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Brominated flame retardants are used in many household products to reduce flammability, but often leach into the surrounding environment over time. Hexabromocyclododecane (HBCD) is one brominated flame retardant detected in human blood across the world. HBCD exposure can result in neurological problems and altered lipid metabolism, but to date the two remain unlinked. As lipids constitute â¼50% of brain dry weight, lipid metabolism plays a critical role in neuronal function and homeostasis. To determine the effect of HBCD exposure on brain lipid metabolism, young adult male C57BL/6 mice were exposed to 1 mg/kg HBCD every 3 days for 28 days. Major lipid classes were found to change across brain regions, including the membrane glycerolipids phosphatidylcholine and phosphatidylethanolamine, and sphingolipids such as hexosylceramide. In addition, saturated, monounsaturated, and polyunsaturated fatty acids were enriched within brain lipid species. To understand the source of the brain lipidomic alterations, the blood and liver lipidomes and the cecal microbiome were evaluated. The liver and blood demonstrated changes amongst multiple lipid classes, including triacylglycerol suppression, as well as altered esterified fatty acid content. Significant alterations were also detected in the cecal microbiome, with decreases in the Firmicutes to Bacteriodetes ratio, changes in beta diversity, and pathway alterations associated with metabolic pathways and amino acid biosynthesis. These data demonstrate that HBCD can induce lipidomic alterations across brain regions and organs and supports a potential role of the microbiome in these alterations.
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Brominated Flame Retardants (BFRs) reduce flammability in a wide range of products including electronics, carpets, and paint, but leach into the environment to result in continuous, population-level exposure. Epidemiology studies have correlated BFR exposure with neurological problems, including alterations in learning and memory. This study investigated the molecular mechanisms mediating BFR-induced cell death in hippocampal cells and clarified the impact of HBCD exposure on gene transcription in the hippocampus, dorsal striatum, and frontal cortex of male mice. Exposure of hippocampus derived HT-22 cells to various flame retardants, including tetrabromobisphenol-A (TBBPA, current use), hexabromocyclododecane (HBCD, phasing out), or 2,2',4,4'-tetrabromodiphenyl ether (BDE-47, phased out) resulted in time, concentration, and chemical-dependent cellular and nuclear morphology alterations, alterations in cell cycle and increases in annexin V staining. All three BFRs increased p53 and p21 expression; however, inhibition of p53 nuclear translocation using pifthrin-α did not decrease cell death. Transcriptomic analysis upon low (10 nM) and cytotoxic (10 µM) BFR exposure indicated that HBCD and BDE-47 altered genes mediating autophagy-related pathways. Further evaluation showed BFR exposure increased LC3-II conversion and autophagosome formation, and co-exposure with the autophagy inhibitor 3-methyladenine (3-MA) attenuated cytotoxicity. Transcriptomic assessment of select brain regions from subchronically HBCD-exposed male mice demonstrated alteration of genes mediating vesicular transport, with greater impact on the frontal cortex and dorsal striatum compared to the dorsal and ventral hippocampus. Immunoblot analysis demonstrated no increases in cell death or autophagy markers, but did demonstrate increases in the SNARE binding complex SNAP29, specifically in the dorsal hippocampus. These data demonstrate that BFRs can induce chemical-dependent autophagy in neural cells in vitro and provide evidence that BFRs induce region-specific transcriptomic and protein expression in the brain suggestive of change in vesicular trafficking.
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Trace minerals and vitamins are essential for optimizing feedlot cattle growth, health, and carcass characteristics. Understanding factors that influence trace mineral and vitamin absorption and metabolism is important when formulating feedlot cattle diets. Current feedlot industry supplementation practices typically exceed published trace mineral requirements by a factor of 2 to 4. Therefore, the intent of this review is to briefly discuss the functions of trace minerals and vitamins that are typically supplemented in feedlot diets and to examine the impact of dose of trace mineral or vitamin on growth performance, health, and carcass characteristics of feedlot cattle.
