G Protein Activation Occurs via a Largely Universal Mechanism.

Understanding how signaling proteins like G proteins are allosterically activated is a long-standing challenge with significant biological and medical implications. Because it is difficult to directly observe such dynamic processes, much of our understanding is based on inferences from a limited number of static snapshots of relevant protein structures, mutagenesis data, and patterns of sequence conservation. Here, we use computer simulations to directly interrogate allosteric coupling in six G protein α-subunit isoforms covering all four G protein families. To analyze this data, we introduce automated methods for inferring allosteric networks from simulation data and assessing how allostery is conserved or diverged among related protein isoforms. We find that the allosteric networks in these six G protein α subunits are largely conserved and consist of two pathways, which we call pathway-I and pathway-II. This analysis predicts that pathway-I is generally dominant over pathway-II, which we experimentally corroborate by showing that mutations to pathway-I perturb nucleotide exchange more than mutations to pathway-II. In the future, insights into unique elements of each G protein family could inform the design of isoform-specific drugs. More broadly, our tools should also be useful for studying allostery in other proteins and assessing the extent to which this allostery is conserved in related proteins.

Addressing Equity Asymmetries in General Chemistry Outcomes Through an Asset-Based Supplemental Course.

Undergraduate first-semester general chemistry (GC1) functions as a gatekeeper to STEM degrees, asymmetrically impacting students who are nonwhite, from lower socioeconomic groups, non-native English speakers, two-year college transfers, and first-generation in college. Nationally, just under 30% of students earn grades of D, F, or withdraw (termed DFW) in GC1; however, DFW rates are much higher for subgroups underrepresented in STEM occupations. Socioeconomic inequalities tend to increase over an individual's lifetime due to the magnification of cumulative disadvantage. Because undergraduate degrees correlate with higher employment and STEM occupations correlate with higher earnings, GC1 represents a critical path point where disparities can be interrupted. The most common strategy employed for GC1 is deficit remediation for students determined to be at risk of DFW. Unfortunately, extensive evidence demonstrates that the use of remediation strategies for GC1 does not sustain benefits for students. In this work, an asset-based approach, less prevalent in higher education than preuniversity, was employed to stress test theories about interrupting disparities in STEM education. This causal-comparative study involving 1,807 observations reports on a 1-credit asset-based supplemental course in which DFW-potential students at a minority-serving institution coenrolled during six semesters. The study outlines this intervention, its impact on GC1 outcomes, and its potential residual impact on progression to the next course in the general chemistry sequence (GC2). Descriptive and hierarchical inferential analysis of the data revealed socially important patterns. The asset-based intervention successfully attracted students with greater cumulative disadvantage. The intervention closed asymmetries between students identified as DFW-potential and ABC-potential in GC1 when a nontraditional curriculum was used but not when a traditional curriculum was used. Mixed results and contingent effects were found for the intervention's impact on subsequent course outcomes. Taking at least 11 credits in the semester of taking GC1 provided an inoculate for participants in the asset-based intervention, increasing the likelihood of passing GC2.

Early-life exercise primes the murine neural epigenome to facilitate gene expression and hippocampal memory consolidation.

Aerobic exercise is well known to promote neuroplasticity and hippocampal memory. In the developing brain, early-life exercise (ELE) can lead to persistent improvements in hippocampal function, yet molecular mechanisms underlying this phenomenon have not been fully explored. In this study, transgenic mice harboring the "NuTRAP" (Nuclear tagging and Translating Ribosome Affinity Purification) cassette in Emx1 expressing neurons ("Emx1-NuTRAP" mice) undergo ELE during adolescence. We then simultaneously isolate and sequence translating mRNA and nuclear chromatin from single hippocampal homogenates containing Emx1-expressing neurons. This approach allowed us to couple translatomic with epigenomic sequencing data to evaluate the influence of histone modifications H4K8ac and H3K27me3 on translating mRNA after ELE. A subset of ELE mice underwent a hippocampal learning task to determine the gene expression and epigenetic underpinnings of ELE's contribution to improved hippocampal memory performance. From this experiment, we discover gene expression - histone modification relationships that may play a critical role in facilitated memory after ELE. Our data reveal candidate gene-histone modification interactions and implicate gene regulatory pathways involved in ELE's impact on hippocampal memory.

