Begell House Inc.
Critical Reviews™ in Neurobiology
CRN
0892-0915
10
2
1996
The Amygdala: Corticotropin-Releasing Factor, Steroids, and Stress
155-168
10.1615/CritRevNeurobiol.v10.i2.10
Thackery S.
Gray
Department of Cell Biology, Neurobiology and Anatomy, Loyola Medical Center, Loyola Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153
Elena W.
Bingaman
Department of Cell Biology, Neurobiology and Anatomy, Loyola Medical Center, Loyola Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153
androgen
anxiety
autonomic
estrogen
glucocorticoids
neuroendocrine
The possible function of corticotropin-releasing factor (CRF), adrenal steroids, and gonadal steroids in amygdala-mediated responses to anxiogenic or stressful stimuli is reviewed. The amygdala is part of an endogenous CRF circuitry within the brain that mediates neuroendocrine, autonomic, and behavioral changes in response to stress. The amygdala contains CRF-expressing neurons that communicate with widespread regions of the neural axis. High densities of CRF, CRF-binding protein, and CRF receptors are located in the amygdala. Direct injections of CRF into the amygdala produce anxiety-like behaviors. Release of endogenous CRF can be measured in the amygdala during stress. Potent anxiolytic actions are observed when CRF receptor antagonists are administered into the amygdala. CRF-containing neurons of the amygdala can be directly modulated by alterations in circulating glucocorticoids through glucocorticoid receptors, which are expressed in amygdaloid CRF-containing neurons. Gonadal steroid hormone receptors are found in the amygdala. They are not located in CRF immunoreactive neurons, but they are located adjacent to CRF-expressing neurons and in amygdaloid neurons that are likely to participate in central autonomic and neuroendocrine circuitry. Differences are noted between the steroid influences in the amygdala of male and female animals. Also, evidence is reviewed suggesting a modulatory role in the amygdala for gonadal and adrenal steroids in behavioral, autonomic, and neuroendocrine responses to anxiogenic stimuli.
Using Fractals and Nonlinear Dynamics to Determine the Physical Properties of Ion Channel Proteins
169-187
10.1615/CritRevNeurobiol.v10.i2.20
Larry S.
Liebovitch
Center for Complex Systems, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991
Angelo T.
Todorov
Center for Complex Systems, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991
fractals
nonlinear dynamics
ion channels
whole cell recording
rescaled range analysis
Three examples are given of how concepts from fractals and nonlinear dynamics have been used to analyze the voltages and currents recorded through ion channels in an attempt to determine the physical properties of ion channel proteins. (1) Early models had assumed that the switching of the ion channel protein from one conformational state to another can be represented by a Markov process that has no long-term correlations. However, one support for the existence of long-term correlations in channel function is that the currents recorded through individual ion channels have self-similar properties. These fractal properties can be characterized by a scaling function determined from the distribution of open and closed time intervals, which provides information on the distribution of activation energy barriers between the open and closed conformational substates of the ion channel protein and/or on how those energy barriers change in time. (2) Another support for such long-term correlations is that the whole-cell membrane voltage recorded across many channels at once may also have a fractal form. The Hurst rescaled range analysis of these fluctuations provides information on the type and degree of correlation in time of the functioning of ion channels. (3) The early models had also assumed that the switching from one state to another is an inherently random process driven by the energy from thermal fluctuations. More recently developed models have shown that deterministic dynamics may also produce the same distributions of open and closed times as those previously attributed to random events. This raises the possibility that the deterministic atomic and electrostatic forces play a role in switching the channel protein from one conformational shape to another. Debate exists about whether random, fractal, or deterministic models best represent the functioning of ion channels. However, fractal and deterministic dynamics provide a new approach to the study of ion channels that should be seriously considered by neuroscientists.
Nongenomic Actions of Estrogen in the Brain: Physiological Significance and Cellular Mechanisms
189-203
10.1615/CritRevNeurobiol.v10.i2.30
Michael
Wong
Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9040
Tina L.
Thompson
Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9040
Robert L.
Moss
Department of Physiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9040
17beta-estradiol
G-protein
direct membrane action
second messenger systems
Estrogen regulates neuroendocrine, reproductive, and behavioral functions of the brain by utilizing a number of diverse cellular mechanisms. In the classical genomic mechanism of steroids, estrogen induces relatively long-term actions on neurons by activating specific intracellular receptors that modulate transcription and protein synthesis. In addition, estrogen can also exert very rapid effects in the brain that cannot be attributed to genomic mechanisms. These nongenomic actions of estrogen influence a variety of neuronal properties, including electrical excitability, synaptic functioning, and morphological features, and are involved in many of the physiological functions and clinical effects of estrogen in the brain. Recently the specific cellular and molecular mechanisms underlying the nongenomic actions of estrogen have begun to be elucidated. Estrogen may utilize direct membrane mechanisms, such as activation of ligand-gated ion channels and G-protein-coupled second messenger systems and regulation of neurotransmitter transporters. Additionally the membrane and genomic actions of estrogen have the potential to interact, producing synergistic effects and dependence between the two types of mechanisms. The combination of nongenomic and genomic mechanisms endows estrogen with considerable diversity, range, and power in regulating neural function.
