Astrocyte, the predominant type of glia in the brain, is involved in complex brain functions including learning, memory, and synaptic plasticity (Santello et al., 2019; Doron et al., 2022). They can modulate neuronal activity by releasing and regulating different neuroactive molecules (Ota et al., 2013; Doron et al., 2022). Astrocytes express numerous transporters and receptors including G protein-coupled receptors (GPCRs) to modulate their own as well as neuronal activity. Designer receptors exclusively activated by designer drugs (DREADDs) are genetically modified GPCRs which allow researchers to control cellular activity via modulation of GPCR signaling with the application of selective ligands (Urban and Roth, 2015; Yu et al., 2020). These chemogenetic tools have been used to modulate the function of neurons and astrocytes in different brain regions (Armbruster et al., 2007; Alexander et al., 2009; Zhu et al., 2014; Koike et al., 2016; Adamsky et al., 2018; Jones et al., 2018; Durkee et al., 2019; Pati et al., 2019; Kol et al., 2020; Oguchi et al., 2021; Lei et al., 2022; Liu et al., 2022). Using chemogenetic approach, astrocytic G_i pathway activation in the hippocampus has recently been shown to modulate cognitive functions (Jones et al., 2018; Kol et al., 2020; Liu et al., 2022), although the mechanism is still not fully understood. Moreover, how astrocytic G_i signaling in the anterior cingulate cortex (ACC) affects cognitive functions – particularly schema memory – is yet unknown.

L-lactate is a metabolic end product of glycolysis and works as an energy substrate for various tissues, including the brain. According to the astrocyte-neuron L-lactate shuttle hypothesis (Pellerin and Magistretti, 1994; Magistretti and Allaman, 2018), L-lactate is produced by astrocytes through glycogenolysis and glycolysis and then transported into the neurons through monocarboxylate transporter 2 (MCT2) to fuel the high metabolic demand in neurons to maintain various physiological activities including neural plasticity and memory formation (Magistretti and Allaman, 2018). However, a recent study has argued that the energy demand during neuronal activation is fueled by glucose rather than astrocyte-derived L-lactate (Díaz-García et al., 2017). Nevertheless, multiple studies clearly demonstrated that L-lactate confers beneficial effect in learning and memory (Newman et al., 2011; Suzuki et al., 2011; Wang et al., 2017; Harris et al., 2019; Netzahualcoyotzi and Pellerin, 2020; Vezzoli et al., 2020; Iqbal et al., 2022). Administration of L-lactate into the hippocampus enhanced memory in rats whereas inhibition of astrocytic glycogenolysis or inhibition of astrocytic or neuronal MCTs in the hippocampus impaired memory formation (Newman et al., 2011; Suzuki et al., 2011; Netzahualcoyotzi and Pellerin, 2020). However, how L-lactate in the ACC affects schema memory is yet unknown.

Using a behavioral paradigm, Tse et al. showed that learning of multiple flavor-place paired associates (PAs) leads to the development of cortical associative schema in rats that allows rapid assimilation of new PAs (NPAs) into the existing schema (Tse et al., 2007; Tse et al., 2011). Previously, our team showed that bilateral infusion of lidocaine (a neuronal blocker) into the hippocampus or the ACC prevents PA learning, schema formation, and memory retrieval (Hasan et al., 2019). The study also showed increased oligodendrogenesis and adaptive myelination in the ACC of rats after repeated PA training. Furthermore, it demonstrated that myelination in the ACC is necessary for PA learning and memory retrieval, suggesting an important role of oligodendrocytes in schema memory. However, the role of astrocytes in the ACC in PA learning, schema formation, and memory retrieval is still unknown. Using hM4Di (a G_i-coupled GPCR) DREADD, here we show that astrocytic G_i pathway activation in the ACC causes significant impairments in PA learning, schema formation, and memory retrieval in rats. We also show that the impairments are mediated by a decrease in L-lactate level in the ACC upon astrocytic G_i activation. Concurrent exogenous L-lactate administration into the ACC rescues these impairments. Furthermore, we discover that astrocytic G_i activation diminishes neuronal mitochondrial biogenesis, which could be rescued by exogenous L-lactate, and that L-lactate-induced neuronal mitochondrial biogenesis requires MCT2 and NMDAR activity – revealing a previously unrecognized L-lactate signaling mechanism in controlling neuronal mitochondrial biogenesis.