"SIT" with Emx1-NuTRAP Mice: Simultaneous INTACT and TRAP for Paired Transcriptomic and Epigenetic Sequencing.

Epigenetic regulation of transcription is gaining increasing importance in the study of neurobiology. The advent of sequencing technology has enabled the study of this regulation across the entire genome and transcriptome. However, modern methods that allow the correlation of transcriptomic data with epigenomic regulation have had several key limitations, including use of separate tissue sources and detection of low-expression genes. This article describes a method combining isolation of nuclei tagged in specific cell types (INTACT) with translating ribosome affinity purification (TRAP) in the same cell homogenate, referred to as Simultaneous INTACT and TRAP (SIT). We used this technical approach to directly couple transcriptomic sequencing with epigenomic data in neurons derived from the mouse hippocampus. We demonstrate this method with an Emx1-NuTRAP transgenic mouse model. Here, we present protocols for SIT and for the generation and validation of the Emx1-NuTRAP mouse model that we used to demonstrate SIT. These methods enable cell type-specific comparison of translating mRNA and chromatin data from the same set of cells. Using SIT and the Emx1-NuTRAP transgenic mouse model, researchers can compare epigenomic data to transcriptomic data in the same set of hippocampal excitatory neurons. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Emx1-NuTRAP transgenic mouse line for labeling excitatory neurons in the hippocampus Basic Protocol 2: SIT: Simultaneous Isolation of nuclei tagged in specific cell types (INTACT) and Translating ribosome affinity purification (TRAP).

Pan-cancer analysis of fear of cancer recurrence among cancer survivors.

BACKGROUND: Fear of cancer recurrence (FCR) is a phenomenon estimated to affect a large portion of cancer survivors. This study sought to determine whether patients from a National Cancer Institute-designated institution had their clinical needs met relating to FCR. PATIENTS AND METHODS: Patients referred to the survivorship clinic completed The Clinical Needs Assessment Tool for Cancer Survivors (CNAT-CS). Correlations between responses were calculated and univariable and multivariable logistic regression was used to identify predictors of met or unmet needs related to FCR. RESULTS: Of 647 patients, 241 (37.2%) reported they did not have clinical needs related to FCR and 386 (59.7%) reported they had clinical needs related to FCR but that the needs had been met. Only 20 (3.09%) reported that clinical needs relating to FCR were unmet. According to univariate logistic regression, sex had no impact on FCR (P = 0.8427), nor did years since diagnosis (P = 0.1014). Results of multivariable regression indicate that the odds ratio of reported FCR as an unmet need (versus not a need) is 0.939; the odds decreased by 6% (P = 0.0023) for every year increase in age. For each unit increase in distress score, the odds of reporting FCR as an unmet need increased by 32% (P = 0.0007). CONCLUSIONS: This study is unique in not only examining the presence of FCR but also whether patients reported that their needs were met for FCR. The study found that most patients had clinical needs for FCR, but the needs were met at the time of the survey. Patients who report higher distress scores are more likely to report FCR as an unmet need. Therefore, cancer survivors reporting high distress scores in clinic visits should be evaluated for FCR.

Multidisciplinary team management of patients with urological cancer.

Several specialist teams are involved in the management of patients with urological cancer. These specialists have been brought together as a multidisciplinary team to discuss, plan and deliver care to patients in an effective, patient-centred approach. This article discusses the benefits of this approach and ways in which multidisciplinary team working can be optimized.

'Desculturización,' urbanization, and nutrition transition among urban Kichwas Indigenous communities residing in the Andes highlands of Ecuador.

BACKGROUND: The nutrition transition continues to affect populations throughout the world. The added impact of market integration and urbanization exacerbates the impact of the nutrition transition upon Indigenous populations worldwide. OBJECTIVES: This study aims to explore the nutritional concerns of the urban Kichwas community residing in the Andes highlands of Ecuador. STUDY DESIGN: This is a qualitative study. METHODS: Eight focus groups were conducted with Kichwas men and women in November 2015 in the Imbabura province of the Andes in Ecuador. DATA ANALYSIS: Applied thematic analysis was used to analyze findings regarding nutrition. RESULTS: The participants shared concerns regarding increased intake of fast food, poor meal timing, and a shift in the child's food preferences that rejects traditional foods. They attributed these concerns to urbanization resulting from an increase in dual-income households and a loss of cultural identity. CONCLUSIONS: Synergistic cultural factors are related to nutritional concerns voiced by the urban Kichwas community. PUBLIC HEALTH IMPLICATIONS: Syndemic theory is a useful interpretive lens regarding nutritional trends within the Kichwas communities as they relate to the increased risk of chronic disease.

