Astrocytic GPCR signaling in the anterior cingulate cortex modulates decision making in rats.

Decision making is a process of selecting a course of action by assessing the worth or value of the potential consequences. Rat Gambling Task (RGT) is a well-established behavioral paradigm that allows for assessment of the decision-making performance of rats. Astrocytes are emerging as key players in modulating cognitive functions. Using repeated RGTs with short intersession time intervals (48 h), the current study demonstrates that Gi pathway activation of astrocytes in the anterior cingulate cortex (ACC) leads to impaired decision-making in consistently good decision-making rats. On the other hand, ACC astrocytic Gq pathway activation improves decision-making in a subset of rats who are not consistently good decision-makers. Furthermore, we show that astrocytic Gq activation is associated with an increase in the L-lactate level in the extracellular fluid of the ACC. Together, these results expand our knowledge of the role of astrocytic GPCR signaling in modulating cognitive functions.

Astrocyte and L-lactate in the anterior cingulate cortex modulate 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 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.

Patients' characteristics and 30-day mortality for those undergoing elective surgeries during the COVID-19 pandemic in Bangladesh.

BACKGROUND: The 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. METHODS: This 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. RESULTS: The 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. CONCLUSIONS: This 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.

Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense.

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.

Erratum: Chemogenetic activation of astrocytes promotes remyelination and restores cognitive deficits in visceral hypersensitive rats.

[This corrects the article DOI: 10.1016/j.isci.2022.105840.].

Chemogenetic activation of astrocytes promotes remyelination and restores cognitive deficits in visceral hypersensitive rats.

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.

Adrenergic signalling to astrocytes in anterior cingulate cortex contributes to pain-related aversive memory in rats.

Pain contains both sensory and affective dimensions. We identify the role of norepinephrine in colorectal distention (sub-threshold for acute pain) induced conditioned place avoidance and plasticity gene expression in the anterior cingulate cortex (ACC). Activating locus coeruleus (LC)-projecting ACC neurons facilitates pain-evoked aversive consolidation and memory, while inhibiting LC-projecting ACC neurons reversibly blocks it. Optogenetic activation of ACC astrocytes facilitates aversive behaviour. ACC astrocytic Gi manipulation suppressed aversive behaviour and early plasticity gene expression induced by opto-activation of LC neurons projecting to ACC. Evidences for the critical role of ß2AR in ACC astrocytes were provided using AAV encoding ß2AR miRNAi to knockdown ß2AR in astrocytes. In contrast, opto-activation of ACC astrocytic ß2ARs promotes aversion memory. Our findings suggest that projection-specific adrenergic astrocytic signalling in ACC is integral to system-wide neuromodulation in response to visceral stimuli, and plays a key role in mediating pain-related aversion consolidation and memory formation.

Astrocyte L-Lactate Signaling in the ACC Regulates Visceral Pain Aversive Memory in Rats.

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.

Multicenter Study of 342 Anorectal Malformation Patients: Age, Gender, Krickenbeck Subtypes, and Associated Anomalies.

INTRODUCTION: Published studies based on Krickenbeck classification of anorectal malformations (ARMs) are still insufficient to assess the global as well as regional relative incidence of different ARM subtypes, gender distribution, and associated anomalies. The primary purpose of this study was to provide an estimate of those in Global Initiative for Children's Surgery (GICS) research group. MATERIALS AND METHODS: We collected ARM data prospectively for 1 year from four institutes of different geographic locations. A total of 342 patients were included in this study (195, 126, 11, and 10 from Bangladesh, Iran, Papua New Guinea, and Oxford, United Kingdom, respectively). RESULTS: Overall male to female ratio was 1:1. The most frequent ARM subtype was perineal fistula (23.7% = 81/342). About 48.5% (166/342) patients had at least one associated anomaly. Cardiac and genitourinary systems were the most commonly affected systems, 31.6% (108/342) and 18.4% (63/342), respectively. These organ-systems were followed by anomalies of vertebral/spinal (9.9% = 34/342), musculoskeletal (4.4% = 15/342), and gastrointestinal/abdominal (3.2% = 11/342) systems. Rectovesical fistula had the highest percentage (96.4% = 27/28) of associated anomalies. About 18.1% (62/342) patients had multiple anomalies. ARMs (both isolated and with associated anomalies) occurred equally in males and females. Comparison between patients from Bangladesh and Iran showed differences in relative incidence in ARM subtypes. In addition, Iranian patient group had higher percentage of associated anomalies compared with Bangladeshi (73 vs. 35.4%). CONCLUSION: Our study provides important insights about ARM subtypes, gender distribution and associated anomalies based on Krickenbeck classification especially from Bangladesh and Iran.

Cost Incurred by the Family for Surgery in Their Children: A Bangladesh Perspective.

BACKGROUND: Cost of getting health services is a major concern in Bangladesh as well as in many other countries. A family has to bear more than half of the health care cost despite many facilities provided by the public hospitals. This out-of-pocket (OOP) expenditure drives many families under the poverty line. The aim of this study was to find out the exact cost incurred by the family for a surgical operation of their child in the public and private sectors in Bangladesh. METHODS: A cross-sectional study was conducted to find out the cost of child surgery in different settings of public and private hospitals in Chittagong division, Bangladesh. Cost of herniotomy was then compared across different settings. RESULTS: In this study, cost of operation in urban private hospitals was highest mostly due to surgeon and anesthetist fee. The cost was lowest in outreach programs as surgeon fee, anesthetist fee and accommodation cost was nil; food and transport cost was minimum. However, cost of accommodation, food, transport and medicine contributed significantly to OOP expenditure especially in tertiary-level public hospitals, in both indoor and day care settings, and also in private urban hospitals. CONCLUSIONS: Our study provides some insight into the OOP expenditure in different health care settings in Bangladesh. This study might be useful in developing a strategy to minimize the OOP expenditure in this country.

Epidemiological characteristics of Hirschsprung's disease (HSCR): Results of a case series of fifty patients from Bangladesh.

BACKGROUND: The epidemiology of Hirschsprung's disease (HSCR) in Bangladesh has never been studied. The aim of this study was to determine the epidemiological characteristics of HSCR in Bangladesh. METHODS: Data from fifty patients were collected prospectively from two hospitals in Chittagong, Bangladesh. RESULTS: The rate of consanguinity (16%) among parents of HSCR patients was higher than that of the general population (10%). Maternal age at the time of birth of the affected child was ≤30years in all cases except one. No association was found between parents' occupation and HSCR. No patient was born preterm and only three patients (6%) had low birth weight. Nine patients (18%) had associated anomalies. We found coexistence of bilateral accessory tragi and ankyloglossia in one patient, and coexistence of rectal duplication cyst in another. Neither anomaly had been previously reported in HSCR patients. CONCLUSIONS: Our study suggests that consanguinity might increase the risk of HSCR whereas advanced maternal age does not. HSCR patients were found more likely to born at term and with normal birth weight. The coexistence of HSCR with previously unreported anomalies highlights the diversity of conditions that can co-occur with HSCR. LEVELS OF EVIDENCE: IV.