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1.
Sci Rep ; 14(1): 14373, 2024 06 22.
Article in English | MEDLINE | ID: mdl-38909151

ABSTRACT

Continued spread of chronic wasting disease (CWD) through wild cervid herds negatively impacts populations, erodes wildlife conservation, drains resource dollars, and challenges wildlife management agencies. Risk factors for CWD have been investigated at state scales, but a regional model to predict locations of new infections can guide increasingly efficient surveillance efforts. We predicted CWD incidence by county using CWD surveillance data depicting white-tailed deer (Odocoileus virginianus) in 16 eastern and midwestern US states. We predicted the binary outcome of CWD-status using four machine learning models, utilized five-fold cross-validation and grid search to pinpoint the best model, then compared model predictions against the subsequent year of surveillance data. Cross validation revealed that the Light Boosting Gradient model was the most reliable predictor given the regional data. The predictive model could be helpful for surveillance planning. Predictions of false positives emphasize areas that warrant targeted CWD surveillance because of similar conditions with counties known to harbor CWD. However, disagreements in positives and negatives between the CWD Prediction Web App predictions and the on-the-ground surveillance data one year later underscore the need for state wildlife agency professionals to use a layered modeling approach to ensure robust surveillance planning. The CWD Prediction Web App is at https://cwd-predict.streamlit.app/ .


Subject(s)
Deer , Machine Learning , Wasting Disease, Chronic , Animals , Wasting Disease, Chronic/epidemiology , Wasting Disease, Chronic/diagnosis , Animals, Wild , United States/epidemiology , Incidence
2.
Angew Chem Int Ed Engl ; : e202404264, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38699962

ABSTRACT

Using single-crystal to single-crystal solid/gas reactivity the gold(I) acetylene complex [Au(L1)(η2-HC≡CH)][BArF 4] is cleanly synthesized by addition of acetylene gas to single crystals of [Au(L1)(CO)][BArF 4] [L1=tris-2-(4,4'-di-tert-butylbiphenyl)phosphine, ArF=3,5-(CF3)2C6H3]. This simplest gold-alkyne complex has been characterized by single crystal X-ray diffraction, solution and solid-state NMR spectroscopy and periodic DFT. Bonding of HC≡CH with [Au(L1)]+ comprises both σ-donation and π-backdonation with additional dispersion interactions within the cavity-shaped phosphine.

3.
Microb Genom ; 10(3)2024 Mar.
Article in English | MEDLINE | ID: mdl-38536208

ABSTRACT

With emerging infectious disease outbreaks in human, domestic and wild animal populations on the rise, improvements in pathogen characterization and surveillance are paramount for the protection of human and animal health, as well as the conservation of ecologically and economically important wildlife. Genomics offers a range of suitable tools to meet these goals, with metagenomic sequencing facilitating the characterization of whole microbial communities associated with emerging and endemic disease outbreaks. Here, we use metagenomic sequencing in a case-control study to identify microbes in lung tissue associated with newly observed pneumonia-related fatalities in 34 white-tailed deer (Odocoileus virginianus) in Wisconsin, USA. We identified 20 bacterial species that occurred in more than a single individual. Of these, only Clostridium novyi was found to substantially differ (in number of detections) between case and control sample groups; however, this difference was not statistically significant. We also detected several bacterial species associated with pneumonia and/or other diseases in ruminants (Mycoplasma ovipneumoniae, Trueperella pyogenes, Pasteurella multocida, Anaplasma phagocytophilum, Fusobacterium necrophorum); however, these species did not substantially differ between case and control sample groups. On average, we detected a larger number of bacterial species in case samples than controls, supporting the potential role of polymicrobial infections in this system. Importantly, we did not detect DNA of viruses or fungi, suggesting that they are not significantly associated with pneumonia in this system. Together, these results highlight the utility of metagenomic sequencing for identifying disease-associated microbes. This preliminary list of microbes will help inform future research on pneumonia-associated fatalities of white-tailed deer.


