Cholinergic and Noradrenergic Modulation of Corticothalamic Synaptic Input From Layer 6 to the Posteromedial Thalamic Nucleus in the Rat

Cholinergic and noradrenergic neuromodulation of the synaptic transmission from cortical layer 6 of the primary somatosensory cortex to neurons in the posteromedial thalamic nucleus (PoM) was studied using an in vitro slice preparation from young rats. Cholinergic agonist carbachol substantially decreased the amplitudes of consecutive excitatory postsynaptic potentials (EPSPs) evoked by a 20 Hz five pulse train. The decreased amplitude effect was counteracted by a parallel increase of synaptic frequency-dependent facilitation. We found this modulation to be mediated by muscarinic acetylcholine receptors. In the presence of carbachol the amplitudes of the postsynaptic potentials showed a higher trial-to-trial coefficient of variation (CV), which suggested a presynaptic site of action for the modulation. To substantiate this finding, we measured the failure rate of the excitatory postsynaptic currents in PoM cells evoked by “pseudominimal” stimulation of corticothalamic input. A higher failure-rate in the presence of carbachol indicated decreased probability of transmitter release at the synapse. Activation of the noradrenergic modulatory system that was mimicked by application of norepinephrine did not affect the amplitude of the first EPSP evoked in the five-pulse train, but later EPSPs were diminished. This indicated a decrease of the synaptic frequency-dependent facilitation. Treatment with noradrenergic α-2 agonist clonidine, α-1 agonist phenylephrine, or β-receptor agonist isoproterenol showed that the modulation may partly rely on α-2 adrenergic receptors. CV analysis did not suggest a presynaptic action of norepinephrine. We conclude that cholinergic and noradrenergic modulation act as different variable dynamic controls for the corticothalamic mechanism of the frequency-dependent facilitation in PoM.

The role of noradrenaline in cognition and cognitive disorders

Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer’s disease, Parkinson’s disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.

Infraslow locus coeruleus activity coordinates spindle rhythms and heart rate to gate fluctuating non-REM sleep substates

The continuity of non-rapid-eye-movement sleep (NREMS) is essential for its functions. However, many mammalian species, including humans, show NREMS fragility to maintain environmental vigilance. The neural substrates balancing NREMS continuity and fragility substates are unexplored. We show that the locus coeruleus (LC) is necessary and sufficient to generate infraslow (∼50 s) continuity-fragility fluctuations in mouse NREMS. Through machine-learning-guided closed-loop optogenetic LC interrogation, we suppressed, locked, or entrained continuity-fragility fluctuations, as evident by LC-mediated regulation of sleep spindle clustering and heart rate variability. Noradrenergic modulation of thalamic but not cortical circuits was required for infraslow sleep spindle clustering and involved rapid noradrenaline increases that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. The LC thus coordinates brain and bodily states during NREMS to engender continuity-fragility, accentuating its role in the physiology of sleep-related sensory uncoupling and as target in sleep disorders showing abnormal cortical and/or autonomic arousability.

Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions

Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain – the locus coeruleus – and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators – including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.

Norepinephrine Regulation of Ventromedial Hypothalamic Nucleus Astrocyte Glycogen Metabolism

The catecholamine norepinephrine (NE) links hindbrain metabolic-sensory neurons with key glucostatic control structures in the brain, including the ventromedial hypothalamic nucleus (VMN). In the brain, the glycogen reserve is maintained within the astrocyte cell compartment as an alternative energy source to blood-derived glucose. VMN astrocytes are direct targets for metabolic stimulus-driven noradrenergic signaling due to their adrenergic receptor expression (AR). The current review discusses recent affirmative evidence that neuro-metabolic stability in the VMN may be shaped by NE influence on astrocyte glycogen metabolism and glycogen-derived substrate fuel supply. Noradrenergic modulation of estrogen receptor (ER) control of VMN glycogen phosphorylase (GP) isoform expression supports the interaction of catecholamine and estradiol signals in shaping the physiological stimulus-specific control of astrocyte glycogen mobilization. Sex-dimorphic NE control of glycogen synthase and GP brain versus muscle type proteins may be due, in part, to the dissimilar noradrenergic governance of astrocyte AR and ER variant profiles in males versus females. Forthcoming advances in the understanding of the molecular mechanistic framework for catecholamine stimulus integration with other regulatory inputs to VMN astrocytes will undoubtedly reveal useful new molecular targets in each sex for glycogen mediated defense of neuronal metabolic equilibrium during neuro-glucopenia.

Dopamine and noradrenaline modulation of goal-directed behaviour in prefrontal areas: Toward a division of labour?

The prefrontal cortex is considered to be at the core of goal-directed behaviours. Notably, the medial prefrontal cortex (mPFC) is known to play an important role in learning action-outcome associations, as well as in detecting changes in this contingency. Previous studies have also highlighted a specific engagement of the dopaminergic pathway innervating the mPFC in adapting to changes in action causality. While previous research on goal-directed actions has primarily focused on the mPFC region, recent findings have revealed a distinct and specific role of the ventral and lateral orbitofrontal cortex (vlOFC). Indeed, vlOFC is not necessary to learn about action-outcome associations but appears specifically involved when outcome identity is unexpectedly changed. Unlike the mPFC, the vlOFC does not receive a strong dopaminergic innervation. However, it receives a dense noradrenergic innervation which might indicate a crucial role for this neuromodulator. In addition, several lines of evidence highlight a role for noradrenaline in adapting to changes in the environment. We therefore propose that the vlOFC’s function in action control might be under the strong influence of the noradrenergic system. In the present paper, we review anatomical and functional evidence consistent with this proposal and suggest a direction for future studies that aims to shed light on the orbitofrontal mechanisms for flexible action control. Specifically, we suggest that dopaminergic modulation in the mPFC and noradrenergic modulation in the vlOFC may underlie distinct processes related to updating one’s actions.

Cholinergic neuromodulation of inhibitory interneurons facilitates functional integration in whole-brain models

Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although computational models have reproduced the effect of neuromodulation at the whole-brain level, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, a newly introduced local inhibitory feedback enables the integration of whole-brain activity, and its modulation interacts with the other neuromodulatory influences to facilitate the transit between different functional states. Moreover, the new proposed model is able to reproduce an inverted-U relationship between noradrenergic modulation and network integration. Our work proposes a new possible mechanism behind segregation and integration in the brain.