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INTRODUCTION: Despite the acknowledged impact of circadian rhythms on various aspects of life, behavioural tests with laboratory animals often overlook alignment with their natural activity patterns. This study aims to evaluate the influence of circadian variations on the results, validity, and reliability of different behavioural tests in rats. METHODS: Three behavioural tests, the Light-Dark Box Test (LDB), assessing anxiety-related behaviour and locomotor activity; the Buried Pellet Test (BPT), revealing olfactory abilities and motivation issues; and the Sucrose Preference Test (SPT), studying the anhedonic response, were employed to encompass multiple daytime-dependent behavioural aspects in male Sprague-Dawley rats. RESULTS: Our findings underscore distinct circadian effects on locomotor activity, exploratory behaviour, olfactory acuity, motivation, and hedonic response. Notably, anxious behaviour remained unaffected by daytime conditions. Furthermore, decreased data variance was found to be correlated with conducting behavioural tests during the subjects' active phase. DISCUSSION: This study demonstrates extensive circadian influences on nearly all parameters investigated, coupled with a significant reduction in data variability during the active phase. Emphasising the importance of aligning experimental timing with rats' natural activity patterns, our results suggest that conducting tests during the active phase of the animals not only refines test sensitivity , reduces stress, and provides more representative data, but also contributes to ethical animal research (3â¯R) and improves test relevance. This, in turn, enhances the reliability and validity of experimental outcomes in behavioural research and promotes animal welfare.
Subject(s)
Anxiety , Behavior, Animal , Circadian Rhythm , Exploratory Behavior , Rats, Sprague-Dawley , Animals , Male , Anxiety/physiopathology , Circadian Rhythm/physiology , Rats , Behavior, Animal/physiology , Exploratory Behavior/physiology , Motivation/physiology , Anhedonia/physiology , Smell/physiology , Locomotion/physiology , Reproducibility of ResultsABSTRACT
BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a successful treatment option in Parkinson's disease (PD) for different motor and non-motor symptoms, but has been linked to postoperative cognitive impairment. AIM: Since both dopaminergic and norepinephrinergic neurotransmissions play important roles in symptom development, we analysed STN-DBS effects on dopamine and norepinephrine availability in different brain regions and morphological alterations of catecholaminergic neurons in the 6-hydroxydopamine PD rat model. METHODS: We applied one week of continuous unilateral STN-DBS or sham stimulation, respectively, in groups of healthy and 6-hydroxydopamine-lesioned rats to quantify dopamine and norepinephrine contents in the striatum, olfactory bulb and dentate gyrus. In addition, we analysed dopaminergic cell counts in the substantia nigra pars compacta and area tegmentalis ventralis and norepinephrinergic neurons in the locus coeruleus after one and six weeks of STN-DBS. RESULTS: In 6-hydroxydopamine-lesioned animals, one week of STN-DBS did not alter dopamine levels, while striatal norepinephrine levels were decreased. However, neither one nor six weeks of STN-DBS altered dopaminergic neuron numbers in the midbrain or norepinephrinergic neuron counts in the locus coeruleus. Dopaminergic fibre density in the dorsal and ventral striatum also remained unchanged after six weeks of STN-DBS. In healthy animals, one week of STN-DBS resulted in increased dopamine levels in the olfactory bulb and decreased contents in the dentate gyrus, but had no effects on norepinephrine availability. CONCLUSIONS: STN-DBS modulates striatal norepinephrinergic neurotransmission in a PD rat model. Additional behavioural studies are required to investigate the functional impact of this finding.
