Locus Coeruleus Norepinephrine Research Articles

Effects of acute and chronic administration of trace amine-associated receptor 1 (TAAR1) ligands on in vivo excitability of central monoamine-secreting neurons in rats

Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future antidepressant, antipsychotic, and anti-addiction drugs. Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic- and anti-addiction-like behavioral effects in rodents and primates. Acute RO5256390 suppressed, and RO5263397 stimulated serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopamine neurons of the ventral tegmental area (VTA) in brain slices, suggesting that the behavioral effects of TAAR1 ligands involve 5-HT and dopamine. For more comprehensive testing of this hypothesis, we examined acute and chronic effects of RO5256390 and RO5263397 on monoamine neurons in in vivo conditions. Excitability of 5-HT neurons of the DRN, noradrenaline neurons of the locus coeruleus (LC), and dopamine neurons of the VTA was assessed using single-unit electrophysiology in anesthetized rats. For acute experiments, RO5256390 and RO5263397 were administered intravenously; neuronal excitability after RO5256390 and RO5263397 administration was compared to the basal activity of the same neuron. For chronic experiments, RO5256390 was administered orally for fourteen days prior to electrophysiological assessments. The neuronal excitability in RO5256390-treated rats was compared to vehicle-treated controls. We found that acute RO5256390 inhibited 5-HT and dopamine neurons. This effect of RO5256390 was reversed by the subsequent and prevented by the earlier administration of RO5263397. Acute RO5256390 and RO5263397 did not alter the excitability of LC noradrenaline neurons in a statistically significant way. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.

Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System

Cognitive impairment is a common central nervous system complication that occurs following surgery or organs damage outside the nervous system. Neuroinflammation plays a key role in the molecular mechanisms of cognitive impairment. Dexmedetomidine alleviates neuroinflammation and reduces cognitive dysfunction incidence; however, the mechanism by which dexmedetomidine alleviates cognitive dysfunction remains unclear. This study evaluated the effect of dexmedetomidine on attenuation of early cognitive impairment induced by intestinal ischemia–reperfusion in mice and examined whether the locus coeruleus norepinephrine (LCNE) system participates in the anti-inflammatory effect of dexmedetomidine. The superior mesenteric artery was clamped for 45 min to induce intestinal ischemia reperfusion injury. Dexmedetomidine alone or combined with DSP-4, a selective locus coeruleus noradrenergic neurotoxin, was used for pretreatment. Postoperative cognition was assessed using the Morris water maze. Serum and hippocampal levels of IL-1β, TNF-α, norepinephrine (NE), and malondialdehyde (MDA) were assessed by enzyme-linked immunosorbent assay. Immunofluorescence, immunohistochemistry, and hematoxylin and eosin staining were used to evaluate the expression of tyrosine hydroxylase (TH) in the locus coeruleus, hippocampal microglia, and intestinal injury. Pretreatment with dexmedetomidine alleviated intestinal injury and decreased the serum and hippocampal levels of NE, IL-1β, TNF-α, and MDA at 24 h after intestinal ischemia reperfusion, decreased TH-positive neurons in the locus coeruleus, and ameliorated cognitive impairment. Similarly, DSP-4 pre-treatment alleviated neuroinflammation and improved cognitive function. Furthermore, α2-adrenergic receptor antagonist atipamezole or yohimbine administration diminished the neuroprotective effects and improved cognitive function with dexmedetomidine. Therefore, dexmedetomidine attenuated early cognitive dysfunction induced by intestinal ischemia–reperfusion injury in mice, which may be related to its anti-inflammatory effects through the LCNE system.

Differential vulnerability of locus coeruleus and dorsal raphe neurons to chronic methamphetamine-induced degeneration.

Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in axons of substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) dopamine neurons. Chronic administration of meth results in SNc degeneration and MAO inhibition is neuroprotective, whereas, the VTA is resistant to degeneration. This differential vulnerability is attributed, at least in part, to the presence of L-type Ca2+ channel-dependent mitochondrial stress in SNc but not VTA dopamine neurons. MAO is also expressed in other monoaminergic neurons such as noradrenergic locus coeruleus (LC) and serotonergic dorsal raphe (DR) neurons. The impact of meth on mitochondrial stress in LC and DR neurons is unknown. In the current study we used a genetically encoded redox biosensor to investigate meth-induced MAO-dependent mitochondrial stress in LC and DR neurons. Similar to SNc and VTA neurons, meth increased MAO-dependent mitochondrial stress in axonal but not somatic compartments of LC norepinephrine and DR serotonin neurons. Chronic meth administration (5 mg/kg; 28-day) resulted in degeneration of LC neurons and MAO inhibition was neuroprotective whereas DR neurons were resistant to degeneration. Activating L-type Ca2+ channels increased mitochondrial stress in LC but not DR axons and inhibiting L-type Ca2+ channels in vivo with isradipine prevented meth-induced LC degeneration. These data suggest that similar to recent findings in SNc and VTA dopamine neurons, the differential vulnerability between LC and DR neurons can be attributed to the presence of L-type Ca2+ channel-dependent mitochondrial stress. Taken together, the present study demonstrates that both meth-induced MAO- and L-type Ca2+ channel-dependent mitochondrial stress are necessary for chronic meth-induced neurodegeneration.

Feasibility of Canine Adenovirus Type 2 (CAV2) Based Vector for the Locus Coeruleus Optogenetic Activation in Non-Transgenic Rats: Implications for Functional Studies

The locus coeruleus norepinephrine (LC-NE) system modulates many visceral and cognitive functions, while LC-NE dysfunction leads to neurological and neurodegenerative conditions such as sleep disorders, depression, ADHD, or Alzheimer’s disease. Innovative viral-vector and gene-engineering technology combined with the availability of cell-specific promoters enabled regional targeting and selective control over phenotypically specific populations of neurons. We transduced the LC-NE neurons in adult male rats by delivering the canine adenovirus type 2-based vector carrying the NE-specific promoter PRSx8 and a light-sensitive channelrhodopsin-2 receptor (ChR2) directly in the LC or retrogradely from the LC targets. The highest ChR2 expression level was achieved when the virus was delivered medially to the trigeminal pathway and ~100 μm lateral to the LC. The injections close or directly in the LC compromised the tissue integrity and NE cell phenotype. Retrograde labeling was more optimal given the transduction of projection-selective subpopulations. Our results highlight a limited inference of ChR2 expression from representative cases to the entire population of targeted cells. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. Thus, besides the cell-type specificity and the transduction efficiency, the between-subject variability in the proportion of the remaining viral-transduced targeted cell population must be considered in any functional connectivity study.

An examination of relations between baseline pupil measures and cognitive abilities.

Examining individual differences in pupil size and pupillary dynamics have revealed important insights into the nature of individual differences in cognitive abilities like working memory capacity, long-term memory, attention control, and fluid intelligence. These findings are often tied to the locus coeruleus-norepinephrine (LC-NE) system, as this system has a tight temporal correlation with pupil diameter. Some recent research has demonstrated positive correlations between resting pupil size and cognitive ability, specifically fluid intelligence. The present study attempted to replicate such relations. Across three studies, a large sample of participants (N = 845) completed batteries of cognitive ability measures and measures of resting pupil size and pupillary hippus (fluctuations in pupil diameter). The cognitive measures comprised tasks previously used to measure attention control, visual short-term memory capacity, fluid intelligence, working memory capacity, and visuospatial ability. At the factor level, cognitive ability and pupil size correlated near zero. We did observe some limited evidence for a negative correlation between resting pupillary hippus and cognitive ability. Given the null findings in the present data, we encourage further replication of relations between resting pupil measures and cognitive abilities before making any strong theoretical conclusions about such relations.

Locus coeruleus noradrenergic neurons mediate panic‐like escape response elicited by CO2

