Critical reviews in neurobiology最新文献

Autoimmune disorders of the peripheral nervous system (PNS) comprise a heterogeneous group of diseases that result from an aberrant immune response. Most of these disorders present severe morbidity and, in some cases, mortality. Even those conditions that are self-limited may display severe disability and necessitate hospitalization. Although their etiology remains elusive, there is increasing knowledge of the pathophysiological mechanisms causing tissue dysfunction and structural damage. The discovery of several mediators that constitute the molecular mechanisms of cell-cell and cell-extracellular-matrix interactions has revealed insight into various aspects of the neuroimmune interaction. Classic animal models associated with new genetic approaches have further increased our comprehension of the molecular pathways that regulate inflammatory disorders of the nervous system. The aim of this review is to describe various types and functions of the principal molecular components of the neuroimmune interaction and their importance in the principal autoimmune disorders of the PNS. We also provide an extensive description of clinical and pathological features of autoimmune disorders of the PNS, along with diagnostic and therapeutic implications.

Free fatty acids (FFAs) are elevated in the brain following both ischemic and traumatic injury. Phospholipase activation, with the subsequent release of FFAs from membrane phospholipids, is the likely mechanism. In addition to phospholipases A1, B, C, and D, there are at least 19 groups of PLA2, including multiple cytosolic, calcium independent, and secretory isoforms. Phospholipase activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. These enzymes normally function in the physiological remodeling of cellular membranes, whereby FFAs are removed by phospholipase activity and then reacylated with a different FFA. However, reductions in the cell's ability to maintain normal metabolic function and the resultant fall in ATP levels can cause the failure of reacylation of membrane phospholipids. Alterations to membrane phospholipids would be expected to compromise many cellular functions, including the ability to accumulate excitotoxic amino acids. This review presents evidence for a central role of phospholipases and their products in the etiology of damage following injury to the brain. Phospholipase expression and activity is increased in animal models of cerebral ischemia and trauma. FFA release from the in vivo rat brain is reduced following the application of selective phospholipase inhibitors, and this inhibition also decreases the severity of cortical damage following forebrain ischemia, focal (middle cerebral artery occlusion) ischemia, and cerebral trauma. Mice with knockouts of PLA2 have decreased infarct volumes. Human data demonstrate a correlation between the elevation of CSF FFAs and worsened outcome following stroke, traumatic brain injury, and subarachnoid hemorrhage. The released FFAs, especially arachidonic and docosahexaenoic acids, together with the production of lysophospholipids, can initiate a chain of events which may be responsible for the development of neuronal damage. Inhibitors of both cyclooxygenase and lipoxygenase pathways have been shown to reduce cerebral deficits following ischemia and trauma. These results suggest therapeutic strategies to reduce morbidity following cerebral injury using selective inhibitors of phospholipases, cyclooxygenases, and lipoxygenases, underlining the need for further investigation of their role in the development of cerebral damage.

Neuroactive steroids are potent endogenous neuromodulators with rapid actions in the central nervous system. Neuroactive steroids have been claimed to have specific physiological roles in normal or pathological brain function. This article reviews the emerging evidence that progesterone-, deoxycorticosterone-, and testosterone-derived endogenous neuroactive steroids play an important role in the modulation of neural excitability and brain function. Neuroactive steroids such as allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) are extremely potent positive allosteric modulators of GABAA receptors with sedative, anxiolytic, and anticonvulsant properties. The sulfated neuroactive steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), which are negative GABAA receptor modulators, induce anxiogenic and proconvulsant effects. Thus, natural fluctuations in neuroactive steroid levels during the menstrual cycle and stress could affect several nervous system functions. There is strong evidence that allopregnanolone and THDOC are involved in the pathophysiology of premenstrual syndrome, catamenial epilepsy, major depression, and stress-sensitive brain disorders. Neuroactive steroids PS and DHEAS have been shown to modulate memory functions. However, the significance of the testosterone-derived neuroactive steroid 3alpha-androstanediol is not well understood. Like naturally occurring neuroactive steroids, synthetic derivatives such as ganaxolone have been proven in preclinical and clinical studies to be effective anticonvulsants with great potential for human use. Future research on inhibition or stimulation of specific neuroactive steroid synthesizing enzymes could provide an improved understanding and novel approaches for the treatment of anxiety, epilepsy, and depression.

Botulinum neurotoxin is the neuromuscular poison that is responsible for the fatal disease botulism. This toxin is also a valued therapeutic agent in the treatment of an increasing number of neuromuscular disorders. Unfortunately, in the wrong hands, botulinum neurotoxin is also a deadly biological "weapon. The diverse health consequences of botulinum neurotoxin combined with the increased threat of bioterrorism underscore the profound importance of understanding exactly how this toxin exerts its effects on the clinically relevant mammalian target site, the neuromuscular junction. Despite the fact that a great deal has been learned about the cellular actions of botulinum neurotoxin during the past three decades, questions still remain. For example, what protein or proteins mediate transport of the toxin into the cholinergic nerve terminal? What factors control the duration of toxin action in the nerve terminal? Until recently, scholarly pursuit of such questions was technically challenging in neuromuscular tissues. Recent advancements in biotechnology have now made it feasible to pursue these important issues at the neuromuscular junction and to correlate biochemical studies in nontarget tissues with clinically relevant functional outcomes. This narrative reviews our current understanding of the actions of botulinum neurotoxin at the neuromuscular junction, presents recent findings from our own work in neuromuscular tissues, and encourages future studies regarding botulinum neurotoxin at its target site.