Risk and resiliency: the syndemic nature of HIV/AIDS in the indigenous highland communities of Ecuador.

OBJECTIVES: This community-based study explores the syndemic nature of HIV/AIDS risk and resilience among Indigenous Kichwa communities in the province of Imbabura, Ecuador. This study elucidates individual and community-level factors that serve to exacerbate HIV/AIDS risk, as they relate to underlying macrolevel, structural forces. Critically, this study also elicited opportunities for community-based opportunities for resiliency from HIV/AIDS. STUDY DESIGN: Exploratory qualitative study. METHODS: Guided by syndemic theory, a qualitative study was conducted to explore HIV risk and resilience among Indigenous Kichwa communities in the Northern Andean highlands of Ecuador. Eight focus groups (n = 59) with men and women from two communities were conducted. The data were analyzed using applied thematic analysis techniques. RESULTS: Identified risk factors for HIV/AIDS centered around the following themes: (1) parents leaving the community for work, (2) alcohol and drug consumption, (3) unprotected sex, and (4) barriers to health care. Identified HIV/AIDS resiliency factors included the preservation of Indigenous culture and family-focused interventions. CONCLUSIONS: The identified risk factors for HIV/AIDS are interrelated within a complex syndemic relationship. The mutually reinforcing individual-level risk factors of substance abuse and risky sexual behavior coalesce with violence to exacerbate the risk for HIV/AIDS acquisition among Ecuadorian Highland Indigenous communities. Moreover, HIV/AIDS risk prevails in the macrolevel context of disproportionate unemployment among Indigenous peoples and a systematically fragmented healthcare system. It is critical that public health professionals work to revolutionize the systematic discrimination that underpins indigenous health disparities at-large.

Targeting nucleotide exchange to inhibit constitutively active G protein α subunits in cancer cells.

Constitutively active G protein α subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in these disorders has yet to be achieved. We found that constitutively active Gαq in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate-for-guanosine triphosphate (GDP/GTP) exchange to trap constitutively active Gαq in inactive, GDP-bound Gαßγ heterotrimers. Allosteric inhibition of other Gα subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active Gαq, FR inhibited second messenger signaling, arrested cell proliferation, reinstated melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF-driven UM cells. FR promoted UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide therapeutic targets for UM. The development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein-coupled receptors (GPCRs) where targeting a single receptor is ineffective.

High-throughput behavioral assay to investigate seizure sensitivity in zebrafish implicates ZFHX3 in epilepsy.

Epilepsy, which affects ∼1% of the population, is caused by abnormal synchronous neural activity in the central nervous system (CNS). While there is a significant genetic contribution to epilepsy, the underlying causes for the majority of genetic cases remain unknown. The NIH Undiagnosed Diseases Project (UDP) utilized exome sequencing to identify genetic variants in patients affected by various conditions with undefined etiology, including epilepsy. Confirming the functional relevance of the candidate genes identified by exome sequencing in a timely manner is crucial to translating exome data into clinically useful information. To this end, we developed a high throughput version of a seizure-sensitivity assay in zebrafish (Danio rerio) to rapidly evaluate candidate genes found by exome sequencing. We developed open access software, Studying Epilepsy In Zebrafish using R (SEIZR), to efficiently analyze the data. SEIZR was validated by disrupting function of a known epilepsy gene, prickle 1. Next, using SEIZR, we analyzed a candidate gene from the UDP screen (Zinc Finger Homeobox 3, ZFHX3), and showed that reduced ZFHX3 function in zebrafish results in a significant hyperactive response to the convulsant drug pentylenetetrazol (PTZ). We find that ZFHX3 shows strong expression in the CNS during neurogenesis including in the pallium, thalamus, tegmentum, reticular formation, and medulla oblongata - all regions which have roles in motor control and coordination. Our findings in the zebrafish confirm human ZFHX3 is a strong candidate for further neurological studies. We offer SEIZR to other researchers as a tool to rapidly and efficiently analyze large behavioral data sets.

