Noradrenergic excitation of astrocytes supports cognitive reserve

The concept of the brain cognitive reserve is derived from the well-acknowledged notion that the degree of brain damage does not always match the severity of clinical symptoms and neurological/cognitive outcomes. It has been suggested that the size of the brain (brain reserve) and the extent of neural connections acquired through life (neural reserve) set a threshold beyond which noticeable impairments occur. In contrast, cognitive reserve refers to the brain’s ability to adapt and reorganize structurally and functionally to resist damage and maintain function, including neural reserve and brain maintenance, resilience, and compensation (Verkhratsky and Zorec, 2024). We propose that noradrenergic regulation of astrocytes plays a key role in defining cognitive reserve. Astrocytes support neural homeostasis through multiple mechanisms and contribute to the pathogenesis of all neurological disorders (Verkhratsky et al., 2023). Astrocytes are key components in maintaining cognitive reserve; they contribute to shaping cytoarchitecture of the nervous tissue and synaptic transmission, thus supporting neural reserve and neural maintenance; astrocytes are central elements of brain defense and regeneration thus supporting brain resilience and compensation. We present an overview of the role of the noradrenergic innervation of astrocytes in both normal and neurodegenerative states, then we point out that the demise of the noradrenergic system is an early event in many, if not all neurodegenerative diseases, acting through astrocytes and limiting their support of cognitive reserve.

Locus coeruleus as a noradrenergic hub: The primary source (~70%) of noradrenaline in the central nervous system is noradrenergic neurons localized in the brainstem locus coeruleus (LC) nucleus; these neurons project throughout the central nervous system (Figure 1). This relatively small nucleus contains 10,000–30,000 pigmented neurons in non-human primates and 20,000–50,000 in humans; these neurons project widely to innervate nearly the entire brain and the spinal cord through branching axons. LC neurons are involved in arousal, wakefulness, memory, focus and attention, and the fight or flight response. Degeneration of the LC neurons is seen in many neurological disorders, including congenital central hypoventilation syndrome, sleep disorders, attention-deficit/hyperactivity disorder, anxiety, depression, and the most prevalent forms of neurodegenerative diseases, Parkinson’s and Alzheimer’s diseases and has been proposed to affect neural reserve (Wilson et al., 2013).

Figure 1.

Noradrenergic innervation of astrocytes.

Left panel: neurons from the Locus coeruleus project axons to most, if not all the brain areas and into the spinal cord as denoted by the arrows. Inset indicates a magnified view (right panel) where Locus coeruleus nerve endings with varicosities (swellings on noradrenergic nerve terminals) diffusely overlay the tissue. About half of these terminals do not form synaptic contacts with target cells, but rather release noradrenaline from varicosities. Adapted from Zorec et al. (2018).

Noradrenaline controls astrocytic morphology and energy metabolism: Memory formation requires an intact noradrenergic control over astrocytes, which links neuronal activity with energy provision (Zorec et al., 2018) as recently confirmed in the case of adenosine signaling to astrocytes (Theparambil et al., 2024). This form of intercellular signaling (metabolic excitability; Zorec et al., 2018) may provide additional energy for neurons during increased fuel demand in the form of an extracellular L-lactate pool. As LC degrades in aging and neurodegeneration this excitation-energy coupling declines, thus impairing cognitive reserve. Recent MRI imaging experiments confirmed that the neurodegenerative process is initiated by LC demise (Bueicheku et al., 2024).

Memory is defined as a retention and reconstruction of learned (acquired) knowledge. Memory is formed through a complex functional and morphological remodeling of neuronal projections and synaptic contacts; as well as morphological adaptation of neuroglia. All these complex changes in cytoarchitecture are generally defined as neuroplasticity. Remodeling of neuronal ensembles and larger neuronal networks ultimately translates into behavioral output. Plastic remodeling of nervous tissue in the process of learning extends to neuroglia and in particular to astrocytes. Noradrenaline mediates relatively rapid and profound morphological changes in astrocytes, which depend on the elevation of cyclic adenosine monophosphate (Zorec et al., 2018). These changes contribute to learning and memory formation, affecting synaptic support, learning (neural reserve) and brain maintenance.

Morphological changes of astrocytes, especially of their fine processes known as leaflets closely associated with synaptic structures strongly affect synaptic transmission. In particular, astrocytic leaflets are central to the regulation of the local extracellular concentration of neurotransmitters, including glutamate, to supplying neurons with neurotransmitter precursors (glutamine and L-serine), and to K⁺ buffering (Verkhratsky and Zorec, 2024). Therefore noradrenaline-mediated change in astrocyte shape plays a key role in supporting homeostasis and neurotransmission.

