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PubMed2000

Plasticity, evolvability, and modularity in RNA.

RNA folding from sequences into secondary structures is a simple yet powerful, biophysically grounded model of a genotype-phenotype map in which concepts like plasticity, evolvability, epistasis, and modularity can not only be precisely defined and statistically measured but also reveal simultaneous and profoundly non-independent effects of natural selection. Molecular plasticity is viewed here as the capacity of an RNA sequence to assume a variety of energetically favorable shapes by equilibrating among them at constant temperature. Through simulations based on experimental designs, we study the dynamics of a population of RNA molecules that evolve toward a predefined target shape in a constant environment. Each shape in the plastic repertoire of a sequence contributes to the overall fitness of the sequence in proportion to the time the sequence spends in that shape. Plasticity is costly, since the more shapes a sequence can assume, the less time it spends in any one of them. Unsurprisingly, selection leads to a reduction of plasticity (environmental canalization). The most striking observation, however, is the simultaneous slow-down and eventual halting of the evolutionary process. The reduction of plasticity entails genetic canalization, that is, a dramatic loss of variability (and hence a loss of evolvability) to the point of lock-in. The causal bridge between environmental canalization and genetic canalization is provided by a correlation between the set of shapes in the plastic repertoire of a sequence and the set of dominant (minimum free energy) shapes in its genetic neighborhood. This statistical property of the RNA genotype-phenotype map, which we call plastogenetic congruence, traps populations in regions where most genetic variation is phenotypically neutral. We call this phenomenon neutral confinement. Analytical models of neutral confinement, made tractable by the assumption of perfect plastogenetic congruence, formally connect mutation rate, the topography of phenotype space, and evolvability. These models identify three mutational regimes: that corresponding to neutral confinement, an exploration threshold corresponding to a breakdown of neutral confinement with the simultaneous persistence of the dominant phenotype, and a classic error threshold corresponding to the loss of the dominant phenotype. In a final step, we analyze the structural properties of canalized phenotypes. The reduction of plasticity leads to extreme modularity, which we analyze from several perspectives: thermophysical (melting--the RNA version of a norm of reaction), kinetic (folding pathways--the RNA version of development), and genetic (transposability--the insensitivity to genetic context). The model thereby suggests a possible evolutionary origin of modularity as a side effect of environmental canalization.

Evolution, Molecular↗
PubMed2004

Activation of long-term synaptic plasticity causes suppression of epileptiform activity in rat hippocampal slices.

Electrical stimulation of cerebral targets for the treatment of epilepsy is an area under active investigation. Recent studies have shown that chronic stimulation of the subthalamic nucleus, fornix, or hippocampus may be effective in attenuating seizure frequency in animal models and in patients with intractable epilepsy. However, many questions exist, such as what are the specific electrical parameters, target sites, and mechanisms, etc., which should be investigated in animal studies before considering the routine use of chronic stimulation in epileptic patients. It is also important to understand what happens to neural activity during repetitive pulse stimulation as well as after stimulation. To this end, we hypothesized: (1) activation of synaptic plasticity suppresses epileptiform activity and (2) low frequency stimulation is an effective stimulation protocol for reducing seizure intensity and frequency. We used rat hippocampal brain slices to study how electrical stimulation affects spontaneous and evoked epileptiform activity. Further, we compared low (1 Hz) versus high (100 Hz) frequency stimulation in the same preparation. We found that orthodromic stimulation of the Schaffer collaterals for 10 min reduces the amplitude of normal responses and diminishes epileptiform activity. The onset of suppression by 1 Hz stimulation was gradual, but persistent, whereas the onset of suppression by 100 Hz was rapid; however, the effects of 100 Hz stimulation were transient. Finally, the NMDA antagonist, AP5 reversed the antiepileptic effects achieved by 1 Hz stimulation. Collectively, these data suggest that using different stimulation parameters prolonged electrical stimulation in the hippocampus may be effective in reducing seizure frequency in patients with epilepsy and that suppression by low frequency stimulation may be mediated by long-term depression (LTD).

