Prefrontal cortex astroglia modulate anhedonia-like behavior.

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

Prefrontal Cortex Astroglia Modulate Anhedonia-like Behavior.

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

Optic nerve sheath diameter measurement: a means of detecting increased intracranial pressure in pseudotumor cerebri patients.

BACKGROUND: Pseudotumor cerebri (PTC) occurs when the pressure inside the skull increases for no obvious reason. The aim of this study was to investigate three different methods: the optic nerve sheath diameter (ONSD) method, ONSD/eyeball transverse diameter (ETD) index, and ONSD/orbital transverse diameter (OTD) index for the initial detection of elevated intracranial pressure in patients with PTC. MATERIALS AND METHODS: A retrospective study of magnetic resonance data from adult PTC patients (n = 42) and control group (n = 40) was performed. ONSD and OTD measurements were made 3 mm and 10 mm posterior to the globe, after intracranial pressure was measured with lumbar puncture. The sensitivity, specificity, and overall accuracy of the findings on magnetic resonance imaging were calculated. RESULTS: The optic nerve sheath was enlarged in the PTC group compared with the control group. It showed 97% sensitivity and 100% specificity and 79% sensitivity and 87.5% specificity for 3 mm and 10 mm, respectively. The ONSD/ETD and ONSD/OTD indices were increased in the PTC group compared with the control group. For 3 mm posterior to the globe, the ONSD/ETD index had 90.5% sensitivity and 92% specificity, and the ONSD/OTD index had 86% sensitivity and 95% specificity. For 10 mm posterior to the globe, the sensitivity and specificity of the ONSD/ETD and ONSD/OTD indices were 86% and 80% and 74% and 82.5%, respectively. CONCLUSIONS: According to our study, the ONSD method and the ONSD/ETD and ONSD/OTD indices are reliable diagnostic markers for PTC. These noninvasive techniques may be useful in monitoring the invasive intracranial catheter and have wide potential clinical applications in district hospitals, emergency departments and intensive care units.

Do SGLT2 inhibitors prevent preclinical diabetic retinopathy? A Prospective Pilot Optical Coherence Tomography Angiography Study.

PURPOSE: To evaluate the effects of metformin alone and combined treatment with metformin and an SGLT2 inhibitor on retinal microvascular morphology using optical coherence tomography angiography (OCTA) in isolated type 2 diabetes mellitus (DM) patients with HbA1c above the expected target (>7%). METHODS: Fifty patients with isolated DM, 7%

Evaluation of thiol-disulfide homeostasis in pseudoexfoliation glaucoma and primary open-angle glaucoma.

AIMS: This study aimed to compare the serum thiol-disulfide homeostasis, total antioxidant status (TAS), and total oxidant status (TOS) in patients with pseudoexfoliation glaucoma (PEG) patients, primary open-angle glaucoma (POAG) patients, and healthy individuals (control). METHODS: Ninety subjects were included in this study. Three groups were separated as PEG, POAG, and control. All groups were chosen to be similar in terms of age and gender. Blood samples were obtained following an overnight fasting state and were collected on the ice at 4°C. The serum samples were separated from the cells by centrifugation at 3000 rpm for 15 min and were stored at -80°C. Serum samples analyzed for TAS and TOS, native thiol, total thiol, disulfide, and native thiol/disulfide ratio. RESULTS: TAS and TOS levels of PEG patients were 1.2892 ± 0.0905 mmol/L; 5.0191 ± 2.7722 µmol/L, respectively. TAS and TOS levels of POAG patients were 1.2741 ± 0.1252 mmol/L; 4.1674 ± 1.7723 µmol/L, respectively. TAS and TOS levels of the control group were 2.3414 ± 0.1409 mmol/L; 4.0931 ± 0.1107 µmol/L, respectively. The TAS level was significantly lower in PEG and POAG groups compared to control. TOS level showed no significant differ ¬ ence between PEG, POAG, and control groups (P > 0.05). The mean serum total thiol and native thiol levels were significantly lower in patients with PEG compared to POAG and control group; there was no significant difference between the POAG and control group (P > 0.05). The mean serum disulfide level was significantly lower in patients with PEG compared to POAG (P = 0.018). CONCLUSION: Low levels of TAS were observed in patients with glaucoma, which was likely a response to the increased oxidative stress observed in these patients. While total thiol and native thiol levels were higher in the PEG group, the disulfide level was higher in the POAG group. TAS and TOS levels showed no significant difference between POAG and PEG groups.

Structural changes of macula and optic disk of the fellow eye in patients with nonarteritic anterior ischemic optic neuropathy.