The brain represents 2% of total human body mass, whereas its metabolic demands are disproportionally high: at rest, the brain uses 20% of total body energy expenditure. Upon arousal and learning noradrenaline is released from projections of LC neurons, while energy consumption also increases, which includes glycogenolysis and L-lactate production in astrocytes. Enhanced energy availability of L-lactate, produced by noradrenaline-activated astrocytes, from which it is released by MCT1 transporters, supports learning. Imaging of ¹⁸F 2-deoxy glucose by the MRI-PET approach revealed reduced D-glucose metabolism indicating a hypometabolic state in patients suffering from neurodegeneration (Rodriguez-Vieitez et al., 2016), reflecting reduced noradrenaline levels. In addition to noradrenaline acting to excite astrocytes for energy provision in the form of L-lactate, other mechanisms may mediate excitation-energy coupling. Metabolic activation of astrocytes in response to neuronal activity may involve adenosine acting on astrocytic A_2B receptors; activation of the latter stimulates astrocyte glucose metabolism and increases L-lactate secretion thus boosting the extracellular pool of readily available energy substrates (Theparambil et al., 2024). The extracellular pool of L-lactate released from astrocytes arguably also enhances LC neuron activity (Tang et al., 2014). Extracellular L-lactate may stimulate the production of L-lactate in astrocytes to maintain the concentration gradient of the extracellular L-lactate pool favoring supplementation of neuronal energy demand. The resilience of the noradrenaline-dependent astrocyte role in excitation-energy coupling may contribute to the cognitive reserve during neurodegeneration.

The demise of LC neurons impairs cognitive reserve: Recent studies in humans revealed that the earliest accumulation of phosphorylated tau, a hallmark of neurodegeneration, occurs in the LC, as spatiotemporal patterns of LC integrity, determined by magnetic resonance imaging, predict cortical tau accumulation and cognition decline (Bueicheku et al., 2024). Animal studies employing immunotoxins specific for noradrenergic and cholinergic neurons found differential regulation of spatial learning and memory associated with hippocampal structures by acetylcholine and noradrenaline. Specifically, ablation of either noradrenergic- or cholinergic-neurons alone did not affect reference memory; conversely simultaneous ablation of both neuronal types impaired the reference memory. In line with this, manipulation with noradrenergic innervation affected of working memory, which was not further impaired by ablation of cholinergic neurons (de Leo et al., 2023) consistent with the view that death of or lesion to LC neurons cause learning deficits at the early stage of the neurodegeneration. Degeneration of LC neurons limits the bioavailability of noradrenaline in the brain, instigating synergistic impairments. As reported by MRI and PET studies in humans, microdegeneration of LC is associated with changes in cortical and subcortical regions mediated by astrocytes (Beckers et al., 2024).

Noradrenaline released by the LC is crucial for maintaining the blood-brain barrier and functional hyperemia in active brain areas under arousal. Noradrenaline exposure triggers Ca²⁺ signaling in astrocytes, anatomically linked with neurons and synapses on one side and the blood-brain barrier on the other (Figure 1; Bekar et al., 2008). Degeneration and death of LC neurons affect the maintenance of the blood-brain barrier, as suppression of astrocytic noradrenaline-mediated Ca²⁺ signaling leads to an altered blood-brain barrier dynamic thus promoting the exposure of neural tissue to harmful agents in the environment. Reduced noradrenaline availability due to LC-neuron demise, affects astrocytic morphological plasticity involving vesicle dynamics. In particular, lysosomal traffic which in astrocytes under pathological conditions transports major histocompatibility complex II molecules, playing a role in antigen presentation during pro-inflammatory pathologic conditions (Bozic et al., 2020), is altered. Therefore, under reduced levels of noradrenaline astrocytes become engaged in pro-inflammatory conditions, which is a characteristic of neurodegeneration.

To preserve or potentiate the noradrenergic innervation to protect several cognitive pharmacological approaches were considered. These included suppression of noradrenaline degradation (by using inhibitors of monoamine oxidase, MAO; incidentally the MAO-B is an astrocyte-specific enzyme), as well as decreasing noradrenaline uptake, mediated mostly by Na⁺-dependent noradrenaline and dopamine transporters noradrenaline transporter and dopamine transporter. These attempts, however, were not proven effective in clinical settings, probably because of the complexity of downstream pathways of noradrenergic innervation. Adrenoceptors, for example, these receptors may get downregulated by pathologically reduced levels of noradrenaline. The strategy to replace noradrenergic neurons is also possible, but challenging. One may maintain the excitation of remaining, non-degenerated, LC neurons by L-lactate for intercellular interaction by alternative pathways that mimic the action of noradrenaline, but independently of adrenergic receptors, including the GPR27 orphan receptor which stimulates L-lactate production in astrocytes and LC neurons (Zorec et al., 2018).

In summary, astrocytes play a role as excitation-energy hubs producing L-lactate to support neurons. Depleted noradrenaline levels during neurodegeneration likely represent a key event in the cognitive reserve decline, which could be pharmacologically reverted by activating mechanisms enhancing L-lactate in astrocytes. One of them could be the adenosine-mediated enhancement of L-lactate production in astrocytes. Other mechanisms may involve the action of the GPR27 receptor, where the endogenous ligand is yet unknown (Dolanc et al., 2022).