There has been a paradigm shift in neuroscience in which animal behavior is now considered as a result arising from the coordinated activity of neurons and glia, especially astrocytes, rather than a result exclusively from neuronal activity (Kofuji and Araque, 2021a). A recent study has revealed that several GPCR genes are expressed in astrocytes across the CNS, whereas some GPCR genes are expressed in a region-specific manner (Endo et al., 2022). GPCRs confer astrocytes with the ability to sense synaptic activity and respond with gliotransmitters to regulate neuronal and synaptic functions (Kofuji and Araque, 2021b). Moreover, astrocytic responses to GPCR activation may show heterogeneity among brain regions or even within a brain region (Kofuji and Araque, 2021b), highlighting the complex roles of GPCRs in astrocytic functioning. L-lactate, derived primarily from astrocytes by glycogenolysis and glycolysis, has increasingly been recognized as a novel gliotransmitter that facilitates cognitive functions (Newman et al., 2011; Suzuki et al., 2011; Wang et al., 2017; Magistretti and Allaman, 2018; Harris et al., 2019; Vezzoli et al., 2020). cAMP in astrocytes acts as a trigger for L-lactate production (Choi et al., 2012; Horvat et al., 2021a; Horvat et al., 2021b; Zhou et al., 2021) by promoting glycogenolysis and glycolysis (Vardjan et al., 2018; Horvat et al., 2021a; Horvat et al., 2021b). Our current study shows that astrocytic G_i activation in the ACC decreases intracellular cAMP and ECF L-lactate levels in the ACC. Therefore, one promising explanation for the reduced L-lactate level observed in our study upon astrocytic G_i activation is decreased glycogenolysis and glycolysis as a result of decreased astrocytic cAMP (Figure 6).

Figure 6

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Schema is defined as a framework of knowledge. New learning occurs rapidly if it occurs against a background of established relevant schema. Rats trained with multiple flavor-place PAs develop schema that enables rapid assimilation of NPA learning (Tse et al., 2007; Tse et al., 2011; Hasan et al., 2019; Liu et al., 2022). Previous studies suggested that PA learning is hippocampus-dependent and the associative schema is stored in the ACC (Tse et al., 2007; Tse et al., 2011). In this study, we have demonstrated that ACC astrocytic G_i activation impairs PA learning and schema formation, PA memory retrieval, and NPA learning and retrieval by decreasing L-lactate level in the ACC. Although we have shown that these impairments are associated with diminished expression of proteins of mitochondrial biogenesis, the precise mechanisms of how astrocytic G_i activation affects neuronal functions and schema memory remain to be elucidated. We previously demonstrated that neuronal inhibition in either the hippocampus or the ACC impairs PA learning and schema formation (Hasan et al., 2019). In another recent study (Liu et al., 2022), we showed that astrocytic G_i activation in the CA1 impaired PA training-associated CA1-ACC projecting neuronal activation. Yao et al., 2023 recently showed that reduction of astrocytic lactate dehydrogenase A (an enzyme that reversibly catalyze L-lactate production from pyruvate) in the dorsomedial prefrontal cortex reduces L-lactate levels and neuronal firing frequencies, promoting depressive-like behaviors in mice. These impairments could be rescued by L-lactate infusion. It is possible that the impairment in PA learning and schema observed in our study might have involved a similar functional consequence of reduced neuronal activity in the ACC neurons upon astrocytic G_i activation.

