Long-Term Connectome Analysis Reveals Reshaping of Visual, Spatial Networks in a Model With Vascular Dementia Features.

Background: Connectome analysis of neuroimaging data is a rapidly expanding field that offers the potential to diagnose, characterize, and predict neurological disease. Animal models provide insight into biological mechanisms that underpin disease, but connectivity approaches are currently lagging in the rodent.

Methods: We present a pipeline adapted for structural and functional connectivity analysis of the mouse brain, and we tested it in a mouse model of vascular dementia.

Structures of the Human SPAK and OSR1 Conserved C-Terminal (CCT) Domains.

STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive 1 (OSR1) kinase are two serine/threonine protein kinases that regulate the function of ion co-transporters through phosphorylation. The highly conserved C-terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream 'With No Lysine Kinases (WNKs), facilitating their activation via phosphorylation. Thus, the inhibition of SPAK and OSR1 binding, via their CCT domains, to WNK kinases is a plausible strategy for inhibiting SPAK and OSR1 kinases.

A pilot of the feasibility and usefulness of an aged obese model for use in stroke research.

Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers.

Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation.

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models.

Immunohistochemical Detection of Modified Cytosine Bases in Rodent Brain.

The modified cytosine base 5-hydroxymethylcytosine (5hmC) is abundantly present in the central nervous system (CNS), and visualization of global 5hmC levels is possible through use of immunohistochemistry. In this chapter we describe an adaptable method of brain tissue collection and immunohistochemical staining that allows for detection of 5hmC in mouse or rat brain, meaning that the method can be applied to many rodent models of CNS diseases and disorders.

CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model.

Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase () gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition.

UK consensus on pre-clinical vascular cognitive impairment functional outcomes assessment: Questionnaire and workshop proceedings.

Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop.

Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.

Background: Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains.

New Method: We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke.

Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology.

Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development.

The IMPROVE Guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments).

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes.

Behavioral outcome measures to improve experimental stroke research.

Functional recovery after an experimental stroke can be assessed by multiple behavioral tests, however, there is no consensus about which test to use in long-term stroke recovery studies or whether the tests are affected by stroke surgery, post-operative care or behavioral compensation due to repeated testing. This review describes the tests most commonly used to assess motor and sensorimotor function, cognition and mood in stroke animals. Although it is difficult to predict the direction of future research, it may be possible to prevent false-positive results by selecting an appropriate task or a battery of tasks.

Infections Up to 76 Days After Stroke Increase Disability and Death.

Early infection after stroke is associated with a poor outcome. We aimed to determine whether delayed infections (up to 76 days post-stroke) are associated with poor outcome at 90 days. Data came from the international Efficacy of Nitric Oxide Stroke (ENOS, ISRCTN99414122) trial.

Neuroimaging Biomarkers Predict Brain Structural Connectivity Change in a Mouse Model of Vascular Cognitive Impairment.

Background And Purpose: Chronic hypoperfusion in the mouse brain has been suggested to mimic aspects of vascular cognitive impairment, such as white matter damage. Although this model has attracted attention, our group has struggled to generate a reliable cognitive and pathological phenotype. This study aimed to identify neuroimaging biomarkers of brain pathology in aged, more severely hypoperfused mice.

Lickometry: A novel and sensitive method for assessing functional deficits in rats after stroke.

The need for sensitive, easy to administer assessments of long-term functional deficits is crucial in pre-clinical stroke research. In the present study, we introduce lickometry (lick microstructure analysis) as a precise method to assess sensorimotor deficits up to 40 days after middle cerebral artery occlusion in rats. Impairments in drinking efficiency compared to controls, and a compensatory increase in the number of drinking clusters were observed.

Developing Mn-doped lead sulfide quantum dots for MRI labels.

Magnetic interactions of Mn ions in lead sulfide (PbS) nanocrystals with protons in water are probed by NMR and MRI. A thin layer of capping molecules enables free solvent diffusion to the nanocrystal surface resulting in a decrease of proton relaxation times. Magnetic resonance imaging of neuronal cell pellets exposed to (PbMn)S at non-toxic concentrations demonstrates their prospects as MRI-labels.

Longitudinal in vivo MRI in a Huntington's disease mouse model: Global atrophy in the absence of white matter microstructural damage.

Huntington's disease (HD) is a genetically-determined neurodegenerative disease. Characterising neuropathology in mouse models of HD is commonly restricted to cross-sectional ex vivo analyses, beset by tissue fixation issues. In vivo longitudinal magnetic resonance imaging (MRI) allows for disease progression to be probed non-invasively.

