Astrocytic L-lactate signaling in the anterior cingulate cortex is essential for schema memory and neuronal mitochondrial biogenesis

Astrocyte-derived L-lactate was 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 schema memory is not clear. Here, 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. These findings expand our understanding of the role of astrocytes and L-lactate in brain functions. ### Competing Interest Statement The authors have declared no competing interest. * AAV8 : Adeno-associated viral vectors serotype 8 ACC : Anterior cingulate cortex ACSF : Artificial cerebrospinal fluid ANLS : Astrocyte-neuron L-lactate shuttle ATP : Adenosine triphosphate cAMP : Cyclic adenosine monophosphate CNO : Clozapine N-oxide DREADD : Designer receptors exclusively activated by designer drug ECF : Extracellular fluid GFAP : Glial fibrillary acidic protein GPCR : G-protein-coupled receptor MCT : Monocarboxylate transporter mtDNA : Mitochondrial DNA nDNA : Nuclear DNA NeuN : Neuronal nuclei NPA : New paired associate OPA : Original paired associate PA : Paired associate PBS : Phosphate buffered saline PFA : Paraformaldehyde PGC-1α : Peroxisome proliferator-activated receptorgamma coactivator 1-alpha PI : Performance index PT : Probe test ROS : Reactive oxygen species SIRT3 : Sirtuin 3