State-dependent Manner Research Articles

State-Dependent TMS over Prefrontal Cortex Disrupts Fear-Memory Reconsolidation and Prevents the Return of Fear

Erasing maladaptive memories has been a challenge for years. A way to change fear memories is to target the process of reconsolidation, during which a retrieved memory transiently returns to a labile state, amenable to modification [1, 2]. Disruption of human fear-memory reconsolidation has been classically attempted with pharmacological [3] or behavioral (e.g., extinction) [4] treatments that, however, do not clarify the underlying brain mechanism. To address this issue, in 84 healthy humans submitted to six experiments, here, we combined a differential fear conditioning paradigm with repetitive transcranial magnetic stimulation (rTMS) administered in a state-dependent manner. In a critical condition, we stimulated the dorsolateral prefrontal cortex (dlPFC) 10min after a reminder cue that reactivated a fear memory acquired 1day before. At testing, 24h after rTMS, participants exhibited decreased physiological expression of fear, as shown by their skin conductance response. Similar reductions were observed when targeting the left and the right dlPFC. In contrast, no decrease was observed in participants tested immediately after dlPFC-rTMS or in participants receiving either control rTMS (i.e., active control site and sham stimulations) or dlPFC-rTMS without preceding fear-memory reactivation, thus showing both the site and time specificity and state dependency of our rTMS intervention. Expression of fear was indeed reduced only when dlPFC-rTMS was administered within the reconsolidation time window. Moreover, dlPFC-rTMS prevented subsequent return of fear after extinction training. These findings highlight the causal role of dlPFC in fear-memory reconsolidation and suggest that rTMS can be used in humans to prevent the return of fear.

Whole-organism behavioral profiling reveals a role for dopamine in state-dependent motor program coupling in C. elegans.

Animal behaviors are commonly organized into long-lasting states that coordinately impact the generation of diverse motor outputs such as feeding, locomotion, and grooming. However, the neural mechanisms that coordinate these distinct motor programs remain poorly understood. Here, we examine how the distinct motor programs of the nematode C. elegans are coupled together across behavioral states. We describe a new imaging platform that permits automated, simultaneous quantification of each of the main C. elegans motor programs over hours or days. Analysis of these whole-organism behavioral profiles shows that the motor programs coordinately change as animals switch behavioral states. Utilizing genetics, optogenetics, and calcium imaging, we identify a new role for dopamine in coupling locomotion and egg-laying together across states. These results provide new insights into how the diverse motor programs throughout an organism are coordinated and suggest that neuromodulators like dopamine can couple motor circuits together in a state-dependent manner.

Inhibition by the atypical antipsychotic risperidone of voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells

We evaluated the inhibitory effects of the atypical antipsychotic drug risperidone on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Risperidone suppressed Kv currents in reversible and concentration-dependent manners with an apparent half-maximal effective concentration (IC50 value) of 5.54 ± 0.66 μM and a slope factor of 1.22 ± 0.07. The inactivation of Kv currents was significantly accelerated by risperidone. The rate constants of association and dissociation for risperidone were 0.25 ± 0.01 μM−1s−1 and 1.36 ± 0.14 s−1, respectively. Application of risperidone shifted the steady-state activation curve in the positive direction and the inactivation curve in the negative direction, suggesting that the risperidone-induced inhibition of Kv channels was mediated by effects on the voltage sensors of the channels. Application of train pulses at 1 and 2 Hz led to a progressive increase in the blockage of Kv currents by risperidone. In addition, the recovery time constants from inactivation were extended in the presence of risperidone, indicating that risperidone inhibited Kv channels in a use (state)-dependent manner. Pretreatment with the Kv1.5 subtype inhibitor reduced the inhibitory effects of risperidone on Kv channels. However, pretreatment with a Kv2.1 or Kv7.X subtype inhibitor did not affect the inhibitory effects of risperidone. Risperidone induced vasoconstriction and membrane depolarization. Based on these results, we conclude that risperidone inhibits Kv channels in a concentration-, time-, and state-dependent manners. Our results should be taken into consideration when using risperidone to study the kinetics of K+ channels in vascular smooth muscle.

