It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress.

Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons in vitro in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms.SIGNIFICANCE STATEMENT Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders.

Gating of the neuroendocrine stress responses by stressor salience in early lactating female rats is independent of infralimbic cortex activation and plasticity.

In early lactation (EL), stressor salience modulates neuroendocrine stress responses, but it is unclear whether this persists throughout lactation and which neural structures are implicated. We hypothesized that this process is specific to EL and that the infralimbic (IL) medial prefrontal cortex (mPFC) might provide a critical link between assessment of threat and activation of the hypothalamo-pituitary-adrenal (HPA) axis in EL. We measured neuroendocrine responses and neuronal Fos induction to a salient (predator odor) or non-salient (tail pinch) psychogenic stressor in EL and late lactation (LL) females. We found that EL females exhibited a large response to predator stress only in the presence of pups, while responses to tail pinch were reduced independently of pup presence. In LL, HPA axis responses were independent of pup presence for both stressors and only responses to tail pinch were modestly reduced compared to virgins. Intracerebral injection of the local anesthetic bupivacaine (BUP) (0.75%; 0.5 µl/side) in the IL mPFC did not differentially affect neuroendocrine responses to predator odor in virgin and EL females, suggesting that lactation-induced changes in this structure might not regulate stressor salience for the HPA axis. However, the IL mPFC displayed morphological changes in lactation, with significant increases in dendritic spine numbers and density in EL compared to LL and virgin females. EL females also showed improved performance in the attention set-shifting task (AST), which could reflect early plasticity in the IL mPFC at a time when rapid adaptation of the maternal brain is necessary for pup survival.

Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential.

The immediate and long-term effects of exposure to early life stress (ELS) have been documented in humans and animal models. Even relatively brief periods of stress during the first 10 days of life in rodents can impact later behavioral regulation and the vulnerability to develop adult pathologies, in particular an impairment of cognitive functions and neurogenesis, but also modified social, emotional, and conditioned fear responses. The development of preclinical models of ELS exposure allows the examination of mechanisms and testing of therapeutic approaches that are not possible in humans. Here, we describe limited bedding and nesting (LBN) procedures, with models that produce altered maternal behavior ranging from fragmentation of care to maltreatment of infants. The purpose of this paper is to discuss important issues related to the implementation of this chronic ELS procedure and to describe some of the most prominent endpoints and consequences, focusing on areas of convergence between laboratories. Effects on the hypothalamic-pituitary adrenal (HPA) axis, gut axis and metabolism are presented in addition to changes in cognitive and emotional functions. Interestingly, recent data have suggested a strong sex difference in some of the reported consequences of the LBN paradigm, with females being more resilient in general than males. As both the chronic and intermittent variants of the LBN procedure have profound consequences on the offspring with minimal external intervention from the investigator, this model is advantageous ecologically and has a large translational potential. In addition to the direct effect of ELS on neurodevelopmental outcomes, exposure to adverse early environments can also have intergenerational impacts on mental health and function in subsequent generation offspring. Thus, advancing our understanding of the effect of ELS on brain and behavioral development is of critical concern for the health and wellbeing of both the current population, and for generations to come.

The Impact of Neonatal Simulations on Trainees' Stress and Performance: A Parallel-Group Randomized Trial.

OBJECTIVES: Assess impact of neonatal simulation and simulated death on trainees' stress and performance. DESIGN: A parallel-group randomized trial (November 2011 to April 2012). SETTING: Sainte-Justine University Hospital, Montreal, Canada. SUBJECTS: Sixty-two pediatric trainees eligible, 59 consented, and 42 completed the study. INTERVENTIONS: Trainees performed two simulations where a term neonate was born pulseless. They were randomized to start with either survival (manikin responded to appropriate resuscitation) or death scenario (manikin remained pulseless despite resuscitation). MEASUREMENTS AND MAIN RESULTS: Performance was assessed using the Neonatal Resuscitation Program megacode score sheet by two reviewers. Subjective stress was assessed with a questionnaire. Three salivary cortisol (objective stress) values were compared: at baseline (T0: during lecture), presimulation (T1), and postsimulation (T2: after first scenario). Performance scores were similar in both groups in the first (83% vs 82%; p = 0.85) and second scenarios (82% vs 79 %; p = 0.87). Salivary cortisol levels at T0 (0.10 vs 0.10; p = 0.54), T1 (0.15 vs 0.11; p = 0.35), and T2 (0.23 vs 0.17; p = 0.23) did not differ between groups. Perceived stress level was six out of 10 in survival group versus seven out of 10 in death group (p = 0.19). Salivary cortisol increased significantly from T0 to T1 (p < 0.01). T2 cortisol levels were significantly higher than T1 (p< 0.001), yet this increase was not scenario dependent (p = 0.41) nor associated with performance on either scenario. Subscores for bag mask ventilation were lower than subscores for advanced resuscitation skills. CONCLUSIONS: Neonatal simulations cause significant anticipatory and participatory stress. Despite this, trainees' performance score in simulation was over 80%. Simulated death did not impact performance, magnitude of rise in salivary cortisol level, and perceived stress level. Trainees performed better at advanced resuscitation skills (which are rarely needed) compared with basic skills routinely performed in practice.