Subject(s)
Deer , Pneumonia , Animals , Humans , Case-Control Studies , Metagenomics , Animals, Wild
4.
PLoS One ; 17(11): e0274531, 2022.
Article in English | MEDLINE | ID: mdl-36383520

ABSTRACT

Chronic wasting disease (CWD) is a fatal prion disease affecting cervids (deer, elk, moose). Current methods to monitor individual disease state include highly invasive antemortem rectal biopsy or postmortem brain biopsy. Efficient, sensitive, and selective antemortem and postmortem testing of populations would increase knowledge of the dynamics of CWD epizootics as well as provide a means to track CWD progression into previously unaffected areas. Here, we analyzed the presence of CWD prions in skin samples from two easily accessed locations (ear and belly) from 30 deceased white-tailed deer (Odocoileus viginianus). The skin samples were enzymatically digested and analyzed by real-time quaking-induced conversion (RT-QuIC). The diagnostic sensitivity of the ear and belly skin samples were both 95%, and the diagnostic specificity of the ear and belly skin were both 100%. Additionally, the location of the skin biopsy on the ear does not affect specificity or sensitivity. These results demonstrate the efficacy of CWD diagnosis with skin biopsies using RT-QuIC. This method could be useful for large scale antemortem population testing.


Subject(s)
Deer , Prions , Wasting Disease, Chronic , Animals , Wasting Disease, Chronic/diagnosis , Wasting Disease, Chronic/pathology , Biopsy
5.
J Wildl Dis ; 58(4): 803-815, 2022 10 01.
Article in English | MEDLINE | ID: mdl-36288680

ABSTRACT

White-tailed deer (WTD; Odocoileus virginianus) are a critical species for ecosystem function and wildlife management. As such, studies of cause-specific mortality among WTD have long been used to understand population dynamics. However, detailed pathological information is rarely documented for free-ranging WTD, especially in regions with a high prevalence of chronic wasting disease (CWD). This leaves a significant gap in understanding how CWD is associated with disease processes or comorbidities that may subsequently alter broader population dynamics. We investigated unknown mortalities among collared WTD in southwestern Wisconsin, USA, an area of high CWD prevalence. We tested for associations between CWD and other disease processes and used a network approach to test for co-occurring disease processes. Predation and infectious disease were leading suspected causes of death, with high prevalence of CWD (42.4%; of 245 evaluated) and pneumonia (51.2%; of 168 evaluated) in our sample. CWD prevalence increased with age, before decreasing among older individuals, with more older females than males in our sample. Females were more likely to be CWD positive, and although this was not statistically significant when accounting for age, females were significantly more likely to die with end-stage CWD than males and may consequently be an underrecognized source of CWD transmission. Presence of CWD was associated with emaciation, atrophy of marrow fat and hematopoietic cells, and ectoparasitism (lice and ticks). Occurrences of severe infectious disease processes clustered together (e.g., pneumonia, CWD), as compared to noninfectious or low-severity processes (e.g., sarcocystosis), although pneumonia cases were not fully explained by CWD status. With the prevalence of CWD increasing across North America, our results highlight the critical importance of understanding the potential role of CWD in favoring or maintaining disease processes of importance for deer population health and dynamics.


Subject(s)
Communicable Diseases , Deer , Wasting Disease, Chronic , Animals , Cause of Death , Communicable Diseases/veterinary , Ecosystem , Wasting Disease, Chronic/epidemiology , Wisconsin
6.
Mov Ecol ; 10(1): 43, 2022 Oct 26.
Article in English | MEDLINE | ID: mdl-36289549