The CO2exposure has been used to investigate the panicogenic response in patients with panic and other anxiety disorders since these patients are more sensitive to this stimulus, and therefore, more likely to experience the “suffocation false alarm” which, in turn, triggers the panic attack. It is well described that imbalances in the modulation of Locus coeruleus noradrenaline (LC‐NE) neurotransmission are responsible for several psychiatric disorders, including panic disorder and these neurons are sensitive to changes in CO2/pH. Therefore, we investigated the participation of LC‐NE neurons in the CO2‐induced panic like scape response by using C56BL/6 mice with a conditional knockout allele of Dbh (DbhcKO) crossed with En1cre (En1CreDbhcKO ‐ LC‐NE mutants). In addition, an intermediate genotype animal of the same genetic background was used (WT DbhcKO) as well as control animals (WT/WT) of both sexes (10‐12 weeks; 20‐25 g). Mice were placed in chamber where behavioral responses such as escape (jumping/running) and time spent immobile (freezing) were recorded under 20% CO2 during 7 min. CO2‐enriched air evoked an active escape response (jumping behavior) interpreted as escape attempts. En1CreDbhcKO mutants had a blunted jumping response (P=0.001) and spent more time in freezing compared to the other groups (P<0.0001). Furthermore, En1CreDbhcKO animals had fewer racing episodes (P=0.028) compared to WT/WT animals, but not different from WT DbhcKO group, that also presented a long freezing time, little movement, and a small number of jumps. No sex difference was observed among groups. These findings suggest that noradrenaline originating from the LC has an important role in the panic‐like escape response elicited in mice by exposure to CO2 in a sex independent way.

Unrelenting Fear Under Stress: Neural Circuits and Mechanisms for the Immediate Extinction Deficit.

Therapeutic interventions for disorders of fear and anxiety rely on behavioral approaches that reduce pathological fear memories. For example, learning that threat-predictive stimuli are no longer associated with aversive outcomes is central to the extinction of conditioned fear responses. Unfortunately, fear memories are durable, long-lasting, and resistant to extinction, particularly under high levels of stress. This is illustrated by the “immediate extinction deficit,” which is characterized by a poor long-term reduction of conditioned fear when extinction procedures are attempted within hours of fear conditioning. Here, I will review recent work that has provided new insight into the neural mechanisms underlying resistance to fear extinction. Emerging studies reveal that locus coeruleus norepinephrine modulates amygdala-prefrontal cortical circuits that are critical for extinction learning. These data suggest that stress-induced activation of brain neuromodulatory systems biases fear memory at the expense of extinction learning. Behavioral and pharmacological strategies to reduce stress in patients undergoing exposure therapy might improve therapeutic outcomes.

Impairment of autonomic emotional response for executive function in children with ADHD: A multi-modal fNIRS and pupillometric study during the Wisconsin Card Sorting Test

ObjectiveChildren with attention deficit hyperactivity disorder (ADHD) often experience difficulties with emotional control and a consequent inability to perform tasks. To clarify the effects of emotional behavior on cognitive functions, we aimed to determine the association between emotional changes and executive functions in children with ADHD by measuring the pupil diameter changes associated with emotional changes. Participants and methodsThis study included 14 children with ADHD and 10 typically developing children (TDC) aged between 10 and 16 years. During the Wisconsin Card Sorting Test (WCST), which is related to context formation and task switching among executive functions, changes in pupil diameter and frontal oxygenated hemoglobin (oxy-Hb) using functional near-infrared spectroscopy (fNIRS) were recorded simultaneously. Pupil diameter changes during “cognitive shift” and “consecutive correction” were compared between both groups. ResultsDuring cognitive shift, the pupils of children with ADHD contracted, whereas those of the TDC were mydriatic. During consecutive correction, the pupils of children with ADHD were mydriatic, whereas those of the TDC tended to contract. These results correlated with WCST performance. Moreover, during cognitive shifts, changes in bilateral frontal blood flow were increased in TDC, but not in children with ADHD. ConclusionThe locus coeruleus-norepinephrine (LC-NE) system plays an important role in pupillary diameter response. These results suggest that the LC-NE system may be dysfunctional in children with ADHD, and the system’s abnormality may lead to affective abnormalities in such patients, which results in poor performance on WCST (i.e., impaired executive functions).

A Computational Model of Hopelessness and Active-Escape Bias in Suicidality.

