M ajor depressive disorder (MDD) is the leading cause of worldwide disability and the most preval... more M ajor depressive disorder (MDD) is the leading cause of worldwide disability and the most prevalent mood disorder 1,2. The prevalence of MDD is two-to threefold higher in patients with cardiovascular disease and, conversely, MDD is associated with an ∼ 80% increased risk of cardiovascular morbidity and mortality 1,3–5. Chronic inflammation and sustained increases in circulating pro-inflammatory cytokines have been associated with atherosclerotic plaque formation, progression and rupture, likely contributing to the pathogenesis of cardiovascular disease and heart failure 6. Concomitantly, clinical studies report higher levels of circulating pro-inflammatory cytokines in patients with MDD, a pattern that has been replicated in preclinical animal models of depression 1,7–10. Individual differences in the peripheral immune system and modulation of cytokine release, notably IL-6, are associated with susceptibility versus resilience to chronic social stress 11. Chronic stress mobilizes the innate immune system and stimulates enhanced proliferation and release of inflammatory monocytes and neutrophils into the bloodstream 12,13. It has been hypothesized that peripheral myeloid cells or pro-inflammatory cytokines can diffuse into the brain of stressed individuals as a result of stress-induced neurovascular damage and increased BBB permeability 7,14–19. Indeed, a clinical study reported an altered cerebrospinal fluid to serum ratio of peripheral markers in depressed patients, suggesting that BBB integrity is compromised 20. However, the possible link between BBB permeability, stress vulnerability and depression is still controversial 21. The BBB is formed by endothelial cells sealed by tight junction proteins, pericytes and astrocytes, and serves to prevent potentially harmful signals in the blood from entering the brain. Here we evaluate the effect of chronic social defeat stress (CSDS), a mouse model of depression, on BBB-related gene expression and define a role for the tight junction protein claudin 5 (Cldn5) in the establishment of depression-like behaviors and MDD. Cldn5 is a major cell adhesion molecule in endothelial cells 22 , and loss of Cldn5 has been shown to promote loosening of the BBB and increased permeability 23. Our study thus characterizes and functionally interrogates the neurovas-cular pathology associated with social stress vulnerability. Results Vulnerability to chronic social stress and MDD are associated with loss of tight junction protein Cldn5 expression. Chronic social stress is a prominent contributor to mood disorder prevalence and suicide attempts in victims of bullying 24. Similarly, in rodents, CSDS induces a depression-like phenotype (social avoidance , anhedonia) in a subset of mice, termed stress-susceptible (SS), that can be reversed by chronic, but not acute, antidepres-sant treatment 25,26. In the CSDS protocol, a male C57BL/6 J mouse is exposed daily (10 min/d) to bouts of social defeat by a larger, physically aggressive CD-1 mouse 27 (Fig. 1a). Defeated mice that do not display social avoidance as assessed with the social interaction (SI) test (Supplementary Fig. 1a–c) are considered resilient (RES). We compared SS to RES mice to identify individual differences in the neurovascular mechanisms potentially underlying chronic stress responses. First, we performed transcriptional profiling of Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein clau-din-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression. NATuRE NEuRoSCiENCE | www.nature.com/natureneuroscience
In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the eld... more In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn Ϫ/Ϫ mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1␣ and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn Ϫ/Ϫ mice. Increased Group 1 mGluR expression in aged Pdyn Ϫ/Ϫ mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn Ϫ/Ϫ mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted -opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn Ϫ/Ϫ mice. Intact cognition in aged Pdyn Ϫ/Ϫ mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn Ϫ/Ϫ mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperg... more Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperglycemia, while brain [18 F]FDG uptake was assessed by PET a marker of cerebral metabolism. As a marker of deleterious gliosis, brain uptake of a TSPO ligand, [11 C]PBR-28, was assessed by PET. In vivo [11 C]PBR-28 uptake was confirmed by autoradiography of brain sections obtained from scanned mice. TSPO expression in glial subpopulations was confirmed by immunohistochemistry, co-staining with the glial markers CD-11b and GFAP. Results: Obesity combined with A b infusion synergistically increased cerebral glucose metabolism and TSPO signals as assessed by PET. In autoradiographic sections, increased TSPO signals were associated with A b -infusion, but not obesity, although severe gliosis was observed by immunohistochemistry in both models of inflammation. In contrast, obesity-induced inflammation alone was associated with reduced TSPO signals detected by PET and autoradiography. Conclusions: FDG and TSPO may be useful imaging biomarkers for the identification of early-stage metabolic and inflammatory pathogenic changes in obesity associated with cognitive decline and AD risk. Increased brain [18 F]FDG uptake observed A b -infused mice may reflect increased metabolic demand resulting from gliosis or seizure activity. Surprisingly, obesity-induced inflammation was associated with decreased TSPO signals, which could potentially indicate qualitative differences in glial function between the two models of inflammation.
Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders 1 and ... more Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders 1 and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli 2. Nuclei within the ventromedial hypothalamus 3–5 , extended amygdala 6 and limbic 7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour 8. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF–lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF–lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF–lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF–lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.
Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore b... more Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30-50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to current antidepressant treatments.
There is growing evidence of a relationship between inflammation and psychiatric illness. In part... more There is growing evidence of a relationship between inflammation and psychiatric illness. In particular, the cytokine Interleukin-6 (IL-6) has been linked to stress-related disorders such as depression and anxiety. Here we discuss evidence from preclinical and clinical studies examining the role of IL-6 in mood disorders. We focus on the functional role of peripheral and central release of IL-6 on the development of stress susceptibility and depression-associated behavior. By examining the contribution of both peripheral and central IL-6 to manifestations of stress-related symptomatology, we hope to broaden the way the field thinks about diagnosing and treating mood disorders.
Major depressive disorder (MDD) will affect one out of every five people in their lifetime and is... more Major depressive disorder (MDD) will affect one out of every five people in their lifetime and is the leading cause of disability worldwide. Nevertheless, mechanisms associated with the pathogenesis of MDD have yet to be completely understood and current treatments remain ineffective in a large subset of patients. In this review, we summarize the most recent discoveries and insights for which parallel findings have been obtained in human depressed subjects and rodent models of mood disorders in order to examine the potential etiology of depression. These mechanisms range from synaptic plasticity mechanisms to epigenetics and the immune system where there is strong evidence to support a functional role in the development of specific depression symptomology. Ultimately we conclude by discussing how novel therapeutic strategies targeting central and peripheral processes might ultimately aid in the development of effective new treatments for MDD and related stress disorders.
Depression and anxiety disorders are more prevalent in females, but the majority of research in a... more Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depressionassociated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences wasDNAmethyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levelswereincreasedintheNAcofdepressedhumans,aneffectseeninbothmalesandfemales.LocaloverexpressionofDnmt3ainNAcrendered male micemoresusceptible to SCVS, whereasDnmt3aknock-out in this region rendered femalesmoreresilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that aDNAmethyltransferase in NAc contributes to sex differences in stress vulnerability.
Current diagnosis of depression is based solely on behavioral symptomatology. The available US Fo... more Current diagnosis of depression is based solely on behavioral symptomatology. The available US Food and Drug Administration-approved treatments for depression have come from serendipitous discovery and are ineffective in nearly 30-50% of patients, which is thought to reflect a lack of specificity in targeting underlying pathophysiological mechanisms. Recent evidence has identified depression-related disruptions in a neuroimmune axis that interfaces the immune system and CNS to control behavior. This Review examines the evidence in patients and in animal models of depression that demonstrates how the peripheral immune system acts on the brain to alter an individual's response to stress, ultimately contributing to their vulnerability to mood disorders.
Handbook of Experimental Pharmacology - Cognitive Enhancement, Jun 14, 2015
Aging is generally associated with a certain cognitive decline. However, individual differences e... more Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.