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Oligoelementos , Vitaminas , Bovinos , Animales , Suplementos Dietéticos , Vitamina A , Dieta/veterinaria , Rumiantes/metabolismo , Alimentación Animal/análisis , Minerales/metabolismoRESUMEN
Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to endure. These symptoms culminate into a disease known as Gulf War Illness (GWI) and affect about a third of the GW veteran population. Currently, comprehensive effective GWI treatment options are unavailable. Here, an established GWI mouse model was utilized to explore the (1) long-term behavioral and neuroinflammatory effects of deployment-related GWI chemicals exposure and (2) ability of the immunotherapeutic lacto-N-fucopentaose III (LNFPIII) to improve deficits when given months after the end of exposure. Male C57BL6/J mice (8-9 weeks old) were administered pyridostigmine bromide (PB) and DEET for 14 days along with corticosterone (CORT; latter 7 days) to emulate wartime stress. On day 15, a single injection of the nerve agent surrogate diisopropylfluorophosphate (DFP) was given. LNFPIII treatment began 7 months post GWI chemicals exposure and continued until study completion. A battery of behavioral tests for assessment of cognition/memory, mood, and motor function in rodents was performed beginning 8 months after exposure termination and was then followed by immunohistochemcal evaluation of neuroinflammation and neurogenesis. Within tests of motor function, prior GWI chemical exposure led to hyperactivity, impaired sensorimotor function, and altered gait. LNFPIII attenuated these motor-related deficits and improved overall grip strength. GWI mice also exhibited more anxiety-like behavior that was reduced by LNFPIII; this was test-specific. Short-term, but not long-term memory, was impaired by prior GWI exposure; LNFPIII improved this measure. In the brains of GWI mice, but not in mice treated with LNFPIII, glial activation was increased. Overall, it appears that months after exposure to GWI chemicals, behavioral deficits and neuroinflammation are present. Many of these deficits were attenuated by LNFPIII when treatment began long after GWI chemical exposure termination, highlighting its therapeutic potential for veterans with GWI.
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During lairage at slaughter plants, cattle can be exposed to extreme heat conditions from pen densities and holding pen microclimates. While research outlining heat mitigation strategies used in other sectors of the beef supply chain is available, there is no published data on the use of heat mitigation strategies at slaughter plants. The objective of this study was to characterize short-term heat mitigation strategies used by commercial beef slaughter plants in the United States. Twenty-one beef slaughter plants, representing an estimated 60% of beef slaughter in the United States, were included in the study. All plants indicated use of at least one heat mitigation strategy, and five of them used more than one type. Sprinklers/misters were the most commonly used heat mitigation type (n = 17, 81%), and fans were the least common type (n = 4, 19%). Shade usage was present in several plants (n = 7, 33%), ranging from barn style roofs to shade cloths. Respondents indicated that they believed heat mitigation strategies provide benefits both to cattle well-being and meat quality outcomes. Future research should focus on the effectiveness of these techniques in improving animal well-being and quality outcomes in the slaughter plant environment and protocols for optimum implementation.
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Drugs of abuse, such as cocaine, produce aberrant changes in synaptic transmission and plasticity that emerge throughout withdrawal. One region of the brain that displays a high degree of synaptic plasticity, as well as connectivity with mesolimbic structures such as the nucleus accumbens, is the ventral hippocampus (vH). Here, we investigated the effects of an escalating cocaine dosing schedule on vH CA1 excitatory transmission by measuring place preference and recording excitatory postsynaptic currents (EPSCs) at three different withdrawal time points: withdrawal day (WD) 2, 9 or 28. Behaviourally, this escalating cocaine-conditioning protocol was capable of producing conditioned place preference that persisted through WD28. Physiologically, cocaine conditioning produced an increase in vH excitatory transmission on WD2 that appeared to be the result of an increase in calcium-impermeable (CI)-AMPA receptor density. Excitatory transmission was still enhanced in cocaine-treated animals on WD9; however, a significant increase in the contribution of calcium-permeable (CP)-AMPA receptors to EPSCs was detected as compared with WD2. By WD28, these CP-AMPA receptors provided a major contribution to vH CA1 excitatory transmission, resulting in synaptic responses distinct from WD2 and WD9. Taken together, these results highlight progressive changes in vH synaptic transmission during withdrawal that may enhance cocaine contextual associations.
