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1.
J Neuroinflammation ; 11: 182, 2014 Oct 25.
Article in English | MEDLINE | ID: mdl-25343964

ABSTRACT

BACKGROUND: Microglial morphology within the healthy brain has been the subject of a number of observational studies. These have suggested that microglia may consist of separate classes, which possess substantially different morphological features. Critically, there have been no systematic quantitative studies of microglial morphology within the healthy brain. METHODS: We examined microglial cells within the adult rat prefrontal cortex. At high magnification, digital reconstructions of cells labelled with the microglial-specific marker ionized calcium-binding adapter molecule-1 (Iba-1) were made in each of the cortical layers. These reconstructions were subsequently analyzed to determine the convex hull area of the cells, their somal perimeter, the length of processes, the number of processes, the extent of process branching and the volume of processes. We additionally examined whether cells' morphological features were associated with cell size or numerical density. RESULTS: Our analysis indicated that while there was substantial variability in the size of cells within the prefrontal cortex, cellular morphology was extremely consistent within each of the cortical layers. CONCLUSIONS: Our results provide quantitative confirmation that microglia are largely homogenous in the uninjured rodent prefrontal cortex.


Subject(s)
Microglia/cytology , Prefrontal Cortex/cytology , Animals , Cell Size , Imaging, Three-Dimensional , Immunohistochemistry , Male , Rats , Rats, Sprague-Dawley
2.
Brain Behav Immun ; 42: 69-80, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24989856

ABSTRACT

A number of studies have identified that mutations in the P2X7 receptor occur with a significantly higher incidence in individuals with major depression. Consistent with these findings, a number of preclinical studies have identified that mice in which the P2X7 receptor has been deleted exhibit a higher level of resilience-like behaviour to acutely aversive situations. At present, however, no studies have examined changes in P2X7 receptor expression in otherwise healthy animals exposed to persistently stressful situations. This is significant as several lines of evidence have demonstrated that it is exposure to persistently aversive, rather than acutely aversive, situations that is associated with the emergence of mood disturbance. Accordingly, the objective of the current study was to examine whether chronic exposure to restraint stress was associated with alterations in the expression of P2X7 within the hippocampal formation. The study involved three principal groups: acute stress (1 session), chronic stress (21 sessions, 1 per day) and a chronic stress with recovery group (21 sessions, 1 per day followed by 7days of no stress) and appropriate control groups. The results of the analysis indicate that all forms of stress, regardless of the duration, provoked a reduction in P2X7 receptor expression. Comparative analysis on normalised data indicated that the magnitude of the P2X7 reduction was significantly greater in the chronic stress relative to the acute stress group. We additionally found that there was a gradual rebound in P2X7 expression, in two of nine regions examined, in animals that were allowed to recover for 7days following the final stress session. Collectively, these findings provide the first evidence that exposure to chronic restraint stress produces a pronounced and relatively persistent suppression of the P2X7 receptor within the hippocampus.


Subject(s)
Hippocampus/metabolism , Receptors, Purinergic P2X7/metabolism , Stress, Physiological/physiology , Stress, Psychological/metabolism , Animals , Depressive Disorder, Major/metabolism , Disease Models, Animal , Down-Regulation , Male , Rats , Rats, Sprague-Dawley , Restraint, Physical
3.
Brain Behav Immun ; 37: 1-14, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24412599

ABSTRACT

Microglia are unique cells within the central nervous system because of their biophysical independence. As a result of this unusual property the cells must undergo significant structural remodelling in order to engage and connect with other elements within the central nervous system. Efficient remodelling is required for all activities that microglia are involved in ranging from monitoring synaptic information flow through to phagocytosis of tissue debris. Despite the fact that morphological remodelling is a pre-requisite to all microglial activities, relatively little research has been undertaken on the topic. This review examines what is known about how microglia transform themselves during development, under physiological conditions in response to changes in neuronal activity, and under pathological circumstances. Specific attention is given to exploring a variety of models that have been proposed to account for microglial transformation as well as the signals that are known to trigger these transformations.


