Wiley

Excitotoxicity refers to the ability of glutamate or related excitatory amino acids to mediate the death of central neurons under certain conditions, for example, after intense exposure. Such excitotoxic neuronal death may contribute to the pathogenesis of brain or spinal cord injury associated with several human disease states. Excitotoxicity has substantial cellular specificity and, in most cases, is mediated by glutamate receptors. On average, NMDA receptors activation may be able to trigger lethal injury more rapidly than AMPA or kainate receptor activation, perhaps reflecting a greater ability to induce calcium influx and subsequent cellular calcium overload. It is possible that excitotoxic death may share some mechanisms with other forms of neuronal death. © 1992 John Wiley & Sons, Inc.

Accumulating evidence indicates that the Trk family of tyrosine protein kinase receptors, Trk (also known as TrkA), TrkB, and TrkC, are responsible for mediating the trophic effects of the NGF family of neurotrophins. Nerve growth factor (NGF) specifically recognizes Trk, a receptor indentified in all major NGF targets, including sympathetic, trigeminal, and dorsal root ganglia as well as in cholinergic neurons of the basal forebrain and the striatum. Brain‐derived neurotropic factor (BDNF) and neurotrophin‐4 (NT‐4) specifically activate the TrkB tyrosine kinase receptor. trkB transcripts encoding this receptor are found throughout multiple structure of the central and peripheral nervous system. Neurotrophin‐3 (NT‐3) primarily activates the TrkC tyrosine protein kinases, four related isoforns encoded by alternative splicing of trkC, a gene also wildely expressed throughtout the mammalian nervous system. Unlike the other neurotrophins, NT‐3 appears to be somewhat promiscuous since it can activate Trk and TrkB kinase receptors, at least in certain cell systems. The trkB and trkC genes also encode noncatalytic neurotrophin receptor isoforms of an as yet, unknown function. Recently, strains of mice lacking each of these tyrosine kinase receptors have been generated. Preliminary characterization of these mutant mice has provided significant information regarding the role of these receptors in the ontogeny of the mammlian nervous system. For instance, mice deficient for Trk receptors lack most sympathetic neurons and do not display nociceptive and temperature sensations, two defects likely to result from severe neuronal cell loss in their trigeminal and dorsal root ganglia. Mice lacking TrkB tyrosine kinase receptors die postnatally due to their inability to intake food. Neuron cell loss in their trigeminal, nodose and pretrosal sensory ganglia as well as in the facial motor nucleus are likely to contribute to this phenotype. Finally, TrkC‐deficient mice display strikingly abnormal movements consistent with loss of proprioception, a defect likely to be a consequence of the complete loss of Ia muscle afferents observed in this mutant mice. 1994 John Wiley & Sons, Inc.

Retinoids (vitamin A) are crucial for most forms of life. In chordates, they have important roles in the developing nervous system and notochord and many other embryonic structures, as well as in maintenance of epithelial surfaces, immune competence, and reproduction. The ability of all‐trans retinoic acid to regulate expression of several hundred genes through binding to nuclear transcription factors is believed to mediate most of these functions. The role of all‐trans retinoic may extend beyond the regulation of gene transcription because a large number of noncoding RNAs also are regulated by retinoic acid. Additionally, extra‐nuclear mechanisms of action of retinoids are also being identified. In organisms ranging from prokaryotes to humans, retinal is covalently linked to G protein‐coupled transmembrane receptors called opsins. These receptors function as light‐driven ion pumps, mediators of phototaxis, or photosensory pigments. In vertebrates phototransduction is initiated by a photochemical reaction where opsin‐bound 11‐cis‐retinal is isomerized to all‐trans‐retinal. The photosensitive receptor is restored via the retinoid visual cycle. Multiple genes encoding components of this cycle have been identified and linked to many human retinal diseases.

