Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development.

RATIONALE: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. OBJECTIVES: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. METHODS AND RESULTS: No difference in atherosclerotic lesion size was found in Ldlr-/- (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl-DTA , Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ-producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti-asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti-asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr-/- mice reconstituted with either wild-type or Ncr1iCreR26Rlsl-DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell-deficient chimeric mice. CONCLUSIONS: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs

Temporal Tuning Properties along the Human Ventral Visual Stream

Both our environment and our behavior contain many spatiotemporal regularities. Preferential and differential tuning of neural populations to these regularities can be demonstrated by assessing rate dependence of neural responses evoked during continuous periodic stimulation. Here, we used functional magnetic resonance imaging to measure regional variations of temporal sensitivity along the human ventral visual stream. By alternating one face and one house stimulus, we combined sufficient low-level signal modulation with changes in semantic meaning and could therefore drive all tiers of visual cortex strongly enough to assess rate dependence. We found several dissociations between early visual cortex and middle- and higher-tier regions. First, there was a progressive slowing down of stimulation rates yielding peak responses along the ventral visual stream. This finding shows the width of temporal integration windows to increase at higher hierarchical levels. Next, for fixed rates, early but not higher visual cortex responses additionally depended on the length of stimulus exposure, which may indicate increased persistence of responses to short stimuli at higher hierarchical levels. Finally, attention, which was recruited by an incidental task, interacted with stimulation rate and shifted tuning peaks toward lower frequencies. Together, these findings quantify neural response properties that are likely to be operational during natural vision and that provide putative neurofunctional substrates of mechanisms that are relevant in several psychophysical phenomena as masking and the attentional blink. Moreover, they illustrate temporal constraints for translating the deployment of attention into enhanced neural responses and thereby account for lower limits of attentional dwell time

Human Screams Occupy a Privileged Niche in the Communication Soundscape

Screaming is arguably one of the most relevant communication signals for survival in humans. Despite their practical relevance and their theoretical significance as innate [1] and virtually universal [2, 3] vocalizations, what makes screams a unique signal and how they are processed is not known. Here, we use acoustic analyses, psychophysical experiments, and neuroimaging to isolate those features that confer to screams their alarming nature, and we track their processing in the human brain. Using the modulation power spectrum (MPS [4, 5]), a recently developed, neurally informed characterization of sounds, we demonstrate that human screams cluster within restricted portion of the acoustic space (between ∼30 and 150 Hz modulation rates) that corresponds to a well-known perceptual attribute, roughness. In contrast to the received view that roughness is irrelevant for communication [6], our data reveal that the acoustic space occupied by the rough vocal regime is segregated from other signals, including speech, a pre-requisite to avoid false alarms in normal vocal communication. We show that roughness is present in natural alarm signals as well as in artificial alarms and that the presence of roughness in sounds boosts their detection in various tasks. Using fMRI, we show that acoustic roughness engages subcortical structures critical to rapidly appraise danger. Altogether, these data demonstrate that screams occupy a privileged acoustic niche that, being separated from other communication signals, ensures their biological and ultimately social efficiency

The rough sound of salience enhances aversion through neural synchronisation

Being able to produce sounds that capture attention and elicit rapid reactions is the prime goal of communication. One strategy, exploited by alarm signals, consists in emitting fast but perceptible amplitude modulations in the roughness range (30-150 Hz). Here, we investigate the perceptual and neural mechanisms underlying aversion to such temporally salient sounds. By measuring subjective aversion to repetitive acoustic transients, we identify a nonlinear pattern of aversion restricted to the roughness range. Using human intracranial recordings, we show that rough sounds do not merely affect local auditory processes but instead synchronise large-scale, supramodal, salience-related networks in a steady-state, sustained manner. Rough sounds synchronise activity throughout superior temporal regions, subcortical and cortical limbic areas, and the frontal cortex, a network classically involved in aversion processing. This pattern correlates with subjective aversion in all these regions, consistent with the hypothesis that roughness enhances auditory aversion through spreading of neural synchronisation

Alpha-Band Phase Synchrony Is Related to Activity in the Fronto-Parietal Adaptive Control Network

Neural oscillations in the alpha band (8-12 Hz) are increasingly viewed as an active inhibitory mechanism that gates and controls sensory information processing as a function of cognitive relevance. Extending this view, phase synchronization of alpha oscillations across distant cortical regions could regulate integration of information. Here, we investigated whether such long-range cross-region coupling in the alpha band is intrinsically and selectively linked to activity in a distinct functionally specialized brain network. If so, this would provide new insight into the functional role of alpha band phase synchrony. We adapted the phase-locking value to assess fluctuations in synchrony that occur over time in ongoing activity. Concurrent EEG and functional magnetic resonance imaging (fMRI) were recorded during resting wakefulness in 26 human subjects. Fluctuations in global synchrony in the upper alpha band correlated positively with activity in several prefrontal and parietal regions (as measured by fMRI). fMRI intrinsic connectivity analysis confirmed that these regions correspond to the well known fronto-parietal (FP) network. Spectral correlations with this network's activity confirmed that no other frequency band showed equivalent results. This selective association supports an intrinsic relation between large-scale alpha phase synchrony and cognitive functions associated with the FP network. This network has been suggested to implement phasic aspects of top-down modulation such as initiation and change in moment-to-moment control. Mechanistically, long-range upper alpha band synchrony is well suited to support these functions. Complementing our previous findings that related alpha oscillation power to neural structures serving tonic control, the current findings link alpha phase synchrony to neural structures underpinning phasic control of alertness and task requirements

Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development.

RATIONALE: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. OBJECTIVES: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. METHODS AND RESULTS: No difference in atherosclerotic lesion size was found in Ldlr-/- (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl-DTA , Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ-producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti-asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti-asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr-/- mice reconstituted with either wild-type or Ncr1iCreR26Rlsl-DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell-deficient chimeric mice. CONCLUSIONS: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs

Selective EGFR (Epidermal Growth Factor Receptor) Deletion in Myeloid Cells Limits Atherosclerosis-Brief Report.

OBJECTIVE: To determine the consequences of specific inhibition of EGFR (epidermal growth factor receptor) in myeloid cells in atherosclerosis development. APPROACH AND RESULTS: Atherosclerotic lesion size was significantly reduced in irradiated Ldlr-/- mice reconstituted with LysMCre+Egfrlox/lox bone marrow, compared with chimeric Ldlr-/- mice reconstituted with LysMCre-Egfrlox/lox bone marrow, after 4 (-43%; P<0.05), 7 (-34%; P<0.05), and 12 weeks (-54%; P<0.001) of high-fat diet. Reduction of lesion size was associated with marked reduction in macrophage accumulation and necrotic core size. Specific deletion of Egfr in myeloid cells reduced TNF-α (tumor necrosis factor-α) and IL (interleukin)-6 production by stimulated macrophages but had no effect on IL-10 and IL-12p70 secretion. Finally, we found that myeloid deletion of Egfr limited cytoskeletal rearrangements and also lipid uptake by macrophages through a downregulation of the scavenger receptor CD36 (cluster of differentiation 36). CONCLUSIONS: Gene deletion of Egfr in myeloid cells limits IL-6 and TNF-α production, lipid uptake, and consecutively reduces atherosclerosis development