Nuria Daviu
email: nuria.daviuabant@ucalgary.ca.

Michael R Bruchas
email: mbrichas@uw.edu.

Bita Moghaddam

Carmen Sandi
email: carmen.sandi@epfl.ch.

Anna Beyeler
email: anna.beyeler@inserm.fr.

Neurobiological links between stress and anxiety

Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxietylike behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. We then report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity.

Introduction

Although the relationship between psychological stress and anxiety seems intuitive, the biological nuances that distinguish the two states are extremely complex. Indeed, after decades of research in psychology, ethology and neurophysiology, overlapping neural substrates of these two psychobiological states have been identified. However, the boundaries between stress and anxiety remain an open discussion.

A stress response, created by a real or perceived threat (stressor), can be defined as an emergency state of an organism in response to a challenge to its homeostasis [START_REF] Chrousos | Stress and disorders of the stress system[END_REF][START_REF] Selye | A Syndrome Produced by Diverse Nocuous Agents[END_REF]. During this emergency state, the organism initiates an integrated reaction including physiological and behavioral responses. Internal threats, or so-called systemic stressors, include physical changes in the body, such as hypoglycemia or hypovolemia (decreased blood volume), happening, for example, after a severe car accident. On the other hand, perceived threats, or socalled psychological stressors, include situations that can potentially lead to a danger and induce a homeostatic challenge, introducing the critical factor of anticipation [START_REF] De Kloet | Stress and the brain: from adaptation to disease[END_REF][START_REF] Koolhaas | Stress revisited: A critical evaluation of the stress concept[END_REF]. The concept of anticipation in the stress response is critical in understanding the relationship between stress and anxiety. In that regard, stress as a physiological reaction to a stimulus is accompanied by a concomitant emotional response. That emotional response is determined in part by the perception of the threat imminence [START_REF] Anderson | A Framework for Studying Emotions across Species[END_REF][START_REF] Davis | Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety[END_REF]. According to the definition of The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (American Psychiatric Association, 2013) "Fear is the emotional response to a real or perceived imminent threat, whereas anxiety is the anticipation of a future threat". Thus, the emotional state that our body experiences differs between fear when we encounter an aggressive dog, and anxiety when we know we will visit a friend which has an aggressive dog.

Anxiety is defined as a temporally diffused emotional state caused by a potentially harmful situation, with the probability or occurrence of harm being low or uncertain [START_REF] Goes | Excitotoxic lesion of the medial prefrontal cortex in Wistar rats: Effects on trait and state anxiety[END_REF][START_REF] Spielberger | Manual for the State-Trait Anxiety Inventory (STAI)[END_REF][START_REF] Takagi | A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity[END_REF]. Historically, psychologists and psychiatrists have differentiated state and trait anxiety [START_REF] Belzung | Measuring normal and pathological anxiety-like behaviour in mice: a review[END_REF][START_REF] Goes | Excitotoxic lesion of the medial prefrontal cortex in Wistar rats: Effects on trait and state anxiety[END_REF][START_REF] Spielberger | Manual for the State-Trait Anxiety Inventory (STAI)[END_REF][START_REF] Takagi | A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity[END_REF]. The diverging element of these two types of anxiety is their duration: state anxiety is an acute response to a potential threat, while trait anxiety is chronic, as it is expressed constantly during the life of the individual, and is therefore considered as a trait of an individual's personality [START_REF] Endler | State and trait anxiety revisited[END_REF][START_REF] Spielberger | Manual for the State-Trait Anxiety Inventory (STAI)[END_REF]. State anxiety, can be defined as hypervigilance in anticipation of a threat that can be triggered by acute stress, and has the primary function of avoiding dangerous situations and also to facilitate memory consolidation [START_REF] Roozendaal | Noradrenergic Activation of the Basolateral Amygdala Modulates Consolidation of Object Recognition Memory[END_REF]. On the other hand, trait anxiety is a predisposition of an individual to express constant anxiety, and increases the probability of state anxiety in potentially dangerous situations [START_REF] Endler | State and trait anxiety revisited[END_REF][START_REF] Spielberger | Manual for the State-Trait Anxiety Inventory (STAI)[END_REF]. State and trait anxiety are not mutually exclusive, and state anxiety triggered by an event can be superimposed on trait anxiety. Importantly, both state and trait anxiety responses represent an evolutionary advantage to anticipate and avoid danger [START_REF] Goes | Excitotoxic lesion of the medial prefrontal cortex in Wistar rats: Effects on trait and state anxiety[END_REF][START_REF] Spielberger | Manual for the State-Trait Anxiety Inventory (STAI)[END_REF][START_REF] Takagi | A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity[END_REF].

Therefore, anxiety per se is not a pathological state, as it can prevent exposure to dangerous situations. However, when anxiety is sustained and/or elicited by non-threating stimuli, it becomes maladaptive [START_REF] Belzung | Measuring normal and pathological anxiety-like behaviour in mice: a review[END_REF][START_REF] Sylvers | Differences between trait fear and trait anxiety: implications for psychopathology[END_REF]. While state and trait anxiety are essential psychological metrics to evaluate normal and pathological levels of anxiety, these metrics do not consider the neural substrate of anxiety, which partly explains the lack of new and effective therapies for anxiety disorders.

Over the past twenty years, human functional imaging has identified multiple brain areas including the hypothalamus, amygdala, prefrontal cortex and nuclei of the brainstem which are active during both stress and anxiety responses in healthy individuals [START_REF] Mobbs | When Fear Is Near: Threat Imminence Elicits Prefrontal-Periaqueductal Gray Shifts in Humans[END_REF][START_REF] Takagi | A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity[END_REF].

Interestingly, a subset of brain regions including the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), locus coeruleus (LC), as well as reward processing areas such as the nucleus accumbens (NAc), appear to be affected in animal models of both stress disorders and anxiety disorders [START_REF] Calhoon | Resolving the neural circuits of anxiety[END_REF][START_REF] Etkin | Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in PTSD, Social Anxiety Disorder, and Specific Phobia[END_REF][START_REF] Sailer | Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder[END_REF][START_REF] Shin | The Neurocircuitry of Fear, Stress, and Anxiety Disorders[END_REF]. The intermingled neural circuits controlling both stress and anxiety suggests a strong bidirectional relationship between stress experiences and anxiety in both healthy and pathological conditions. Therefore, alterations of the connectivity between the brain regions influencing both stress and anxiety behaviors might contribute to the etiology of psychopathologies such as generalized anxiety disorders, social anxiety disorders or posttraumatic stress disorder (PTSD).

Herein, we summarize the views of the panel on Stress, Anxiety and Corticolimbic Pathways, presented at the 2018 Stress Neurobiology meeting, held in Banff, Canada. This perspective reflects the diverse and shared structures involved in both stress and anxiety responses. We aim to reveal common subcortical processes that could support the interplay between stress and anxiety-related behaviors.

Coding of emotional valence in the basolateral amygdala (BLA)

The attribution of emotional valence to sensory information is a key process that allows individuals to navigate the world, and has been shown to be altered in both anxiety and stress disorders [START_REF] Etkin | Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in PTSD, Social Anxiety Disorder, and Specific Phobia[END_REF][START_REF] Sailer | Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder[END_REF]. Valence is the subjective value assigned to sensory stimuli, which determines subsequent behavior. Positive valence leads to approach and consummatory behaviors while negative valence leads to defensive and avoidance behaviors [START_REF] Pignatelli | Valence coding in amygdala circuits[END_REF][START_REF] Russell | A circumplex model of affect[END_REF]. Attentional bias for stimuli of negative valence have been extensively demonstrated in patients with anxiety disorders [START_REF] Macleod | Anxiety-Linked Attentional Bias: Is It Reliable?[END_REF]. For example, anxiety increases negative interpretations of ambiguous sentences [START_REF] Richards | An anxiety-related bias in semantic activation when processing threat/neutral homographs[END_REF] and scenarios [START_REF] Hirsch | Interpretative inferences when reading about emotional events[END_REF] suggesting an anxiety-induced valence bias. Recent publications showed that high trait anxiety individuals exhibit a bias towards negative interpretations of surprised faces (Park et al., 2016). The existence of a correlation between negative valence bias and the level of anxiety in health and disease observed in human studies supports the hypothesis that the circuits encoding emotional valence could be dysfunctional in anxiety disorders [START_REF] Etkin | Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in PTSD, Social Anxiety Disorder, and Specific Phobia[END_REF][START_REF] Lammel | Progress in understanding mood disorders: optogenetic dissection of neural circuits[END_REF][START_REF] Mervaala | Quantitative MRI of the hippocampus and amygdala in severe depression[END_REF][START_REF] Pignatelli | Valence coding in amygdala circuits[END_REF]. A key structure encoding emotional valence and therefore guiding animal behavior is the basolateral nucleus of the amygdala (BLA). This region receives sensory inputs of multiple modalities, and projects to output structures controlling behavioral responses [START_REF] Janak | From circuits to behaviour in the amygdala[END_REF][START_REF] Mcdonald | Cortical pathways to the mammalian amygdala[END_REF]. This central connectivity has made the BLA a focus for identifying the neural substrate of valence processing. Moreover, a vast body of literature has shown that BLA integrity is critical for processing positive [START_REF] Bucy | An anatomical investigation of the temporal lobe in the monkey (Macaca mulatta)[END_REF][START_REF] Tye | Rapid strengthening of thalamoamygdala synapses mediates cue-reward learning[END_REF][START_REF] Weiskrantz | Behavioral changes associated with ablation of the amygdaloid complex in monkeys[END_REF] and negative valence [START_REF] Bucy | An anatomical investigation of the temporal lobe in the monkey (Macaca mulatta)[END_REF][START_REF] Ledoux | The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning[END_REF][START_REF] Mcdonald | Cortical pathways to the mammalian amygdala[END_REF][START_REF] Tye | Rapid strengthening of thalamoamygdala synapses mediates cue-reward learning[END_REF][START_REF] Weiskrantz | Behavioral changes associated with ablation of the amygdaloid complex in monkeys[END_REF].