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Cocaína/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/efectos de los fármacos , Receptores AMPA/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Factores de TiempoRESUMEN
Twelve Angus steers (BW 452.8 ± 6.1 kg) fitted with ruminal cannulae were used to determine the impact of trace mineral (TM) source on digestibility, ruminal volatile fatty acid (VFA) composition, ruminal soluble concentrations of Cu, Zn, and Mn, and relative binding strength of trace minerals located in the rumen insoluble digesta fraction. Steers were fed a medium-quality grass hay diet (DM basis: 10.8% CP, 63.1% neutral detergent fiber [NDF], 6.9 mg Cu/kg, 65.5 mg Mn/kg, and 39.4 mg Zn/kg) supplemented with protein for 21 d. Treatments consisted of either sulfate (STM) or hydroxy (HTM) sources (n = 6 steers/treatment) to provide 20, 40, and 60 mg supplemental Cu, Mn, and Zn/kg DM, respectively. Following a 21-d adaptation period, total fecal output was collected for 5 d. Dry matter (P < 0.07) and CP (P < 0.06) digestibility tended to be reduced, and NDF (P < 0.04) and acid detergent fiber (ADF) (P < 0.05) digestibility were reduced in STM- vs. HTM-supplemented steers. On day 6, ruminal fluid was collected at 0, 2, and 4 h post-feeding and analyzed for VFA. There were no treatment x time interactions for VFA. Steers receiving HTM had less (P < 0.02) molar proportions of butyric acid and greater (P < 0.05) total VFA concentrations than STM-supplemented steers. Steers were then fed the same diet without supplemental Cu, Zn, or Mn for 14 d. On day 15 steers received a pulse dose of 20 mg Cu, 40 mg Mn, and 60 mg Zn/kg DM from either STM or HTM (n = 6 steers/treatment). Ruminal samples were obtained at 2-h intervals starting at -4 and ending at 24 h relative to dosing. There was a treatment x time interaction (P < 0.03) for ruminal soluble Cu, Mn, and Zn concentrations. Ruminal soluble mineral concentrations were greater (P < 0.05) for Cu at 4, 6, 8, 10, 12, and 14 h; for Mn at 4 and 6 h; and for Zn at 4, 6, and 8 h post-dosing in STM compared with HTM-supplemented steers. Copper concentrations were greater (P < 0.05) at 12 and 24 h and Zn concentrations in ruminal solid digesta were greater at 24 h in HTM-supplemented steers. Upon dialysis against Tris-EDTA, the percent Zn released from digesta was greater (P < 0.05) at 12 h (P < 0.03) and 24 h (P < 0.05), and the percent Cu released was greater (P < 0.02) at 24 h post-dosing in HTM steers when compared with STM-supplemented steers. Results indicate that Cu and Zn from HTM have low solubility in the rumen and appear to be less tightly bound to ruminal solid digesta than Cu and Zn from STM. The lower ruminal soluble concentrations of Cu and Zn in steers given HTM were associated with greater fiber digestibility.
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Oligoelementos , Animales , Dieta/veterinaria , Fibras de la Dieta , Digestión , RumenRESUMEN
The majority of Mo research has focused on the antagonist effect of Mo, alone or in combination with elevated dietary S, on Cu absorption and metabolism in ruminants. Diets containing both >5.0 mg of Mo/kg DM and >0.33% S have been reported to reduce the Cu status in cattle and sheep. Therefore, due to the potential for inducing Cu deficiency, Mo and S concentrations in the diet should be monitored and kept within appropriate values. Elevated sulfate concentrations in drinking water can also be detrimental to livestock production, especially in ruminants. High concentrations of sulfate in water have been extensively studied in cattle because high-sulfate water induces polioencephalomalacia in ruminants. However, little research has been conducted investigating the impact of Mo in water on Cu metabolism in ruminants. Based on the limited number of published experiments, it appears that Mo in drinking water may have a lower antagonistic impact on the Cu status in cattle when compared to Mo consumed in the diet. This response may be due to a certain percentage of water bypassing the rumen when consumed by ruminants. Therefore, the objective of this review was to examine the impact of Mo in drinking water on cattle performance and Mo and Cu metabolism.