ABSTRACT

BACKGROUND: Dispersal is a fundamental process to animal population dynamics and gene flow. In white-tailed deer (WTD; Odocoileus virginianus), dispersal also presents an increasingly relevant risk for the spread of infectious diseases. Across their wide range, WTD dispersal is believed to be driven by a suite of landscape and host behavioral factors, but these can vary by region, season, and sex. Our objectives were to (1) identify dispersal events in Wisconsin WTD and determine drivers of dispersal rates and distances, and (2) determine how landscape features (e.g., rivers, roads) structure deer dispersal paths. METHODS: We developed an algorithmic approach to detect dispersal events from GPS collar data for 590 juvenile, yearling, and adult WTD. We used statistical models to identify host and landscape drivers of dispersal rates and distances, including the role of agricultural land use, the traversability of the landscape, and potential interactions between deer. We then performed a step selection analysis to determine how landscape features such as agricultural land use, elevation, rivers, and roads affected deer dispersal paths. RESULTS: Dispersal predominantly occurred in juvenile males, of which 64.2% dispersed, with dispersal events uncommon in other sex and age classes. Juvenile male dispersal probability was positively associated with the proportion of the natal range that was classified as agricultural land use, but only during the spring. Dispersal distances were typically short (median 5.77 km, range: 1.3-68.3 km), especially in the fall. Further, dispersal distances were positively associated with agricultural land use in potential dispersal paths but negatively associated with the number of proximate deer in the natal range. Lastly, we found that, during dispersal, juvenile males typically avoided agricultural land use but selected for areas near rivers and streams. CONCLUSION: Land use-particularly agricultural-was a key driver of dispersal rates, distances, and paths in Wisconsin WTD. In addition, our results support the importance of deer social environments in shaping dispersal behavior. Our findings reinforce knowledge of dispersal ecology in WTD and how landscape factors-including major rivers, roads, and land-use patterns-structure host gene flow and potential pathogen transmission.

7.
Environ Toxicol ; 37(2): 335-348, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34741586

ABSTRACT

Cadmium (Cd) is a toxic heavy metal and a significant public health concern. Epidemiological studies suggest that Cd is a potential neurotoxicant, and its exposure is associated with cognitive deficits in children, adults, and seniors. Our previous study has found that adulthood-only Cd exposure can impair cognition in mice. However, few studies have addressed the effects of Cd exposure during adolescence on cognitive behavior in animals later in life. In the present study, we exposed 4-week-old male C57BL/6 mice to 3 mg/L Cd via drinking water for 28 weeks and assessed their hippocampus-dependent learning and memory. Cd did not affect anxiety or locomotor activity in the open field test. However, Cd exposure impaired short-term spatial memory and contextual fear memory in mice. A separate cohort of 4-week-old mice was similarly exposed to Cd for 13 weeks to investigate the potential mechanism of Cd neurotoxicity on cognition. We observed that Cd-treated mice had fewer adult-born cells, adult-born neurons, and a reduced proportion of adult-born cells that differentiated into mature neurons in the subgranular zone of the dentate gyrus. These results suggest that Cd exposure from adolescence to adulthood is sufficient to cause cognitive deficits and impair key processes of hippocampal neurogenesis in mice.


Subject(s)
Cadmium , Memory , Animals , Cadmium/toxicity , Cognition , Hippocampus , Male , Mice , Mice, Inbred C57BL , Neurogenesis
8.
World J Psychiatry ; 11(2): 35-49, 2021 Feb 19.
Article in English | MEDLINE | ID: mdl-33643860

ABSTRACT

BACKGROUND: Major depressive disorder (MDD) is a highly disabling psychiatric syndrome associated with deficits of specific subpopulations of cortical GABAergic interneurons; however, the underlying molecular mechanism remains unknown. Type 3 adenylyl cyclase (ADCY3, AC3), which is important for neuronal excitability, has been implicated in MDD in a genome-wide association study in humans. Moreover, a study reported that ablation of AC3 in mice caused similar symptoms as MDD patients. AIM: To determine if disruption of the AC3 gene in different subtypes of GABAergic interneurons of mice causes depression-like behaviors. METHODS: Using immunohistochemistry, we investigated the expression of AC3 in two major subtypes GABAergic interneurons: Somatostatin-positive (SST+) and parvalbumin-positive (PV+) neurons. Genetic manipulations were used to selectively disrupt AC3 expression in SST+ or PV+ interneurons. A series of behavior tests including rotarod test, open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) were used to evaluate the motor ability, anxiety- and depression- like behaviors, respectively. RESULTS: Our results indicate that approximately 90.41% of SST+ and 91.22% of PV+ interneurons express AC3. After ablation of AC3 in SST+ interneurons, the mice spent comparable time in the center area in OFT, but significantly less time in the open arms and low frequency of entries to the open arms in EPM. Furthermore, these mice showed prolonged immobility in FST and more freezing in TST. However, there were no significant changes in these behaviors after specific disruption of AC3 in PV+ interneurons. CONCLUSION: This study indicates that ablation of AC3 in SST+ interneurons of mice increases anxiety- and depression-like behaviors in mice, supporting the general hypothesis that decreased AC3 activity may play a role in human depression.

