Long-term impact of neonatal injury in male and female rats: Sex differences, mechanisms and clinical implications.

Over the last several decades, the relative contribution of early life events to individual disease susceptibility has been explored extensively. Only fairly recently, however, has it become evident that abnormal or excessive nociceptive activity experienced during the perinatal period may permanently alter the normal development of the CNS and influence future responses to somatosensory input. Given the significant rise in the number of premature infants receiving high-technology intensive care over the last 20 years, ex-preterm neonates may be exceedingly vulnerable to the long-term effects of repeated invasive interventions. The present review summarizes available clinical and laboratory findings on the lasting impact of exposure to noxious stimulation during early development, with a focus on the structural and functional alterations in nociceptive circuits, and its sexually dimorphic impact.

Predictors of neonatal hypothalamic-pituitary-adrenal axis activity at delivery.

OBJECTIVE: Clinical and preclinical studies indicate that maternal stress during pregnancy may exert long-lasting adverse effects on offspring. This investigation sought to identify factors mediating the relationship between maternal and neonatal hypothalamic-pituitary-adrenal (HPA) axes in pregnant women with past or family psychiatric history. PATIENTS: Two hundred and five pairs of maternal and umbilical cord blood samples from a clinical population were collected at delivery. MEASUREMENTS: Maternal and neonatal HPA axis activity measures were plasma adrenocorticotrophic hormone (ACTH), total cortisol, free cortisol and cortisol-binding globulin concentrations. The effects of maternal race, age, body mass index, psychiatric diagnosis (DSM-IV), birth weight, delivery method and estimated gestational age (EGA) at delivery on both maternal and neonatal HPA axis measures were also examined. Incorporating these independent predictors as covariates where necessary, we evaluated whether neonatal HPA axis activity measures could be predicted by the same maternal measure using linear regression. RESULTS: Delivery method was associated with umbilical cord plasma ACTH and both total and free cord cortisol concentrations (T = 10·53-4·21; P < 0·0001-0·010). After accounting for method of delivery and EGA, we found that maternal plasma ACTH concentrations predicted 23·9% of the variance in foetal plasma ACTH concentrations (T = 6·76; P < 0·0001), and maternal free and total plasma cortisol concentrations predicted 39·8% and 32·3% of the variance in foetal plasma free and total cortisol concentrations (T = 5·37-6·90; P < 0·0001), respectively. CONCLUSION: These data suggest that neonatal response is coupled with maternal HPA axis activity at delivery. Future investigations will scrutinize the potential long-term sequelae for the offspring.

Preemptive morphine analgesia attenuates the long-term consequences of neonatal inflammation in male and female rats.

Despite mounting evidence on the importance of pain management in preterm infants, clinical use of analgesics in this population is limited. Our previous studies have shown that neonatal inflammation results in long-term alterations in adult somatosensory thresholds, characterized by decreased baseline nociceptive sensitivity, and enhanced hyperalgesia after a subsequent inflammatory insult. The present studies were conducted to determine whether preemptive morphine attenuates these negative consequences. At P0, pups received an injection of morphine sulfate before an intraplantar injection of 1% carrageenan. Control pups received either saline (SAL) followed by intraplantar carrageenan, morphine sulfate followed by intraplantar SAL, or SAL followed by intraplantar SAL. Preemptive morphine significantly attenuated neonatal injury-induced hypoalgesia in adolescence and adulthood. Similarly, morphine pretreated animals displayed significantly less hyperalgesia and recovered faster from a subsequent inflammatory insult compared with controls. Neonatal morphine had no significant effect on morphine analgesia in adulthood. Interestingly, neonatally injured animals that did not receive morphine displayed a significant rightward shift in the morphine dose-response curve in the absence of peripheral inflammation. Together, these results demonstrate that preemptive morphine significantly attenuates the long-term behavioral impact of neonatal inflammatory injury.

Neuroanatomical distribution of oxytocin receptor binding in the female rabbit forebrain: Variations across the reproductive cycle.

