Mental representation of the future is a fundamental component of goal-directed behavior. Computational and animal models highlight prospective spatial coding in the hippocampus, mediated by ...interactions with the prefrontal cortex, as a putative mechanism for simulating future events. Using whole-brain high-resolution functional magnetic resonance imaging and multi-voxel pattern classification, we tested whether the human hippocampus and interrelated cortical structures support prospective representation of navigational goals. Results demonstrated that hippocampal activity patterns code for future goals to which participants subsequently navigate, as well as for intervening locations along the route, consistent with trajectory-specific simulation. The strength of hippocampal goal representations covaried with goal-related coding in the prefrontal, medial temporal, and medial parietal cortex. Collectively, these data indicate that a hippocampal-cortical network supports prospective simulation of navigational events during goal-directed planning.
Intense debate surrounds the role of medial temporal lobe (MTL) structures in recognition memory. Using high-resolution fMRI and analyses of pattern similarity in humans, we examined the encoding ...computations subserved by MTL subregions. Specifically, we tested the theory that MTL cortex supports memory by encoding overlapping representations, whereas hippocampus supports memory by encoding pattern-separated representations. Consistent with this view, the relationship between encoding pattern similarity and subsequent memory dissociated MTL cortex and hippocampus: later memory was predicted by greater across-item pattern similarity in perirhinal cortex and in parahippocampal cortex, but greater pattern distinctiveness in hippocampus. Additionally, by comparing neural patterns elicited by individual stimuli regardless of subsequent memory, we found that perirhinal cortex and parahippocampal cortex exhibited differential content sensitivity for multiple stimulus categories, whereas hippocampus failed to demonstrate content sensitivity. These data provide novel evidence that complementary MTL encoding computations subserve declarative memory.
Older adults experience impairments in episodic memory, ranging from mild to clinically significant. Given the critical role of the medial temporal lobe (MTL) in episodic memory, age-related changes ...in MTL structure and function may partially account for individual differences in memory. Using ultra–high-field 7T structural MRI and high-resolution 3T functional MRI (hr-fMRI), we evaluated MTL subfield thickness and function in older adults representing a spectrum of cognitive health. Participants performed an associative memory task during hr-fMRI in which they encoded and later retrieved face–name pairs. Motivated by prior research, we hypothesized that differences in performance would be explained by the following: (i) entorhinal cortex (ERC) and CA1 apical neuropil layer CA1–stratum radiatum lacunosum moleculare (SRLM) thickness, and (ii) activity in ERC and the dentate gyrus (DG)/CA3 region. Regression analyses revealed that this combination of factors significantly accounted for variability in memory performance. Among these metrics, CA1-SRLM thickness was positively associated with memory, whereas DG/CA3 retrieval activity was negatively associated with memory. Furthermore, including structural and functional metrics in the same model better accounted for performance than did single-modality models. These results advance the understanding of how independent but converging influences of both MTL subfield structure and function contribute to age-related memory impairment, complementing findings in the rodent and human postmortem literatures.
High-resolution functional MRI (hr-fMRI) affords unique leverage on the functional properties of human medial temporal lobe (MTL) substructures. We review initial hr-fMRI efforts to delineate (1) ...encoding and retrieval processes within the hippocampal circuit, (2) hippocampal subfield contributions to pattern separation and pattern completion, and (3) the representational capabilities of distinct MTL subregions. Extant data reveal functional heterogeneity within human MTL and highlight the promise of hr-fMRI for bridging human, animal, and computational approaches to understanding MTL function.
Assembled genome sequences are being generated at an exponential rate. Here we present FCS-GX, part of NCBI's Foreign Contamination Screen (FCS) tool suite, optimized to identify and remove ...contaminant sequences in new genomes. FCS-GX screens most genomes in 0.1-10 min. Testing FCS-GX on artificially fragmented genomes demonstrates high sensitivity and specificity for diverse contaminant species. We used FCS-GX to screen 1.6 million GenBank assemblies and identified 36.8 Gbp of contamination, comprising 0.16% of total bases, with half from 161 assemblies. We updated assemblies in NCBI RefSeq to reduce detected contamination to 0.01% of bases. FCS-GX is available at https://github.com/ncbi/fcs/ or https://doi.org/10.5281/zenodo.10651084 .
An 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.
MRI 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.
The 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.
The 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.
Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance ...is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide (Agrp) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in Agrp neuron biology, possibly secondary to altered CREB signaling.
Background and aim
Experience of stigma towards methadone maintenance treatment (MMT) may be a barrier to the use of this treatment by people with opioid use disorder. We evaluated the factor ...structure, internal reliability, construct and criterion validity of a theory‐based stigma measure, the Methadone Maintenance Treatment Stigma Mechanisms Scale (MMT‐SMS) and compared this with the Substance Use Stigma Mechanism Scale (SU‐SMS).
Design
Surveys at the beginning and end of a prospective study together with records of drug use and treatment attendance during that study.
Setting
Community methadone clinic in the Northeastern USA.
Participants
Ninety‐three participants who were receiving MMT; the average daily methadone dose was 84.8 mg/day (standard deviation = 28.39 mg/day).
Measurements
The MMT‐SMS uses a self‐report questionnaire to assess three dimensions reflecting experiences of anticipated (nine items), enacted (nine items) and internalized stigma (seven items) specifically related to receiving MMT. Anticipated and enacted scales include three stigma source subscales (family, employers, health care workers; three items each). Responses are recorded on a five‐point Likert‐type scale, then averaged to produce the MMT‐SMS scale/subscale scores. The SU‐SMS is a self‐report questionnaire to assess experiences of anticipated, enacted and internalized stigma regarding substance use history. Both scales were administered at the final parent study visit. Other measures included were assessed in the parent study and used to assess life‐time and recent MMT (e.g. current MMT dose) and drug use experiences (e.g. past 30‐day heroin injection).