9.
Neurotoxicology ; 81: 127-136, 2020 12.
Article in English | MEDLINE | ID: mdl-33039505

ABSTRACT

Cadmium (Cd) is a heavy metal that is one of the most toxic environmental pollutants throughout the world. We previously reported that Cd exposure impairs olfactory memory in mice. However, the underlying mechanisms for its neurotoxicity for olfactory function are not well understood. Since adult Subventricular zone (SVZ) and Olfactory Bulb (OB) neurogenesis contributes to olfaction, olfactory memory defects caused by Cd may be due to inhibition of neurogenesis. In this study, using bromodeoxyuridine (BrdU) labeling and immunohistochemistry, we found that 0.6 mg/L Cd exposure through drinking water impaired adult SVZ/OB neurogenesis in C57BL/6 mice. To determine if the inhibition of olfactory memory by Cd can be reversed by stimulating adult neurogenesis, we utilized the transgenic caMEK5 mouse strain to conditional stimulate of adult neurogenesis by activating the endogenous ERK5 MAP kinase signaling pathway. This was accomplished by conditionally induced expression of active MEK5 (caMEK5) in adult neural stem/progenitor cells. The caMEK5 mice were exposed to 0.6 mg/L Cd for 38 weeks, and tamoxifen was administered to induce caMEK5 expression and stimulate adult SVZ/OB neurogenesis during Cd exposure. Short-term olfactory memory test and sand-digging based, odor-cued olfactory learning and memory test were conducted after Cd and tamoxifen treatments to examine their effects on olfaction. Here we report that Cd exposure impaired short-term olfactory memory and odor-cued associative learning and memory in mice. Furthermore, the Cd-impaired olfactory memory deficits were rescued by the tamoxifen-induction of caMEK5 expression. This suggests that Cd exposure impairs olfactory function by affecting adult SVZ/OB neurogenesis in mice.


Subject(s)
Behavior, Animal , Lateral Ventricles/enzymology , Memory , Mitogen-Activated Protein Kinase 7/metabolism , Neurogenesis , Olfaction Disorders/prevention & control , Olfactory Bulb/enzymology , Olfactory Perception , Smell , Animals , Association Learning , Cadmium Chloride , Cues , Disease Models, Animal , Enzyme Activation , Female , Lateral Ventricles/pathology , Lateral Ventricles/physiopathology , Mice, Inbred C57BL , Mice, Transgenic , Mitogen-Activated Protein Kinase 7/genetics , Odorants , Olfaction Disorders/chemically induced , Olfaction Disorders/enzymology , Olfaction Disorders/physiopathology , Olfactory Bulb/pathology , Olfactory Bulb/physiopathology , Time Factors
10.
Toxicol Sci ; 177(1): 263-280, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32617577

ABSTRACT

Cadmium (Cd) is a heavy metal and an environmental pollutant. However, the full spectrum of its neurotoxicity and the underlying mechanisms are not completely understood. Our previous studies demonstrated that Cd exposure impairs adult hippocampal neurogenesis and hippocampus-dependent memory in mice. This study aims to determine if these adverse effects of Cd exposure can be mitigated by genetically and conditionally enhancing adult neurogenesis. To address this issue, we utilized the transgenic constitutive active MEK5 (caMEK5) mouse strain we previously developed and characterized. This mouse strain enables us to genetically and conditionally activate adult neurogenesis by administering tamoxifen to induce expression of a caMEK5 in adult neural stem/progenitor cells, which stimulates adult neurogenesis through activation of the endogenous extracellular signal-regulated kinase 5 mitogen-activated protein kinase pathway. The caMEK5 mice were exposed to 0.6 mg/l Cd through drinking water for 38 weeks. Once impairment of memory was confirmed, tamoxifen was administered to induce caMEK5 expression and to activate adult neurogenesis. Behavior tests were conducted at various time points to monitor hippocampus-dependent memory. Upon completion of the behavior tests, brain tissues were collected for cellular studies of adult hippocampal neurogenesis. We report here that Cd impaired hippocampus-dependent spatial memory and contextual fear memory in mice. These deficits were rescued by the tamoxifen induction of caMEK5 expression. Furthermore, Cd inhibition of adult hippocampal neurogenesis was also reversed. This rescue experiment provides strong evidence for a direct link between Cd-induced impairments of adult hippocampal neurogenesis and hippocampus-dependent memory.


