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Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT, 5-HT, 5-HT, and 5-HT receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter. We demonstrate that the SERT Met172 substitution induces an ∼19-fold loss in vortioxetine potency for SERT inhibition in midbrain synaptosomes. Moreover, in these mice, we observed reduced SERT occupancy, a diminished ability to prolong 5-HT clearance, and a reduced capacity to elevate extracellular 5-HT. Despite reduced interactions with SERT, vortioxetine maintained its ability to enhance mobility in tail suspension and forced swim tests, reduce consumption latency in the novelty induced hypophagia test, and promoted proliferation and survival of subgranular zone hippocampal stem cells. Our findings suggest that the antidepressant actions of vortioxetine may be SERT-independent, and encourage consideration of agents that mimic one or more actions of the drug in the development of improved depression treatments.
BACKGROUND - Cognitive bias is a common characteristic of major depressive disorder (MDD) and is posited to remain during remission and contribute to recurrence risk. Attention bias may be related to enhanced amygdala activity or altered amygdala functional connectivity in depression. The current study examined attention bias, brain activity for emotional images, and functional connectivity in post-menopausal women with and without a history of major depression.
METHODS - Attention bias for emotionally valenced images was examined in 33 postmenopausal women with (n=12) and without (n=21) a history of major depression using an emotion dot probe task during fMRI. Group differences in amygdala activity and functional connectivity were assessed using fMRI and examined for correlations to attention performance.
RESULTS - Women with a history of MDD showed greater attentional bias for negative images and greater activity in brain areas including the amygdala for both positive and negative images (pcorr <0.001) than women without a history of MDD. In all participants, amygdala activity for negative images was correlated with attention facilitation for emotional images. Women with a history of MDD had significantly greater functional connectivity between the amygdala and hippocampal complex. In all participants amygdala-hippocampal connectivity was positively correlated with attention facilitation for negative images.
LIMITATIONS - Small sample with unbalanced groups.
CONCLUSIONS - These findings provide evidence for negative attentional bias in euthymic, remitted depressed individuals. Activity and functional connectivity in limbic and attention networks may provide a neurobiological basis for continued cognitive bias in remitted depression.
Copyright © 2016 Elsevier B.V. All rights reserved.
Plasma levels of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with Alzheimer's disease (AD) and brain atrophy. Some evidence suggests a potential synergistic effect of IGFBP-2 and AD neuropathology on neurodegeneration, while other evidence suggests the effect of IGFBP-2 on neurodegeneration is independent of AD neuropathology. Therefore, the current study investigated the interaction between plasma IGFBP-2 and cerebrospinal fluid (CSF) biomarkers of AD neuropathology on hippocampal volume and cognitive function. AD Neuroimaging Initiative data were accessed (n = 354, 75 ± 7 years, 38 % female), including plasma IGFBP-2, CSF total tau, CSF Aβ-42, MRI-quantified hippocampal volume, and neuropsychological performances. Mixed effects regression models evaluated the interaction between IGFBP-2 and AD biomarkers on hippocampal volume and neuropsychological performance, adjusting for age, sex, education, APOE ε4 status, and cognitive diagnosis. A baseline interaction between IGFBP-2 and CSF Aβ-42 was observed in relation to left (t(305) = -6.37, p = 0.002) and right hippocampal volume (t(305) = -7.74, p = 0.001). In both cases, higher IGFBP-2 levels were associated with smaller hippocampal volumes but only among amyloid negative individuals. The observed interaction suggests IGFBP-2 drives neurodegeneration through a separate pathway independent of AD neuropathology.
OBJECTIVE - To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.
METHODS - Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.
RESULTS - Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < -4.7, p < 2 × 10). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline.
CONCLUSIONS - Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.
© 2016 American Academy of Neurology.
We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer's disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.
AIMS - To assess associations between body mass index (BMI), waist circumference (WC), and computed tomography-determined volumes of pericardial, visceral, and subcutaneous adipose tissue with magnetic resonance imaging-(MRI) based cerebral structure and cognitive performance in individuals with type 2 diabetes (T2D).
METHODS - This study was performed in 348 African Americans (AAs) and 256 European Americans (EAs) with T2D. Associations between adiposity measures with cerebral volumes of white matter (WMV), gray matter (GMV), white matter lesions, hippocampal GMV, and hippocampal WMV, cognitive performance and depression were examined using marginal models incorporating generalized estimating equations. All models were adjusted for age, sex, education, smoking, HbA1c, hypertension, statins, cardiovascular disease, MRI scanner (MRI outcomes only), and time between scans; some neuroimaging measures were additionally adjusted for intracranial volume.