Decreased fecundity and sperm DNA methylation patterns.

OBJECTIVE: To evaluate the relationship between epigenetic patterns in sperm and fecundity. DESIGN: Prospective study. SETTING: Academic andrology and in vitro fertilization laboratory. PATIENT(S): Twenty-seven semen samples from couples who conceived within 2 months of attempting a pregnancy and 29 semen samples from couples unable to achieve a pregnancy within 12 months. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genomewide assessment of differential sperm DNA methylation and standard semen analysis. RESULT(S): We analyzed DNA methylation alterations associated with fecundity in 124 semen samples, and identified regions of interest in 27 semen samples from couples who conceived within 2 months of attempting a pregnancy and a total of 29 semen samples from couples who were unable to achieve a pregnancy within 12 months. No differences in sperm count, sperm morphology, or semen volume were observed between the patients achieving a pregnancy within 2 months of study time and those not obtaining a pregnancy within 12 months. However, using data from the human methylation 450k array analysis we did identify two genomic regions with statistically significantly decreased (false discovery rate <0.01) methylation and three genomic regions with statistically significantly increased methylation in the failure-to-conceive group. The only two sites where decreased methylation was associated with reduced fecundity are at closely related genes known to be expressed in sperm, HSPA1L and HSPA1B. CONCLUSION(S): Our data suggest that there are genomic loci where DNA methylation alterations are associated with decreased fecundity. We have thus identified candidate loci for future study to verify these results and investigate the causative or contributory relationship between altered sperm methylation and decreased fecundity.

Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy.

BACKGROUND: In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. METHODS: A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels. RESULTS: An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs. CONCLUSION: We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.

Forelimb amputation-induced reorganization in the ventral posterior lateral nucleus (VPL) provides a substrate for large-scale cortical reorganization in rat forepaw barrel subfield (FBS).

In this study, we examined the role of the ventral posterior lateral nucleus (VPL) as a possible substrate for large-scale cortical reorganization in the forepaw barrel subfield (FBS) of primary somatosensory cortex (SI) that follows forelimb amputation. Previously, we reported that, 6 weeks after forelimb amputation in young adult rats, new input from the shoulder becomes expressed throughout the FBS that quite likely has a subcortical origin. Subsequent examination of the cuneate nucleus (CN) 1 to 30 weeks following forelimb amputation showed that CN played an insignificant role in cortical reorganization and led to the present investigation of VPL. As a first step, we used electrophysiological recordings in forelimb intact adult rats (n=8) to map the body representation in VPL with particular emphasis on the forepaw and shoulder representations and showed that VPL was somatotopically organized. We next used stimulation and recording techniques in forelimb intact rats (n=5) and examined the pattern of projection (a) from the forelimb and shoulder to SI, (b) from the forepaw and shoulder to VPL, and (c) from sites in the forepaw and shoulder representation in VPL to forelimb and shoulder sites in SI. The results showed that the projections were narrowly focused and homotopic. Electrophysiological recordings were then used to map the former forepaw representation in forelimb amputated young adult rats (n=5) at 7 to 24 weeks after amputation. At each time period, new input from the shoulder was observed in the deafferented forepaw region in VPL. To determine whether the new shoulder input in the deafferented forepaw VPL projected to a new shoulder site in the deafferented FBS, we examined the thalamocortical pathway in 2 forelimb-amputated rats. Stimulation of a new shoulder site in deafferented FBS antidromically-activated a cell in the former forepaw territory in VPL; however, similar stimulation from a site in the original shoulder representation, outside the deafferented region, in SI did not activate cells in the former forepaw VPL. These results suggest that the new shoulder input in deafferented FBS is relayed from cells in the former forepaw region in VPL. In the last step, we used anatomical tracing and stimulation and recording techniques in forelimb intact rats (n=9) to examine the cuneothalamic pathway from shoulder and forepaw receptive field zones in CN to determine whether projections from the shoulder zone might provide a possible source of shoulder input to forepaw VPL. Injection of biotinylated dextran amine (BDA) into physiologically identified shoulder responsive sites in CN densely labeled axon terminals in the shoulder representation in VPL, but also gave off small collateral branches into forepaw VPL. In addition, microstimulation delivered to forepaw VPL antidromically-activated cells in shoulder receptive field sites in CN. These results suggest that forepaw VPL also receives input from shoulder receptive sites in CN that are latent or subthreshold in forelimb intact rats. However, we speculate that following amputation these latent shoulder inputs become expressed, possibly as a down-regulation of GABA inhibition from the reticular nucleus (RTN). These results, taken together, suggest that VPL provides a substrate for large-scale cortical reorganization that follows forelimb amputation.

