Depression gets old fast: do stress and depression accelerate cell aging?

Depression has been likened to a state of “accelerated aging,” and depressed individuals have a higher incidence of various diseases of aging, such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and dementia. Chronic exposure to certain interlinked biochemical pathways that mediate stress‐related depression may contribute to “accelerated aging,” cell damage, and certain comorbid medical illnesses. Biochemical mediators explored in this theoretical review include the hypothalamic–pituitary–adrenal axis (e.g., hyper‐ or hypoactivation of glucocorticoid receptors), neurosteroids, such as dehydroepiandrosterone and allopregnanolone, brain‐derived neurotrophic factor, excitotoxicity, oxidative and inflammatory stress, and disturbances of the telomere/telomerase maintenance system. A better appreciation of the role of these mediators in depressive illness could lead to refined models of depression, to a re‐conceptualization of depression as a whole body disease rather than just a “mental illness,” and to the rational development of new classes of medications to treat depression and its related medical comorbidities. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Pathology of small cerebral arteries demonstrated by MRI: a marker of aging?

Brain magnetic resonance imaging frequently identifies signal abnormalities in the white matter and cerebral cortex in the elderly. They are related to a degenerative disease of the small vessels that may be of ischemic (leukoaraiosis, lacunae and infarct) or hemorrhagic (microbleeds and hematomas) origin. These lesions are part of the aging process, and compounded by vascular risk factors. They increase the occurrence frequency and severity of ischemic or hemorrhagic stroke. Their importance is also associated with the presence of cognitive and/or affective symptoms, and their impact on the occurrence and evolution of dementia remains to be evaluated. The visible consequences of this microangiopathy on MRI probably represent the focal mark of a widespread cerebrovascular disease in the brain parenchyma.     

Photoperiod-induced neurotransmitter plasticity declines with aging: An epigenetic regulation?

Neuroplasticity has classically been understood to arise through changes in synaptic strength or synaptic connectivity. A newly discovered form of neuroplasticity, neurotransmitter switching, involves changes in neurotransmitter identity. Chronic exposure to different photoperiods alters the number of dopamine (tyrosine hydroxylase, TH+) and somatostatin (SST+) neurons in the paraventricular nucleus (PaVN) of the hypothalamus of adult rats and results in discrete behavioral changes. Here, we investigate whether photoperiod-induced neurotransmitter switching persists during aging and whether epigenetic mechanisms of histone acetylation and DNA methylation may contribute to this neurotransmitter plasticity. We show that this plasticity in rats is robust at 1 and at 3 months but reduced in TH+ neurons at 12 months and completely abolished in both TH+ and SST+ neurons by 18 months. De novo expression of DNMT3a catalyzing DNA methylation and anti-AcetylH3 assessing histone 3 acetylation were observed following short-day photoperiod exposure in both TH+ and SST+ neurons at 1 and 3 months while an overall increase in DNMT3a in SST+ neurons paralleled neuroplasticity reduction at 12 and 18 months. Histone acetylation increased in TH+ neurons and decreased in SST+ neurons following short-day exposure at 3 months while the total number of anti-AcetylH3+ PaVN neurons remained constant. Reciprocal histone acetylation in TH+ and SST+ neurons indicates the importance of studying epigenetic regulation at the circuit level for identified cell phenotypes. The findings may be useful for developing approaches for noninvasive treatment of disorders characterized by neurotransmitter dysfunction.     

p75 neurotrophin receptor signaling: mechanisms for neurotrophic modulation of cell stress?

The recent recognition that the p75 neurotrophin receptor, p75((NTR)), can induce apoptotic signals has contributed to the perception that it acts primarily as a death receptor. Although the molecular mechanisms of p75(NTR) signaling remain to be fully characterized, many of the currently identified pathways activated by p75(NTR) may be generally characterized as stress response signals. This review describes recent advances in identifying the molecular components involved in p75(NTR) signal transduction and suggests that p75(NTR) signaling may more aptly serve as a general mechanism for the transduction and modulation of stress signals.     