Schema consolidation is associated with synaptic plasticity-related gene expression (such as Zif268, Arc) in the ACC (Tse et al., 2011). L-lactate, after entry into neurons, can be converted to pyruvate during which NADH is also produced, promoting synaptic plasticity-related gene expression by potentiating NMDA signaling in neurons (Yang et al., 2014; Margineanu et al., 2018). Furthermore, L-lactate acts as an energy substrate to fuel learning-induced de novo neuronal translation critical for long-term memory (Descalzi et al., 2019). On the other hand, mitochondria play crucial role in fueling local translation during synaptic plasticity (Rangaraju et al., 2019). Therefore, it could be hypothesized that the rescue of astrocytic G_i activation-mediated impairment of schema by exogenous L-lactate could have been mediated by facilitating synaptic plasticity-related gene expression by directly fueling the protein translation, potentiating NMDA signaling, as well as increasing mitochondrial capacity for ATP production by promoting mitochondrial biogenesis. Furthermore, the potential involvement of HCAR1, a receptor for L-lactate that may regulate neuronal activity (Bozzo et al., 2013; Tang et al., 2014; Herrera-López and Galván, 2018; Abrantes et al., 2019), cannot be excluded. Future research could explore these potential mechanisms, examining the interactions among them, and determining their relative contributions to schema.

Our previous study also showed that ACC myelination is necessary for PA learning and schema formation, and that repeated PA training is associated with oligodendrogenesis in the ACC (Hasan et al., 2019). Oligodendrocytes facilitate fast, synchronized, and energy efficient transfer of information by wrapping axons in myelin sheath. Furthermore, they supply axons with glycolysis products, such as L-lactate, to offer metabolic support (Fünfschilling et al., 2012; Lee et al., 2012). The association of oligodendrogenesis and myelination with schema memory may suggest an adaptive response of oligodendrocytes to enhance metabolic support and neuronal energy efficiency during PA learning. Given the impairments in PA learning observed in the ACC astrocytic G_i-activated rats in the current study, it is reasonable to conclude that the direct metabolic support to axons provided by oligodendrocytes is not sufficient to rescue the schema impairments caused by decreased L-lactate levels upon astrocytic G_i activation. On the other hand, L-lactate was shown to be important for oligodendrogenesis and myelination (Sánchez-Abarca et al., 2001; Rinholm et al., 2011; Ichihara et al., 2017). Therefore, it is tempting to speculate that a decrease in L-lactate level may also impede oligodendrogenesis and myelination, consequently preventing the enhanced axonal support provided by oligodendrocytes and myelin during schema learning. Recently, a study has demonstrated that upon demyelination, mitochondria move from the neuronal cell body to the demyelinated axon (Licht-Mayer et al., 2020). Enhancement of this axonal response of mitochondria to demyelination, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. Given the connection between schema and increased myelination, it remains an open question whether L-lactate-induced mitochondrial biogenesis plays a beneficial role in schema through a similar mechanism. Nevertheless, our results contribute to the mounting evidence of the glial role in cognitive functions and underscores the new paradigm in which glial cells are considered as integral players in cognitive functions alongside neurons. Disruption of neurons, myelin, or astrocytes in the ACC can disrupt PA learning and schema memory. These discoveries have clinical implications, as they suggest that pathological processes involving any of these cell types can eventually result in a loss of harmony among these cells and manifest as cognitive impairments. Indeed, accumulating evidence suggests the crucial contributions of non-neuronal cells in the pathology of diverse neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (Brandebura et al., 2023).