Derivation and experimental comparison of cell-division probability densities.

Experiments have shown that, even in a homogeneous population of cells, the distribution of division times is highly variable. In addition, a homogeneous population of cells will exhibit a heterogeneous response to drug therapy. We present a simple stochastic model of the cell cycle as a multistep stochastic process. The model, which is based on our conception of the cell cycle checkpoint, is used to derive an analytical expression for the distribution of cell cycle times. We demonstrate that this distribution provides an accurate representation of cell cycle time variability and show how the model relates drug-induced changes in basic biological parameters to variability in response to drug treatment.

Vapor-phase transport of trichloroethene in an intermediate-scale vadose-zone system: retention processes and tracer-based prediction.

Gas-phase transport experiments were conducted using a large weighing lysimeter to evaluate retention processes for volatile organic compounds (VOCs) in water-unsaturated (vadose-zone) systems, and to test the utility of gas-phase tracers for predicting VOC retardation. Trichloroethene (TCE) served as a model VOC, while trichlorofluoromethane (CFM) and heptane were used as partitioning tracers to independently characterize retention by water and the air-water interface, respectively. Retardation factors for TCE ranged between 1.9 and 3.5, depending on water content. The results indicate that dissolution into the bulk water was the primary retention mechanism for TCE under all conditions studied, contributing approximately two-thirds of the total measured retention. Accumulation at the air-water interface comprised a significant fraction of the observed retention for all experiments, with an average contribution of approximately 24%. Sorption to the solid phase contributed approximately 10% to retention. Water contents and air-water interfacial areas estimated based on the CFM and heptane tracer data, respectively, were similar to independently measured values. Retardation factors for TCE predicted using the partitioning-tracer data were in reasonable agreement with the measured values. These results suggest that gas-phase tracer tests hold promise for characterizing the retention and transport of VOCs in the vadose-zone.

Prenatal alcohol exposure reduces the size of the forelimb representation in motor cortex in rat: an intracortical microstimulation (ICMS) mapping study.

Children with fetal alcohol spectrum disorder (FASD) often exhibit sensorimotor dysfunctions that include deficits in motor coordination and fine motor control. Although the underlying causes for these motor abnormalities are unknown, they likely involve interactions between sensory and motor systems. Rodent animal models have been used to study the effects of prenatal alcohol exposure (PAE) on skilled reaching and on the development and organization of somatosensory barrel field cortex. To this end, PAE delayed the development of somatosensory cortex, reduced the size of whisker and forelimb representations in somatosensory barrel field cortex, and delayed acquisition time to learn a skilled reaching task. However, whether PAE also affects the motor cortex (MI) remains to be determined. In the present study, we investigated the effect of PAE on the size of the forelimb representation in rat MI, thresholds for activation, and the overlap between motor and sensory cortical forelimb maps in sensorimotor cortex. Pregnant Sprague-Dawley rats were assigned to alcohol (Alc), pair-fed (PF), and chow-fed (CF) groups on gestation day 1 (GD1). Rats in the Alc group (n=4) were chronically intubated daily with binge doses of alcohol (6g/kg body weight) from GD1 to GD20 that resulted in averaged blood alcohol levels measured on GD10 (mean=191.5+/-41.9mg/dL) and on GD17 (mean=247.0+/-72.4mg/dL). PF (n=2) and CF (n=3) groups of pregnant rats served as controls. The effect of PAE on the various dependent measures was obtained from multiple male offspring from each dam within treatment groups, and litter means were compared between the groups from alcohol-treated and control (Ct: CF and PF) dams. At approximately 8 weeks of age, rats were anesthetized with ketamine/xylazine and the skull opened over sensorimotor cortex. A tungsten microelectrode was then inserted into the depths of layer V and intracortical microstimulation was used to deliver trains of pulses to evoke muscle contractions and/or movements; maximum stimulating < or =100microA. When a motor response was observed, the threshold for movement was measured and the motor receptive field projected to the cortical surface to serve as representative point for that location. A motor map for the forelimb representation was generated by systematically stimulating at adjacent sites until current thresholds reached the maximum and/or motor responses were no longer evoked. The major findings in this study were as follows: (1) PAE significantly reduced the area of the forelimb representation in the Alc offspring (6.01mm(2), standard error of the mean=+/-0.278) compared with the Ct offspring (8.03mm(2)+/-0.586), (2) PAE did not significantly reduce the averaged threshold for activation of movements between groups, (3) PAE significantly reduced the percent overlap (Alc=31.1%, Ct=55.4%) between the forelimb representation in sensory and motor cortices, and (4) no significant differences were observed in averaged body weight, hemisphere weight, or age of animal between treatment groups. These findings suggest that the effects of PAE are not restricted to somatosensory barrel field cortex but also involve the MI and may underlie deficits in motor control and sensorimotor integration observed among children with FASD.