Domain-dependent modulation of PDGFRβ by ganglioside GM1

The regulation of receptor tyrosine kinases (RTKs) is important in several cellular events, including proliferation, differentiation, and apoptosis. Gangliosides are sialic acid-containing glycosphingolipids that can regulate RTK activity. The addition of ganglioside GM1 to the medium of Swiss 3T3 fibroblasts inhibits both platelet-derived growth factor (PDGF)-mediated tyrosine phosphorylation of PDGF receptor β (PDGFRβ) and receptor-mediated endocytosis. However, GM1 did not affect PDGF-mediated receptor phosphorylation, neuritogenesis, or endocytosis in PC12 cells stably transfected with the gene for PDGFRβ. The ability of GM1 to modulate PDGFRβ in 3T3 cells but not in transfected PC12 cells indicates a cell context-dependent response. We hypothesized that this inhibition of PDGFRβ by GM1 must map to one or more domains of the receptor. Thus, a chimeric receptor was created that possessed the extracellular and transmembrane domains of the nerve growth factor (NGF) receptor TrkA and the cytoplasmic domain of PDGFRβ (TTβ). In 3T3 cells transfected with the TTβ construct, GM1 did not inhibit NGF-induced tyrosine phosphorylation of the chimeric receptor or of Erk1/2 in this cell line. GM1 still inhibited PDGF-mediated tyrosine phosphorylation of endogenous PDGFRβ and of Erk1/2 in Swiss TTβ cells. Thus, the cytoplasmic domain of PDGFRβ is not required for GM1-dependent inhibition of PDGFRβ in 3T3 cells. This suggests that the inhibition of PDGFRβ by GM1 in Swiss 3T3 fibroblasts maps to either the extracellular and/or transmembrane domain of PDGFRβ.     

Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation

Adult hippocampal neurogenesis is modulated by a number of intrinsic and extrinsic factors including local signalling molecules, exercise, aging and inflammation. Inflammation is also a major contributor to several hippocampal-associated disorders. Interleukin-1beta (IL-1β) is the most predominant pro-inflammatory cytokine in the brain, and an increase in its concentration is known to decrease the proliferation of both embryonic and adult hippocampal neural precursor cells (NPCs). Recent research has focused on the role of nuclear receptors as intrinsic regulators of neurogenesis, and it is now established that the orphan nuclear receptor TLX is crucial in maintaining the NPC pool in neurogenic brain regions. To better understand the involvement of TLX in IL-1β-mediated effects on hippocampal NPC proliferation, we examined hippocampal NPC proliferation and TLX expression in response to IL-1β treatment in an adult rat hippocampal neurosphere culture system. We demonstrate that IL-1β reduced the proliferation of hippocampal NPCs and TLX expression in a dose and time-dependent manner and that co-treatment with IL-1β receptor antagonist or IL-1 receptor siRNA prevented these effects. We also report a dose-dependent effect of IL-1β on the composition of cell phenotypes in the culture and on expression of TLX in these cells. This study thus provides evidence of an involvement of TLX in IL-1β-induced changes in adult hippocampal neurogenesis, and offers mechanistic insight into disorders in which neuroinflammation and alterations in neurogenesis are characteristic features.     

Activation and modulation of human α4β2 nicotinic acetylcholine receptors by the neonicotinoids clothianidin and imidacloprid

Neonicotinoids are synthetic, nicotine-derived insecticides used for agricultural and household pest control. Though highly effective at activating insect nicotinic receptors, many neonicotinoids are also capable of directly activating and/or modulating the activation of vertebrate nicotinic receptors. In this study, we have investigated the actions of the neonicotinoids clothianidin (CTD) and imidacloprid (IMI) on human neuronal α4β2 nicotinic acetylcholine receptors. The data demonstrate that the compounds are weak agonists of the human receptors with relative peak currents of 1-4% of the response to 1 mM acetylcholine (ACh). Coapplication of IMI strongly inhibited currents elicited by ACh. From Schild plot analysis, we estimate that the affinity of IMI for the human α4β2 receptor is 18 μM. The application of low concentrations of CTD potentiated responses to low concentrations of ACh, suggesting that receptors occupied by one ACh and one CTD molecule have a higher gating efficacy than receptors with one ACh bound. Interestingly, subunit stoichiometry affected inhibition by CTD, with (α4)(2) (β2)(3) receptors significantly more strongly inhibited than the (α4)(3) (β2)(2) receptors.     

