Noradrenergic Activity Research Articles

Celiac Vagus Nerve Stimulation Recapitulates Angiotensin II-Induced Splenic Noradrenergic Activation, Driving Egress of CD8 Effector Cells

SummaryAngiotensin II (AngII) is a peptide hormone that affects the cardiovascular system, not only through typical effects on the vasculature, kidneys, and heart, but also through less understood roles mediated by the brain and the immune system. Here, we address the hard-wired neural connections within the autonomic nervous system that modulate splenic immunity. Chronic AngII infusion triggers burst firing of the vagus nerve celiac efferent, an effect correlated with noradrenergic activation in the spleen and T cell egress. Bioelectronic stimulation of the celiac vagus nerve, in the absence of other challenges and independently from afferent signals to the brain, evokes the noradrenergic splenic pathway to promote release of a growth factor mediating neuroimmune crosstalk, placental growth factor (PlGF), and egress of CD8 effector T cells. Our findings also indicate that the neuroimmune interface mediated by PlGF and necessary for transducing the neural signal into an effective immune response is dependent on α-adrenergic receptor signaling.

Noradrenergic responsiveness supports selective attention across the adult lifespan

AbstractBackgroundTheories of healthy and pathological aging assume a critical role of the locus coeruleus (LC), the main cortical norepinephrine (NE) supply, in shaping late‐life cognition. Postmortem analyses identified the LC as one of the first brain sites that accumulates tau pathology. However, in‐vivo research linking the noradrenergic system to senescent cognitive decline in humans is rare.Here we used a multimodal assessment to investigate whether individual differences in attention are related to the noradrenergic system.MethodIn younger (n = 39) and older adults (n = 38) we applied fear conditioning, an experimental manipulation known to modulate arousal‐related noradrenergic drive. Concurrently, we assessed pupil dilation, a non‐invasive proxy for noradrenergic activity, and the electroencephalogram (EEG) as indicators for successful NE manipulation. Reliable pupil and EEG signatures associated with elevated LC‐NE activity were identified in repeated conditioning sessions. We further evaluated participants’ general attention ability using a multimodal cognitive assessment. During one of the attention tasks (dichotic listening), fear‐conditioned (CS+) or perceptually matched control stimuli (CS–) were presented on a trial‐by‐trial basis to dynamically modulate arousal‐related noradrenergic drive.ResultRelative to younger adults, older adults demonstrated compromised performance across a variety of attention tasks. On a physiological level, presentation of fear‐conditioned stimuli during dichotic listening reinstated the acquired arousal response. Relative to control stimuli (CS–), conditioned stimuli (CS+) induced a multimodal response, consisting of pupil dilation and EEG desynchronization. Crucially, greater pupil dilation in response to the CS+ was associated with a stronger transient alpha–beta desynchronization (9–30 Hz), indicating a common dependence on phasic NE release. Using structural equation modeling, we integrated over EEG desynchronization and pupil dilation markers to derive a single index reflecting the responsiveness of the noradrenergic system to arousing stimuli. Combining behavioral and physiological data, we observed that a more responsive noradrenergic system was associated with better performance across attention tasks. Finally, we found that older age is associated with lower pupil‐ and EEG‐indexed noradrenergic responsiveness.ConclusionTaken together, our findings indicate that (1) noradrenergic neuromodulation dynamically sculpts low frequency oscillatory dynamics in posterior brain areas and (2) this interaction supports attention across the lifespan.

P.087 The relationship between the noradrenergic system activity and the expression of cytokines in the neonatal rat brain

P.087 The relationship between the noradrenergic system activity and the expression of cytokines in the neonatal rat brain

Noradrenergic Activity in the Olfactory Bulb Is a Key Element for the Stability of Olfactory Memory.

