Astrocytic L-lactate signaling in the anterior cingulate cortex is essential for schema memory and neuronal mitochondrial biogenesis
eLife(2023)
Abstract
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
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