Interestingly, studies have shown that when defined by their projection target, neurons of the BLA differentially control and encode emotional valence (Figure 1A). A set of studies revealed that photostimulation of BLA neurons synapsing in the medial core/shell section of the NAc (BLA-NAc) support reward seeking [START_REF] Namburi | A Circuit Mechanism for Differentiating Positive and Negative Associations[END_REF]. Meanwhile, BLA neurons projecting to the medial section of the central amygdala (BLA-CeA) mediated place avoidance [START_REF] Namburi | A Circuit Mechanism for Differentiating Positive and Negative Associations[END_REF].

Importantly, these two different BLA populations have divergent responses to valence predicting cues. Indeed, single-unit in vivo recordings combined with optogenetic photoidentification indicated that a higher proportion of BLA-NAc neurons were excited by a cue predicting a reward, while BLA-CeA neurons showed a higher proportion of neurons excited by a stimulus predicting an aversive outcome [START_REF] Beyeler | Divergent routing of positive and negative information from the amygdala during memory retrieval[END_REF].

Furthermore, the authors identified a synaptic mechanism for learning of valence associations. Specifically, synaptic inputs onto BLA-NAc neurons and BLA-CeA neurons undergo opposing synaptic changes following reward or fear conditioning (Figure 1C, [START_REF] Namburi | A Circuit Mechanism for Differentiating Positive and Negative Associations[END_REF]. Notably, BLA neurons projecting to those distinct areas are intermingled within the BLA, but are distributed following topographical gradients (Figure 1D, [START_REF] Beyeler | Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala[END_REF], which are correlated with a dorso-ventral bias of negative to positive valence coding [START_REF] Beyeler | Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala[END_REF].

Another set of optogenetic experiments have shown that activation of the BLA projection to the ventral hippocampus (vHPC) is sufficient to induce real time anxiogenic effects and that conversely, inhibition of those projections causes an anxiolytic effect (Figure 1B, Felix-Ortiz et al., 2013). Surprisingly, single-unit recordings combined with optogenetic photoidentification have shown that BLA-vHPC neurons have no coding bias for learned stimuli predicting outcomes of positive or negative valence compared the entire BLA [START_REF] Beyeler | Divergent routing of positive and negative information from the amygdala during memory retrieval[END_REF]. This observation supports the idea that BLA-vHPC neurons may mediate anxiety-related behaviors which can be defined as an innate state of negative valence, rather than learned valence.

Altogether, the BLA is a single structure which includes neural populations that underlie processing of learned emotional valence (BLA-NAc and BLA-CeA) and a population that generates innate emotional states (BLA-vHPC). This finding suggests that BLA is a key structure to study how emotional states such as anxiety interfere with emotional valence processing.

Locus coeruleus noradrenergic (LC-NE) projections to BLA: acute stress-induced anxiety

Stressful experiences engage multiple structures to generate a coordinated physical and psychological response to a challenge. The locus coeruleus noradrenergic system (LC-NE) presents a brain-wide projection pattern [START_REF] Schwarz | Viral-genetic tracing of the input-output organization of a central noradrenaline circuit[END_REF] and is linked to both physical and emotional responses to stress [START_REF] Berridge | The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes[END_REF][START_REF] Valentino | Convergent Regulation of Locus Coeruleus Activity as an adaptive Response to Stress[END_REF], as well as aversive memory consolidation [START_REF] Roozendaal | Noradrenergic Activation of the Basolateral Amygdala Modulates Consolidation of Object Recognition Memory[END_REF]. Noradrenaline release during an acute stress induces state anxiety responses that allow the organism to maintain high attention, facilitate sensory processing and enhance executive functions in order to increase memory consolidation during stressful experiences [START_REF] Berridge | The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes[END_REF][START_REF] Sara | Orienting and Reorienting: The Locus Coeruleus Mediates Cognition through Arousal[END_REF].

Electrophysiological and optogenetic studies indicate that LC-NE neurons normally display three activation profiles: low tonic (1-2 Hz), high tonic (3-8 Hz) and phasic activity [START_REF] Carter | Tuning arousal with optogenetic modulation of locus coeruleus neurons[END_REF].

Acute stress causes a robust increase in tonic firing rate in LC-NE [START_REF] Valentino | Convergent Regulation of Locus Coeruleus Activity as an adaptive Response to Stress[END_REF] and this stress-induced tonic firing is associated with an increase in anxiety-like behavior.

The key role of tonic activation of LC-NE neurons is further supported by the observations that optogenetic stimulation of NE cell bodies in the LC, in the absence of a stressor, mimics LC-NE tonic activity as well as acute-stress induced anxiety [START_REF] Mccall | CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety[END_REF]. Furthermore, they suggest that this increase of activity in LC-NE neurons is caused by synaptic inputs into the LC containing corticotropin releasing hormone (CRH + ). Specifically, stimulation of CRH + CeA-LC terminals increases activity in LC and drives anxiety-like behaviors through type 1 CRH receptor (CRH1R) activation [START_REF] Mccall | CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety[END_REF].

Acute stress also promotes anxiety and other stress related behaviors through BLA adrenergic receptor activation [START_REF] Chang | Amygdala β-Noradrenergic Receptors Modulate Delayed Downregulation of Dopamine Activity following Restraint[END_REF]. Even though the anatomical projections from LC and the role of NE in stress and anxiety have been studied extensively, the mechanism by which LC-NE influences BLA function to promote negative emotional states has only recently been unravelled. McCall and collaborators (2017) demonstrated that optogenetic activation of LC-NE fibers in the BLA in acute brain slices causes norepinephrine release into the BLA. In vivo, photostimulation of these terminals modulates BLA activity, and LC-BLA stimulation is sufficient to cause conditioned place aversion as well as anxiety-like behaviors. These stimulation-induced behavioral changes require β-adrenergic receptor activity in the BLA, providing in vivo evidence that endogenous NE release from LC terminals alters BLA function and, as a consequence, modifies behavior. Additional support for β-adrenergic signaling promoting anxiety-like behaviors is provided in [START_REF] Siuda | Optodynamic simulation of β-adrenergic receptor signalling[END_REF], whereby selective optical activation of β-adrenergic signaling in CaMKII(+) neurons of the BLA produces robust anxiety-like phenotypes.

LC-NE neurons preferentially target neurons in the BLA that project to the ventral hippocampus (BLA-vHPC) and CeA (BLA-CeA), both downstream structures involved in negative valence and anxiety-related behaviors [START_REF] Beyeler | Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala[END_REF][START_REF] Felix-Ortiz | BLA to vHPC Inputs Modulate Anxiety-Related Behaviors[END_REF][START_REF] Namburi | A Circuit Mechanism for Differentiating Positive and Negative Associations[END_REF]. This suggests that LC-NE projections to BLA increase anxiety-like behaviors following stress exposure, through projections to downstream structures such as CeA or vHPC (Figure 2A). This recent work reveals that part of the circuit underlying acute-stress, induces state anxiety.

