The Locus Coeruleus Noradrenaline System in Delirium

Delirium is a brain state involving severe brain dysfunction affecting cognitive and attentional capacities. Our opinion statement review aims to elucidate the relationship between abnormal arousal and locus coeruleus (LC) activity in cognitive dysfunction and inattention in delirium states. We propose (1) that enhanced noradrenaline release caused by altered arousal in hyperactive delirium states leads to increased noradrenergic transmission within the LC and subcortical and cortical brain regions including the prefrontal cortex and hippocampus, thus affecting how attention and cognition function. In hypoactive delirium states, however, we are presuming (2) that less arousal will cause the release of noradrenaline to diminish in the LC, followed by reduced noradrenergic transmission in cortical and subcortical brain areas concentrated within the prefrontal cortex and hippocampus, leading to deficient attention and cognitive processing. Studies addressing the measurement of noradrenaline and its derivatives in biomaterial probes regarding delirium are also covered in this article. In conclusion, the LC-NA system plays a crucial role in generating delirium. Yet there have been no large-scale studies investigating biomarkers of noradrenaline to help us draw conclusions for improving delirium’s diagnosis, treatment, and prognosis, and to better understand its pathogenesis.

Deep hierarchical sensory processing accounts for effects of arousal state on perceptual decision-making

An organism's level of arousal strongly affects task performance. Yet, what level of arousal is optimal for performance depends on task difficulty. For easy tasks, performance is best at higher arousal levels, whereas arousal levels show an inverted-U-shaped relationship with performance for difficult tasks, with best performance at medium arousal levels. This interaction between arousal and task difficulty is known as the Yerkes-Dodson effect (1908) and is thought to reflect sensory decision-making in the locus coeruleus and associated widespread release of noradrenaline. Yet, this account does not explain why perceptual performance decays with high levels of arousal in difficult, but not in simple tasks. Recent studies suggest that arousal may also affect performance by modulating sensory processes. Here, we augment a deep convolutional neural network (DCNN) with a global gain mechanism to mimic the effects of arousal on sensory processing. This allowed us to reproduce the Yerkes-Dodson effect in the model's performance. Investigating our network furthermore revealed that for easy tasks, early network features contained most task-relevant information during high global gain states, resulting in model performance on easy tasks being best at high global gain states. In contrast, later layers featured most information at medium global gain states and were essential for performance on challenging tasks. Our results therefore establish a novel account of the Yerkes-Dodson effect, where the interaction between arousal state and task difficulty directly results from an interaction between arousal states and hierarchical sensory processing.

Noradrenaline Release from Locus Coeruleus Terminals in the Hippocampus Enhances Excitation-Spike Coupling in CA1 Pyramidal Neurons Via β-Adrenoceptors

Release of the neuromodulator noradrenaline signals salience during wakefulness, flagging novel or important experiences to reconfigure information processing and memory representations in the hippocampus. Noradrenaline is therefore expected to enhance hippocampal responses to synaptic input; however, noradrenergic agonists have been found to have mixed and sometimes contradictory effects on Schaffer collateral synapses and the resulting CA1 output. Here, we examine the effects of endogenous, optogenetically driven noradrenaline release on synaptic transmission and spike output in mouse hippocampal CA1 pyramidal neurons. We show that endogenous noradrenaline release enhances the probability of CA1 pyramidal neuron spiking without altering feedforward excitatory or inhibitory synaptic inputs in the Schaffer collateral pathway. β-adrenoceptors mediate this enhancement of excitation-spike coupling by reducing the charge required to initiate action potentials, consistent with noradrenergic modulation of voltage-gated potassium channels. Furthermore, we find the likely effective concentration of endogenously released noradrenaline is sub-micromolar. Surprisingly, although comparable concentrations of exogenous noradrenaline cause robust depression of slow afterhyperpolarization currents, endogenous release of noradrenaline does not, indicating that endogenous noradrenaline release is targeted to specific cellular locations. These findings provide a mechanism by which targeted endogenous release of noradrenaline can enhance information transfer in the hippocampus in response to salient events.

Effects of Prenatal Exposure to a Low-Dose of Bisphenol A on Sex Differences in Emotional Behavior and Central Alpha2-Adrenergic Receptor Binding

Prenatal exposure to bisphenol A (BPA) influences the development of sex differences neurologically and behaviorally across many species of vertebrates. These effects are a consequence of BPA’s estrogenic activity and its ability to act as an endocrine disrupter even, at very low doses. When exposure to BPA occurs during critical periods of development, it can interfere with the normal activity of sex steroids, impacting the fate of neurons, neural connectivity and the development of brain regions sensitive to steroid activity. Among the most sensitive behavioral targets of BPA action are behaviors that are characterized by a sexual dimorphism, especially emotion and anxiety related behaviors, such as the amount of time spent investigating a novel environment, locomotive activity and arousal. Moreover, in some species of rodents, BPA exposure affected males’ sexual behaviors. Interestingly, these behaviors are at least in part modulated by the catecholaminergic system, which has been reported to be a target of BPA action. In the present study we investigated the influence of prenatal exposure of mice to a very low single dose of BPA on emotional and sexual behaviors and on the density and binding characteristics of alpha2 adrenergic receptors. Alpha2 adrenergic receptors are widespread in the central nervous system and they can act as autoreceptors, inhibiting the release of noradrenaline and other neurotransmitters from presynaptic terminals. BPA exposure disrupted sex differences in behavioral responses to a novel environment, but did not affect male mice sexual behavior. Importantly, BPA exposure caused a change in the binding affinity of alpha2 adrenergic receptors in the locus coeruleus and medial preoptic area (mPOA) and it eliminated the sexual dimorphism in the density of the receptors in the mPOA.

Environmental Training and Synaptic Functions in Young and Old Brain: A Presynaptic Perspective

Background:Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in Central Nervous System (CNS), having profound implications for human well-being. The term “cognitive reserve” refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term “Cognitive training” indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. “Cognitive training” reinforces the “cognitive reserve” permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the “cognitive training” in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, from a preclinical point of view, whether “cognitive training” promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals.Conclusion:Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by “cognitive training”. The impact of “cognitive training” on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of “cognitive reserve” in young and old animals.

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1–3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.

Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery

The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala. We have determined whether acute systemic and intra-amygdala administration of clonidine, and chronic immunotoxin-mediated destruction of the noradrenergic innervation of the amygdala, impairs salience-related vasoconstrictor episodes in the tail artery of conscious freely moving Sprague-Dawley rats. After acute intraperitoneal injection of clonidine (10, 50, and 100 μg/kg), there was a dose-related decrease in the reduction in tail blood flow elicited by alerting stimuli, an effect prevented by prior administration of the α2-adrenergic blocking drug idazoxan (1 mg/kg ip or 75 nmol bilateral intra-amygdala). A dose-related decrease in alerting-induced tail artery vasoconstriction was also observed after bilateral intra-amygdala injection of clonidine (5, 10, and 20 nmol in 200 nl), an effect substantially prevented by prior bilateral intra-amygdala injection of idazoxan. Intra-amygdala injection of idazoxan by itself did not alter tail artery vasoconstriction elicited by alerting stimuli. Intra-amygdala injection of saporin coupled to antibodies to dopamine-β-hydroxylase (immunotoxin) destroyed the noradrenergic innervation of the amygdala and the parent noradrenergic neurons in the locus coeruleus. The reduction in tail blood flow elicited by standardized alerting stimuli was substantially reduced in immunotoxin-treated rats. Thus, inhibiting the release of noradrenaline within the amygdala reduces activation of the sympathetic outflow to the vascular beds elicited by salient events.