Animals↗
PubMed1990

Target regulation of neurotransmitter phenotype.

Studies of sympathetic neurons developing in cell culture revealed a surprising degree of transmitter plasticity and established the role of environmental factors in determining transmitter choice. The sympathetic neurons that innervate sweat glands undergo a change in neurotransmitter phenotype from noradrenergic to cholinergic during normal development similar to that observed in culture. Cross-innervation experiments indicate that the target sweat glands induce the switch and thereby specify the phenotype of the neurons that innervate them. Thus, both the transmitter plasticity and the role of environmental influences initially elucidated in culture are part of the developmental repertoire of sympathetic neurons in vivo. Further, these findings extend considerably our understanding of the role that targets may play during development; targets may not only determine how many neurons survive but also what their properties will be.

Animals↗
PubMed2003

Mutations in deadly seven/notch1a reveal developmental plasticity in the escape response circuit.

The relatively simple neural circuit driving the escape response in zebrafish offers an excellent opportunity to study properties of neural circuit formation. The hindbrain Mauthner cell is an essential component of this circuit. Mutations in the zebrafish deadly seven/notch1a (des) gene result in supernumerary Mauthner cells. We addressed whether and how these extra cells are incorporated into the escape-response circuit. Calcium imaging revealed that all Mauthner cells in desb420 mutants were active during an elicited escape response. However, the kinematic performance of the escape response in mutant larvae was very similar to wild-type fish. Analysis of the relationship between Mauthner axon collaterals and spinal neurons revealed that there was a decrease in the number of axon collaterals per Mauthner axon in mutant larvae compared with wild-type larvae, indicative of a decrease in the number of synapses formed with target spinal neurons. Moreover, we show that Mauthner axons projecting on the same side of the nervous system have primarily nonoverlapping collaterals. These data support the hypothesis that excess Mauthner cells are incorporated into the escape-response circuit, but they divide their target territory to maintain a normal response, thus demonstrating plasticity in the formation of the escape-response circuit. Such plasticity may be key to the evolution of the startle responses in mammals, which use larger populations of neurons in circuits similar to those in the fish escape response.

Animals↗
PubMed2001

Interactive pathology following traumatic brain injury modifies hippocampal plasticity.

Hippocampal afferents terminate in well-defined laminae, with a morphological segregation of input which has facilitated the interpretation of structural and functional synaptic reorganization observed after deafferentiation. Historically, most studies have induced hippocampal plasticity using single deafferentiation paradigms, however recent evidence indicates that sequential lesions or models based on combined injuries alter the pattern of dendritic structural reorganization and axonal sprouting. A better understanding of the interaction between deafferentiation-induced structural remodeling and other pathological mechanisms, which commonly coexist in central nervous system trauma, will require the use of combined injury paradigms where such plasticity can be systematically manipulated. In the context of traumatic brain injury, we have developed an injury model that combines the excessive neuroexcitation of concussive brain insult with the targeted hippocampal deafferentation of entorhinal cortical lesion. This review discusses the role of such an approach in defining posttraumatic hippocampal vulnerability, out- lining the effects of combined pathology on hippocampal circuitry, and considers the greater clinical relevance inherent in the combined injury approach. Experimental evidence obtained with the combined concussive plus deafferentation model is presented, detailing the interaction of injury components and highlighting structural, behavioral and electrophysiological evidence for maladaptive hippocampal plasticity. Subsequent studies utilizing pharmacological methods to manipulate this maladaptive plasticity are described, first targeting glutamate, acetylcholine and dopamine receptor pathways, and then applying select drugs to explore how various molecular mechanisms underlying combined neuroexcitation and deafferentation pathology might affect regenerative plasticity. Evidence implicating postinjury neurotransmitter modulation of exeitatory/inhibitory homeostasis, metalloproteinase regulation of extracellular matrix, and mitochondrial metabolic vulnerability is presented. Finally, the effect of age on outcome after combined neuroexcitation plus deafferentation insult is considered, as well as how future studies in such combined injury models will better define the full range of postinjury hippocampal plasticity possible after brain trauma.