A new mitochondrial function linking stress and emotional traits

Even in our modern society, the necessity of positioning ourselves in a social group through social competition has an enormous impact on our daily lives. In spite of the importance that social competition has in organizing and structuring our society, the psychological characteristics that affect social competitiveness of an individual have been largely overlooked. Several brain regions such as amygdala and the NAc have been implicated in social status and competition in both humans [START_REF] Zink | Know Your Place: Neural Processing of Social Hierarchy in Humans[END_REF], and rodents [START_REF] Goette | Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress[END_REF]. Recent studies have specifically revealed the critical role of the NAc in social competition and the establishment of social status [START_REF] Hollis | Mitochondrial function in the brain links anxiety with social subordination[END_REF][START_REF] Larrieu | Hierarchical Status Predicts Behavioral Vulnerability and Nucleus Accumbens Metabolic Profile Following Chronic Social Defeat Stress[END_REF][START_REF] Van Der Kooij | Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors | Molecular Psychiatry[END_REF]. During social competition, D1-containing medium spiny neurons (MSNs) in the NAc are activated and show a positive correlation with the level of offensive behavior observed in a social hierarchy test. In addition, when the NAc, but not the BLA, is inactivated with a GABAA receptor agonist during a social competition test, rats showed reduced social dominance [START_REF] Hollis | Mitochondrial function in the brain links anxiety with social subordination[END_REF].

The NAc is involved in motivation and has been implicated in the regulation of anxiety and depressive-like symptoms [START_REF] Lüthi | Pathological circuit function underlying addiction and anxiety disorders[END_REF]. The neural mechanism through which anxiety might affect social hierarchy has been poorly investigated. In humans, high-anxiety individuals tend to display subordinate roles and to be less competitive in social environments [START_REF] Gilbert | The dark side of competition: How competitive behaviour and striving to avoid inferiority are linked to depression, anxiety, stress and self-harm[END_REF]. Likewise, high-anxiety rats showed less social dominance after a social competition for a territory [START_REF] Hollis | Mitochondrial function in the brain links anxiety with social subordination[END_REF]. These results are consistent with data obtained in humans where high anxiety traits predispose subjects for social submission [START_REF] Goette | Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress[END_REF].

These behavioral results, together with the new data revealing a unique role of the NAc in the establishment of social hierarchy open a new path to investigating how NAc function can bridge anxiety and social competition. In search of potential mechanisms within the NAc, which could differentiate low and high anxiety rats, [START_REF] Hollis | Mitochondrial function in the brain links anxiety with social subordination[END_REF] showed that high anxiety rats had lower mitochondrial activity in NAc, compared to low anxiety rats. Specifically, with similar mitochondrial numbers and density, highly anxious rats have lower levels of respiratory complexes I and II of the electron transport chain, resulting in reduced mitochondrial function (Figure 2B). Furthermore, social status also predicts behavioral stress susceptibility and metabolic profile in the NAc after chronic social defeat [START_REF] Larrieu | Hierarchical Status Predicts Behavioral Vulnerability and Nucleus Accumbens Metabolic Profile Following Chronic Social Defeat Stress[END_REF]. These studies establish a key role of mitochondrial function in individual differences that impact social dominance in a non-pathological condition.

Altogether, the newly discovered role of mitochondrial energy metabolism in the NAc in anxietyinduced social deficits opens a new path for therapeutic treatment that targets cell metabolism.

In regards to the relationship between stress and anxiety, social competition itself induces an endocrine stress response [START_REF] Turan | Coordination of the cortisol and testosterone responses: A dual axis approach to understanding the response to social status threats[END_REF]. In humans, stress exposure differentially affects low and high anxiety subjects in a competitive task. Under stress conditions, low-anxiety individuals become overconfident, while high-anxiety individuals show less social confidence after a stress [START_REF] Goette | Stress pulls us apart: Anxiety leads to differences in competitive confidence under stress[END_REF]. Several studies have reported increased risk of adult psychopathologies after early life adversity [START_REF] Haller | Effects of Adverse Early-Life Events on Aggression and Anti-Social Behaviours in Animals and Humans[END_REF][START_REF] Maccari | The consequences of earlylife adversity: neurobiological, behavioural and epigenetic adaptations[END_REF]. In preclinical models, early life stress paradigms have been proposed as a tool to program or bias anxiety traits and, as a consequence, have negative impact in social competence [START_REF] Tzanoulinou | The Programming of the Social Brain by Stress During Childhood and Adolescence: From Rodents to Humans[END_REF]. Indeed, peri-pubertal stress leads to enhanced anxiety [START_REF] Cordero | Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum[END_REF] and changes in social behavior in adulthood [START_REF] Haller | Effects of Adverse Early-Life Events on Aggression and Anti-Social Behaviours in Animals and Humans[END_REF]. Interestingly, play-fighting is a peri-pubertal social behavior which has been linked to aggression in adulthood. Specifically, peri-puberal stress increases play-fighting and increases the chances to display abnormal aggressive behaviors later in adulthood [START_REF] Papilloud | Peripubertal stress increases play fighting at adolescence and modulates nucleus accumbens CB1 receptor expression and mitochondrial function in the amygdala[END_REF]. Importantly, this study also revealed a role of mitochondrial energy balance in regulating stress-induced behaviors, by showing that enhanced play-fighting behaviors following peri-pubertal stress was accompanied by enhanced mitochondrial function in the amygdala.

Encoding reward-directed behavior under anxiety

In humans, patients suffering from anxiety disorders have impaired decision making and behavioral flexibility (Park and Moghaddam, 2017a). For example, high levels of anxiety are accompanied by difficulty of shifting between strategies in the presence of changes in task demand, and/or are easily distracted by irrelevant stimuli [START_REF] Eysenck | Anxiety and cognitive performance: Attentional control theory[END_REF]. That inability to change strategies during a task can have detrimental consequences in a person, by affecting personal life and professional performance. The prefrontal cortex (PFC) is a pivotal structure in organizing behavior in a context dependent-manner [START_REF] Bechara | Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions[END_REF][START_REF] Miller | An Integrative Theory of Prefrontal Cortex Function[END_REF]. Thus, during stress, the PFC controls high order adaptive responses such as choosing optimal behavioral output with an online evaluation of the situation [START_REF] Moghaddam | The Complicated Relationship of Stress and Prefrontal Cortex[END_REF].

In rodents, anxiety levels are also related to decreased cognitive flexibility (Park and Moghaddam, 2017a). Recent studies have revealed the functional consequence of anxiety upon PFC activity, by identifying that a negative emotional state elicits sustained reduction of spontaneous firing rate in the dorso-medial PFC (dmPFC) and orbitofrontal cortex (OFC, Park et al., 2016). This hypofrontality, and specifically the reduced activity in the dmPFC, is linked to decreased behavioral flexibility in the set-shifting task (Park et al., 2016). In this task the subjects learn an instrumental behavioral response based on two different rules that sit on two different dimensions (for example: shape and color). The ability to switch between rules to maximize the profit (number of rewards) is PFC-dependent. The ventral tegmental area (VTA) is also a critical component of reward-guided behavior, and together with the PFC, has been proposed as a circuit underlying decisions during reward-seeking under punishment. VTA neurons are a key component of the reward circuit [START_REF] Morales | Ventral tegmental area: cellular heterogeneity, connectivity and behaviour[END_REF][START_REF] Wood | Networks of VTA Neurons Encode Real-Time Information about Uncertain Numbers of Actions Executed to Earn a Reward[END_REF] and their projections to the mPFC are involved in regulating mood and emotional states [START_REF] Lammel | Progress in understanding mood disorders: optogenetic dissection of neural circuits[END_REF].

Park and Moghaddam designed and developed a task to study the dynamics of reward-based behavior while risking potential punishment (Park and Moghaddam, 2017b). The task was designed to link instrumental action to reward, but at the same time, the same action will be followed by a punishment with varying probabilities. This task aims to recreate an environment where uncertainty of a negative outcome induces anxiety. The probability of getting punished affects behavioral performance by increasing the variability of the time to react, suggesting a transitory anxiety state caused by the possibility of being punished. Single-unit recordings from both dopaminergic (DA) VTA neurons, and mPFC neurons, during this task revealed that their firing rate around the motor response (time surrounding the action execution) is correlated with the punishment risk, suggesting both neural populations encode the risk probability. Even though both VTA-DA and non-DA neurons as well as mPFC neurons, showed punishment risk encoding responses, VTA-DA neurons showed a higher temporal resolution around the action time than mPFC neurons, which showed a more diffuse response around the action window. Interestingly, the single-unit recordings did not correlate with the behavioral changes during the task, and a more detailed analysis revealed that the variability in the reaction time was related to a circuit dynamic. The correlation of the firing of VTA and mPFC neurons, with the reaction time was evident only in the riskiest part of the session, when the probability to be punished was higher.

At the network level, the synchronicity of the theta oscillations is important to coordinate groups of neurons to complete a behavioral response [START_REF] Akam | Oscillations and Filtering Networks Support Flexible Routing of Information[END_REF][START_REF] Buschman | Synchronous Oscillatory Neural Ensembles for Rules in the Prefrontal Cortex[END_REF].

