Targeting Noradrenergic Regulation of the Astrocyte–Neuron Lactate Shuttle in Recognition Memory

<title>Abstract</title> <p>Introduction: Noradrenergic signaling is a well-established modulator of memory formation. In astrocytes, noradrenaline (NA) activates β₂-adrenergic receptors (β₂-AR), promoting glycogenolysis and lactate production. This process supports activation of the astrocyte–neuron lactate shuttle (ANLS), through which astrocyte-derived lactate sustains synaptic plasticity and memory consolidation. Here, we investigated the role of β₂-AR-dependent lactate signaling in object recognition memory (ORM) using the Novel Object Recognition (NOR) task and examined whether β₂-AR mediate NA-induced lactate production in cultured astrocytes. Methods Female Swiss mice were trained in the NOR task and treated with atomoxetine (ATO), a NA reuptake inhibitor, alone or combined with the monocarboxylate transporter (MCT) inhibitor α-cyano-4-hydroxycinnamic acid (4CIN), which blocks lactate transport between astrocytes and neurons. Additional groups received the selective β₂-AR antagonist ICI-118,551 (ICI) alone or combined with L-lactate. In parallel, primary rat astrocyte cultures expressing a FRET-based lactate sensor were used to assess intracellular lactate dynamics following NA application, MCT inhibition, or β₂-AR blockade with butaxamine (BUT). Results ATO enhanced ORM, whereas co-administration of 4CIN prevented this effect and impaired memory performance. β₂-AR blockade with ICI disrupted ORM, an effect rescued by L-lactate administration. In cultured astrocytes, NA increased intracellular lactate levels, while 4CIN blocked lactate efflux. Importantly, BUT abolished the NA-induced lactate increase, demonstrating that β₂-AR activation mediates astrocytic lactate production. Conclusions These findings identify ANLS activation as a critical mechanism underlying NA-dependent ORM and establish astrocytic β₂-AR signaling as a key link between noradrenergic modulation and memory-related plasticity.</p>