To test the hypothesis that hypoxia centrally affects performance independently of afferent feedback and peripheral fatigue, we conducted two experiments under complete vascular occlusion of the ...exercising muscle under different systemic O(2) environmental conditions. In experiment 1, 12 subjects performed repeated submaximal isometric contractions of the elbow flexor to exhaustion (RCTE) with inspired O(2) fraction fixed at 9% (severe hypoxia, SevHyp), 14% (moderate hypoxia, ModHyp), 21% (normoxia, Norm), or 30% (hyperoxia, Hyper). The number of contractions (performance), muscle (biceps brachii), and prefrontal near-infrared spectroscopy (NIRS) parameters and high-frequency paired-pulse (PS100) evoked responses to electrical muscle stimulation were monitored. In experiment 2, 10 subjects performed another RCTE in SevHyp and Norm conditions in which the number of contractions, biceps brachii electromyography responses to electrical nerve stimulation (M wave), and transcranial magnetic stimulation responses (motor-evoked potentials, MEP, and cortical silent period, CSP) were recorded. Performance during RCTE was significantly reduced by 10-15% in SevHyp (arterial O(2) saturation, SpO(2) = ∼75%) compared with ModHyp (SpO(2) = ∼90%) or Norm/Hyper (SpO(2) > 97%). Performance reduction in SevHyp occurred despite similar 1) metabolic (muscle NIRS parameters) and functional (changes in PS100 and M wave) muscle states and 2) MEP and CSP responses, suggesting comparable corticospinal excitability and spinal and cortical inhibition between SevHyp and Norm. It is concluded that, in SevHyp, performance and central drive can be altered independently of afferent feedback and peripheral fatigue. It is concluded that submaximal performance in SevHyp is partly reduced by a mechanism related directly to brain oxygenation.
Gamma oscillations appear to be dependent on inhibitory neurotransmission from parvalbumin (PV)-containing gamma-amino butyric acid neurons. Thus, the abnormalities in PV neurons found in ...schizophrenia may underlie the deficits of gamma-band synchrony in the illness. Because gamma-band synchrony is thought to be crucial for cognition, cognitive deficits in schizophrenia may reflect PV neuron dysfunction in cortical neural circuits. Interestingly, it has been suggested that PV alterations in schizophrenia are the consequence of a hypofunction of signaling through N-methyl-D-aspartate (NMDA) receptors (NMDARs). Here, we review recent findings that address the question of how NMDAR hypofunction might produce deficits of PV neuron-mediated inhibition in schizophrenia. We conclude that while dysregulation of NMDARs may play an important role in the pathophysiology of schizophrenia, additional research is required to determine the particular cell type(s) that mediate dysfunctional NMDAR signaling in the illness.
Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic ...tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
The neuronal circuits of the basolateral amygdala (BLA) are crucial for acquisition, consolidation, retrieval, and extinction of associative emotional memories. Synaptic plasticity in BLA neurons is ...essential for associative emotional learning and is a candidate mechanism through which subsets of BLA neurons (commonly termed “engram”) are recruited during learning and reactivated during memory retrieval. In parallel, synchronous oscillations in the theta and gamma bands between the BLA and interconnected structures have been shown to occur during consolidation and retrieval of emotional memories. Understanding how these cellular and network phenomena interact is vital to decipher the roles of emotional memory formation and storage in the healthy and pathological brain. Here, we review data on synaptic plasticity, engrams, and network oscillations in the rodent BLA. We explore mechanisms through which synaptic plasticity, engrams, and long-range synchrony might be interconnected.
Bocchio et al. review how synaptic plasticity, engrams, and network oscillations in amygdala circuits contribute to the encoding of emotional memories. They explore mechanisms through which these cellular and network phenomena could interact.
Differentiation of insulin producing beta-cells is a genetically well defined process that involves functions of various conserved transcription factors. Still, the transcriptional mechanisms ...underlying specification and determination of beta-cell fate are poorly defined. Here we provide the description of a beta-cell progenitor specific enhancer as a model to study initial steps of beta-cell differentiation. We show that evolutionary non-conserved upstream sequences of the zebrafish hb9 gene are required and sufficient for regulating expression in beta-cells prior to the onset of insulin expression. This enhancer contains binding sites for paired-box transcription factors and two E-boxes that in EMSA studies show interaction with Pax6b and NeuroD, respectively. We show that Pax6b is a potent activator of endodermal hb9 expression and that this activation depends on the beta-cell enhancer. Using genetic approaches we show that pax6b is crucial for maintenance but not induction of pancreatic hb9 transcription. As loss of Pax6b or Hb9 independently results in the loss of insulin expression, the data reveal a novel cross-talk between the two essential regulators of early beta-cell differentiation. While we find that the known pancreatic E-box binding proteins NeuroD and Ngn3 are not required for hb9 expression we also show that removal of both E-boxes selectively eliminates pancreatic specific reporter expression. The data provide evidence for an Ngn3 independent pathway of beta-cell specification that requires function of currently not specified E-box binding factors.