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Residual effects of the 1990-1991 Gulf War (GW) still plague veterans 30 years later as Gulf War Illness (GWI). Thought to stem mostly from deployment-related chemical overexposures, GWI is a disease with multiple neurological symptoms with likely immunological underpinnings. Currently, GWI remains untreatable, and the long-term neurological disease manifestation is not characterized fully. The present study sought to expand and evaluate the long-term implications of prior GW chemicals exposure on neurological function 6-8 months post GWI-like symptomatology induction. Additionally, the beneficial effects of delayed treatment with the glycan immunotherapeutic lacto-N-fucopentaose III (LNFPIII) were evaluated. Male C57BL/6J mice underwent a 10-day combinational exposure (i.p.) to GW chemicals, the nerve agent prophylactic pyridostigmine bromide (PB) and the insecticide permethrin (PM; 0.7 and 200 mg/kg, respectively). Beginning 4 months after PB/PM exposure, a subset of the mice were treated twice a week until study completion with LNFPIII. Evaluation of cognition/memory, motor function, and mood was performed beginning 1 month after LNFPIII treatment initiation. Prior exposure to PB/PM produced multiple locomotor, neuromuscular, and sensorimotor deficits across several motor tests. Subtle anxiety-like behavior was also present in PB/PM mice in mood tests. Further, PB/PM-exposed mice learned at a slower rate, mostly during early phases of the learning and memory tests employed. LNFPIII treatment restored or improved many of these behaviors, particularly in motor and cognition/memory domains. Electrophysiology data collected from hippocampal slices 8 months post PB/PM exposure revealed modest aberrations in basal synaptic transmission and long-term potentiation in the dorsal or ventral hippocampus that were improved by LNFPIII treatment. Immunohistochemical analysis of tyrosine hydroxylase (TH), a dopaminergic marker, did not detect major PB/PM effects along the nigrostriatal pathway, but LNFPIII increased striatal TH. Additionally, neuroinflammatory cells were increased in PB/PM mice, an effect reduced by LNFPIII. Collectively, long-term neurobehavioral and neurobiological dysfunction associated with prior PB/PM exposure was characterized; delayed LNFPIII treatment provided multiple behavioral and biological beneficial effects in the context of GWI, highlighting its potential as a GWI therapeutic.
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Agentes Nerviosos/farmacología , Síndrome del Golfo Pérsico/tratamiento farmacológico , Polisacáridos/farmacología , Tiempo de Tratamiento , Animales , Cognición/fisiología , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Permetrina/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
AIMS: The present study investigated if treatment with the immunotherapeutic, lacto-N-fucopentaose-III (LNFPIII), resulted in amelioration of acute and persisting deficits in synaptic plasticity and transmission as well as trophic factor expression along the hippocampal dorsoventral axis in a mouse model of Gulf War Illness (GWI). MAIN METHODS: Mice received either coadministered or delayed LNFPIII treatment throughout or following, respectively, exposure to a 15-day GWI induction paradigm. Subsets of animals were subsequently sacrificed 48 h, seven months, or 11 months post GWI-related (GWIR) exposure for hippocampal qPCR or in vitro electrophysiology experiments. KEY FINDINGS: Progressively worsened impairments in hippocampal synaptic plasticity, as well as a biphasic effect on hippocampal synaptic transmission, were detected in GWIR-exposed animals. Dorsoventral-specific impairments in hippocampal synaptic responses became more pronounced over time, particularly in the dorsal hippocampus. Notably, delayed LNFPIII treatment ameliorated GWI-related aberrations in hippocampal synaptic plasticity and transmission seven and 11 months post-exposure, an effect that was consistent with enhanced hippocampal trophic factor expression and absence of increased interleukin 6 (IL-6) in animals treated with LNFPIII. SIGNIFICANCE: Approximately a third of Gulf War Veterans have GWI; however, GWI therapeutics are presently limited to targeted and symptomatic treatments. As increasing evidence underscores the substantial role of persisting neuroimmune dysfunction in GWI, efficacious neuroactive immunotherapeutics hold substantial promise in yielding GWI remission. The findings in the present report indicate that LNFPIII may be an efficacious candidate for ameliorating persisting neurological abnormalities presented in GWI.