Subject(s)
Cadmium , Neurogenesis , Animals , Cadmium/toxicity , Female , Hippocampus , Male , Memory , Mice , Mice, Inbred C57BL , Mice, Transgenic
11.
Toxicol Sci ; 173(1): 189-201, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31626305

ABSTRACT

Cadmium (Cd) is a heavy metal of great public health concern. Recent studies suggested a link between Cd exposure and cognitive decline in humans. The ε4 allele, compared with the common ε3 allele, of the human apolipoprotein E gene (ApoE) is associated with accelerated cognitive decline and increased risks for Alzheimer's disease (AD). To investigate the gene-environment interactions (GxE) between ApoE-ε4 and Cd exposure on cognition, we used a mouse model of AD that expresses human ApoE-ε3 (ApoE3-KI [knock-in]) or ApoE-ε4 (ApoE4-KI). Mice were exposed to 0.6 mg/l CdCl2 through drinking water for 14 weeks and assessed for hippocampus-dependent memory. A separate cohort was sacrificed immediately after exposure and used for Cd measurements and immunostaining. The peak blood Cd was 0.3-0.4 µg/l, within levels found in the U.S. general population. All Cd-treated animals exhibited spatial working memory deficits in the novel object location test. This deficit manifested earlier in ApoE4-KI mice than in ApoE3-KI within the same sex and earlier in males than females within the same genotype. ApoE4-KI but not ApoE3-KI mice exhibited reduced spontaneous alternation later in life in the T-maze test. Finally, Cd exposure impaired neuronal differentiation of adult-born neurons in the hippocampus of male ApoE4-KI mice. These data suggest that a GxE between ApoE4 and Cd exposure leads to accelerated cognitive impairment and that impaired adult hippocampal neurogenesis may be one of the underlying mechanisms. Furthermore, male mice were more susceptible than female mice to this GxE effect when animals were young.


Subject(s)
Apolipoprotein E4/metabolism , Cadmium/toxicity , Hazardous Substances/toxicity , Memory/drug effects , Alzheimer Disease , Animals , Apolipoprotein E3 , Behavior, Animal , Brain , Cognition , Disease Models, Animal , Female , Gene-Environment Interaction , Hippocampus , Humans , Male , Maze Learning , Memory Disorders , Mice , Mice, Transgenic
12.
Toxicol Sci ; 171(2): 501-514, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31271426

ABSTRACT

Cadmium (Cd) is an environmental pollutant of considerable interest throughout the world and potentially a neurotoxicant. Our recent data indicate that Cd exposure induces impairment of hippocampus-dependent learning and memory in mice. However, the underlying mechanisms for this defect are not known. The goal of this study was to determine if Cd inhibits adult neurogenesis and to identify underlying signaling pathways responsible for this impairment. Adult hippocampal neurogenesis is a process in which adult neural progenitor/stem cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate functional new neurons in the hippocampus which contributes to hippocampus-dependent learning and memory. However, studies concerning the effects of neurotoxicants on adult hippocampal neurogenesis and the underlying signaling mechanisms are limited. Here, we report that Cd significantly induces apoptosis, inhibits proliferation, and impairs neuronal differentiation in primary cultured aNPCs derived from the SGZ. In addition, the c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase signaling pathways are activated by Cd and contribute to its toxicity. Furthermore, we exposed 8-week-old male C57BL/6 mice to Cd through drinking water for 13 weeks to assess the effects of Cd on adult hippocampal neurogenesis in vivo. Cd treatment reduced the number of 5-week-old adult-born cells in the DG and impaired the differentiation of adult-born hippocampal neurons. These results suggest that Cd exposure impairs adult hippocampal neurogenesis both in vitro and in vivo. This may contribute to Cd-mediated inhibition of hippocampus-dependent learning and memory.