Adenosine in the lateral hypothalamus/perifornical area does not participate on the CO2 chemoreflex

The Lateral Hypothalamus/Perifornical Area (LH/PFA) has been shown to be involved with the hypercapnic ventilatory response, in a state-dependent manner. We have demonstrated that purinergic signaling through ATP in the LH/PFA has an excitatory effect in ventilatory response to CO2 in awake rats in the dark phase of the diurnal cycle, but it is unknown whether the ATP metabolite adenosine, acting in the LH/PFA, modulates the ventilatory responses to hypercapnia. Here, we studied the effects of the microdialysis of adenosine (A1/A2 adenosine receptors agonist; 17 mM) and an A1 receptor antagonist (DPCPX; 0.1 mM) into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 during the light and the dark phases of the diurnal cycle. The microdialysis of adenosine and DPCPX caused no change in the CO2 ventilatory responses of rats during wakefulness or NREM sleep in either the dark or light period. Our data suggest that adenosine in the LH/PFA does not contribute to the hypercapnic ventilatory response in conscious rats.

State-dependent brainstem ensemble dynamics and their interactions with hippocampus across sleep states.

The brainstem plays a crucial role in sleep-wake regulation. However, the ensemble dynamics underlying sleep regulation remain poorly understood. Here, we show slow, state-predictive brainstem ensemble dynamics and state-dependent interactions between the brainstem and the hippocampus in mice. On a timescale of seconds to minutes, brainstem populations can predict pupil dilation and vigilance states and exhibit longer prediction power than hippocampal CA1 neurons. On a timescale of sub-seconds, pontine waves (P-waves) are accompanied by synchronous firing of brainstem neurons during both rapid eye movement (REM) and non-REM (NREM) sleep. Crucially, P-waves functionally interact with CA1 activity in a state-dependent manner: during NREM sleep, hippocampal sharp wave-ripples (SWRs) precede P-waves. On the other hand, P-waves during REM sleep are phase-locked with ongoing theta oscillations and are followed by burst firing of CA1 neurons. This state-dependent global coordination between the brainstem and hippocampus implicates distinct functional roles of sleep.

Orexin A as a modulator of dorsal lateral geniculate neuronal activity: a comprehensive electrophysiological study on adult rats

Orexins (OXA, OXB) are hypothalamic peptides playing crucial roles in arousal, feeding, social and reward-related behaviours. A recent study on juvenile rats suggested their involvement in vision modulation due to their direct action on dorsal lateral geniculate (dLGN) neurons. The present study aimed to verify whether a similar action of OXA can be observed in adulthood. Thus, in vivo and in vitro electrophysiological recordings on adult Wistar rats across light-dark and cortical cycles were conducted under urethane anaesthesia. OXA influenced ~28% of dLGN neurons recorded in vivo by either excitation or suppression of neuronal firing. OXA-responsive neurons did not show any spatial distribution nor represent a coherent group of dLGN cells, and responded to OXA similarly across the light–dark cycle. Interestingly, some OXA-responsive neurons worked in a cortical state-dependent manner, especially during the dark phase, and ‘preferred’ cortical activation over slow-wave activity induced by urethane. The corresponding patch clamp study confirmed these results by showing that < 20% of dLGN neurons were excited by OXA under both light regimes. The results suggest that OXA is involved in the development of the visual system rather than in visual processes and further implicate OXA in the mediation of circadian and arousal-related activity.

物质相关线索对成瘾者反应抑制的影响

<p id="C2">Loss of control in substance seeking and use of addicts is closely related to response inhibition. Many studies have explored this relationship in context of substance-related cues. Substance cues can be automatically captured by attention and also induce non-automatic approach-motivated state. As a consequence, these cues may consume limited cognitive resources through a stimulus-driven and a state-dependent manner in order to influence addicts' response inhibition. And these effects also play important roles in the development and maintenance of addictive behaviors. Further research should be carried out to reveal the neural mechanisms of both manners, clarify how motivations and attitudes towards substance use modulate these effects, conduct research in real situations, and discover more effective interventions.

Introducing a Bayesian model of selective attention based on active inference

Information gathering comprises actions whose (sensory) consequences resolve uncertainty (i.e., are salient). In other words, actions that solicit salient information cause the greatest shift in beliefs (i.e., information gain) about the causes of our sensations. However, not all information is relevant to the task at hand: this is especially the case in complex, naturalistic scenes. This paper introduces a formal model of selective attention based on active inference and contextual epistemic foraging. We consider a visual search task with a special emphasis on goal-directed and task-relevant exploration. In this scheme, attention modulates the expected fidelity (precision) of the mapping between observations and hidden states in a state-dependent or context-sensitive manner. This ensures task-irrelevant observations have little expected information gain, and so the agent – driven to reduce expected surprise (i.e., uncertainty) – does not actively seek them out. Instead, it selectively samples task-relevant observations, which inform (task-relevant) hidden states. We further show, through simulations, that the atypical exploratory behaviours in conditions such as autism and anxiety may be due to a failure to appropriately modulate sensory precision in a context-specific way.

