Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, with increasing prevalence affecting millions of people worldwide. Currently, only autopsy is able to confirm the diagnosis with a 100% certainty, therefore, biomarkers from body fluids obtained by non-invasive means provide an attractive alternative for the diagnosis of Alzheimer`s disease. Global changes of the protein profile were examined by quantitative proteomics; firstly, electrophoresis and LC-MS/MS were used, thereafter, SRM-based targeted proteomics method was developed and applied to examine quantitative changes of tear proteins. Alterations in the tear flow rate, total tear protein concentration and composition of the chemical barrier specific to AD were demonstrated, and the combination of lipocalin-1, dermcidin, lysozyme-C and lacritin was shown to be a potential biomarker, with an 81% sensitivity and 77% specificity.
Major depressive disorder is a common and complex mental disorder with unknown etiology. GABAergic dysfunction is likely to contribute to the pathophysiology since disrupted GABAergic systems are well documented in depressed patients. Here we studied structural changes in the hippocampal GABAergic network using the chronic mild stress (CMS) model, as one of the best validated animal models for depression. Rats were subjected to 9 weeks of daily stress and behaviorally characterized using the sucrose consumption test into anhedonic and resilient animals based on their response to stress. Different subtypes of GABAergic interneurons were visualized by immunohistochemistry using antibodies for parvalbumin (PV), calretinin (CR), calbindin (CB), cholecystokinin (CCK), somatostatin (SOM), and neuropeptide Y (NPY). We used an unbiased quantification method to systematically count labeled cells in different subareas of the dorsal and ventral hippocampus. Chronic stress reduced the number of specific interneurons in distinct hippocampal subregions significantly. PV+ and CR+ neurons were reduced in all dorsal subareas, whereas in the ventral part only the CA1 was affected. Stress had the most pronounced effect on the NPY+ and SOM+ cells and reduced their number in almost all dorsal and ventral subareas. Stress had no effect on the CCK+ and CB+ interneurons. In most cases the effect of stress was irrespective to the behavioral phenotype. However, in a few specific areas the number of SOM+, NPY+, and CR+ neurons were significantly reduced in anhedonic animals compared to the resilient group. Overall, these data clearly demonstrate that chronic stress affects the structural integrity of specific GABAergic neuronal subpopulations and this should also affect the functioning of these hippocampal GABAergic networks.
Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II–III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABAB receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.
Dendritic cells are considered as the main coordinators of both mucosal and systemic immune responses, thus playing a determining role in shaping the outcome of effector cell responses. However, it is still uncovered how primary human monocyte-derived DC (moDC) populations drive the polarization of helper T (Th) cells in the presence of commensal bacteria harboring unique immunomodulatory properties. Furthermore, the individual members of the gut microbiota have the potential to modulate the outcome of immune responses and shape the immunogenicity of differentiating moDCs via the activation of retinoic acid receptor alpha (RARα). Here, we report that moDCs are able to mediate robust Th1 and Th17 responses upon stimulation by Escherichia coli Schaedler or Morganella morganii, while the probiotic Bacillus subtilis strain limits this effect. Moreover, physiological concentrations of all-trans retinoic acid (ATRA) are able to re-program the differentiation of moDCs resulting in altered gene expression profiles of the master transcription factors RARα and interferon regulatory factor 4, and concomitantly regulate the cell surface expression levels of CD1 proteins and also the mucosa-associated CD103 integrin to different directions. It was also demonstrated that the ATRA-conditioned moDCs exhibited enhanced pro-inflammatory cytokine secretion while reduced their co-stimulatory and antigen-presenting capacity thus reducing Th1 and presenting undetectable Th17 type responses against the tested microbiota strains. Importantly, these regulatory circuits could be prevented by the selective inhibition of RARα functionality. These results altogether demonstrate that selected commensal bacterial strains are able to drive strong effector immune responses by moDCs, while in the presence of ATRA, they support the development of both tolerogenic and inflammatory moDC in a RARα-dependent manner.
Stress can alter the number and morphology of excitatory synapses in the hippocampus, but nothing is known about the effect of stress on inhibitory synapses. Here, we used an animal model for depression, the chronic mild stress model, and quantified the number of perisomatic inhibitory neurons and their synapses. We found reduced density of parvalbumin‐positive (PV+) neurons in response to stress, while the density of cholecystokinin‐immunoreactive (CCK+) neurons was unaffected. We did a detailed electron microscopic analysis to quantify the frequency and morphology of perisomatic inhibitory synapses in the hippocampal CA1 area. We analyzed 1100 CA1 pyramidal neurons and 4800 perisomatic terminals in five control and four chronically stressed rats. In the control animals we observed the following parameters: Number of terminals/soma = 57; Number of terminals/100 µm cell perimeter = 10; Synapse/terminal ratio = 32%; Synapse number/100 terminal = 120; Average terminal length = 920nm. None of these parameters were affected by the stress exposure. Overall, these data indicate that despite the depressive‐like behavior and the decrease in the number of perisomatic PV+ neurons in the light microscopic preparations, the number of perisomatic inhibitory synapses on CA1 pyramidal cells was not affected by stress. In the electron microscope, PV+ neurons and the axon terminals appeared to be normal and we did not find any apoptotic or necrotic cells. This data is in sharp contrast to the remarkable remodeling of the excitatory synapses on spines that has been reported in response to stress and depressive‐like behavior. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.