Animals↗
PubMed2002

Deployment of fingertip forces in tactile exploration.

The purpose of this study was to examine how contact forces normal to the skin surface and shear forces tangential to the skin surface are deployed during tactile exploration of a smooth surface in search of a tactile target. Six naive subjects participated in two experiments. In the first experiment, the subjects were asked to explore a series of unseen smooth plastic surfaces by using the index finger to search for either a raised or recessed target. The raised targets were squares with a height of 280 micro m above the background surface and that varied in side lengths from 0.2 mm to 8.0 mm. A second series of smooth plastic surfaces consisted of small recessed squares (side lengths: 2.0, 3.0, 4.0 and 8.0 mm) that were etched to a depth of 620 micro m. Although made of an identical material, the plastic substrate had a lower coefficient of friction against the skin because only the recessed square had been subjected to the electrolytic etching process. The surfaces were mounted on a six-axes force and torque sensor connected to a laboratory computer. From the three axes of linear force, the computer was able to calculate the instantaneous position of the index finger and the instantaneous tangential force throughout the exploratory period. When exploring for the raised squares, the subjects maintained a relatively constant, average normal force of about 0.49 N with an average exploration speed of 8.6 cm/s. In contrast, all subjects used a significantly higher average normal force (0.64 N) and slightly slower mean exploration speed (7.67 cm/s) when searching for the small recessed squares. This appeared to be an attempt to maximize the amount of skin penetrating the recessed squares to improve the probability of target detection. In a second experiment, subjects were requested to search for an identical set of raised squares but with the fingertip having been coated with sucrose to impede the scanning movement by increasing the friction. Overall, the subjects maintained the same constant normal force that they used on the uncoated surface. However, they increased the tangential force significantly. The similarity of the search strategy employed by all subjects supports the hypothesis that shear forces on the skin provide a significant stimulus to mechanoreceptors in the skin during tactile exploration. Taken together, these data suggest that, in active tactile exploration with the fingertip, the tangential finger speed, the normal contact force, and the tangential shear force are adjusted optimally depending on the surface friction and whether the target is a raised asperity or a recessed indentation.

Adult↗
PubMed2004

Decreased plasma membrane targeting of NMDA-NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self-administering morphine.

Opioid abuse is associated with repeated administration and escalation of dose that can result in profound adaptations in homeostatic processes. Potential cellular mechanisms and neural sites mediating opiate-dependent adaptations may involve NMDA-dependent synaptic plasticity within brain areas participating in behaviors related to consumption of natural reinforcers, as well as affective-autonomic integration, notably the medial nucleus tractus solitarius (mNTS). NMDA-dependent synaptic plasticity may be mediated by changes in the intracellular and surface targeting of NMDA receptors, particularly in postsynaptic sites including spines or small distal dendrites. High-resolution immunogold electron microscopic immunocytochemistry combined with morphometry were used to measure changes in targeting of the NMDA-NR1 (NR1) receptor subunit between intracellular and plasmalemmal sites in dendrites of neurons of the intermediate mNTS of rats self-administering escalating doses of morphine (EMSA). In control and EMSA rats, the density of plasmalemmal and cytosolic gold particles was inversely related to profile size. Collapsed across all NR1-labeled dendrites, rats self-administering morphine had a lower number of plasmalemmal gold particles per unit surface area (7.1 +/- 0.8 vs. 14.4 +/- 1 per 100 microm), but had a higher number of intracellular gold particles per unit cross-sectional area (169 +/- 6.1 vs. 148 +/- 5.1 per 100 microm2) compared to saline self-administering rats. Morphometric analysis showed that the decrease in plasma membrane labeling of NR1 was most robust in small dendritic profiles (<1 microm), where there was a reciprocal increase in the density of intracellular particles. These results indicate that the plasmalemmal distribution of the essential NR1 subunits in distal sites may prominently contribute to NMDA receptor-dependent modulation of neural circuitry regulating homeostatic processes, and targeting of these proteins can be prominently affected by morphine self-administration.