Interestingly, during non-punished trials, the oscillations that emerged in the VTA and mPFC, are in the theta range (around 8 Hz, Park and Moghaddam, 2017b). Moreover, increased probability of punishment decreases the oscillations in both areas and weakens synchrony within and between both structures.

These studies revealed that synchrony between the VTA and PFC decreases with punishment probability, suggesting that VTA-PFC network encodes punishment risk (Figure 2C). Under normal conditions, VTA drives oscillation synchronicity between both regions exerting a bottomup control of the network. When there is risk of punishment, this bottom-up network control is diminished. Transient anxiety may, therefore, affect behavior in a reward-based task by disrupting the VTA-PFC functional circuit.

Role of hypothalamic corticotropin (CRH-PVN) neurons in stress-related behaviors

Although the relationship between stress and anxiety is bidirectional, the influence of stress as a risk factor for anxiety disorders has been extensively studied [START_REF] Armario | Long-term neuroendocrine and behavioural effects of a single exposure to stress in adult animals[END_REF][START_REF] Tye | Optogenetic investigation of neural circuits underlying brain disease in animal models[END_REF]. Mapping of neural circuits involved in stress-induced anxiety have mostly revolved around structures of the amygdala and extended amygdala [START_REF] Davis | Phasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety[END_REF][START_REF] Gross | The many paths to fear[END_REF]. Surprisingly, relatively less attention has been directed towards the paraventricular nucleus of the hypothalamus (PVN), which is a crucial component of the visceral stress response. The PVN receives and integrates information about the stressor and controls the endocrine, behavioral and autonomic response to stress [START_REF] Denver | Structural and functional evolution of vertebrate neuroendocrine stress systems[END_REF][START_REF] Herman | Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamopituitary-adrenocortical responsiveness[END_REF][START_REF] Ulrich-Lai | Neural regulation of endocrine and autonomic stress responses[END_REF]. Specifically, parvocellular neurosecretory cells release corticotropin-releasing hormone (CRH) into the anterior pituitary that stimulates the synthesis and release in the blood stream of adrenocorticotropic hormone (ACTH). Once ACTH reaches the adrenal glands it stimulates the release of glucocorticoid [START_REF] Denver | Structural and functional evolution of vertebrate neuroendocrine stress systems[END_REF][START_REF] Herman | Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamopituitary-adrenocortical responsiveness[END_REF][START_REF] Ulrich-Lai | Neural regulation of endocrine and autonomic stress responses[END_REF]. In the past five years, the classical view of CRH-PVN neurons has been challenged by demonstrations that these neurons also control multiple and complex behaviors that are linked to stress [START_REF] De Marco | Optogenetically enhanced pituitary corticotroph cell activity post-stress onset causes rapid organizing effects on behaviour[END_REF][START_REF] Füzesi | Hypothalamic CRH neurons orchestrate complex behaviours after stress[END_REF][START_REF] Sterley | Social transmission and buffering of synaptic changes after stress[END_REF][START_REF] Zhang | Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice[END_REF]. These observations open an exciting line of research to investigate how this specific set of neurons can drive stress-induced behavioral alterations.

The standard methods to study anxiety in rodents have relied on established laboratory tests such as the elevated plus maze. However, over the last decade, an increasing number of studies have focused on developing new tools of behavioral analysis that are less invasive, require less subjective interpretation, and harken back to original ethological approaches [START_REF] Lezak | Behavioral methods to study anxiety in rodents[END_REF].

One of these approaches relies on monitoring freely-behaving mice in their home-cage environment without any intervention (Figure 3A). Multiple behaviors such as grooming, freezing, rearing or surveying can be detected. Importantly, these behaviors show a specific but flexible temporal distribution. Using this approach, it was shown that a single stressful experience results in the emergence of an organized and structured behavioral pattern where self-directed behaviors such as grooming become predominant, taking over exploratory behaviors such as locomotion or rearing (Figure 3B, [START_REF] Füzesi | Hypothalamic CRH neurons orchestrate complex behaviours after stress[END_REF]. The role of brainstem in generating stress-induced behavioral responses such as freezing [START_REF] Deng | Periaqueductal Gray Neuronal Activities Underlie Different Aspects of Defensive Behaviors[END_REF][START_REF] Silva | Are periaqueductal gray and dorsal raphe the foundation of appetitive and aversive control? A comprehensive review[END_REF], grooming [START_REF] Kalueff | Neurobiology of rodent self-grooming and its value for translational neuroscience[END_REF], defensive behaviors or even anxiety-like behavior [START_REF] Mccall | CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety[END_REF], has been extensively studied over the years [START_REF] Myers | Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses[END_REF]. A recent study from [START_REF] Füzesi | Hypothalamic CRH neurons orchestrate complex behaviours after stress[END_REF] proposes the contribution of a different structure, by revealing a new role for CRH-PVN neurons in coordinating the spontaneous behavioral patterns that emerge after acute stress. Specifically, optogenetic silencing of CRH-PVN activity during the post-stress period reduces grooming in a safe environment. On the contrary, activating CRH-PVN neurons modifies the intensity, but not necessarily the temporal sequence of context appropriate behaviors (Figure 3C). The behavioral profile that arises after an acute stress experience is context dependent and related to CRH-PVN neuron activity.

Further work on CRH-PVN has revealed that these cells are necessary and sufficient for stressinduced social investigation after stress that is required for the transmission of stress from one individual to another [START_REF] Sterley | Social transmission and buffering of synaptic changes after stress[END_REF]. This social transmission of stress results in changes in synaptic function and metaplasticity in the recipient mice, which mirror the synaptic changes observed in stressed mice. This study positions CRH-PVN neurons as a critical node for alarm signal processing and offers a potential explanation for how individuals who have not had a firsthand traumatic experience can develop symptomology consistent with post-traumatic stress disorders [START_REF] Haugen | Treating posttraumatic stress disorder in first responders: A systematic review[END_REF][START_REF] Sial | Vicarious social defeat stress: Bridging the gap between physical and emotional stress[END_REF].

Recent studies have shown that CRH-PVN neurons are able to respond differentially to stimuli with positive or negative valence [START_REF] Kim | Rapid, biphasic CRF neuronal responses encode positive and negative valence[END_REF][START_REF] Yuan | Reward Inhibits Paraventricular CRH Neurons to Relieve Stress[END_REF]. Using in vivo fiber photometry to monitor population calcium dynamics, [START_REF] Kim | Rapid, biphasic CRF neuronal responses encode positive and negative valence[END_REF] have shown that the activity of CRH-PVN neurons rapidly increases in response to stimuli with negative valence, and decreases when an appetitive stimulus such as food or social interaction is presented. Moreover, a reward presentation during stress can buffer CRH-PVN activation, and, as a consequence stress-related behaviors, such as grooming, correlate with the activity of those neurons [START_REF] Yuan | Reward Inhibits Paraventricular CRH Neurons to Relieve Stress[END_REF]. The bidirectional response of CRH-PVN neurons based on stimulus valence opens a new perspective to study stress coping and relieve.

Beyond CRH neurons, a distinct neuronal population in the PVN containing CRH1R has been recently described. This population is 90% GABAergic and has direct synaptic contact with CRH-PVN neurons, and CRH, released from CRH-PVN neurons, modulates signaling between both populations [START_REF] Jiang | Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus[END_REF][START_REF] Ramot | Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress[END_REF]. This intra-PVN network of CRH1R+ and CRF+ neurons has been associated with anxiety-like behavior, as knocking out CRH1R from PVN neurons has anxiolytic effects [START_REF] Ramot | Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress[END_REF][START_REF] Zhang | Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice[END_REF].

All these new data are contributing to updating the role of hypothalamic neural populations in stress-related behaviors. Specifically, growing evidence implicates CRH-PVN neurons in modulating specific behaviors in a stress-related context. From controlling how an individual responds to stress exposure [START_REF] Füzesi | Hypothalamic CRH neurons orchestrate complex behaviours after stress[END_REF][START_REF] Kim | Rapid, biphasic CRF neuronal responses encode positive and negative valence[END_REF][START_REF] Yuan | Reward Inhibits Paraventricular CRH Neurons to Relieve Stress[END_REF] to controlling anxiety-like behaviors [START_REF] Ramot | Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress[END_REF][START_REF] Zhang | Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice[END_REF] or driving social transmission of stress [START_REF] Sterley | Social transmission and buffering of synaptic changes after stress[END_REF], the PVN-CRH neuron population appears to be a central player linking stress and anxiety.

