Alcohol, HMGB1, and Innate Immune Signaling in the Brain.

Purpose: Binge drinking (i.e., consuming enough alcohol to achieve a blood ethanol concentration of 80 mg/dL, approximately 4-5 drinks within 2 hours), particularly in early adolescence, can promote progressive increases in alcohol drinking and alcohol-related problems that develop into compulsive use in the chronic relapsing disease, alcohol use disorder (AUD).

Epigenetic regulation of microglia and neurons by proinflammatory signaling following adolescent intermittent ethanol (AIE) exposure and in human AUD.

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.

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent.

Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990-1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients.

Leptin activation of dorsal raphe neurons inhibits feeding behavior.

Unlabelled: Leptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes-which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, and hybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake.

Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure.

Background: Adolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE-induced (1) loss of adult neurogenesis (i.e.

Targeting Persistent Changes in Neuroimmune and Epigenetic Signaling in Adolescent Drinking to Treat Alcohol Use Disorder in Adulthood.

Studies universally find early age of drinking onset is linked to lifelong risks of alcohol problems and alcohol use disorder (AUD). Assessment of the lasting effect of drinking during adolescent development in humans is confounded by the diversity of environmental and genetic factors that affect adolescent development, including emerging personality disorders and progressive increases in drinking trajectories into adulthood. Preclinical studies using an adolescent intermittent ethanol (AIE) exposure rat model of underage binge drinking avoid the human confounds and support lifelong changes that increase risks.

Pyridostigmine bromide elicits progressive and chronic impairments in the cholinergic anti-inflammatory pathway in the prefrontal cortex and hippocampus of male rats.

Gulf War Illness (GWI) is a multi-symptom illness that continues to affect over 250,000 American Gulf War veterans. The causes of GWI remain equivocal; however, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB), and the stress of combat have been identified as two potential causative factors. Both PB and stress alter acetylcholine (ACh), which mediates both cognition and anti-inflammatory responses.

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development.

Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world.

The role of sex in the persistent effects of adolescent alcohol exposure on behavior and neurobiology in rodents.

Alcohol drinking is often initiated during adolescence, and this frequently escalates to binge drinking. As adolescence is also a period of dynamic neurodevelopment, preclinical evidence has highlighted that some of the consequences of binge drinking can be long lasting with deficits persisting into adulthood in a variety of cognitive-behavioral tasks. However, while the majority of preclinical work to date has been performed in male rodents, the rapid increase in binge drinking in adolescent female humans has re-emphasized the importance of addressing alcohol effects in the context of sex as a biological variable.

Chronic alcohol exposure during critical developmental periods differentially impacts persistence of deficits in cognitive flexibility and related circuitry.

Cognitive flexibility in decision making depends on prefrontal cortical function and is used by individuals to adapt to environmental changes in circumstances. Cognitive flexibility can be measured in the laboratory using a variety of discrete, translational tasks, including those that involve reversal learning and/or set-shifting ability. Distinct components of flexible behavior rely upon overlapping brain circuits, including different prefrontal substructures that have separable impacts on decision making.

Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure.

Background: Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis.

Hippocampal-specific insulin resistance elicits behavioral despair and hippocampal dendritic atrophy.

Insulin resistance is a major contributor to the neuroplasticity deficits observed in patients with metabolic disorders. However, the relative contribution of peripheral versus central insulin resistance in the development of neuroplasticity deficits remains equivocal. To distinguish between peripheral and central insulin resistance, we developed a lentiviral vector containing an antisense sequence selective for the insulin receptor (LV-IRAS).

Adolescent Alcohol Exposure Produces Protracted Cognitive-Behavioral Impairments in Adult Male and Female Rats.

Binge drinking is common in adolescence. Rodent studies modeling adolescent binge drinking find persistent effects on the brain's physiology, including increased expression of neuroimmune genes, impaired neurogenesis, and changes in behavioral flexibility. This study used females and males to investigate the effects of adolescent intermittent ethanol (AIE) on a battery of behaviors assessing spatial navigation using a radial arm water maze, working memory using the Hebb-Williams maze, non-spatial long-term memory using novel object recognition, and dominance using a tube dominance test.

Interactions between pyridostigmine bromide and stress on glutamatergic neurochemistry: Insights from a rat model of Gulf War Illness.

Pyridostigmine bromide (PB) was administered to soldiers during the first Gulf War as a prophylactic treatment to protect against toxicity in the event of exposure to nerve agents. Although originally thought to pose minimal risk to soldiers, epidemiological studies have since correlated PB administration with the development of a variety of symptoms, including cognitive dysfunction, termed Gulf War Illness (GWI). We previously demonstrated in a rodent model of GWI that central cholinergic responses were altered to various stimuli.