In this study, we have demonstrated that ACC astrocytic G_i activation impairs NPA learning even if a prior associative schema exists. This impairment is the result of impaired activation and retrieval of prior associative schema from the ACC neuronal network mediated by decreased L-lactate in ACC as exogenous L-lactate administration abolished the impairment. After an associative schema is formed in the ACC due to repeated PA training with multiple PAs, the effect of astrocytic G_i activation in the ACC is different from the effect of astrocytic G_i activation in the hippocampus. Whereas G_i activation in the ACC leads to impairment in both PA memory retrieval and NPA learning as shown in the current study, G_i activation in the hippocampus primarily affects the NPA learning but not the memory retrieval of the previously learned PAs (Liu et al., 2022). This indicates that once associative schema is formed in the ACC, it becomes independent of the hippocampus, and disruption of either hippocampal neuronal (Hasan et al., 2019) or astrocytic (Liu et al., 2022) functions does not impact retrieval of the previously learned PAs. However, NPA learning in the setting of the existence of a prior associative schema can be impaired by disruption of either hippocampal functions (neuronal inhibition [Hasan et al., 2019] or astrocytic G_i activation [Liu et al., 2022]) or ACC functions (neuronal inhibition [Hasan et al., 2019] or astrocytic G_i activation [current study]), indicating that NPA learning requires simultaneous activation of both the hippocampus and ACC with optimal functioning of both neurons and astrocytes.

After entry into a neuron, L-lactate can be converted to pyruvate, during which NADH is also produced. Pyruvate can enter the mitochondria and be processed through Kreb’s cycle and oxidative phosphorylation to generate ATP. Demand of ATP is high in active neurons to maintain various physiological activities, including neural plasticity and memory formation (Magistretti and Allaman, 2018). Although L-lactate’s beneficial effect on cognitive functions has been clearly demonstrated in the current study and several other previous studies (Newman et al., 2011; Suzuki et al., 2011; Wang et al., 2017; Harris et al., 2019; Vezzoli et al., 2020), whether the beneficial effect is conferred by its usefulness as an energy substrate has been debated (Díaz-García et al., 2017). Intriguingly, a recent study has demonstrated that glucose and L-lactate metabolism are differentially engaged in neuronal fueling depending on neural computational and cognitive loads (Dembitskaya et al., 2022). The study showed that L-lactate is necessary for a cognitive task requiring high attentional load but is not needed for a less demanding task. This suggests that cognitive functions may exhibit varying degrees of sensitivity to L-lactate. In addition to its function as an energy source, the signaling role of L-lactate is increasingly being acknowledged. NADH produced during the conversion of L-lactate into pyruvate can induce plasticity-related gene expression by activating NMDA and/or MAPK signaling pathways (Yang et al., 2014; Magistretti and Allaman, 2018; Margineanu et al., 2018). The results of the current study suggest the existence of another MCT2 and NMDAR-dependent signaling role of L-lactate. We used MCT2 ODN to decrease the expression of MCT2 in the ACC and showed that MCT2 is necessary for L-lactate-induced mitochondrial biogenesis, indicating that L-lactate’s entry into the neuron is required. We further investigated whether NMDAR activity is required for L-lactate-induced mitochondrial biogenesis. We used D-APV to inhibit NMDAR and found that L-lactate does not increase mtDNA copy number abundance if D-APV is given, suggesting that NMDAR activity is required for L-lactate to promote mitochondrial biogenesis. While these results suggest the involvement of MCT2 and NMDAR in the upregulation of mitochondrial biogenesis by L-lactate (Figure 6), we have not investigated other mechanisms and pathways modulating mitochondrial biogenesis that are either dependent or independent of MCT2 and NMDAR activity. Further studies are needed to better understand the detailed mechanisms. Moreover, it remains to be explored whether L-pyruvate, a metabolite that shares certain functional similarities with L-lactate, such as oxidative stress resistance (Tauffenberger et al., 2019) and neuroprotection against excitotoxicity (Jourdain et al., 2018), but exhibits differences in other aspects like plasticity gene expression (Yang et al., 2014), can effectively rescue the astrocytic G_i activation-mediated schema or mitochondrial biogenesis impairments.