From research to clinics: new categorization of post-traumatic stress disorder (PTSD)

The idea that stress and anxiety have segregated neurobiological substrates despite their reciprocal influence has now moved beyond the research field to reach the clinical practice, resulting in changes in diagnostic tools. Specifically, according to the DSM-5 (American Psychiatric Association, 2013) PTSD is not classified as an anxiety disorder anymore, and the new manual categorizes it among the trauma or stressor-related disorders. This new category requires explicitly an exposure to a traumatic or stressful event as a diagnostic criterion, and in particular, the PTSD requires a life threatening experience. Removing PTSD from anxiety disorders to this newly created trauma or stressor-related disorders category has helped to move the focus away from anxiety, which is now rather considered as comorbid pathology. The new classification in DSM-5 also emphasizes the abnormal reactivity to a stimulus. Interestingly, an altered "flight" response has been observed in patients with PTSD (Park et al., 2017) and, in the last five years, the interest in how microcircuits controlling threat processing are altered in PTSD has grown considerably. This emergent literature supports the idea that aberrant subconscious threat-related processes are underlying part of the PTSD symptomatology [START_REF] Lanius | The innate alarm system in PTSD: conscious and subconscious processing of threat[END_REF].

Current data indicates an increased connectivity between areas involved in the innate alarm system, such as the LC, amygdala, hypothalamus, and PFC in PTSD patients [START_REF] Rabellino | The innate alarm circuit in post-traumatic stress disorder: Conscious and subconscious processing of fear-and traumarelated cues[END_REF]. In humans, when a challenge is not life-threating, the subjects choose the most suitable cost-effective strategy to overcome that situation by engaging the vmPFC, medial orbitofrontal cortex (mOFC) and other non-cortical structures including the BLA which is causally involved in valence processing. However, when the level of danger is life threatening and the organism must prepare for a defensive response, subcortical structures, such as the periaqueductal gray area (PAG) and CeA overrule the cognitive control, and guide the behavioral response [START_REF] Mobbs | When Fear Is Near: Threat Imminence Elicits Prefrontal-Periaqueductal Gray Shifts in Humans[END_REF]. The balance between cortical and subcortical systems could also cast out key points to understand some anxiety disorders. Negative emotional states such as anxiety may lead a person to overestimate the possibility of danger, leading to a shift in the balance of these two systems.

The dynamics between the cognitive and innate circuitry in response to a challenge may reveal a path to a better comprehension of how stressful experiences influence our emotional state, and in turn, shape our future behaviors.

Perspective

Although the dissection of multiple brain circuits controlling anxiety-and stress-related behaviors has made substantial advances, our understanding of the neural substrates underlying the interplay between these two psychophysiological responses remains fragmented. Here, we described specific roles of neural populations in the amygdala, nucleus accumbens, prefrontal cortex, hypothalamus and locus coeruleus in emotional valence, stress and anxiety. The work described here is providing foundational knowledge, however future investigation is necessary to unravel the contribution of specific circuits to stress and/or anxiety. Specifically, future work should use activity dependent mapping and recordings of genetically or anatomically defined neural populations during stress exposure and at different levels of anxiety within the same animal.

Beyond the technical advances catalyzing our understanding of the neural circuits underpinning stress and anxiety, disentangling them will require the development of new behavioral paradigms in pre-clinical models in order to finely capture the changes of neural coding in these two conditions.

Figure 1 :

 1 Figure 1: Valence coding in the basolateral amygdala (BLA) projector populations. A. Projector valence coding (adapted from Beyeler et al. 2016). a. Schematic of Pavlovian conditioning paradigm. Head-fixed mice were trained to discriminate between one cue paired with sucrose (CS-S) and a different cue paired with quinine (CS-Q). b. Peri-stimulus time histogram (PSTH) of the firing rates of representative units excited (top) or inhibited (bottom) during a CS-S presentation followed by a sucrose delivery. c. Fraction of BLA neurons excited or inhibited by CS-S, CS-Q or both. d. PSTH of action potentials of a BLA single-unit photoidentified as a BLA-NAc projector. e. Within-cell difference of response to CS-S and CS-Q depending on the neurons projection targets. f. Percentage of positive and negative valence units in the BLA. B. Behavioral impact of optogenetic activation of different BLA pathways (BLA-NAc and BLA-CeA projectors and BLA-vHPC terminals). C. Synaptic plasticity mechanism observed in BLA-NAc and BLA-CeA projection neurons after learning of valence associations. D. Topographic maps of three projectors populations in the BLA. CS: conditioned stimuli, S: sucorse, Q: quinine, NAc: nucleus accumbens, CeA: central amygdala, vHPC: ventral hippocampus.

Figure 2 :

 2 Figure 2: Circuit and molecular mechanisms of stress and anxiety. A. LC-NE projections to BLA increases anxiety-like behaviors acting on β-adrenergic receptors (βARs) and through

Figure 3 :

 3 Figure 3: PVN-CRH neurons coordinate behavioral patterns after stress (adapted from Füzesi et al., 2016). A. Behavioral quantification of mice in their home-cage, before (naïve) and immediately after a footshock (stress). Eight distinct behaviors are prominent. Each row represents one mouse. B. Histogram of grooming behavior at each time-point for naïve and stress mice. C. Schematic of in vivo photostimulation of PVN-CRH to LH projections (20 Hz, 5 min) increases grooming time and stimulated CORT release. PVN: paraventricular nucleus of the hypothalamus CRH: corticotropin-releasing hormone LH: lateral hypothalamus ME: medial eminence CORT: corticosterone.

  Figure3

Acknowledgments

We thank Matt Hill and Jaideep Bains for organizing the 2018 Stress Neurobiology Workshop, and for their invitation to write this review to summarize the major findings presented during the sessions including the authors of this review. ND is supported by Fellowships from Alberta Innovates-Health Solutions. We acknowledge the support of the Région Nouvelle-Aquitaine and the INSERM-Avenir program of the French NIH to the Beyeler Lab and of the Brain and Behavior Research Foundation NARSAD young investigator grant to AB.

Conflict of interests

The authors have no conflict of interest to declare.

D. Projector topography

A. Valence coding in BLA projectors


Josefine Schneeoriana Norosoa

Maxwell Quezada

Oriana Norosoajosefine Schnee

Federico Azzolina-Jury
email: federico.azzolina-jury@ensicaen.fr

ZSM-5 surface modification by plasma for catalytic activity improvement in the gas phase methanol-to-dimethylether reaction

Keywords: Alternative fuels, Dimethylether, Methanol condensation, Plasma, Zeolites, Dealumination

Dimethylether (DME) is nowadays considered as one of the most promising alternative fuels for the future. It has a very low climate impact, as it burns without emission of soot or SOx, and with extremely reduced emission of NOx, CO and CO2. It, and can be produced in a renewable way, namely from the gas phase condensation of methanol (available from biomass) over common acid catalysts such as γ-Al2O3 or zeolites. The challenge today is to switch from high reaction temperatures (300-350°C) to lower ones (ideally 100-150°C) in order to operate 1) more energy-efficiently and 2) with 100% selectivity to DME, thus by avoiding the formation of coke which blocks the access to the acid sites and thereby deactivates the catalyst (an important issue with zeolites). The methanol conversion needs to be increased below 300°C in order to get high yields of DME even in that low temperature range. In the present paper, we show a way to achieve this in the case of the widely studied ZSM-5 zeolite. We show that submitting the zeolite to a cold plasma treatment before using it as a catalyst in the methanol-to-DME reaction allows significantly increasing the yield of DME up to 300°C. Indeed, the plasma treatment (monitored thanks to operando FTIR) leads to a partial dealumination of the zeolite (as shown by XRD and MAS 27 Al NMR), and thereby to an increase of the number of strong Brønsted acid sites (as evaluated thanks to in situ FTIR upon pyridine adsorption) which play a key role in the methanol-to-DME reaction mechanism.

Introduction

Dimethylether (DME) is nowadays of great interest in energy and environmental chemistry. It is called "the fuel for the 21 st Century" by some research teams [1]. It can be used in diesel engines instead of conventional fuels, as hydrogen source in fuel cells, or as cooking gas instead of LPG (Liquefied Petroleum Gas) [1-3]. Actually, it should be considered as the fuel of choice for eliminating the dependency on petroleum [4]. As it has no C-C bond and contains no sulfur, DME burns with no emission of soot or SOx. It also leads to extremely reduced NOx, CO and CO2 emissions [4]. Moreover, DME is non-toxic, non-corrosive and biodegradable [2-5] and it is qualified as clean alternative fuel [1,4,6]. Besides, DME can also be used as an intermediate for the synthesis of various important chemical compounds such as light olefins and aromatics, or it 2 could be also transformed into methyl acetate, formaldehyde and ethanol via reaction with CO or syngas [3].

