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PubMedDate not supplied

The neural cell adhesion molecule in synaptic plasticity and ageing.

By mediating cell adhesion and signal transduction, the neural cell adhesion molecule (NCAM) regulates neurite outgrowth, fasciculation and target recognition in the developing nervous system. In addition, a number of studies suggest an important role for the NCAM in regeneration and learning in the adult nervous system. NCAM-deficient mice are impaired in spatial learning. Moreover, by interfering with normal NCAM function by intracranial injections of NCAM-antibodies, long-term potentiation (LTP) in rat hippocampal slices and learning in rats and chicks have been inhibited. In the vertebrate nervous system, NCAM is the dominant carrier of polysialic acid (PSA), an unusual carbohydrate consisting of long homopolymers of sialic acid. The PSA-NCAM expression decreases markedly during development. However, an upregulation of polysialic acid (PSA) in restricted brain areas including the hippocampus has been observed following learning. Moreover, enzymatic removal of PSA results in impaired LTP and learning. In muscle, the PSA-NCAM expression is upregulated following denervation. This response is weakened in aging rats. The expression of NCAM and PSA have been shown to be regulated by neuronal activity suggesting that the NCAM may promote structural remodelling in an activity dependent manner associated with learning and regeneration.

Aging↗
PubMed1996

Autonomic nervous system as a model of neuronal aging: the role of target tissues and neurotrophic factors.

The aim of this study was to determine the role of target tissues and neurotrophic factors in the growth and atrophy of autonomic neurons during development and aging. Using quantitative neuroanatomical techniques, it is shown that, although axonal and dendritic growth is apparent throughout postnatal development, different patterns of growth are found in autonomic neurons innervating different target tissues. For example, sympathetic neurons innervating the submandibular gland continue to grow well into maturity, but those innervating the iris cease net growth early in postnatal development. Similarly, although neuronal atrophy was observed in aged autonomic ganglia, this was not a general phenomenon but was specific to neurons innervating particular target tissues. Sympathetic neurons innervating the middle cerebral artery showed significant axonal and dendritic atrophy in old age, whereas neurons innervating the iris were morphologically unchanged. The trophic influence of peripheral target tissues on their innervating neurons has been shown to decline in old age possibly as a result of decreased availability of target-derived neurotrophic factors such as nerve growth factor (NGF) [Gavazzi et al. (1992) Neuroreport, 3:717-720]. Therefore, in an attempt to reverse neuronal atrophy where it occurred, NGF was infused via miniosmotic pumps over the peripheral axons of aged neurons. NGF induced increases in soma size, dendritic length and axonal arborization. However, in contrast to young adult neurons, no increase in the number of dendritic branch points or primary dendrites was observed, suggesting that some aspects of neuronal plasticity are impaired in old age. In sum, these results show a range of age- and target-specific differences in the axonal and dendritic morphology of autonomic neurons that may result from differing trophic interactions with their target tissues.

Aging↗
PubMed2006

Phenotypic plasticity and experimental evolution.

