Electrophysiological characterization of chronic stress-induced sensitization of noradrenergic neurons of the locus coeruleus

Chronic stress exposure can produce sensitization of norepinephrine release in the terminal fields of locus coeruleus (LC) neurons. The present studies explore the potential localization and mechanism underlying the sensitized response of LC neurons in rats following chronic exposure to cold (2 weeks; 5*C). Single unit recordings of LC neurons in halothane-anesthetized rats were used to compare the effect of intraventricular administration of corticotropin releasing hormone (CRH; 0.3-3.0µg) in control and previously cold-exposed rats. The CRH-evoked increase in LC neuron activity was enhanced following chronic cold exposure, without alteration in basal activity. The enhanced activation was only apparent at higher doses of CRH, resulting in an increased slope of the dose-response relationship for CRH in previously cold-exposed rats. It is concluded that the sensitization of CRH-evoked norepinephrine release in cold-exposed rats is accompanied by sensitization of LC neuron activity. We hypothesized that the response of LC neurons to multiple excitatory inputs is enhanced. Using in vitro intracellular recordings, we subsequently examined whether CRH exerts a direct effect on LC neurons, and which ionic currents and second messenger systems are likely affected by CRH. It was demonstrated that CRH dose-dependently increases the firing rate of LC neurons through a direct (TTX-insensitive) mechanism by decreasing a potassium conductance via adenylate cyclase and protein kinase A. The CRH-evoked activation of LC neurons is, at least in part, mediated by CRH1 receptors. In subsequent in vitro experiments using intracellular recordings, the electrophysiological properties of LC neurons were compared between control and cold-exposed rats. We observed that the excitability and input resistance of LC neurons was enhanced in slices from cold-exposed rats. In addition, the accommodation of spike firing was reduced and there was a strong trend toward a reduction of the post-activation inhibitory period. These data demonstrate that the stress-induced sensitization of LC neurons is, at least in part, maintained in vitro and suggest that alterations in electrophysiological properties of LC neurons contribute to the chronic stress-induced sensitization of central noradrenergic function observed in vivo. Furthermore, these data suggest that an alteration in auto-inhibitory control of LC activity is involved in chronic stress-induced alterations

Tonic exploration governs both flexibility and lapses.

In many cognitive tasks, lapses (spontaneous errors) are tacitly dismissed as the result of nuisance processes like sensorimotor noise, fatigue, or disengagement. However, some lapses could also be caused by exploratory noise: randomness in behavior that facilitates learning in changing environments. If so, then strategic processes would need only up-regulate (rather than generate) exploration to adapt to a changing environment. This view predicts that more frequent lapses should be associated with greater flexibility because these behaviors share a common cause. Here, we report that when rhesus macaques performed a set-shifting task, lapse rates were negatively correlated with perseverative error frequency across sessions, consistent with a common basis in exploration. The results could not be explained by local failures to learn. Furthermore, chronic exposure to cocaine, which is known to impair cognitive flexibility, did increase perseverative errors, but, surprisingly, also improved overall set-shifting task performance by reducing lapse rates. We reconcile these results with a state-switching model in which cocaine decreases exploration by deepening attractor basins corresponding to rule states. These results support the idea that exploratory noise contributes to lapses, affecting rule-based decision-making even when it has no strategic value, and suggest that one key mechanism for regulating exploration may be the depth of rule states

Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment

Abstract Background Damage to the central nervous system during HIV infection can lead to variable neurobehavioral dysfunction termed HIV-associated neurocognitive disorders (HAND). There is no clear consensus regarding the neuropathological or cellular basis of HAND. We sought to study the potential contribution of aging to the pathogenesis of HAND. Aged (range = 14.7–24.8 year) rhesus macaques of Chinese origin (RM-Ch) (n = 23) were trained to perform cognitive tasks. Macaques were then divided into four groups to assess the impact of SIVmac251 infection (n = 12) and combined antiretroviral therapy (CART) (5 infected; 5 mock-infected) on the execution of these tasks. Results Aged SIV-infected RM-Ch demonstrated significant plasma viremia and modest CSF viral loads but showed few clinical signs, no elevations of systemic temperature, and no changes in activity levels, platelet counts or weight. Concentrations of biomarkers of acute and chronic inflammation such as soluble CD14, CXCL10, IL-6 and TNF-α are known to be elevated following SIV infection of young adult macaques of several species, but concentrations of these biomarkers did not shift after SIV infection in aged RM-Ch and remained similar to mock-infected macaques. Neither acute nor chronic SIV infection or CART had a significant impact on accuracy, speed or percent completion in a sensorimotor test. Conclusions Viremia in the absence of a chronic elevated inflammatory response seen in some aged RM-Ch is reminiscent of SIV infection in natural disease resistant hosts. The absence of cognitive impairment during SIV infection in aged RM-Ch might be in part attributed to diminishment of some facets of the immunological response. Additional study encompassing species and age differences is necessary to substantiate this hypothesis