Animals↗
PubMed2007

PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction.

Targeting of synaptic molecules to their proper location is essential for synaptic differentiation and plasticity. PSD-95/Dlg proteins have been established as key components of the postsynapse. However, the molecular mechanisms regulating the synaptic targeting, assembly, and disassembly of PSD-95/Dlg are not well understood. Here we show that PAR-1 kinase, a conserved cell polarity regulator, is critically involved in controlling the postsynaptic localization of Dlg. PAR-1 is prominently localized at the Drosophila neuromuscular junction (NMJ). Loss of PAR-1 function leads to increased synapse formation and synaptic transmission, whereas overexpression of PAR-1 has the opposite effects. PAR-1 directly phosphorylates Dlg at a conserved site and negatively regulates its mobility and targeting to the postsynapse. The ability of a nonphosphorylatable Dlg to largely rescue PAR-1-induced synaptic defects supports the idea that Dlg is a major synaptic substrate of PAR-1. Control of Dlg synaptic targeting by PAR-1-mediated phosphorylation thus constitutes a critical event in synaptogenesis.

Animals↗
PubMed2004

Endocrine disrupters as disrupters of brain function: a neurosteroid viewpoint.

The mechanisms of neurosteroid synthesis in the rat hippocampus were investigated. Metabolism assay demonstrated the pathway of "cholesterol alpha pregnenolone --> dehydroepiandrosterone --> androstenedione --> testosterone --> estradiol." Upon exposure of pups to bisphenol A (BPA) from the embryonic stage until 3 week-old stage, a significant facilitation of the synthesis of estradiol was observed in the hippocampus. The localization of cytochrome P450s (P450scc, P45017alpha, and P450arom) as well as estrogen receptor alpha (ER(alpha)) was observed in pyramidal and granule neurons, using immunohistochemical staining. Furthermore, the synaptic localization of P45017alpha, P450arom and ER(alpha) was demonstrated with immuno-electron microscopic analysis. The acute action of estradiol and endocrine disrupters were then analyzed with an electrophysiological measurement of hippocampal pyramidal neurons. A 30 min preperfusion of diethylstylbesterol (DES) enhanced the induction of long-term potentiation (LTP) by almost an identical magnitude to that obtained by estradiol perfusion. On the other hand, although the application of BPA alone did not affect LTP-induction, the co-perfusion of BPA with estradiol completely suppressed the enhancement effect of LTP by estradiol. The current investigations demonstrate in the hippocampus (1) that locally synthesized estrogen rapidly enhances the synaptic plasticity of neurons, and (2) that BPA and DES modulate the synaptic plasticity as well as the synthesis of estradiol. The probable targets of BPA and DES are ER(alpha) and steroidogenic proteins.

Animals↗
PubMed2006

Fingerprinting of Campylobacter jejuni by using resolution-optimized binary gene targets derived from comparative genome hybridization studies.

