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ABSTRACTPrenatal ethanol exposure causes a variety of cognitive deficits that have a persistent impact on quality of life, some of which may be explained by ethanol-induced alterations in interneuron function. Studies from several laboratories, including our own, have demonstrated that a single binge-like ethanol exposure during the equivalent to the third trimester of human pregnancy leads to acute apoptosis and long-term loss of interneurons in the rodent retrosplenial cortex (RSC). The RSC is interconnected with the hippocampus, thalamus, and other neocortical regions and plays distinct roles in visuospatial processing and storage, as well as retrieval of hippocampal-dependent episodic memories. Here we used slice electrophysiology to characterize the acute effects of ethanol on GABAergic neurotransmission in the RSC of neonatal mice, as well as the long-term effects of neonatal ethanol exposure on parvalbumin-interneuron mediated neurotransmission in adolescent mice. Mice were exposed to ethanol using vapor inhalation chambers. In postnatal day (P) 7 mouse pups, ethanol unexpectedly failed to potentiate GABAAreceptor-mediated synaptic transmission. Binge-like ethanol exposure of P7 mice expressing channel rhodopsin in parvalbumin-positive interneurons enhanced the peak amplitudes, asynchronous activity and total charge, while decreasing the rise-times of optically-evoked GABAAreceptor-mediated inhibitory postsynaptic currents in adolescent animals. These effects could partially explain the learning and memory deficits that have been documented in adolescent and young adult mice exposed to ethanol during the third trimester-equivalent developmental period.

AbstractBackgroundBinge alcohol exposure during adolescence results in long‐lasting alterations in the brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long‐term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) that surround some interneurons, particularly PV+ interneurons, further regulate cellular plasticity. The effect of AIE exposure on the expression of these markers within the PFC is not well understood.MethodsThe present study tested the hypothesis that AIE exposure reduces the expression of PV+ and choline acetyltransferase (ChAT)+ interneurons in the adult PFC and striatum and increases the related expression of PNNs (marked by binding of Wisteria floribunda agglutinin lectin) in adulthood. Male rats were exposed to AIE (5 g/kg/day, 2‐days‐on/2‐days‐off, i.e., P25 to P54) or water (CON), and brain tissue was harvested in adulthood (>P80). Immunohistochemistry and co‐immunofluorescence were used to assess the expression of ChAT, PV, and PNNs within the adult PFC and striatum following AIE exposure.ResultsChAT and PV interneuron densities in the striatum and PFC were unchanged after AIE exposure. However, PNN density in the PFC of AIE‐exposed rats was greater than in CON rats. Moreover, significantly more PV neurons were surrounded by PNNs in AIE‐exposed subjects than controls in both PFC subregions assessed: orbitofrontal cortex (CON = 34%; AIE = 40%) and medial PFC (CON = 10%; AIE = 14%).ConclusionsThese findings indicate that, following AIE exposure, PV interneuron expression in the adult PFC and striatum is unaltered, while PNNs surrounding these neurons are increased. This increase in PNNs may restrict the plasticity of the ensheathed neurons, thereby contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

AbstractBillions of years ago, the Earth's waters were dominated by cyanobacteria. These microbes amassed to such formidable numbers, they ushered in a new era—starting with the Great Oxidation Event—fuelled by oxygenic photosynthesis. Throughout the following eon, cyanobacteria ceded portions of their global aerobic power to new photoautotrophs with the rise of eukaryotes (i.e. algae and higher plants), which co‐existed with cyanobacteria in aquatic ecosystems. Yet while cyanobacteria's ecological success story is one of the most notorious within our planet's biogeochemical history, scientists to this day still seek to unlock the secrets of their triumph. Now, the Anthropocene has ushered in a new era fuelled by excessive nutrient inputs and greenhouse gas emissions, which are again reshaping the Earth's biomes. In response, we are experiencing an increase in global cyanobacterial bloom distribution, duration, and frequency, leading to unbalanced, and in many instances degraded, ecosystems. A critical component of the cyanobacterial resurgence is the freshwater‐marine continuum: which serves to transport blooms, and the toxins they produce, on the premise that “water flows downhill”. Here, we identify drivers contributing to the cyanobacterial comeback and discuss future implications in the context of environmental and human health along the aquatic continuum. This Minireview addresses the overlooked problem of the freshwater to marine continuum and the effects of nutrients and toxic cyanobacterial blooms moving along these waters. Marine and freshwater research have historically been conducted in isolation and independently of one another. Yet, this approach fails to account for the interchangeable transit of nutrients and biology through and between these freshwater and marine systems, a phenomenon that is becoming a major problem around the globe. This Minireview highlights what we know and the challenges that lie ahead.