DME can be produced from the one-step conversion of syngas using a bifunctional catalyst (typically based on Zn and Cu supported on Al2O3), or from the gas phase condensation of methanol (the intermediate of the two-step conversion of syngas) over an acid catalyst [3,7]. In any case, as syngas can be produced from biomass, DME appears as a renewable fuel.

The gas phase condensation of methanol (2 CH3OH ⇋ CH3OCH3 + H2O) is the most mature route and is therefore widely used in chemical industries [3]. It is generally performed at atmospheric pressure over common acid catalysts such as γ-Al2O3 or zeolites (ZSM-5, ZSM-22, Y, SAPO-34...), at reaction temperatures between 200 and 360°C [3,6,8]. γ-Al2O3 is reported to be highly selective to DME (near to 100%) up to a temperature of ca. 325°C, above which CO and CH4 appear [9]. In contrast, over zeolites, generally leading to higher methanol conversions than γ-Al2O3 due to their higher acid strength, undesired by-products and coke (carbonaceous deposits hindering the access to the acid sites) are formed reducing the selectivity to DME and leading to catalyst deactivation [6,8,10]. Among the volatiles, typical by-products are alkanes (such as methane, propane, butane, pentane, heptane), olefins (such as ethylene and propylene), and aromatics (such as toluene and xylene) [11]. Actually, consecutively to the methanol-to-DME reaction, the methanol-to-hydrocarbons (MTH) process gets additionally activated, leading to a so-called "hydrocarbon pool" [6,12].

In order to limit the MTH process, responsible for coke deposition, researchers are generally focused on the development of new catalyst design and/or on the modification of experimental conditions [3,6,7]. For example, supporting ZSM-5 on SiC foams was shown to lead to the formation of small zeolite crystals that favors the diffusion of DME throughout the porous network and thereby significantly reduces the consecutive formation of hydrocarbons [13]. However, the preparation of such catalysts is deemed quite complex [6] and 100% of selectivity to DME is not achieved. Performing the reaction under air was also tried. Indeed, over SAPO-34 and ZSM-5, the presence of air in the feed was shown to negatively impact the production of olefins at 350°C. Nevertheless, again, 100% of selectivity to DME was not achieved [6,14]. Actually, to really minimize the MTH process, the methanol reaction should be operated at lower temperature (typically 100-150°C) [8], what would be also, by the way, more energy-efficient. A more efficient methanol production at low temperature can be performed using alternative catalysts with higher acid strength, such as heteropolyacids [8,15,16], or finding new strategies to increase the acidity of the catalysts.

Zeolites are crystalline aluminosilicates with 3D regular structure. They are widely used in the industry and academic world [START_REF] Guisnet | Zeolites for Cleaner Technologies[END_REF][18][19][20][21][22][23][24][25]. Several studies have been addressed in order to increase zeolites catalytic activity. One interesting approach is based on zeolite partial dealumination for acidity modification. González et al. performed HCl acid treatment of several zeolites under microwave irradiation [26]. They observed an increase in surface area, mesoporosity and strength of Brønsted acid sites. Another interesting proposal is the zeolite acidity modification by acid leaching treatment using HF aqueous solutions [27-29]. After the acid treatment of zeolites, the number of strong Brønsted acid sites is decreased and the number of Lewis acid sites increased via partial dealumination of zeolites. Moreover, the concentration of HF acid solutions was found to play a crucial role on the strength of acid sites. Desilication of zeolites in an alkaline medium such as NaOH has also been proposed for the selective framework silicon etching [30,31]. Intercrystalline mesoporosity is observed after silicon leaching. The secondary mesoporosity usually involves aluminium redistribution towards the external surface of zeolite crystals increasing thus Lewis acidity without modifying Brønsted acidity [30].

Besides, the desilication process shortens the micropores length, which is desirable for reactants diffusion, and also increases the number of available active acid sites at the pore months [31].

The use of plasmas has gained attention during the last decades and it has been proven to be a very promising technology for the preparation of efficient catalysts. Liu et al. [32,33] reported, in a very interesting review, the use of cold and thermal plasmas in the preparation of materials. Plasmas could be used in the different steps of catalysts preparation or synthesis such as drying, decomposition, reduction, oxidation and regeneration [33]. Plasmas are also used for catalyst surface modification. Plasma surface modification treatment of materials has shown to improve catalytic activity of materials and to reduce their deactivation through the improvement of metal dispersion. Low temperature plasmas have been applied as well for zeolites activation including organic template removal and cold calcination of NH4-zeolites [34][35][36].

We have recently reported the use of cold plasma (low pressure glow-like discharge) for the novel preparation of alumina from boehmite with a remarkably improvement of final textural properties [37]. We have also recently reported basicity improvement of Ni(Mg,Al)O hydrotalcite-derived catalysts promoted by low pressure glow plasma discharge [38]. Liu et al. [39,40] reported catalytic activity and stability enhancement as well as Brønsted and Lewis acidities improvement of ZSM-5 catalysts after plasma treatment using a glow discharge.

In this work, we put in evidence the acidity improvement of organic-free template ZSM-5 zeolite by cold plasma activation using a glow-like discharge at low pressure. Indeed, we demonstrate that the plasma activation allows significantly increasing the ZSM-5 catalytic performance in the subsequent methanol-to-DME reaction, in particular at temperatures as low as 150°C as a consequence of zeolite acidity enhancement.

Experimental section 2.1 Organic template-free ZSM-5 synthesis

ZSM-5 organic template-free hydrothermal synthesis has been widely studied [41][42][START_REF] Hartati | AIP Conference Proceedings[END_REF][START_REF] Zhang | [END_REF][45]. In this work, ZSM-5 without organic template was synthesized with a Si/Al molar ratio of 40 with the following molar gel composition: 100SiO2:12Na2O:5Al2O3:2500H2O. Ludox HS-40 colloidal silica was used as silica source (40% SiO2 in water, Sigma Aldrich). Sodium aluminate (technical, anhydrous Sigma Aldrich) was used as aluminum source. Sodium hydroxide (BDH Prolabo VWR Chemicals; 98% purity) was adopted as alkali metal salt.

In a PFTE flask, 0.8 g of NaOH and 1.15 g of AlNaO2 were dissolved in 43 mL of distilled water under continuous stirring. Afterwards, 23.25 mL of Ludox solution were slowly added. The homogeneous synthesis gel was aged during 24 h at room temperature and then introduced into a PFTE reactor of 100 mL. The synthesis mixture was then placed in an oven at 180°C for 48 h. At the end of the crystallization step, the reactor was cooled down to room temperature. The solid product was recovered by filtration and exhaustively washed with distilled water until reaching a pH of 7. Finally, the powder was dried in an oven at 120°C for 1 h. The final zeolite powder was weighed and a yield of 80% was obtained on the basis of SiO2. After the synthesis, the Na-ZSM-5 form was obtained. In order to obtain the NH4-ZSM-5 form, sodium ion was exchanged by ammonium ion via ion exchange at 80°C using a 1M solution of NH4NO3 in distilled water. The ion exchange process was carried out during 3 h and repeated three times. The zeolite powder was filtered and dried in an oven at 120°C for 1 h between the successive ion exchange steps. The final NH4-ZSM-5 form was divided into two batches. The first one was calcined under air at 400°C during 4 h with a heating/cooling rate of 3°C.min -1 in order to obtain the H-ZSM-5 form via thermal calcination. This zeolite will be named hereafter as H-ZSM-5 without plasma treatment. The second one was calcined using cold plasma at low temperature (near room temperature) using a glow-like discharge under partial vacuum (3 mbar) during 20 minutes. This zeolite will be named hereafter as H-ZSM-5 with plasma treatment. Before catalytic testing, the two zeolites were pre-treated/activated both in the same way inside the catalytic reactor, as described in section 2.4.

Zeolite activation by low temperature plasma

A plasma operando IR-cell detailed in a previous work [23,24,37,38] was used for cold calcination (plasma treatment) of NH4-ZSM-5 zeolites. Zeolite powder was pressed (1.96.10 5 Pa) into self-supported wafers (2 cm 2 , ~20 mg) for infrared (IR) measurements during plasma treatment. In this IR plasma cell, the wafer was located in down position in order to be irradiated by the glow-like discharge within the zone located between the two electrodes. The plasma discharge was generated using a high voltage AC power supply (Resinblock transformer FART, 50 mA) at 2 kV and 50 Hz. The gas system including mass flow controllers (Brooks) was connected to the top of the plasma IR cell. A molar mixture of 80% Ar and 20% O2 was used for plasma treatment. The latter was followed by operando IR spectroscopy with a Bruker Vertex 80 v FTIR spectrometer between 4000 and 1000 cm -1 (1 cm -1 optical resolution) and an MCT detector.

