K. Ryan Thompson

Bio: K. Ryan Thompson is an academic researcher from University of Texas at Austin. The author has contributed to research in topics: Dentate gyrus & Alcohol dependence. The author has an hindex of 2, co-authored 3 publications receiving 24 citations.

Its complicated: The relationship between alcohol and microglia in the search for novel pharmacotherapeutic targets for alcohol use disorders

Abstract: Alcohol use disorder (AUD) is a chronic relapsing disorder with wide-ranging health consequences. Alcohol targets the central nervous system producing neurodegeneration and subsequent cognitive and behavioral deficits, but the mechanisms behind these effects remain unclear. Recently, evidence has been mounting for the role of neuroimmune activation in the pathogenesis of AUDs, but our nascent state of knowledge about the interaction of alcohol with the neuroimmune system supports that the relationship is complicated. As the resident macrophage of the central nervous system, microglia are a central focus. Human and animal research on the interplay between microglia and alcohol in AUDs has proven to be complex, and though early research focused on a pro-inflammatory phenotype of microglia, the anti-inflammatory and homeostatic roles of microglia must be considered. How these new roles for microglia should be incorporated into our thinking about the neuroimmune system in AUDs is discussed in the context of developing novel pharmacotherapies for AUDs.

Recovery of Hippocampal-Dependent Learning Despite Blunting Reactive Adult Neurogenesis After Alcohol Dependence.

Abstract: Background The excessive alcohol drinking that occurs in alcohol use disorder (AUD) causes neurodegeneration in regions such as the hippocampus, though recovery may occur after a period of abstinence. Mechanisms of recovery are not clear, though reactive neurogenesis has been observed in the hippocampal dentate gyrus following alcohol dependence and correlates to recovery of granule cell number. Objective We investigated the role of neurons born during reactive neurogenesis in the recovery of hippocampal learning behavior after 4-day binge alcohol exposure, a model of an AUD. We hypothesized that reducing reactive neurogenesis would impair functional recovery. Methods Adult male rats were subjected to 4-day binge alcohol exposure and two approaches were tested to blunt reactive adult neurogenesis, acute doses of alcohol or the chemotherapy drug, temozolomide (TMZ). Results Acute 5 g/kg doses of EtOH gavaged T6 and T7 days post binge did not inhibit significantly the number of Bromodeoxyuridine-positive (BrdU+) proliferating cells in EtOH animals receiving 5 g/kg EtOH versus controls. A single cycle of TMZ inhibited reactive proliferation (BrdU+ cells) and neurogenesis (NeuroD+ cells) to that of controls. However, despite this blunting of reactive neurogenesis to basal levels, EtOH-TMZ rats were not impaired in their recovery of acquisition of the Morris water maze (MWM), learning similarly to all other groups 35 days after 4-day binge exposure. Conclusions These studies show that TMZ is effective in decreasing reactive proliferation/neurogenesis following 4-day binge EtOH exposure, and baseline levels of adult neurogenesis are sufficient to allow recovery of hippocampal function.

Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats.

Abstract: Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.

2010 National and State Costs of Excessive Alcohol Consumption

Abstract: Excessive alcohol use cost the U.S. $223.5 billion in 2006. Given economic shifts in the U.S. since 2006, more-current estimates are needed to help inform the planning of prevention strategies.

Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence

Abstract: Neuroinflammatory signaling pathways in the central nervous system are of current interest as potential pharmacotherapy targets for alcohol dependence. In this study, we examined the ability of ibudilast, a non-selective phosphodiesterase inhibitor, to reduce alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure. When administered twice daily, ibudilast reduced alcohol drinking in rats by approximately 50% and reduced drinking by alcohol-dependent mice at doses which had no effect in non-dependent mice. These findings support the viability of ibudilast as a possible treatment for alcohol dependence.

Microglia Dystrophy Following Binge-Like Alcohol Exposure in Adolescent and Adult Male Rats.

Abstract: Microglia are dynamic cells that have roles in neuronal plasticity as well as in recovery responses following neuronal injury. Although many hypothesize that hyperactivation of microglia contributes to alcohol-induced neuropathology, in other neurodegenerative conditions disruption of normal microglial processes also contributes to neuronal loss, particularly as microglia become dystrophic or dysfunctional. Based on the observation of a striking, abnormal morphology in microglia during binge-like ethanol exposure, the present study investigated the impact of excessive ethanol exposure on microglia number and dystrophic morphology in a model of alcohol dependence that includes neurodegeneration in both adult and adolescent rats. Following 2- and 4-day binge ethanol exposure, the number of microglia was decreased in the hippocampus and the perirhinal and entorhinal cortices of both adult and adolescent rats. Furthermore, a significant number of microglia with a dystrophic morphology were observed in ethanol-exposed tissue, accompanied by a significant decrease in brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Together these findings suggest another means by which microglia may contribute to alcohol-induced neurodegeneration, specifically dystrophic microglia and/or loss of microglia may disrupt homeostatic and recovery mechanisms. These results demonstrate that microglia also degenerate with excessive alcohol exposure, which has important implications for understanding the role of microglia-and specifically their contributions to plasticity and neuronal survival-in neurodegenerative disease.

Alcohol use and dementia: new research directions

Abstract: Purpose of review Alcohol is gaining increased recognition as an important risk factor for dementia. This review summarises recent evidence on the relationship between alcohol use and dementia, focusing on studies published from January 2019 to August 2020. Recent findings Epidemiological data continues to yield results consistent with protective effects of low-to-moderate alcohol consumption for dementia and cognitive function. However, recent literature highlights the methodological limitations of existing observational studies. The effects of chronic, heavy alcohol use are clearer, with excessive consumption causing alcohol-related brain damage. Several pathways to this damage have been suggested, including the neurotoxic effects of thiamine deficiency, ethanol and acetaldehyde. Summary Future research would benefit from greater implementation of analytical and design-based approaches to robustly model the alcohol use-dementia relationship in the general population, and should make use of large, consortia-level data. Early intervention to prevent dementia is critical: thiamine substitution has shown potential but requires more research, and psychosocial interventions to treat harmful alcohol use have proven effective. Finally, diagnostic criteria for alcohol-related dementia require formal validation to ensure usefulness in clinical practice.

Role of cannabinoids in alcohol-induced neuroinflammation.

Abstract: Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure. Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response. Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades. Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.