Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression.

Ketamine - An Imperfect Wonder Drug?

Ketamine is a potent sedative and dissociative anesthetic agent that has been used clinically for over 50 years since it was first developed in the 1960 s as an alternative to phencyclidine (PCP). When compared to PCP, ketamine exhibited a much lower incidence of severe side effects, including hallucinations, leading to its increased popularity in clinical practice. Ketamine was initially used as an anesthetic agent, especially in emergency medicine and in surgical procedures where rapid induction and recovery was necessary.

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is in turn regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression.

Models of Inflammation: Carrageenan Air Pouch.

The subcutaneous air pouch is an in vivo model that can be used to study the components of acute and chronic inflammation, the resolution of the inflammatory response, the oxidative stress response, and potential therapeutic targets for treating inflammation. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators. The model presented in this article has been extensively used to identify potential anti-inflammatory drugs.

Models of Inflammation: Carrageenan- or Complete Freund's Adjuvant (CFA)-Induced Edema and Hypersensitivity in the Rat.

Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the processing of pain sensation at CNS sites, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds in reversing cutaneous hypersensitivity. Detailed in this article are methods to elicit and measure carrageenan- and complete Freund's adjuvant (CFA)-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections into either the footpad or vibrissal pad are described.

Hippocampal mitogen-activated protein kinase phosphatase-1 regulates behavioral and systemic effects of chronic corticosterone administration.

Clinical reports indicate a bidirectional relationship between mental illness and chronic systemic diseases. However, brain mechanisms linking chronic stress and development of mood disorders to accompanying peripheral organ dysfunction are still not well characterized in animal models. In the current study, we investigated whether activation of hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1), a key factor in depression pathophysiology, also acts as a mediator of systemic effects of stress.

Strategies for Behaviorally Phenotyping the Transgenic Mouse.

The techniques and protocols to modify the mouse genome described in this volume allow researchers to produce genetic models of a remarkable number and breadth of human disease. The generation of gene-modified mice offers profoundly powerful approaches for bringing known or purported human gene disruptions into mouse models, but the degree to which the resultant mutant mouse recapitulates the complex physiological and behavioral features of the human disease state is a key variable in the ultimate usefulness of the mouse model organism. Accordingly, the behavioral characterization of mice with novel targeted gene mutations is an important initial step in determining the potential impact of a novel mouse model.

Assessing complex movement behaviors in rodent models of neurological disorders.

Behavioral phenotyping is a crucial step in validating animal models of human disease. Most traditional behavioral analyses rely on investigator observation of animal subjects, which can be confounded by inter-observer variability, scoring consistency, and the ability to observe extremely rapid, small, or repetitive movements. Force-Plate Actimeter (FPA)-based assessments can quantify locomotor activity and detailed motor activity with an incredibly rich data stream that can reveal details of movement unobservable by the naked eye.

Rats bred for low and high running capacity display alterations in peripheral tissues and nerves relevant to neuropathy and pain.

Introduction: Diet and activity are recognized as modulators of nervous system disease, including pain. Studies of exercise consistently reveal a benefit on pain. This study focused on female rats to understand differences related to metabolic status and peripheral nerve function in females.

NCB5OR Deficiency in the Cerebellum and Midbrain Leads to Dehydration and Alterations in Thirst Response, Fasted Feeding Behavior, and Voluntary Exercise in Mice.

Cytosolic NADH-cytochrome-b5-oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues. We have previously reported that global ablation of NCB5OR in mice results in early-onset lean diabetes with decreased serum leptin levels and increased metabolic and feeding activities. The conditional deletion of NCB5OR in the mouse cerebellum and midbrain (conditional knock out, CKO mice) results in local iron dyshomeostasis and altered locomotor activity.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice.

Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice.

Models of Inflammation: Carrageenan- or Complete Freund's Adjuvant (CFA)-Induced Edema and Hypersensitivity in the Rat.

Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the processing of pain sensation at CNS sites, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds in reversing cutaneous hypersensitivity. Detailed in this unit are methods to elicit and measure carrageenan- and complete Freund's adjuvant (CFA)-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections into either the footpad or vibrissal pad are described.

Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat.

Migraine is one of the most common neurological disorders, leading to more than 1% of total disability reported and over 68 million visits to emergency rooms or physician's offices each year in the United States. Three times as many women as men have migraine, and while the mechanism behind this is not well understood, 17β-estradiol (estradiol) has been implicated to play a role. Studies have demonstrated that exposure to estrogen can lead to activation of inflammatory pathways, changes in sodium gated channel activity, as well as enhanced vasodilation and allodynia.

Acute estrogen surge enhances inflammatory nociception without altering spinal Fos expression.