In humans, memory capacities are generally affected with aging, even without any reported neurolo... more In humans, memory capacities are generally affected with aging, even without any reported neurologic disorders. The mechanisms behind cognitive decline are not well understood. We studied here whether postsynaptic glutamate receptor and presynaptic vesicular glutamate transporters (VGLUTs) levels may change in the course of aging and be related to cognitive abilities using various age-impaired (AI) or age-unimpaired rat strains. Twenty-four-month-old Long-Evans (LE) rats with intact spatial memory maintained postsynaptic ionotropic glutamate receptor levels in the hippocampal-adjacent cortex similar to those of young animals. In contrast, AI rats showed significantly reduced expression of ionotropic glutamate receptor GluR2, NR2A and NR2B subunits. In AI LE rats, VGLUT1 and VGLUT2 levels were increased and negatively correlated with receptor levels as shown by principal component analysis and correlation matrices. We also investigated whether glutamatergic receptors and VGLUT levels were altered in the obesity-resistant LOU/C/Jall (LOU) rat strain which is characterized by intact memory despite aging. No difference was observed between 24-month-old LOU rats and their young counterparts. Taken together, the unaltered spatial memory performance of 24-month-old age-unimpaired LE and LOU rats suggests that intact coordination of the presynaptic and postsynaptic hippocampal-adjacent cortex glutamatergic networks may be important for successful cognitive aging. Accordingly, altered expression of presynaptic and postsynaptic glutamatergic components, such as in AI LE rats, could be considered a marker of age-related cognitive deficits.
Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders includ... more Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders including macular degeneration, stroke, and cognitive deficits with or without dementia. Resveratrol has been considered as one of the key ingredients responsible for the preventive action of red wine since the stilbene displays a neuroprotective action in various models of toxicity. Besides its well documented free radical scavenging and anti-inflammatory properties, resveratrol has been shown to increase the clearance of beta-amyloid, a key feature of Alzheimer's disease, and to modulate intracellular effectors associated with oxidative stress (e.g. heme oxygenase), neuronal energy homeostasis (e.g. AMP kinase), program cell death (i.e. AIF) and longevity (i.e. sirtuins). This article summarizes the most recent findings on mechanisms of action involved in the protective effects of this multi target polyphenol, and discusses its possible roles in the prevention of various age-related neurological disorders. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperg... more Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperglycemia, while brain [18 F]FDG uptake was assessed by PET a marker of cerebral metabolism. As a marker of deleterious gliosis, brain uptake of a TSPO ligand, [11 C]PBR-28, was assessed by PET. In vivo [11 C]PBR-28 uptake was confirmed by autoradiography of brain sections obtained from scanned mice. TSPO expression in glial subpopulations was confirmed by immunohistochemistry, co-staining with the glial markers CD-11b and GFAP. Results: Obesity combined with A b infusion synergistically increased cerebral glucose metabolism and TSPO signals as assessed by PET. In autoradiographic sections, increased TSPO signals were associated with A b -infusion, but not obesity, although severe gliosis was observed by immunohistochemistry in both models of inflammation. In contrast, obesity-induced inflammation alone was associated with reduced TSPO signals detected by PET and autoradiography. Conclusions: FDG and TSPO may be useful imaging biomarkers for the identification of early-stage metabolic and inflammatory pathogenic changes in obesity associated with cognitive decline and AD risk. Increased brain [18 F]FDG uptake observed A b -infused mice may reflect increased metabolic demand resulting from gliosis or seizure activity. Surprisingly, obesity-induced inflammation was associated with decreased TSPO signals, which could potentially indicate qualitative differences in glial function between the two models of inflammation.
The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longe... more The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6-42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats.
BACKGROUND/AIMS:Expression of dynorphin, an endogenous opioid peptide, increases with age and has... more BACKGROUND/AIMS:Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD.
METHODS:Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice.
RESULTS:We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals.
CONCLUSIONS:These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.
