Closed-Loop Interruption of Hippocampal Ripples through Fornix Stimulation in the Non-Human Primate

AbstractBackgroundHippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples.ObjectiveThe aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples.MethodStimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred.ResultsThe closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates.ConclusionAnalogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit

Organization of the human tarbp2 gene reveals two promoters that are repressed in an astrocytic cell line

C1 - Journal Articles RefereedTRBP1 and TRBP2 are isoforms of a double-stranded RNA-binding protein that differ in their N-terminal end and were each identified by binding to human immunodeficiency virus type 1 (HIV-1) trans-activation-responsive RNA. TRBP1 and TRBP2 also bind and modulate the function of the double-stranded RNA-activated protein kinase, protein kinase R. Both proteins increase long terminal repeat expression in human and murine cells, and their gene has been mapped to human chromosome 12. We have isolated and characterized the complete tarbp2 gene (5493 bp) coding for the two TRBP proteins. Two adjacent promoters initiate transcription of alternative first exons for TRBP1 and TRBP2 mRNAs that are spliced onto common downstream exons. TRBP2 transcription and translation start sites are localized within the first intron of TRBP1. TRBP promoters are TATA-less but have CCAAT boxes, a CpG island, and several potential binding sites for transcriptional factors. Promoter deletion analysis identified two regions from position -1397 to -330 for TRBP1 and from position -330 to +38 for TRBP2 that are important for promoter function. TRBP2 promoter activity was expressed at a higher level compared with TRBP1 promoter. In addition, a specific down-regulation of TRBP1 and TRBP2 promoter activity was identified in human astrocytic cell line U251MG compared with HeLa cells. This minimal TRBP promoter activity may account for minimal HIV-1 replication in astrocytes

Course and Variation of the Intercostal Artery by CT Scan

BACKGROUND: It is conventionally taught that the intercostal artery is shielded in the intercostal groove of the superior rib. The continuous course and variability of the intercostal artery, and factors that may influence them, have not been described in a large number of arteries in vivo. METHODS: Maximal intensity projection reformats in the coronal plane were produced from CT scan pulmonary angiograms to identify the posterolateral course of the intercostal artery (seventh to 11th rib spaces). A novel semiautomated computer segmentation algorithm was used to measure distances between the lower border of the superior rib, the upper border of the inferior rib, and the position of the intercostal artery when exposed in the intercostal space. The position and variability of the artery were analyzed for association with clinical factors. RESULTS: Two hundred ninety-eight arteries from 47 patients were analyzed. The mean lateral distance from the spine over which the artery was exposed within the intercostal space was 39 mm, with wide variability (SD, 10 mm; 10th-90th centile, 28-51 mm). At 3 cm lateral distance from the spine, 17% of arteries were shielded by the superior rib, compared with 97% at 6 cm. Exposed artery length was not associated with age, sex, rib space, or side. The variability of arterial position was significantly associated with age (coefficient, 0.91; P < .001) and rib space number (coefficient, - 2.60; P < .001). CONCLUSIONS: The intercostal artery is exposed within the intercostal space in the first 6 cm lateral to the spine. The variability of its vertical position is greater in older patients and in more cephalad rib spaces

Serum androgen levels in healthy premenopausal women with and\ud without sexual dysfunction: part A: serum androgen levels in\ud women aged 20–49 years with no complaints of sexual dysfunction

Androgen insufficiency is a recognized cause of sexual dysfunction in men and women. Age-related decrements in adrenal and gonadal androgen levels also occur naturally in both sexes. At present, it is unclear if a woman's low serum androgen level is a reflection of the expected normal age-related decline or indicative of an underlying androgen-deficient state. We studied premenopausal women with no complaints of sexual dysfunction to help define a normal female androgen profile. In all, 60 healthy, normally menstruating women, ages 20–49 y, were studied. The Abbreviated Sexual Function Questionnaire was administered along with a detailed interview. Radioimmunoassay measurements of morning serum testosterone (T), free testosterone (fT), dehydroepiandrosterone-sulfate (DHEAS), sex hormone-binding globulin (SHBG), and free androgen index (FAI) were measured during days 8–15 of the menstrual cycle. In women 20–49 y old without complaints of sexual dysfunction, serum androgen levels exhibit a progressive stepwise decline. Comparing values obtained in women age 20–29 y to those obtained in women 40–49 y, specific hormone decrements were DHEAS 195.6–140.4 mug/dl, serum T 51.5–33.7 ng/dl, fT 1.51–1.03 pg/ml. SHBG did not change significantly in women in this age group. The FAI reflected the age-related decrease in female androgen levels. The framework for the development of a female androgen profile in women with no complaints of sexual dysfunction has been established, and an age-related decrease in testosterone and its adrenal precursor, DHEAS, has been demonstrated. The FAI mirrors these decreases and its usefulness in clinical practice is confirmed. A precipitous decline in all androgens occurs after the decade of the 20s, yet SHBG does not show a significant change throughout the premenopausal years

Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: part B: reduced serum androgen levels in healthy premenopausal women with complaints of sexual dysfunction

Androgen insufficiency has been associated with decreased libido and arousal in postmenopausal women, but rarely has been evaluated in healthy premenopausal women. In all, 32 healthy premenopausal women were enrolled in this study, 18 with one or more complaints of sexual dysfunction and 14 without. Assays of ovarian and adrenal androgens were measured before and after ACTH stimulation. The women with complaints of sexual dysfunction had significantly lower adrenal androgens than did the control women. There were no differences in the basal ovarian androgens or cortisol levels. After ACTH, both groups stimulated cortisol as well as adrenal and ovarian androgens. In conclusion, premenopausal women with complaints of sexual dysfunction had lower adrenal androgen precursors and testosterone than age-matched control women without such complaints. Further study is required to determine how lower adrenal androgens contribute to female sexual dysfunction