Memory stability is essential for animal survival when environment and behavioral state change over short or long time spans. The stability of a memory can be expressed by its duration, its perseverance when conditions change as well as its specificity to the learned stimulus. Using optogenetic and pharmacological manipulations in male mice, we show that the presence of noradrenaline in the olfactory bulb during acquisition renders olfactory memories more stable. We show that while inhibition of noradrenaline transmission during an odor-reward acquisition has no acute effects, it alters perseverance, duration, and specificity of the memory. We use a computational approach to propose a proof of concept model showing that a single, simple network effect of noradrenaline on olfactory bulb dynamics can underlie these seemingly different behavioral effects. Our results show that acute changes in network dynamics can have long-term effects that extend beyond the network that was manipulated.SIGNIFICANCE STATEMENT Olfaction guides the behavior of animals. For successful survival, animals have to remember previously learned information and at the same time be able to acquire new memories. We show here that noradrenaline in the olfactory bulb, the first cortical relay of the olfactory information, is important for creating stable and specific olfactory memories. Memory stability, as expressed in perseverance, duration and specificity of the memory, is enhanced when noradrenergic inputs to the olfactory bulb are unaltered. We show that, computationally, our diverse behavioral results can be ascribed to noradrenaline-driven changes in neural dynamics. These results shed light on how very temporary changes in neuromodulation can have a variety of long-lasting effects on neural processing and behavior.

Mental Effort When Playing, Listening, and Imagining Music in One Pianist's Eyes and Brain.

We investigated “musical effort” with an internationally renowned, classical, pianist while playing, listening, and imagining music. We used pupillometry as an objective measure of mental effort and fMRI as an exploratory method of effort with the same musical pieces. We also compared a group of non-professional pianists and non-musicians by the use of pupillometry and a small group of non-musicians with fMRI. This combined approach of psychophysiology and neuroimaging revealed the cognitive work during different musical activities. We found that pupil diameters were largest when “playing” (regardless of whether there was sound produced or not) compared to conditions with no movement (i.e., “listening” and “imagery”). We found positive correlations between pupil diameters of the professional pianist during different conditions with the same piano piece (i.e., normal playing, silenced playing, listen, imagining), which might indicate similar degrees of load on cognitive resources as well as an intimate link between the motor imagery of sound-producing body motions and gestures. We also confirmed that musical imagery had a strong commonality with music listening in both pianists and musically naïve individuals. Neuroimaging provided evidence for a relationship between noradrenergic (NE) activity and mental workload or attentional intensity within the domain of music cognition. We found effort related activity in the superior part of the locus coeruleus (LC) and, similarly to the pupil, the listening and imagery engaged less the LC–NE network than the motor condition. The pianists attended more intensively to the most difficult piece than the non-musicians since they showed larger pupils for the most difficult piece. Non-musicians were the most engaged by the music listening task, suggesting that the amount of attention allocated for the same task may follow a hierarchy of expertise demanding less attentional effort in expert or performers than in novices. In the professional pianist, we found only weak evidence for a commonality between subjective effort (as rated measure-by-measure) and the objective effort gauged with pupil diameter during listening. We suggest that psychophysiological methods like pupillometry can index mental effort in a manner that is not available to subjective awareness or introspection.

Taking advantage of fear generalization-associated destabilization to attenuate the underlying memory via reconsolidation intervention

Upon retrieval, an aversive memory can undergo destabilization and reconsolidation. A traumatic-like memory, however, may be resistant to this process. The present study sought to contribute with a strategy to overcome this potential issue by investigating whether generalized fear retrieval is susceptible to destabilization-reconsolidation that can be pharmacologically modified. We hypothesized that exposure to a context that elicits moderate generalization levels would allow a malleable memory state. We developed a fear conditioning protocol in context A (cxt-A) paired with yohimbine administration to promote significant fear to a non-conditioned context B (cxt-B) in rats, mimicking the enhanced noradrenergic activity reported after traumatic events in humans. Next, we attempted to impair the reconsolidation phase by administering clonidine (CLO) immediately after exposure to cxt-A, cxt-B, or a third context C (cxt-C) neither conditioned nor generalized. CLO administered post-cxt-B exposure for two consecutive days subsequently resulted in decreased freezing levels in cxt-A. CLO after cxt-B only once, after cxt-A or cxt-C in two consecutive days, or independently of cxt-B exposures did not affect fear in a later test. A 6-h-delay in CLO treatment post-cxt-B exposures produced no effects, and nimodipine administered pre-cxt-B exposures precluded the CLO action. We then quantified the Egr1/Zif268 protein expression following cxt-B exposures and CLO treatments. We found that these factors interact to modulate this memory destabilization-reconsolidation mechanism in the basolateral amygdala but not the dorsal CA1 hippocampus. Altogether, memory destabilization can accompany generalized fear expression; thus, we may exploit it to potentiate reconsolidation blockers' action.