Alcoholism is associated with a higher incidence of smoking. In addition to the stimulatory effects of both ethanol and nicotine on the mesolimbic reward pathway, nicotine's ability to counteract some of the adverse effects of ethanol (e.g. ataxia) may be a powerful incentive for alcohol consumers to increase their tobacco (nicotine) intake. The cerebellum is believed to play an important role in ethanol-induced ataxia. In this study, we sought to test the hypothesis that nicotine would protect against toxic effects of ethanol in primary cultures of cerebellar granule cells. Moreover, it was postulated that the effects of nicotine would be mediated through nicotinic receptors. Primary cultures of cerebellar granule cells were prepared from 20-day embryos obtained from timed-pregnant Sprague Dawley rats. Cells were cultured for 10 days and were then exposed for 3 days to various concentrations of ethanol with and without pretreatment with nicotine and nicotinic antagonists. Cellular toxicity was evaluated by measuring the lactate dehydrogenase level. Administration of ethanol (10-100 mM) resulted in a dose-dependent toxicity. Pretreatment with nicotine 1-20 micro M resulted in a dose-dependent protection against ethanol-induced toxicity. The effects of nicotine were blocked by pretreatment with nicotinic antagonists such as mecamylamine 1-20 micro M, dihydro-beta-erythroidine 1.0 nM-1.0 micro M and methyllycaconitine 5 nM-5 micro M in a dose-dependent manner. Thus, ethanol-induced cytotoxicity in primary cultures of cerebellar granule cells is blocked by pretreatment with nicotine. The effects of nicotine, in turn, may be blocked by nicotinic antagonists, implicating both high and low affinity nicotinic receptors in mediating the actions of nicotine. The exact mechanism of ethanol-induced toxicity and/or neuroprotection through activation of nicotinic receptors in this paradigm remains to be elucidated. The neuroprotective effect of nicotine against ethanol-induced toxicity in cerebellar neurons may be a contributing factor to the high incidence of smoking among alcoholics.

Epidemiologic studies have shown that individuals who consume low to moderate alcohol have a lower risk of cardiovascular disease developing compared with abstainers. Although experimental studies confirmed this observation, the effect of alcohol on ischemic myocardium is still unclear. We developed a clinically relevant animal model of chronic myocardial ischemia to investigate the effects of moderate alcohol consumption on the myocardium.Fourteen Yorkshire swine underwent placement of an ameroid constrictor to induce chronic myocardial ischemia. Postoperatively, one group was supplemented with 90 mL 50% EtOH daily (n = 7) and one group was supplemented with 80 g sucrose daily to normalize caloric intake between groups (n = 7). After 7 weeks, all animals underwent sternotomy, and harvest of the chronically ischemic myocardium and nonischemic myocardium. Tissues were analyzed for protein expression and stained for apoptosis quantification.In the ischemic myocardium, alcohol down-regulated the following proapoptotic proteins: tumor necrosis factor-α, forkhead box protein 03, BCL2-associated death promoter, and cysteine aspartic acid-specific protease 9; up-regulated the following prosurvival proteins: 5'adenosine monophosphate-activated protein kinase, phosphorylated 5'adenosine monophosphate-activated protein kinase, and phosphorylated forkhead box protein 03; and down-regulated mammalian target of rapamycin (MTOR) signaling by down-regulating MTOR, phosphorylated MTOR, and up-regulating Deptor. In the nonischemic myocardium, alcohol up-regulated prosurvival proteins: protein kinase B, phosphorylated protein kinase B, phosphorylated B-cell CLL/lymphoma 2, 5'adenosine monophosphate-activated protein kinase, phosphorylated BCL2-associated death promoter, phosphorylated forkhead box protein 03, and down-regulated MTOR signaling by down-regulating phosphorylated MTOR and up-regulating Deptor. Alcohol also decreased cell death as measured by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling staining in the ischemic and nonischemic myocardium.Alcohol consumption down-regulates apoptosis and promotes cell survival in the ischemic and nonischemic myocardium. Alcohol also modulates MTOR signaling, which regulates senescence and apoptosis. Perhaps MTOR and apoptosis regulation is another mechanism by which moderate EtOH consumption is cardioprotective.