Natural or artificial selection that favors higher values of a particular trait within a given population should engender an evolutionary response that increases the mean value of the trait. For this prediction to hold, the phenotypic variance of the trait must be caused in part by additive effects of alleles segregating in the population, and also the trait must not be too strongly genetically correlated with other traits that are under selection. Another prediction, rarely discussed in the literature, is that directional selection should favor alleles that increase phenotypic plasticity in the direction of selection, where phenotypic plasticity is defined as the ability of one genotype to produce more than one phenotype when exposed to different environments. This prediction has received relatively little empirical attention. Nonetheless, many laboratory experiments impose selection regimes that could allow for the evolution of enhanced plasticity (e.g. desiccation trials with Drosophila that last for several hours or days). We review one example that involved culturing of Drosophila on lemon for multiple generations and then tested for enhanced plasticity of detoxifying enzymes. We also review an example with vertebrates that involves selective breeding for high voluntary activity levels in house mice, targeting wheel-running behavior on days 5+6 of a 6-day wheel exposure. This selection regime allows for the possibility of wheel running itself or subordinate traits that support such running to increase in plasticity over days 1-4 of wheel access. Indeed, some traits, such as the concentration of the glucose transporter GLUT4 in gastrocnemius muscle, do show enhanced plasticity in the selected lines over a 5-6 day period. In several experiments we have housed mice from both the Selected (S) and Control (C) lines with or without wheel access for several weeks to test for differences in plasticity (training effects). A variety of patterns were observed, including no training effects in either S or C mice, similar changes in both the S and C lines, greater changes in the S lines but in the same direction in the C lines, and even opposite directions of change in the S and C lines. For some of the traits that show a greater training effect in the S lines, but in the same direction as in C lines, the greater effect can be explained statistically by the greater wheel running exhibited by S lines ('more pain, more gain'). For others, however, the differences seem to reflect inherently greater plasticity in the S lines (i.e. for a given amount of stimulus, such as wheel running/day, individuals in the S lines show a greater response as compared with individuals in the C lines). We suggest that any selection experiment in which the selective event is more than instantaneous should explore whether plasticity in the appropriate (adaptive) direction has increased as a component of the response to selection.

Adaptation, Physiological↗
PubMed2006

Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons.

The mammalian target of rapamycin kinase (mTOR) regulates protein synthesis in neurons at the translational level through phosphorylation of several intracellular targets. Recent work in invertebrates indicates that mTOR-dependent translational control may be critical for the induction and maintenance of activity-dependent synaptic plasticity underlying memory formation. Here, we report that training rats in a simple fear conditioning procedure evokes a time-dependent increase in the phosphorylation of p70s6 kinase, a major direct downstream target of mTOR. When the activation of mTOR was prevented by posttraining injection of rapamycin into the amygdala, formation of the memory and the increase in p70s6 kinase phosphorylation was attenuated. Furthermore, when rapamycin was applied to the amygdala after the recall of a previously stored fear memory, subsequent retention was disrupted, indicating that local translational control at active synapses is required for the stability as well as the formation of long-term memory in this system.

Acoustic Stimulation↗
PubMed2005

Multiplicity and plasticity of natural killer cell signaling pathways.

Natural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3zeta, and/or FcRgamma ITAM (immunoreceptor tyrosine-based activation motif)-bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non-T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-gamma secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of NK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Modulation of neurotransmitter release by the second messenger-activated protein kinases: implications for presynaptic plasticity.

Activity-dependent modulation of synaptic function and structure is emerging as one of the key mechanisms underlying synaptic plasticity. Whereas over the past decade considerable progress has been made in identifying postsynaptic mechanisms for synaptic plasticity, the presynaptic mechanisms involved have remained largely elusive. Recent evidence implicates that second messenger regulation of the protein interactions in synaptic vesicle release machinery is one mechanism by which cellular events modulate synaptic transmission. Thus, identifying protein kinases and their targets in nerve terminals, particularly those functionally regulated by synaptic activity or intracellular [Ca2+], is critical to the elucidation of the molecular mechanisms underlying modulation of neurotransmitter release and presynaptic plasticity. The phosphorylation and dephosphorylation states of synaptic proteins that mediate vesicle exocytosis could regulate the biochemical pathways leading from synaptic vesicle docking to fusion. However, functional evaluation of the activity-dependent phosphorylation events for modulating presynaptic functions still represents a considerable challenge. Here, we present a brief overview of the data on the newly identified candidate targets of the second messenger-activated protein kinases in the presynaptic release machinery and discuss the potential impact of these phosphorylation events in synaptic strength and presynaptic plasticity.

Animals↗
PubMed2006

Summary of evidence pointing to a role of the dorsal cochlear nucleus in the etiology of tinnitus.