Neuroimmune and epigenetic mechanisms underlying persistent loss of hippocampal neurogenesis following adolescent intermittent ethanol exposure.

Alcohol abuse and binge drinking are common during adolescence - a maturational period characterized by heightened hippocampal neuroplasticity and neurogenesis. Preclinical rodent models of adolescent binge drinking (i.e.

Insulin resistance and hippocampal dysfunction: Disentangling peripheral and brain causes from consequences.

In the periphery insulin plays a critical role in the regulation of metabolic homeostasis by stimulating glucose uptake into peripheral organs. In the central nervous system (CNS), insulin plays a critical role in the formation of neural circuits and synaptic connections from the earliest stages of development and facilitates and promotes neuroplasticity in the adult brain. Beyond these physiological roles of insulin, a shared feature between the periphery and CNS is that decreases in insulin receptor activity and signaling (i.

Pyridostigmine bromide and stress interact to impact immune function, cholinergic neurochemistry and behavior in a rat model of Gulf War Illness.

Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB) in combination with the stress of deployment has been proposed to be among the causes of the cognitive dysfunction in GWI. Mechanistically, clinical studies suggest that altered immune function may be an underlying factor in the neurochemical and neurobehavioral complications of GWI.

Pathophysiology in a model of Gulf War Illness: Contributions of pyridostigmine bromide and stress.

During the Gulf War, prophylactic treatment with pyridostigmine bromide (PB) along with the stress of deployment may have caused unexpected alterations in neural and immune function, resulting in a host of cognitive deficits which have become clinically termed Gulf War Illness (GWI). In order to test this interaction between PB and stress, the following study used a rodent model of GWI to examine how combinations of repeated restraint stress and PB induced alterations of peripheral cholinesterase (ChE) activity, corticosterone (CORT) levels, and cytokines on the last day of treatment, and then 10 days and three months post-treatment. Results indicate that PB decreases ChE activity acutely but sensitizes it by three months post-treatment selectively in rats subjected to stress.

Chronic stress from adolescence to aging in the prefrontal cortex: A neuroimmune perspective.

The development of the organism is a critical variable which influences the magnitude, duration, and reversibility of the effects of chronic stress. Such factors are relevant to the prefrontal cortex (PFC), as this brain region is the last to mature, the first to decline, and is highly stress-sensitive. Therefore, this review will examine the intersection between the nervous system and immune system at glutamatergic synapses in the PFC across three developmental periods: adolescence, adulthood, and aging.

Sex-specific effects of developmental alcohol exposure on cocaine-induced place preference in adulthood.

Fetal Alcohol Syndrome (FAS) is associated with high rates of drug addiction in adulthood. One possible basis for increased drug use in this population is altered sensitivity to drug-associated contexts. This experiment utilized a rat model of FASD to examine behavioral and neural changes in the processing of drug cues in adulthood.

Upregulation of orexin/hypocretin expression in aged rats: Effects on feeding latency and neurotransmission in the insular cortex.

Aging is associated with changes in numerous homeostatic functions, such as food intake, that are thought to be mediated by the hypothalamus. Orexin/hypocretin neurons of the hypothalamus regulate several physiological functions, including feeding, sleep and wakefulness. Evidence from both clinical and animal studies supports the notion that aging is associated with loss or dysregulation of the orexin system.

Leptin resistance and hippocampal behavioral deficits.

The adipocyte-derived hormone leptin is an important regulator of body weight and metabolism through activation of brain leptin receptors expressed in regions such as the hypothalamus. Beyond these well described and characterized activities of leptin in the hypothalamus, it is becoming increasingly clear that the central activities of leptin extend to the hippocampus. Indeed, leptin receptors are expressed in the hippocampus where these receptors are proposed to mediate various aspects of hippocampal synaptic plasticity that ultimately impact cognitive function.

Neuro-immune interactions across development: A look at glutamate in the prefrontal cortex.

Although the primary role for the immune system is to respond to pathogens, more recently, the immune system has been demonstrated to have a critical role in signaling developmental events. Of particular interest for this review is how immunocompetent microglia and astrocytes interact with glutamatergic systems to influence the development of neural circuits in the prefrontal cortex (PFC). Microglia are the resident macrophages of the brain, and astrocytes mediate both glutamatergic uptake and coordinate with microglia to respond to the general excitatory state of the brain.