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Abstract Many animal species do not breathe in a continuous, rhythmic fashion, but rather display a variety of breathing patterns characterized by prolonged periods between breaths (inter‐breath intervals), during which the heart continues to beat. Examples of intermittent breathing abound across the animal kingdom, from crustaceans to cetaceans. With respect to human physiology, intermittent breathing—also termed ‘periodic’ or ‘episodic’ breathing—is associated with a variety of pathologies. Cardiovascular phenomena associated with intermittent breathing in diving species have been termed ‘diving bradycardia’, ‘submersion bradycardia’, ‘immersion bradycardia’, ‘ventilation tachycardia’, ‘respiratory sinus arrhythmia’ and so forth. An examination across the literature of terminology applied to these physiological phenomena indicates, unfortunately, no attempt at standardization. This might be viewed as an esoteric semantic problem except for the fact that many of the terms variously used by different authors carry with them implicit or explicit suggestions of underlying physiological mechanisms and even human‐associated pathologies. In this article, we review several phenomena associated with diving and intermittent breathing, indicate the semantic issues arising from the use of each term, and make recommendations for best practice when applying specific terms to particular cardiorespiratory patterns. Ultimately, we emphasize that the biology—not the semantics—is what is important, but also stress that confusion surrounding underlying mechanisms can be avoided by more careful attention to terms describing physiological changes during intermittent breathing and diving.

Data variability complicates reproducibility and the interpretation of experimental results. Different animal models have been employed to decrease variability to enhance experimental power. However, variation frequently persists among and within strains/lines. In zebrafish (Danio rerio), inbred lines (e.g., NHGRI-1) derived from wild-type lines have been produced to greatly decrease genetic variation, with the goal of providing better understanding of genetic backgrounds that may influence the experimental outcome of studies employing such lines. We hypothesized that variations in morphological phenotypes shaped by environmental stressors early in development are correlated with the intrinsic degree of genetic variability of zebrafish lines. We compared morphological variability (yolk–chorion ratio, body mass, embryo mass, total length, condition factor, and specific growth rate) in wild-type AB and NHGRI-1 zebrafish lines as a function of their responses to altered temperature and oxygen availability during the first 7 days post-fertilization. Overall, both lines showed similar developmental trajectories for yolk–chorion ratio, embryo mass, and total length. Additionally, condition factor and specific growth rate showed similar responses within each line, regardless of temperature and hypoxia. Importantly, the coefficient of variation for each variable was significantly lower in NHGRI-1 than AB larvae for 151 of 187 assessed morphological endpoints. Thus, the low-heterozygosity NHGRI-1 zebrafish line can be useful for decreasing inter-individual variation in morphological responses to environmental stressors, thereby aiding in the interpretation of results and enhancing experimental reproducibility.

Animals from embryos to adults experiencing stress from climate change have numerous mechanisms available for enhancing their long-term survival. In this review we consider these options, and how viable they are in a world increasingly experiencing extreme weather associated with climate change. A deeply understood mechanism involves natural selection, leading to evolution of new adaptations that help cope with extreme and stochastic weather events associated with climate change. While potentially effective at staving off environmental challenges, such adaptations typically occur very slowly and incrementally over evolutionary time. Consequently, adaptation through natural selection is in most instances regarded as too slow to aid survival in rapidly changing environments, especially when considering the stochastic nature of extreme weather events associated with climate change. Alternative mechanisms operating in a much shorter time frame than adaptation involve the rapid creation of alternate phenotypes within a life cycle or a few generations. Stochastic gene expression creates multiple phenotypes from the same genotype even in the absence of environmental cues. In contrast, other mechanisms for phenotype change that are externally driven by environmental clues include well-understood developmental phenotypic plasticity (variation, flexibility), which can enable rapid, within-generation changes. Increasingly appreciated are epigenetic influences during development leading to rapid phenotypic changes that can also immediately be very widespread throughout a population, rather than confined to a few individuals as in the case of favorable gene mutations. Such epigenetically-induced phenotypic plasticity can arise rapidly in response to stressors within a generation or across a few generations and just as rapidly be “sunsetted” when the stressor dissipates, providing some capability to withstand environmental stressors emerging from climate change. Importantly, survival mechanisms resulting from adaptations and developmental phenotypic plasticity are not necessarily mutually exclusive, allowing for classic “bet hedging”. Thus, the appearance of multiple phenotypes within a single population provides for a phenotype potentially optimal for some future environment. This enhances survival during stochastic extreme weather events associated with climate change. Finally, we end with recommendations for future physiological experiments, recommending in particular that experiments investigating phenotypic flexibility adopt more realistic protocols that reflect the stochastic nature of weather.

IntroductionHeterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence.MethodsOur international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption.ResultsThis progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures.DiscussionA harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Background: Cannabis is the most widely used illicit substance worldwide, and legalization for recreational and medical purposes has substantially increased its availability and use in the United States.Objectives: Decades of research have suggested that recreational cannabis use confers risk for cognitive impairment across various domains, and structural and functional differences in the brain have been linked to early and heavy cannabis use.Methods: With substantial evidence for the role of the endocannabinoid system in neural development and understanding that brain development continues into early adulthood, the rising use of cannabis in adolescents and young adults raises major concerns. Yet some formulations of cannabinoid compounds are FDA-approved for medical uses, including applications in children.Results: Potential effects on the trajectory of brain morphology and cognition, therefore, should be considered. The goal of this review is to update and consolidate relevant findings in order to inform attitudes and public policy regarding the recreational and medical use of cannabis and cannabinoid compounds.Conclusions: The findings point to considerations for age limits and guidelines for use.

BackgroundMahi-mahi (Coryphaena hippurus) is a commercially and ecologically important fish species that is widely distributed in tropical and subtropical waters. Biological attributes and reproductive capacities of mahi-mahi make it a tractable model for experimental studies. In this study, life development of cultured mahi-mahi from the zygote stage to adult has been described.ResultsA comprehensive developmental table has been created reporting development as primarily detailed observations of morphology. Additionally, physiological, behavioral, and molecular landmarks have been described to significantly contribute in the understanding of mahi life development.ConclusionRemarkably, despite the vast difference in adult size, many developmental landmarks of mahi map quite closely onto the development and growth of Zebrafish and other warm-water, active Teleost fishes.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p

The 2010 Deepwater Horizon oil spill coincided with the spawning season of many pelagic fish species in the Gulf of Mexico. Yet, few studies have investigated physiological responses of larval fish to interactions between anthropogenic crude oil exposure and natural factors (e.g. temperature, oxygen levels). Consequently, mahi mahi (Coryphaena hippurus) embryos were exposed for 24 hours to combinations of two temperatures (26 and 30°C) and six concentrations of oiled fractions of weathered oil (from 0 to 44.1 μg ∑50PAHs·L-1). In 56 hours post-fertilization larvae, heart rate, stroke volume and cardiac output were measured as indicators of functional cardiac phenotypes. Fluid accumulation and incidence of edema and hematomas were quantified as indicators of morphological impairments. At both 26 and 30°C, oil-exposed larvae suffered dose-dependent morphological impairments and functional heart failure. Elevation of temperature to 30°C appeared to induce greater physiological responses (bradycardia) at PAH concentrations in the range of 3.0-14.9 μg·L-1. Conversely, elevated temperature in oil-exposed larvae reduced edema severity and hematoma incidence. However, the apparent protective role of warmer temperature does not appear to protect against enhanced mortality. Collectively, our findings show that elevated temperature may slightly decrease larval resilience to concurrent oil exposure.

BackgroundPhysical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.ObjectiveTo examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.MethodsTwenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.ResultsTwenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.ConclusionOlder non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.

BackgroundThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer's disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding values in MTL.MethodsA total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed genotyping for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14-20 repeats; S), long (21-29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates.ResultsData from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 S/VL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3,p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 S/VL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning.ConclusionsThis is the first report to demonstrate a significant association between longer TOMM40 poly-T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments.

Atrophy of the medial temporal lobe (MTL) occurs with aging, resulting in impaired episodic memory. Aerobic fitness is positively correlated with total hippocampal volume, a heavily studied memory-critical region within the MTL. However, research on associations between sedentary behavior and MTL subregion integrity is limited. Here we explore associations between thickness of the MTL and its subregions (namely CA1, CA23DG, fusiform gyrus, subiculum, parahippocampal, perirhinal and entorhinal cortex,), physical activity, and sedentary behavior. We assessed 35 non-demented middle-aged and older adults (25 women, 10 men; 45-75 years) using the International Physical Activity Questionnaire for older adults, which quantifies physical activity levels in MET-equivalent units and asks about the average number of hours spent sitting per day. All participants had high resolution MRI scans performed on a Siemens Allegra 3T MRI scanner, which allows for detailed investigation of the MTL. Controlling for age, total MTL thickness correlated inversely with hours of sitting/day (r = -0.37, p = 0.03). In MTL subregion analysis, parahippocampal (r = -0.45, p = 0.007), entorhinal (r = -0.33, p = 0.05) cortical and subiculum (r = -0.36, p = .04) thicknesses correlated inversely with hours of sitting/day. No significant correlations were observed between physical activity levels and MTL thickness. Though preliminary, our results suggest that more sedentary non-demented individuals have less MTL thickness. Future studies should include longitudinal analyses and explore mechanisms, as well as the efficacy of decreasing sedentary behaviors to reverse this association.

IntroductionThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising gene in Alzheimer's disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes.MethodsIn this study, we examined the effects of TOMM40 using high-resolution magnetic resonance imaging in 65 healthy, older subjects with and without the APOE ε4 AD-risk variant.ResultsExamining individual subregions within the MTL, we found a significant relationship between increasing poly-T lengths of the TOMM40 variant and thickness of the entorhinal cortex only in subjects who did not carry the APOE ε4 allele.DiscussionOur data provide support for TOMM40 variant repeat length as an important contributor to AD-like MTL pathology in the absence of APOE ε4.

Cardiovascular performance is altered by temperature in larval fishes, but how acute versus chronic temperature exposures independently affect cardiac morphology and physiology in the growing larva is poorly understood. Consequently, we investigated the influence of water temperature on cardiac plasticity in developing mahi-mahi. Morphological (e.g. standard length, heart angle) and physiological cardiac variables (e.g. heart rate fH, stroke volume, cardiac output) were recorded under two conditions by imaging: (i) under acute temperature exposure where embryos were reared at 25°C up to 128 h post-fertilization (hpf) and then acutely exposed to 25 (rearing temperature), 27 and 30°C; and (ii) at two rearing (chronic) temperatures of 26 and 30°C and performed at 32 and 56 hpf. Chronic elevated temperature improved developmental time in mahi-mahi. Heart rates were 1.2-1.4-fold higher under exposure of elevated acute temperatures across development (Q10≥2.0). Q10 for heart rate in acute exposure was 1.8-fold higher compared to chronic exposure at 56 hpf. At same stage, stroke volume was temperature independent (Q10∼1.0). However, larvae displayed higher stroke volume later in stage. Cardiac output in developing mahi-mahi is mainly dictated by chronotropic rather than inotropic modulation, is differentially affected by temperature during development and is not linked to metabolic changes.

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Variations from a relative humidity (RH) of ∼50–60% can unfavorably alter chicken embryo development, but little is known of whether the embryo can mitigate these effects through physiological regulation. We examined effects of Low RH (25–35%), and High RH (85–93%) compared to Control RH (50–60%) on hatchability, embryonic growth, hematology and blood gases and pH. Mean hatchability was not affected by RH. Yet, Low RH decreased wet body mass of advanced embryos (days 17–19; d17-19), with lowered body water content compared with embryos of Control and High RH. However, dry body mass of developing (d11-19) embryos was not different between the three RH groups. Mean blood osmolality across development was higher in Low RH embryos and lower in High RH embryos compared with Control embryos. Mean blood lactate was higher in both Low and High RH embryos compared to Control embryos. Unexpectedly, hematological respiratory variables (Hct, [RBC], MCV, [Hb]) and blood gas variables (Po2, Pco2, pH, [HCO3−]) across development were not affected by RH. Mean wet body mass at hatch (d20-22) was larger in High RH embryos compared with Low RH embryos, but mean wet and dry body mass upon euthanasia on d22 was unaffected. The ability of the three populations to physiologically regulate blood respiratory variables and blood acid-base balance was then examined by observing their responses to intrinsic hypoxemia and hypercapnia created by controlled partial egg submersion in water. Hct and [RBC] responses were less disturbed by submersion in High RH embryos compared with both Control and Low RH embryos, which showed major disturbance. Acid-base regulatory responses did not differ between RH groups. We conclude that, while different incubation RHs cause large differences in tissue water content and body mass, most hematological and acid-base regulatory capabilities are regulated near Control values.