Long-term effects of prenatal alcohol exposure on the size of the whisker representation in juvenile and adult rat barrel cortex.

Children of mothers who abused alcohol during pregnancy are often reported to suffer from growth retardation and central nervous system (CNS) abnormalities. The use of prenatal alcohol exposed (PAE) animal models has revealed reductions in body and brain weights as well as regional specific brain deficits in neonatal pups. Recently, we and others reported reductions in the size of the posteromedial barrel subfield (PMBSF) in first somatosensory cortex (SI) associated with the representation of the large mystacial vibrissae in neonatal rats and mice that were exposed to alcohol at various times during gestation. While these reductions in barrel field size were reported in neonates, it was unclear whether similar reductions persisted later in life or whether some catch-up might take place in older animals. In the present study, we examined the effect of PAE on measures of barrel field size in juvenile (6 weeks of age) and adult (7 months of age) rats; body and brain weights were also measured. Pregnant rats (Sprague-Dawley) were intragastrically gavaged during gestational days 1-20 with alcohol (6 g/kg) to simulate a binge-like pattern of alcohol consumption (Alc); 6 g/kg alcohol produced blood alcohol levels ranging between 207.4 and 478.6 mg/dl. Chow-fed (CF), pair-fed (PF), and cross-foster (XF) groups served as normal, nutritional/stress, and maternal controls, respectively, for juvenile rats; an XF group was not included for adult rats. The major findings in the present study are (i) PAE significantly reduced the size of the total barrel field in Alc juvenile rats (13%) and adult rats (9%) compared to CF controls, (ii) PAE significantly reduced the total averaged sizes of individual PMBSF barrels in juvenile (14%) and adult (13%) rats, (iii) PAE did not significantly alter the septal area between barrels or the barrel pattern, (iv) PAE significantly reduced body weight of juvenile rats but only in comparison to PF controls (18%), (v) PAE significantly reduced whole brain (8%) and forebrain (7%) weights of juvenile rats but not adult rats, (vi) no differences were observed in forebrain/PMBSF body ratios nor was forebrain weight correlated with PMBSF area, and (vii) PAE resulted in a greater reduction in anterior barrels compared to posterior barrels. These results suggest that the effects of PAE previously reported in neonate PMBSF areas persist into adulthood.

Early postnatal alcohol exposure reduced the size of vibrissal barrel field in rat somatosensory cortex (SI) but did not disrupt barrel field organization.