Inhibition of anandamide hydrolysis dampens the neuroendocrine response to stress in neonatal rats subjected to suboptimal rearing conditions.

Exposure to stress during early development can exert profound effects on the maturation of the neuroendocrine stress axis. The endocannabinoid (ECB) system has recently surfaced as a fundamental component of the neuroendocrine stress response; however, the effect of early-life stress on neonatal ECB signaling and the capacity to which ECB enhancement may modulate neonatal stress responses is relatively unknown. The present study assessed whether exposure to early-life stress in the form of limited access to nesting/bedding material (LB) from postnatal (PND) day 2 to 9 alters neuroendocrine activity and hypothalamic ECB content in neonatal rats challenged with a novel immobilization stressor. Furthermore, we examined whether inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of anandamide (AEA) affects neuroendocrine responses in PND10 pups as a function of rearing conditions. Neonatal rats showed a robust increase in corticosterone (CORT) and adrenocorticotropin hormone (ACTH) secretion in response to immobilization stress, which was significantly blunted in pups reared in LB conditions. Accordingly, LB pups exhibited reduced stress-induced Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, with no significant differences in hypothalamic ECB content. Administration of the FAAH inhibitor URB597 (0.3 mg/kg, ip) 90 min prior to immobilization stress significantly dampened stress-induced CORT release, but only in pups reared in LB conditions. These results suggest that rearing in restricted bedding conditions dampens the neuroendocrine response to stress, while augmenting AEA mitigates stress-induced alterations in glucocorticoid secretion preferentially in pups subjected to early-life stress.

Acute ingestion of beetroot bread increases endothelium-independent vasodilation and lowers diastolic blood pressure in healthy men: a randomized controlled trial.

Dietary nitrate, from beetroot, has been reported to lower blood pressure (BP) by the sequential reduction of nitrate to nitrite and further to NO in the circulation. However, the impact of beetroot on microvascular vasodilation and arterial stiffness is unknown. In addition, beetroot is consumed by only 4.5% of the UK population, whereas bread is a staple component of the diet. Thus, we investigated the acute effects of beetroot bread (BB) on microvascular vasodilation, arterial stiffness, and BP in healthy participants. Twenty-three healthy men received 200 g bread containing 100 g beetroot (1.1 mmol nitrate) or 200 g control white bread (CB; 0 g beetroot, 0.01 mmol nitrate) in an acute, randomized, open-label, controlled crossover trial. The primary outcome was postprandial microvascular vasodilation measured by laser Doppler iontophoresis and the secondary outcomes were arterial stiffness measured by Pulse Wave Analysis and Velocity and ambulatory BP measured at regular intervals for a total period of 6 h. Plasma nitrate and nitrite were measured at regular intervals for a total period of 7 h. The incremental area under the curve (0-6 h after ingestion of bread) for endothelium-independent vasodilation was greater (P = 0.017) and lower for diastolic BP (DBP; P = 0.032) but not systolic (P = 0.99) BP after BB compared with CB. These effects occurred in conjunction with increases in plasma and urinary nitrate (P < 0.0001) and nitrite (P < 0.001). BB acutely increased endothelium-independent vasodilation and decreased DBP. Therefore, enriching bread with beetroot may be a suitable vehicle to increase intakes of cardioprotective beetroot in the diet and may provide new therapeutic perspectives in the management of hypertension.

Exposure to high fat during early development impairs adaptations in dopamine and neuroendocrine responses to repeated stress.

