Intracranial Recordings of the Human Orbitofrontal Cortical Activity during Self-Referential Episodic and Valenced Self-Judgments.

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in ∼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.

Comparative and Functional Genomic Resource for Mechanistic Studies of Human Blood Pressure-Associated Single Nucleotide Polymorphisms.

The objective of the current study is to use comparative and functional genomic analysis to help to understand the biological mechanism mediating the effect of single nucleotide polymorphisms (SNPs) on blood pressure. We mapped 26 585 SNPs that are in linkage disequilibrium with 1071 human blood pressure-associated sentinel SNPs to 9447 syntenic regions in the mouse genome. Approximately 21.8% of the 1071 linkage disequilibrium regions are located at least 10 kb from any protein-coding gene. Approximately 300 blood pressure-associated SNPs are expression quantitative trait loci for a few dozen known blood pressure physiology genes in tissues including specific kidney regions. Blood pressure-associated sentinel SNPs are significantly enriched for expression quantitative trait loci for blood pressure physiology genes compared with randomly selected SNPs (P<0.00023, Fisher exact test). Using a newly developed deep learning method and other methods, we identified SNPs that were predicted to influence the conservation of CTCF (CCCTC-binding factor) binding across cell types, transcription factor binding, mRNA splicing, or secondary structures of RNA including long noncoding RNA. The SNPs were more likely to be located in CTCF-binding regions than what would be expected from the whole genome (P=4.90×10-7, Pearson χ2 test). One example synonymous SNP rs9337951 was predicted to influence the secondary structure of its host mRNA JCAD (junctional cadherin 5 associated) and was experimentally validated to influence JCAD protein expression. These findings provide an extensive comparative and functional genomic resource for developing experiments to test the functional significance of human blood pressure-associated SNPs in human cells and animal models.

Long Noncoding RNA: Genomics and Relevance to Physiology.

The mammalian cell expresses thousands of long noncoding RNAs (lncRNAs) that are longer than 200 nucleotides but do not encode any protein. lncRNAs can change the expression of protein-coding genes through both cis and trans mechanisms, including imprinting and other types of transcriptional regulation, and posttranscriptional regulation including serving as molecular sponges. Deep sequencing, coupled with analysis of sequence characteristics, is the primary method used to identify lncRNAs. Physiological roles of specific lncRNAs can be examined using genetic targeting or knockdown with modified oligonucleotides. Identification of nucleic acids or proteins with which an lncRNA interacts is essential for understanding the molecular mechanism underlying its physiological role. lncRNAs have been reported to contribute to the regulation of physiological functions and disease development in several organ systems, including the cardiovascular, renal, muscular, endocrine, digestive, nervous, respiratory, and reproductive systems. The physiological role of the majority of lncRNAs, many of which are species and tissue specific, remains to be determined. © 2019 American Physiological Society. Compr Physiol 9:933-946, 2019.