Subject(s)
Deep Brain Stimulation , Disease Models, Animal , Dopamine , Norepinephrine , Oxidopamine , Subthalamic Nucleus , Synaptic Transmission , Animals , Subthalamic Nucleus/metabolism , Deep Brain Stimulation/methods , Male , Oxidopamine/toxicity , Synaptic Transmission/physiology , Dopamine/metabolism , Norepinephrine/metabolism , Rats , Parkinson Disease/metabolism , Parkinson Disease/therapy , Dopaminergic Neurons/metabolism , Olfactory Bulb/metabolism , Rats, Sprague-Dawley , Corpus Striatum/metabolism , Dentate Gyrus/metabolism , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/therapy , Parkinsonian Disorders/physiopathologyABSTRACT
Introduction: Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. Methods: In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. Results: STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Discussion: Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease.
ABSTRACT
BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been a highly effective treatment option for mid-to-late-stage Parkinson's disease (PD) for decades. Besides direct effects on brain networks, neuroprotective effects of STN-DBS - potentially via alterations of growth factor expression levels - have been proposed as additional mechanisms of action. OBJECTIVE: In the context of clarifying DBS mechanisms, we analyzed brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) levels in the basal ganglia, motor and parietal cortices, and dentate gyrus in an animal model of stable, severe dopaminergic deficiency. METHODS: We applied one week of continuous unilateral STN-DBS in a group of stable 6-hydroxydopamine (6-OHDA) hemiparkinsonian rats (6-OHDASTIM) in comparison to a 6-OHDA control group (6-OHDASHAM) as well as healthy controls (CTRLSTIM and CTRLSHAM). BDNF and GDNF levels were determined via ELISAs. RESULTS: The 6-OHDA lesion did not result in a persistent alteration in either BDNF or GDNF levels in a model of severe dopaminergic deficiency after completion of the dopaminergic degeneration. STN-DBS modestly increased BDNF levels in the entopeduncular nucleus, but even impaired BDNF and GDNF expression in cortical areas. CONCLUSIONS: STN-DBS does not increase growth factor expression when applied to a model of completed, severe dopaminergic deficiency in contrast to other studies in models of modest and ongoing dopaminergic degeneration. In healthy controls, STN-DBS does not influence BDNF or GDNF expression. We consider these findings relevant for clinical purposes since DBS in PD is usually applied late in the course of the disease.
Subject(s)
Deep Brain Stimulation , Parkinson Disease , Subthalamic Nucleus , Rats , Animals , Subthalamic Nucleus/physiology , Brain-Derived Neurotrophic Factor/metabolism , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Oxidopamine/toxicity , Oxidopamine/metabolism , Parkinson Disease/therapy , Parkinson Disease/metabolismABSTRACT
In high-rise buildings earthquake ground motions induce bending deformation of the host structure. Large dynamic displacements at the top of the building can be observed which in turn lead to the excitation of the cables/ropes within lift installations. In this paper, the stochastic dynamics of a cable with a spring-damper and a mass system deployed in a tall cantilever structure under earthquake excitation is considered. The non-linear system is developed to describe lateral displacements of a vertical cable with a concentrated mass attached at its lower end. The system is moving slowly in the vertical direction. The horizontal displacements of the main mass are constrained by a spring-viscous damping element. The earthquake ground motions are modelled as a filtered Gaussian white noise stochastic process. The equivalent linearization technique is then used to replace the original non-linear system with a linear one with the coefficients determined by utilising the minimization of the mean-square error between both systems. Mean values, variances and covariances of particular random state variables have been obtained by using the numerical calculation. The received results were compared with the deterministic response of the system to the harmonic process and were verified against results obtained by Monte Carlo simulation.
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The present study has examined the relationship between school based effort avoidance tendencies and problem behavior in children aged 9 to 16 years. Effort avoidance tendencies were assessed in 367 children with and without child care. Teachers and social workers rated children on behavioral and emotional problems with the Strengths and Difficulties Questionnaire (SDQ). Results confirmed significant but low correlations between teacher ratings of behavior and emotional problems in children and selected subscales of self-reported effort avoidance in school, especially for children in child care institutions. For them "conduct problems" were significantly correlated with three of the four subscales and the total sum score of effort avoidance whereas "hyperactivity" was the only scale which was significantly associated with the fourth subscale. In the school sample only "hyperactivity" and "peer problems" were significantly correlated with one subscale of school-based effort avoidance. The findings suggest that more problem behavior is in relation to more school based effort avoidance tendencies.