Perturbations in the perinatal environment have been shown to significantly alter mesolimbic dopamine (DA) and hypothalamic-pituitary-adrenal (HPA) responses to stressors in adulthood. We have previously demonstrated that adult offspring exposed to high fat during the last week of gestation and throughout lactation display permanent alterations in mesolimbic DA function and behavior. The goal of the present study was to investigate nucleus accumbens (NAc) DA and HPA responses to acute and repeated stress in high fat exposed (HFD, 30% fat) and control (CD, 5% fat) offspring. Using microdialysis to monitor extracellular DA, we report that adult HFD offspring show an enhanced NAc DA response to acute tail-pinch compared to CD offspring. With repeated tail-pinch, the response of the HFD animals remains unchanged while CD offspring exhibit a sensitized DA response. The pattern of the DA response to both acute and repeated stress is also significantly altered by early diet exposure with an earlier peak and faster return to baseline levels in CD compared with HFD offspring. Similarly, neuroendocrine adaptations to repeated tail-pinch are observed in CD animals, but not in HFD animals. While controls display a habituated adrenocorticotropic hormone (ACTH) response to repeated tail-pinch, and an exacerbated ACTH response to a novel stressor, this effect was not observed in the HFD offspring. Together, our data demonstrate that exposure to high fat during early development impairs adaptations in NAc DA and HPA responses usually observed with repeated stress.

Trial of repeated analgesia with Kangaroo Mother Care (TRAKC Trial).

BACKGROUND: Skin-to-skin contact (SSC) between mother and infant, commonly referred to as Kangaroo Mother Care (KMC), is recommended as an intervention for procedural pain. Evidence demonstrates its consistent efficacy in reducing pain for a single painful procedure. The purpose of this study is to examine the sustained efficacy of KMC, provided during all routine painful procedures for the duration of Neonatal Intensive Care Unit (NICU) hospitalization, in diminishing behavioral pain response in preterm neonates. The efficacy of KMC alone will be compared to standard care of 24% oral sucrose, as well as the combination of KMC and 24% oral sucrose. METHODS/DESIGN: Infants admitted to the NICU who are less than 36 6/7 weeks gestational age (according to early ultrasound), that are stable enough to be held in KMC, will be considered eligible (N = 258). Using a single-blinded randomized parallel group design, participants will be assigned to one of three possible interventions: 1) KMC, 2) combined KMC and sucrose, and 3) sucrose alone, when they undergo any routine painful procedure (heel lance, venipuncture, intravenous, oro/nasogastric insertion). The primary outcome is infant's pain intensity, which will be assessed using the Premature Infant Pain Profile (PIPP). The secondary outcome will be maturity of neurobehavioral functioning, as measured by the Neurobehavioral Assessment of the Preterm Infant (NAPI). Gestational age, cumulative exposure to KMC provided during non-pain contexts, and maternal cortisol levels will be considered in the analysis. Clinical feasibility will be accounted for from nurse and maternal questionnaires. DISCUSSION: This will be the first study to examine the repeated use of KMC for managing procedural pain in preterm neonates. It is also the first to compare KMC to sucrose, or the interventions in combination, across time. Based on the theoretical framework of the brain opioid theory of attachment, it is expected that KMC will be a preferred standard of care. However, current pain management guidelines are based on minimal data on repeated use of either intervention. Therefore, regardless of the outcomes of this study, results will have important implications for guidelines and practices related to management of procedural pain in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01561547.

Peripheral clock gene oscillations are perturbed in neonatal and adult rat offspring raised under adverse limited bedding conditions.

Circadian (24-h) rhythms in the suprachiasmatic nucleus (SCN) are established in utero in rodents, but rhythmicity of peripheral circadian clocks appears later in postnatal development. Since peripheral oscillators can be influenced by maternal feeding and behavior, we investigated whether exposure to the adverse environmental conditions of limited bedding (LB) during postnatal life would alter rhythmicity in the SCN, adrenal gland and liver in neonatal (postnatal day PND10), juvenile (PND28) and adult rats. We also examined locomotor activity in adults. Limited bedding increased nursing time and slightly increased fragmentation of maternal behavior. Exposure to LB reduced the amplitude of Per2 in the SCN on PND10. Adrenal clock gene expression (Bmal1, Per2, Cry1, Rev-erbα, Dbp) and corticosterone secretion were rhythmic at all ages in NB offspring, whereas rhythmicity of Bmal1, Cry1 and corticosterone was abolished in neonatal LB pups. Circadian gene expression in the adrenal and liver was well established by PND28. In adults, liver expression of several circadian genes was increased at specific daytimes by LB and the microstructure of locomotor behavior was altered. Thus, changes in maternal care and behavior might provide important signals to the maturing peripheral oscillators and modify, in particular their output functions in the long-term.