Ce numéro spécial de MSA permet de mettre en valeur une publication d'Alexandra J Fiocco et colla... more Ce numéro spécial de MSA permet de mettre en valeur une publication d'Alexandra J Fiocco et collaborateurs, parue dans la revue Neurobiology of Aging en 2012 (33 : 829.e21-829.e28), intitulée « Sodium intake and physical activity impact cognitive maintenance in older adults: L'étude NuAge a été fi nancée par les Instituts de recherche en santé du Canada (MOP-62842) de même que la sous-étude (MOP-81217). Vol. 2 n o 3 drial content and function in humans.PLoS One. 2012;7:e36320.
Polyphenols such as epigallocatechin gallate (EGCG) and resveratrol have received a great deal of... more Polyphenols such as epigallocatechin gallate (EGCG) and resveratrol have received a great deal of attention because they may contribute to the purported neuroprotective action of the regular consumption of green tea and red wine. Many studies, including those published by our group, suggest that this protective action includes their abilities to prevent the neurotoxic effects of beta-amyloid, a protein whose accumulation likely plays a pivotal role in Alzheimer's disease. Moreover, the scavenging activities of polyphenols on reactive oxygen species and their inhibitory action of cyclooxygenase likely explain, at least in part, their antioxidant and anti-inflammatory activities. Besides these well-documented properties, the modulatory action of these polyphenols on intracellular signaling pathways related to cell death/survival (e.g., protein kinase C, PKC) has yet to be investigated in detail. Using rat hippocampal neuronal cells, we aimed to investigate here the effects of EGCG and resveratrol on cell death induced by GF 109203X, a selective inhibitor of PKC. The MTT/resazurin and spectrin assays indicated that EGCG and resveratrol protected against GF 109203X-induced cell death and cytoskeleton degeneration, with a maximal effect at 1 and 3 μM, respectively. Moreover, immunofluorescence data revealed that cells treated with these polyphenols increased PKC gamma (γ) activation and promoted neuronal interconnections. Finally, we found that the protective effects of both polyphenols on the cytoskeleton and synaptic plasticity were mediated by the PKCγ subunit. Taken together, the results suggest that PKC, and more specifically its γ subunit, plays a critical role in the protective action of EGCG and resveratrol on neuronal integrity.
Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated... more Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
The relationship between heightened neuroinflammation and cognitive decline in the normally aged ... more The relationship between heightened neuroinflammation and cognitive decline in the normally aged brain is still debatable, as most data are derived from insult-related models. Accordingly, the aim of the current study was to determine whether a link could be established for 2 immune markers at the post-transcriptional level; CD68 and MHC-II, in a normally aged (24-month-old) rat population discriminated for their learning abilities. Using the Morris Water Maze (MWM) task, aged rats were divided into aged learning-impaired (AI) or -unimpaired (AU) groups. Western immunoblots of hippocampal tissue revealed a significant increase of CD68 in AI rats compared to the AU group. Moreover, up-regulated CD68 expression correlated with increased latency times in the MWM task. Immunofluorescence for CD68 revealed intense staining in the white matter regions and CA3 subregion of the hippocampus in the AI group. Despite expression of MHC-II in the AI group, no correlation was found. Overall, these data suggest that CD68 could play a role associated with cognitive decline in a subgroup of the normally aged population.