► Beta-cell progenitor enhancer localizes to non-conserved hb9 promoter sequences. ► E-boxes are required for hb9 induction. ► Induction is independent of Ngn3 and NeuroD. ► Pax6b activates enhancer. ► Pax6b is required for hb9 maintenance.
Dopaminergic ventral tegmental area (VTA) neurons are critically involved in a variety of behaviors that rely on heightened arousal, but whether they directly and causally control the generation and ...maintenance of wakefulness is unknown. We recorded calcium activity using fiber photometry in freely behaving mice and found arousal-state-dependent alterations in VTA dopaminergic neurons. We used chemogenetic and optogenetic manipulations together with polysomnographic recordings to demonstrate that VTA dopaminergic neurons are necessary for arousal and that their inhibition suppresses wakefulness, even in the face of ethologically relevant salient stimuli. Nevertheless, before inducing sleep, inhibition of VTA dopaminergic neurons promoted goal-directed and sleep-related nesting behavior. Optogenetic stimulation, in contrast, initiated and maintained wakefulness and suppressed sleep and sleep-related nesting behavior. We further found that different projections of VTA dopaminergic neurons differentially modulate arousal. Collectively, our findings uncover a fundamental role for VTA dopaminergic circuitry in the maintenance of the awake state and ethologically relevant sleep-related behaviors.
Brown fat (brown adipose tissue, BAT) primary function is to produce heat. There is now compelling evidence to indicate that brown fat cells in some BAT depots share their predecessor cells with ...myocytes. Brown adipocyte (trans)differentiation depends on various receptors / transcription factors that include peroxisome proliferator-activated receptor g (PPARgamma), PPARgamma-coactivator-1alpha (PGC1alpha), PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM16), CCAAT/enhancer-binding protein beta (C/EBP-beta) and bone morphogenetic protein 7 (BMP7). Such mediators also help BAT to acquire its thermogenic phenotype, which is essentially conferred by uncoupling protein 1 (UCP1). UCP1 uncouples adenosine-5'-triphosphate (ATP) synthesis from substrate oxidation in brown adipocytes. Its activity depends on the availability of fatty acids delivered upon BAT's beta)-adrenergic activation, which, physiologically, ensues from the sympathetic nervous system (SNS) activation of the tissue. SNS-mediated thermogenesis is largely controlled by the hypothalamus and brainstem. Recently, positron emission tomography / computed tomography (PET/CT) scanning investigations have revealed the presence in adult humans of important neck and shoulder BAT depots. That finding has contributed to reinstate a strong interest for brown adipocyte biology and thermogenesis. This review aims at the unique biology of BAT with the emphasis put on the recent discoveries regarding the brown adipocyte development and function.
Stimulation of almost all mammalian cell types leads to the release of cellular ATP and autocrine feedback through a diverse array of purinergic receptors. Depending on the types of purinergic ...receptors that are involved, autocrine signalling can promote or inhibit cell activation and fine-tune functional responses. Recent work has shown that autocrine signalling is an important checkpoint in immune cell activation and allows immune cells to adjust their functional responses based on the extracellular cues provided by their environment. This Review focuses on the roles of autocrine purinergic signalling in the regulation of both innate and adaptive immune responses and discusses the potential of targeting purinergic receptors for treating immune-mediated disease.
Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults ...(adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.
Transcranial magnetic stimulation (TMS) of human occipital and posterior parietal cortex can give rise to visual sensations called phosphenes. We used near-threshold TMS with concurrent EEG ...recordings to measure how oscillatory brain dynamics covary, on single trials, with the perception of phosphenes after occipital and parietal TMS. Prestimulus power and phase, predominantly in the alpha band (8-13 Hz), predicted occipital TMS phosphenes, whereas higher-frequency beta-band (13-20 Hz) power (but not phase) predicted parietal TMS phosphenes. TMS-evoked responses related to phosphene perception were similar across stimulation sites and were characterized by an early (200 ms) posterior negativity and a later (>300 ms) parietal positivity in the time domain and an increase in low-frequency (∼5-7 Hz) power followed by a broadband decrease in alpha/beta power in the time-frequency domain. These correlates of phosphene perception closely resemble known electrophysiological correlates of conscious perception of near-threshold visual stimuli. The regionally differential pattern of prestimulus predictors of phosphene perception suggests that distinct frequencies may reflect cortical excitability in occipital versus posterior parietal cortex, calling into question the broader assumption that the alpha rhythm may serve as a general index of cortical excitability.
Alpha-band oscillations are thought to reflect cortical excitability and are therefore ascribed an important role in gating information transmission across cortex. We probed cortical excitability directly in human occipital and parietal cortex and observed that, whereas alpha-band dynamics indeed reflect excitability of occipital areas, beta-band activity was most predictive of parietal cortex excitability. Differences in the state of cortical excitability predicted perceptual outcomes (phosphenes), which were manifest in both early and late patterns of evoked activity, revealing the time course of phosphene perception. Our findings prompt revision of the notion that alpha activity reflects excitability across all of cortex and suggest instead that excitability in different regions is reflected in distinct frequency bands.
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