Oxytocin receptors (OTR) have been characterized in the brains of several mammals, including rodents, carnivores, and primates. Their species-specific distribution in the brain has been associated with species differences in social organization, including mating strategy and parenting behavior. In several species, the density of OTR binding in specific brain regions varies according to reproductive condition, including ovarian cycle, pregnancy and lactation. Rabbits are induced ovulators, polygamous, and monoparental but their distribution and regulation of brain OTR has not been described. Here we used receptor autoradiography to quantitatively characterize OTR binding in the brains of estrous, ovariectomized, late pregnant, and lactating does. Intense binding occurred in the prefrontal cortex (PFC), preoptic area (POA), lateral septum (LS; dorsal and ventral), hippocampus, and medial amygdala. Variations among the experimental groups were seen only in PFC, POA, LS. Ovariectomy increased OTR density in PFC but had the opposite effect in POA. Lactating does had significantly reduced OTR density, relative to late pregnancy, in PFC and POA. Our results are consistent with a possible role of OT in modulating social and maternal behavior in rabbits since the brain regions sensitive to OT have been implicated in social interaction, learning and memory, olfactory processing and maternal behavior.

RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles.

Oxytocin modulates many aspects of social cognition and behaviors, including maternal nurturing, social recognition and bonding. Natural variation in oxytocin receptor (OXTR) density in the nucleus accumbens (NAcc) is associated with variation in alloparental behavior, and artificially enhancing OXTR expression in the NAcc enhances alloparental behavior and pair bonding in socially monogamous prairie voles. Furthermore, infusion of an OXTR antagonist into the NAcc inhibits alloparental behavior and partner preference formation. However, antagonists can promiscuously interact with other neuropeptide receptors. To directly examine the role of OXTR signaling in social bonding, we used RNA interference to selectively knockdown, but not eliminate, OXTR in the NAcc of female prairie voles and examined the impact on social behaviors. Using an adeno-associated viral vector expressing a short hairpin RNA (shRNA) targeting Oxtr mRNA, we reduced accumbal OXTR density in female prairie voles from juvenile age through adulthood. Females receiving the shRNA vector displayed a significant reduction in alloparental behavior and disrupted partner preference formation. These are the first direct demonstrations that OXTR plays a critical role in alloparental behavior and adult social attachment, and suggest that natural variation in OXTR expression in this region alone can create variation in social behavior.

Prenatal antipsychotic exposure and neuromotor performance during infancy.

CONTEXT: Despite the expanding clinical utility of antipsychotics beyond psychotic disorders to include depressive, bipolar, and anxiety disorders, reproductive safety data regarding the neurodevelopmental sequelae of fetal antipsychotic exposure are scarce. OBJECTIVE: To examine whether intrauterine antipsychotic exposure is associated with deficits in neuromotor performance and habituation in 6-month-old infants. DESIGN, SETTING, AND PARTICIPANTS: A prospective controlled study was conducted from December 1999 through June 2008 at the Infant Development Laboratory of the Emory Psychological Center examining maternal-infant dyads (N=309) at 6 months postpartum with pregnancy exposure to antipsychotics (n=22), antidepressants (n=202), or no psychotropic agents (n=85). Examiners masked to maternal-infant exposure status administered a standardized neuromotor examination (Infant Neurological International Battery [INFANIB]) that tests posture, tone, reflexes, and motor skills and a visual habituation paradigm using a neutral female face. MAIN OUTCOME MEASURES: The INFANIB composite score; number of trials required to achieve a 50% decrease in infant fixation during a visual habituation task; and mean time looking at the stimulus across 10 trials. RESULTS: Infants prenatally exposed to antipsychotics (mean=64.71) showed significantly lower INFANIB scores than those with antidepressant (mean=68.57) or no psychotropic (mean=71.19) exposure, after controlling for significant covariates (F(2,281)=4.51; P=.01; partial η(2)=0.033). The INFANIB scores were also significantly associated with maternal psychiatric history, including depression, psychosis, and overall severity/chronicity (P's.05) and maternal depression during pregnancy was associated with less efficient habituation (r(245)=0.16; P.02). There were no significant differences regarding habituation between medication exposure groups. CONCLUSIONS: Among 6-month-old infants, a history of intrauterine antipsychotic exposure, compared with antidepressant or no psychotropic exposure, was associated with significantly lower scores on a standard test of neuromotor performance, highlighting the need for further scrutiny of the reproductive safety and neurodevelopmental sequelae of fetal antipsychotic exposure. Disentangling medication effects from maternal illness effects, which also contributed, remains a critical challenge.

Differences between trait fear and trait anxiety: implications for psychopathology.