Currently, psychiatric practice lacks reliable predictive tools and a sufficiently detailed mechanistic understanding of suicidal thoughts and behaviors (STB) to provide timely and personalized interventions. Developing computational models of STB that integrate across behavioral, cognitive and neural levels of analysis could help better understand STB vulnerabilities and guide personalized interventions. To that end, we present a computational model based on the active inference framework. With this model, we show that several STB risk markers - hopelessness, Pavlovian bias and active-escape bias - are interrelated via the drive to maximize one's model evidence. We propose four ways in which these effects can arise: (1) increased learning from aversive outcomes, (2) reduced belief decay in response to unexpected outcomes, (3) increased stress sensitivity and (4) reduced sense of stressor controllability. These proposals stem from considering the neurocircuits implicated in STB: how the locus coeruleus - norepinephrine (LC-NE) system together with the amygdala (Amy), the dorsal prefrontal cortex (dPFC) and the anterior cingulate cortex (ACC) mediate learning in response to acute stress and volatility as well as how the dorsal raphe nucleus - serotonin (DRN-5-HT) system together with the ventromedial prefrontal cortex (vmPFC) mediate stress reactivity based on perceived stressor controllability. We validate the model by simulating performance in an Avoid/Escape Go/No-Go task replicating recent behavioral findings. This serves as a proof of concept and provides a computational hypothesis space that can be tested empirically and be used to distinguish planful versus impulsive STB subtypes. We discuss the relevance of the proposed model for treatment response prediction, including pharmacotherapy and psychotherapy, as well as sex differences as it relates to stress reactivity and suicide risk.

Event-related transcutaneous vagus nerve stimulation modulates behaviour and pupillary responses during an auditory oddball task

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that is thought to activate the Locus Coeruleus-Noradrenaline (LC-NA) system. Standard taVNS protocols consist of the administration of intermittent or continuous stimulation over long periods. However, there is currently a limited understanding of the temporal dynamics of taVNS modulation of cognitive processes, as well as its mechanisms of action. We argue that novel stimulation approaches, informed by established theories of the LC-NA system, are needed to further our understanding of the neurocognitive underpinnings of taVNS. In this pre-registered study, we tested whether an “event-related” taVNS protocol can modulate the LC-NA system. In a within-subject design (single session) we delivered brief trains of taVNS (3 s) during an auditory oddball paradigm. The taVNS was time-locked to the target stimuli presentation and randomly interleaved with sham stimulation. Response times (RT) and stimuli-driven pupillary diameter (PD) were used as indices of LC-NA activity. Results revealed that active taVNS increased RT to targets, as compared to sham trials. Notably, in line with current theories of LC-NA functioning, taVNS modulation of target-related pupil dilation depended on pre-stimulation PD, an index of baseline LC-NA activity. In particular, active (vs. sham) taVNS was associated with smaller pupil dilation in trials where the baseline PD was small. These results demonstrate, for the first time, the effectiveness of brief event-related taVNS in the modulation of cognitive processes and highlight the importance of using pupil size as an index of tonic and phasic LC-NA activity.

Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors

Empathy involves integrated affective and cognitive processes to share the emotional state of others. This evolutionarily conserved ability has also been identified in nonhuman primates and rodents. Our previous work demonstrated that social interaction with a cagemate rat in pain induces mechanical pain hypersensitivity in cagemate observer (CO) rats. Moreover, we also demonstrated that the medial prefrontal cortex (mPFC) and the locus coeruleus-norepinephrine (LC-NE) system are involved in this process. The LC sends noradrenergic innervations throughout the brain, and its innervation of the prefrontal cortex plays important roles in working memory and attention. The present study seeks to study the roles of the LC-to-mPFC pathway in pain empathy in rats. Selective ablation of the noradrenergic innervations of the mPFC through bilateral injections of the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-β-hydroxylase into the mPFC diminished mechanical pain hypersensitivity in CO rats. Bilateral intra-mPFC applications of the adrenergic α1 receptor antagonist prazosin and the β receptor antagonist propranolol, but not the adrenergic α2 antagonist yohimbine, eliminated mechanical pain hypersensitivity in CO rats. In contrast, intra-mPFC applications of prazosin, yohimbine or propranolol did not affect the mechanical pain sensitivity of rats per se. Our results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and β receptors.

The role of the locus coeruleus/norepinephrine system in the pathogenesis of neurodegenerative disorders: An update.

