Sex Differences in Binge Alcohol-Induced Brain Damage and Recovery of Function

Evidence suggests that women are more sensitive to the neurotoxic effects of alcohol and more vulnerable to the adverse medical consequences of heavy alcohol consumption than men. Despite this few studies have directly compared the consequences of binge alcohol between the male and female brain, and the mechanisms that underlie increased female vulnerability remain poorly understood. The present studies investigated sex differences in alcohol-induced neurodegeneration, and associated cognitive deficits and disruption of trophic support, using a rodent model of an alcohol use disorder (AUD). Binge exposure resulted in a significant loss of granule neurons and significantly more degenerating and dead cells in the hippocampal dentate gyrus of females compared to males. This was associated with a binge-induced spatial reference memory deficits in the Morris water maze for females but not males. Binge-induced neurodegeneration in the female hippocampus was associated with a decrease of BDNF, TrkB, CREB, and pCREB protein expression; however only BDNF was disrupted in the hippocampus of males. Further, we investigated if exercise-driven recovery from binge-induced neurodegeneration was associated with increased trophic support. One to two weeks of voluntary exercise reversed the binge-induced reduction of dentate gyrus granule neurons in females, likely via an increase in BDNF, pCREB, and Iba1 (microglia). We conclude that the female hippocampus is more sensitive to binge-induced neurodegeneration and associated cognitive consequences than males, like due to the disruption of protective tropic support. Voluntary exercise however, can enhance endogenous recovery processes by increasing trophic support that aids in recovery.Psychology, Department o

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

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

Thinking after Drinking: Impaired Hippocampal-Dependent Cognition in Human Alcoholics and Animal Models of Alcohol Dependence

Alcohol use disorder currently affects approximately 18 million Americans, with at least half of these individuals having significant cognitive impairments subsequent to their chronic alcohol use. This is most widely apparent as frontal cortex dependent cognitive dysfunction, where executive function and decision making are severely compromised, as well as hippocampus dependent cognitive dysfunction, where contextual and temporal reasoning are negatively impacted. This review discusses the relevant clinical literature to support the theory that cognitive recovery in tasks dependent on the prefrontal cortex and hippocampus is temporally different across extended periods of abstinence from alcohol. Additional studies from preclinical models are discussed to support clinical findings. Finally, the unique cellular composition of the hippocampus and cognitive impairment dependent on the hippocampus is highlighted in the context of alcohol dependence

Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

Functional Activation of Newborn Neurons Following Alcohol-Induced Reactive Neurogenesis

Abstinence after alcohol dependence leads to structural and functional recovery in many regions of the brain, especially the hippocampus. Significant increases in neural stem cell (NSC) proliferation and subsequent “reactive neurogenesis” coincides with structural recovery in hippocampal dentate gyrus (DG). However, whether these reactively born neurons are integrated appropriately into neural circuits remains unknown. Therefore, adult male rats were exposed to a binge model of alcohol dependence. On day 7 of abstinence, the peak of reactive NSC proliferation, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells. After six weeks, rats underwent Morris Water Maze (MWM) training then were sacrificed ninety minutes after the final training session. Using fluorescent immunohistochemistry for c-Fos (neuronal activation), BrdU, and Neuronal Nuclei (NeuN), we investigated whether neurons born during reactive neurogenesis were incorporated into a newly learned MWM neuronal ensemble. Prior alcohol exposure increased the number of BrdU+ cells and newborn neurons (BrdU+/NeuN+ cells) in the DG versus controls. However, prior ethanol exposure had no significant impact on MWM-induced c-Fos expression. Despite increased BrdU+ neurons, no difference in the number of activated newborn neurons (BrdU+/c-Fos+/NeuN+) was observed. These data suggest that neurons born during alcohol-induced reactive neurogenesis are functionally integrated into hippocampal circuitry

THE EFFECT OF NICOTINE CO-ADMINISTRATION ON ALCOHOL-INDUCED REACTIVE HIPPOCAMPAL CELL PROLIFERATION DURING ABSTINENCE IN AN ADOLESCENT MODEL OF AN ALCOHOL USE DISORDER

A significant consequence of alcohol use disorders (AUDs) is hippocampal neurodegeneration. The hippocampus is responsible for learning and memory, and neurodegeneration in this brain region has been shown to result in cognitive deficits. Interestingly, some alcoholics demonstrate improvements in hippocampus-dependent functions, potentially due the phenomenon termed adult neurogenesis. Adult neurogenesis, the process by which neural stem cells (NSCs) proliferate, differentiate into neurons, migrate into the granule cell layer, and survive, occurs in two brain regions; however, this study examines only neurogenesis occurring in the subgranular zone of the hippocampal dentate gyrus. Four-day binge ethanol exposure in an animal model causes a decrease in neurogenesis during intoxication; however, there is a reactive increase in cell proliferation on day seven of abstinence. The purpose of this study was to determine the timing of increased cell proliferation. Furthermore, most alcoholics also smoke tobacco, and nicotine, the addictive component of tobacco, has also been shown to affect hippocampal neurogenesis. As many people initiate alcohol and tobacco use during adolescence, the second experiment herein examined the effect of nicotine coadministration on alcohol-induced reactive hippocampal cell proliferation

