Memory deficits are a common comorbid disorder in patients suffering from neuropathic pain. The mechanisms underlying the comorbidities remain elusive. The hypothesis of this study was that impaired lactate release from dysfunctional astrocytes in dorsal hippocampal CA1 contributed to memory deficits.


A spared nerve injury model was established to induce both pain and memory deficits in rats and mice of both sexes. von Frey tests, novel object recognition, and conditioned place preference tests were applied to evaluate the behaviors. Whole-cell recording, fiber photometry, Western blotting, and immunohistochemistry combined with intracranial injections were used to explore the underlying mechanisms.


Animals with spared sciatic nerve injury that had displayed nociception sensitization or memory deficit comorbidities demonstrated a reduction in the intrinsic excitability of pyramidal neurons, accompanied by reduced Ca2+ activation in astrocytes (ΔF/F, sham: 6 ± 2%; comorbidity: 2 ± 0.4%) and a decrease in the expression of glial fibrillary acidic protein and lactate levels in the dorsal CA1. Exogenous lactate supply or increasing endogenous lactate release by chemogenetic activation of astrocytes alleviated this comorbidity by enhancing the cell excitability (129 ± 4 vs. 88 ± 10 for 3.5 mM lactate) and potentiating N-methyl-d-aspartate receptor–mediated excitatory postsynaptic potentials of pyramidal neurons. In contrast, inhibition of lactate synthesis, blocking lactate transporters, or chemogenetic inhibition of astrocytes resulted in comorbidity-like behaviors in naive animals. Notably, β2-adrenergic receptors in astrocytes but not neurons were downregulated in dorsal CA1 after spared nerve injury. Microinjection of a β2 receptor agonist into dorsal CA1 or activation of the noradrenergic projections onto the hippocampus from the locus coeruleus alleviated the comorbidity, possibly by increasing lactate release.


Impaired lactate release from dysfunctional astrocytes, which could be rescued by activation of the locus coeruleus, led to nociception and memory deficits after peripheral nerve injury.

Editor’s Perspective
What We Already Know about This Topic
  • Memory deficits are often encountered in patients with chronic pain, and experimental models of chronic pain suggest hippocampal dysfunction as one underlying mechanism
  • Lactate released from astrocytes is an important fuel to support higher metabolic brain activities, such as memory formation
  • The contribution of impaired lactate release from hippocampal astrocytes in nociceptive sensitization and the related memory deficits after peripheral nerve injury are incompletely understood
What This Article Tells Us That Is New
  • Nociception and impaired cognitive function in rodents after spared sciatic nerve injury were associated with reduced intrinsic excitability of pyramidal neurons and reduced lactate levels in the dorsal CA1 hippocampus
  • Both exogenous lactate supply and increasing endogenous lactate release by chemogenetic activation of hippocampal astrocytes improved these deficits
  • These observations suggest that impaired lactate release from astrocytes contributes to nociceptive sensitization and memory dysfunction after peripheral nerve injury