MOESM1 of Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment

Additional file 1: Figure S1. Effect of age and SIV-infection on weight. In comparison to mock-infected macaques, SIV-infection of aged Chinese rhesus macaques does not impact weight. Animals were weighed on a weekly basis. Median longitudinal weight (kg) over the course of infection for each group (A). Change in median weight (kg) from baseline in SIV-infected (red) and mock-infected (blue) macaques during the acute phase of infection (B). Both SIV-infected and mock infected macaques lost weight at 2 and 3 wpi. At 4 wpi, SIV-infected macaques lost a small amount of mass while mock-infected macaques slightly gained mass. Change in median weight (kg) from baseline in SIV-infected (red) and mock-infected (blue) macaques at time of necropsy (C). Mock-infected macaques gained over 1 kg by the end of the study whereas SIV-infected macaques were similar to their starting weight. Figure S2. Effect of age, SIV-infection and cART on body temperature. There were no changes in body temperature after SIV-infection in aged Chinese rhesus macaques. Body temperature was recorded at least once a day and the median temperature determined in two week intervals. Baseline temperature (week 0 post-infection) was the average of 12 weeks of preinoculation measurements. Time course of body temperature in SIV-infected macaques and controls (A). Lines represent median values. Time course of change in temperature (Δ °C) from baseline (B). Change in temperature from baseline during the first 4 weeks post-infection (C). Change in temperature from baseline at necropsy (D). Figure S3. Effect of age, SIV-infection and cART on platelet counts. Platelet counts are not significantly altered during acute SIV infection in aged rhesus macaques of Chinese origin. Time course of median platelet counts during the duration of infection (A). Lines represent median values. Platelet counts of SIV-infected and mock-infected macaques during the first 4 weeks post-infection (B). Figure S4. Total cell counts during the course of SIV infection. Total CD4+ T-cell counts decrease during SIV infection in aged rhesus macaques of Chinese origin. Total CD8+ T-cell and NK-cell counts shown an elevation during acute infection then fall to similar levels as mock-infected macaques. Time course change in CD4+ T-cell (A), CD8+ T-cell (B), NK-cell (C), and B-cell counts (D) during SIV and mock infection. Lines represent median values. Figure S5. Total monocyte subset counts during the course of SIV infection. CD14+CD16- (A), CD14+CD16+ (B), CD14-CD16+ (C) monocyte subset counts during SIV infection in aged rhesus macaques of Chinese origin. Lines represent median values. Figure S6. Plasma and CSF viral load versus temperature in individual SIV-infected macaques. Each graph shows the time course of plasma SIV loads, CSF SIV loads and temperature in an individual aged Chinese rhesus macaque during SIV infection. Graphs of SIV-infected macaques that did not receive treatment (Group 1) are shown in (a) and graphs of SIV-infected macaques that were treated with CART (Group 4) are shown in (b). The green shaded area represents the period macaques received CART or saline. Figure S7. Plasma and CSF viral load versus CD4+ and CD8+ T-cell count in SIV-infected macaques. Each graph shows the time course of plasma SIV loads, CSF SIV loads, CD4+ T-cell counts, and CD8+ T-cell counts in an individual aged Chinese rhesus macaque during SIV infection. Graphs of SIV-infected macaques that did not receive treatment (Group 1) are shown in (a) and graphs of SIV-infected macaques that were treated with CART (Group 4) are shown in (b). The green shaded area represents the period macaques received CART or saline. Figure S8. Plasma and CSF viral load versus reaction time and accuracy in SIV-infected macaques. Each graph shows the time course of plasma SIV loads, CSF SIV loads, reaction time (RT), and percent accuracy (Acc) in an individual aged Chinese rhesus macaque during SIV infection. Graphs of SIV-infected macaques that did not receive treatment (Group 1) are shown in (a) and graphs of SIV-infected macaques that were treated with CART (Group 4) are shown in (b). The green shaded area represents the period macaques received CART or saline. Figure S9. Time and accuracy in mock-infected macaques. Each graph shows the reaction time (RT) and percent accuracy (Acc) in a speeded motor task for an individual aged Chinese rhesus macaque over the study period. Graphs of mock-infected macaques that did not receive treatment (Group 2) are shown in (a) and graphs of mock-infected macaques that were treated with CART (Group 3) are shown in (b). The green shaded area represents the period macaques received CART or saline

Strengths and challenges of longitudinal non-human primate neuroimaging

International audienceLongitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power

Orbitofrontal cortex is selectively activated in a primate model of attentional bias to cocaine cues

© 2019, The Author(s).Attentional bias to drug-associated cues correlates with extent of current use, and risk of relapse among those attempting abstinence. Electroencephalogram (EEG) and functional imaging measures in clinical studies have previously investigated the neural basis of attentional bias, but the lack of animal models precluded investigation at the single-unit level. To complement results obtained from clinical studies, we have employed a non-human primate model of attentional bias to cocaine cues while simultaneously recording single-unit activity in cortical and striatal regions implicated in reward processing. Rhesus macaques conditioned to associate particular colors with cocaine or water reward performed an attentional bias task, in which those colors served as irrelevant distractors. Concurrently, multiple electrode arrays for recording single-unit activity were acutely implanted into the orbitofrontal cortex, anterior cingulate cortex, dorsal anterior striatum, and ventral striatum. As in clinical studies, attentional bias was indicated by elongated response times on trials with cocaine-associated distractors compared with trials with water-associated, or control unconditioned distractors. In both animals studied, across an unbiased sample of neurons, the orbitofrontal cortex differentiated distractor condition by the proportion of single-units activated, as well as by population response. In one of the two, the anterior cingulate cortex did as well, but neither striatal region did in either animal. These direct measures of single-unit activity in a primate model complement clinical imaging observations suggesting that cortical mechanisms, especially in orbitofrontal cortex, are likely involved in attentional bias to cocaine-associated environmental cues11sciescopu