ZSM-5 physico-chemical characterization

The ZSM-5 structure and crystallinity were verified after synthesis and after plasma treatment using a PANalytical X'Pert PRO diffractometer with CuKα radiation (λ = 0.15418 nm, 40 mA, 45 kV). The X-ray diffractrograms were acquired between 2θ = 5-60° at intervals of 0.1° with a scan speed of 2° per min.

Nitrogen adsorption-desorption isotherms were measured at 77 K with a Micrometrics Model ASAP 2020 volumetric adsorption analyzer. Zeolite samples were outgassed at 220°C overnight before analysis. The ZSM-5 specific surface area was determined from the Brunauer-Emmet-Teller (BET) equation and the average pore volume was estimated from the N2 adsorbed volume at P/P 0 = 0.99.

Magic angle spinning 27 Al nuclear magnetic resonance (MAS 27 Al NMR) was used to investigate the ZSM-5 dealumination after plasma treatment. Analysis was carried out at room temperature on a Bruker Avance-500 spectrometer operating at 11.74 T (500 MHz), using a 4 mm zirconia rotor with a spinning rate of 14 kHz (radiofrequency of 107.1 kHz (ν1 Al ), recycle delay of 1 s, 512 scans). The chemical shift scale was calibrated with respect to a sample of liquid Al(NO3)3.

In situ Fourier-transform infrared (FT-IR) spectroscopy upon pyridine adsorption-desorption was used to quantify the total number of acid sites of ZSM-5 zeolite before and after plasma treatment ("total" means both outside and inside the pores, as pyridine is able to enter the pores). Samples were pressed into a self-supported disc (2 cm 2 , ~20 mg). The resulting pellets were placed into a homemade IR cell equipped with KBr windows. Nicolet Nexus one equipped with a KBr beam splitter and DTGS detector was used. Spectra were recorded with a 4 cm -1 optical resolution. The samples were pre-treated for 4 hours under vacuum (until reaching 10 -6 Torr) at 400°C before pyridine adsorption. A 3°C min -1 ramp was used to heat the pellets from room temperature to 400°C. Afterwards, they were exposed to 1 Torr of pyridine, first at room temperature and then at 100°C, both times for 1 hour. Finally, during pyridine evacuation (until reaching 10 -6 Torr), the samples were left at room temperature for 1 hour and then heated successively up to 100-150-200-250-300-350-400-450°C (by moving the pellet down to the IR beam and up again to the furnace in-between two successive temperatures), for 40 minutes at each temperature. FT-IR spectra were measured at room temperature during and/or after each step (always after in the case of heating steps because of the setup configuration).

Thermogravimetric analysis (TGA) was used to determine the amount of coke deposited on the samples at the end of the catalytic tests. It was performed on a thermogravimetric analyzer (PerkinElmer, Pyris 1) under a nitrogen flow of 80 mL.min -1 (STP). Samples of 5 mg samples were placed in ceramic pans and analyzed from 30 to 900°C with a heating rate of 20°C min -1 .

Methanol-to-DME catalytic tests

ZSM-5 zeolite powder (100 mg sieved within 150-300 µm) was introduced into a packed bed reactor and placed inside an oven. ZSM-5 zeolite powder with plasma treatment was obtained by grinding the wafers of 20 mg used during the FTIR operando study described in section 2.2. The experimental set-up was connected to a gas distribution system and to a gas chromatograph. First of all, the catalyst was activated for 4 hours under air at 400°C with a flow rate of 25mL.min -1 (STP). A 3°C min -1 ramp was used to heat from room temperature to 400°C. Before reaction, the catalyst was cooled down from 400 to 100°C. 25 mL.min -1 (STP) of nitrogen (Linde gas, 99.995%) saturated with 17 vol.% of methanol was introduced to the reactor (Acros Organics, 99+% extra pure) at atmospheric pressure. The reaction was performed from 100 to 450°C. The outlet gas flow was analyzed with a Varian CP 3900 gas chromatograph equipped with a WCOT CP-Wax 52 CB 2.0 µm column (35 m x 0.25 mm) and a FID detector. Analyses were performed 10 times for each temperature every 50°C from 100 to 450°C. A heating rate ramp of 3°C.min -1 was used for changing the reaction temperature. The reaction temperature was recorded using an 8 channels temperature data logger TC-08 of Pico Technology.

Results and discussions

ZSM-5 crystallinity and textural properties after plasma treatment

The XRD patterns of the ZSM-5 samples are shown in Figure 1. The initial crystallinity of ZSM-5 was not modified after all chemical and thermal treatments. However, a shift was observed at 7.9° of 2θ between the H-ZSM-5 with and without plasma treatment indicating a possible dealumination after plasma treatment.

The XRD patterns of the ZSM-5 samples are shown in Figure 1. The initial crystallinity of ZSM-5 was not modified after all chemical and thermal treatments. All samples presented characteristic XRD peaks of MFI structure at 2θ = 7.90°, 9.04°, 23.28°, 24.16° and 25.63°. Not any amorphous phases or other crystalline phases were observed, indicating that all zeolites, with and without ammonium and after treatment with and without plasma, were pure ZSM-5 crystals. However, a variation in the relative intensity of XRD peaks was evidenced indicating a relative crystallinity loss of ZSM-5 zeolite after plasma treatment. This loss of crystallinity by plasma treatment has already been reported in literature [46]. The decrease in XRD relative intensity of ZSM-5 characteristic peaks after plasma treatment could suggest some morphologic changes in zeolite crystallites. The peak at 9.04°, ascribed to {200} facet, was increased and the one at 7.9° associated to {101} plane, decreased when plasma was used. This is probably due to a partial dealumination caused by plasma which is later discussed in this work. The plasma induced a morphologic change of zeolite crystallites by shortening their size along the c-axis and by increasing their size along the b-axis. This can present an influence on the mass transfer properties of zeolites (tortuosity) and on their catalytic activity. Moreover, a shift was observed at 7.9° of 2θ between the H-ZSM-5 with and without plasma treatment indicating a possible dealumination after plasma treatment. The textural properties of H-ZSM-5 zeolites with and without plasma treatment are presented in Table 1. BET total surface area was decreased by 5% when plasma was used for obtaining the H-ZSM-5 form from the NH4-ZSM-5 form. The micropore area was diminished by 15% and the external surface area improved by 49% when plasma was applied. This can be explained by the fact that plasma treatment is a surface treatment only since Debye length (µm), for this kind of plasma [23,24,37,38], is 1000 orders of magnitude higher than the pore size (nm) and plasma cannot be formed inside the zeolite pores. Pore volume and sizes as well as particle size were not significantly different with and without plasma treatment.

Partial ZSM-5 dealumination and acidity improvement after plasma treatment

Operando FTIR cold plasma calcination of NH4-ZSM-5 zeolites

The temporal evolution of NH4-ZSM-5 IR bands followed by operando FTIR spectroscopy during cold plasma calcination is shown in Figure 2. Cold plasma calcination allowed removing ammonia and adsorbed water. The IR bands at 3200 cm -1 and 1400 cm -1 assigned to N-H stretching vibrations and NH4 deformation respectively [47,48] were completely removed after 15 minutes of cold plasma treatment. The IR band at 1650 cm -1 attributed to the bending mode (ν2) of adsorbed water molecules over the catalyst is also removed after 15 minutes of cold plasma treatment.

Partial ZSM-5 dealumination

H-ZSM-5 zeolites with and without plasma treatment were analyzed by Magic angle spinning 27 Al nuclear magnetic resonance. The 27 Al-MAS-NMR spectra are presented in Figure 3.

Chemical shifts at 55 and 0 ppm are ascribed to tetracoordinated and hexacoordinated aluminium, respectively [49,50]. When calcination was carried out under thermal heating, exclusively tetracoordinated aluminium (FAL) is observed. However, when calcination of ZSM-5 is performed under plasma assistance, both kinds of aluminium, tetracoordinated (FAL) and hexacoordinated (EFAL) were observed. This fact evidences the partial dealumination of ZSM-5 zeolite calcined by cold plasma. In general, after partial dealumination of zeolites, Lewis acidity should be improved.

ZSM-5 template-free zeolite is a very interesting material due to its environmental friendly character. However, it is well-known that template-free zeolites are less stable than zeolites which are synthesized using an organic template. The structure of the template-free ZSM-5 zeolite of this work can more easily collapse during the several physical and chemical treatments needed after its synthesis than that of those synthesized with organic template.