The circadian variation of sleep and alertness of postmenopausal women.

STUDY OBJECTIVES: Several factors may contribute to the high prevalence of sleep disturbances occurring in postmenopausal women. However, the contribution of the circadian timing system to their sleep disturbances remains unclear. In the present study, we aim to understand the impact of circadian factors on changes of sleep and alertness occurring after menopause. METHODS: Eight healthy postmenopausal women and 12 healthy young women in their mid-follicular phase participated in an ultradian sleep-wake cycle procedure (USW). This protocol consisted of alternating 60-min wake periods and nap opportunities for ≥ 48 h in controlled laboratory conditions. Core body temperature (CBT), salivary melatonin, self-reported alertness, and polysomnographically recorded sleep were measured across this procedure. RESULTS: In both groups, all measures displayed a circadian variation throughout the USW procedure. Compared to young women, postmenopausal women presented lower CBT values, more stage N1 and N2 sleep, and number of arousals. They also showed a reduced amplitude of the circadian variation of melatonin, total sleep time (TST), sleep onset latency (SOL), stage N3 sleep, and alertness levels. Postmenopausal women fell asleep faster and slept more during the biological day and presented higher alertness levels during the biological night than young women. CONCLUSION: These results support the hypothesis of a weakened circadian signal promoting sleep and wakefulness in older women. Aging processes including hormonal changes may be main contributors to the increased sleep-wake disturbances after menopause.

Outcome Expectancies, Effects, and Mechanisms of Brief Training in Mindfulness Meditation vs. Loving-Kindness Meditation vs a Control Condition for Pain Management: A Randomized Pilot Study.

This study investigated the analgesic effects of a single session of mindfulness meditation (MM) and loving-kindness meditation (LKM) relative to a control. A total of 100 adults with chronic or current problematic pain completed a survey and were randomized to a 20-minute MM, LKM, or audiobook control. Co-primary outcomes of pain intensity and unpleasantness and mediators of mindfulness and self-compassion were assessed pre- and posttraining. Expectancies were assessed pretraining. Pain type (chronic vs current problematic) was a covariate. Relative to the control, higher expectancies were reported for MM and LKM (P < .001). MM (d = 0.41, P = .032) and LKM (d = 0.38, P = .027) had medium effects on pain intensity, with greater decreases than control (d = 0.05, P = .768). All conditions had small effects on unpleasantness. Mindful observing increased more within MM (d = 0.52, P = .022) and the control (d = 0.50, P = .011) than LKM (d = 0.12, P = .50); self-compassion increased more in LKM (d = 0.36, P = .042) than MM (d = 0.27, P = .201) and the control (d = 0.22, P = .249). The mediation models were nonsignificant. Pain type was a nonsignificant covariate. Overall, MM and LKM were associated with positive expectancies and small-medium pain intensity reductions, which did not differ by pain type. Although MM and LKM were associated with changes in theorized mediators, these changes did not underlie improvement.

Impact of a bronchiolitis clinical care pathway on treatment and hospital stay.

UNLABELLED: Bronchiolitis is a common lower respiratory tract infection of infancy where management has varied considerably in the past. The aim of the present study was to determine whether patient treatment and outcomes changed after introduction of a clinical care pathway. Infants aged up to 6 months admitted to hospital with bronchiolitis were identified as part of an annual audit of bronchiolitis management between winters 2003/2004 and 2009/2010. The primary outcome, duration of stay (DOS), was compared before and after the clinical pathway was introduced before the winter 2005/2006. There were 328 infants identified, mean age 75 days, respiratory syncitial virus was detected in 89%. After the clinical pathway was introduced, the proportion of infants prescribed salbutamol fell from 50% to 8% (p < 0.001) and ipratropium bromide from 38% to 0% (p < 0.001) but the proportion prescribed antibiotics was unchanged. The median DOS was 79 h prior to the clinical pathway and 66 h afterwards (p = 0.010) but there was no difference in days where supplemental oxygen or nasogastric feeding was required. CONCLUSIONS: A clinical pathway for the management of acute bronchiolitis can be implemented in the hospital setting and the conservative approach, in particular not prescribing bronchodilators, is not associated with prolonged duration of stay.

Brief communication: prenatal and early postnatal stress exposure influences long bone length in adult rat offspring.

