Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from ...recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPARs) contributed background depolarization to sustain network firing. In contrast, many Response cells were sensitive to AMPAR blockade and increased firing after systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s disease profoundly impair cognition.
► Primate prefrontal cortical working memory circuits require NMDA NR2B receptors ► Blocking NMDA, but not AMPA receptors, markedly reduced Delay cell firing ► Systemic ketamine also reduced Delay cell firing but increased Response cell firing ► These primate data should redefine NMDA glutamate theories of cognitive disorders
Wang et al. assess the effect of blocking glutamate receptors on working memory and neuronal firing in primate dlPFC. Delay cell firing is abolished by NMDAR block, while many Response cells are sensitive to AMPAR block. Blocking NR2B receptors impairs working memory, underscoring their role in cognitive function.
Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour ...and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.
The Juno Microwave Radiometer (MWR) is a six-frequency scientific instrument designed and built to investigate the deep atmosphere of Jupiter. It is one of a suite of instruments on NASA’s New ...Frontiers Mission Juno launched to Jupiter on August 5, 2011. The focus of this paper is the description of the scientific objectives of the MWR investigation along with the experimental design, observational approach, and calibration that will achieve these objectives, based on the Juno mission plan up to Jupiter orbit insertion on July 4, 2016. With frequencies distributed approximately by octave from 600 MHz to 22 GHz, the MWR will sample the atmospheric thermal radiation from depths extending from the ammonia cloud region at around 1 bar to pressure levels as deep as 1000 bars. The primary scientific objectives of the MWR investigation are to determine the presently unknown dynamical properties of Jupiter’s subcloud atmosphere and to determine the global abundance of oxygen and nitrogen, present in the atmosphere as water and ammonia deep below their respective cloud decks. The MWR experiment is designed to measure both the thermal radiation from Jupiter and its emission-angle dependence at each frequency relative to the atmospheric local normal with high accuracy. The antennas at the four highest frequencies (21.9, 10.0, 5.2, and 2.6 GHz) have ∼12° beamwidths and will achieve a spatial resolution approaching 600 km near perijove. The antennas at the lowest frequencies (0.6 and 1.25 GHz) are constrained by physical size limitations and have 20° beamwidths, enabling a spatial resolution of as high as 1000 km to be obtained. The MWR will obtain Jupiter’s brightness temperature and its emission-angle dependence at each point along the subspacecraft track, over angles up to 60° from the normal over most latitudes, during at least six perijove passes after orbit insertion. The emission-angle dependence will be obtained for all frequencies to an accuracy of better than one part in
10
3
, sufficient to detect small variations in atmospheric temperature and absorber concentration profiles that distinguish dynamical and compositional properties of the deep Jovian atmosphere.
Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men.
To ...determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels.
Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004.
Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months.
The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression.
Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL 9.8 nmol/L; median at 6 months, 640 ng/dL 22.2 nmol/L) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU Clusterin), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor.
These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.
Context.
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's ...Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change.
Methods.
Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared.
Results.
Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change.
Conclusions.
Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
Spatial frequency (SF) and orientation tuning are intrinsic properties of neurons in primary visual cortex (area V1). To investigate the neural mechanisms mediating selectivity in the awake animal, ...we measured the temporal dynamics of SF and orientation tuning. We adapted a high-speed reverse-correlation method previously used to characterize orientation tuning dynamics in anesthetized animals to estimate efficiently the complete spatiotemporal receptive fields in area V1 of behaving macaques. We found that SF and orientation tuning are largely separable over time in single neurons. However, spatiotemporal receptive fields also contain a small nonseparable component that reflects a significant difference in response latency for low and high SF stimuli. The observed relationship between stimulus SF and latency represents a dynamic shift in SF tuning, and suggests that single V1 neurons might receive convergent input from the magno- and parvocellular processing streams. Although previous studies with anesthetized animals suggested that orientation tuning could change dramatically over time, we find no substantial evidence of dynamic changes in orientation tuning.
The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. ...We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause.
Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone.
The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter 4.5 to 23.6 pmol per liter). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly.
In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.
Natural exploration of complex visual scenes depends on saccadic eye movements toward important locations. Saccade targeting is thought to be mediated by a retinotopic map that represents the ...locations of salient features. In this report, we demonstrate that extrastriate ventral area V4 contains a retinotopic salience map that guides exploratory eye movements during a naturalistic free viewing visual search task. In more than half of recorded cells, visually driven activity is enhanced prior to saccades that move the fovea toward the location previously occupied by a neuron's spatial receptive field. This correlation suggests that bottom-up processing in V4 influences the oculomotor planning process. Half of the neurons also exhibit top-down modulation of visual responses that depends on search target identity but not visual stimulation. Convergence of bottom-up and top-down processing streams in area V4 results in an adaptive, dynamic map of salience that guides oculomotor planning during natural vision.
Introduction: Direct oral anticoagulant (DOAC) use for thrombosis treatment and prophylaxis is a popular alternative to warfarin. This study compares rates of traumatic intracranial hemorrhage (ICH) ...for patients on anticoagulant therapies and the effect of combined anticoagulant and antiplatelet therapies. Methods: A retrospective observational study of trauma patients was conducted at two level I trauma centers. Patients aged ≥18 years with preinjury use of an anticoagulant (warfarin, rivaroxaban, apixaban, or dabigatran) who sustained a blunt head injury within the past day were included. Patients were evaluated by head CT to evaluate for ICH. Results: Three hundred and eighty-eight patients were included (140 on warfarin, 149 on a DOAC, and 99 on combined anticoagulant and antiplatelet therapies). Seventy-nine patients (20.4%) had an acute ICH, while 16 patients (4.1%) had a delayed ICH found on routine repeat CT. Those on combination therapy were not at increased risk of acute ICH (relative risk RR 0.90, confidence interval CI: 0.56-1.44; P > 0.5) or delayed ICH (RR 2.19, CI: 0.84-5.69; P = 0.10) compared to anticoagulant use only. Those on warfarin were at increased risk of acute ICH (RR 1.75, CI: 1.10-2.78, P = 0.015), but not delayed ICH (RR 0.99, CI 0.27-3.59, P > 0.5), compared to those on DOACs. No delayed ICH patients died or required neurosurgical intervention. Conclusion: Patients on warfarin had a higher rate of acute ICH, but not delayed ICH, compared to those on DOACs. Given the low rate of delayed ICH with no resultant morbidity or mortality, routine observation and repeat head CT on patients with no acute ICH may not be necessary.
Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it ...induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with beta-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.
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