This review aims to stimulate new ways of thinking about how to model depression in rats and mice. The article is founded on the premise that anthropomorphic inferences should be removed entirely from research involving rodents. The application of animal models to study depression over the past 30 years has been based largely on nonempirical and hence nonscientific assumptions about psychological states that probably do not exist and certainly cannot be measured in rodents. Such assumptions may have led to the misinterpretation of some behaviors, such as decreased locomotor activity or decreased sucrose consumption, as symptoms of depression in rats. Previous research has also overemphasized the causal role of stress in depression. After reviewing major features of several commonly employed models, this article challenges traditional concepts about validity. Models are first evaluated based on the goals of the research. Screening for potential antidepressant compounds requires little or no consideration of the validity of the model. Issues of validity become more critical when attempting to study the neurobiological basis of depression. The primary importance of face validity is emphasized, and the value of various behavioral measures is assessed based on how directly they resemble discrete behavioral symptoms seen in depressed humans. A "neurobehaviorally mechanistic" approach is described. This approach relies on formulating discrete, neurobiological hypotheses to explain individual symptoms rather than to explain collections of symptoms or the entire disorder. The approach thus relies on pragmatic measures of operationally well-defined behavioral variables. The review concludes with the proposal that understanding the neurobiological basis for individual symptoms will ultimately yield a better understanding of depression.

Marijuana produces a number of characteristic behaviors in humans and animals, including memory impairment, antinociception, and locomotor and psychoactive effects. However, tolerance and dependence to cannabinoids develops after chronic use, as demonstrated both clinically and in animal models. The potential therapeutic benefits of certain cannabinoid-mediated effects, as well as the use of marijuana for its psychoactive properties, has raised interest in understanding the cellular adaptations produced by chronic administration of this class of drugs. The primary active constituent of marijuana, delta9-tetrahydrohydrocannabinol (THC), binds to specific G-protein-coupled receptors. The central nervous system (CNS) effects of THC are mediated by CB1 receptors, which couple primarily to inhibitory G-proteins. High levels of CB1 receptors are found in the basal ganglia, hippocampus, cortex, and cerebellum, consistent with the profile of behavioral effects. Studies over the past decade have determined that CB1 receptors undergo downregulation and desensitization following chronic administration of THC or synthetic cannabinoid agonists. In general, these adaptations are regionally widespread and of considerable magnitude, and are thought to contribute to tolerance to cannabinoid-mediated behavioral effects. Adaptation at the effector level has been more difficult to characterize, although it appears that alterations in cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity may be particularly important in cannabinoid dependence. A striking characteristic of CB 1 receptor adaptation is the region dependence of the magnitude and rate of development of downregulation and desensitization. These regional differences may provide interesting insights into the mechanisms of CB1 receptors receptor signaling in different brain regions. Moreover, region-specific adaptations in CB1 receptors following chronic cannabinoid administration may produce differential adaptations at the in vivo level.

For many years, researchers have avoided including females in their research because of the poorly understood influences of cycling hormones. However, we are becoming increasingly aware that sex matters, showing that it is important to conduct studies in females as well as males. This review will focus on the central nervous system (CNS) actions of alcohol (ethanol) because we have found significant sex differences in ethanol actions at the molecular as well as the behavioral level. Most recently, in our studies of ethanol dependence and withdrawal, we found that female rats displayed a shorter time for recovery from ethanol withdrawal, assessed by measuring seizure susceptibility. We now report that this finding was confirmed with a second convulsant agent. Moreover, GABAA receptor function was differentially altered in ethanol-withdrawn female compared to male rats. Studies by other investigators have reported additional significant sex differences in ethanol seeking and drinking behaviors and across several measures of ethanol dependence and withdrawal. We are gaining a better understanding of how the actions of ethanol in the CNS overlay sex differences in brain architecture and the hormonal milieu. Therefore, it is not surprising to observe sex-selective effects on cellular and behavioral outcomes from ethanol consumption. While current research is focused on characterizing sex differences in the actions of ethanol, it has not yet reached the point where we can integrate our findings into a unifying concept of how being female differentially regulates CNS responses to ethanol. This is likely a result of the complexity of ethanol actions, involving multiple neurotransmitter systems and responses covering the spectrum from drug seeking behaviors to neuropathological consequences of ethanol misuse. Regardless, the observed sex differences in ethanol withdrawal are noteworthy because they suggest that treatment of alcoholism should be managed differently in women than in men. Finally, it remains important to compare and contrast responses in males and females because recent studies of sex differences in basic physiology have made it clear that being female impacts health and disease.

The goal of the present paper is to elucidate and to resolve contradictions in the relationships among different forms of stress, sleep deprivation, and paradoxical sleep (PS) functions. Acute immobilization stress and the stress of learned helplessness are accompanied by an increase of PS, whereas the stress of defense behavior and the stress of self-stimulation cause PS reduction. Recovery sleep after total sleep deprivation performed on the rotating platform is marked by a dramatic rebound of PS although NREM (non-rapid eye movement) sleep deprivation is more prominent than PS deprivation. This PS rebound leads to a quick reversal of the pathology caused by prolonged sleep deprivation. The search activity (SA) concept presents an explanation for these contradictions. SA increases body resistance to stress and diseases, whereas renunciation of search (giving up, helplessness) decreases body resistance. PS and dreams contain covert SA, which compensates for the lack of the overt SA in the preceding period of wakefulness. The requirement for PS increases after giving up and decreases after active defense behavior and self-stimulation. Immobilization stress prevents SA in waking behavior and increases the need in PS. Sleep deprivation on the rotating platform, like immobilization stress, prevents SA, produces conditions for learned helplessness and, suppresses PS. Such a combination increases PS pressure and decreases body resistance.