PURPOSE: The aim was to assess the ganglion cell complex (GCC) thickness, retinal nerve fiber layer (RNFL) thickness and optic disk features in the affected eyes (AE) and unaffected fellow eyes (FE) of subjects with unilateral nonarteritic anterior ischemic optic neuropathy (NAION) and to compare with healthy control eyes (CE) using spectral domain-optical coherence tomography (SD-OCT). METHODS: This study included 28 patients and age, sex and refraction-matched 28 control subjects. Mean GCC thickness and peripapillary RNFL thickness in four quadrants measured by cirrus SD-OCT were evaluated in both AE and FE of patients and CE. In addition, optic disk measurements obtained with OCT were evaluated. RESULTS: Mean GCC thickness was significantly lower in AE compared with both FE and CE (P < 0.001), and mean GCC thickness in FE was significantly lower than CE (P = 0.022). In addition, mean RNFL thickness in superior and nasal quadrants significantly decreased in FE compared with CE (P = 0.020 and 0.010, respectively). Furthermore, AE had significantly greater optic disk cupping compared with both FE and CE (P < 0.001). CONCLUSIONS: GCC and RNFL thickness decreased significantly at late stages of NAION, in both AE and FE compared with CE, suggesting that some subclinical structural changes may occur in FE despite lack of obvious visual symptoms. In addition, there was no significant difference in optic disk features between the CE and FE. And significantly greater optic disk cupping in the AE compared with both FE and CE supports the acquired enlargement of cupping after the onset of NAION.

Ocular adnexal lymphomas: An eye care service experience in Turkey.

AIM: This study aimed to evaluate the clinical and pathological features of ocular adnexal lymphoma (OAL) and the treatment results in an eye care service center in Turkey. MATERIALS AND METHODS: The data sets of the patients diagnosed with OAL acquired between January 2008 and January 2016 were collected and analyzed. RESULTS: Fifteen patients were included in our study. The mean age was 55.80 ± 17.85 years. The age range was 7-85 years. Most of the lesions originated from orbital tissue, and histopathological and immunohistochemistry examinations of the lesions were consistent with non-Hodgkin's lymphoma in 14 patients and Hodgkin's lymphoma in 1 patient. The most common subtype of OAL, accounting for 40% of cases, is extranodular marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type. CONCLUSION: Most of our patients' histopathological and immunohistochemistry examinations are non-Hodgkin's type and also involve the orbits. Ocular adnexal lymphomatosis is not a rare disorder and could be treated if there is no systemic involvement at first diagnosis.

Analysis of corneal astigmatism with NIDEK axial length scan in caucasian cataract surgery candidates.

AIMS AND OBJECTIVES: The aim of the study was to analyze and quantify the pattern of corneal astigmatism in Caucasian cataract surgery patients using a new optical biometer (axial length [AL] Scan, NIDEK Co., Gamagori, Japan). PATIENTS AND METHODS: The datasets of cataract surgery patients acquired between March 1, 2014, and April 15, 2016, were collected and analyzed. The corneal power (flat keratometry, steep keratometry, and mean keratometry), negative cylinder power, and axis of astigmatism were recorded. Keratometry values were optically measured by optical low coherence interferometry (AL-Scan, NIDEK Co., Ltd.,) before cataract extraction. RESULTS: The study comprised 1233 eyes of 838 consecutive cataract candidates with a mean age of 66.8 ± 10.7 years (range 40-97 years). The mean keratometry value and corneal astigmatism were 43.69 ± 1.61 D and 0.84 ± 0.70 D, respectively. Corneal astigmatism of 1.00 D or greater was found in 344 eyes (27.9%), and 548 eyes (44.4%) had against-the-rule astigmatism. A trend toward decreasing J0 and J45 with age was found by linear regression models. The per-year increase in age was associated with a J0 and J45 decrease of 0.002 D and 0.001D, respectively. CONCLUSION: This study provides the distribution of astigmatism axis and power for cataract patients in age subsets from Turkey.

BDNF release and signaling are required for the antidepressant actions of GLYX-13.

Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-D-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized. Here we use a combination of neutralizing antibody (nAb), mutant mouse and pharmacological approaches to test the role of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TrkB) signaling in the actions of GLYX-13. The results demonstrate that the antidepressant effects of GLYX-13 are blocked by intra-medial prefrontal cortex (intra-mPFC) infusion of an anti-BDNF nAb or in mice with a knock-in of the BDNF Val66Met allele, which blocks the processing and activity-dependent release of BDNF. We also demonstrate that pharmacological inhibitors of BDNF-TrkB signaling or of L-type voltage-dependent Ca2+ channels (VDCCs) block the antidepressant behavioral actions of GLYX-13. Finally, we examined the role of the Rho GTPase proteins by injecting a selective inhibitor into the mPFC and found that activation of Rac1 but not RhoA is involved in the antidepressant effects of GLYX-13. Together, these findings indicate that enhanced release of BDNF through exocytosis caused by activation of VDCCs and subsequent TrkB-Rac1 signaling is required for the rapid and sustained antidepressant effects of GLYX-13.