13.
PLoS One ; 14(7): e0219152, 2019.
Article in English | MEDLINE | ID: mdl-31269057

ABSTRACT

Although the biochemical signaling events in area CA1 of the hippocampus underlying memory acquisition, consolidation, retrieval, and extinction have been extensively studied, little is known about the activity dynamics of hippocampal neurons in CA1 during Pavlovian fear conditioning. Here, we use fiber-optic confocal microscopy coupled with the calcium indicator GCaMP6m to monitor neuron activity in freely moving mice during trace fear conditioning. We show that the activity of a group of CA1 neurons increases not only after the stimulus presentations, but also during the stimulus-free trace period when the conditioned mice exhibit a high level of freezing behavior. Therefore, we designate these cells "trace cells". Interestingly, the activity of the trace cells increases in response to the conditioned stimuli during memory retrieval but diminishes during memory extinction. Importantly, the dynamics of neuron activity exhibit a high degree of correlation with the freezing behavior of the mice, suggesting that a neuronal ensemble responsible for encoding the trace fear memory is repeatedly reactivated during memory retrieval and later extinguished during memory extinction.


Subject(s)
CA1 Region, Hippocampal/physiology , Calcium Signaling/physiology , Fear/physiology , Memory/physiology , Animals , CA1 Region, Hippocampal/cytology , Conditioning, Classical/physiology , Indicators and Reagents , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Neurons/physiology
14.
Ecol Evol ; 8(1): 509-520, 2018 01.
Article in English | MEDLINE | ID: mdl-29321889

ABSTRACT

Implicit and explicit use of expert knowledge to inform ecological analyses is becoming increasingly common because it often represents the sole source of information in many circumstances. Thus, there is a need to develop statistical methods that explicitly incorporate expert knowledge, and can successfully leverage this information while properly accounting for associated uncertainty during analysis. Studies of cause-specific mortality provide an example of implicit use of expert knowledge when causes-of-death are uncertain and assigned based on the observer's knowledge of the most likely cause. To explicitly incorporate this use of expert knowledge and the associated uncertainty, we developed a statistical model for estimating cause-specific mortality using a data augmentation approach within a Bayesian hierarchical framework. Specifically, for each mortality event, we elicited the observer's belief of cause-of-death by having them specify the probability that the death was due to each potential cause. These probabilities were then used as prior predictive values within our framework. This hierarchical framework permitted a simple and rigorous estimation method that was easily modified to include covariate effects and regularizing terms. Although applied to survival analysis, this method can be extended to any event-time analysis with multiple event types, for which there is uncertainty regarding the true outcome. We conducted simulations to determine how our framework compared to traditional approaches that use expert knowledge implicitly and assume that cause-of-death is specified accurately. Simulation results supported the inclusion of observer uncertainty in cause-of-death assignment in modeling of cause-specific mortality to improve model performance and inference. Finally, we applied the statistical model we developed and a traditional method to cause-specific survival data for white-tailed deer, and compared results. We demonstrate that model selection results changed between the two approaches, and incorporating observer knowledge in cause-of-death increased the variability associated with parameter estimates when compared to the traditional approach. These differences between the two approaches can impact reported results, and therefore, it is critical to explicitly incorporate expert knowledge in statistical methods to ensure rigorous inference.