Stress-induced modulation of multiple memory systems during retrieval requires noradrenergic arousal

Stress has been shown to favor dorsal striatum-dependent ‘habit’ memory over hippocampus-dependent ‘cognitive’ memory during learning. Here, we investigated whether stress may modulate the engagement of these ‘cognitive’ and ‘habit’ systems also during memory retrieval and if so, whether such a stress-induced shift in the control of memory retrieval depends on noradrenergic activation. To this end, participants acquired a probabilistic classification learning (PCL) task that can be solved by both the ‘cognitive’ and the ‘habit’ system, reflected in the distinct behavioral strategies. Twenty-four hours later, participants received either the beta-adrenergic receptor antagonist propranolol or a placebo before they underwent a psychosocial stressor or a non-stressful control manipulation, followed by a retrieval version of the PCL task. Overall, participants showed a practice-dependent shift from ‘cognitive’ to ‘habit’ memory. Stressed participants that had received a placebo fell back to a ‘cognitive’ strategy during retrieval, which was linked to an impairment in retrieval performance. Propranolol blocked this stress-induced shift towards the less efficient strategy. Moreover, our results showed that salivary cortisol was related to the retrieval strategy only when paralleled by increased autonomic arousal. Together, these results indicate that stress effects on the modulation of multiple memory system during retrieval necessitate noradrenergic arousal, with relevant implications for retrieval performance under stress.

Effects of glucocorticoid and noradrenergic activity on implicit and explicit facial emotion recognition in healthy men

Autism spectrum disorder (ASD) has been associated with imbalance between excitatory and inhibitory (E/I) neurotransmission systems, as well as with neuroinflammation. Sitting at the crossroads between E/I imbalance and neuroinflammation is a class of endogenous hormones known as neurosteroids. Current literature points to dysregulated steroid metabolism and atypical neurosteroid levels in ASD as early as in utero. However, due to the complexity of neurosteroid metabolomics, including possible sex differences, the impact of neurosteroids on ASD symptomatology remains unclear. In this study, we assessed neurosteroid levels and ASD symptom severity of 21 males with ASD and 20 full-scale-IQ-matched typically developing (TD) males, all aged 18–39. Using liquid chromatography-tandem mass spectrometry, concentrations of allopregnanolone, cortisol, dehydroepiandrosterone, progesterone, and testosterone were measured in saliva and serum. With the exception of cortisol’s, all neurosteroids’ concentrations were found to have ASD vs. TD group differences in distribution, where one group was normally distributed and the other non-normally distributed. Serum allopregnanolone levels in males with ASD were found to negatively correlate with clinician-rated measures of restricted and repetitive behavior measures (ADOS-2 RRB and ADI-R RRSB domain scores). Additionally, lower serum allopregnanolone levels were found to predict more negative camouflaging scores, which represent greater differences in self- and clinician-rated symptom severity, of both ASD symptomatology overall and repetitive behaviors in particular. Taken together, our findings demonstrate that in adult males with ASD, decreased serum allopregnanolone levels are associated with more severe restricted and repetitive behaviors and with less insight into the severity of these behaviors.

Effects of chronic exposure to low doses of Δ9- tetrahydrocannabinol in adolescence and adulthood on serotonin/norepinephrine neurotransmission and emotional behaviors.

BackgroundChronic exposure to D9-tetrahydrocannabinol (THC), the main pharmacological component of cannabis, during adolescence has been shown to be associated with an increased risk of depression and suicidality in humans. Little is known about the impact of the long-term effects of chronic exposure to low doses of THC in adolescent compared with adult rodents.MethodsTHC (1 mg/kg i.p., once per day) or vehicle was administered for 20 days in both adolescent (post-natal day 30–50) and young adult rats (post-natal day 50–70). After a long washout period (20 days), behavioral tests and electrophysiological recordings of serotonin and norepinephrine neurons were carried out.ResultsAdolescent THC exposure resulted in depressive behaviors: decreased latency to first immobility in the forced swim test and increased anhedonia in the sucrose preference test. Decreased entries in the open arms were observed in the elevated plus maze after adolescent and adult exposure, indicating an anxious phenotype. A significant reduction in dorsal raphe serotonergic neural activity without a change in locus coeruleus noradrenergic neural activity was found after adolescent and adult exposure.ConclusionsAltogether, these findings suggest that chronic low-dose THC exposure during the critical developmental period of adolescence and during adulthood could result in increased vulnerability of the serotonin system accompanied by anxiety symptoms. However, depressive phenotypes occur only after adolescent exposure but not after adult exposure, underscoring the greater vulnerability of young ages to the mental effects of cannabis.