Chronic pain is a major neurological disorder that can manifest differently between genders or sexes. The complex actions of sex hormones may underlie these differences; previous studies have suggested that elevated estrogen levels can enhance pain perception. The purpose of this study was to investigate the hypothesis that acute, activational effects of estradiol (E2) increase persistent inflammatory nociception, and anatomically where this modulation occurs.

GABA pharmacology: the search for analgesics.

Decades of research have been devoted to defining the role of GABAergic transmission in nociceptive processing. Much of this work was performed using rigid, orthosteric GABA analogs created by Povl Krogsgaard-Larsen and his associates. A relationship between GABA and pain is suggested by the anatomical distribution of GABA receptors and the ability of some GABA agonists to alter nociceptive responsiveness.

Characterization of GABA receptors.

Described in this unit are ligand-binding assays for GABAA , GABAB , and the homomeric ρ GABAA (formerly GABAC ) receptor recognition sites in brain tissue. Although GABA binding sites are present in peripheral organs, most research is directed toward examining these receptors in the CNS. These assays may also be used to determine the affinity of an unlabeled compound for the GABA binding sites.

Gait analysis at multiple speeds reveals differential functional and structural outcomes in response to graded spinal cord injury.

Open-field behavioral scoring is widely used to assess spinal cord injury (SCI) outcomes, but has limited usefulness in describing subtle changes important for posture and locomotion. Additional quantitative methods are needed to increase the resolution of locomotor outcome assessment. This study used gait analysis at multiple speeds (GAMS) across a range of mild-to-severe intensities of thoracic SCI in the rat.

Exposure to bisphenol A exacerbates migraine-like behaviors in a multibehavior model of rat migraine.

Migraine is a common and debilitating neurological disorder suffered worldwide. Women experience this condition 3 times more frequently than men, with estrogen strongly implicated to play a role. Bisphenol A (BPA), a highly prevalent xenoestrogen, is known to have estrogenic activity and may have an effect in migraine onset, intensity, and duration through estrogen receptor signaling.

Neurochemical analysis of primary motor cortex in chronic low back pain.

The involvement of the primary motor cortex (M1) in chronic low back pain (LBP) is a relatively new concept. Decreased M1 excitability and an analgesic effect after M1 stimulation have been recently reported. However, the neurochemical changes underlying these functional M1 changes are unknown.

Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation.

Musculoskeletal pain affects nearly half of all adults, most of whom are vitamin D deficient. Previous findings demonstrated that putative nociceptors ("pain-sensing" nerves) express vitamin D receptors (VDRs), suggesting responsiveness to 1,25-dihydroxyvitamin D. In the present study, rats receiving vitamin D-deficient diets for 2-4 weeks showed mechanical deep muscle hypersensitivity, but not cutaneous hypersensitivity.

Mechanisms of pain modulation by sex hormones in migraine.

A number of pain conditions, acute as well as chronic, are much more prevalent in women, such as temporomandibular disorder (TMD), irritable bowel syndrome, fibromyalgia, and migraine. The association of female sex steroids with these nociceptive conditions is well known, but the mechanisms of their effects on pain signaling are yet to be deciphered. We reviewed the mechanisms through which female sex steroids might influence the trigeminal nociceptive pathways with a focus on migraine.

Sex differences in behavior and expression of CGRP-related genes in a rodent model of chronic migraine.

Objective: The objectives of this study were to develop a preclinical rodent model that produces migraine-like behaviors based on International Headache Society diagnostic criteria, to determine whether sex differences are present, and to determine whether expression of calcitonin gene-related peptide (CGRP) and the genes encoding its receptor in trigeminal ganglion or medulla correlates with those behaviors.

Background: Few animal studies of migraine have tested behaviors associated with migraine diagnostic criteria. In this study, changes in activity and in mechanical sensitivity of facial regions following application of inflammatory soup (IS) or vehicle (phosphate-buffered saline [PBS]) to the dura were measured to model changes in routine activity and allodynia.

Hypersensitivity and hyperinnervation of the rat hind paw following carrageenan-induced inflammation.

Studies of human tissue show that many chronic pain syndromes are accompanied by abnormal increases in numbers of peripheral sensory nerve fibers. It is not known if sensory nerve sprouting occurs as a result of inflammation present in these conditions, or other factors such as infection or extensive tissue damage. In the present study, we used a well established model of inflammation to examine cutaneous innervation density in relation to mechanical and thermal hypersensitivity.

The GABAβ receptor as a target for antidepressant drug action.

Preclinical and clinical data suggest that a modification in GABA(B) receptor expression and function may contribute to the symptoms of major depression and the response to antidepressants. This includes laboratory animal experiments demonstrating that antidepressants modify brain GABA(B) receptor expression and function and that GABA(B) receptor antagonists display antidepressant potential in animal models of this condition. Clinical and post-mortem studies reveal changes in GABAergic transmission associated with depression as well as depression-related changes in GABA(B) subunit expression that are localized to the cortical depression network.