Illuminating the landscape of sibling relationship quality: An evidence and gap map.

This paper used an evidence and gap map (EGM) to advance the scientific understanding of sibling relationship quality among children aged 2 to 18 years by synthesizing literature on 277 empirical studies from 1985 to 2022 to delineate patterns of study design, sampling, and measurement. Most existing research has utilized majority of White, middle-to-upper class, and/or two-caregiver family samples. Nearly 85% (n = 235) of studies used quantitative methods to measure sibling relationship quality across eight domains: conflict, warmth/affection, quality, cohesion, hostility, power/control, positive engagement, and conflict management. A total of 122 studies used a measure of sibling relationship quality as a predictor of sibling behavior, social, psychological, cognitive, health, or physiological outcomes. Future directions for research are discussed.

Examination of protective factors that promote prosocial skill development among children exposed to intimate partner violence.

This retrospective cohort study examined prosocial skills development in child welfare-involved children, how intimate partner violence (IPV) exposure explained heterogeneity in children's trajectories of prosocial skill development, and the degree to which protective factors across children's ecologies promoted prosocial skill development. Data were from 1,678 children from the National Survey of Child and Adolescent Well-being I, collected between 1999 and 2007. Cohort-sequential growth mixture models were estimated to identify patterns of prosocial skill development between the ages of 3 to 10 years. Four diverse pathways were identified, including two groups that started high (high subtle-decreasing; high decreasing-to-increasing) and two groups that started low (low stable; low increasing-to-decreasing). Children with prior history of child welfare involvement, preschool-age IPV exposure, school-age IPV exposure, or family income below the federal poverty level had higher odds of being in the high decreasing-to-increasing group compared with the high subtle-decreasing group. Children with a mother with greater than high school education or higher maternal responsiveness had higher odds of being in the low increasing-to-decreasing group compared with the low stable group. The importance of maternal responsiveness in fostering prosocial skill development underlines the need for further assessment and intervention. Recommendations for clinical assessment and parenting programs are provided.

Ontogenetic changes in bite force and gape in tufted capuchins.

Bite force and gape are two important performance metrics of the feeding system, and these metrics are inversely related for a given muscle size because of fundamental constraints in sarcomere length-tension relationships. How these competing performance metrics change in developing primates is largely unknown. Here, we quantified in vivo bite forces and gapes across ontogeny and examined these data in relation to body mass and cranial measurements in captive tufted capuchins, Sapajus spp. Bite force and gape were also compared across geometric and mechanical properties of mechanically challenging foods to investigate relationships between bite force, gape and food accessibility (defined here as the ability to breach shelled nuts). Bite forces at a range of gapes and feeding behavioral data were collected from a cross-sectional ontogenetic series of 20 captive and semi-wild tufted capuchins at the Núcleo de Procriação de Macacos-Prego Research Center in Araçatuba, Brazil. These data were paired with body mass, photogrammetric measures of jaw length and facial width, and food geometric and material properties. Tufted capuchins with larger body masses had absolutely higher in vivo bite forces and gapes, and animals with wider faces had absolutely higher bite forces. Bite forces and gapes were significantly smaller in juveniles compared with subadults and adults. These are the first primate data to empirically demonstrate the gapes at which maximum active bite force is generated and to demonstrate relationships to food accessibility. These data advance our understanding of how primates meet the changing performance demands of the feeding system during development.

Corticosteroid Receptors in Cardiac Health and Disease.

Nuclear receptors play a central role in both energy metabolism and cardiomyocyte death and survival in the heart. Recent evidence suggests they may also influence cardiomyocyte endowment. Although several members of the nuclear receptor family play key roles in heart maturation (including thyroid hormone receptors) and cardiac metabolism, here, the focus will be on the corticosteroid receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). The heart is an important target for the actions of corticosteroids, yet the homeostatic role of GR and MR in the healthy heart has been elusive. However, MR antagonists are important in the treatment of heart failure, a condition associated with mitochondrial dysfunction and energy failure in cardiomyocytes leading to mitochondria-initiated cardiomyocyte death (Ingwall and Weiss, Circ Res 95:135-145, 2014; Ingwall , Cardiovasc Res 81:412-419, 2009; Zhou and Tian , J Clin Invest 128:3716-3726, 2018). In contrast, animal studies suggest GR activation in cardiomyocytes has a cardioprotective role, including in heart failure.

A preventable, life-altering case of fluoroquinolone-associated tendonitis.