The aim of this review was to provide an update on current and emerging knowledge of the neuropathological processes affecting the locus coeruleus/norepinephrine (LC/NE) system, their effect on Alzheimer's disease and Parkinson's disease symptomatology, including efforts to translate these notions into therapeutic actions targeting the noradrenergic system. Over the past 2 years, work from multiple groups has contributed to support an early role of locus coeruleus degeneration and/or hyperactivation in the neurodegenerative process, including a trigger of neuroinflammation. Imaging advances are allowing the quantification of locus coeruleus structural features in vivo, which is critical in the early stages of disease. Nonmotor and noncognitive symptoms, often secondary to the involvement of the LC/NE system, are becoming more important in the definition of these diseases and their treatment. The diverse symptomatology of Parkinson's disease and Alzheimer's disease, which is not limited to cardinal motor and cognitive abnormalities, strongly suggests a multisystem neurodegenerative process. In this context, it is increasingly clear how the LC/NE system plays a key role in the initiation and maintenance of the neurodegenerative process.

Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: An exploratory study

Late-life depression (LLD) is a risk factor for age-dependent cognitive deterioration. Norepinephrine-related degeneration in the locus coeruleus (LC) may explain this link. To examine the LC norepinephrine system in vivo, we acquired neuromelanin-sensitive MRI (NM-MRI) in a sample of 48 participants, including 25 with LLD (18 women, age 68.08 ± 5.41) and 23 never-depressed comparison participants (ND, 12 women, age 70 ± 8.02), matched on age and cognitive status. We employed a semi-automated procedure to segment the LC into three bilateral sections along its rostro-caudal extent, and calculated relative contrast as a proxy of integrity. Then, we examined associations between integrity and LLD diagnosis, age, and cognition, as measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Delis-Kaplan Executive Function System (D-KEFS). We did not identify an effect of LLD diagnosis nor age on LC integrity, but exploratory canonical correlation analysis across the combined participant sample revealed a strong (Rc = 0.853) and significant multivariate relationship between integrity and cognition (Wilks’ λ = 0.03, F(84, 162.44) = 1.66, p = <.01). The first and only significant variate explained 72.83% model variance, and linked better attention and delayed memory performance, faster processing speed, and lower verbal fluency performance with higher integrity in the right rostral but lower integrity in the left caudal LC. Our results complement prior evidence of LC involvement in cognition in healthy older adults, and extend this association to individuals with LLD.

Altered locus coeruleus activity and neurochemistry in the presence of Alzheimer's disease-like hyperphosphorylated tau pathology.

The locus coeruleus (LC), the main source of norepinephrine (NE) in the brain, develops tau pathology prior to other brain regions and later degenerates in Alzheimer's disease (AD). Emergence of prodromal symptoms before cognitive impairment is evident, such as anxiety, agitation, and sleep disturbances, parallels development of hyperphosphorylated tau in the LC. Although pathogenic tau can alter the activity of other neurons, and noradrenergic dysfunction likely contributes to prodromal AD symptoms, the consequences of hyperphosphorylated tau on LC function are unknown. TgF344-AD rats, which develop hyperphosphorylated tau in the LC prior to other brain regions, and wild-type (WT) littermates aged 6 and 15 months (3-10 rats/group) were used. Baseline and footshock (0.5ms and 5ms 10mA)-evoked single unit LC activity (27-111 neurons/group) were recorded in chloral hydrate anesthetized rats. LC sections from duplicate groups of rats were immunostained for tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) to proxy NE synthesis capacity, NE transporter (NET) to assess somatodendritic LC integrity and NE uptake, monoamine oxidase A (MAOA) to evaluate NE metabolism, galanin to measure peptide co-transmitter levels, and GAD67 to investigate local inhibitory networks (3-4 slices/animal, 2-7 animals/group). Grayscaled fluorescence was measured in ImageJ. Electrophysiology revealed a trend towards increased LC baseline firing rates in WT and TgF344-AD rats at 15 months vs 6 months, with no genotype differences. Footshock-evoked LC activity tended to be exaggerated in TgF344-AD rats at 6 months, but blunted or unchanged at 15 months compared to WT. Immunofluorescence indicated decreased NET in TgF344-AD rats at 6 months, with both genotypes showing a reduction at 15 months compared to younger animals. GAD67 was significantly higher in 15-month animals compared to 6 months, with no genotype differences. No significant effects of genotype or age were found for MAOA, DBH, or galanin. These results suggest early LC dysfunction that coincides with the onset of hyperphosphorylated tau pathology. Further studies investigating the time course of LC dysfunction in AD, as well as therapies aimed at correcting these abnormalities, are warranted.