Since more than two decades, the use of cold plasma in the catalysts preparation has been reported [51]. In general, zeolites crystallinity can be decreased; their total acidity can be improved and dealumination can be observed after cold plasma treatment. Hu et al. [46] reported a partial dealumination of a MCM-22 material after being irradiated by cold DBD plasma for the elimination of its organic template. In 1989, Maesen et al. [52] studied the deammoniation by dry oxygen cold plasma of NH4-Y zeolite. They found out that faujasite crystallinity is not affected after cold calcination. However, they observed a dealumination of the material. Authors proposed as a possible dealumination mechanism the hydrolysis of framework aluminum (FAL) by protons in Si-OH-Al groupings. Since the temperature of the material is low (cold plasma), low-temperature dealumination cannot be caused through dehydroxylation [52]. At high temperature, the dealumination mechanism has been widely proposed [53,[START_REF] Karge | Post-Synthesis Modification I[END_REF]. In this case, successive Al-O bonds are hydrolyzed until dislodgement of the framework Al to a nonframework position to form EFAL species. In the present work, the dealumination mechanism of template-free ZSM-5 during cold oxygen plasma deammoniation could be produced as follows:

i) Highly reactive oxygen species are generated within the low pressure cold glow-like oxygen discharge such as O -, O + , metastable O2, O2 -, O3 -and O3.

ii) The O -species is the dominant ion in the low pressure (3 mbar) oxygen plasma discharge. This ion is created from dissociative attachments of the O2 ground state molecule ( 3 Σg - ) and the metastable O2 molecule (a 1 ∆g). These species can be consumed by recombination of O - and O + ions. O3 molecules can be generated by detachment through collision between O -ions and O2 metastable molecules. O2 -species can be as well further created by dissociative attachment of O3 molecules [START_REF] Gudmundsson | [END_REF].

iii) The previous highly reactive oxygen species generated in the gas phase could interact with protons from NH4 + ions after ammonia desorption to form water molecules. The H2O molecules could hydrolyze the Al-O bonds displacing thus the FAL species to non-framework positions to give EFAL species. At 25°C, the amount of LPy is higher for the plasma-activated zeolite, reflecting that the latter possesses a higher number of Lewis acid sites compared to the reference zeolite. At higher temperatures, however, the amount of LPy is nearly the same for both zeolites (lower than at 25 °C), indicating that the additional Lewis acid sites possessed by the plasma-activated zeolite are weak (easily leaving pyridine to desorb). Regarding the amount of BPy, it is also higher for the plasma-activated zeolite at 25°C, indicating that the latter zeolite possesses also a higher number of Brønsted acid sites compared to the reference sample. From 25 to 100°C, the gap of BPy amount between the two samples decreases but remains significant. From 100 to 400°C, the gap is even smaller than at 100°C, but it remains quite constant. At 450°C, the amount of BPy is finally the same for both samples. The fact that the amount of BPy is systematically higher for the plasma-activated zeolite up to 400°C can have two possible origins: i) a part of the additional Brønsted acid sites possessed by the plasma-activated zeolite is strong enough to retain pyridine up to 400°C, and ii) a part of the Brønsted acid sites initially present in the zeolite before the plasma treatment became stronger acids due to the plasma treatment, and thus became able to retain pyridine up to 400°C. The second origin is indeed plausible for H-ZSM-5 possessing extraframework Al species. As reported in [63], the spatial proximities between framework Al (Brønsted acid sites) and extra-framework Al (Lewis acid sites) leads to a synergetic effect that can remarkably enhance the Brønsted acid strength of dealuminated zeolites. In any case, the number of strong Brønsted acid sites (i.e. retaining pyridine up to high temperature) is higher here in the plasma-activated zeolite than in the reference one.

In situ FT-IR upon pyridine desorption

ZSM-5 catalytic activity in the methanol-to-DME reaction

Catalytic activity of H-ZSM-5 zeolites with and without plasma activation in the methanol-to-DME reaction is presented in Figure 5. The experimental relative error was estimated at 0.5% (error bars are not shown in Figure 5 for clarity improvement).

With its higher number of Lewis and strong Brønsted acid sites, the plasma-activated zeolite leads to a higher methanol conversion (Figure 5A) than the reference zeolite all over the considered range of reaction temperatures, except at 450°C (same conversion for both samples). Up to 250°C, the selectivity to DME is close to 100% for both samples. Thus, the yield of DME (Figure 5B) is higher for the plasma-activated sample. Above 250°C, by-products start to be formed (alkanes and alkenes and also coke as reflected by Figure 6), making the DME yield of the plasma-activated zeolite decrease to the same level as observed with the reference zeolite.

Indeed, in all mechanisms having been proposed in literature for the condensation of methanol over zeolites, Brønsted acid sites play a key role. In one of the proposed mechanisms, the reaction of methanol requires one Brønsted acid site and one adjacent Lewis basic site to yield two surface species, namely In Figure 6, the TGA curves of zeolites with and without plasma activation after catalytic test are shown, as well as a reference (zeolite before reaction). It is possible to observe only water desorption from the reference sample since it was not used in the methanol-to-DME reaction. Water removal is complete for all samples at 220°C. Coke is decomposed from 420°C . The fact that the plasma-activated zeolite leads to a higher amount of coke deposited after the catalytic test is due to its higher activity above 250°C (see Figure 5).

Conclusions

ZSM-5 organic template-free was successfully synthesized by hydrothermal synthesis. NH4-ZSM-5 zeolite was calcined by thermal heating (without plasma treatment) and by cold plasma (with plasma treatment). In the latter case, only 15 minutes were enough to obtain the H-ZSM-5 form. When plasma was used as zeolite activation method, BET surface area and micropore area were decreased by 5 and 15%, respectively. However, the external surface area was improved by 49% compared to the conventional thermal activation. Pore volume and sizes as well as particle size were not significantly different for both activation methods. When plasma was used as zeolite activation method, a partial zeolite dealumination was verified by XRD, 27Al-MAS-and NMR. As shown through FTIR upon pyridine adsorption-desorption, this partial dealumination increased the number of Lewis acid sites (weak) and the number of Brønsted acid sites (strong) causing an enhancement in the ZSM-5 zeolite catalytic activity in the methanol-to-DME reaction in the whole temperature range under study.

Cold plasma technology is a powerful tool that can be used to activate catalysts (such as zeolites) to improve both Lewis and Brønsted acidity for being used in reactions that require acid catalysts.

Figure 1 :

 1 Figure 1: XRD patterns of ZSM-5 zeolites

Figure 2 :

 2 Figure 2: Temporal evolution of NH4-ZSM-5 IR bands during cold plasma calcination

Figure 3 :

 3 Figure 3: 27 Al-MAS-NMR spectra of H-ZSM-5 with and without plasma treatment

Figure 4

 4 Figure4shows the amount of pyridine adsorbed onto Lewis (A) and Brønsted (B) acid sites (pyridine denoted as LPy and BPy, respectively), as a function of the evacuation temperature, for both the plasma-activated and reference zeolites. According to references [56-59], the amount of LPy was determined by integrating the IR bands in the region from 1430 to 1470 cm -1 (different ones here depending on the evacuation temperature, but same wavenumbers from one sample to the other at each temperature), while the amount of BPy was determined by

Figure 4 :

 4 Figure 4: Number of moles of pyridine adsorbed onto Lewis (A) and Brønsted (B) acid sites acidity as a function of evacuation temperature. At 25 °C, this number directly reflects the number of acid sites.

  [CH3OH2] + and [CH3O] -, which upon condensation give DME and water [64]. In another mechanism proposed in literature [64], methanol gets protonated on a Brønsted acid site, and the resulting [CH3OH2] + ion gets dehydrated, so leaving a methyl group bonded to the zeolite surface, in other words a methoxy group. The latter then reacts with another methanol molecule to form DME. Blaszkowski et al. proposed that both the latter mechanisms can occur in parallel [65]. Actually, Brønsted acidity is what makes zeolites much more active in methanol condensation than the commercially used γ-Al2O3 on which Lewis acid sites (weaker) are the active species [64].

Figure 5 :Figure 6 :

 56 Figure 5: Catalytic activity of H-ZSM-5 zeolites with and without plasma activation

Table 1 : H-ZSM-5 zeolite textural properties with and without plasma treatment

 1

	H-ZSM-5	BET surface area (m 2 .g -1 )	t-Plot micropore area (m 2 .g -1 )	t-Plot external surface area (m 2 .g -1 )	Pore volume (cm 3 .g -1 )	BJH Pore size (nm)	Average particle size (nm)
	Without plasma treatment	168.6	152.7	15.9	0.1	7.4	35.6
	With plasma treatment	159.9	128.5	31.4	0.1	6.7	37.5

Acknowledgements

O.N., J.S. and M.Q. thank F.A.J. for his invitation to work in the LCS Plasma group on this subject. J.S. and F.A.J. acknowledge Marco Daturi for giving J.S. the opportunity to work on this project. Authors finally thank Florian Klipfel and Loïc Le Pluart for TGA analyses.