PRECLINICAL DEVELOPMENT OF PHYTOCANNABINOID- AND ENDOCANNABINOID- BASED PHARMACOTHERAPIES FOR THE TREATMENT OF ETHANOL-INDUCED NEURODEGENERATION

Excessive ethanol consumption, characteristic of alcohol use disorders (AUDs), is associated with widespread neurodegeneration and cognitive and behavioral impairments that may contribute to the chronic and relapsing nature of alcoholism. Therefore, identifying novel targets that can afford neuroprotection will undoubtedly aid current treatment strategies for AUDs. The cannabinoids have been shown to provide neuroprotection in a variety of preclinical models of neurodegeneration; however minimal data is available regarding the use of cannabinoid-based pharmacotherapies for treating ethanol-induced neurodegeneration. Therefore, the current dissertation examined the overarching hypothesis: the cannabinoids are a therapeutic strategy to afford neuroprotection in the context of ethanol-induced neurodegeneration. Importantly, this overarching hypothesis was approached with translational considerations in mind. Specifically, the use of many cannabinoids in the clinic is hindered due to multiple unfavorable pharmacokinetic/pharmacodynamic profiles, including high first pass metabolism and untoward psychoactivity. Therefore, the studies herein were designed to circumvent these PK/PD obstacles. The first set of studies examined whether transdermal delivery of the phytocannabinoid, cannabidiol (CBD), could attenuate binge ethanol induced neurodegeneration. Transdermal CBD afforded neuroprotection in the entorhinal cortex and neuroprotection was similar in magnitude as intraperitoneal administration. The second set of studies found that binge ethanol treatment transiently down-regulated the main CNS cannabinoid receptor, CB1R. Interestingly, these changes were not accompanied by alterations in one of the major endogenous ligands, anandamide (AEA), or other related n-acylethanolamides (NAEs). The latter finding is in contrast to other literature reports demonstrating that endocannabinoid content is substantially elevated in response to a CNS insult. Nevertheless, studies were carried out to determine if administration of the AEA and NAE catabolism inhibitor, URB597, could attenuate binge ethanol induced neurodegeneration. URB597 failed to produce neuroprotection in the entorhinal cortex and dentate gyrus of the hippocampus. However, additional studies found that URB597 failed to elevate AEA in the entorhinal cortex, and in general the biological activity of URB597 was impaired by ethanol exposure. Therefore, with further drug discovery/development efforts, it may be feasible to optimize such treatment strategies. In conclusion, the studies within the current dissertation demonstrated the feasibility of using some cannabinoid-based agents to prevent ethanol-induced neurodegeneration

Hippocampal insult and recovery from ethanol dependence in females and males

Alcohol use and misuse is common and presents a public health concern. The consequence of excessive alcohol (ethanol) consumption is neurodegeneration and cognitive decline. Women, compared to men, are drinking at higher rates and may be more sensitive to the negative effects of ethanol. In abstinence, recovery of brain structure and function may occur, however, the mechanisms of recovery are not well known. Neurogenesis, the birth of new neurons, occurs throughout life in areas of the brain like the hippocampus, an area also sensitive to ethanol. The hippocampus is associated with multiple brain functions with the dorsal portion closely linked to learning and memory, and the ventral portion linked to emotions like stress and anxiety. In male rodents, ethanol dependence impairs neurogenesis. After a period of abstinence, a burst in neurogenesis occurs in reaction to ethanol that is hypothesized to be reparative. It is not well understood if the effect of ethanol on neurogenesis occurs similarly in females. Therefore, experiments were conducted to test sex differences following ethanol dependence. First, reactive neurogenesis was measured in both the dorsal and ventral poles of the hippocampus of females and males. In the dorsal hippocampus, both sexes experience a reactive increase in neurogenesis following ethanol exposure. In the ventral hippocampus, there was an increase in the number of new cells that were born but not an increase in neurons. Next, the number, location and complexity of newborn neurons in ethanol-exposed and control animals were analyzed. Results indicated that cells born following ethanol exposure migrated normally into the granule cell layer, but had smaller, less complex dendritic arbors. Finally, hippocampal and non-hippocampal linked associative fear learning was tested following ethanol dependence. Surprisingly, ethanol-exposed rats were not impaired in hippocampally-linked contextual fear recall. Additionally, ethanol-exposed females, but not males, showed enhanced amygdalar-linked cue recall. Overall, these results expand our understanding of ethanol-related brain damage and recovery in both sexes. Understanding the complex cellular processes that occur in the brain following alcohol use could lead to more targeted therapies and improved recovery outcomes in individuals with AUD.Pharmaceutical Science