Evidence has accumulated in the last decade that the dorsal cochlear nucleus (DCN) may be an important site in the etiology of tinnitus. This evidence comes from a combination of studies conducted in animals and humans. This paper will review the key findings, as follows. 1) Direct electrical stimulation of the DCN leads to changes in the loudness of tinnitus. This suggests that the loudness of tinnitus may be linked to changes in the level of neural activity in the DCN. 2) Exposure to tinnitus inducers, such as intense sound or cisplatin, causes neural activity in the DCN to become chronically elevated, a condition known as neuronal hyperactivity. 3) This hyperactivity is very similar to the activity that is evoked in the DCN by sound stimulation, suggesting that the hyperactivity represents a code that signals the presence of sound, even when there is no longer any sound stimulus. 4) Noise-induced hyperactivity in the DCN is correlated with tinnitus. Behavioral studies have demonstrated that animals exposed to the same intense sound that causes hyperactivity in the DCN develop tinnitus-like percepts. The correlation between the level of hyperactivity and the behavioral index of tinnitus was found to be statistically significant. 5) The DCN is a polysensory integration center, and electrophysiological studies have shown that both spontaneous activity and hyperactivity of neurons in the DCN can be modulated by stimulation of certain ipsilateral cranial nerves, such as the sensory branch of the trigeminal nerve. This ipsilateral modulation of DCN activity offers a plausible explanation of how tinnitus, when perceived on one side, can be modulated by certain manipulations of the head and neck on the side ipsilateral to the tinnitus, but rarely on the contralateral side. 6) The DCN exhibits various forms of neuronal plasticity that parallel the various forms of plasticity that characterize tinnitus. These findings collectively strengthen the view that the DCN may be a key structure that should be included as a target of anti-tinnitus treatment.

Acoustic Stimulation↗
PubMed1999

Bladder afferent pathway and spinal cord injury: possible mechanisms inducing hyperreflexia of the urinary bladder.

Lower urinary tract dysfunction is a common problem in patients with spinal cord injury (SCI). Since the coordination of the urinary bladder and urethra is controlled by the complex mechanisms in spinal and supraspinal neural pathways, SCI rostral to the lumbosacral level disrupts voluntary and supraspinal control of voiding and induces a considerable reorganization of the micturition reflex pathway. Following SCI, the urinary bladder is initially areflexic. but then becomes hyperreflexic because of the emergence of a spinal micturition reflex pathway. Recent electrophysiologic and histologic studies in rats have revealed that chronic SCI induces various phenotypic changes in bladder afferent neurons such as: (1) somal hypertrophy along with increased expression of neurofilament protein; and (2) increased excitability due to the plasticity of Na+ and K+ ion channels. These results have now provided detailed information to support the previous notion that capsaicin-sensitive, unmyelinated C-fiber afferents innervating the urinary bladder change their properties after SCI and are responsible for inducing bladder hyperreflexia in both humans and animals. It is also suggested that the changes in bladder reflex pathways following SCI are influenced by neural-target organ interactions probably mediated by neurotrophic signals originating in the hypertrophied bladder. Thus, increased knowledge of the plasticity in bladder afferent pathways may help to explain the pathogenesis of lower urinary tract dysfunctions after SCI and may provide valuable insights into new therapeutic strategies for urinary symptoms in spinal cord-injured patients.

Afferent Pathways↗
PubMed2003

[Misdirected nerve regeneration: clinical implications].

Although peripheral nerve regeneration is not a precise renewal of primary connections, it often leads to successful return of their function. Moreover, in some cases, an injured nerve is aimly stitched to another one. A good example of such a procedure is intercostal neurotization of avulsed brachial plexus. Despite the fact that neural centers are not primarily suitable for their new function, they often fulfill it successfully. This respecification of function requires some changes in the central nervous system called "plasticity". Discussed are the potential mechanisms controlling these changes. The role of hypothetic proteins reversely transported from the target organ to the neuron's body, proprioceptive fibers and volitional control is mentioned. The punctual understanding of these mechanisms may appear not only very scientifically wonderful but also useful in clinical practice.

Humans↗
PubMed1998

Localization accuracy of AC-PC line and functional pallidal target using BRW stereotactic implementation system and axial CT scanning. An experimental study.