Stress during the prenatal and early postnatal periods (perinatal stress, PS) is known to impact offspring cognitive, behavioral, and physical development, but effects on skeletal growth are not clear. Our objective was to analyze effects of variable, mild, daily PS exposure on adult offspring long bone length. Twelve pregnant rat dams were randomly assigned to receive variable stress from gestational days 14-21 (Prenatal group), postpartum days 2-9 (Postnatal), both periods (Pre-Post), or no stress (Control). Differences in adult offspring tibia and femur length were analyzed among treatment groups. Mean tibia length differed among groups for males (P = 0.016) and females (P = 0.009), and differences for femur length approached significance for males (P = 0.051). Long bone length was shorter among PS-exposed offspring, especially those exposed to postnatal stress (Postnatal and Pre-Post groups). Results persisted when controlling for nose-tail length. These differences might reflect early stunting that is maintained in adulthood, or delayed growth among PS-exposed offspring. This study suggests that PS results in shorter long bones in adulthood, independently of effects on overall body size. Stunting and growth retardation are major global health burdens. Our study adds to a growing body of evidence suggesting that PS is a risk factor for poor linear growth.

The critical role of S-lactoylglutathione formation during methylglyoxal detoxification in Escherichia coli.

Survival of exposure to methylglyoxal (MG) in Gram-negative pathogens is largely dependent upon the operation of the glutathione-dependent glyoxalase system, consisting of two enzymes, GlxI (gloA) and GlxII (gloB). In addition, the activation of the KefGB potassium efflux system is maintained closed by glutathione (GSH) and is activated by S-lactoylGSH (SLG), the intermediate formed by GlxI and destroyed by GlxII. Escherichia coli mutants lacking GlxI are known to be extremely sensitive to MG. In this study we demonstrate that a ΔgloB mutant is as tolerant of MG as the parent, despite having the same degree of inhibition of MG detoxification as a ΔgloA strain. Increased expression of GlxII from a multicopy plasmid sensitizes E. coli to MG. Measurement of SLG pools, KefGB activity and cytoplasmic pH shows these parameters to be linked and to be very sensitive to changes in the activity of GlxI and GlxII. The SLG pool determines the activity of KefGB and the degree of acidification of the cytoplasm, which is a major determinant of the sensitivity to electrophiles. The data are discussed in terms of how cell fate is determined by the relative abundance of the enzymes and KefGB.

Effects of stress across the lifespan.

Stress is a known precipitant for metabolic and neurological diseases, with sensitive periods identified across the developmental continuum from conception to old age. However, the effects of stress may vary depending on the point or points along the developmental trajectory when adversity strikes. Past research has emphasized the consequences of stress on fully developed physiological systems in the brain and periphery, but more recent studies have explored the impact of stress on systems at different stages of maturation, with differential effects being revealed. This review provides an overview of the diverse effects of stress at critical developmental stages and the potential outcomes that may be associated with experiencing environmental adversity during ontogeny.

Melanin externalization in Candida albicans depends on cell wall chitin structures.

The fungal pathogen Candida albicans produces dark-pigmented melanin after 3 to 4 days of incubation in medium containing l-3,4-dihydroxyphenylalanine (l-DOPA) as a substrate. Expression profiling of C. albicans revealed very few genes significantly up- or downregulated by growth in l-DOPA. We were unable to determine a possible role for melanin in the virulence of C. albicans. However, we showed that melanin was externalized from the fungal cells in the form of electron-dense melanosomes that were free or often loosely bound to the cell wall exterior. Melanin production was boosted by the addition of N-acetylglucosamine to the medium, indicating a possible association between melanin production and chitin synthesis. Melanin externalization was blocked in a mutant specifically disrupted in the chitin synthase-encoding gene CHS2. Melanosomes remained within the outermost cell wall layers in chs3Delta and chs2Delta chs3Delta mutants but were fully externalized in chs8Delta and chs2Delta chs8Delta mutants. All the CHS mutants synthesized dark pigment at equivalent rates from mixed membrane fractions in vitro, suggesting it was the form of chitin structure produced by the enzymes, not the enzymes themselves, that was involved in the melanin externalization process. Mutants with single and double disruptions of the chitinase genes CHT2 and CHT3 and the chitin pathway regulator ECM33 also showed impaired melanin externalization. We hypothesize that the chitin product of Chs3 forms a scaffold essential for normal externalization of melanosomes, while the Chs8 chitin product, probably produced in cell walls in greater quantity in the absence of CHS2, impedes externalization.

Effects of Early Life Stress on the Developing Basolateral Amygdala-Prefrontal Cortex Circuit: The Emerging Role of Local Inhibition and Perineuronal Nets.