 Central aspects of vitamin A absorption, enzymatic oxidation of all‐trans retinol to all‐trans retinal and all‐trans retinoic acid, and esterification of all‐trans retinol have been clarified. Furthermore, specific binding proteins are involved in several of these enzymatic processes as well as in delivery of all‐trans retinoic acid to nuclear receptors. Thus, substantial progress has been made in our understanding of retinoid metabolism and function. This insight has improved our view of retinoids as critical molecules in vision, normal embryonic development, and in control of cellular growth, differentiation, and death throughout life. © 2006 Wiley Periodicals, Inc. J Neurobiol 66: 606–630, 2006

Psychological researchers typically distinguish five major domains of individual differences in human behavior: cognitive abilities, personality, social attitudes, psychological interests, and psychopathology (Lubinski, 2000). In this article we: discuss a number of methodological errors commonly found in research on human individual differences; introduce a broad framework for interpreting findings from contemporary behavioral genetic studies; briefly outline the basic quantitative methods used in human behavioral genetic research; review the major criticisms of behavior genetic designs, with particular emphasis on the twin and adoption methods; describe the major or dominant theoretical scheme in each domain; and review behavioral genetic findings in all five domains. We conclude that there is now strong evidence that virtually all individual psychological differences, when reliably measured, are moderately to substantially heritable. © 2003 Wiley Periodicals, Inc. J Neurobiol 54: 4–45, 2003

Behavior is a manifestation of temporally and spatially defined neuronal activities. To understand how behavior is controlled by the nervous system, it is important to identify the neuronal substrates responsible for these activities, and to elucidate how they are integrated into a functional circuit. I introduce a novel and general method to conditionally perturb anatomically defined neurons in intactDrosophila. In this method, a temperature‐sensitive allele ofshibire(shi^ts1) is overexpressed in neuronal subsets using theGAL4/UASsystem. Because theshigene product is essential for synaptic vesicle recycling, andshi^ts1is semidominant, a simple temperature shift should lead to fast and reversible effects on synaptic transmission ofshi^ts1expressing neurons. Whenshi^ts1expression was directed to cholinergic neurons, adult flies showed a dramatic response to the restrictive temperature, becoming motionless within 2 min at 30°C. This temperature‐induced paralysis was reversible. After being shifted back to the permissive temperature, they readily regained their activity and started to walk in 1 min. Whenshi^ts1was expressed in photoreceptor cells, adults and larvae exhibited temperature‐dependent blindness. These observations show that theGAL4/UASsystem can be used to expressshi^ts1in a specific subset of neurons to cause temperature‐dependent changes in behavior. Because this method allows perturbation of the neuronal activities rapidly and reversibly in a spatially and temporally restricted manner, it will be useful to study the functional significance of particular neuronal subsets in the behavior of intact animals. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 81–92, 2001

Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. Medial prefrontal cortex is a target for glucocorticoids involved in the stress response. We have previously demonstrated that 3 weeks of daily corticosterone injections result in dendritic reorganization in pyramidal neurons in layer II–III of medial prefrontal cortex. To determine if similar morphological changes occur in response to chronic stress, we assessed the effects of daily restraint stress on dendritic morphology in medial prefrontal cortex. Male rats were exposed to either 3 h of restraint stress daily for 3 weeks or left unhandled except for weighing during this period. On the last day of restraint, animals were overdosed and brains were stained using a Golgi‐Cox procedure. Pyramidal neurons in lamina II–III of medial prefrontal cortex were drawn in three dimensions, and the morphology of apical and basilar arbors was quantified. Sholl analyses demonstrated a significant alteration of apical dendrites in stressed animals: overall, the number and length of apical dendritic branches was reduced by 18 and 32%, respectively. The reduction in apical dendritic arbor was restricted to distal and higher‐order branches, and may reflect atrophy of terminal branches: terminal branch number and length were reduced by 19 and 35%. On the other hand, basilar dendrites were not affected. This pattern of dendritic reorganization is similar to that seen after daily corticosterone injections. This reorganization likely reflects functional changes in prefrontal cortex and may contribute to stress‐induced changes in cognition. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 236–248, 2004