The aim of this investigation was to exploit the vast comparative data generated by comparative genome hybridization (CGH) studies of Campylobacter jejuni in developing a genotyping method. We examined genes in C. jejuni that exhibit binary status (present or absent between strains) within known plasticity regions, in order to identify a minimal subset of gene targets that provide high-resolution genetic fingerprints. Using CGH data from three studies as input, binary gene sets were identified with "Minimum SNPs" software. "Minimum SNPs" selects for the minimum number of targets required to obtain a predefined resolution, based on Simpson's index of diversity (D). After implementation of stringent criteria for gene presence/absence, eight binary genes were found that provided 100% resolution (D=1) of 20 C. jejuni strains. A real-time PCR assay was developed and tested on 181 C. jejuni and Campylobacter coli isolates, a subset of which have previously been characterized by multilocus sequence typing, flaA short variable region sequencing, and pulsed-field gel electrophoresis. In addition to the binary gene real-time PCR assay, we refined the seven-member single nucleotide polymorphism (SNP) real-time PCR assay previously described for C. jejuni and C. coli. By normalizing the SNP assay with the respective C. jejuni and C. coli ubiquitous genes, mapA and ceuE, the polymorphisms at each SNP could be determined without separate reactions for every polymorphism. We have developed and refined a rapid, highly discriminatory genotyping method for C. jejuni and C. coli that uses generic technology and is amenable to high-throughput analyses.

Animals↗
PubMed1995

Decoding Ca2+ signals to the nucleus by multifunctional CaM kinase.

Multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) is one of the major protein kinases coordinating cellular responses to neurotransmitters and hormones. CaM kinase transduces changes in intracellular free Ca2+ into changes in the phosphorylation state and activity of target proteins involved in neurotransmitter synthesis and release, neuronal plasticity and gene expression. Structure/function analyses of the kinase reveal the kinase is kept inactive in its basal state by a regulatory domain that is displaced by the binding of Ca2+/calmodulin. Once activated by Ca2+/calmodulin, autophosphorylation occurs if a pair of proximate subunits of the decameric kinase have calmodulin bound. The frequency of Ca2+ oscillations or spikes may be decoded by CaM kinase via this autophosphorylation. Calmodulin is essentially trapped by autophosphorylation which converts CaM kinase into a high affinity calmodulin-binding protein. Repetitive stimulation of the kinase may promote recruitment of calmodulin to the kinase so that it becomes increasingly active with each stimulus in a frequency-dependent manner. The association domain at the C-terminal end of CaM kinase contains a variable region that targets isoforms of the kinase to the nucleus or cytoskeleton and assembles the kinase into a decameric structure. Alternative splicing introduces a short nuclear localization signal that targets transfected kinase to the nucleus where it may regulate nuclear functions. The regulatory properties of CaM kinase provide for molecular potentiation of Ca2+ signals and frequency detection whereas its association domain should enable it to decode such Ca2+ fluctuations in the nucleus.

Amino Acid Sequence↗
PubMedDate not supplied

Leaching of organic acids from irradiated EVA plastic as a function of solution pH and polarity.

The leaching of several target organic acids from an irradiated ethylene vinyl acetate material, such as those used as a solution product container, is examined as a function of solution pH and polarity. The targeted compounds included highly soluble weak acids such as acetic and formic acids, and larger, more lipophillic acids such as myristic, palmitic, and stearic acids. The leaching of these compounds was examined over a pH range of 3 to 11 and in various ethanol/water proportions. While pH and solution polarity had only a modest impact on the accumulation of the acetic and formic acids, the accumulation of the fatty acids was greatly affected by both factors. It is suggested that the accumulation of these leachables at high pH is influenced by two processes. The first process, partitioning, the speciation of the acidic leachables (protonated versus dissociated form) contributes to the pH trends observed. In this case, entities that already exist in the plastic partition themselves between the plastic and solution via migration. A second, more important, contributor to the leaching of these acids is a pH-dependent increase in their availability arising from an unspecified reactive process.

Acids↗
PubMed1997

[Morphologic plasticity as a component of cognition].