15.
Neuroscience ; 370: 101-111, 2018 02 01.
Article in English | MEDLINE | ID: mdl-28366664

ABSTRACT

The hippocampus enables a range of behaviors through its intrinsic circuits and concerted actions with other brain regions. One such important function is the retrieval of episodic memories. How hippocampal cells support retrieval of contextual fear memory remains largely unclear. Here we monitored phospho-activation of extracellular-regulated kinase (Erk1/2) across neuronal populations of the hippocampus to find that CA1 pyramidal neurons, but not cells in CA3 or dentate gyrus, specifically respond to retrieval of an aversive context. In contrast, retrieval of a neutral context that fails to elicit a threat response did not activate Erk1/2. Moreover, retrieval preferentially re-activated Erk1/2 in the same set of CA1 neurons previously activated during conditioning in a context-specific manner. By confining drug inhibition within dorsal CA1, we established the crucial role for Erk1/2 activity in retrieval of long-term memory, as well as in amygdala activation associated with fear expression. These data provide functional evidence that Erk1/2 signaling in CA1 encodes a specific neural representation of contextual memory with emotional value.


Subject(s)
CA1 Region, Hippocampal/enzymology , Conditioning, Psychological/physiology , Mental Recall/physiology , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinases/metabolism , Neurons/enzymology , Animals , CA1 Region, Hippocampal/cytology , CA1 Region, Hippocampal/drug effects , Cells, Cultured , Conditioning, Psychological/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Enzyme Inhibitors/pharmacology , Fear/drug effects , Fear/physiology , Indazoles/pharmacology , Memory, Long-Term/drug effects , Memory, Long-Term/physiology , Mental Recall/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Neurons/cytology , Neurons/drug effects , Piperazines/pharmacology
16.
Toxicol Sci ; 161(1): 87-102, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29029324

ABSTRACT

Cadmium (Cd) is a heavy metal of high interest to the superfund initiative. Recent epidemiology studies have suggested a possible association between Cd exposure and cognitive as well as olfactory impairments in humans. However, studies in animal models are needed to establish a direct causal relationship between Cd exposure and impairments in cognition and olfaction. This study aims to investigate the toxic effect of Cd on cognition and olfactory function in mice. One group of 8-week-old C57BL/6 male mice was exposed to 3 mg/l Cd (in the form of CdCl2) through drinking water for 20 weeks for behavior tests and final blood Cd concentration analysis. The behavior tests were conducted before, during, and after Cd exposure to analyze the effects of Cd on cognition and olfactory function. Upon completion of behavior tests, blood was collected to measure final blood Cd concentration. Two additional groups of mice were similarly exposed to Cd for 5 or 13 weeks for peak blood Cd concentration measurement. The peak blood Cd concentration was 2.125-2.25 µg/l whereas the final blood Cd concentration was 0.18 µg/l. At this exposure level, Cd impaired hippocampus-dependent learning and memory in novel object location test, T-maze test, and contextual fear memory test. It also caused deficits in short-term olfactory memory and odor-cued olfactory learning and memory. Results in this study demonstrate a direct relationship between Cd exposure and cognitive as well as olfactory impairments in an animal model.


Subject(s)
Behavior, Animal/drug effects , Cadmium/toxicity , Cognitive Dysfunction/chemically induced , Environmental Pollutants/toxicity , Memory/drug effects , Olfaction Disorders/chemically induced , Animals , Cadmium/blood , Disease Models, Animal , Environmental Pollutants/blood , Hippocampus/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL
17.
Sci Rep ; 7: 44989, 2017 03 22.
Article in English | MEDLINE | ID: mdl-28327638

ABSTRACT

Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson's disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson's disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson's disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson's disease and reduces dopamine content in the absence of dopamine neuron loss.


Subject(s)
Dopaminergic Neurons/metabolism , Electron Transport Complex I/genetics , Gene Deletion , Motor Activity , Animals , Anxiety/genetics , Behavior, Animal , Cell Death , Cognitive Dysfunction , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/metabolism , Male , Maze Learning , Mice , Mice, Knockout , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Parkinson Disease/psychology , Serotonin/metabolism , Substantia Nigra/metabolism , Substantia Nigra/pathology , Tyrosine 3-Monooxygenase/metabolism
18.
Front Cell Neurosci ; 11: 1, 2017.
Article in English | MEDLINE | ID: mdl-28154525