RNA Binding Protein CELF2 Regulates Signal-Induced Alternative Polyadenylation by Competing with Enhancers of the Polyadenylation Machinery

SUMMARYThe 3′ UTR (UTR) of human mRNAs plays a critical role in controlling protein expression and function. Importantly, 3′ UTRs of human messages are not invariant for each gene but rather are shaped by alternative polyadenylation (APA) in a cell state-dependent manner, including in response to T cell activation. However, the proteins and mechanisms driving APA regulation remain poorly understood. Here we show that the RNA-binding protein CELF2 controls APA of its own message in a signal-dependent manner by competing with core enhancers of the polyadenylation machinery for binding to RNA. We further show that CELF2 binding overlaps with APA enhancers transcriptome-wide, and almost half of 3′ UTRs that undergo T cell signaling-induced APA are regulated in a CELF2-dependent manner. These studies thus reveal CELF2 to be a critical regulator of 3′ UTR identity in T cells and demonstrate an additional mechanism for CELF2 in regulating polyadenylation site choice.

Cortex-wide Changes in Extracellular Potassium Ions Parallel Brain State Transitions in Awake Behaving Mice

Brain state fluctuations modulate sensory processing, but the factors governing state-dependent neural activity remain unclear. Here, we tracked the dynamics of cortical extracellular K+ concentrations ([K+]o) during awake state transitions and manipulated [K+]o in slices, during visual processing, and during skilled motor execution. When mice transitioned from quiescence to locomotion, [K+]o increased by 0.6-1.0mM in all cortical areas analyzed, and this preceded locomotion by 1 s. Emulating the state-dependent [K+]o increase in cortical slices caused neuronal depolarization and enhanced input-output transformation. Invivo, locomotion increased the gain of visually evoked responses in layer 2/3 of visual cortex; this effect was recreated by imposing a [K+]o increase. Elevating [K+]o in the motor cortex increased movement-induced neuronal spiking in layer 5 and improved motor performance. Thus, [K+]o increases in a cortex-wide state-dependent manner, and this [K+]o increase affects both sensory and motor processing through the dynamic modulation of neural activity.

Global Shifts in Gene Expression Profiles Accompanied with Environmental Changes in Cnidarian-Dinoflagellate Endosymbiosis.

Stable endosymbiotic relationships between cnidarian animals and dinoflagellate algae are vital for sustaining coral reef ecosystems. Recent studies have shown that elevated seawater temperatures can cause the collapse of their endosymbiosis, known as ‘bleaching’, and result in mass mortality. However, the molecular interplay between temperature responses and symbiotic states still remains unclear. To identify candidate genes relevant to the symbiotic stability, we performed transcriptomic analyses under multiple conditions using the symbiotic and apo-symbiotic (symbiont free) Exaiptasia diaphana, an emerging model sea anemone. Gene expression patterns showed that large parts of differentially expressed genes in response to heat stress were specific to the symbiotic state, suggesting that the host sea anemone could react to environmental changes in a symbiotic state-dependent manner. Comparative analysis of expression profiles under multiple conditions highlighted candidate genes potentially important in the symbiotic state transition under heat-induced bleaching. Many of these genes were functionally associated with carbohydrate and protein metabolisms in lysosomes. Symbiont algal genes differentially expressed in hospite encode proteins related to heat shock response, calcium signaling, organellar protein transport, and sugar metabolism. Our data suggest that heat stress alters gene expression in both the hosts and symbionts. In particular, heat stress may affect the lysosome-mediated degradation and transportation of substrates such as carbohydrates through the symbiosome (phagosome-derived organelle harboring symbiont) membrane, which potentially might attenuate the stability of symbiosis and lead to bleaching-associated symbiotic state transition.