M ajor depressive disorder (MDD) is the leading cause of worldwide disability and the most preval... more M ajor depressive disorder (MDD) is the leading cause of worldwide disability and the most prevalent mood disorder 1,2. The prevalence of MDD is two-to threefold higher in patients with cardiovascular disease and, conversely, MDD is associated with an ∼ 80% increased risk of cardiovascular morbidity and mortality 1,3–5. Chronic inflammation and sustained increases in circulating pro-inflammatory cytokines have been associated with atherosclerotic plaque formation, progression and rupture, likely contributing to the pathogenesis of cardiovascular disease and heart failure 6. Concomitantly, clinical studies report higher levels of circulating pro-inflammatory cytokines in patients with MDD, a pattern that has been replicated in preclinical animal models of depression 1,7–10. Individual differences in the peripheral immune system and modulation of cytokine release, notably IL-6, are associated with susceptibility versus resilience to chronic social stress 11. Chronic stress mobilizes the innate immune system and stimulates enhanced proliferation and release of inflammatory monocytes and neutrophils into the bloodstream 12,13. It has been hypothesized that peripheral myeloid cells or pro-inflammatory cytokines can diffuse into the brain of stressed individuals as a result of stress-induced neurovascular damage and increased BBB permeability 7,14–19. Indeed, a clinical study reported an altered cerebrospinal fluid to serum ratio of peripheral markers in depressed patients, suggesting that BBB integrity is compromised 20. However, the possible link between BBB permeability, stress vulnerability and depression is still controversial 21. The BBB is formed by endothelial cells sealed by tight junction proteins, pericytes and astrocytes, and serves to prevent potentially harmful signals in the blood from entering the brain. Here we evaluate the effect of chronic social defeat stress (CSDS), a mouse model of depression, on BBB-related gene expression and define a role for the tight junction protein claudin 5 (Cldn5) in the establishment of depression-like behaviors and MDD. Cldn5 is a major cell adhesion molecule in endothelial cells 22 , and loss of Cldn5 has been shown to promote loosening of the BBB and increased permeability 23. Our study thus characterizes and functionally interrogates the neurovas-cular pathology associated with social stress vulnerability. Results Vulnerability to chronic social stress and MDD are associated with loss of tight junction protein Cldn5 expression. Chronic social stress is a prominent contributor to mood disorder prevalence and suicide attempts in victims of bullying 24. Similarly, in rodents, CSDS induces a depression-like phenotype (social avoidance , anhedonia) in a subset of mice, termed stress-susceptible (SS), that can be reversed by chronic, but not acute, antidepres-sant treatment 25,26. In the CSDS protocol, a male C57BL/6 J mouse is exposed daily (10 min/d) to bouts of social defeat by a larger, physically aggressive CD-1 mouse 27 (Fig. 1a). Defeated mice that do not display social avoidance as assessed with the social interaction (SI) test (Supplementary Fig. 1a–c) are considered resilient (RES). We compared SS to RES mice to identify individual differences in the neurovascular mechanisms potentially underlying chronic stress responses. First, we performed transcriptional profiling of Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein clau-din-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression. NATuRE NEuRoSCiENCE | www.nature.com/natureneuroscience
In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the eld... more In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn Ϫ/Ϫ mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1␣ and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn Ϫ/Ϫ mice. Increased Group 1 mGluR expression in aged Pdyn Ϫ/Ϫ mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn Ϫ/Ϫ mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted -opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn Ϫ/Ϫ mice. Intact cognition in aged Pdyn Ϫ/Ϫ mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn Ϫ/Ϫ mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperg... more Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperglycemia, while brain [18 F]FDG uptake was assessed by PET a marker of cerebral metabolism. As a marker of deleterious gliosis, brain uptake of a TSPO ligand, [11 C]PBR-28, was assessed by PET. In vivo [11 C]PBR-28 uptake was confirmed by autoradiography of brain sections obtained from scanned mice. TSPO expression in glial subpopulations was confirmed by immunohistochemistry, co-staining with the glial markers CD-11b and GFAP. Results: Obesity combined with A b infusion synergistically increased cerebral glucose metabolism and TSPO signals as assessed by PET. In autoradiographic sections, increased TSPO signals were associated with A b -infusion, but not obesity, although severe gliosis was observed by immunohistochemistry in both models of inflammation. In contrast, obesity-induced inflammation alone was associated with reduced TSPO signals detected by PET and autoradiography. Conclusions: FDG and TSPO may be useful imaging biomarkers for the identification of early-stage metabolic and inflammatory pathogenic changes in obesity associated with cognitive decline and AD risk. Increased brain [18 F]FDG uptake observed A b -infused mice may reflect increased metabolic demand resulting from gliosis or seizure activity. Surprisingly, obesity-induced inflammation was associated with decreased TSPO signals, which could potentially indicate qualitative differences in glial function between the two models of inflammation.
Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders 1 and ... more Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders 1 and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli 2. Nuclei within the ventromedial hypothalamus 3–5 , extended amygdala 6 and limbic 7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour 8. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF–lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF–lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF–lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF–lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.
Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore b... more Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30-50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to current antidepressant treatments.
There is growing evidence of a relationship between inflammation and psychiatric illness. In part... more There is growing evidence of a relationship between inflammation and psychiatric illness. In particular, the cytokine Interleukin-6 (IL-6) has been linked to stress-related disorders such as depression and anxiety. Here we discuss evidence from preclinical and clinical studies examining the role of IL-6 in mood disorders. We focus on the functional role of peripheral and central release of IL-6 on the development of stress susceptibility and depression-associated behavior. By examining the contribution of both peripheral and central IL-6 to manifestations of stress-related symptomatology, we hope to broaden the way the field thinks about diagnosing and treating mood disorders.
Major depressive disorder (MDD) will affect one out of every five people in their lifetime and is... more Major depressive disorder (MDD) will affect one out of every five people in their lifetime and is the leading cause of disability worldwide. Nevertheless, mechanisms associated with the pathogenesis of MDD have yet to be completely understood and current treatments remain ineffective in a large subset of patients. In this review, we summarize the most recent discoveries and insights for which parallel findings have been obtained in human depressed subjects and rodent models of mood disorders in order to examine the potential etiology of depression. These mechanisms range from synaptic plasticity mechanisms to epigenetics and the immune system where there is strong evidence to support a functional role in the development of specific depression symptomology. Ultimately we conclude by discussing how novel therapeutic strategies targeting central and peripheral processes might ultimately aid in the development of effective new treatments for MDD and related stress disorders.
Depression and anxiety disorders are more prevalent in females, but the majority of research in a... more Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depressionassociated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences wasDNAmethyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levelswereincreasedintheNAcofdepressedhumans,aneffectseeninbothmalesandfemales.LocaloverexpressionofDnmt3ainNAcrendered male micemoresusceptible to SCVS, whereasDnmt3aknock-out in this region rendered femalesmoreresilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that aDNAmethyltransferase in NAc contributes to sex differences in stress vulnerability.
Current diagnosis of depression is based solely on behavioral symptomatology. The available US Fo... more Current diagnosis of depression is based solely on behavioral symptomatology. The available US Food and Drug Administration-approved treatments for depression have come from serendipitous discovery and are ineffective in nearly 30-50% of patients, which is thought to reflect a lack of specificity in targeting underlying pathophysiological mechanisms. Recent evidence has identified depression-related disruptions in a neuroimmune axis that interfaces the immune system and CNS to control behavior. This Review examines the evidence in patients and in animal models of depression that demonstrates how the peripheral immune system acts on the brain to alter an individual's response to stress, ultimately contributing to their vulnerability to mood disorders.
Handbook of Experimental Pharmacology - Cognitive Enhancement, Jun 14, 2015
Aging is generally associated with a certain cognitive decline. However, individual differences e... more Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.
