71 research outputs found
Subcutaneous Versus Intraperitoneal Placement of Radiotelemetry Transmitters for Long-term Recording of Electroencephalography
H. Lundbeck has been one of the pioneers in the use of implantable radiotelemetry devices for the collection of electroencephalographic (EEG) and electromyographic (EMG) data in rats. This technology is useful both for sleep research (Vogel et al., 2002: J. Neurosci. Methods 118, 89-96) and epilepsy research (Bastlund et al., 2004 J. Neurosci. Methods 138, 65-72). As part of an ongoing process to improve the ethical and technical aspects of our animal models with focus on the 3R’s, we are engaged in continuous dialogue with our in-house veterinary staff, the equipment manufacturers and other research groups using the telemetry technology. At Lundbeck, we had formerly been implanting the transmitter devices in the intraperitoneal (IP) cavity, however, we were experiencing a number of difficulties with this method. For example, this procedure requires multiple incisions as well as turning the rat over during surgery, compromising the aseptic conditions and thereby increasing the risk of infection. Past experience with subcutaneous (SC) implantation revealed that this technique may also lead to infection, seromas and in some cases penetration of the leads and/or the transmitter body through the skin. However we have further developed our surgical procedure for the SC implantation, optimising and focusing on aseptic surgery without compromising the quality of the data.
An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7
The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation
The effect of ketamine and D-cycloserine on the high frequency resting EEG spectrum in humans
Rationale
Preclinical studies indicate that high-frequency oscillations, above 100 Hz (HFO:100–170 Hz), are a potential translatable biomarker for pharmacological studies, with the rapid acting antidepressant ketamine increasing both gamma (40–100 Hz) and HFO.
Objectives
To assess the effect of the uncompetitive NMDA antagonist ketamine, and of D-cycloserine (DCS), which acts at the glycine site on NMDA receptors on HFO in humans.
Methods
We carried out a partially double-blind, 4-way crossover study in 24 healthy male volunteers. Each participant received an oral tablet and an intravenous infusion on each of four study days. The oral treatment was either DCS (250 mg or 1000 mg) or placebo. The infusion contained 0.5 mg/kg ketamine or saline placebo. The four study conditions were therefore placebo-placebo, 250 mg DCS-placebo, 1000 mg DCS-placebo, or placebo-ketamine.
Results
Compared with placebo, frontal midline HFO magnitude was increased by ketamine (p = 0.00014) and 1000 mg DCS (p = 0.013). Frontal gamma magnitude was also increased by both these treatments. However, at a midline parietal location, only HFO were increased by DCS, and not gamma, whilst ketamine increased both gamma and HFO at this location. Ketamine induced psychomimetic effects, as measured by the PSI scale, whereas DCS did not increase the total PSI score. The perceptual distortion subscale scores correlated with the posterior low gamma to frontal high beta ratio.
Conclusions
Our results suggest that, at high doses, a partial NMDA agonist (DCS) has similar effects on fast neural oscillations as an NMDA antagonist (ketamine). As HFO were induced without psychomimetic effects, they may prove a useful drug development target
Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 micro-deletion syndrome – a study in male mice
Background: The hemizygous 22q11.2 micro-deletion is a common
copy number variant in humans. The deletion confers high risk
of neurodevelopmental disorders including autism and
schizophrenia. Up to 41% of deletion carriers experience
psychotic symptoms. Methods: We present a new mouse model
(Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report
on the most comprehensive study undertaken in 22q11.2DS
models. The study was conducted in male mice. Results: We
found elevated post-pubertal NMDA receptor antagonist induced
hyper-locomotion, age-independent prepulse inhibition (PPI)
deficits and increased acoustic startle response (ASR). The
PPI deficit and increased ASR was resistant to antipsychotic
treatment. The PPI deficit was not a consequence of impaired
hearing measured by auditory brain stem responses. The
Df(h22q11)/+ mice also displayed increased amplitude of
loudness-dependent auditory evoked potentials. Prefrontal
cortex and dorsal striatal (DStr) elevations of the dopamine
metabolite DOPAC and increased DStr expression of the AMPA
receptor subunit GluR1 was found. The Df(h22q11)/+ mice did
not deviate from wild-type mice in a wide range of other
behavioural and biochemical assays. Limitations: The 22q11.2
micro-deletion has incomplete penetrance in humans and the
severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more
marked phenotypes reflecting the severe conditions related to
22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to
environmental stressors which may unmask latent
psychopathology. Conclusion: The Df(h22q11)/+ model will be a
valuable tool for increasing our understanding of the
aetiology of schizophrenia and other psychiatric disorders
associated with the 22q11DS.The research leading to these results was conducted as
part of NEWMEDS and received support from the Innovative
Medicine Initiative Joint Undertaking under grant agreement n°
115008 of which resources are composed of EFPIA in-kind
contribution and financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013). This work
was further supported by grants from the Danish Advanced
Technology Foundation (File no. 001-2009-2) and by the
Instituto de Salud Carlos III, Centro de Investigación
Biomédica en Red de Salud Mental (CIBERSAM)
Opportunities for improving animal welfare in rodent models of epilepsy and seizures
Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs)
A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment.
RATIONALE: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. OBJECTIVES: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. METHOD: Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. RESULTS: In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12. CONCLUSION: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The Behavioural and Clinical Neuroscience Institute is co-funded by the Medical Research Council and the Wellcome Trust. This study was also supported by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The authors would like to thank Mercedes Nuñez, Noemí Jurado, Edita Bulovaitė, Sueda Tunçak, Lewis Buss, and Diab Ali for skillful technical assistance.This is the final version of the article. It first appeared from Springer via https://doi.org/10.1007/s00213-016-4265-
The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders
Abstract
There is emerging evidence of the beneficial role of the melatonin system in a wide range of psychiatric and neurologic disorders, including anxiety, depression, and epilepsy. Although melatoninergic drugs have chronobiotic and antioxidant properties that positively influence circadian rhythm desynchronization and neuroprotection in neurodegenerative disorders, studies examining the use of melatonin for epilepsy's comorbid psychiatric and neurological symptomatology are still limited. Preclinical and clinical findings on the beneficial effects of the melatonin system on anxiety, depression, and epilepsy suggest that melatoninergic compounds might be effective in treating comorbid behavioral complications in epilepsy beyond regulation of a disturbed sleep-wake cycle
Jose Luis Sert: Architecture, City Planning Urban Design
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