Fear and anxiety are poorly delineated in much of the clinical and research literatures. Although some theorists and researchers have posited explanations for how trait fear and trait anxiety differ, many others conceptualize the constructs as largely or entirely interchangeable. The primary goals of this review are to examine clinical conceptualizations and neurobiological studies of fear and anxiety, examine the animal and human literatures on the correlates of fear and anxiety, provide clearer definitions of these two constructs, and discuss their implications for psychopathology. A secondary goal is to evaluate content of self-report measures of trait fear and anxiety, and meta-analyze the relations between self-reported trait fear and anxiety. We found that existing measures share significant content overlap across constructs. Despite this overlap, our meta-analysis revealed only a moderate (r=0.32) relationship between measures of trait fear and anxiety, with an even lower relationship (r=0.14) when we examined trait fear measures operationalized in terms of harm avoidance. These findings suggest that fear and anxiety are largely distinct emotions, and that psychological disorders of trait fear and trait anxiety warrant classification in separate higher-order categories. Moreover, they suggest that future research should focus on deriving more content valid measures of trait fear and trait anxiety from the neurobiological and diagnostic literatures.

Perinatal risk factors in the development of aggression and violence.

Over the past several decades, the relative contribution of both environmental and genetic influences in the development of aggression and violence has been explored extensively. Only fairly recently, however, has it become increasingly evident that early perinatal life events may substantially increase the vulnerability toward the development of violent and aggressive behaviors in offspring across the lifespan. Early life risk factors, such as pregnancy and birth complications and intrauterine exposure to environmental toxins, appear to have a profound and enduring impact on the neuroregulatory systems mediating violence and aggression, yet the emergence of later adverse behavioral outcomes appears to be both complex and multidimensional. The present chapter reviews available experimental and clinical findings to provide a framework on perinatal risk factors that are associated with altered developmental trajectories leading to violence and aggression, and also highlights the genetic contributions in the expression of these behaviors.

Neonatal injury alters adult pain sensitivity by increasing opioid tone in the periaqueductal gray.

Studies in both rodents and humans have shown that acute inflammatory pain experienced during the perinatal period produces long-term decreases in pain sensitivity (hypoalgesia) (Grunau et al., 1994a, 2001; Ren et al., 2004; LaPrairie and Murphy, 2007). To date, the mechanisms underlying these long-term adaptations, however, have yet to be elucidated. The present studies tested the hypothesis that neonatal inflammatory pain induces an upregulation in endogenous opioid tone that is maintained into adulthood, and that this increase in opioid tone provides the underlying mechanism for the observed hypoalgesia. On the day of birth (P0), inflammatory pain was induced in male and female Sprague-Dawley rats by intraplantar administration of carrageenan (CGN; 1%). In adulthood (P60), these animals displayed significantly increased paw withdrawal latencies in response to a noxious thermal stimulus in comparison to controls. Systemic administration of the brain-penetrant opioid receptor antagonist naloxone HCl, but not the peripherally restricted naloxone methiodide, significantly attenuated the injury-induced hypoalgesia. Direct administration of naloxone HCl or antagonists directed at the mu or delta opioid receptors into the midbrain periaqueductal gray (PAG) also significantly reversed the injury-induced hypoalgesia in adult rats. Parallel anatomical studies revealed that inflammatory pain experienced on the day of birth significantly increased beta-endorphin and met/leu-enkephalin protein levels and decreased opioid receptor expression in the PAG of the adult rat. Thus, early noxious insult produces long-lasting alterations in endogenous opioid tone, thereby profoundly impacting nociceptive responsiveness in adulthood.

Female rats are more vulnerable to the long-term consequences of neonatal inflammatory injury.

Premature infants are routinely exposed to invasive medical procedures during neonatal intensive care treatment that are largely performed in the absence of anesthetics or analgesics. Data collected to date suggest that exposure to early insult during this time of increased plasticity alters the development of the CNS and influences future pain responses. As previous studies examining the impact of neonatal injury on nociception have been conducted primarily in males, the potential adverse effects on females are not known. Therefore, the present studies were conducted to determine whether neonatal injury differentially impacts male and female sensory thresholds in adulthood. A short lasting inflammatory response was evoked in male and female rats on the day of birth with an injection of carrageenan (CGN; 1% or 2%) into the right hindpaw. Nociceptive thresholds were assessed using a noxious thermal stimulus at both adolescence (P40) and adulthood (P60). A more persistent inflammation was subsequently evoked in adult rats with an intraplantar injection of Complete Freund's adjuvant (CFA). Neonatally injured females exhibited significantly greater hypoalgesia at P60, and displayed enhanced inflammatory hyperalgesia following re-injury in adulthood compared to neonatally injured males and controls. These results demonstrate that the long-term adverse effects of neonatal injury are exacerbated in females, and may contribute to the higher prevalence, severity and duration of pain syndromes noted in women compared to men.