In humans, memory capacities are generally affected with aging, even without any reported neurolo... more In humans, memory capacities are generally affected with aging, even without any reported neurologic disorders. The mechanisms behind cognitive decline are not well understood. We studied here whether postsynaptic glutamate receptor and presynaptic vesicular glutamate transporters (VGLUTs) levels may change in the course of aging and be related to cognitive abilities using various age-impaired (AI) or age-unimpaired rat strains. Twenty-four-month-old Long-Evans (LE) rats with intact spatial memory maintained postsynaptic ionotropic glutamate receptor levels in the hippocampal-adjacent cortex similar to those of young animals. In contrast, AI rats showed significantly reduced expression of ionotropic glutamate receptor GluR2, NR2A and NR2B subunits. In AI LE rats, VGLUT1 and VGLUT2 levels were increased and negatively correlated with receptor levels as shown by principal component analysis and correlation matrices. We also investigated whether glutamatergic receptors and VGLUT levels were altered in the obesity-resistant LOU/C/Jall (LOU) rat strain which is characterized by intact memory despite aging. No difference was observed between 24-month-old LOU rats and their young counterparts. Taken together, the unaltered spatial memory performance of 24-month-old age-unimpaired LE and LOU rats suggests that intact coordination of the presynaptic and postsynaptic hippocampal-adjacent cortex glutamatergic networks may be important for successful cognitive aging. Accordingly, altered expression of presynaptic and postsynaptic glutamatergic components, such as in AI LE rats, could be considered a marker of age-related cognitive deficits.
Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders includ... more Low-to-moderate red wine consumption appeared to reduce age-related neurological disorders including macular degeneration, stroke, and cognitive deficits with or without dementia. Resveratrol has been considered as one of the key ingredients responsible for the preventive action of red wine since the stilbene displays a neuroprotective action in various models of toxicity. Besides its well documented free radical scavenging and anti-inflammatory properties, resveratrol has been shown to increase the clearance of beta-amyloid, a key feature of Alzheimer's disease, and to modulate intracellular effectors associated with oxidative stress (e.g. heme oxygenase), neuronal energy homeostasis (e.g. AMP kinase), program cell death (i.e. AIF) and longevity (i.e. sirtuins). This article summarizes the most recent findings on mechanisms of action involved in the protective effects of this multi target polyphenol, and discusses its possible roles in the prevention of various age-related neurological disorders. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperg... more Ab-42. Fasting levels of blood glucose and insulin were measured as a marker of peripheral hyperglycemia, while brain [18 F]FDG uptake was assessed by PET a marker of cerebral metabolism. As a marker of deleterious gliosis, brain uptake of a TSPO ligand, [11 C]PBR-28, was assessed by PET. In vivo [11 C]PBR-28 uptake was confirmed by autoradiography of brain sections obtained from scanned mice. TSPO expression in glial subpopulations was confirmed by immunohistochemistry, co-staining with the glial markers CD-11b and GFAP. Results: Obesity combined with A b infusion synergistically increased cerebral glucose metabolism and TSPO signals as assessed by PET. In autoradiographic sections, increased TSPO signals were associated with A b -infusion, but not obesity, although severe gliosis was observed by immunohistochemistry in both models of inflammation. In contrast, obesity-induced inflammation alone was associated with reduced TSPO signals detected by PET and autoradiography. Conclusions: FDG and TSPO may be useful imaging biomarkers for the identification of early-stage metabolic and inflammatory pathogenic changes in obesity associated with cognitive decline and AD risk. Increased brain [18 F]FDG uptake observed A b -infused mice may reflect increased metabolic demand resulting from gliosis or seizure activity. Surprisingly, obesity-induced inflammation was associated with decreased TSPO signals, which could potentially indicate qualitative differences in glial function between the two models of inflammation.
The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longe... more The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6-42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats.
BACKGROUND/AIMS:Expression of dynorphin, an endogenous opioid peptide, increases with age and has... more BACKGROUND/AIMS:Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD.
METHODS:Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice.
RESULTS:We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals.
CONCLUSIONS:These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.
Ce numéro spécial de MSA permet de mettre en valeur une publication d'Alexandra J Fiocco et colla... more Ce numéro spécial de MSA permet de mettre en valeur une publication d'Alexandra J Fiocco et collaborateurs, parue dans la revue Neurobiology of Aging en 2012 (33 : 829.e21-829.e28), intitulée « Sodium intake and physical activity impact cognitive maintenance in older adults: L'étude NuAge a été fi nancée par les Instituts de recherche en santé du Canada (MOP-62842) de même que la sous-étude (MOP-81217). Vol. 2 n o 3 drial content and function in humans.PLoS One. 2012;7:e36320.