Findings
The MMT‐SMS demonstrated good internal reliability (α = 0.806–0.952 for components). Confirmatory factor analysis supported the seven‐factor scale structure, distinguishing between experiences of anticipated, enacted and internalized stigma, and anticipated and enacted stigma source subscales (family, employers, health care workers) root mean square error of approximation (RMSEA) = 0.076, 90% confidence interval (CI) = 0.061–0.090, P‐close = 0.003; confirmatory fit index (CFI) = 0.974; Tucker–Lewis index (TLI) = 0.971. Construct validity helped to distinguish the MMT‐SMS from established substance use stigma constructs. Criterion validity observed associations with substance use experiences while on MMT, likely to predict future MMT success. Internalized MMT stigma was uniquely associated with daily MMT dose. Regarding criterion validity: anticipated MMT and enacted substance use stigma were associated with past 30‐day heroin injection, MMT stigma uniquely associated with opioid use behaviors while receiving MMT, and substance use stigma broadly associated with injection‐related behaviors.
Conclusions
The Methadone Maintenance Treatment Stigma Mechanisms Scale appears to be a reliable measure of methadone maintenance treatment stigma with robust validity in a sample of people with opioid use disorders receiving methadone maintenance treatment.
Central obesity, high blood pressure, dyslipidemia, and insulin resistance are a collection of cardiovascular and metabolic risk factors that form the basis of the Metabolic Syndrome (MetS) and ...represent a major public health burden worldwide. The phenotypes that define MetS are all highly heritable, but their genetic complexity necessitates the use of animal models to tease apart novel pathways.
The Lyon Hypertensive (LH) rat is a well‐characterized model of MetS, exhibiting spontaneous and profound differences in features of MetS compared to its metabolically healthy control, the Lyon Normotensive (LN) rat. To understand the genomic causes of MetS in the LH rat, we developed a congenic rat model, where a portion of LN chromosome 17 is introgressed on the LH genomic background. Our hypothesis was that differences in metabolic features between the LH controls and the congenic rats (LH17LNa) would be due to the replaced region of the genome. Male and female LH17LNa rats and LH controls were phenotyped for a variety of MetS characteristics, including weekly body growth until tissue collection at 15 weeks of age, body composition by nuclear magnetic resonance (NMR) at 8, 11, and 14 weeks of age, metabolic rate (Promethion system) between 10 and 12 weeks of age, and adipose tissue collection and histological examination.
We observed a significant decrease in total body growth in female congenics, beginning at 12 weeks of age and persisting throughout the rest of the study. Prior to the divergence in body weight, female congenics showed significant increases in fat mass and significant decreases in fat free mass that remained consistent at all timepoints measured. We also found significant female‐specific decreases in metabolic rate. Tissue collection revealed the source of the increased adiposity in the female LH17LNa rats was specific to abdominal white adipose tissue, and this phenomenon was further explained by significant hypertrophy in those adipocytes, with no evidence of adipocyte hyperplasia.
Genome resequencing of the parental strains identified a nonsense mutation in Ercc6l2, implicating this gene as a strong contender underlying the phenotype differences in the congenics. Ercc6l2 is a helicase involved in transcription‐coupled DNA repair, which is specifically mobilized to repair oxidative stress‐induced DNA damage in post‐mitotic cells. Truncating mutations in Ercc6l2 have previously been implicated in genome instability and premature aging in hematopoetic stem cells in patients with bone marrow failure. The discovery of the significance of Ercc6l2 in the context of female‐specific adipocyte biology could represent a novel role of DNA repair syndromes in MetS pathogenesis.
Abstract
Metabolic diseases are a host of complex conditions, including obesity, diabetes mellitus, and metabolic syndrome. Endocrine control systems (eg, adrenals, thyroid, gonads) are causally ...linked to metabolic health outcomes. N/NIH Heterogeneous Stock (HS) rats are a genetically heterogeneous outbred population developed for genetic studies of complex traits. Genetic mapping studies in adult HS rats identified loci associated with cardiometabolic risks, such as glucose intolerance, insulin resistance, and increased body mass index. This study determined underappreciated metabolic health traits and the associated endocrine glands within available substrains of the HS rat founders. We hypothesize that the genetic diversity of the HS rat founder strains causes a range of endocrine health conditions contributing to the diversity of cardiometabolic disease risks. ACI/EurMcwi, BN/NHsdMcwi, BUF/MnaMcwi, F344/StmMcwi, M520/NRrrcMcwi, and WKY/NCrl rats of both sexes were studied from birth until 13 weeks of age. Birth weight was recorded, body weight was measured weekly, metabolic characteristics were assessed, and blood and tissues were collected. Our data show wide variation in endocrine traits and metabolic health states in ACI, BN, BUF, F344, M520, and WKY rat strains. This is the first report to compare birth weight, resting metabolic rate, endocrine gland weight, hypothalamic–pituitary–thyroid axis hormones, and brown adipose tissue weight in these rat strains. Importantly, this work unveils new potential for the HS rat population to model early life adversity and adrenal and thyroid pathophysiology. The HS population likely inherited risk alleles for these strain-specific traits, making the HS rat a powerful model to investigate interventions on endocrine and metabolic health.
PDF