Persistent pain is associated with lower locus coeruleus integrity in older adults

AbstractBackgroundPersistent pain has been recently linked to increased Alzheimer’s disease (AD) risk, calling for the identification of related AD biomarkers. One biomarker of interest is integrity of the locus coeruleus (LC), a brainstem region that is thought to be the earliest site of tau deposition in the brain. The LC is also the main projection site for norepinephrine (NE), a major neurotransmitter inhibiting pain via rostral and caudal LC projections. A recently proposed mechanism suggests that persistent pain alters LC‐NE function and advances AD pathology in this region, explaining increased AD risk. Here we examined the association between persistent pain and LC integrity in older adults.MethodData were derived from the Vietnam Era Twin Study of Aging (VETSA) in which community‐dwelling men were assessed across up to 12 years in 3 waves. At the third wave, 426 community‐dwelling men (mean age = 67.55) underwent MRI‐assessment sensitive to neuromelanin, a byproduct of LC NE production. Using neuromelanin signal intensities, we calculated contrast‐to‐noise ratios between LC regions (i.e., rostral and caudal) and a pontine tegmentum reference region. Higher contrast‐to‐noise ratios indicate better LC integrity. Persistent pain was defined as reporting 2 or more waves of moderate‐to‐severe pain on the SF‐36 Bodily Pain Scale (n = 80, 16.5%). Generalized linear models examined associations between persistent pain and LC integrity after weighting for survival effects and adjusting for demographic (i.e., age, race, young adult general cognitive ability, income) and health confounders (i.e., comorbidities, depressive symptoms, opioid use), and nested twin observations.ResultPersistent pain was associated with .21 standard deviation lower rostral LC integrity (95% CI: ‐.40 to ‐.03) and .23 standard deviation lower caudal LC integrity at the third wave (95% CI: ‐.44 to ‐.04).ConclusionPersistent pain was associated with worse LC integrity in older adults. Persistent pain related to worse integrity in both the rostral and caudal LC regions. These associations are consistent with the recent proposed mechanism emphasizing the role of pain on LC‐NE dysfunction, but this relationship may also be bidirectional. Longitudinal designs would be informative, as would studies looking at later dementia trajectories.

Locus coeruleus hypopigmentation is associated with an increased risk of cerebral microangiopathy in autopsy cases with cognitive impairment.

The locus coeruleus (LC) is the main source of noradrenaline (NA) production in the brain, and one of the earliest sites of hyperphosphorylated tau in Alzheimer's disease (AD). LC degeneration is a common feature of AD. The NA LC neurons innervate the cerebrovasculature and play an important role in neurovascular coupling. Therefore, LC degeneration has been posited to contribute to vascular dysfunction and remodeling. However, this hypothesis has been rarely studied. Therefore, we explored associations between LC degeneration and microangiopathy in cases with cognitive impairment from a large human neuropathology dataset. We included data from participants with significant cognitive and/or behavioral impairment (determined by clinician(s) during visit closest to autopsy) from the National Alzheimer's Coordinating Center database (Uniform Data Set 2005 through February 2020). Participants with non-AD tauopathies or other pathologic diagnoses were excluded. Generalized estimating equations for logistic regression were used to examine associations between LC degeneration (dichotomized as moderate or severe vs none to mild LC hypopigmentation) as independent variable, and cerebral amyloid angiopathy (CAA) or arteriolosclerosis (dichotomized as moderate or severe vs none or mild) as dependent variable. Analyses were corrected for age at death, sex, AD neuropathologic change (ADNC) (dichotomized as intermediate or high vs not or low), Lewy body pathology (present vs absent), and presence of vascular (hypertension, hypercholesterolemia, angina pectoris) or genetic (ApoE4 genotype) risk factors. Cases with missing data on any of the variables of interest or covariates were excluded. We assumed a logit link function for binary outcome with an exchangeable correlation structure to account for within-center correlation, using package "gee" for R statistical software. The analyses included n=617 individuals (see table 1 for case characteristics). LC degeneration predicted an increased risk of both CAA (B (SE) = 0.47(0.19), p<0.05; OR [95% CI] = 1.61 [1.10; 2.35]), and arteriolosclerosis (B (SE) = 0.42 (0.20), p<0.05; OR [95% CI] = 1.52 [1.03; 2.24]) (table 2). LC degeneration may be associated with an increased risk for developing microvascular pathology, independent of other common pathologies. Degeneration of the LC-NA system may form an important missing link between vascular and amyloid pathology.