Long-wavelength macromolecular crystallography - First successful native SAD experiment close to the sulfur edge.

Phasing of novel macromolecular crystal structures has been challenging since the start of structural biology. Making use of anomalous diffraction of natively present elements, such as sulfur and phosphorus, for phasing has been possible for some systems, but hindered by the necessity to access longer X-ray wavelengths in order to make most use of the anomalous scattering contributions of these elements. Presented here are the results from a first successful experimental phasing study of a macromolecular crystal structure at a wavelength close to the sulfur K edge. This has been made possible by the in-vacuum setup and the long-wavelength optimised experimental setup at the I23 beamline at Diamond Light Source. In these early commissioning experiments only standard data collection and processing procedures have been applied, in particular no dedicated absorption correction has been used. Nevertheless the success of the experiment demonstrates that the capability to extract phase information can be even further improved once data collection protocols and data processing have been optimised.

Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects.

Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in the medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1H-[13C]-nuclear magnetic resonance spectroscopy. Rats were acutely pretreated by intraperitoneal injection with a single dose of ketamine (1, 3, 10, 30 and 80 mg kg-1), Ro 25-6981 (1, 3 and 10 mg kg-1), scopolamine (5, 25 and 100 µg kg-1) or vehicle (controls). At fixed times after drug injection, animals received an intravenous infusion of [1,6-13C2]glucose for 8 min to enrich the amino-acid pools of the brain with 13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13C enrichments were measured. We found a clear dose-dependent effect of ketamine and Ro 25-6981 on behavior and the percentage of 13C enrichment of glutamate, glutamine and GABA (γ-aminobutyric acid). Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggest that the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity.

A micro-patterned silicon chip as sample holder for macromolecular crystallography experiments with minimal background scattering.

At low emittance synchrotron sources it has become possible to perform structure determinations from the measurement of multiple microcrystals which were previously considered too small for diffraction experiments. Conventional mounting techniques do not fulfill the requirements of these new experiments. They significantly contribute to background scattering and it is difficult to locate the crystals, making them incompatible with automated serial crystallography. We have developed a micro-fabricated sample holder from single crystalline silicon with micropores, which carries up to thousands of crystals and significantly reduces the background scattering level. For loading, the suspended microcrystals are pipetted onto the chip and excess mother liquor is subsequently soaked off through the micropores. Crystals larger than the pore size are retained and arrange themselves according to the micropore pattern. Using our chip we were able to collect 1.5 Å high resolution diffraction data from protein microcrystals with sizes of 4 micrometers and smaller.

Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression.

Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. Moreover, there is now evidence that medication-induced recovery involves changes in synaptic plasticity and dendrite morphology, including increased expression of pre- and postsynaptic plasticity-related proteins, as well as the density and function of axo-spinous synapses. Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents.

The roles of neurotrophic factor and Wnt signaling in depression.

Depression is a debilitating disease with a lifetime prevalence of ~16% in the American population. In addition to the monoamine hypothesis, altered expressions of neurotrophic factors, growth factors, and Wnt signaling are implicated in the pathophysiology and treatment of depression. This review focuses on intracellular signaling cascades that underlie depression and treatment response.

Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole.

Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.

Neurobiology and treatment of anxiety: signal transduction and neural plasticity.

The stress-dependence and chronic nature of anxiety disorders along with the anxiolytic effectiveness of antidepressant drugs suggests that neuronal plasticity may play a role in the pathophysiology of anxiety. Intracellular signaling pathways are known in many systems to be critical links in the cascades from surface signals to the molecular alterations that result in functional plasticity. Chronic antidepressant treatments can regulate intracellular signaling pathways and can induce molecular, cellular, and structural changes over time. These changes may be important to the anxiolytic effectiveness of these drugs. In addition, the signaling proteins implicated in the actions of chronic antidepressant action, such as cAMP response element binding protein (CREB), have also been implicated in conditioned fear and in anxiety. The cellular mechanisms underlying conditioned fear indicate roles for additional signaling pathways; however, less is known about such mechanisms in anxiety. The challenge to identify intracellular signaling pathways and related molecular and structural changes that are critical to the etiology and treatment of anxiety will further establish the importance of mechanisms of neuronal plasticity in functional outcome and improve treatment strategies.