BackgroundThe aim of our study was to assess psychiatric symptoms in patients with genetically proven primary mutation of the mitochondrial DNA.Methods19 adults with known mitochondrial mutation (MT) have been assessed with the Stanford Health Assessment Questionnaire 20-item Disability Index (HAQ-DI), the Symptom Check List-90-Revised (SCL-90-R), the Beck Depression Inventory-Short Form (BDI-SF), the Hamilton Depression Rating Scale (HDRS) and the clinical version of the Structured Clinical Interview for the the DSM-IV (SCID-I and SCID-II) As control, 10 patients with hereditary sensorimotor neuropathy (HN), harboring the peripheral myelin protein-22 (PMP22) mutation were examined with the same tools.ResultsThe two groups did not differ significantly in gender, age or education. Mean HAQ-DI score was 0.82 in the MT (range: 0-1.625) and 0.71 in the HN group (range: 0-1.625). Level of disability between the two groups did not differ significantly (p = 0.6076). MT patients scored significantly higher on the BDI-SF and HDRS than HN patients (12.85 versus 4.40, p = 0.031, and 15.62 vs 7.30, p = 0.043, respectively). The Global Severity Index (GSI) of SCL-90-R also showed significant difference (1.44 vs 0.46, p = 0.013) as well as the subscales except for somatization. SCID-I interview yielded a variety of mood disorders in both groups. Eight MT patient (42%) had past, 6 (31%) had current, 5 (26%) had both past and current psychiatric diagnosis, yielding a lifetime prevalence of 9/19 (47%) in the MT group. In the HN group, 3 patients had both past and current diagnosis showing a lifetime prevalence of 3/10 (30%) in this group. SCID-II detected personality disorder in 8 MT cases (42%), yielding 3 avoidant, 2 obsessive-compulsive and 3 personality disorder not otherwise specified (NOS) diagnosis. No personality disorder was identified in the HN group.ConclusionsClinicians should be aware of the high prevalence of psychiatric symptoms in patients with mitochondrial mutation which has both etiologic and therapeutic relevance.
Marijuana is a widely used recreational drug with increasing legalization worldwide for medical purposes. Most experimental studies use either synthetic or plant-derived cannabinoids to investigate the effect of cannabinoids on anxiety and cognitive functions. The aim of this study was to mimic real life situations where young people smoke cannabis regularly to relax from everyday stress. Therefore, we exposed young adult male NMRI mice to daily stress and concomitant marijuana smoke for 2 months and investigated the consequences on physiology, behavior and adult hippocampal neurogenesis. Animals were restrained for 6-h/day for 5-days a week. During the stress, mice were exposed to cannabis smoke for 2 × 30 min/day. We burned 2 “joints” (2 × 0.8 g marijuana) per occasion in a whole body smoking chamber. Cannabinoid content of the smoke and urine samples was measured by HPLC and SFC-MS/MS. Body weight gain was recorded daily and we did unrestrained, whole body plethysmography to investigate pulmonary functions. The cognitive performance of the animals was evaluated by the novel object recognition and Y maze tests. Anxietyrelated spontaneous locomotor activity and self-grooming were assessed in the open field test (OFT). Adult neurogenesis was quantified post mortem in the hippocampal dentate gyrus. The proliferative activity of the precursor cells was detected by the use of the exogenous marker 5-bromo-20-deoxyuridine. Treatment effects on maturing neurons were studied by the examination of doublecortin-positive neurons. Both stress and cannabis exposure significantly reduced body weight gain. Cannabis smoke had no effect on pulmonary functions, but stress delayed the maturation of several lung functions. Neither stress, nor cannabis smoke affected the cognitive functioning of the animals. Results of the OFT revealed that cannabis had a mild anxiolytic effect and markedly increased self-grooming behavior. Stress blocked cell proliferation in the dentate gyrus, but cannabis had no effect on this parameter. Marijuana smoke however had a pronounced impact on doublecortin-positive neurons influencing their number, morphology and migration. In summary, we report here that long-term stress in combination with cannabis smoke exposure can alter several health-related measures, but the present experimental design could not reveal any interaction between these two treatment factors except for body weight gain.
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