RESULTS - Participants were 59.9% female with mean (SD) age 57.7(9.3)years, diabetes duration 9.6(6.8)years, and HbA1c 7.8(1.9)%. In AAs, inverse associations were detected between hippocampal GMV and both BMI (β [95% CI]-0.18 [-0.30, -0.07], P=0.0018) and WC (-0.23 [-0.35, -0.12], P=0.0001). In the full bi-ethnic sample, inverse associations were detected between hippocampal WMV and WC (P≤0.0001). Positive relationships were observed between BMI (P=0.0007) and WC (P<0.0001) with depression in EAs.
CONCLUSIONS - In patients with T2D, adiposity is inversely associated with hippocampal gray and white matter volumes.
Copyright © 2016 Elsevier Inc. All rights reserved.
Long-term potentiation (LTP) and long-term depression (LTD) are two distinct forms of synaptic plasticity that have been extensively characterized at the Schaffer collateral-CA1 (SCCA1) synapse and the mossy fiber (MF)-CA3 synapse within the hippocampus, and are postulated to be the molecular underpinning for several cognitive functions. Deficits in LTP and LTD have been implicated in the pathophysiology of several neurological and psychiatric disorders. Therefore, there has been a large effort focused on developing an understanding of the mechanisms underlying these forms of plasticity and novel therapeutic strategies that improve or rescue these plasticity deficits. Among many other targets, the metabotropic glutamate (mGlu) receptors show promise as novel therapeutic candidates for the treatment of these disorders. Among the eight distinct mGlu receptor subtypes (mGlu1-8), the mGlu1,2,3,5,7 subtypes are expressed throughout the hippocampus and have been shown to play important roles in the regulation of synaptic plasticity in this brain area. However, development of therapeutic agents that target these mGlu receptors has been hampered by a lack of subtype-selective compounds. Recently, discovery of allosteric modulators of mGlu receptors has provided novel ligands that are highly selective for individual mGlu receptor subtypes. The mGlu receptors modulate the multiple forms of synaptic plasticity at both SC-CA1 and MF synapses and allosteric modulators of mGlu receptors have emerged as potential therapeutic agents that may rescue plasticity deficits and improve cognitive function in patients suffering from multiple neurological and psychiatric disorders.
Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in non-synaptic proteins suggests that AIE may prime this signaling pathway for future ethanol exposures in adulthood.
Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism.
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RATIONALE - Resveratrol participates in regulating abnormal behaviors in psychostimulant-exposed animals.
OBJECTIVES - To examine effects of resveratrol on relapse and anxiety-like behaviors in cocaine withdrawn rats and to investigate possible molecular mechanisms underlying resveratrol effects in hippocampus (HP) and prefrontal cortex (PFC).
METHODS - Conditioned place preference (CPP) assay and elevated plus maze (EPM) test were used to examine cocaine CPP behavior and anxiety-like behaviors in rats, respectively. Resveratrol was administrated to cocaine withdrawn rats. Levels of MDA, GSH and SOD were examined to evaluate oxidative status, and levels of IL-6, IL-1β and TNF α were measured to examine inflammatory status and levels of caspase-3 and BAX was examined to evaluate apoptotic status in HP and PFC. SIRT expression was also examined here.
RESULTS - Resveratrol did not affect cocaine CPP behaviors, but attenuated anxiety-like behaviors in cocaine withdrawn rats. Levels of MDA and TNFα in PFC, and levels of MDA, SOD, GSH, IL-6, IL-1β, TNFα, caspase-3 and BAX in HP, but not SIRT1 expression in both regions were significantly changed during cocaine withdrawal period. Except SOD, resveratrol reversed above neurochemical changes induced by cocaine withdrawal. Furthermore, RSV induced a greater upregulation of SIRT1 expression in PFC in cocaine withdrawn rats than that in saline controls.
CONCLUSIONS - Current findings suggest that resveratrol may influence behaviors in cocaine withdrawn rats. Oxidative stress, inflammation, apoptosis, and SIRT1 signaling pathway in HP or PFC might be involved in mediating effects of RSV on behaviors in cocaine withdrawn rats.