Data variability complicates reproducibility and the interpretation of experimental results. Different animal models have been employed to decrease variability to enhance experimental power. However, variation frequently persists among and within strains/lines. In zebrafish (Danio rerio), inbred lines (e.g., NHGRI-1) derived from wild-type lines have been produced to greatly decrease genetic variation, with the goal of providing better understanding of genetic backgrounds that may influence the experimental outcome of studies employing such lines. We hypothesized that variations in morphological phenotypes shaped by environmental stressors early in development are correlated with the intrinsic degree of genetic variability of zebrafish lines. We compared morphological variability (yolk–chorion ratio, body mass, embryo mass, total length, condition factor, and specific growth rate) in wild-type AB and NHGRI-1 zebrafish lines as a function of their responses to altered temperature and oxygen availability during the first 7 days post-fertilization. Overall, both lines showed similar developmental trajectories for yolk–chorion ratio, embryo mass, and total length. Additionally, condition factor and specific growth rate showed similar responses within each line, regardless of temperature and hypoxia. Importantly, the coefficient of variation for each variable was significantly lower in NHGRI-1 than AB larvae for 151 of 187 assessed morphological endpoints. Thus, the low-heterozygosity NHGRI-1 zebrafish line can be useful for decreasing inter-individual variation in morphological responses to environmental stressors, thereby aiding in the interpretation of results and enhancing experimental reproducibility. [ABSTRACT FROM AUTHOR]

ObjectiveExercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP).MethodsVolunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET.ResultsMCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES = 1.04, t(35) = 3.3, p = 0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES = 1.13, t(35) = -3.1, p = 0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES = 0.02, t(35) = -0.1, p = 0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES = 0.72, t(35) = -2.1, p = 0.04).ConclusionThese preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498).

The current study examined the independent and combined effects of HIV and marijuana (MJ) use (no use, light use, and moderate-to-heavy use) on neurocognitive functioning among a convenience sample of HIV-positive (HIV+) and HIV-negative (HIV-) individuals recruited from HIV community care clinics and advertisements in the Greater Los Angeles area. MJ users consisted of individuals who reported regular use of MJ for at least 12 months, with last reported use within the past month. Participants included 89 HIV+ (n = 55) and HIV- (n = 34) individuals who were grouped into non-users, light users, and moderate-to-heavy users based on self-reported MJ use. Participants were administered a brief cognitive test battery and underwent laboratory testing for CD4 count and viral load. HIV+ individuals demonstrated lower performance on neurocognitive testing than controls, and moderate-to-heavy MJ users performed more poorly on neurocognitive testing than light users or non-users. Moderate-to-heavy HIV+ users performed significantly lower on learning/memory than HIV- moderate-to-heavy users (MD = -8.34; 95% CI: -16.11 to -0.56) as well as all other comparison groups. In the domain of verbal fluency, HIV+ light users outperformed HIV- light users (MD = 7.28; 95% CI: 1.62-12.39), but no HIV group differences were observed at other MJ use levels. HIV+ MJ users demonstrated lower viral load (MD = -0.58; 95% CI: -1.30 to 0.14) and higher CD4 count than non-users (MD = 137.67; 95% CI: 9.48-265.85). The current study findings extend the literature by demonstrating the complex relationship between HIV status and MJ use on neurocognitive and clinical outcomes.

Variants at 21 genetic loci have been associated with an increased risk for Alzheimer's disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = -0.40; p = 0.003; WRS: r = -0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = -0.35; p = 0.009; WRS: r = -0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.

The hippocampal complex is affected early in Alzheimer's disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOEɛ4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired-associates memory task to examine differences in task-dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOEɛ4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOEɛ4-mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context-dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOEɛ4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOEɛ4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOEɛ4 and are consistent with the anterior-to-posterior theory of AD progression in the hippocampus.

Abstract Introduction Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. Methods Our international working group, funded by the EU Joint Programme–Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. Results This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. Discussion A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

ObjectiveAn increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MethodMRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.ResultsThe differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.ConclusionsThe combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Biomedical research focusing on physiological, morphological, behavioral, and other aspects of development has long depended upon the chicken (Gallus gallus domesticus) as a key animal model that is presumed to be typical of birds and generally applicable to mammals. Yet, the modern chicken in its many forms is the result of artificial selection more intense than almost any other domesticated animal. A consequence of great variation in genotype and phenotype is that some breeds have inherent aberrant physiological and morphological traits that may show up relatively early in development (e.g., hypertension, hyperglycemia, and limb defects in the broiler chickens). While such traits can be useful as models of specific diseases, this high degree of specialization can color general experimental results and affect their translational value. Against this background, in this review we first consider the characteristics that make an animal model attractive for developmental research (e.g., accessibility, ease of rearing, size, fecundity, development rates, genetic variation, etc.). We then explore opportunities presented by the embryo to adult continuum of alternative bird models, including quail, ratites, songbirds, birds of prey, and corvids. We conclude by indicating that expanding developmental studies beyond the chicken model to include additional avian groups will both validate the chicken model as well as potentially identify even more suitable avian models for answering questions applicable to both basic biology and the human condition.