Prestimulus cortical EEG oscillations can predict the excitability of the primary motor cortex

BackgroundThe motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS) vary considerably at rest, but the mechanism underlying this amplitude variation is largely unknown. We hypothesized that prestimulus EEG oscillations modulate the subsequent MEPs in a state-dependent manner. ObjectiveWe studied the relationship between prestimulus alpha/beta oscillations and MEPs during eyes open (EO)/closed (EC) conditions, and then modulated TMS intensity in the EO condition. Furthermore, we developed an EEG-triggered TMS system (“informed open-loop”) to verify our hypothesis. MethodsTMS was applied to the left motor cortex. We first compared EEG power differences between high- and low-amplitude MEP epochs in the EO and EC conditions when using a high TMS intensity. Next, we evaluated the effects of varying TMS intensities (high vs. low) on the EEG–MEP relationship. Finally, we used EEG-triggered TMS to determine whether prestimulus EEG oscillations predicted MEP amplitudes. ResultsPrestimulus higher-power alpha/low-beta bands produced larger MEPs only in the high-intensity EO condition. A positive relationship between EEG power and MEP amplitude was observed at C3 and left frontal electrodes. This relationship was obscured when using the lower TMS intensity but was observed in the high-intensity condition at the C3 electrode. EEG-triggered TMS demonstrated that higher alpha power predicted higher MEP amplitudes, but beta power at around 20 Hz did not. ConclusionsA causal relationship between alpha/low-beta oscillations and MEP amplitudes at rest requires high TMS intensity delivered when eyes are open. This association may allow us to develop a new informed open-loop TMS protocol.

TDCS to the left DLPFC modulates cognitive and physiological correlates of executive function in a state-dependent manner

BackgroundThe use of transcranial Direct Current Stimulation (tDCS) to study anatomical and physiological dynamics and circuits supporting cognition and executive functions in particular has dramatically increased in recent years. However, its mechanisms of action remain only partially understood. ObjectiveIn this study we assess the cognitive and physiological effects of anodal tDCS to the DLPFC on executive function in order to understand (1) the role of DLPFC laterality, (2) the physiological dynamics sustaining the modulation of executive function by tDCS, and (3) the impact of state-dependent dynamics. MethodsIn a randomized, placebo-controlled, cross-over study, we applied anodal tDCS targeting the left vs. right DLPFC vs. sham in 20 healthy individuals (10 males, 10 females). Immediately before and after tDCS, subjects performed the Flanker Task while we measured behavioral (reaction time and accuracy) and neurophysiological (ERP) responses. Specifically, the amplitude of N200, P300, ERN and Pe is compared before and after stimulation. ResultsAnodal tDCS to the left DLPFC lead to a significant improvement in reaction time, an increase in P300 amplitude and a decrease in N200 amplitude in a state-dependent manner: baseline ERP amplitudes conditioned the effects of tDCS. ConclusionGiven the role of these ERPs in conflict-related tasks, we speculate that tDCS is modulating the subconstructs of selective attention, conflict monitoring and response inhibition. These findings contribute to a further understanding of the role of left DLPFC in the modulation of executive function, and shed light into the mechanisms of action and the state dependent nature of tDCS.

Inhibitory Effect of Tricyclic Antidepressant Doxepin on Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells.

Doxepin, tricyclic antidepressant, is widely used for the treatment of depressive disorders. Our present study determined the inhibitory effect of doxepin on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Vascular Kv currents were inhibited by doxepin in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC50) value of 6.52 ± 1.35μM and a Hill coefficient of 0.72 ± 0.03. Doxepin did not change the steady-state activation curve or inactivation curve, suggesting that doxepin does not alter the gating properties of Kv channels. Application of train pulses (1 or 2Hz) slightly reduced the amplitude of Kv currents. However, the inhibition of Kv channels by train pulses were not changed in the presence of doxepin. Pretreatment with Kv1.5 inhibitor, DPO-1, effectively reduced the doxepin-induced inhibition of the Kv current. However, pretreatment with Kv2.1 inhibitor (guangxitoxin) or Kv7 inhibitor (linopirdine) did not change the inhibitory effect of doxepin on Kv currents. Inhibition of Kv channels by doxepin caused vasoconstriction and membrane depolarization. Therefore, our present study suggests that doxepin inhibits Kv channels in a concentration-dependent, but not use-, and state-dependent manners, irrespective of its own function.