Transcutaneous Vagus Nerve Stimulation (tVNS) Improves High-Confidence Recognition Memory but Not Emotional Word Processing.

Previous clinical research found that invasive vagus nerve stimulation (VNS) enhanced word recognition memory in epileptic patients, an effect assumed to be related to the activation of brainstem arousal systems. In this study, we applied non-invasive transcutaneous auricular VNS (tVNS) to replicate and extend the previous work. Using a single-blind, randomized, between-subject design, 60 healthy volunteers received active or sham stimulation during a lexical decision task, in which emotional and neutral stimuli were classified as words or non-words. In a subsequent recognition memory task (1 day after stimulation), participants' memory performance on these words and their subjective memory confidence were tested. Salivary alpha-amylase (sAA) levels, a putative indirect measure of central noradrenergic activation, were also measured before and after stimulation. During encoding, pleasant words were more accurately detected than neutral and unpleasant words. However, no tVNS effects were observed on task performance or on overall sAA level changes. tVNS also did not modulate overall recognition memory, which was particularly enhanced for pleasant emotional words. However, when hit rates were split based on confidence ratings reflecting familiarity- and recollection-based memory, higher recollection-based memory performance (irrespective of emotional category) was observed during active stimulation than during sham stimulation. To summarize, we replicated prior findings of enhanced processing and memory for emotional (pleasant) words. Whereas tVNS showed no effects on word processing, subtle effects on recollection-based memory performance emerged, which may indicate that tVNS facilitates hippocampus-mediated consolidation processes.

The Rostral Agranular Insular Cortex, a New Site of Oxytocin to Induce Antinociception.

The rostral agranular insular cortex (RAIC) is a relevant structure in nociception. Indeed, recruitment of GABAergic activity in RAIC promotes the disinhibition of the locus ceruleus, which in turn inhibits (by noradrenergic action) the peripheral nociceptive input at the spinal cord level. In this regard, at the cortical level, oxytocin can modulate the GABAergic transmission; consequently, an interaction modulating nociception could exist between oxytocin and GABA at RAIC. Here, we tested in male Wistar rats the effect of oxytocin microinjection into RAIC during an inflammatory (by subcutaneous peripheral injection of formalin) nociceptive input. Oxytocin microinjection produces a diminution of (1) flinches induced by formalin and (2) spontaneous firing of spinal wide dynamic range cells. The above antinociceptive effect was abolished by microinjection (at RAIC) of the following: (1) L-368899 (an oxytocin receptor [OTR] antagonist) or by (2) bicuculline (a preferent GABAA receptor blocker), suggesting a GABAergic activation induced by OTR. Since intrathecal injection of an α2A-adrenoceptor antagonist (BRL 44408) partially reversed the oxytocin effect, a descending noradrenergic antinociception is suggested. Further, injection of L-368899 per se induces a pronociceptive behavioral effect, suggesting a tonic endogenous oxytocin release during inflammatory nociceptive input. Accordingly, we found bilateral projections from the paraventricular nucleus of the hypothalamus (PVN) to RAIC. Some of the PVN-projecting cells are oxytocinergic and destinate GABAergic and OTR-expressing cells inside RAIC. Aside from the direct anatomic link between PVN and RAIC, our findings provide evidence about the role of oxytocinergic mechanisms modulating the pain process at the RAIC level.SIGNIFICANCE STATEMENT Oxytocin is a neuropeptide involved in several functions ranging from lactation to social attachment. Over the years, the role of this molecule in pain processing has emerged, showing that, at the spinal level, oxytocin blocks pain transmission. The present work suggests that oxytocin also modulates pain at the cortical insular level by favoring cortical GABAergic transmission and activating descending spinal noradrenergic mechanisms. Indeed, we show that the paraventricular hypothalamicnucleus sends direct oxytocinergic projections to the rostral agranular insular cortex on GABAergic and oxytocin receptor-expressing neurons. Together, our data support the notion that the oxytocinergic system could act as an orchestrator of pain modulation.