ABSTRACT: Fluoroquinolones, such as ciprofloxacin and levofloxacin, are broad-spectrum antibacterial agents that have historically been widely used for urinary tract infections, pneumonia, and intra-abdominal infections but are associated with several serious adverse reactions, including tendinopathy and tendon rupture, peripheral neuropathy, and aortic aneurysm. These drugs should not be used for uncomplicated infections unless no other antimicrobial treatment is feasible. This article describes a patient who experienced life-altering disability from a fluoroquinolone, reviews the adverse reactions of this drug class, and discusses recommended treatment for acute uncomplicated cystitis and asymptomatic bacteriuria.

Fiber-type phenotype of the jaw-closing muscles in Gorilla gorilla, Pan troglodytes, and Pan paniscus: A test of the Frequent Recruitment Hypothesis.

Skeletal muscle fiber types are important determinants of the contractile properties of muscle fibers, such as fatigue resistance and shortening velocity. Yet little is known about how jaw-adductor fiber types correlate with feeding behavior in primates. Compared with chimpanzees and bonobos, gorillas spend a greater percentage of their daily time feeding and shift to herbaceous vegetation when fruits are scarce. We thus used the African apes to test the hypothesis that chewing with unusually high frequency is correlated with the expression in the jaw adductors of a high proportion of type 1 (slow, fatigue-resistant) fibers at the expense of other fiber types (the Frequent Recruitment Hypothesis). We used immunohistochemistry to determine the presence and distribution of the four major myosin heavy chain (MHC) isoforms in the anterior superficial masseter (ASM), superficial anterior temporalis, and deep anterior temporalis of four Gorilla gorilla, two Pan paniscus, and four Pan troglodytes. Serial sections were stained against slow (MHC-1/-α-cardiac) and fast (MHC-2/-M) fibers. Fibers were counted and scored for staining intensity, and fiber cross-sectional areas (CSAs) were measured and used to estimate percentage of CSA of each MHC isoform. Hybrid fibers accounted for nearly 100% of fiber types in the masseter and temporalis of all three species, resulting in three main hybrid phenotypes. As predicted, the gorilla ASM and deep anterior temporalis comprised a greater percentage of CSA of the slower, fatigue-resistant hybrid fiber type, significantly so for the ASM (p = 0.015). Finally, the results suggest that fiber phenotype of the chewing muscles contributes to behavioral flexibility in ways that would go undetected in paleontological studies relying solely on morphology of the bony masticatory apparatus.

11ß-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action.

Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11ß-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11ß-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11ß-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11ß-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11ß-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11ß-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11ß-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11ß-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11ß-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11ß-HSD2 as a marker of programming is being explored. The 11ß-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

The Role of 11ß-Hydroxy Steroid Dehydrogenase Type 2 in Glucocorticoid Programming of Affective and Cognitive Behaviours.

Developmental exposure to stress hormones, i.e. glucocorticoids, is central to the process of prenatal programming of later-life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in a reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolizing enzyme 11ß-hydroxysteroid dehydrogenase type 2 (HSD2). HSD2 is highly expressed in 2 hubs during development, i.e. the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in a reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development are observed. However, brain-specific HSD2 removal (HSD2BKO) also generated adult phenotypes of depressive-like behaviour and memory deficits, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

The Source and the Course of the Articular Branches to the T4-T8 Zygapophysial Joints.

OBJECTIVE: To define the source and the course of the articular branches to the midthoracic zygapophysial ("z") joints. DESIGN: Cadaveric dissection. SETTING: The Gross Anatomy Laboratory of the Duke University School of Medicine. SUBJECTS: Ten human cadaveric thoraces. METHODS: Gross and stereoscopic dissection of dorsal rami T4-T8 was performed bilaterally on 10 adult embalmed cadavers. The medial and lateral branches were traced to their origins from the dorsal rami, and the course of the articular nerves was documented through digital photography. Radio-opaque wire (20 gauge) was applied to the nerves. Fluoroscopic images were obtained to delineate their radiographic course with respect to osseous landmarks. RESULTS: Forty-eight inferior articular branches were identified. Three (6.3%) originated from the medial branch and 44 (91.7%) from the dorsal ramus. One was indeterminate. Fifty-one superior articular branches were identified. Eight (15.7%) originated from the medial branch and 43 (84.3%) from the dorsal ramus. In 12% of cases (6/50), there was side-to-side asymmetry in the origins of the articular branches. Nerves were commonly suspended in the intertransverse space. The articular branches contacted an osseous structure in only 39% of cases. As previously reported, a "descending branch" was not identified in any specimen. CONCLUSIONS: Articular branches to the T4-T8 z-joints have substantial inter- and intraspecimen variability of origin. They typically arise from the dorsal ramus rather than the medial branch and frequently do not contact any osseous structure to allow percutaneous needle placement.

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess.

Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11ß-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11ß-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.