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Amino Azúcares/farmacología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Síndrome del Golfo Pérsico/prevención & control , Polisacáridos/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Síndrome del Golfo Pérsico/etiología , Síndrome del Golfo Pérsico/patologíaRESUMEN
Approximately one-third of Persian Gulf War veterans are afflicted by Gulf War Illness (GWI), a chronic multisymptom condition that fundamentally presents with cognitive deficits (i.e., learning and memory impairments) and neuroimmune dysfunction (i.e., inflammation). Factors associated with GWI include overexposures to neurotoxic pesticides and nerve agent prophylactics such as permethrin (PM) and pyridostigmine bromide (PB), respectively. GWI-related neurological impairments associated with PB-PM overexposures have been recapitulated in animal models; however, there is a paucity of studies assessing PB-PM-related aberrations in hippocampal synaptic plasticity and transmission that may underlie behavioral impairments. Importantly, FDA-approved neuroactive treatments are currently unavailable for GWI. In the present study, we assessed the efficacy of an immunomodulatory therapeutic, lacto-N-fucopentaose-III (LNFPIII), on ameliorating acute effects of in vivo PB-PM exposure on synaptic plasticity and transmission as well as trophic factor/cytokine expression along the hippocampal dorsoventral axis. PB-PM exposure resulted in hippocampal synaptic transmission deficits 48 h post-exposure, a response that was ameliorated by LNFPIII coadministration, particularly in the dorsal hippocampus (dH). LNFPIII coadministration also enhanced synaptic transmission in the dH and the ventral hippocampus (vH). Notably, LNFPIII coadministration elevated long-term potentiation in the dH. Further, PB-PM exposure and LNFPIII coadministration uniquely altered key inflammatory cytokine and trophic factor production in the dH and the vH. Collectively, these findings demonstrate that PB-PM exposure impaired hippocampal synaptic responses 48 h post-exposure, impairments that differentially manifested along the dorsoventral axis. Importantly, LNFPIII ameliorated GWI-related electrophysiological deficits, a beneficial effect indicating the potential efficacy of LNFPIII for treating GWI.
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Amino Azúcares/uso terapéutico , Modelos Animales de Enfermedad , Hipocampo/fisiopatología , Síndrome del Golfo Pérsico/tratamiento farmacológico , Síndrome del Golfo Pérsico/fisiopatología , Polisacáridos/uso terapéutico , Transmisión Sináptica/fisiología , Amino Azúcares/farmacología , Animales , Dimetilsulfóxido/toxicidad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Técnicas de Cultivo de Órganos , Material Particulado/toxicidad , Síndrome del Golfo Pérsico/inducido químicamente , Polisacáridos/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
Shade is a mechanism to reduce heat load providing cattle with an environment supportive of their welfare needs. Although heat stress has been extensively reviewed, researched, and addressed in dairy production systems, it has not been investigated in the same manner in the beef cattle supply chain. Like all animals, beef cattle are susceptible to heat stress if they are unable to dissipate heat during times of elevated ambient temperatures. There are many factors that impact heat stress susceptibility in beef cattle throughout the different supply chain sectors, many of which relate to the production system, that is, availability of shade, microclimate of environment, and nutrition management. The results from studies evaluating the effects of shade on production and welfare are difficult to compare due to variation in structural design, construction materials used, height, shape, and area of shade provided. Additionally, depending on operation location, shade may or may not be beneficial during all times of the year, which can influence the decision to make shade a permanent part of management systems. Shade has been shown to lessen the physiologic response of cattle to heat stress. Shaded cattle exhibit lower respiration rates, body temperatures, and panting scores compared with unshaded cattle in weather that increases the risk of heat stress. Results from studies investigating the provision of shade indicate that cattle seek shade in hot weather. The impact of shade on behavioral patterns is inconsistent in the current body of research, with some studies indicating that shade provision impacts behavior and other studies reporting no difference between shaded and unshaded groups. Analysis of performance and carcass characteristics across feedlot studies demonstrated that shaded cattle had increased ADG, improved feed efficiency, HCW, and dressing percentage when compared with cattle without shade. Despite the documented benefits of shade, current industry statistics, although severely limited in scope, indicate low shade implementation rates in feedlots and data in other supply chain sectors do not exist. Industry guidelines and third-party on-farm certification programs articulate the critical need for protection from extreme weather but are not consistent in providing specific recommendations and requirements. Future efforts should include: updated economic analyses of cost vs. benefit of shade implementation, exploration of producer perspectives and needs relative to shade, consideration of shade impacts in the cow-calf and slaughter plant segments of the supply chain, and integration of indicators of affective (mental) state and preference in research studies to enhance the holistic assessment of cattle welfare.
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Enfermedades de los Bovinos , Trastornos de Estrés por Calor , Animales , Temperatura Corporal , Bovinos , Femenino , Trastornos de Estrés por Calor/veterinaria , Respuesta al Choque Térmico , Frecuencia Respiratoria , Luz SolarRESUMEN
The microbiota's influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut-brain-immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 µg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.