Adrenergic β receptor activation reduces amyloid β1-42-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP

Adrenergic β receptor activation prevents human soluble amyloid β (Aβ)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aβ1–42-induced impairment of LTP is due to Aβ1–42-mediated Zn2+ toxicity, we postulated that adrenergic β receptor activation reduces Aβ1–42-mediated intracellular Zn2+ toxicity followed by rescuing Aβ1–42 toxicity. To test the effect of adrenergic β receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aβ1–42 injection into the dentate granule cell layer. Human Aβ1–42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic β receptor agonist, but not by co-injection of phenylephrine, an adrenergic α1 receptor agonist. Isoproterenol did not reduce Aβ1–42 uptake into dentate granule cells, but reduced increase in intracellular Zn2+ in dentate granule cells induced by Aβ1–42. In contrast, phenylephrine did not reduce both Aβ1–42 uptake and increase in intracellular Zn2+ by Aβ1–42. In the case of human Aβ1−40 and rat Aβ1–42, which do not increase intracellular Zn2+, human Aβ1−40- and rat Aβ1–42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic β receptor activation reduces Aβ1–42-mediated increase in intracellular Zn2+ in dentate granule cells, resulting in rescuing Aβ1–42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aβ1–42-induced cognitive decline that is caused by intracellular Zn2+ dysregulation in the hippocampus.

Circadian-timed dopamine agonist treatment reverses high-fat diet-induced diabetogenic shift in ventromedial hypothalamic glucose sensing.

IntroductionWithin the ventromedial hypothalamus (VMH), glucose inhibitory (GI) neurons sense hypoglycaemia while glucose excitatory (GE) neurons sense hyperglycaemia to initiate counter control mechanisms under normal conditions. However, potential electrophysiological alterations of these two neuronal types in vivo in insulin‐resistant states have never been simultaneously fully documented. Further, the anti‐diabetic effect of dopamine agonism on this VMH system under insulin resistance has not been studied.MethodsThis study examined the impact of a high‐fat diet (HFD) on in vivo electrophysiological recordings from VMH GE and GI neurons and the ability of circadian‐timed dopamine agonist therapy to reverse any adverse effect of the HFD on such VMH activities and peripheral glucose metabolism.ResultsHFD significantly inhibited VMH GE neuronal electrophysiological response to local hyperglycaemia (36.3%) and augmented GI neuronal excitation response to local hypoglycaemia (47.0%). Bromocriptine (dopamine agonist) administration at onset of daily activity (but not during the daily sleep phase) completely reversed both VMH GE and GI neuronal aberrations induced by HFD. Such timed treatment also normalized glucose intolerance and insulin resistance. These VMH and peripheral glucose metabolism effects of circadian‐timed bromocriptine may involve its known effect to reduce elevated VMH noradrenergic activity in insulin‐resistant states as local VMH administration of norepinephrine was observed to significantly inhibit VMH GE neuronal sensing of local hyperglycaemia in insulin‐sensitive animals on regular chow diet (52.4%).ConclusionsHFD alters VMH glucose sensing in a manner that potentiates hyperglycaemia and this effect on the VMH can be reversed by appropriately circadian‐timed dopamine agonist administration.

Cognitive load amplifies Parkinson's tremor through excitatory network influences onto the thalamus.

Parkinson's tremor is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. It is a common clinical observation that tremor markedly increases during cognitive load (such as mental arithmetic), leading to serious disability. Previous research has shown that this tremor amplification is associated with reduced efficacy of dopaminergic treatment. Understanding the mechanisms of tremor amplification and its relation to catecholamines might help to better control this symptom with a targeted therapy. We reasoned that, during cognitive load, tremor amplification might result from modulatory influences onto the cerebello-thalamo-cortical circuit controlling tremor amplitude, from the ascending arousal system (bottom-up), a cognitive control network (top-down), or their combination. We have tested these hypotheses by measuring concurrent EMG and functional MRI in 33 patients with tremulous Parkinson's disease, OFF medication, during alternating periods of rest and cognitive load (mental arithmetic). Simultaneous heart rate and pupil diameter recordings indexed activity of the arousal system (which includes noradrenergic afferences). As expected, tremor amplitude correlated with activity in a cerebello-thalamo-cortical circuit; and cognitive load increased tremor amplitude, pupil diameter, heart rate, and cerebral activity in a cognitive control network distributed over fronto-parietal cortex, insula, thalamus and anterior cingulate cortex. The novel finding, obtained through network analyses, indicates that cognitive load influences tremor by increasing activity in the cerebello-thalamo-cortical circuit in two different ways: by stimulating thalamic activity, likely through the ascending arousal system (given that this modulation correlated with changes in pupil diameter), and by strengthening connectivity between the cognitive control network and the cerebello-thalamo-cortical circuit. We conclude that both the bottom-up arousal system and a top-down cognitive control network amplify tremor when a Parkinson's patient experiences cognitive load. Interventions aimed at attenuating noradrenergic activity or cognitive demands may help to reduce Parkinson's tremor.

