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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 the ACC causes significant impairments in flavor-place paired associates (PAs) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments are mediated by decreased L-lactate in the 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 is associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in the ACC upon astrocytic Gi activation. Our study also reveals that L-lactate-mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 (MCT2) 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 the brain functions.

Chemogenetic and optogenetic profiling in a rat model of acute pain-related unpleasantness suggests that colorectal distention-induced place aversion is mediated by locus coeruleus noradrenergic signalling to astrocytes in anterior cingulate cortex.

L-lactate plays a critical role in learning and memory. Studies in rats showed that administration of exogenous L-lactate into the anterior cingulate cortex and hippocampus (HPC) improved decision-making and enhanced long-term memory formation, respectively. Although the molecular mechanisms by which L-lactate confers its beneficial effect are an active area of investigations, one recent study found that L-lactate supplementation results in a mild reactive oxygen species burst and induction of pro-survival pathways. To further investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF bilaterally into the dorsal HPC and collected the HPC after 60 minutes for mass spectrometry. We identified increased levels of several proteins that include SIRT3, KIF5B, OXR1, PYGM, and ATG7 in the HPC of the L-lactate treated rats. SIRT3 (Sirtuin 3) is a key regulator of mitochondrial functions and homeostasis and protects cells against oxidative stress. Further experiments identified increased expression of the key regulator of mitochondrial biogenesis (PGC-1α) and mitochondrial proteins (ATPB, Cyt-c) as well as increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats. OXR1 (Oxidation resistance protein 1) is known to maintain mitochondrial stability. It mitigates the deleterious effects of oxidative damage in neurons by inducing a resistance response against oxidative stress. Together, our study suggests that L-lactate can induce expression of key regulators of mitochondrial biogenesis and antioxidant defense. These findings create new research avenues to explore their contribution to the L-lactate’s beneficial effect in cognitive functions as these cellular responses might enable neurons to generate more ATP to meet energy demand of neuronal activity and synaptic plasticity as well as attenuate the associated oxidative stress.

Summary: Using a well-established chronic visceral hypersensitivity (VH) rat model, we characterized the decrease of myelin basic protein, reduced number of mature oligodendrocytes (OLs), and hypomyelination in the anterior cingulate cortex (ACC). The results of rat gambling test showed impaired decision-making, and the results of electrophysiological studies showed desynchronization in the ACC to basolateral amygdala (BLA) neural circuitry. Astrocytes release various factors that modulate oligodendrocyte progenitor cell proliferation and myelination. Astrocytic Gq-modulation through expression of hM3Dq facilitated oligodendrocyte progenitor cell proliferation and OL differentiation, and enhanced ACC myelination in VH rats. Activating astrocytic Gq rescued impaired decision-making and desynchronization in ACC-BLA. These data indicate that ACC hypomyelination is an important component of impaired decision-making and network desynchronization in VH. Astrocytic Gq activity plays a significant role in oligodendrocyte myelination and decision-making behavior in VH. Insights from these studies have potential for interventions in myelin-related diseases such as chronic pain-associated cognitive disorders.

BackgroundThe COVID-19 pandemic has significantly impacted the surgical practice throughout the world, including elective surgical care. This study investigated the characteristics of patients undergoing elective surgery, the prevalence of COVID-19 infection, the surgical procedures performed, and 30-day mortality in general and pediatric surgical settings in selected tertiary-level hospitals in Bangladesh from November 2020 to August 2021.MethodsThis serial cross-sectional study included 264 patients scheduled for elective surgeries during the study period. All patients underwent COVID-19 real-time polymerase chain reaction (RT-PCR) testing within 24 hours before surgery. Data on age, sex, common comorbidities, surgical procedures, and 30-day mortality were collected and analyzed. Furthermore, comparisons were made between COVID-19 positive and negative patients.ResultsThe prevalence of COVID-19 infection among patients was 10.6%. Older age, a history of major surgery within the last three months, hypertension, and diabetes mellitus were significantly associated with COVID-19 infection. All COVID-19-negative patients underwent surgery, while only 46.4% of COVID-19-positive patients underwent surgery. The most common surgical procedures were related to the digestive system, breast, and urinary system. Only one patient (0.4%) died within 30 days after surgery among the COVID-19-negative patients, whereas two patients (7.1%) died among the COVID-19-positive patients: one before surgery and one after surgery.ConclusionsThis study provides valuable insights into the characteristics, burden of COVID-19 infection, and 30-day mortality of patients undergoing elective surgery in tertiary care centers in Bangladesh during the pandemic.

Pain involves both sensory and affective elements. An aspect of the affective dimension of pain is its sustained unpleasantness, characterized by emotional feelings. Pain results from interactions between memory, attentional, and affective brain circuitry, and it has attracted enormous interest in pain research. However, the brain targets and signaling mechanism involved in pain remain elusive. Using a conditioned place avoidance (CPA) paradigm, we show that colorectal distention (CRD magnitude ≤ 35 mmHg, a subthreshold for pain) paired with a distinct environment can cause significant aversion to a location associated with pain-related insults in rats. We show a substantial increase in the L-lactate concentration in the anterior cingulate cortex (ACC) following CPA training. Local exogenous infusion of lactate into the ACC enhances aversive memory and induces the expression of the memory-related plasticity genes pCREB, CREB, and Erk1/2. The pharmacological experiments revealed that the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) impairs memory consolidation. Furthermore, short-term Gi pathway activation of ACC astrocytes before CPA training significantly decreases the lactate level and suppresses pain-related aversive learning. The effects were reversed by the local infusion of lactate into the ACC. Our study demonstrates that lactate is released from astrocytes in vivo following visceral pain-related aversive learning and memory retrieval and induces the expression of the plasticity-related immediate early genes CREB, pCREB, and Erk1/2 in the ACC. Chronic visceral pain is an important factor in the pathophysiology of irritable bowel syndrome (IBS). The current study provides evidence that astrocytic activity in the ACC is required for visceral pain-related aversive learning and memory.