Our study demonstrates that ACC astrocytic G_i activation resulted in a downregulation of neuronal PGC-1α and SIRT3. These proteins are key regulators of mitochondrial biogenesis and homeostasis. SIRT3, a member of sirtuin family, is a protein deacetylase that is exclusively found in mitochondria and is known to promote mitochondrial biogenesis and reduce ROS production (Fu et al., 2012; Ansari et al., 2017; Sun et al., 2021). Several recent studies have demonstrated that SIRT3 plays important role in learning and memory (Kim et al., 2019; Liu et al., 2019; Liu et al., 2021). Sirt3^−/− mice demonstrated impaired remote memory function and decreased synaptic plasticity and neuronal number in the ACC (Kim et al., 2019). Another study in aged mice showed that SIRT3 overexpression can provide protection against anesthesia/surgery-induced synaptic plasticity dysfunction in the hippocampus and attenuate hippocampus-dependent cognitive decline (Liu et al., 2021). SIRT3 was shown to be required for the anxiolytic and cognition-enhancing effects of intermittent fasting (Liu et al., 2019). The study demonstrated that mice lacking SIRT3 in the hippocampal neurons have heightened anxiety, poor memory retention, and impaired long-term potentiation at hippocampal synapses. Recently, it has been demonstrated that PGC-1α overexpression in neurons can improve hippocampal neuronal function, increase ATP production, reduce oxidative stress, and attenuate cognitive impairment after chronic cerebral hypoperfusion in mice (Han et al., 2020). Another study has suggested that upregulation of PGC-1α and mitochondrial biogenesis in the hippocampus enhances spatial learning and short-term memory (Jacobs et al., 2021). Mitochondrial dysfunction was shown to impair hippocampus-dependent learning and memory in mice (Khacho et al., 2017). On the other hand, another study showed that ameliorating mitochondrial dysfunction rescues carbon ion-induced hippocampal cognitive deficits (Liu et al., 2018). Mitochondrial dysfunction is a hallmark of numerous diseases that causes cognitive decline (Golpich et al., 2017). Collectively, these reports provided striking evidence of the role of mitochondrial homeostasis in cognitive functions. Therefore, the associations observed from the current study set up an interesting premise for further studies to investigate whether disruption of the L-lactate-regulated neuronal mitochondrial biogenesis plays a causal role in the cognitive impairment due to astrocytic G_i activation. Based on the known functions, one might hypothesize that L-lactate-induced upregulation of PGC-1α/SIRT3/mitochondrial biogenesis could enable the neurons to generate more ATP while reducing oxidative stress during bioenergetic challenges as in cognitively demanding tasks of PA learning. In line with this, a recent study has demonstrated that L-lactate causes a mild ROS burst that induces antioxidant defenses and pro-survival pathways (Tauffenberger et al., 2019).

In summary, the present study illustrates that ACC astrocytic G_i pathway activation impairs schema memory in rats by decreasing L-lactate levels in the ACC, which is associated with impaired mitochondrial biogenesis in neurons. These impairments can be rescued by exogenous L-lactate administration. Furthermore, we demonstrated that L-lactate-mediated neuronal mitochondrial biogenesis is dependent on MCT2 and NMDAR activity – uncovering a novel signaling mechanism of L-lactate in the brain. These results might have implications in understanding how perturbation in astrocytic functions could impair cognitive functions as well as providing the potential therapeutic targets for ameliorating such impairments.

All data generated or analysed during this study are included in the manuscript, source data files, and supplementary files.

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Author details

1. Mastura Akter

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China

   Present address

   Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0007-6075

2. Mahadi Hasan

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

3. Aruna Surendran Ramkrishnan

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Zafar Iqbal

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
   3. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2604-7184

5. Xianlin Zheng

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China

   Present address

   Krieger School of Arts & Sciences, Johns Hopkins University, Baltimore, Maryland, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Zhongqi Fu

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. Zhuogui Lei

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

8. Anwarul Karim

   Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China

   Present address

   Department of Neurology, Baylor College of Medicine, Houston, Texas, United States

   Contribution

   Formal analysis, Visualization, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5795-6674

9. Ying Li

   1. Department of Neuroscience, City University of Hong Kong, Hong Kong SAR, China
   2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
   3. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China
   4. Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong SAR, China

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Project administration, Writing - review and editing

   For correspondence

   yingli@cityu.edu.hk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3683-9695

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