Polyphenols such as epigallocatechin gallate (EGCG) and resveratrol have received a great deal of... more Polyphenols such as epigallocatechin gallate (EGCG) and resveratrol have received a great deal of attention because they may contribute to the purported neuroprotective action of the regular consumption of green tea and red wine. Many studies, including those published by our group, suggest that this protective action includes their abilities to prevent the neurotoxic effects of beta-amyloid, a protein whose accumulation likely plays a pivotal role in Alzheimer's disease. Moreover, the scavenging activities of polyphenols on reactive oxygen species and their inhibitory action of cyclooxygenase likely explain, at least in part, their antioxidant and anti-inflammatory activities. Besides these well-documented properties, the modulatory action of these polyphenols on intracellular signaling pathways related to cell death/survival (e.g., protein kinase C, PKC) has yet to be investigated in detail. Using rat hippocampal neuronal cells, we aimed to investigate here the effects of EGCG and resveratrol on cell death induced by GF 109203X, a selective inhibitor of PKC. The MTT/resazurin and spectrin assays indicated that EGCG and resveratrol protected against GF 109203X-induced cell death and cytoskeleton degeneration, with a maximal effect at 1 and 3 μM, respectively. Moreover, immunofluorescence data revealed that cells treated with these polyphenols increased PKC gamma (γ) activation and promoted neuronal interconnections. Finally, we found that the protective effects of both polyphenols on the cytoskeleton and synaptic plasticity were mediated by the PKCγ subunit. Taken together, the results suggest that PKC, and more specifically its γ subunit, plays a critical role in the protective action of EGCG and resveratrol on neuronal integrity.
Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated... more Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
The relationship between heightened neuroinflammation and cognitive decline in the normally aged ... more The relationship between heightened neuroinflammation and cognitive decline in the normally aged brain is still debatable, as most data are derived from insult-related models. Accordingly, the aim of the current study was to determine whether a link could be established for 2 immune markers at the post-transcriptional level; CD68 and MHC-II, in a normally aged (24-month-old) rat population discriminated for their learning abilities. Using the Morris Water Maze (MWM) task, aged rats were divided into aged learning-impaired (AI) or -unimpaired (AU) groups. Western immunoblots of hippocampal tissue revealed a significant increase of CD68 in AI rats compared to the AU group. Moreover, up-regulated CD68 expression correlated with increased latency times in the MWM task. Immunofluorescence for CD68 revealed intense staining in the white matter regions and CA3 subregion of the hippocampus in the AI group. Despite expression of MHC-II in the AI group, no correlation was found. Overall, these data suggest that CD68 could play a role associated with cognitive decline in a subgroup of the normally aged population.
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Papers by Caroline Menard
treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depressionassociated
behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these
different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing
(RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex
differences wasDNAmethyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression
levelswereincreasedintheNAcofdepressedhumans,aneffectseeninbothmalesandfemales.LocaloverexpressionofDnmt3ainNAcrendered
male micemoresusceptible to SCVS, whereasDnmt3aknock-out in this region rendered femalesmoreresilient, directly implicating this gene in
stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female
transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional
regulation in response to stress and that aDNAmethyltransferase in NAc contributes to sex differences in stress vulnerability.
METHODS:Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice.
RESULTS:We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals.
CONCLUSIONS:These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.
treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depressionassociated
behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these
different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing
(RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex
differences wasDNAmethyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression
levelswereincreasedintheNAcofdepressedhumans,aneffectseeninbothmalesandfemales.LocaloverexpressionofDnmt3ainNAcrendered
male micemoresusceptible to SCVS, whereasDnmt3aknock-out in this region rendered femalesmoreresilient, directly implicating this gene in
stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female
transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional
regulation in response to stress and that aDNAmethyltransferase in NAc contributes to sex differences in stress vulnerability.
METHODS:Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice.
RESULTS:We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals.
CONCLUSIONS:These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.