A Noradrenergic Lesion Attenuates Surgery-Induced Cognitive Impairment in Rats by Suppressing Neuroinflammation.

Postoperative cognitive dysfunction (POCD) is a common postoperative neurocognitive complication in elderly patients. However, the specific pathogenesis is unknown, and it has been demonstrated that neuroinflammation plays a key role in POCD. Recently, increasing evidence has proven that the locus coeruleus noradrenergic (LCNE) system participates in regulating neuroinflammation in some neurodegenerative disorders. We hypothesize that LCNE plays an important role in the neuroinflammation of POCD. In this study, 400 μg of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected intracerebroventricularly into each rat 7 days before anesthesia/surgery to deplete the locus coeruleus (LC) noradrenaline (NE). We applied a simple laparotomy and brief upper mesenteric artery clamping surgery as the rat POCD model. The open field test, novel objection and novel location (NL) recognition, and Morris water maze (MWM) were performed to assess postoperative cognition. High-performance liquid chromatography (HPLC) was used to measure the level of NE in plasma and brain tissues, and immunofluorescence staining was applied to evaluate the activation of microglia and astrocytes. We also used enzyme-linked immune-sorbent assay (ELISA) to assess the levels of inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Pretreatment with DSP-4 decreased the levels of systemic and central NE, increased the level of interleukin-6 (IL-6) in the plasma at 6 h after the surgery, decreased the concentration of IL-6 in the prefrontal cortex and hippocampus, and decreased the level of interleukin-1β (IL-1β) in the plasma, prefrontal cortex, and hippocampus at 1 week postoperatively. In addition, DSP-4 treatment attenuated hippocampal-dependent learning and memory impairment in rats with POCD, with a downregulation of the activation of microglia and astrocytes in the prefrontal cortex and hippocampus. In conclusion, these findings provide evidence of the effects of LCNE in modulating neuroinflammation in rats with POCD and provide a new perspective in the prevention and treatment of POCD.

Fluid intelligence and the locus coeruleus–norepinephrine system

SignificanceTo understand mind and behavior we must understand the biological basis of intelligence. Despite significant progress, we lack a complete picture that integrates different levels of brain function and explains individual differences in cognitive ability. We propose that the locus coeruleus, the source of norepinephrine for the brain, plays a key role in this puzzle. It does so at all levels of brain function, regulating processes of learning, memory, and attention. We use baseline pupil size, which covaries with locus coeruleus activity, to anchor the present analyses of the role of the locus coeruleus in cognitive ability. This work provides a foundation for future research integrating different levels of brain function with individual differences in cognitive ability.

T1 difficulty does not modulate the magnitude of the attentional blink.

When the visual system is busy processing one stimulus, it has problems processing a subsequent stimulus if it arrives soon after the first. Laboratory studies of this second-stimulus impairment—known as attentional blink (AB)—have employed two targets (T1, T2) presented in rapid sequence, and have found identification accuracy to be nearly perfect for T1, but impaired for T2. It is commonly believed that the magnitude of the AB is related directly to the difficulty of T1: the greater the T1 difficulty, the larger the AB. A survey of the experimental literature disconfirms that belief showing it to have arisen from artificial constraints imposed by the 100% limit of the response scale. Removal of that constraint, either using reaction time (RT) instead of accuracy as the dependent measure, or in experiments in which the functions of T2 accuracy over lags do not converge to the limit of the response scale, reveals parallel functions for the easy-T1 and the hard-T1 conditions, consistent with the idea that T1 difficulty does not modulate AB magnitude. This finding is problematic for all, but the Boost and Bounce (B&B) and the Locus Coeruleus–Norepinephrine (LC–NE) theories in which T1 acts merely as a trigger for an eventual refractory period that leads to the failure to process T2, rendering T1 difficulty and its relationship to the AB an irrelevant consideration.

Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer's Disease in Females.

This article aims to reevaluate our approach to female vulnerability to Alzheimer's disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOEɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.