ABSTRACT

Type 3 adenylyl cyclase (Adcy3) is localized to the cilia of olfactory sensory neurons (OSNs) and is an essential component of the olfactory cyclic adenosine monophosphate (cAMP) signaling pathway. Although the role of this enzyme in odor detection and axonal projection in OSNs was previously characterized, researchers will still have to determine its function in the maturation of postnatal OSNs and olfactory cilium ultrastructure. Previous studies on newborns showed that the anatomic structure of the main olfactory epithelium (MOE) of Adcy3 knockout mice (Adcy3-/-) is indistinguishable from that of their wild-type littermates (Adcy3+/+), whereas the architecture and associated composition of MOE are relatively underdeveloped at this early age. The full effects of sensory deprivation on OSNs may not also be exhibited in such age. In the present study, following a comparison of postnatal OSNs in seven-, 30-, and 90-day-old Adcy3-/- mice and wild-type controls (Adcy3+/+), we observed that the absence of Adcy3 leads to cumulative defects in the maturation of OSNs. Upon aging, Adcy3-/- OSNs exhibited increase in immature cells and reduction in mature cells along with elevated apoptosis levels. The density and ultrastructure of Adcy3-/- cilia were also disrupted in mice upon aging. Collectively, our results reveal an indispensable role of Adcy3 in postnatal maturation of OSNs and maintenance of olfactory cilium ultrastructure in mice through adulthood.

19.
J Environ Qual ; 46(6): 1341-1348, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29293843

ABSTRACT

Due to a shortage of available phosphorus (P)-loss datasets, simulated data from an accurate quantitative P transport model could be used to evaluate a P Index. The objective of this study was to compare predictions from the Texas Best Management Practice Evaluation Tool (TBET) against measured P-loss data to determine whether the model could be used to improve P Indices in the southern region. Measured P-loss data from field-scale study sites in Arkansas, Georgia, and North Carolina were used to assess the accuracy of TBET for predicting field-scale loss of P. We found that event-based predictions using an uncalibrated model were generally poor. Calibration improved runoff predictions and produced scatterplot regression lines that had slopes near one and intercepts near zero. However, TBET predictions of runoff met the performance criteria (Nash-Sutcliffe efficiency ≥ 0.3, percent bias ≤ 35%, and mean absolute error ≤ 10 mm) in only one out of six comparisons: North Carolina during calibration. Sediment predictions were imprecise, and dissolved P predictions underestimated measured losses. In North Carolina, total P-loss predictions were reasonably accurate because TBET did a slightly better job of predicting sediment losses from cultivated land. In Arkansas and Georgia, where the experimental sites were in forage production, the underprediction of dissolved P led directly to the underpredictions of total P. We conclude that TBET cannot be used to improve southern P Indices, but a curve number approach could be incorporated into P Indices to improve runoff predictions.


Subject(s)
Models, Theoretical , Phosphorus/analysis , Water Quality , Arkansas , North Carolina , Texas
20.
J Environ Qual ; 46(6): 1314-1322, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29293849

ABSTRACT

A wide range of mathematical models are available for predicting phosphorus (P) losses from agricultural fields, ranging from simple, empirically based annual time-step models to more complex, process-based daily time-step models. In this study, we compare field-scale P-loss predictions between the Annual P Loss Estimator (APLE), an empirically based annual time-step model, and the Texas Best Management Practice Evaluation Tool (TBET), a process-based daily time-step model based on the Soil and Water Assessment Tool. We first compared predictions of field-scale P loss from both models using field and land management data collected from 11 research sites throughout the southern United States. We then compared predictions of P loss from both models with measured P-loss data from these sites. We observed a strong and statistically significant ( < 0.001) correlation in both dissolved (ρ = 0.92) and particulate (ρ = 0.87) P loss between the two models; however, APLE predicted, on average, 44% greater dissolved P loss, whereas TBET predicted, on average, 105% greater particulate P loss for the conditions simulated in our study. When we compared model predictions with measured P-loss data, neither model consistently outperformed the other, indicating that more complex models do not necessarily produce better predictions of field-scale P loss. Our results also highlight limitations with both models and the need for continued efforts to improve their accuracy.


Subject(s)
Models, Theoretical , Phosphorus/analysis , Agriculture , Soil , Texas , Water Pollutants
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