S06 ROLE OF INNATE IMMUNE SYSTEM IN THE ETHANOL-INDUCED BRAIN DAMAGE, BEHAVIOURAL DYSFUNCTIONS AND ADDICTION
S06.1 BINGE DRINKING INDUCES SIGNIFICANT CHANGES IN THE INNATE IMMUNE SYSTEM
- R. Ward1,
- P. De Witte2,
- F. Lallemand3,
- L. Della Corte4 and
- D. T. Dexter5
+ Author Affiliations
Abstract
Chronic and intermittent alcohol consumption leads to cognitive impairment in the brain due to the ethanol's action on specific neurotransmitter systems and intricate signalling pathways. Glial cells actively participate in brain function by nurturing neurons and facilitating neuronal activity as well having an immunological role to protect brain cells from invading pathogens. Dysregulation of this immune function induced by intermittent alcohol abuse may shift the homeostatic balance of inflammatory mediators to a proinflammatory state, activating microglia and inducing neuronal loss thereby inducing behavioural and cognitive impairments. Molecules, which could prevent the microglial activation and cytokine production would downregulate the pro-inflammatory state and help to prevent the decline of cognitive impairment. Studies of a ‘binge drinking’ adolescent female rats identified increased levels of glutamate in the dentate gyrus region of the hippocampus, which were associated with activated microglia. Such microglia will release glutamate when activated as well as a plethora of pro-inflammatory cytokines, e.g. IL-6 and TNFα. Oral administration of a taurine analogue, ethane-β-sultam to such ‘binge drinking’ rats for a 3-week period stabilized IKBα within the microglial cell, thereby preventing NFkappaB translocation to the nucleus and cytokine production. Activated microglia were no longer visible after immunohistochemical staining of the dentate gyrus brain region. The innate immune system, which is activated by intermittent alcohol use, can be suppressed by the use of molecules which target specific activators of this system, i.e. NFkappaB.
ERAB funding is gratefully acknowledged.
- © The Author 2011. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
- G. Bakalkin and
- T. Yakovleva
+ Author Affiliations
Abstract
Alcohol dependence and associated cognitive impairment appear to result from maladaptive neuroplasticity in response to chronic alcohol consumption, neuroinflammation and neurodegeneration. The inherent stability of behavioral alterations associated with the addicted state suggests that transcriptional and epigenetic mechanisms are operative. NF-kappaB transcription factors are regulators of synaptic plasticity and inflammation, and responsive to a variety of stimuli including alcohol. These factors are abundant in the brain where they have diverse functions that depend on the composition of the NF-kappaB complex and cellular context. In neuron cell bodies, NF-kappaB is constitutively active, and involved in neuronal injury and neuroprotection. However, at the synapse, NF-kappaB is present in a latent form and upon activation is transported to the cell nucleus. In glia, NF-kappaB is inducible and regulates inflammatory processes that exacerbate alcohol-induced neurodegeneration. Animal studies demonstrate that acute alcohol exposure transiently activates NF-kappaB, which induces neuroinflammatory responses and neurodegeneration. Our postmortem studies of brains of human alcoholics suggest that cycles of alcohol consumption/withdrawal cause adaptive changes in the NF-kappaB system that permit the system to better tolerate excessive stimulation. This tolerance, ensuring a low degree of responsiveness to applied stimuli, may represent a compensatory response that protects brain cells against alcohol neurotoxicity. This is supported by findings showing preferential downregulation of pro-apoptotic gene expression in the affected brain areas in human alcoholics. Although further verification is needed, we speculate that NF-kappaB-driven neuroinflammation and disruption to neuroplasticity play a significant role in regulating alcohol dependence and cognitive impairment.
- M. Pascual-Mora1,
- P. Baliño2,
- S. Alfonso-Loeches1,
- C. Aragón2 and
- C. Guerri1
+ Author Affiliations
Abstract
Toll-like receptors (TLRs) play an important role in the innate immune response, and emerging evidence indicates their role in brain injury and neurodegeneration. Our recent results have demonstrated that ethanol is capable of activating glial TLR4 receptors and that the elimination of these receptors in mice protects against ethanol-induced glial activation, induction of inflammatory mediators and apoptosis. However, whether ethanol-induced inflammatory damage causes behavioural and cognitive consequences, and if behavioural alterations are dependent of TLR4 functions are presently unknown. Here we show in mice drinking alcohol for 5 months, followed by a 15-day withdrawal period, that activation of the astroglial and microglial cells in frontal cortex and striatum is maintained and that these events are associated with cognitive and anxiety-related behavioural impairments in wild-type (WT) mice, as demonstrated by testing the animals with object memory recognition, conditioned taste aversion and dark and light box anxiety tasks. Mice lacking TLR4 receptors (TLR4−/−) are protected against ethanol-induced inflammatory damage, and behavioural associated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioural effects associated with neuroinflammatory damage. We show that chronic alcohol treatment decreases H4 histone acetylation and histone acetyltransferases activity in frontal cortex, striatum and hippocampus of WT mice. Alterations in chromatin structure were not observed in TLR4−/− mice. These results provide the first evidence of the role that TLR4 functions play in the behavioural consequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-induced behavioural or cognitive dysfunctions.
This study was supported by SAF-2009-07503, Institute of Heath, Carlos III (RTA-Network).
- F. Crews
+ Author Affiliations
Abstract
Addiction evolves through progressively reduced behavioral control and cognitive flexibility with increasing negative emotion and craving. Recent discoveries indicating neuroimmune signaling contribute to addiction and co-morbid depression. Low threshold microglia undergoes progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress and immune signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and neuroimmune gene expression. Human post-mortem alcoholic brain has increased microglial markers, chemokine-MCP1, TLR receptors and endogenous TLR agonists. Ethanol activates persistent neuroimmune signaling through the formation of loops of NF-κB transcription in glia contributing to a hyperglutamate state. Chronic ethanol treatment induces reversal learning deficits coincident with frontal cortical damage mimicking human drug addict deficits in behavioral flexibility. Increasing limbic negative emotion and depression-like behavior are reflected in hippocampal neurogenesis. Chronic ethanol inhibits neurogenesis coincident with depression-like behavior with both reversed by antidepressants. Antidepressants, naltrexone and anti-inflammatory drugs block ethanol neuroimmune activation, inhibition of neurogenesis and neurotoxicity. The hypothesis that neuroimmune gene induction underlies addiction and affective disorders creates new targets for therapy.
This study was supported by NIH and NIAAA.