Dopamine (DA) is the only catecholaminergic neurotransmitter in the fruit fly Drosophila melanogaster. Dopaminergic neurons have been identified in the larval and adult central nervous system (CNS) in Drosophila and other insects, but no specific genetic tool was available to study their development, function, and degeneration in vivo. In Drosophila as in vertebrates, the rate‐limiting step in DA biosynthesis is catalyzed by the enzyme tyrosine hydroxylase (TH). The Drosophila TH gene (DTH) is specifically expressed in all dopaminergic cells and the corresponding mutant, pale (ple), is embryonic lethal. We have performed ple rescue experiments with modified DTH transgenes. Our results indicate that partially redundant regulatory elements located in DTH introns are required for proper expression of this gene in the CNS. Based on this study, we generated a GAL4 driver transgene, TH‐GAL4, containing regulatory sequences from the DTH 5′ flanking and downstream coding regions. TH‐GAL4 specifically expresses in dopaminergic cells in embryos, larval CNS, and adult brain when introduced into the Drosophila genome. As a first application of this driver, we observed that in vivo inhibition of DA release induces a striking hyperexcitability behavior in adult flies. We propose that TH‐GAL4 will be useful for studies of the role of DA in behavior and disease models in Drosophila. © 2003 Wiley Periodicals, Inc. J Neurobiol 54: 618–627, 2003

The properties of the cholinesterase activity in homogenates of whole rat diaphragm and of innervated (+EP) and non‐innervated (−EP) regions of the muscle have been investigated. Under standard assay conditions, over 90% of the cholinesterase activity of whole muscle homogenates was due to specific acetylcholinesterases. The specific activity of acetylcholinesterase was higher in +EP regions of muscle than in −EP regions. About 40% of the total activity was calculated to be specifically associated with the endplates. When a high speed supernatant fraction of muscles homogenized in 1 M NaCl, 0.5% Triton X‐100 was subjected to velocity sedimentation in a sucrose gradient, and three species of acetylcholinesterase activity with sedimentation constants of 4 S, 10 S and 16 S were observed. All three forms were stable under the conditions of sedimentation and had buoyant densities of approximately 1.28. All three hydrolyzed β‐methylacetylcholine at approximately 30% the rate that acetylcholine was hydrolyzed. The 10 S and 16 S forms were inhibited by concentrations of acetylcholine over 1.25 mM, but no substrate inhibition was observed with the 4 S enzyme. Velocity sedimentation of extracts from +EP and −EP regions of muscle demonstrated that the 4 S and 10 S forms of the enzyme were distributed throughout the muscle while the 16 S form was found only in +EP regions. Extracts of the phrenic nerve contained only 4 S and 10 S forms. Thus, the 16 S form of acetylcholinesterase is specifically associated with endplate regions of muscle and may correspond to the endplate enzyme. Seven days after denervation of the diaphragm, both endplate‐specific cholinesterase activity and the cholinesterase activity in −EP regions of muscle were decreased. Although the activity of all three forms of acetylcholinesterase were decreased in denervated muscle, the largest proportional decrease occurred in the activity of the 16 S form.

The tragic health effects of nicotine addiction highlight the importance of investigating the cellular mechanisms of this complex behavioral phenomenon. The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkaloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CNS, including the mesoaccumbens DA system, which ultimately leads to behavioral reinforcement and addiction. Recent findings from a number of laboratories have provided new insights into the biologic processes that contribute to nicotine self‐administration. Examination of the nAChR subtypes expressed within the reward centers has identified potential roles for these receptors in normal physiology, as well as the effects of nicotine exposure. The high nicotine sensitivity of some nAChR subtypes leads to rapid activation followed in many cases by rapid desensitization. Assessing the relative importance of these molecular phenomena in the behavioral effects of nicotine presents an exciting challenge for future research efforts. © 2002 Wiley Periodicals, Inc. J Neurobiol 53: 606–617, 2002

The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning. © 2002 Wiley Periodicals, Inc. J Neurobiol 53: 590–605, 2002