Subject(s)
Affective Symptoms/diagnosis , Affective Symptoms/psychology , Child Behavior Disorders/diagnosis , Child Behavior Disorders/psychology , Learning Disabilities/diagnosis , Learning Disabilities/psychology , Motivation , Problem Behavior/psychology , Underachievement , Adolescent , Child , Child Protective Services , Cooperative Behavior , Female , Humans , Interdisciplinary Communication , Male , Self Efficacy , Statistics as Topic , Surveys and QuestionnairesABSTRACT
An isostructural series of 15 structurally flexible microporous silver metal-organic frameworks (MOFs) is presented. The compounds with a dinuclear silver core as secondary building unit (Ag2N4) can be obtained under solvothermal conditions from substituted triazolyl benzoate linkers and AgNO3 or Ag2SO4; they exhibit 2-fold network interpenetration with lvt topology. Besides the crystal structures, the calculated pore size distributions of the microporous MOFs are reported. Simultaneous thermal analyses confirm the stability of the compounds up to 250 °C. Interconnected pores result in a three-dimensional pore structure. Although the porosity of the novel coordination polymers is in the range of only 20-36%, this series can be regarded as a model system for investigation of network flexibility, since the pore diameters and volumes can be gradually adjusted by the substituents of the 3-(1,2,4-triazol-4-yl)-5-benzamidobenzoates. The pore volumes of selected materials are experimentally determined by nitrogen adsorption at 77 K and carbon dioxide adsorption at room temperature. On the basis of the flexible behavior of the linkers a reversible framework transformation of the 2-fold interpenetrated network is observed. The resulting adsorption isotherms with one or two hysteresis loops are interpreted by a gate-opening process. Due to external stimuli, namely, the adsorptive pressure, the materials undergo a phase transition confirming the structural flexibility of the porous coordination polymer.
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BACKGROUND: Published clinical trials of the treatment of HCV are largely multicentre prospective pharmaceutical trials. Patients in clinical trials tend to have more favorable outcomes than patients in the 'real-world', due to strict patient selection and differences in treatment conditions and available resources. OBJECTIVES: To assess the outcomes of Hepatitis C infected patients treated at the Barwon Health Liver Clinic with combination Pegylated interferon (PEG-IFN) and Ribavirin (RBV) therapy and to determine factors associated with a treatment response. METHODS: Retrospective review of patients who received treatment for Hepatitis C at our institution's Liver Clinic from January 2001-September 2011. Patient demographics, comorbidities, treatment-related parameters and side effects were extracted from medical records and analyzed. RESULTS: A total of 190 patients (120 male, 70 female) with a mean age of 42.8 years (range 20-68 years) commenced treatment. The most common genotype was genotype 3 (48.9%), followed by genotype 1 (42.6%). 150 of 190 patients (78.9%) completed treatment and had end of treatment data available. 107 of 182 patients, (58.8%) for whom sustained virologic response (SVR) rate data was available achieved an SVR. Overall response rates were; 46.9%, 68.8% and 62.4% in genotypes 1, 2 and 3 respectively. The response rate was significantly lower in 29 patients with documented cirrhosis (20.7%). Age, diabetes and alcohol abuse did not predict treatment response in our cohort. Side effects reported in 81.6% of patients included general malaise, hematological disturbance and psychiatric issues, and necessitated cessation of therapy in 16 patients (8.4%) and dose reduction in 26 patients (13.7%). CONCLUSIONS: Response rates to combination PEG-IFN and RBV therapy at our institution are comparable to other 'real-world' and pharmaceutical registration trials. Side effects of combination therapy were prominent but resulted in fewer discontinuations of therapy compared to pharmaceutical trials.