-related processes. Previous experiments have shown that the amount of maternal care received by individual pups varies substantially, even within one litter. During adolescence, mammals display high levels of social play behavior, a rewarding form of social interaction that is of great importance for social and cognitive development. In order to investigate how maternal care influences adaptive social behavior later in life, we here examined whether individual differences in maternal licking and grooming (%LG) received during the first postnatal week affect social play behavior during adolescence. We observed that %LG received by male rats early in life correlates positively with the frequency and duration of pouncing and pinning, the two most characteristic behavioral expressions of social play behavior in rats. The latency to engage in social exploration also correlated with %LG. In female rats we observed no correlation between %LG and any social parameter. The data indicate that subtle variations in maternal care received early in life influence social interactions in male adolescent rats. These changes in social play likely have repercussions for the social development of male rats, suggesting that maternal care can have both direct and indirect effects on the behavioral development of the offspring.     

Adolescent social stress and social context influence the intake of ethanol and sucrose in male rats soon and long after the stress exposures

Social instability stress in adolescent rats (SS; postnatal day 30–45, daily 1 hr isolation +new cage partner) alters behavioural responses to psychostimulants, but differences in voluntary consumption of natural and drug rewards are unknown. SS also is associated with an atypical behavioural repertoire, for example reduced social interactions. Here, we investigated whether SS rats differ from control (CTL) rats in ethanol (EtOH) or sucrose intake in experiments involving different social contexts: alone, in the presence of an unfamiliar peer, in the presence of its cage partner, or in competition against its cage partner. SS rats drank more EtOH than CTL rats irrespective of social context, although the effects were driven primarily by those tested soon after the test procedure rather than weeks later in adulthood. SS and CTL rats did not differ in sucrose intake, except in adulthood under conditions of competition for limited access (SS>CTL). Adolescent rats drank more sucrose than adults, in keeping with evidence that adolescents are more sensitive to natural rewards than adult animals. Overall, adolescent SS modified the reward value of EtOH and sucrose, perhaps through stress/glucocorticoids modifying the development of the mesocorticolimbic system.     

Neonatal maternal separation exacerbates the reward-enhancing effect of acute amphetamine administration and the anhedonic effect of repeated social defeat in adult rats

Early life adversity or parental neglect is linked to the development of a number of psychiatric illnesses, including major depression and substance use disorder. These two disorders are often comorbid and characterized by anhedonia, defined as the reduced ability to experience pleasure or reward. The aim of the present study was to determine the effects of neonatal maternal separation in Long Evans rats, a model of early life stress, on anhedonia under baseline conditions and in response to drug and stress exposure during adulthood. Three hours of daily maternal separation from postnatal day 1 to 14 led to marked decreases in arched-back nursing, licking, and grooming of pups by their dams. In adulthood, brain reward function was assessed using intracranial self-stimulation of the lateral hypothalamus. Lowered current thresholds derived from this procedure are interpreted as reward-enhancing effects, whereas elevations in thresholds are an operational measure of anhedonia. Maternally separated rats did not exhibit anhedonia under baseline conditions compared with non-handled controls but exhibited a greater reward-enhancing effect of acute amphetamine administration. Acute social defeat produced anhedonia in non-handled controls, but not in maternally separated rats. Conversely, control rats habituated to 7 days of repeated social defeat, whereas maternally separated rats developed an increased anhedonic response to the repeated stressor. One week after termination of stress exposure, maternally separated rats still exhibited an increased reward-enhancing effect of acute amphetamine administration compared with non-handled controls, regardless of prior social defeat experience. These data indicate that early life stress increases the reward-enhancing properties of amphetamine, protects against the anhedonic effects of acute stress exposure, and exacerbates the anhedonic response to repeated stress. Thus, early life stress may increase an individual's vulnerability to depressive or addictive disorders when confronted with stress or drug challenge in adulthood.     

Effect of maternal separation on feeding behavior of rats in later life

Effects of maternal separation on feeding behavior, particularly on rebound hyperphagia, in adult rats were examined. Time-restricted scheduled feeding (2 h per day for 6 days), was given at the age of 3, 6, 9 or 12 weeks in rats that were maternal separated from postnatal days (PD) 1–21 and control rats. Following the time-restricted scheduled feeding, rats were fed freely for 24 h (rebound hyperphagia). Body weight, daily normal food consumption and food consumption during time-restricted scheduled feeding and rebound hyperphagia were measured. Body weight of 3-week-old maternally separated rats were less than those of control rats. There was no significant difference in normal daily food consumption. Food consumption during rebound hyperphagia was significantly increased in 6- to 9-week-old female maternally separated rats, but there was no difference observed in males. Postnatal maternal separation enhanced rebound hyperphagia of female rats in later life. These results indicate that postnatal maternal separation made rats more vulnerable to the development of abnormal feeding behavior in response to food restriction in later life.