Biological Therapies for Alzheimer's Disease: Focus on Trophic Factors
205-238
10.1615/CritRevNeurobiol.v10.i2.40
Vassilis E.
Koliatsos
Neuropathology Laboratory, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205-2196
nerve growth factor
neurodegenerative
cholinergic neurons
clinical trials
memory
dementia
Recent revolutionary discoveries in the structure and function of the nervous system have substantiated the early optimism expressed by Ramón y Cajal on the regenerative potential of neurons. A systematic study of the mechanisms of neural injury and repair has generated exciting new ideas on how to assist the innate restorative potential of the nervous system by using substances that address specific pathogenetic events (biological or rational therapies). The greatest challenge for these interventions is the prevention of neuronal cell death, which is the inevitable outcome of many common diseases of the nervous system and which limits the efficacy of more traditional treatment approaches (i.e., approaches to restore the neuronal phenotype). Trophic factors are excellent candidates because they are naturally implemented to promote the survival of neurons in development. Among many neurological diseases, Alzheimer's disease (AD) is a model for consideration of a trophic therapy because of its grave epidemiological impact and the massive death of neurons in multiple brain sites. In the present paper, we propose an approach to design trophic therapies for AD, considering also the pertinent clinical and ethical issues. We also integrate the trophic approach with other ways to promote neural regeneration, including the use of small organic molecules. Nerve growth factor (NGF) is used as a paradigmatic trophic factor, because of a wealth of evidence for its robust effects on working memory (i.e., a type of cognition that is severely impaired in AD); other trophic factors, discussed in the text, may also have the potential as drugs for this disorder. It is likely that a comprehensive approach to treat AD will involve multiple substances selective for particular pathogenetic events and nerve cell types.
Neurodegenerative Disorders: Clues from Glutamate and Energy Metabolism
239-263
10.1615/CritRevNeurobiol.v10.i2.50
Lechoslaw
Turski
Research Laboratories of Schering AG, MĂĽllerstrasse 178, 13342 Berlin, Germany
Chrysanthy
Ikonomidou
Department of Pediatric Neurology, Children's Hospital, Virchow Clinics, Humboldt University, Augustenburgerplatz 1,13353 Berlin, Germany
excitotoxicity
neurodegeneration
ischemia
trauma
Parkinson's disease
Huntington's disease
aging
mitochondrial toxins
It is well established that glutamate receptors play a major role in mediating acute ischemic neuronal degeneration in the CNS. Cerebral ischemia and head or spinal cord trauma are associated with excessive release and extracellular accumulation of glutamate, which leads to persistent activation of glutamate receptors and acute neurotoxic degeneration of the hyperstimulated neuron. It has been more difficult to link neuronal degeneration that occurs in chronic neurodegenerative disorders to an excitotoxic mechanism. However, accumulating evidence suggests that impairment of intracellular energy metabolism associated with hyperactivation of glutamate receptors may be a common mechanism contributing to neuronal death in such disorders. It is proposed that impaired energy metabolism results in deterioration of membrane function and loss of the voltage-dependent Mg2+ block of N-methyl-D-aspartate receptors, which allows persistent activation of these receptors by glutamate, even if concentrations of glutamate at the receptor are within the normal physiological range. Studies in rodents using mitochondrial respiratory chain toxins, such as aminooxyacetic acid, l-methyl-4-phenylpyridinium ion, malonic acid, and 3-nitropropionic acid, suggest that these agents do induce CNS degeneration by a process involving an excitotoxic mechanism. Striatal and nigral degeneration induced by mitochondrial toxins in rodents resembles neuropathology seen in humans suffering from Huntington's or Parkinson's disease and can be attenuated by glutamate receptor antagonists and agents that improve energy metabolism. Such experimental observations suggest that disturbed energy metabolism and glutamate may be involved in neuronal death leading to abiotrophic/neurodegenerative disorders in humans. If so, glutamate antagonists or agents that improve energy metabolism may slow the degenerative process and offer a therapeutic approach for temporarily retarding the progression of these disabling disorders.