Brain state-dependent alterations of corticostriatal synchronized oscillations in awake and anesthetized parkinsonian rats

The exaggerated beta synchronized oscillation in the cortico-basal ganglia circuit is a hallmark of disease-specific motor symptoms in Parkinson’s disease (PD). The functional connectivity between the cortex and basal ganglia was influenced by anesthesia. However, the correlation between anesthesia-dependent brain states and the alterations of synchronized network oscillations remains unclear. In this study, local field potentials (LFPs) were simultaneously recorded in the motor cortex and striatum of dopamine-intact and dopamine-depleted hemiparkinsonian rats. Levodopa and three anesthetics (urethane, pentobarbital, and isoflurane) were utilized to assess the changes in neural activity under different brain states. Enhanced high beta (25–40 Hz) oscillations and coherence between the cortex and striatum were found under the wakefulness in 6-OHDA-lesioned rats. Urethane-anesthetized rats exhibited both the activated state and slow wave activity intermittently, while the enhanced synchronized low beta oscillations between the cortex and striatum were observed only during the activated state, which exhibiting a pattern of activity analogous to those observed during the awake state. Notably, urethane significantly reduced the beta peak frequency during the activated state compared to wakefulness in 6-OHDA-lesioned rats. Although both pentobarbital and isoflurane commonly reduced beta oscillations and coherence between the cortex and striatum in 6-OHDA-lesioned rats, they exhibited the distinct influence over the alpha band activity. In addition, isoflurane regulated the burst suppression in a dose-dependent manner. Our data support that synchronized high beta oscillations are directly related to the motor symptoms of PD. Anesthesia regimes influence the excessive synchronized oscillations between the cortex and striatum in a brain state-dependent manner.

Reduced Serum and Cerebrospinal Fluid Levels of Autotaxin in Major Depressive Disorder.

BackgroundThe autotaxin/lysophosphatidic acid axis is involved in diverse biological processes including neurodevelopment, inflammation, and immunological functioning. The lysophosphatidic acid 1 receptor has been implicated in the pathophysiology of major depressive disorder and in the mechanism of action of antidepressants. However, it is unclear whether central or peripheral autotaxin levels are altered in patients with major depressive disorder.MethodsSerum autotaxin levels were measured by an enzyme-linked immunosorbent assay in 37 patients with major depressive disorder diagnosed using DSM-IV-TR who underwent electroconvulsive therapy and were compared with those of 47 nondepressed controls matched for age and sex between January 2011 and December 2015. Patient serum levels of autotaxin before and after electroconvulsive therapy were also compared. In a separate sample set, cerebrospinal fluid autotaxin levels were compared between 26 patients with major depressive disorder and 27 nondepressed controls between December 2010 and December 2015. A potential association was examined between autotaxin levels and clinical symptoms assessed with the Hamilton Depression Rating Scale.ResultsBefore electroconvulsive therapy, both serum and cerebrospinal fluidautotaxin levels were significantly lower in major depressive disorder patients than in controls (serum: P = .001, cerebrospinal fluid: P = .038). A significantly negative correlation between serum, but not cerebrospinal fluid, autotaxin levels and depressive symptoms was observed (P = .032). After electroconvulsive therapy, a parallel increase in serum autotaxin levels and depressive symptoms improvement was observed (P = .005).ConclusionThe current results suggest that serum autotaxin levels are reduced in a state-dependent manner. The reduction of cerebrospinal fluid autotaxin levels suggests a dysfunction in the autotaxin/lysophosphatidic acid axis in the brains of patients with major depressive disorder.

Control of the cardiovascular and respiratory systems during sleep.

Sleep and arousal from sleep are associated with profound changes in cardiovascular and respiratory functions. Fluctuations of arterial blood pressure (ABP), heart rate (HR), and respiration occur both during non-rapid eye movement (NREM) and REM sleep and during transitions between sleep and behavioral arousal. These changes reflect complex, state-dependent interactions among several neuronal groups in the hypothalamus and brainstem. These neurons utilize the excitatory amino-acid L-glutamate or the inhibitory amino acid γ-aminobutyric acid (GABA) and are modulated in a state-dependent manner by inputs from cholinergic, monoaminergic, and hypothalamic orexin/hypocretin and melanin-concentrating hormone (MCH) neurons. These different neuronal populations mediate continuous interactions between cortical state and subcortical circuits modulating sympathetic and cardiovagal output, respiratory pattern, and chemosensitivity. Reciprocally, brainstem areas involved in these functions promote behavioral arousal in the setting of hypoxia, hypercapnia, or other stressors. Studies in rodents using optogenetic and other approaches for selective activation or inactivation of specific neuronal groups identified by their unique neurochemical markers, combined with recording of cortical activity, cardiovascular responses, and respiration, have provided new information on the brainstem mechanisms controlling arousal, wake-sleep cycle, cardiovascular and respiratory control (Luppi et al., 2017; Saper and Fuller, 2017; Scammell et al., 2017; Dampney, 2016; Del Negro et al., 2018; Guyenet, 2006; Guyenet and Abbott, 2013; Smith et al., 2013). These findings also provide further insight into the pathophysiology of sleep-related cardiovascular and respiratory disorders including sleep apnea, narcolepsy, congenital central hypoventilation syndrome, sudden infantile death syndrome, and sudden unexpected death in epilepsy.