Inducible, brain region-specific expression of a dominant negative mutant of c-Jun in transgenic mice decreases sensitivity to cocaine.

Administration of cocaine induces the Fos family of transcription factors in the striatum, including the nucleus accumbens (NAc), a brain region important for the rewarding effects of addictive drugs. Several Fos proteins are induced acutely by cocaine, with stable isoforms of DeltaFosB predominating after chronic drug administration. However, it has been difficult to study the functional consequences of these Fos responses in vivo. Fos proteins heterodimerize with members of the Jun family to form active AP-1 transcription factor complexes. In the present study, we took advantage of this property and generated transgenic mice, using the tetracycline gene regulation system, that support the inducible, brain region-specific expression of a dominant negative mutant form of c-Jun (Deltac-Jun), which can antagonize the actions of Fos proteins. Expression of Deltac-Jun in the striatum and certain other brain regions of adult mice decreases their development of cocaine-induced conditioned place preference, suggesting reduced sensitivity to the rewarding effects of cocaine. In contrast, Deltac-Jun expression had no effect on cocaine-induced locomotor activity or sensitization. However, expression of Deltac-Jun in adult mice blocked the ability of chronic cocaine administration to induce three known targets for AP-1 in the NAc: the AMPA glutamate receptor subunit GluR2, the cyclin-dependent protein kinase Cdk5, and the transcription factor nuclear factor-kappaB (NFkappaB), without affecting several other proteins examined for comparison. Taken together, these results provide further support for an important role of AP-1-mediated transcription in some of the behavioral and molecular mechanisms underlying cocaine addiction.

Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus.

Neurogenesis continues to occur in the adult hippocampus, although many of the newborn cells degenerate 1-2 weeks after birth. The number and survival of newborn cells are regulated by a variety of environmental stimuli, but very little is known about the intracellular signal transduction pathways that control adult neurogenesis. In the present study, we examine the expression of the phosphorylated cAMP response element-binding protein (pCREB) in immature neurons in adult hippocampus and the role of the cAMP cascade in the survival of new neurons. The results demonstrate that virtually all immature neurons, identified by triple immunohistochemistry for bromodeoxyuridine (BrdU) and polysialic acid-neural cell adhesion molecule (PSA-NCAM), are also positive for pCREB. In addition, upregulation of cAMP (via pharmacological inhibition of cAMP breakdown or by antidepressant treatment) increases the survival of BrdU-positive cells. A possible role for pCREB in the regulation of PSA-NCAM, a marker of immature neurons involved in neuronal remodeling and neurite outgrowth, is supported by cell culture studies demonstrating that the cAMP-CREB pathway regulates the expression of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM. These findings indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation and function, of newborn neurons.

[Molecular aspects of antidepressive therapy. Transsynaptic effects on signal transduction, gene expression and neuronal plasticity]. / Molekulare Aspekte antidepressiver Therapie. Transsynaptische Effekte auf Signaltransduktion, Genexpression und neuronale Plastizität.

Simple neurotransmitter theories cannot sufficiently explain the mode of action of antidepressant drugs. Molecular pharmacological studies demonstrate that antidepressive treatment initially modulates the neurotransmitter-receptor interaction, subsequently influences signal transduction cascades beyond the synapse and gene transcription mechanisms, and ultimately triggers the expression of specific target genes. Such genes often code for molecules which play an important role in the maintenance of neural and synaptic plasticity. Chronic (but not acute) treatment with antidepressants modulates, for example, the cAMP-second-messenger system and increases the expression of neurotrophic factors. Furthermore, antidepressants promote hippocampal neurogenesis. Stress, an important risk factor for psychiatric disorders, often induces opposite effects. A better understanding of the molecular and cellular effects of stress and therapy with psychotropic drugs will stimulate the development of innovative treatment strategies for which an optimised antidepressant efficacy with a simultaneously improved tolerance is expected.

Synaptic plasticity and mood disorders.

Recent studies demonstrate that the molecular elements known to regulate neuronal plasticity in models of learning and memory are also involved in the actions of drugs used for the treatment of depression and bipolar disorder. This includes up-regulation of transcription factors, such as the cAMP response element binding protein and neurotrophic factors, such as brain derived neurotrophic factor. These findings raise the possibility that regulation of neural plasticity in specific neuronal circuits is integrally involved in the therapeutic intervention of mood disorders. Atypical antipsychotic drugs, including clozapine and olanzapine, are also effective for the treatment of bipolar disorder, and are used as add-on medication for unipolar depression. The possibility that these atypical antipsychotic drugs also influence the molecular determinants of synaptic plasticity that are involved in the response to drugs used for the treatment of mood disorders, is discussed.