BACKGROUND: Ventriculography is still considered an unavoidable step for functional target localization, even though this method is invasive and requires stereotactic rooms, orthogonal frames, and parallax-free X-ray equipment. In this experimental study, the authors investigated the feasibility of performing stereotactic lesions using a conventional, widely employed frame, such as the Brown-Roberts-Wells (BRW) apparatus, and computerized axial tomography (CAT) imaging. METHODS: Five ex vivo models consisting of cadaveric brains enclose in a plastic shell were fixed in a BRW frame. A simple BRW implementation was used to ensure more symmetrical placement of the basal ring. Two-millimeter plastic balls were inserted at the level of the anterior (AC) and posterior commissures (PC) and at the target in the pallidus. Their final position was measured on the anatomical specimens and compared with Schaltenbrand Atlas maps. RESULTS: The error in estimating the length of the intercommissural line ranged from 0.5 mm to 2.0 mm, with a maximum backward angulation of four degrees in predicting the AC-PC plane. Upon dissection, in four out of five cases, the balls were found within the area of the pallidus defined by Laitinen for posteroventral pallidotomy. CONCLUSIONS: The authors conclude that anatomical identification of the AC-PC line and the pallidus target, using the BRW stereotactic system and CAT axial images alone offers sufficient accuracy. They suggest that functional neurosurgery for movement disorders could be safely and successfully carried out without ventriculography if neurophysiological monitoring is also employed.

Cadaver↗
PubMed1978

Cell-mediated cytotoxicity of desialylated human lymphocytes induced by a mitogenic mammalian liver protein.

The ability of a purified rabbit liver membrane protein that selectively binds desialylated glycoproteins to induce desialylated human peripheral blood lymphocytes to mediate mitogen-induced cellular cytotoxicity has been determined. After short term exposure to purified hepatic binding protein, desialylated, but not intact, lymphocytes exhibited mitogen-induced cellular cytotoxicity against Chang target cells, which do not have exposed hepatic binding protein on their surface membrane. Furthermore, desialylated lymphocytes, in the absence of purified hepatic binding protein, reduced the proportion of isolated rabbit hepatocytes that adhered to plastic to a significantly greater extent than did intact lymphocytes, suggesting that the exposed hepatic binding protein demonstrated on the surface membrane of these target cells is capable of inducing mitogen-induced cellular cytotoxicity. The specific inhibition of this effect by asialo-orosomucoid, but not by intact orosomucoid, indicates that the site involved in the binding of asialo-glycoproteins to hepatic binding protein is probably also responsible for the induction of mitogen-induced cellular cytoxocity. The demonstration that hepatic binding protein, a normal constituent of the surface, membrane of mammalian hepatocytes, can induce mitogen-induced cellular cytotoxicity, suggests that mitogen-induced cellular cytotoxicity may be a mechanism of cellular injury in vivo.

Animals↗
PubMed2003

The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity.

Synaptic GTPase-activating protein (SynGAP) is a neuronal RasGAP (Ras GTPase-activating protein) that is selectively expressed in brain and highly enriched at excitatory synapses, where it negatively regulates Ras activity and its downstream signaling pathways. To investigate the physiological role of SynGAP in the brain, we have generated mutant mice lacking the SynGAP protein. These mice exhibit postnatal lethality, indicating that SynGAP plays a critical role during neuronal development. In addition, cell biological experiments show that neuronal cultures from mutant mice have more synaptic AMPA receptor clusters, suggesting that SynGAP regulates glutamate receptor synaptic targeting. Moreover, electrophysiological studies demonstrated that heterozygous mutant mice have a specific defect in hippocampal long-term potentiation (LTP). These studies show that the regulation of synaptic Ras signaling by SynGAP is important for proper neuronal development and glutamate receptor trafficking and is critical for the induction of LTP.

Animals↗
PubMed2002

High sensitivity PCR assay in plastic micro reactors.