CAMP binds to closed, inactivated, and open sea urchin HCN channels in a state-dependent manner.

Hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels are nonselective cation channels that regulate electrical activity in the heart and brain. Previous studies of mouse HCN2 (mHCN2) channels have shown that cAMP binds preferentially to and stabilizes these channels in the open state-a simple but elegant implementation of ligand-dependent gating. Distinct from mammalian isoforms, the sea urchin (spHCN) channel exhibits strong voltage-dependent inactivation in the absence of cAMP. Here, using fluorescently labeled cAMP molecules as a marker for cAMP binding, we report that the inactivated spHCN channel displays reduced cAMP binding compared with the closed channel. The reduction in cAMP binding is a voltage-dependent process but proceeds at a much slower rate than the movement of the voltage sensor. A single point mutation in the last transmembrane domain near the channel's gate, F459L, abolishes inactivation and concurrently reverses the response to hyperpolarizing voltage steps from a decrease to an increase in cAMP binding. ZD7288, an open channel blocker that interacts with a region close to the activation/inactivation gate, dampens the reduction of cAMP binding to inactivated spHCN channels. In addition, compared with closed and "locked" closed channels, increased cAMP binding is observed in channels purposely locked in the open state upon hyperpolarization. Thus, the order of cAMP-binding affinity, measured by the fluorescence signal from labeled cAMP, ranges from high in the open state to intermediate in the closed state to low in the inactivated state. Our work on spHCN channels demonstrates intricate state-dependent communications between the gate and ligand-binding domain and provides new mechanistic insight into channel inactivation/desensitization.

Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation.

Despite its widespread use in cognitive studies, there is still limited understanding of whether and how transcranial direct current stimulation (tDCS) modulates brain network function. To clarify its physiological effects, we assessed brain network function using functional magnetic resonance imaging (fMRI) simultaneously acquired during tDCS stimulation. Cognitive state was manipulated by having subjects perform a Choice Reaction Task or being at “rest.” A novel factorial design was used to assess the effects of brain state and polarity. Anodal and cathodal tDCS were applied to the right inferior frontal gyrus (rIFG), a region involved in controlling activity large‐scale intrinsic connectivity networks during switches of cognitive state. tDCS produced widespread modulation of brain activity in a polarity and brain state dependent manner. In the absence of task, the main effect of tDCS was to accentuate default mode network (DMN) activation and salience network (SN) deactivation. In contrast, during task performance, tDCS increased SN activation. In the absence of task, the main effect of anodal tDCS was more pronounced, whereas cathodal tDCS had a greater effect during task performance. Cathodal tDCS also accentuated the within‐DMN connectivity associated with task performance. There were minimal main effects of stimulation on network connectivity. These results demonstrate that rIFG tDCS can modulate the activity and functional connectivity of large‐scale brain networks involved in cognitive function, in a brain state and polarity dependent manner. This study provides an important insight into mechanisms by which tDCS may modulate cognitive function, and also has implications for the design of future stimulation studies.

ATP in the lateral hypothalamus/perifornical area enhances the CO2 chemoreflex control of breathing.

What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO2 /H+ -dependent drive to breathe. The lateral hypothalamus/perifornical area (LH/PFA) is a central chemoreceptor site, which acts in an arousal state-dependent manner. It has been shown that purinergic signalling through ATP influences the CO2 /H+ responsiveness of other chemosensitive regions, but it is unknown whether ATP is also involved in the mechanisms that underlie LH/PFA chemoreception. Here, we studied the effects of microdialysis of a P2X-receptor agonist [α,β-methylene ATP (α,β-meATP), 10mm] and a non-selective P2-receptor antagonist [pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), 1mm] into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 . In the dark (active) phase, but not in the light, microdialysis of α,β-meATP caused an augmented hypercapnic ventilatory response during wakefulness, but not during non-REM sleep (P< 0.001). PPADS caused no change in CO2 ventilatory responses in either the dark period or the light period. Our data suggest that ATP in LH/PFA contributes to the hypercapnic ventilatory response in conscious rats during wakefulness in the dark phase of the diurnal cycle.