12 research outputs found
Perirhinal cortex and the recognition of relative familiarity
Spontaneous object recognition (SOR) is a widely used task of recognition memory in rodents which relies on their propensity to explore novel (or relatively novel) objects. Network models typically define perirhinal cortex as a region required for recognition of previously seen objects largely based on findings that lesions or inactivations of this area produce SOR deficits. However, relatively little is understood about the relationship between the activity of cells in the perirhinal cortex that signal novelty and familiarity and the behavioural responses of animals in the SOR task. Previous studies have used objects that are either highly familiar or absolutely novel, but everyday memory is for objects that sit on a spectrum of familiarity which includes objects that have been seen only a few times, or objects that are similar to objects which have been previously experienced. We present two studies that explore cellular activity (through c-fos imaging) within perirhinal cortex of rats performing SOR where the familiarity of objects has been manipulated. Despite robust recognition memory performance, we show no significant changes in perirhinal activity related to the level of familiarity of the objects. Reasons for this lack of familiarity-related modulation in perirhinal cortex activity are discussed. The current findings support emerging evidence that perirhinal responses to novelty are complex and that task demands are critical to the involvement of perirhinal cortex in the control of object recognition memory
Can harmonisation of outcomes bridge the translation gap for pre-clinical research? A systematic review of outcomes measured in mouse models of type 2 diabetes
Background:
In pre-clinical research, systematic reviews have the potential to mitigate translational challenges by facilitating understanding of how pre-clinical studies can inform future clinical research. Yet their conduct is encumbered by heterogeneity in the outcomes measured and reported, and those outcomes may not always relate to the most clinically important outcomes. We aimed to systematically review outcomes measured and reported in pre-clinical in vivo studies of pharmacological interventions to treat high blood glucose in mouse models of type 2 diabetes.
Methods:
A systematic review of pre-clinical in vivo studies of pharmacological interventions aimed at addressing elevated blood glucose in mouse models of type 2 diabetes was completed. Studies were screened for eligibility and outcomes extracted from the included studies. The outcomes were recorded verbatim and classified into outcome domains using an existing outcome taxonomy. Outcomes were also compared to those identified in a systematic review of registered phase 3/4 clinical trials for glucose lowering interventions in people with type 2 diabetes.
Results:
Review of 280 included studies identified 532 unique outcomes across 19 domains. No single outcome, or domain, was measured in all studies and only 132 (21%) had also been measured in registered phase 3/4 clinical trials. A core outcome set, representing the minimum that should be measured and reported, developed for type 2 diabetes effectiveness clinical trials includes 18 core outcomes, of these 12 (71%) outcomes were measured and reported in one or more of the included pre-clinical studies.
Conclusions:
There is heterogeneity of outcomes reported in pre-clinical research. Harmonisation of outcomes across the research pathway using a core outcome set may facilitate interpretation, evidence synthesis and translational success, and may contribute to the refinement of the use of animals in research.
Systematic review registration: The study was prospectively registered on the PROSPERO Database, registration number CRD4201810683
Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change
Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (nā=ā12) or Alzheimerās disease neuropathologic change (nā=ā4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC
Loss of capillary pericytes and the bloodābrain barrier in white matter in poststroke and vascular dementias and Alzheimerās disease
White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the bloodābrain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet derived growth factor receptorāĪ² (PDGFRāĪ²) antibodies with further verification using PDGFRāĪ² specific ELISA. We evaluated a total of 124 postāmortem brains from subjects with postāstroke dementia (PSD), vascular dementia (VaD), Alzheimerās disease (AD), ADāVaD (Mixed), and postāstroke nonādemented (PSND) stroke survivors as well as normal ageing controls. COL4 and PDGFRāĪ² reactive pericytes adopted the characteristic ācrescentā or noduleālike shapes around capillary walls. We estimated densities of pericyte somata to be 225 Ā±38 and 200 Ā±13 (SEM) per COL4 mm2 area or 2.0 Ā±0.1 and 1.7 Ā±0.1 per mm capillary length in young and older ageing controls. Remarkably, WM pericytes were reduced by ~35ā45 percent in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P<0.001). We also found pericyte numbers were correlated with PDGFRāĪ² reactivity in the WM. Our results first demonstrate a reliable method to quantify COL4āpositive pericytes and then indicate that deep WM pericytes are decreased across different dementias including PSD, VaD, Mixed and AD. Our findings suggest that down regulation of pericytes is associated with the disruption of the BBB in the deep WM in several ageingārelated dementias
Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change.
Impaired episodic simulation in a patient with visual memory deficit amnesia
For the first time, we assess episodic simulation in a patient with visual memory deficit amnesia, following damage to visual association cortices. Compared to control participants, the patient with visual memory deficit amnesia shows severely restricted responses when asked to simulate different types of future episodic scenarios. Surprisingly, the patientās responses are more limited in cases where the scenarios require less reliance on visual information. We explain this counterintuitive finding through discussing how the severe retrograde amnesia in visual memory deficit amnesia limits the patientās access to episodic memories in which vision has not been a focus of their life. As a result, we argue that the deficits in visual memory deficit amnesia continue to distinguish it from amnesia after direct damage to the hippocampus
MOUSE - Mapping OUtcomes measured in pre-clinical Studies against randomised phase 3/4 Effectiveness trials. Do core outcome sets developed for phase3/4 effectiveness trials translate to pre-clinical research?
Differential perivascular microglial activation in the deep white matter in Vascular Dementia developed post Stroke
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Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change.
Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (nā=ā12) or Alzheimer's disease neuropathologic change (nā=ā4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC