[An evaluation of a Hungarian questionnaire to assess childhood adversities: A pilot study].

BACKGROUND: Detection of childhood traumas is important both in clinical practice and in research. There is a pressing need for methods that are relatively simple but comprehensive, non-intrusive, and possess adequate psyc - ho metric properties. In this study we translated one of the most widely used and well-studied measure of childhood abuse and neglect and explored the psychometrical properties of this questionnaire. METHODS: The study was based on data from a clinical (N=171) and a normative (N=358) sample. In total 529 adults participated in the testing process. Beside the trauma questionnaire Parental Bonding Inventory, Impact of Events Scale and Dissociative Experiences Scale were administered. RESULTS: We examined the internal consistency of the translated trauma questionnaire. The Cronbach's a coefficients for the five subscales ranged from 0,639 to 0,934. Participants in the clinical sample reached higher scores on all trauma subscales except sexual abuse, than normative adults [PA: t (398)=-2,771; p=0,006; PN: t (398)=-5,990; p=0,000; EA: t (398)=-3,679; p=0,000; EN: t (398)=-4,759; p=0,000; total score: t (398)=-4,669; p=0,000]. Correlations among the trauma questionnaire total score and the scales of Parental Bonding Inventory indicating some medium effects (with maternal care: r=-0,661; p=0,000; with paternal care: r=-0,483; p=0,000). CONCLUSION: Our preliminary findings suggest that this trauma questionnaire is practical and facilitates the systema - tic evaluation of adverse early life events and maximizes the possibility of detecting childhood abuse and neglect.

Much More Than a Pleasant Scent: A Review on Essential Oils Supporting the Immune System.

The augmenting acceptance and application of herbal medicine in prevention and treatment of diseases also involve the use of plant essential oils (EOs) through different routes of administration (aromatherapy). Scientific data supporting the efficacy of certain herbal products are continuously growing; however, the cumulative evidence is not always sufficient. The anti-inflammatory properties of EOs have been investigated more extensively and also reviewed in different settings, but so far, our review is the first to summarize the immune-supporting properties of EOs. Our aim here is to synthesize the currently available data on the immune function enhancing effects of EOs. An online search was conducted in the PubMed database, which was terminated at the end of July 2019. Other articles were found in the reference lists of the preselected papers. Studies that applied whole EOs with known components, or single EO constituents under in vitro or in vivo laboratory conditions, or in human studies, and de facto measured parameters related to immune function as outcome measures were included. Two specific fields, EO dietary supplementation for livestock and fish, and forest bathing are also explored. Some EOs, particularly eucalyptus and ginger, seem to have immune function enhancing properties in multiple studies.

Electron Microscopic Analysis of Hippocampal Axo-Somatic Synapses in a Chronic Stress Model for Depression.

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.

Chronic stress reduces the number of GABAergic interneurons in the adult rat hippocampus, dorsal-ventral and region-specific differences.

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.

Neuropathology of stress.

Environmental challenges are part of daily life for any individual. In fact, stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Using a broad definition of pathology, we here review the "neuropathology of stress" and focus on structural consequences of stress exposure for different regions of the rodent, primate and human brain. We discuss cytoarchitectural, neuropathological and structural plasticity measures as well as more recent neuroimaging techniques that allow direct monitoring of the spatiotemporal effects of stress and the role of different CNS structures in the regulation of the hypothalamic-pituitary-adrenal axis in human brain. We focus on the hypothalamus, hippocampus, amygdala, nucleus accumbens, prefrontal and orbitofrontal cortex, key brain regions that not only modulate emotions and cognition but also the response to stress itself, and discuss disorders like depression, post-traumatic stress disorder, Cushing syndrome and dementia.

Depressed patients with childhood maltreatment display altered intra- and inter-network resting state functional connectivity.

BACKGROUND: Childhood maltreatment (CM) is a major risk factor for the development of major depressive disorder (MDD). To gain more knowledge on how adverse childhood experiences influence the development of brain architecture, we studied functional connectivity (FC) alterations of neural networks of depressed patients with, or without the history of CM. METHODS: Depressed patients with severe childhood maltreatment (n = 18), MDD patients without maltreatment (n = 19), and matched healthy controls (n = 20) were examined with resting state functional MRI. History of maltreatment was assessed with the 28-item Childhood Trauma Questionnaire. Intra- and inter-network FC alterations were evaluated using FMRIB Software Library and CONN toolbox. RESULTS: We found numerous intra- and inter-network FC alterations between the maltreated and the non-maltreated patients. Intra-network FC differences were found in the default mode, visual and auditory networks, and cerebellum. Network modelling revealed several inter-network FC alterations connecting the default mode network with the executive control, salience and cerebellar networks. Increased inter-network FC was found in maltreated patients between the sensory-motor and visual, cerebellar, default mode and salience networks. LIMITATIONS: Relatively small sample size, cross-sectional design, and retrospective self-report questionnaire to assess adverse childhood experiences. CONCLUSIONS: Our findings confirm that severely maltreated depressed patients display numerous alterations of intra- and inter-network FC strengths, not only in their fronto-limbic circuits, but also in sensory-motor, visual, auditory, and cerebellar networks. These functional alterations may explain that maltreated individuals typically display altered perception and are prone to develop functional neurological symptom disorder (conversion disorder) in adulthood.

Novel multitarget analgesic candidate SZV-1287 demonstrates potential disease-modifying effects in the monoiodoacetate-induced osteoarthritis mouse model.

Introduction: Monoiodoacetate (MIA)-induced osteoarthritis (OA) is the most commonly used rodent model for testing anti-OA drug candidates. Herein, we investigated the effects of our patented multitarget drug candidate SZV-1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl) propanal oxime) that is currently under clinical development for neuropathic pain and characterized the mouse model through complex functional, in vivo imaging, and morphological techniques. Methods: Knee OA was induced by intraarticular MIA injection (0.5 and 0.8 mg). Spontaneous pain was assessed based on weight distribution, referred pain by paw mechanonociception (esthesiometry), edema by caliper, neutrophil myeloperoxidase activity by luminescence, matrix metalloproteinase activity, vascular leakage and bone remodeling by fluorescence imaging, bone morphology by micro-CT, histopathological alterations by semiquantitative scoring, and glia activation by immunohistochemistry. Then, SZV-1287 (20 mg/kg/day) or its vehicle was injected intraperitoneally over a 21-day period. Results: MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord. There were no major differences between the two MIA doses in most outcome measures. SZV-1287 inhibited MIA-induced weight bearing reduction, hyperalgesia, edema, myeloperoxidase activity, histopathological damage, and astrocyte and microglia density. Conclusion: SZV-1287 may have disease-modifying potential through analgesic, anti-inflammatory, and chondroprotective effects. The MIA mouse model is valuable for investigating OA-related mechanisms and testing compounds in mice at an optimal dose of 0.5 mg.

Circulating microRNAs correlate with structural and functional MRI parameters in patients with multiple sclerosis.

Introduction: Circulating microRNAs are promising biomarkers for multiple sclerosis (MS). Our aim was to correlate serum microRNA levels with various magnetic resonance imaging (MRI) parameters. Methods: We recruited 50 MS patients and measured cervical spine and cerebral white matter lesions together with regional brain volumes. Microstructural changes in the white matter were investigated with diffusion tensor imaging. Magnetic resonance spectroscopy was performed to measure cerebral metabolites. Functional connectivity within the default mode network was examined with resting-state functional MRI. On the day of the MRI measurements, we collected serum samples and carried out quantitative analysis of ten pre-selected microRNAs using droplet digital PCR. Results: Serum level of miR-143.3p could differentiate between MS subtypes and had lower levels in progressive MS types. We found significant associations between microRNA levels and MRI measures: (1) higher miR-92a.3p and miR-486.5p levels were associated with greater total white matter lesion volumes within the cervical spine, (2) decreased miR-142.5p levels was associated with reduced total creatinine concentration and (3) miR-92a.3p, miR-142.5p and miR-486.5p levels were associated with functional connectivity strengths between specific nodes of the default mode network. Specifically, we found a negative association between miR-92a.3p and miR-486.5p levels and connectivity strength between the lateral temporal cortex and posterior inferior parietal lobule, and a positive association between miR-142.5p level and connectivity strength between the retrosplenial cortex and temporal pole. However, miRNA levels were not associated with regional brain volumes. Conclusion: We provide here further evidence that circulating microRNAs may show correlation with both structural and functional neuroimaging outcomes in patients with MS.

Psychometric properties of the Hungarian childhood trauma questionnaire short form and its validity in patients with adult attention-deficit hyperactivity disorder or borderline personality disorder.

BACKGROUND: Compelling evidence supports the role of childhood traumatization in the etiology of psychiatric disorders, including adult attention-deficit hyperactivity disorder (aADHD) and borderline personality disorder (BPD). The aim of this study was to examine the psychometric properties of the Hungarian version of the Childhood Trauma Questionnaire Short Form (H-CTQ-SF) and to investigate the differences between patients diagnosed with aADHD and BPD in terms of early traumatization. METHODS: Altogether 765 (mean age = 32.8 years, 67.7% women) patients and control subjects were enrolled from different areas of Hungary. Principal component analysis and confirmatory factor analysis were carried out to explore the factor structure of H-CTQ-SF and test the validity of the five-factor structure. Discriminative validity was assessed by comparing clinical and non-clinical samples. Subsequently, aADHD and BPD subgroups were compared with healthy controls to test for the role of early trauma in aADHD without comorbid BPD. Convergent validity was explored by measuring correlations with subscales of the Personality Inventory for DSM-5 (PID-5). RESULTS: The five scales of the H-CTQ-SF demonstrated adequate internal consistency and reliability values. The five-factor model fitted the Hungarian version well after exclusion of one item from the physical neglect scale because of its cross-loading onto the emotional neglect subscale. The H-CTQ-SF effectively differentiated between the clinical and non-clinical samples. The BPD, but not the aADHD group showed significant differences in each CTQ domain compared with the healthy control group. All CTQ domains, except for physical abuse, demonstrated medium to high correlations with PID-5 emotional lability, anxiousness, separation insecurity, withdrawal, intimacy avoidance, anhedonia, depressivity, suspiciousness, and hostility subscales. CONCLUSIONS: Our study confirmed the psychometric properties of the H-CTQ-SF, an easy-to-administer, non-invasive, ethically sound questionnaire. In aADHD patients without comorbid BPD, low levels of traumatization in every CTQ domain were comparable to those of healthy control individuals. Thus, the increased level of traumatization found in previous studies of aADHD might be associated with the presence of comorbid BPD. Our findings also support the role of emotional neglect, emotional abuse and sexual abuse in the development of BPD.

Lacking ARHGAP25 mitigates the symptoms of autoantibody-induced arthritis in mice.

Objective: Despite intensive research on rheumatoid arthritis, the pathomechanism of the disease is still not fully understood and the treatment has not been completely resolved. Previously we demonstrated that the GTPase-activating protein, ARHGAP25 has a crucial role in the regulation of basic phagocyte functions. Here we investigate the role of ARHGAP25 in the complex inflammatory process of autoantibody-induced arthritis. Methods: Wild-type and ARHGAP25 deficient (KO) mice on a C57BL/6 background, as well as bone marrow chimeric mice, were treated i.p. with the K/BxN arthritogenic or control serum, and the severity of inflammation and pain-related behavior was measured. Histology was prepared, leukocyte infiltration, cytokine production, myeloperoxidase activity, and superoxide production were determined, and comprehensive western blot analysis was conducted. Results: In the absence of ARHGAP25, the severity of inflammation, joint destruction, and mechanical hyperalgesia significantly decreased, similarly to phagocyte infiltration, IL-1ß, and MIP-2 levels in the tibiotarsal joint, whereas superoxide production or myeloperoxidase activity was unchanged. We observed a significantly mitigated phenotype in KO bone marrow chimeras as well. In addition, fibroblast-like synoviocytes showed comparable expression of ARHGAP25 to neutrophils. Significantly reduced ERK1/2, MAPK, and I-κB protein signals were detected in the arthritic KO mouse ankles. Conclusion: Our findings suggest that ARHGAP25 has a key role in the pathomechanism of autoantibody-induced arthritis in which it regulates inflammation via the I-κB/NF-κB/IL-1ß axis with the involvement of both immune cells and fibroblast-like synoviocytes.

A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress.

Exposure to severe, uncontrollable and long-lasting stress is a strong risk factor for the development of numerous mental and somatic disorders. Animal studies document that chronic stress can alter neuronal morphology and functioning in limbic brain structures such as the prefrontal cortex. Mitochondria are intracellular powerhouses generating chemical energy for biochemical reactions of the cell. Recent findings document that chronic stress can lead to changes in mitochondrial function and metabolism. Here, we studied putative mitochondrial damage in response to chronic stress in neurons of the medial prefrontal cortex. We performed a systematic quantitative ultrastructural analysis to examine the consequences of 9-weeks of chronic mild stress on mitochondria number and morphology in the infralimbic cortex of adult male rats. In this preliminary study, we analyzed 4,250 electron microscopic images and 67000 mitochondria were counted and examined in the brains of 4 control and 4 stressed rats. We found significantly reduced number of mitochondria in the infralimbic cortex of the stressed animals, but we could not detect any significant alteration in mitochondrial morphology. These data support the concept that prolonged stress can lead to mitochondrial loss. This in turn may result in impaired energy production. Reduced cellular energy may sensitize the neurons to additional injuries and may eventually trigger the development of psychopathologies.

Mossy cells of the dentate gyrus: Drivers or inhibitors of epileptic seizures?

Mossy cells (MCs) are glutamatergic cells of the dentate gyrus with an important role in temporal lobe epilepsy. Under physiological conditions MCs can control both network excitations via direct synapses to granule cells and inhibition via connections to GABAergic interneurons innervating granule cells. In temporal lobe epilepsy mossy cell loss is one of the major hallmarks, but whether the surviving MCs drive or inhibit seizure initiation and generalization is still a debate. The aim of the present review is to summarize the latest findings on the role of mossy cells in healthy and overexcited hippocampus.

Novel drug developmental strategies for treatment-resistant depression.

Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment-resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I-III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu5 receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S-ketamine, but add-on therapies with second-generation antipsychotics, certain nutritive, anti-inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large-scale, high-throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies.

Experimental Arthritis Inhibits Adult Hippocampal Neurogenesis in Mice.

Background: Adult-born neurons of the hippocampal dentate gyrus play a role in specific forms of learning, and disturbed neurogenesis seems to contribute to the development of neuropsychiatric disorders, such as major depression. Neuroinflammation inhibits adult neurogenesis, but the effect of peripheral inflammation on this form of neuroplasticity is ambiguous. Objective: Our aim was to investigate the influence of acute and chronic experimental arthritis on adult hippocampal neurogenesis and to elucidate putative regulatory mechanisms. Methods: Arthritis was triggered by subcutaneous injection of complete Freund's adjuvant (CFA) into the hind paws of adult male mice. The animals were killed either seven days (acute inflammation) or 21 days (chronic inflammation) after the CFA injection. Behavioral tests were used to demonstrate arthritis-related hypersensitivity to painful stimuli. We used in vivo bioluminescence imaging to verify local inflammation. The systemic inflammatory response was assessed by complete blood cell counts and by measurement of the cytokine/chemokine concentrations of TNF-α, IL-1α, IL-4, IL-6, IL-10, KC and MIP-2 in the inflamed hind limbs, peripheral blood and hippocampus to characterize the inflammatory responses in the periphery and in the brain. In the hippocampal dentate gyrus, the total number of newborn neurons was determined with quantitative immunohistochemistry visualizing BrdU- and doublecortin-positive cells. Microglial activation in the dentate gyrus was determined by quantifying the density of Iba1- and CD68-positive cells. Results: Both acute and chronic arthritis resulted in paw edema, mechanical and thermal hyperalgesia. We found phagocytic infiltration and increased levels of TNF-α, IL-4, IL-6, KC and MIP-2 in the inflamed hind paws. Circulating neutrophil granulocytes and IL-6 levels increased in the blood solely during the acute phase. In the dentate gyrus, chronic arthritis reduced the number of doublecortin-positive cells, and we found increased density of CD68-positive macrophages/microglia in both the acute and chronic phases. Cytokine levels, however, were not altered in the hippocampus. Conclusions: Our data suggest that acute peripheral inflammation initiates a cascade of molecular and cellular changes that eventually leads to reduced adult hippocampal neurogenesis, which was detectable only in the chronic inflammatory phase.

Benefits of animal models to understand the pathophysiology of depressive disorders.

Major depressive disorder (MDD) is a potentially life-threatening mental disorder imposing severe social and economic burden worldwide. Despite the existence of effective antidepressant treatment strategies the exact pathophysiology of the disease is still unknown. Large number of animal models of MDD have been developed over the years, but all of them suffer from significant shortcomings. Despite their limitations these models have been extensively used in academic research and drug development. The aim of this review is to highlight the benefits of animal models of MDD. We focus here on recent experimental data where animal models were used to examine current theories of this complex disease. We argue, that despite their evident imperfections, these models provide invaluable help to understand cellular and molecular mechanisms contributing to the development of MDD. Furthermore, animal models are utilized in research to find clinically useful biomarkers. We discuss recent neuroimaging and microRNA studies since these investigations yielded promising candidates for biomarkers. Finally, we briefly summarize recent progresses in drug development, i.e. the FDA approval of two novel antidepressant drugs: S-ketamine and brexanolone (allopregnanolone). Deeper understanding of the exact molecular and cellular mechanisms of action responsible for the antidepressant efficacy of these rapid acting drugs could aid us to design further compounds with similar effectiveness, but less side effects. Animal studies are likely to provide valuable help in this endeavor.

Childhood maltreatment results in altered deactivation of reward processing circuits in depressed patients: A functional magnetic resonance imaging study of a facial emotion recognition task.

IMPORTANCE AND OBJECTIVES: Childhood adversity is a strong risk factor for the development of various psychopathologies including major depressive disorder (MDD). However, not all depressed patients experience early life trauma. Functional magnetic resonance imaging (fMRI) studies using facial emotion processing tasks have documented altered blood-oxygen-level-dependent (BOLD) responses in specific cortico-limbic networks both in MDD patients and in individuals with a history of childhood maltreatment (CM). Therefore, a history of maltreatment may represent a key modulating factor responsible for the altered processing of socio-affective stimuli. To test this hypothesis, we recruited MDD patients with and without of maltreatment history to study the long-term consequences of childhood trauma and examined the impact of CM on brain activity using a facial emotion recognition fMRI task. METHODS: MDD patients with childhood maltreatment (MDD + CM, n = 21), MDD patients without maltreatment (MDD, n = 19), and healthy controls (n = 21) matched for age, sex and intelligence quotient underwent fMRI while performing a block design facial emotion matching task with images portraying negative emotions (fear, anger and sadness). The history of maltreatment was assessed with the 28-item Childhood Trauma Questionnaire. RESULTS: Both MDD and MDD + CM patients displayed impaired accuracy to recognize sad faces. Analysis of brain activity revealed that MDD + CM patients had significantly reduced negative BOLD signals in their right accumbens, subcallosal cortex, and anterior paracingulate gyrus compared to controls. Furthermore, MDD + CM patients had a significantly increased negative BOLD response in their right precentral and postcentral gyri compared to controls. We found little difference between MDD and MDD + CM patients, except that MDD + CM patients had reduced negative BOLD response in their anterior paracingulate gyrus relative to the MDD group. CONCLUSIONS: Our present data provide evidence that depressed patients with a history of maltreatment are impaired in facial emotion recognition and that they display altered functioning of key reward-related fronto-striatal circuits during a facial emotion matching task.

Quantitative changes in hippocampal microvasculature of chronically stressed rats: no effect of fluoxetine treatment.

Exposure to chronic stress alters the number and morphology of neurons and glia in the hippocampal formation; however, little is known about possible changes in vasculature. Here, we examined the effect of chronic social defeat stress on hippocampal vascular supply in rats. Recent reports document that antidepressant treatment can influence angiogenesis in the hippocampus; therefore, we also studied the effect of antidepressant drug treatment on hippocampal capillarization. Animals were subjected to 5 weeks of daily social defeat by an aggressive conspecific and received concomitant, daily, oral fluoxetine (10 mg/kg) treatment during the last 4 weeks. Rat endothelial cell antigen-1 (RECA-1)-labeling of capillaries and quantitative stereological techniques were used to evaluate the treatment effects on capillary number. Special attention was paid to analysis of the vascular supply of the subgranular zone, which is regarded as an important component of the neurogenic niche for adult hippocampal neurogenesis. Chronic stress significantly decreased the number of microvessels by 30% in all hippocampal subregions, whereas fluoxetine treatment had no influence on capillary number. Furthermore, chronic stress decreased the capillarization of the subgranular zone to a similar extent, indicating that chronic stress affects the vascular niche for adult hippocampal neurogenesis. However, fluoxetine treatment had no impact on capillarization in the subgranular zone. We also detected a decrease in hippocampal volume in the animals as a result of stress, which was mildly altered by fluoxetine treatment. These pronounced changes in vascular supply may explain why the hippocampus is more vulnerable to insults when chronic stress precedes or coincides with other harmful conditions. Reduced microvasculature may also contribute to hippocampal volume decrease in stress-related disorders.

Examining the Relationship Between Executive Functions and Mentalizing Abilities of Patients With Borderline Personality Disorder.