Abstract Background Environmental factors such as temperature, rainfall, and vegetation cover play a critical role in malaria transmission. However, quantifying the relationships between environmental factors and measures of disease burden relevant for public health can be complex as effects are often non-linear and subject to temporal lags between when changes in environmental factors lead to changes in malaria incidence. The study investigated the effect of environmental covariates on malaria incidence in high transmission settings of Uganda. Methods This study leveraged data from seven malaria reference centres (MRCs) located in high transmission settings of Uganda over a 24-month period. Estimates of monthly malaria incidence (MI) were derived from MRCs’ catchment areas. Environmental data including monthly temperature, rainfall, and normalized difference vegetation index (NDVI) were obtained from remote sensing sources. A distributed lag nonlinear model was used to investigate the effect of environmental covariates on malaria incidence. Results Overall, the median (range) monthly temperature was 30 °C (26–47), rainfall 133.0 mm (3.0–247), NDVI 0.66 (0.24–0.80) and MI was 790 per 1000 person-years (73–3973). Temperature of 35 °C was significantly associated with malaria incidence compared to the median observed temperature (30 °C) at month lag 2 (IRR: 2.00, 95% CI: 1.42–2.83) and the increased cumulative IRR of malaria at month lags 1–4, with the highest cumulative IRR of 8.16 (95% CI: 3.41–20.26) at lag-month 4. Rainfall of 200 mm significantly increased IRR of malaria compared to the median observed rainfall (133 mm) at lag-month 0 (IRR: 1.24, 95% CI: 1.01–1.52) and the increased cumulative IRR of malaria at month lags 1–4, with the highest cumulative IRR of 1.99(95% CI: 1.22–2.27) at lag-month 4. Average NVDI of 0.72 significantly increased the cumulative IRR of malaria compared to the median observed NDVI (0.66) at month lags 2–4, with the highest cumulative IRR of 1.57(95% CI: 1.09–2.25) at lag-month 4. Conclusions In high-malaria transmission settings, high values of environmental covariates were associated with increased cumulative IRR of malaria, with IRR peaks at variable lag times. The complex associations identified are valuable for designing strategies for early warning, prevention, and control of seasonal malaria surges and epidemics.

Reduced responses to N-methyl-D-aspartate (NMDA) glutamate receptor antagonists in alcohol-dependent animals and humans provided evidence that chronic alcohol consumption increased NMDA receptor function. To further probe alterations in NMDA glutamate receptor function associated with human alcohol dependence, this study examined the interactive effects of agents acting at the glycine(B) coagonist site of the NMDA receptor. In doing so, it tested the hypothesis that raising brain glycine concentrations would accentuate the antagonist-like effects of the glycine(B) partial agonist, D-cycloserine (DCS). Twenty-two alcohol-dependent men and 22 healthy individuals completed 4 test days, during which glycine 0.3 g/kg or saline were administered intravenously and DCS 1000 mg or placebo were administered orally. The study was conducted under double-blind conditions with randomized test day assignment. In this study, DCS produced alcohol-like effects in healthy subjects that were deemed similar to a single standard alcohol drink. The alcohol-like effects of DCS were blunted in alcohol-dependent patients, providing additional evidence of increased NMDA receptor function in this group. Although glycine administration reduced DCS plasma levels, glycine accentuated DCS effects previously associated with the NMDA receptor antagonists, ketamine and ethanol. Thus, this study provided evidence that raising glycine levels accentuated the NMDA receptor antagonist-like effects of DCS and that alcohol-dependent patients showed tolerance to these DCS effects.