Activation of mixed glia by Aβ-specific Th1 and Th17 cells and its regulation by Th2 cells

Microglia are innate immune cells of the CNS, that act as antigen-presenting cells (APC) for antigen-specific T cells and respond to inflammatory stimuli, such as amyloid-beta (Aβ), resulting in the release of neurotoxic factors and pro-inflammatory cytokines. Astrocytes can also act as APC and modulate the function of microglia. However, the role of distinct T cell subtypes, in particular Th17 cells, in glial activation and subsequent modulatory effects of Th2 cells are poorly understood. Here, we generated Aβ-specific Th1, Th2, and Th17 cells and examined their role in modulating Aβ-induced activation of microglia in a mixed glial culture, a preparation which mimics the complex APC types in the brain. We demonstrated that mixed glia acted as an effective APC for Aβ-specific Th1 and Th17 cells. Addition of Aβ-specific Th2 cells suppressed the Aβ-induced IFN-γ production by Th1 cells and IL-17 production by Th17 cells with glia as the APC. Co-culture of Aβ-specific Th1 or Th17 cells with glia markedly enhanced Aβ-induced pro-inflammatory cytokine production and expression of MHC class II and co-stimulatory molecules on the microglia. Addition of Aβ-specific Th2 cells inhibited Th17 cell-induced IL-1β and IL-6 production by mixed glia and attenuated Th1 cell-induced CD86 and CD40 expression on microglia. The modest enhancement of MHC class II and CD86 expression on astrocytes by Aβ-specific Th1 and Th17 was not attenuated by Th2 cells. These data indicate that Aβ-specific Th1 and Th17 cells induce inflammatory activation of glia, and that this is in part regulated by Th2 cells.     

Cytokine production by a human microglial cell line: Effects of ßamyloid and α-melanocyte-stimulating hormone

Senile plaques in the Alzheimer's disease (AD) are formed by aggregation of beta-amyloid (Abeta) peptide. Abeta peptide has been shown to activate microglia and stimulate their production of inflammatory factors, such as cytokines. In the AD brain, the continued presence of amyloid plaques may keep microglia persistently activated, leading to chronic inflammation in the CNS. It is well established that alpha-melanocyte-stimulating hormone (alpha-MSH) gives rise to anti-inflammatory and anti-pyretic effects. The biological activities of alpha-MSH are mediated by one or more of the melanocortin receptor (MCR) subtypes, i.e. MCR1 - MCR5. The aim of the present study was to determine the effect of alpha-MSH alone and on Abeta-activated microglial cells with regard to the secretion of inflammatory cytokines, such as interleukin-6 (IL-6), and to determine which receptor subtype mediates the effects of alpha-MSH. The human microglial cell line, CHME3, was incubated for 24 h with freshly dissolved Abeta(1-40), interferon-gamma (IFN-gamma) and/or alpha-MSH. Freshly dissolved Abeta(1-40) (5-60 microM) resulted in a dose-dependent decrease in cell viability, along with a dose-dependent increase in IL-6 release. Neither IFN-gamma nor alpha-MSH affected the Abeta-induced secretion of IL-6, but resulted in a dose-dependent increase in basal IL-6 release. Agouti, the endogenous antagonist of MCR1 and 4, further increased the alpha-MSH-induced secretion of IL-6. RT-PCR showed the expression of MCR1, MCR3, MCR4 and MCR5 mRNA. The combined data suggest that the effect of alpha-MSH in increasing IL-6 release from the human microglial cell line is mediated by MCR3 or MCR5.     

Inhibition of lysophosphatidic acid-induced neurite retraction and cell rounding by SR 57746A

Rapid neurite retraction and transient rounding of serum-starved NG108-15 and PC12 cells by lysophosphatidic acid (LPA) is retarded and reduced by pre-incubation of the cells with the small non-peptidic molecule, SR 57746A, which exhibits neurotrophic properties. The compound also antagonizes the redistribution of filamentous actin by LPA in both cell types. We hypothesize that the SR 57746A attenuation of LPA-induced effects may account for at least some of the neuroprotective properties of this molecule.     

Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus–CSF nexus

In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)–cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood–CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF–brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is faciltated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI.     

Towards an understanding of women’s brain aging: the immunology of pregnancy and menopause

Women are at significantly greater risk of developing Alzheimer’s disease and show higher prevalence of autoimmune conditions relative to men. Women’s brain health is historically understudied, and little is therefore known about the mechanisms underlying epidemiological sex differences in neurodegenerative diseases, and how female-specific factors may influence women’s brain health across the lifespan. In this review, we summarize recent studies on the immunology of pregnancy and menopause, emphasizing that these major immunoendocrine transition phases may play a critical part in women’s brain aging trajectories.     

Anxiety modulation by the heart? Aerobic exercise and atrial natriuretic peptide

Exercise has an anxiolytic activity and it increases the concentrations of atrial natriuretic peptide (ANP). Because ANP has an anxiolytic activity, this hormone might contribute to the anxiolytic effects of aerobic exercise. Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks were studied in 10 healthy subjects after "quiet rest" or 30 min of aerobic exercise. Plasma ANP concentrations were measured before and after exercise or quiet rest using a commercial IRMA kit. Compared to quiet rest, CCK-4-induced anxiety was reduced and plasma ANP concentrations were increased by prior exercise. This anxiolytic activity of exercise was correlated with the increase in plasma ANP concentrations. Our results suggest that besides other mechanisms, ANP might be a physiologically relevant humoral link between the heart and anxiety-related behavior contributing to the acute anxiolytic effects of exercise.     

Dose-related modulation of event-related potentials to novel and target stimuli by intravenous Δ?-THC in humans

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ?-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ?-THC (placebo, 0.015 and 0.03?mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory 'oddball' P300 task). Δ?-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ?-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ?-THC induced psychotomimetic effects, perceptual alterations, and subjective 'high' in a dose-dependent manner. Δ?-THC -induced reductions in P3b amplitude correlated with Δ?-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ(9)-THC, there were no dose-related effects of Δ?-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ?-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing.     

Differential galanin receptor-1 and galanin expression by 5-HT neurons in dorsal raphé nucleus of rat and mouse: evidence for species-dependent modulation of serotonin transmission

Galanin and galanin receptors are widely expressed by neurons in rat brain that either synthesize/release and/or are responsive to, classical transmitters such as gamma-aminobutyric acid, acetylcholine, noradrenaline, histamine, dopamine and serotonin (5-hydroxytryptamine, 5-HT). The dorsal raphé nucleus (DRN) contains approximately 50% of the 5-HT neurons in the rat brain and a high percentage of these cells coexpress galanin and are responsive to exogenous galanin in vitro. However, the precise identity of the galanin receptor(s) present on these 5-HT neurons has not been previously established. Thus, the current study used a polyclonal antibody for the galanin receptor-1 (GalR1) to examine the possible expression of this receptor within the DRN of the rat and for comparative purposes also in the mouse. In the rat, intense GalR1-immunoreactivity (IR) was detected in a substantial population of 5-HT-immunoreactive neurons in the DRN, with prominent receptor immunostaining associated with soma and proximal dendrites. GalR1-IR was also observed in many cells within the adjacent median raphé nucleus. In mouse DRN, neurons exhibited similar levels and distribution of 5-HT-IR to that in the rat, but GalR1-IR was undetectable. Consistent with this, galanin and GalR1 mRNA were also undetectable in mouse DRN by in situ hybridization histochemistry, despite the detection of GalR1 mRNA (and GalR1-IR) in adjacent cells in the periaqueductal grey and other midbrain areas. 5-HT neuron activity in the DRN is primarily regulated via 5-HT1A autoreceptors, via inhibition of adenylate cyclase and activation of inward-rectifying K+ channels. Notably, the GalR1 receptor subtype signals via identical mechanisms and our findings establish that galanin modulates 5-HT neuron activity in the DRN of the rat via GalR1 (auto)receptors. However, these studies also identify important species differences in the relationship between midbrain galanin and 5-HT systems, which should prompt further investigations in relation to comparative human neurochemistry and which have implications for studies of animal models of relevant neurological conditions such as stress, anxiety and depression.