March 2024
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3 Citations
Advances in Drug and Alcohol Research
Adolescent alcohol drinking is linked to high rates of adult alcohol problems and alcohol use disorder (AUD). The Neurobiology of Alcohol Drinking in Adulthood (NADIA) consortium adolescent intermittent ethanol (AIE) models adolescent binge drinking, followed by abstinent maturation to adulthood to determine the persistent AIE changes in neurobiology and behavior. AIE increases adult alcohol drinking and preference, increases anxiety and reward seeking, and disrupts sleep and cognition, all risks for AUD. In addition, AIE induces changes in neuroimmune gene expression in neurons and glia that alter neurocircuitry and behavior. HMGB1 is a unique neuroimmune signal released from neurons and glia by ethanol that activates multiple proinflammatory receptors, including Toll-like receptors (TLRs), that spread proinflammatory gene induction. HMGB1 expression is increased by AIE in rat brain and in post-mortem human AUD brain, where it correlates with lifetime alcohol consumption. HMGB1 activation of TLR increase TLR expression. Human AUD brain and rat brain following AIE show increases in multiple TLRs. Brain regional differences in neurotransmitters and cell types impact ethanol responses and neuroimmune gene induction. Microglia are monocyte-like cells that provide trophic and synaptic functions, that ethanol proinflammatory signals sensitize or “prime” during repeated drinking cycles, impacting neurocircuitry. Neurocircuits are differently impacted dependent upon neuronal-glial signaling. Acetylcholine is an anti-inflammatory neurotransmitter. AIE increases HMGB1-TLR4 signaling in forebrain, reducing cholinergic neurons by silencing multiple cholinergic defining genes through upregulation of RE-1 silencing factor (REST), a transcription inhibitor known to regulate neuronal differentiation. HMGB1 REST induction reduces cholinergic neurons in basal forebrain and cholinergic innervation of hippocampus. Adult brain hippocampal neurogenesis is regulated by a neurogenic niche formed from multiple cells. In vivo AIE and in vitro studies find ethanol increases HMGB1-TLR4 signaling and other proinflammatory signaling as well as reducing trophic factors, NGF, and BDNF, coincident with loss of the cholinergic synapse marker vChAT. These changes in gene expression-transcriptomes result in reduced adult neurogenesis. Excitingly, HMGB1 antagonists, anti-inflammatories, and epigenetic modifiers like histone deacetylase inhibitors restore trophic the neurogenesis. These findings suggest anti-inflammatory and epigenetic drugs should be considered for AUD therapy and may provide long-lasting reversal of psychopathology.
![Mechanisms underlying AIE-induced hippocampal pathology. Progenitor cells in the subgranular zone of the hippocampus go through a multiweek maturation where they (1) proliferate and (2) differentiate and develop into immature neurons, during which they functionally integrate within hippocampal circuitry. Damaged or otherwise deficient cells do not survive this process, and activation of cell-apoptotic pathways is an important normal physiological checkpoint (3). However, AIE increases cell death beyond normal apoptotic levels (3), as evidenced by increases in immunoreactivity of cleaved Casp3 in immature neurons. While these neuroimmune changes are persistent despite abstinence, they are not permanent and can be prevented and reversed by pharmacological intervention with galantamine. More specifically, galantamine rescues AIE-induced deficits in hippocampal neurogenesis (2) by driving increases in cell proliferation (1) and preventing overactivation of cell death pathways in newborn neurons (3). AIE-induced proinflammatory cascades is a critical mechanism underlying AIE-induced neurogenic deficits as increased proinflammatory signaling upsets the environmental milieu necessary for healthy levels of hippocampal neurogenesis. Specifically, AIE increases HMGB1 expression, which we have previously shown activates RAGE and TLR4 receptors (as reviewed by [47]). RAGE and TLR4 signaling cascades induce phosphorylation of the transcription factors NF-ĸB and AP-1, ultimately resulting in downstream induction of other proinflammatory signaling, including COX-2. Conversely, the chemokine CCL2 is expressed in the hilus and released as a neuromodulator to activate CCR2 receptors. CCR2 receptors are expressed in the subgranular zone of the dentate where they have also been shown to influence downstream proinflammatory cascades including NF-ĸB and AP-1 phosphorylation and COX-2 signaling. These pathways create a network of positive feedback for proinflammatory signaling cascades after AIE, which are prevented and restored by galantamine](https://www.researchgate.net/publication/354649107/figure/fig2/AS:1068894928261122@1631855818547/Mechanisms-underlying-AIE-induced-hippocampal-pathology-Progenitor-cells-in-the_Q320.jpg)
