Astrocyte-derived L-lactate as well as exogenous L-lactate were shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic Gi signaling in the anterior cingulate cortex (ACC) modulates L-lactate levels and cognitive functions – particularly schema memory - is not clear. Moreover, the molecular changes at proteomics level induced by L-lactate are largely unknown.

To investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF (ACSF) bilaterally into the dorsal hippocampus (HPC) and collected the HPC after 60 mins for mass spectrometry, western blot (WB), and immunohistochemistry (IHC). We identified increased expression of key regulators of mitochondrial biogenesis and antioxidant defense including SIRT3, PGC-1α, KIF5B, OXR1, and PYGM. Further experiments identified increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats.

Using chemogenetic approach and well-established behavioral paradigm, we demonstrate that astrocytic Gi pathway activation in ACC causes significant impairment in flavor-place paired associates (PA) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments were mediated by decreased L-lactate in ACC due to astrocytic Gi activation. Concurrent exogenous L-lactate administration bilaterally into the ACC rescues these impairments. Furthermore, we show that the impaired schema memory formation was associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in ACC upon Gi activation. Our study also reveals that L-lactate mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 and NMDA receptor activity – discovering a previously unrecognized signaling role of L-lactate.

Together, these findings expand our understanding of the role of astrocytes and L-lactate in brain functions.