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Microbioma Gastrointestinal , Síndrome del Golfo Pérsico , Amino Azúcares/química , Animales , Guerra del Golfo , Masculino , Ratones , Ratones Endogámicos C57BL , Polisacáridos/química , ARN Ribosómico 16S/genéticaRESUMEN
Although there has been an increasing appreciation for functional differences between the dorsal (dH) and ventral (vH) hippocampal sectors, there is a lack of information characterizing the cholinergic and noncholinergic mechanisms of acetylcholinesterase inhibitors on synaptic transmission along the hippocampal dorsoventral axis. Diisopropylfluorophosphate (DFP) is an organophosphate (OP) that is commonly employed as a nerve agent surrogate in vitro as well as in rodent models of disease states, such as Gulf War Illness. The present study investigated the cholinergic and noncholinergic mechanisms responsible for the effects of acute DFP exposure on dH and vH synaptic transmission in a hippocampal slice preparation. A paired-pulse extracellular recording protocol was used to monitor the population spike (PS) amplitude as well as the PS paired-pulse ratio (PS-PPR) in the CA1 subfield of the dH and the vH. We observed that DFP-induced PS1 inhibition was produced by a cholinergic mechanism in the dH, whereas a noncholinergic mechanism was indispensable in mediating the inhibitory effect of DFP on the PS1 in the vH. PS-PPR in both dH and vH sectors was increased by acute DFP exposure, an effect that was blocked by an N-methyl-D-aspartate receptor antagonist but not by cholinergic antagonists. Clinical reports have indicated dorsoventral-specific hippocampal abnormalities in cases of OP intoxications. Therefore, the observed dorsoventral-specific noncholinergic mechanisms underlying the effects of DFP on hippocampal synaptic transmission may have important implications for the treatment of OP overexposures. SIGNIFICANCE STATEMENT: It is unknown if acetylcholinesterase inhibitors differentially impact dorsal and ventral hippocampal synaptic transmission. The data in the present study show that an organophosphate, diisopropylfluorophosphate, impacts glutamatergic transmission along the dorsoventral axis in a hippocampal slice preparation via distinct cholinergic and noncholinergic mechanisms. These findings may provide insight into investigations of therapeutic agents that target noncholinergic mechanisms in cases of organophosphate overexposures.
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Inhibidores de la Colinesterasa/farmacología , Hipocampo/efectos de los fármacos , Isoflurofato/farmacología , Agentes Nerviosos/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Hipocampo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
INTRODUCTION: Cocaine dependence affects millions of individuals worldwide; however, there are no pharmacotherapeutic and/or diagnostic solutions. Recent evidence suggests a role for lipid signaling in the development and maintenance of addiction, highlighting the need to understand how lipid remodeling mediates neuroadaptation after cocaine exposure. METHODS: This study utilized shotgun lipidomics to assess cocaine-induced lipid remodeling in rats using a novel behavioral regimen that incorporated multiple sessions of extinction training and reinstatement testing. RESULTS: Mass spectrometric imaging demonstrated widespread decreases in phospholipid (PL) abundance throughout the brain, and high-spatial resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry indicated hippocampus-specific PL alterations following cocaine exposure. We analyzed the expression of genes involved in hippocampal lipid metabolism and observed region-specific regulation. In addition, we found that cocaine exposure differentially regulates mitochondrial biogenesis in the brain. CONCLUSIONS: This work presents a comprehensive lipidomic assessment of cocaine-induced lipid remodeling in the rat brain. Further, these findings indicate a potential interplay between CNS energetics and differential lipid regulation and suggest a role for cocaine in the maintenance of energy homeostasis.