The links between early life stress (ELS) and the emergence of psychopathology such as increased anxiety and depression are now well established, although the specific neurobiological and developmental mechanisms that translate ELS into poor health outcomes are still unclear. The consequences of ELS are complex because they depend on the form and severity of early stress, duration, and age of exposure as well as co-occurrence with other forms of physical or psychological trauma. The long term effects of ELS on the corticolimbic circuit underlying emotional and social behavior are particularly salient because ELS occurs during critical developmental periods in the establishment of this circuit, its local balance of inhibition:excitation and its connections with other neuronal pathways. Using examples drawn from the human and rodent literature, we review some of the consequences of ELS on the development of the corticolimbic circuit and how it might impact fear regulation in a sex- and hemispheric-dependent manner in both humans and rodents. We explore the effects of ELS on local inhibitory neurons and the formation of perineuronal nets (PNNs) that terminate critical periods of plasticity and promote the formation of stable local networks. Overall, the bulk of ELS studies report transient and/or long lasting alterations in both glutamatergic circuits and local inhibitory interneurons (INs) and their associated PNNs. Since the activity of INs plays a key role in the maturation of cortical regions and the formation of local field potentials, alterations in these INs triggered by ELS might critically participate in the development of psychiatric disorders in adulthood, including impaired fear extinction and anxiety behavior.

High cortisol levels in the offspring of parents with bipolar disorder during two weeks of daily sampling.

OBJECTIVES: The hypothalamic-pituitary-adrenal (HPA) axis is compromised in major depression, bipolar disorder (BD), and in the offspring of parents with major depression. Less is known about the offspring of parents with BD (FH+). The present project provides follow-up to a previous study showing that the adolescent (mean age 16.7 years) FH+ offspring had higher salivary cortisol levels than the offspring of parents with no mental disorder (FH-) throughout the day in their natural environment, and that girls had higher cortisol levels than boys (Ellenbogen MA, Hodgins S, Walker C-D, Adam S, Couture S. Daytime cortisol and stress reactivity in the offspring of parents with bipolar disorder. Psychoneuroendocrinology 2006; 31: 1164-1180). The goal of the present study was to determine whether FH+ offspring, approximately two years later, continued to exhibit elevated cortisol levels relative to FH- offspring during two weeks of daily sampling. METHODS: The present study examined salivary cortisol levels in 24 (18.3 +/- 2.6 years) FH+ and 22 (18.0 +/- 2.3 years) FH- offspring who are part of the same longitudinal cohort as the previous study. Saliva was collected at 1300 h and 1500 h in the natural environment of the offspring during 14 consecutive days. RESULTS: Multilevel modelling analyses indicated that FH+ offspring had higher afternoon levels of cortisol in their natural environment than FH- offspring, but group differences in slope and gender differences were not found. CONCLUSIONS: The FH+ offspring exhibited increased daytime secretion of cortisol that, at the level of the group, persisted into late adolescence and young adulthood. Perhaps this change in HPA functioning is associated with an increased vulnerability for the development of an affective disorder.

Maternal touch and feed as critical regulators of behavioral and stress responses in the offspring.

For half a century, Seymour Levine's pioneering work on the interactions between mother and infant have helped us understand the critical early factors that shape physiology and behavior in the adult offspring. The work from my laboratory described in this review was based on many experiments by Levine and coworkers demonstrating that the quantity and quality of maternal milk and of maternal-infant contact influence different aspects of the hypothalamus-pituitary-adrenal (HPA) activity in the neonate. We have extended this work by showing that maternal high-fat feeding during the prenatal and lactational period blunts stress responsiveness in neonatal pups, in part mediated by increased circulating leptin levels in the offspring. The blunting of stress responses during this specific neonatal period might be beneficial to prevent the negative effects of exaggerated glucocorticoid secretion on the developing brain. In line with Levine's previous work, we found that maternal licking of the pups reduced stress responsiveness and inflammation in pups subjected to modest repeated pain during the first weeks of life and that it also blunted adult sensitivity to thermal pain. These studies have important implications for human infants as mechanisms aimed at reducing stress responsiveness can be considered protective to the developing brain from exaggerated and untimely neuroendocrine and sympathetic stimulation. Non-invasive interventions targeted at maternal nutrition and maternal care are relatively easy to implement and might have a significant effect on the health outcome of the offspring, particularly in a vulnerable population of term and pre-term babies.