Toxicants are commonly administered to experimental organisms using solvents as vehicles. One common vehicle for dissolving toxicants is methanol (CH3OH), a solvent which on its own is capable of altering physiology and behavior high concentrations. This dataset describes behavioral results in zebrafish (Danio rerio) individually exposed to methanol (0.25%, 2.5% vol/vol), or control water, for 30 min prior to behavioral testing. Zebrafish were placed into an open field arena to examine locomotion and zone preference, which was recorded and quantified with motion-tracking software (EthoVision XT). Time spent in the outer (“thigmotaxis”) zone of the arena is a proxy for increased anxiety-like behavior in zebrafish. Additionally, a novel object was placed into the center of the arena to quantify relative increases in boldness/exploration between the methanol and control groups. There were no differences in time spent in any zone of the arena or distance travelled between either group, in either test.

The recent Deoni et al. (2013) manuscript proposed that breastfeeding was associated with increased cognitive ability and white-matter in older children (over 26 months), using ms-DESPOT MRI imaging to indirectly measure white matter in children who were either breastfed, formula fed, or combined breast+formula fed. In this response, we identify limitations in drawing causal inference among white matter, cognitive ability, and breastfeeding. We propose that the observed cognitive and neurodevelopmental differences between breastfed and formula-fed infants might actually be caused by the premature introduction of cow's milk in the second year of life, among other contributing factors. The implication of a causal relationship between intelligence and white matter metrics, especially in a developmentally young population, is premature given the recency of this field. The original analyses did not control for important covariates; when comparing both white matter and test scores, mothers were not controlled for age and socio-economic status (SES) and their children were not controlled for gender. Raw test scores, instead of age-adjusted test scores, were used even though the children were of different ages. Mothers were not controlled for reason(s) not to breastfeed, even though many prenatal factors are known to predict this such as stress, parity, obesity, and smoking habits. The observed cognitive ability and white matter benefits identified primarily within the long-term breastfed children are at least partially attributable to other factors such as age, gender, and SES. We suggest methodological approaches to removing such ambiguity, and ways to dissociate cause from effect. The formula and breastfeeding groups didn't show differences until the "formula fed" children likely had been fed cow's milk for longer than they had been fed formula, at 2.2 years. The greatest cognitive differences however were observed within the high SES breastfed infants depending on breastfeeding duration; infants who were breastfed over 15 months showed increased cognitive ability compared to those breastfed less than months. This implicates the source of dairy during the second year of life, and not other SES factors or infant formula, as the most likely nutritional factor responsible for the observed differences within the breastfed children. Given the known nutritional deficiencies of cow's milk, these findings imply infants who received cow's milk during the second year of life were at a disadvantage compared to those who were breastfed, independent of whether they were fed formula or breast milk during the first year of life. This evidence suggests that infants should receive formula in lieu of cow's milk when breast milk is unavailable as a dairy source, until roughly 2 years of age.

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer's disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer's disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer's disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer's disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.

Despite the current knowledge of the devastating effects of external exposure to crude oil on animal mortality, the study of developmental, transgenerational effects of such exposure has received little attention. We used the king quail as an animal model to determine if chronic dietary exposure to crude oil in a parental population would affect morpho-physiological phenotypic variables in their immediate offspring generation. Adult quail were separated into three groups: (1) Control, and two experimental groups dietarily exposed for at least 3 weeks to (2) Low (800 PAH ng/g food), or (3) High (2,400 PAH ng/g food) levels of crude oil. To determine the parental influence on their offspring, we measured metabolic and respiratory physiology in exposed parents and in their non-exposed eggs and hatchlings. Body mass and numerous metabolic (e.g., O2 consumption, CO2 production) and respiratory (e.g., ventilation frequency and volume) variables did not vary between control and oil exposed parental groups. In contrast, blood PO2, PCO2, and SO2 varied among parental groups. Notably, water loss though the eggshell was increased in eggs from High oil level exposed parents. Respiratory variables of hatchlings did not vary between populations, but hatchlings obtained from High oil-exposed parents exhibited lower capacities to maintain body temperature while exposed to a cooling protocol in comparison to hatchlings from Low- and Control-derived parents. The present study demonstrates that parental exposure to crude oil via diet impacts some aspects of physiological performance of the subsequent first (F1) generation.