Resilient and depressive-like rats show distinct cognitive impairments in the touchscreen paired-associates learning (PAL) task.

Depression-associated cognitive impairments persist after remission from affective symptoms of major depressive disorder (MDD), decreasing quality of life and increasing risk of relapse in patients. Conventional antidepressants are ineffective in restoring cognitive functions. Therefore, novel antidepressants with improved efficacy for ameliorating cognitive symptoms are required. For tailoring such antidepressants, translational animal models are in demand. The chronic mild stress (CMS) model is a well-validated preclinical model of depression and known for eliciting the MDD core symptom "anhedonia" in stress-susceptible rats. Thus, cognitive performance was assessed in rats susceptible (depressive-like) or resilient to CMS and in unchallenged controls. The rodent analogue of the human touchscreen Paired-Associates Learning (PAL) task was used for cognitive assessment. Both stress groups exhibited a lack of response inhibition compared to controls while only the depressive-like group was impaired in task acquisition. The results indicate that cognitive deficits specifically associate with the anhedonic-like state rather than being a general consequence of stress exposure. Hence, we propose that the application of a translational touchscreen task on the etiologically valid CMS model, displaying depression-associated cognitive impairments, provides a novel platform for pro-cognitive and clinically pertinent antidepressant drug screening.

11ß-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation.

Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11ß-hydroxysteroid dehydrogenase type-1 (11ß-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11ß-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11ß-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11ß-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11ß-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Highly active spore biocatalyst by self-assembly of co-expressed anchoring scaffoldin and multimeric enzyme.

We report a spore-based biocatalysis platform capable of producing and self-assembling active multimeric enzymes on a spore surface with a high loading density. This was achieved by co-expressing both a spore surface-anchoring scaffoldin protein containing multiple cohesin domains and a dockerin-tagged enzyme of interest in the mother cell compartment during Bacillus subtilis sporulation. Using this method, tetrameric ß-galactosidase was successfully displayed on the spore surface with a loading density of 1.4 × 104 active enzymes per spore particle. The resulting spore biocatalysts exhibited high conversion rates of transgalactosylation in water/organic emulsions. With easy manufacture, enhanced thermostability, excellent reusability, and long-term storage stability at ambient temperature, this approach holds a great potential in a wide range of biocatalysis applications especially involving organic phases.

Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer.

Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. In this study, hyaluronic acid derived nanoparticles with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG was not cytotoxic to healthy pancreatic epithelial cells and did not induce chemotaxis or phagocytosis, it accumulated significantly within the pancreas in an orthotopic pancreatic ductal adenocarcinoma model, and demonstrated contrast-enhancement for pancreatic lesions relative to non-diseased portions of the pancreas. Fluorescence microscopy showed higher fluorescence intensity in pancreatic lesions and splenic metastases due to NanoICG compared to ICG alone. The in vivo safety profile of NanoICG, including, biochemical, hematological, and pathological analysis of NanoICG-treated healthy mice, indicates negligible toxicity. These results suggest that NanoICG is a promising contrast agent for intraoperative detection of pancreatic tumors.

Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension.

BACKGROUND: The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11ßHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11ßHSD2 brain-specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults. METHODS AND RESULTS: Basal blood pressure, electrolytes, and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3 times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing the intrinsic salt resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals. CONCLUSIONS: Reduced 11ßHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11ßHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.

Maternal depression and intimate partner violence exposure: Longitudinal analyses of the development of aggressive behavior in an at-risk sample.

A substantial body of literature has documented the negative effects of intimate partner violence (IPV) on a wide range of children's developmental outcomes. However, whether a child's exposure to IPV leads to increased adjustment difficulties is likely to depend on a variety of factors, including the caregiver's mental health and the developmental time period when IPV exposure occurs. The present study seeks to improve our understanding of the long-term effects of IPV exposure and maternal depression on the development of children's overt aggressive behavior. Longitudinal analyses (i.e., latent growth curve modeling) examining three time points (toddler: age 2-3 years, preschool/kindergarten: age 4-5 years, and elementary school: age 6-8 years) were conducted using 1,399 at-risk children drawn from the National Survey of Child and Adolescent Well-Being (NSCAW-I). IPV exposure during age 2-3 years was significantly related to concurrent aggressive behavior and aggressive behavior during age 4-5 years. At all three time points, IPV was significantly associated with maternal depression, which in turn, was significantly related to higher levels of aggressive behavior. There was also a significant indirect lagged effect of IPV exposure at age 2-3 years through maternal depression on aggressive behavior at age 4-5 years. Results indicated that maternal depression was a strong predictor of increased reports of overt aggressive behavior, suggesting that interventions to buffer the effects of IPV exposure should focus on relieving maternal depression and fostering productive social behavior in children. Aggr. Behav. 43:375-385, 2017. © 2017 Wiley Periodicals, Inc.