Prenatal alcohol exposure (PAE) has been shown to alter the somatosensory cortex in both human and animal studies. In rodents, PAE reduced the size, but not the pattern of the posteromedial barrel subfield (PMBSF) associated with the representation of the whiskers, in newborn, juvenile, and adult rats. However, the PMBSF is not present at birth, but rather first appears in the middle of the first postnatal week during the brain-growth spurt period. These findings raise questions whether early postnatal alcohol exposure might disrupt both barrel field pattern and size, questions that were investigated in the present study. Newborn Sprague-Dawley rats were assigned into alcohol (Alc), nutritional gastric control (GC), and suckle control (SC) groups on postnatal day 4 (P4). Rat pups in Alc and GC were artificially fed with alcohol and maltose-dextrin dissolved in milk, respectively, via an implant gastrostomy tube, from P4 to P9. Pups in the Alc group received alcohol (6.0 g/kg) in milk, while the GC controls received isocaloric equivalent maltose-dextrin dissolved in milk. Pups in the SC group remained with their mothers and breast fed throughout the experimental period. On P10, pups in each group were weighed, sacrificed, and their brains removed and weighed. Cortical hemispheres were separated, weighed, flattened, sectioned tangentially, stained with cytochrome oxidase, and PMBSF measured. The sizes of barrels and the interbarrel septal region within PMBSF, as well as body and brain weights were compared between the three groups. The sizes of PMSBF barrel and septal areas were significantly smaller (P<.01) in Alc group compared to controls, while the PMBSF barrel pattern remained unaltered. Body, whole-brain, forebrain, and hemisphere weights were significantly reduced (P<.01) in Alc pups compared to control groups. GC and SC groups did not differ significantly in all dependent variables, except body weight at P9 and P10 (P<.01). These results suggest that postnatal alcohol exposure, like prenatal exposure, significantly influenced the size of the barrel field, but not barrel field pattern formation, indicating that barrel field pattern formation consolidated prior to P4. These results are important for understanding sensorimotor deficits reported in children suffering from fetal alcohol spectrum disorder (FASD).

Dissonance and the honor system: extending the severity of threat phenomenon.

In this field experiment, the authors extended the severe threat of punishment paradigm to the honor system. Participants (N = 80) came from two small colleges that differ in the severity of threats of punishment for honor code violations. The authors placed participants in situations in which they came upon money that did not belong to them, in both public and private settings. Using the framework of insufficient justification, the authors hypothesized that participants from the military school, who face a severe threat of punishment for honor code violations, would be less likely to pick up the money in the public setting than in the private setting. The authors predicted that, in contrast, at the nonmilitary college, where students face only a mild threat of punishment for honor code violations, there would be no difference in how participants behaved across the two settings. The results supported both hypotheses. The authors discuss the implications of their findings for understanding and improving the nature of the punishment structure for honor systems.

Prenatal alcohol exposure delays the development of the cortical barrel field in neonatal rats.

In-utero alcohol exposure produces sensorimotor developmental abnormalities that often persist into adulthood. The rodent cortical barrel field associated with the representation of the body surface was used as our model system to examine the effect of prenatal alcohol exposure (PAE) on early somatosensory cortical development. In this study, pregnant female rats were intragastrically gavaged daily with high doses of alcohol (6 gm/kg body weight) throughout the first 20 days of pregnancy. Blood alcohol levels were measured in the pregnant dams on gestational days 13 (G13) and G20. The ethanol treated group (EtOH) was compared to the normal control chowfed (CF) group, nutritionally matched pairfed (PF) group, and cross-foster (XF) group. Cortical barrel development was examined in pups across all treatment groups from G25, corresponding to postnatal day 2 (P2), to G32 corresponding to P9. The EtOH and control group pups were weighed, anesthetized, and perfused. Brains were removed and weighed with, and without cerebellum and olfactory bulbs, and neocortex was removed and weighed. Cortices were then flattened, sectioned tangentially, and stained with a metabolic marker, cytochrome oxidase (CO) to reveal the barrel field. Progression of barrel development was distinguished into three categories: (a) absent, (b) cloudy barrel-like pattern, and (c) well-formed barrels with intervening septae. The major findings are: (1) PAE delayed barrel field development by one or more days, (2) the barrel field first appeared as a cloudy pattern that gave way on subsequent days to an adult-like pattern with clearly demarcated intervening septal regions, (3) the barrel field developed differentially in a lateral-to-medial gradient in both alcohol and control groups, (4) PAE delayed birth by one or more days in 53% of the pups, (5) regardless of whether pups were born on G23 (normal expected birth date for non-alcohol controls) or as in the case for the alcohol-delayed pups born as late as G27, the barrel field was never present at birth suggesting the importance of postnatal experience on barrel field development, and (6) PAE did not disrupt the normal barrel field pattern, although both total body and brain weights were compromised. These findings suggest that PAE delays the development of the somatosensory cortex (SI); such delays may interfere with timing and formation of cortical circuits. It is unknown whether other nuclei along the somatosensory pathway undergo similar delays in development or if PAE selectively disrupts cortical circuitry.