Small volume operation and rapid thermal cycling have been subjects of numerous reports in micro reactor chip development. Sensitivity aspects of the micro PCR reactor have not been studied in detail, however, despite the fact that detection of rare targets or trace genomic material from clinical and/or environmental samples has been a great challenge for microfluidic devices. In this study, a serpentine shaped thin (0.75 mm) polycarbonate plastic PCR micro reactor was designed, constructed, and tested for not only its rapid operation and efficiency, but also its detection sensitivity and specificity, in amplification of Escherichia coli (E. coli) K12-specific gene fragment. At a template concentration as low as 10 E. coli cells (equivalent to 50 fg genomic DNA), a K12-specific gene product (221 bp) was adequately amplified with a total of 30 cycles in 30 min. Sensitivity of the PCR micro reactor was demonstrated with its ability to amplify K12-specific gene from 10 cells in the presence of 2% blood. Specificity of the polycarbonate PCR micro reactor was also proven through multiplex PCR and/or amplification of different pathogen-specific genes. This is, to our knowledge, the first systematic study of assay sensitivity and specificity performed in plastic, disposable micro PCR devices.

Base Sequence↗
PubMed2006

Hot receptors in the brain.

Two major approaches have been employed for the development of novel drugs to treat chronic pain. The most traditional approach identifies molecules involved in pain as potential therapeutic targets and has focused mainly on the periphery and spinal cord. A more recent approach identifies molecules that are involved in long-term plasticity. Drugs developed through the latter approach are predicted to treat chronic, but not physiological or acute, pain. The TRPV1 (transient receptor potential vanilloid-1) receptor is involved in nociceptive processing, and is a candidate therapeutic target for pain. While most research on TRPV1 receptors has been conducted at the level of the spinal cord and peripheral structures, considerably less research has focused on supraspinal structures. This short paper summarizes progress made on TRPV1 receptors, and reviews research on the expression and function of TRPV1 receptors in supraspinal structures. We suggest that the TRPV1 receptor may be involved in pain processing in higher brain structures, such as the anterior cingulate cortex. In addition, some regions of the brain utilize the TRPV1 receptor for functions apparently unrelated to pain.

Analgesics, Non-Narcotic↗
PubMed2002

Field evaluation of female attractants for monitoring Ceratitis capitata (Diptera: Tephritidae) under a range of climatic conditions and population levels in Western Australia.

Field trials were conducted in Western Australia to compare captures of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann), in a standard male-targeted trap (Lynfield trap baited with Capilure) with a synthetic, female-targeted attractant marketed as BioLure. BioLure was also compared with other fenale attractants (orange ammonia, liquid protein bait) and tested in plastic McPhail, Tephri, and Lynfield traps. The possibility of using one trap to monitor female and male C. capitata populations was also tested by combining BioLure in a trap with the male attractant, Capilure. The results of these experiments show that BioLure outperformed the female-targeted system currently used for monitoring female C. capitala (liquid protein in MePhail trap). More male C. capitata were caught in the standard male-targeted trap, but more females were caught in traps baited with BioLure irrespective of trap type, climate, host tree, or population level. Combined lure traps caught equivalent total numbers of C. capitata to the standard male-targeted trap, but fewer females were captured. Tephri traps caught more flies than McPhail traps, but McPhail traps caught equivalent proportions of females. We compared the performance in commercial orchards of the standard male-targeted trap with a female-targeted trap (McPhail with BioLure). We found that the male trap detected C. capitata more often, caught more flies, triggered the economic threshold more often (66% of the time) and was more cost effective. The male-targeted trap is recommended for use on commercial orchards if cost is limiting. However, using both male and female-targeted traps increases the chance of detecting flies and triggering the economic threshold level. The synthetic female attractant is recommended for replacement of protein hydrolysate lures and may be used in either Tephri or McPhail traps.