Children's Exposure to Violence: The Underlying Effect of Posttraumatic Stress Symptoms on Behavior Problems.

In this study we investigated whether witnessing violence and violence victimization were associated with children's internalizing and externalizing behavior problems and examined the mediating role of posttraumatic stress (PTS) symptoms in these relationships. Secondary data analysis was conducted using 3 waves of data from the National Survey of Child and Adolescent Well-Being. Path analyses were conducted to test direct and indirect effects of violence exposure on behavior problems, using 2,064 children (ages 8-15 years) reported to Child Protective Services for maltreatment. Being a victim of violence in the home was directly associated with more internalizing (ß = .06, p = .007) and externalizing behavior problems (ß = .07, p = .002), whereas witnessing violence was not directly related to either internalizing (ß = .04, p = .056) or externalizing behavior problems (ß = .03, p = .130). PTS symptoms mediated the effects of witnessing violence and violence victimization on internalizing behavior problems (ß = .02, p = .002). Our findings suggest that PTS symptoms may be a mechanism underlying the association between violence exposure and internalizing behavior problems (R(2) = .23), underscoring the potential importance of assessing PTS symptoms and providing targeted trauma-focused interventions for children exposed to violence at home.

Glucocorticoid receptor is required for foetal heart maturation.

Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet excessive foetal exposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late-gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them with mice with global deficiency in GR (GR(-/-)). Echocardiography shows impaired heart function in both SMGRKO and GR(-/-) mice at embryonic day (E)17.5, associated with generalized oedema. Cardiac ultrastructure is markedly disrupted in both SMGRKO and GR(-/-) mice at E17.5, with short, disorganized myofibrils and cardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR(-/-) mice are smaller, with 22% reduced ventricular volume at E17.5, SMGRKO hearts are normally sized. Moreover, while levels of mRNA encoding atrial natriuretic peptide are reduced in E17.5 GR(-/-) hearts, they are normal in foetal SMGRKO hearts. These data demonstrate that structural, functional and biochemical maturation of the foetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites.

Imaging learned fear circuitry in awake mice using fMRI.

Functional magnetic resonance imaging (fMRI) of learned behaviour in 'awake rodents' provides the opportunity for translational preclinical studies into the influence of pharmacological and genetic manipulations on brain function. fMRI has recently been employed to investigate learned behaviour in awake rats. Here, this methodology is translated to mice, so that future fMRI studies may exploit the vast number of genetically modified mouse lines that are available. One group of mice was conditioned to associate a flashing light (conditioned stimulus, CS) with foot shock (PG; paired group), and another group of mice received foot shock and flashing light explicitly unpaired (UG; unpaired group). The blood oxygen level-dependent signal (proxy for neuronal activation) in response to the CS was measured 24 h later in awake mice from the PG and UG using fMRI. The amygdala, implicated in fear processing, was activated to a greater degree in the PG than in the UG in response to the CS. Additionally, the nucleus accumbens was activated in the UG in response to the CS. Because the CS signalled an absence of foot shock in the UG, it is possible that this region is involved in processing the safety aspect of the CS. To conclude, the first use of fMRI to visualise brain activation in awake mice that are completing a learned emotional task is reported. This work paves the way for future preclinical fMRI studies to investigate genetic and environmental influences on brain function in transgenic mouse models of disease and aging.

Prepubertal stress and hippocampal function: sex-specific effects.

The chances of developing psychiatric disorders in adulthood are increased when stress is experienced early in life. In particular, stress experienced in the childhood or 'prepubertal' phase is associated with the later development of disorders such as depression, anxiety, post-traumatic stress disorder, and psychosis. Relatively little is known about the biological basis of this effect, but one hypothesis is that prepubertal stress produces long-lasting changes in brain development, particularly in stress sensitive regions such as the hippocampus, leaving an individual vulnerable to disorders in adulthood. In this study, we used an animal model of prepubertal stress to investigate the hypothesis that prepubertal stress induces alterations in hippocampal function in adulthood. Male and female rats were exposed to a brief, variable prepubertal stress protocol (postnatal days 25-27), and their performance in two distinct hippocampal-dependent tasks (contextual fear and spatial navigation) was compared with controls in adulthood. Prepubertal stress significantly impaired contextual fear responses in males and enhanced performance in spatial navigation in females. These results demonstrate that exposure to a brief period of stress in the prepubertal phase alters hippocampal-dependent behaviors in adulthood in a sex-specific manner.