Systematic and detailed analysis of behavioural tests in the rat middle cerebral artery occlusion model of stroke: Tests for long-term assessment.

In order to test therapeutics, functional assessments are required. In pre-clinical stroke research, there is little consensus regarding the most appropriate behavioural tasks to assess deficits, especially when testing over extended times in milder models with short occlusion times and small lesion volumes. In this study, we comprehensively assessed 16 different behavioural tests, with the aim of identifying those that show robust, reliable and stable deficits for up to two months.

In Vivo MRI Evidence that Neuropathology is Attenuated by Cognitive Enrichment in the Yac128 Huntington's Disease Mouse Model.

Background: Environmental enrichment has been shown to improve symptoms and reduce neuropathology in mouse models of Huntington's disease (HD); however results are limited to ex vivo techniques with associated shortcomings. In-vivo magnetic resonance imaging (MRI) can overcome some of the shortcomings and is applied for the first time here to assess the effect of a cognitive intervention in a mouse model of HD.

Objectives: We aimed to investigate whether in-vivo high-field MRI can detect a disease-modifying effect in tissue macrostructure following a cognitive enrichment regime.

Robust MR-based approaches to quantifying white matter structure and structure/function alterations in Huntington's disease.

Background: Huge advances have been made in understanding and addressing confounds in diffusion MRI data to quantify white matter microstructure. However, there has been a lag in applying these advances in clinical research. Some confounds are more pronounced in HD which impedes data quality and interpretability of patient-control differences.

Assessment of Motor Coordination and Balance in Mice Using the Rotarod, Elevated Bridge, and Footprint Tests.

In order fully to utilize animal models of disease states, to test experimental therapeutics, and to understand the underlying pathophysiology of neurodegenerative disease, behavioral characterization of the model is essential. Deterioration of normal motor function within a disease state signals the progression of an underlying pathological process, and identifies disease-sensitive time points according to which the onset of therapeutic trials may be scheduled. Deterioration in the performance of motor tasks may also indicate the point when motor deficits begin to compromise our ability to measure other deficits within cognitive and behavioral domains.

A Critical Re-Examination of the Intraluminal Filament MCAO Model: Impact of External Carotid Artery Transection.

The intraluminal filament procedure is the most common model of middle cerebral artery occlusion (MCAO). However, consequences of subtle variations in surgical technique on behavioral outcome measures have not been sufficiently explored, which is the aim of this study. Rats randomly received one of three types of transient MCAO (60 min) surgeries.

Time course of choice reaction time deficits in the Hdh(Q92) knock-in mouse model of Huntington's disease in the operant serial implicit learning task (SILT).

A range of transgenic and knock-in mouse models of Huntington's disease have been created since identification in 1993 of the disease mutation in the HD gene. Knock-in models that express the full-length mutant protein tend to exhibit less severe behavioural deficits than transgenic models and so require more sensitive tasks in order to reveal impairments. To achieve this, we therefore used a Serial Implicit Learning Task (SILT), which measures serial reaction times to visual stimuli, requiring detection and responding in both predictable and unpredictable locations in the 9-hole operant chamber.

Striatal lesions in the mouse disrupt acquisition and retention, but not implicit learning, in the SILT procedural motor learning task.

People with Huntington's disease (HD) have been found to have an implicit learning deficit whereby they are typically unable to detect repeated sequences embedded within randomly presented stimuli. The operant serial implicit learning task (SILT) was designed to probe animal models of HD for implicit learning deficits using the 9-hole box apparatus. The present study used mice to determine whether "early" striatal lesions would prevent SILT acquisition and to confirm previous findings that post-training "late lesions" would impair the retention of task performance.

The operant serial implicit learning task reveals early onset motor learning deficits in the Hdh knock-in mouse model of Huntington's disease.

A range of genetic mouse models of Huntington's disease have been created. However, as knock-in models typically have milder phenotypes, they have frequently been overlooked as therapeutic tools in favour of the transgenic models that display severe behavioural symptoms. More sensitive tests are therefore required to reveal abnormalities and release the potential of knock-in lines.

Implicit learning in a serial choice visual discrimination task in the operant 9-hole box by intact and striatal lesioned mice.

Within a broader programme developing murine models of Huntington's disease (HD), we have sought to develop a test of implicit learning for the mouse. Mice were trained in a novel serial visual discrimination task in the '9-hole box' operant test apparatus, followed by retesting after either bilateral quinolinic acid striatal lesions or sham lesions. In the task, each trial involves two sequential responses: an initial light stimulus is presented randomly in one of five holes, to which a nose-poke response results in the first light being extinguished and a second light is illuminated in a different hole.