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Trastornos Relacionados con Cocaína/metabolismo , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Hipocampo/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipidómica , Animales , Conducta Adictiva/metabolismo , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Hipocampo/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Eight crossbred steers (BW 719.0 ± 65.0 kg) with ruminal and duodenal cannulae were used to examine the effect of trace mineral (TM) source on digestibility; ruminal and duodenal solubility of Cu, Zn, and Mn; and in vitro release of Cu, Zn, and Mn from the solid fraction of ruminal digesta. Experiment 1 determined the effect of TM source on DM and NDF digestibility in steers fed a corn silage and steam-flaked corn-based diet. Treatments consisted of 10 mg Cu, 20 mg Mn, and 30 mg Zn/kg DM from either sulfate TM (STM) or hydroxy TM (HTM) sources. Following a 14-d adaptation period, total fecal output was collected for 5 d. Dry matter digestibility was not affected by treatment, but NDF digestibility tended (P < 0.09) to be greater in HTM vs. STM supplemented steers. In Exp. 2, steers were fed a diet without supplemental Cu, Zn, or Mn for 19 d. Steers were then administrated a pulse dose of STM or HTM (2× the National Research Council requirements for Cu, Mn, and Zn) via the rumen fistula. Ruminal and duodenal samples were obtained at 2-h intervals starting at -4 and ending at 24 h relative to dosing. Ruminal soluble Cu and Zn concentrations were affected by treatment, time, and treatment × time. Soluble concentrations and percent soluble Cu and Zn in ruminal digesta increased (P < 0.05) above 0-h values for 10 h following dosing with STM, but not HTM. Concentrations of Cu and Zn in ruminal solid digesta were also affected by treatment, time, and treatment × time. Steers dosed with STM had greater (P < 0.05) solid digesta Cu concentrations at 2 and 4 h but lesser (P < 0.05) concentrations from 6 to 20 h post-dosing than those receiving HTM. Ruminal solid digesta Zn concentrations were greater (P < 0.05) in HTM vs. STM-dosed steers from 6 through 24 h post-dosing. Distribution of Mn in ruminal digesta was affected by TM source, but to a lesser extent than Zn and Cu. Duodenal soluble TM concentrations were variable and not affected by treatment. Binding strength of TM to ruminal solid digesta was estimated at 0, 6, and 12 h post-dosing using dialysis against chelating agents. The percentage of Cu and Zn released from ruminal solid digesta by dialysis against Tris-EDTA was greater (P < 0.05) at 12 h post-dosing from steers receiving HTM vs. STM. Results indicate that Cu and Zn from HTM have low solubility in the rumen and appear to be less tightly bound to ruminal solid digesta than Cu and Zn from STM.
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Bovinos/fisiología , Cobre/metabolismo , Suplementos Dietéticos , Oligoelementos/metabolismo , Zinc/metabolismo , Animales , Dieta/veterinaria , Masculino , Rumen/metabolismo , Ensilaje/análisis , Solubilidad , Zea maysRESUMEN
The effects of drugs of abuse, such as cocaine, on learning and memory processes are thought to contribute to drug craving and relapse susceptibility. Using an Escalating (Esc) or Double Escalating (2x Esc) cocaine i.p. dosing schedule with the conditioned place preference (CPP) model we investigated the persisting effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of the ventral hippocampus (vH), and spatial working memory in a radial arm maze (RAM) task. Interestingly, vH LTP was increased 4 weeks after the last injection day in animals that received only saline vehicle injections. A single pre-treatment with the kappa-opioid receptor antagonist, norbinaltorphimine (norBNI), blocks this stress-like effect of the conditioning protocol on vH LTP without altering the behavioral responses of the animals to cocaine. In animals that received the 2x Esc/norBNI cocaine conditioning, vH LTP was significantly decreased compared to those that received saline vehicle 4 weeks after the last dose. These 2x Esc/norBNI treated animals also exhibited a significant leftward shift in the stimulus-response curve of the baseline field excitatory postsynaptic potential (fEPSP) measurements. A separate group of 2x Esc/norBNI displayed an impaired ability to learn a spatial working memory RAM task compared to saline-conditioned mice following a similar 4 week abstinence period. Together, these results demonstrate that cocaine-induced alterations in synaptic transmission and LTP in the vH are associated with persisting drug-induced impairments in learning and memory performance.
Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacosRESUMEN
Four hundred crossbred steers were used in a randomized complete block design to investigate the effects of supplemental Zn source and concentration, and dietary Cr on performance and carcass characteristics of feedlot steers fed a steam-flaked corn-based finishing diet. Steers were blocked by initial BW within cattle source (3 sources) and randomly assigned within block to 1 of 5 treatments. Before the initiation of the experiment, trace mineral supplement sources were analyzed for Zn and Cr. Zinc and Cr concentrations of the Zn sources were used to balance all dietary treatments to obtain correct Zn and Cr experimental doses. Treatments were the addition of: 1) 90 mg Zn/kg DM from ZnSO4 and 0.25 mg Cr/kg DM from Cr propionate (90ZS+Cr); 2) 30 mg Zn/kg DM from Zn hydroxychloride and 0.25 mg Cr/kg DM from Cr propionate (30ZH+Cr); 3) 90 mg Zn/kg DM from Zn hydroxychloride and 0.25 mg Cr/kg DM from Cr propionate (90ZH+Cr); 4) 60 mg Zn/kg DM from ZnSO4 and 30 mg Zn/kg DM from Zn methionine (90ZSM); and 5) 90 mg Zn/kg DM from Zn hydroxychloride (90ZH). Steers were individually weighed on d-2 and on 2 consecutive days at the end of the experiment. Initial liver biopsies were obtained from all steers at processing. Equal numbers of pen replicates per treatment were slaughtered at a commercial abattoir on day 162, 176, and 211; individual carcass data and final liver samples were collected. Total finishing dietary Zn and Cr concentrations were 118.4, 58.2, 114.2, 123.0, and 108.2 mg Zn/kg DM and 0.740, 0.668, 0.763, 0.767, and 0.461 mg Cr/kg DM, for treatments 1 to 5, respectively. Data were analyzed statistically using preplanned single degree of freedom contrasts. Steers receiving 90ZH+Cr had greater final BW (P < 0.04) and ADG (P < 0.03) when compared with steers receiving 90ZH. Additionally, hot carcass weight was 8.5 kg greater (P < 0.03) for 90ZH+Cr compared with 90ZH supplemented steers. Steers receiving 90ZH+Cr had greater longissimus muscle area when compared with steers receiving 90ZSM. Dry matter intake, G:F, morbidity and mortality, and all other carcass measurements were similar across treatments. These data indicate that under the conditions of this experiment, Zn source and concentration had no impact on live performance, liver Zn and Cu concentrations, and carcass characteristics. Supplemental Cr in diets containing 90 mg of supplemental Zn/kg DM from ZH improved final BW, ADG, and hot carcass weights.
Asunto(s)
Alimentación Animal/análisis , Bovinos/fisiología , Cromo/farmacología , Suplementos Dietéticos , Zinc/farmacología , Mataderos , Animales , Composición Corporal , Dieta/veterinaria , Hígado/metabolismo , Masculino , Distribución Aleatoria , Zea maysRESUMEN
Phosphatidylcholine (PC) is a primary phospholipid and major source of secondary lipid messengers and also serves as a biosynthetic precursor for other membrane phospholipids. Phosphocholine cytidylyltransferase (CCT) is the rate-limiting enzyme responsible for catalyzing the formation of PC. Changes in CCT activity have been associated with lipid dysregulation across various neurological disorders. Additionally, intermediates in PC synthesis, such as CDP-choline, have been suggested to attenuate drug craving during cocaine addiction. Recent work from our group demonstrated that cocaine exposure and conditioning alter the level of PC in the brain, specifically in the cerebellum and hippocampus. The present study examines the role of CCT expression in the brain and determines the effect of cocaine exposure on CCT expression. Immunohistochemical analysis (IHC) was performed to assess region-specific expression of CCT, including both of its isoforms; alpha (CCTα) and beta (CCTß). IHC did not detect any staining of CCTα throughout the rat brain. In contrast, CCTß expression was detected in the Purkinje cells of the cerebellum with decreases in expression following cocaine exposure. Collectively, these data demonstrate the region- and cell-specific localization of CCTα and CCTß in the rat brain, as well as the altered expression of CCTß in the cerebellum following cocaine exposure.
Asunto(s)
Encéfalo/efectos de los fármacos , Citidililtransferasa de Colina-Fosfato/efectos de los fármacos , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Animales , Encéfalo/enzimología , Citidililtransferasa de Colina-Fosfato/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
This Research Communication describes an investigation of the nutritional depletion of total mixed rations (TMR) by pest birds. We hypothesized that species-specific bird depredation of TMR can alter the nutritional composition of the ration and that these changes can negatively impact the performance of dairy cows. Blackbirds selected the high energy fraction of the TMR (i.e., flaked corn) and reduced starch, crude fat and total digestible nutrients during controlled feeding experiments. For Holsteins producing 37·1 kg of milk/d, dairy production modeling illustrated that total required net energy intake (NEI) was 35·8 Mcal/d. For the reference TMR unexposed to blackbirds and the blackbird-consumed TMR, NEI supplied was 41·2 and 37·8 Mcal/d, and the resulting energy balance was 5·4 and 2·0 Mcal/d, respectively. Thus, Holsteins fed the reference and blackbird-consumed TMR were estimated to gain one body condition score in 96 and 254 d, and experience daily weight change due to reserves of 1·1 and 0·4 kg/d, respectively. We discuss these results in context of an integrated pest management program for mitigating the depredation caused by pest birds at commercial dairies.