Subject(s)
Microglia/cytology , Microglia/physiology , Animals , Humans , Models, Neurological , Nervous System Diseases/pathology
4.
PLoS One ; 8(4): e59586, 2013.
Article in English | MEDLINE | ID: mdl-23560052

ABSTRACT

Recent human trials of treatments for Alzheimer's disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-ßAß? plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Aß were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Aß. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , CA1 Region, Hippocampal/pathology , Gliosis/pathology , Memory Disorders/pathology , Microglia/pathology , Plaque, Amyloid/pathology , Age Factors , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Biomarkers/metabolism , CA1 Region, Hippocampal/metabolism , CA3 Region, Hippocampal/cytology , CA3 Region, Hippocampal/metabolism , Cell Count , Disease Models, Animal , Early Diagnosis , Gene Expression , Gliosis/diagnosis , Gliosis/genetics , Gliosis/metabolism , Humans , Inflammation , Male , Memory Disorders/diagnosis , Memory Disorders/genetics , Memory Disorders/metabolism , Mice , Mice, Transgenic , Microglia/metabolism , Neurons/metabolism , Neurons/pathology , Plaque, Amyloid/diagnosis , Plaque, Amyloid/genetics , Plaque, Amyloid/metabolism , Stereotaxic Techniques
5.
Acta Neuropathol ; 126(1): 75-91, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23512378

ABSTRACT

Chronic stress is well recognized to decrease the number of GFAP⁺ astrocytes within the prefrontal cortex (PFC). Recent research, however, has suggested that our understanding of how stress alters astrocytes may be incomplete. Specifically, chronic stress has been shown to induce a unique form of microglial remodelling, but it is not yet clear whether astrocytes also undergo similar structural modifications. Such alterations may be significant given the role of astrocytes in modulating synaptic function. Accordingly, in the current study we have examined changes in astrocyte morphology following exposure to chronic stress in adult rats, using three-dimensional digital reconstructions of astrocytes. Our analysis indicated that chronic stress produced profound atrophy of astrocyte process length, branching and volume. We additionally examined changes in astrocyte-specific S100ß, which are both a putative astrocyte marker and a protein whose expression is associated with astrocyte distress. While we found that S100ß levels were increased by stress, this increase was not correlated with atrophy. We further established that while chronic stress was associated with a decrease in astrocyte numbers when GFAP labelling was used as a marker, we could find no evidence of a decrease in the total number of cells, based on Nissl staining, or in the number of S100ß⁺ cells. This finding suggests that chronic stress may not actually reduce astrocyte numbers and may instead selectively decrease GFAP expression. The results of the current study are significant as they indicate stress-induced astrocyte-mediated disturbances may not be due to a loss of cells but rather due to significant remodeling of the astrocyte network.


Subject(s)
Astrocytes/pathology , Brain/pathology , Stress, Psychological/pathology , Animals , Astrocytes/metabolism , Astrocytes/ultrastructure , Atrophy , Cell Count , Chronic Disease , Disease Models, Animal , Glial Fibrillary Acidic Protein/metabolism , Imaging, Three-Dimensional , Male , Neuroimaging , Rats , Rats, Sprague-Dawley
6.
Cereb Cortex ; 23(8): 1784-97, 2013 Aug.
Article in English | MEDLINE | ID: mdl-22710611

ABSTRACT

Recently, it has been discovered that the working memory deficits induced by exposure to chronic stress can be prevented by treating stressed animals with minocycline, a putative inhibitor of microglial activity. One of the pressing issues that now requires clarification is exactly how exposure to chronic stress modifies microglial morphology, this being a significant issue as microglial morphology is tightly coupled with their function. To examine how chronic stress alters microglial morphology, we digitally reconstructed microglia within the rat medial prefrontal cortex. Our analysis revealed that stress increased the internal complexity of microglia, enhancing ramification (i.e. branching) without altering the overall area occupied by the cell and that this effect was more pronounced in larger cells. We subsequently determined that minocycline treatment largely abolished the pro-ramifying effects of stress. With respect to mechanisms, we could not find any evidence of increased inflammation or neurodegeneration (interleukin-1ß, MHC-II, CD68, terminal deoxynucleotidyl transferase dUTP nick end labeling, and activated caspase-3). We did, however, find that chronic stress markedly increased the expression of ß1-integrin (CD29), a protein previously implicated in microglial ramification. Together, these findings highlight that increased ramification of microglia may represent an important neurobiological mechanism through which microglia mediate the behavioral effects of chronic psychological stress.


Subject(s)
Microglia/cytology , Minocycline/pharmacology , Prefrontal Cortex/cytology , Stress, Physiological/physiology , Animals , Male , Microglia/drug effects , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley
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