Patients with borderline personality disorder (BPD) experience interpersonal dysfunctions; therefore, it is important to understand their social functioning and the confounding factors. We aimed to investigate the mentalizing abilities and executive functioning (EF) of BPD patients and healthy subjects and to determine the relative importance of BPD diagnosis and EF in predicting mentalizing abilities while controlling for general IQ and comorbid symptom severity. Self-oriented mentalizing (operationalized as emotional self-awareness/alexithymia), other-oriented mentalizing [defined as theory of mind (ToM)], and several EF domains were examined in 18 patients with BPD and 18 healthy individuals. Decoding and reasoning subprocesses of ToM were assessed by standard tasks (Reading the Mind in the Eyes Test and Faux Pas Test, respectively). Relative to controls, BPD patients exhibited significant impairments in emotional self-awareness and ToM reasoning; however, their ToM decoding did not differ. Multivariate regression analyses revealed that comorbid psychiatric symptoms were negative predictors of alexithymia and ToM decoding. Remarkably, the diagnosis of BPD was a positive predictor of ToM decoding but negatively influenced reasoning. Moreover, EF had no impact on alexithymia, while better IQ, and EF predicted superior ToM reasoning. Despite the small sample size, our results provide evidence that there is a dissociation between mental state decoding and reasoning in BPD. Comorbid psychiatric symptoms could be considered as significant negative confounds of self-awareness and ToM decoding in BPD patients. Conversely, the impairment of ToM reasoning was closely related to the diagnosis of BPD itself but not to the severity of the psychopathology.

Stress-Induced Morphological, Cellular and Molecular Changes in the Brain-Lessons Learned from the Chronic Mild Stress Model of Depression.

Major depressive disorder (MDD) is a severe illness imposing an increasing social and economic burden worldwide. Numerous rodent models have been developed to investigate the pathophysiology of MDD. One of the best characterized and most widely used models is the chronic mild stress (CMS) model which was developed more than 30 years ago by Paul Willner. More than 2000 published studies used this model, mainly to assess novel compounds with potential antidepressant efficacy. Most of these studies examined the behavioral consequences of stress and concomitant drug intervention. Much fewer studies focused on the CMS-induced neurobiological changes. However, the stress-induced cellular and molecular changes are important as they may serve as potential translational biomarkers and increase our understanding of the pathophysiology of MDD. Here, we summarize current knowledge on the structural and molecular alterations in the brain that have been described using the CMS model. We discuss the latest neuroimaging and postmortem histopathological data as well as molecular changes including recent findings on microRNA levels. Different chronic stress paradigms occasionally deliver dissimilar findings, but the available experimental data provide convincing evidence that the CMS model has a high translational value. Future studies examining the neurobiological changes in the CMS model in combination with clinically effective antidepressant drug intervention will likely deliver further valuable information on the pathophysiology of MDD.

Stress-Induced Microstructural Alterations Correlate With the Cognitive Performance of Rats: A Longitudinal in vivo Diffusion Tensor Imaging Study.

Background: Stress-induced cellular changes in limbic brain structures contribute to the development of various psychopathologies. In vivo detection of these microstructural changes may help us to develop objective biomarkers for psychiatric disorders. Diffusion tensor imaging (DTI) is an advanced neuroimaging technique that enables the non-invasive examination of white matter integrity and provides insights into the microstructure of pathways connecting brain areas. Objective: Our aim was to examine the temporal dynamics of stress-induced structural changes with repeated in vivo DTI scans and correlate them with behavioral alterations. Methods: Out of 32 young adult male rats, 16 were exposed to daily immobilization stress for 3 weeks. Four DTI measurements were done: one before the stress exposure (baseline), two scans during the stress (acute and chronic phases), and a last one 2 weeks after the end of the stress protocol (recovery). We used a 4.7T small-animal MRI system and examined 18 gray and white matter structures calculating the following parameters: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). T2-weighted images were used for volumetry. Cognitive performance and anxiety levels of the animals were assessed in the Morris water maze, novel object recognition, open field, and elevated plus maze tests. Results: Reduced FA and increased MD and RD values were found in the corpus callosum and external capsule of stressed rats. Stress increased RD in the anterior commissure and reduced MD and RD in the amygdala. We observed time-dependent changes in several DTI parameters as the rats matured, but we found no evidence of stress-induced volumetric alterations in the brains. Stressed rats displayed cognitive impairments and we found numerous correlations between the cognitive performance of the animals and between various DTI metrics of the inferior colliculus, corpus callosum, anterior commissure, and amygdala. Conclusions: Our data provide further support to the translational value of DTI studies and suggest that chronic stress exposure results in similar white matter microstructural alterations that have been documented in stress-related psychiatric disorders. These DTI findings imply microstructural abnormalities in the brain, which may underlie the cognitive deficits that are often present in stress-related mental disorders.