Animals↗
PubMed2003

Cycles of aberrant synaptic sprouting and neurodegeneration in Alzheimer's and dementia with Lewy bodies.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative disorders affecting the elderly. The cognitive and motor deficits in these diseases are associated with the disruption of neuritic substructure, loss of synaptic contacts in selectively vulnerable circuitries, and aberrant sprouting. Where as in AD, accumulation of misfolded forms of Abeta triggers neurodegeneration, in DLB accumulation of alpha-synuclein might play a central role. The mechanisms by which oligomeric forms of these proteins might lead to cycles of synapse loss and aberrant sprouting are currently under investigation. Several possibilities are being considered, including mitochondrial damage, caspase activation, lysosomal leakage, fragmentation of the Golgi apparatus, interference with synaptic vesicle transport and function, and interference with gene transcription and signaling. Among them, recent lines of research support the possibility that alterations in signaling pathways such extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 relevant to synaptic plasticity and cell survival might play a pivotal role. A wide range of cellular functions are affected by the accumulation of misfolded Abeta and alpha-synuclein; thus it is possible that a more fundamental cellular alteration may underlie the mechanisms of synaptic pathology in these disorders. Among them, one possibility is that scaffold proteins, such as caveolin and JNK-interacting protein (JIP), which are necessary to integrate signaling pathways, are affected, leading to cycles of synapse loss and aberrant sprouting. This is significant because both caveolar dysfunction and altered axonal plasticity might be universally important in the pathogenesis of various neurodegenerative disorders, and therefore these signaling pathways might be common therapeutic targets for these devastating diseases.

Alzheimer Disease↗
PubMed2006

Identification of sequence motifs that target neuronal nicotinic receptors to dendrites and axons.

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a family of ligand-gated ion channels that play important roles in central and peripheral nervous systems. The subcellular distribution of neuronal nAChRs has important implications for function and is not well understood. Here, we analyzed the targeting of two major types of neuronal nAChRs by expressing epitope-tagged subunits in cultured hippocampal neurons. Surprisingly, the alpha7 nAChR (alpha7) and alpha4/beta2 nAChR (alpha4beta2) displayed distinct patterns of expression, with alpha7 targeted preferentially to the somatodendritic compartments, whereas alpha4beta2 was localized to both axonal and dendritic domains. When fused to CD4 or IL2RA (interleukin 2 receptor alpha subunit) proteins, which are normally distributed ubiquitously, the M3-M4 intracellular loop from the alpha7 subunit promoted dendritic expression, whereas the homologous M3-M4 loop from the alpha4 subunit led to surface axonal expression. Systemic screening and alanine substitution further identified a 25-residue leucine motif ([DE]XXXL[LI]) containing an axonal targeting sequence within the alpha4 loop and a 48-residue dileucine and tyrosine motif (YXXØ) containing a dendritic targeting sequence from the alpha7 loop. These results provide valuable information in understanding diverse roles of neuronal nAChRs in mediating and modulating synaptic transmission, synaptic plasticity, and nicotine addiction.

Amino Acid Motifs↗
PubMed2000

Serotonergic gene transcriptional control regions: targets for antidepressant drug development?

The formation and integration of neural networks is dependent on the actions of the master control neurotransmitter serotonin (5-HT) acting through multiple 5-HT receptor subtypes. During brain development 5-HT regulates morphogenetic activities, such as neural differentiation, axon outgrowth, and configuration of synaptic connections. In the adult brain, midbrain raphe serotonergic neurons project to a variety of brain regions and modulate a wide range of physiological functions. Several lines of evidence indicate that genetically determined variability in serotonergic gene expression influences complex behaviour and may lead to conditions with increased anxiety, depression, and aggression. Investigation of the regulation of serotonergic gene transcription and its impact on neural development and plasticity will spur general interest to identify serotonergic gene-related molecular factors underlying disease states and to develop more effective treatment strategies. Gene targeting strategies have increasingly been integrated into investigations of brain function and along with the fading dogma of a limited capacity of neurons for regeneration, reproducibility, and plasticity, it is realized that gene transfer techniques using efficient viral vectors in conjunction with neuron-selective transcriptional control systems may also be applicable to complex disorders of the brain. Given the fact that the 5-HT system continues to be an important target for large-scale drug development and production, novel strategies aiming toward the modification of 5-HT function at the level of gene expression are likely to be exploited by enterprises participating actively in the introduction of alternative therapeutic approaches.

Journal Article↗