Efecto del manejo farmacológico del sistema nervioso autónomo en la pancreatitis aguda inducida por el veneno de escorpión Tityus zulianus en un modelo ex vivo

Introducción: La pancreatitis es una de las consecuencias principales del envenenamiento escorpiónico producido por el género Tityus. El manejo farmacológico mediante el uso de agonistas y antagonistas α adrenérgicos en modelos experimentales in vivo e in vitro, permiten establecer una aproximación del papel del Sistema Nervioso Simpático (SNS) en el desarrollo de la pancreatitis. Objetivo: determinar el papel del SNS en el desarrollo de la pancreatitis aguda inducida por el veneno de escorpión Tityus zulianus (TzV), por medio del uso de simpaticolíticos como la clonidina y el prazosin. Métodos: La Extravasación de Proteínas Plasmáticas (EPP) en el páncreas se evaluó mediante el método de Azul de Evans (AE), modificado de Saria y Lundberg (1983) a 620 nm; n=3 ratones NIH en cada grupo experimental. Las comparaciones se hicieron por ANOVA de una vía y las pruebas post HOC por Tukey-Kramer. Resultados: Ambos fármacos (1mg/Kg), disminuyeron significativamente p< 0,01 (**) la EPP en el páncreas inducida por el TzV, en comparación con los animales inoculados solo con TzV. No hubo diferencias significativas entre los animales del grupo control y los grupos tratados con los fármacos más el TzV. Conclusiones: El efecto pancreatotóxico del TzV en ratones podría tener un componente autonómico dado que drogas simpaticolíticas al disminuir la actividad noradrenérgica reducen la magnitud del edema. Esto sugiere que ambos fármacos pueden usarse como estrategia terapéutica en estos casos.

Noradrenergic Responsiveness Supports Selective Attention across the Adult Lifespan.

Selectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in noninvasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a noninvasive marker of arousal-related norepinephrine (NE) release, while concurrently recording the EEG of male younger (N = 39; 25.2 ± 3.2 years) and older adults (N = 38; 70.6 ± 2.7 years). Arousal was modulated on a trial-by-trial basis using fear-conditioned (CS+) stimuli. During conditioning, pupil and EEG markers related to heightened arousal were identified. Afterward, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears. During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired arousal response, as reflected in pupil and EEG α-β band responses. Critically, pupil dilation to CS+ was correlated with stronger EEG α-β desynchronization, suggesting a common dependence on NE release. On a behavioral level, stronger arousal reactions were associated with better attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the lifespan.SIGNIFICANCE STATEMENT In old age, the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants' noradrenergic system while recording pupillometry and EEG to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups, a more responsive noradrenergic system was strongly associated with attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late-life cognition.

Enhanced mnemonic discrimination for emotional memories: the role of arousal in interference resolution

In the present study we investigated the long-standing question whether and why emotionally arousing memories are more distinct as compared to neutral experiences. We assumed that memory benefits from the distinctiveness of emotional information, and that emotions affect encoding by reducing interference among overlapping memory representations. Since pattern separation is the process which minimizes interference between memory representations with similar features, we examined the behavioral manifestation of putative neural mechanisms enabling pattern separation (i.e. mnemonic discrimination) for emotionally arousing materials using the Mnemonic Similarity Task with negative, positive, and neutral images as stimuli. Immediately after incidental encoding, subjects were presented with stimuli they had seen at encoding and also with new items. Crucially, participants were also presented with lure images that were visually similar to ones they had seen before. Response options were old, new, and similar. Our results showed that individuals were better in discriminating between similar, emotionally arousing memories, when compared to the neutral stimuli. Moreover, this so-called lure discrimination performance was better for the negative images, than it was for the positive stimuli. Finally, we showed that the high arousing negative stimuli were better separated than the low arousing negative stimuli, and a similar pattern of results was found for the positive items. Altogether, these findings suggest that lure discrimination is modulated by arousal and not by valence. We argue that noradrenergic activity might facilitate interference resolution among memory representations with similar features, and that superior pattern separation might play a key role in memory enhancement for emotional experiences.

Noradrenergic enhancement of object recognition and object location memory in mice

Extensive evidence indicates that noradrenergic activation is essentially involved in mediating the enhancing effects of emotional arousal on memory consolidation. Our current understanding of the neurobiological mechanisms underlying the memory-modulatory effects of the noradrenergic system is primarily based on pharmacological studies in rats, employing targeted administration of noradrenergic drugs into specific brain regions. However, the further delineation of the specific neural circuitry involved would benefit from experimental tools that are currently more readily available in mice. Previous studies have not, as yet, investigated the effect of noradrenergic enhancement of memory in mice, which show different cognitive abilities and higher endogenous arousal levels induced by a training experience compared to rats. In the present study, we investigated the effect of posttraining noradrenergic activation in male C57BL/6J mice on the consolidation of object recognition and object location memory. We found that the noradrenergic stimulant yohimbine (0.3 or 1.0 mg/kg) administered systemically immediately after an object training experience dose-dependently enhanced 24-h memory of both the identity and location of the object. Thus, these findings indicate that noradrenergic activation also enhances memory consolidation processes in mice, paving the way for a systematic investigation of the neural circuitry underlying these emotional arousal effects on memory. LAY SUMMARY: The current study successfully validated the effect of noradrenergic activation on both object recognition and object location memory in mice. This study thereby provides a fundamental proof-of-principle for the investigation of the neural circuitry underlying noradrenergic and arousal effects on long-term memory in mice.

From ear to eye? No effect of transcutaneous vagus nerve stimulation on human pupil dilation: A report of three studies

Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) has been proposed as a treatment for a spectrum of physical and psychological disorders. One of the proposed working mechanisms of tVNS is a modulatory effect on the locus coeruleus – noradrenaline (LC-NA) network. We tested this hypothesis in humans in a series of three studies: one focusing on high trait worriers, and two in healthy populations. In all three studies, we tested whether tVNS increases resting pupil diameter – as an index of LC-NA network activity. Additionally, we tested whether tVNS affects task performance and task-related pupil dilation during an Attentional Blink task. We found no evidence that tVNS increases pupil diameter or task-related pupil dilation in any of the tasks. No consistent effects of tVNS on performance on the attentional blink task were found. Overall, the results of these studies indicate that tVNS does not affect these behavioral and physiological indices of noradrenergic activity.

Silk sericin intake leads to increases in L-serine and L-tyrosine levels in the mouse brain and the simultaneous facilitation of brain noradrenergic turnover.

Sericin is a protein component of the silkworm cocoon, and contains a high proportion of L-serine, but it has been mostly disposed of as an industrial waste. However, recent studies have revealed its unique biological functionalities beneficial to human health. This study aimed to evaluate the effect of acute oral intake of sericin on amino acid and neurotransmitter metabolism in the mouse brain. Acute administration of chemically modified sericin (0.26g/30g body weight) increased L-serine and L-tyrosine levels in the serum and brain, although the L-tyrosine content in the sericin was less than 3% (w/w). In addition, sericin administration led to a significant facilitation of noradrenergic turnover via enhancement of 3-methoxy-4-hydroxyphenylethyleneglycol, a principal metabolite of noradrenaline, in several of the brain regions examined. These present findings suggest that oral intake of sericin efficiently delivers L-serine and L-tyrosine to the brain, thus stimulating noradrenergic activity in the brain.Abbreviations: DA: dopamine; 5-HIAA: 5-hydroxyindoleicetic acid; 5-HT: 5-hydroxytryptamine; HVA: homovanillic acid; MHPG: 3-methoxy-4-hydroxyphenylethyleneglycol; 3-MT: 3-methoxytyramine; NA: noradrenaline; NM: normetanephrine; Veh: vehicle.