Two recent developmental genetics studies suggest an important role for transcription factors of the homeodomain protein class in the morphogenesis of cerebral structures and the form and extent of the various domains that constitute the nervous system (Krumlauf, 1994; Rubenstein and Puelles, 1994). Our team recently took a look at the hypothesis that the same transcription parameters have a function in axonal growth and recognition of paths and targets. It has been shown that cortical or spinal medullary neurons are capable of responding, by a change in axonal growth rate, to regulation of the activity of certain transcription factors (Prochiantz and Théodore, 1995). This demonstration was facilitated by a particular property of the DNA binding region of the transcription factors. This property consists in crossing plasmic membranes and addressing cell nuclei directly (Prochiantz, 1996). The homeodomain proteins are expressed not only during development but also in adulthood. It is possible that their continuous expression or reactivation may be associated with the morphological changes in neurons observed in the mature nervous system. The latter hypothesis will be discussed on the basis of our current knowledge of the expression and role of the transcription factors. The authors will draw some conclusions regarding the possibility of considering these nuclear factors as agents of cerebral plasticity and as targets of potential pharmacological value.

Animals↗
PubMed1997

[Knockout mouse--its characteristics and application (1): NMDA receptor subunit knockout mouse].

The N-methyl-D-aspartate (NMDA) type of glutamate receptors is thought to be essential in many central actions of neurotransmitter glutamate, including learning, memory, neurodevelopment and neurodegenerative disorders. Recent molecular cloning has revealed that the NMDA receptor has multiple subunits with distinct distribution, properties and regulation. This implies that NMDA receptors are different in molecular architecture and functional properties, depending on the brain region and developmental stage. To clarify the significance of the molecular diversity of NMDA receptors in vivo, a gene-targeting technique was applied to NMDA receptor subunit genes and several strains of mutant mice lacking targeted NMDA receptor subunit molecules were created. Using these NMDA receptor subunit knockout mice, various physiological, histological and behavioral analyses were performed. In this article, after briefly reviewing recent findings, we discuss the advantages and disadvantages of the NMDA receptor subunit knockout mouse as a tool for the studies of NMDA receptors and synaptic plasticity.

Animals↗
PubMed2005

Plasticity in rat uterine sympathetic nerves: the role of TrkA and p75 nerve growth factor receptors.

Uterine sympathetic innervation undergoes profound remodelling in response to physiological and experimental changes in the circulating levels of sex hormones. It is not known, however, whether this plasticity results from changes in the innervating neurons, the neuritogenic properties of the target tissue or both. Using densitometric immunohistochemistry, we analysed the effects of prepubertal chronic oestrogen treatment (three subcutaneous injections of 20 microg of beta-oestradiol 17-cypionate on days 25, 27 and 29 after birth), natural peripubertal transition and late pregnancy (19-20 days post coitum) on the levels of TrkA and p75 nerve growth factor receptors in uterine-projecting sympathetic neurons of the thoraco-lumbar paravertebral sympathetic chain (T7-L2) identified using the retrograde tracer Fluorogold. For comparative purposes, levels of TrkA and p75 were assessed in the superior cervical ganglion (SCG) following prepubertal chronic oestrogen treatment. These studies showed that the vast majority of uterine-projecting neurons expressed both TrkA and p75. Both prepubertal chronic oestrogen treatment and the peripubertal transition increased the ratio p75 to TrkA in uterine-projecting neurons, whereas pregnancy elicited the opposite effect. Prepubertal chronic oestrogen treatment had no effects on levels of TrkA or p75 in sympathetic neurons of the SCG. Taken together, our data suggest that neurotrophin receptor-mediated events may contribute to regulate sex hormone-induced plasticity in uterine sympathetic nerves, and are in line with the idea that, in vivo, plasticity in uterine nerves involves changes in both the target and the innervating neurons.

Animals↗
PubMed1991

Plasticity of sympathetic reflex organization following cross-union of inappropriate nerves in the adult cat.

1. The present study has investigated the reflex organization of sympathetic neurones and its control of autonomic effector organs following nerve injury and repair. A well-defined population of vasoconstrictor neurones supplying blood vessels of the hairy skin was forced to innervate a territory that contained some appropriate, but mainly inappropriate autonomic effector organs. For this purpose the central stump of the cut sural nerve was sutured to the peripheral stump of the cut tibial nerve 11-12 months prior to the terminal experiment. 2. The activity of postganglionic sympathetic neurones was recorded from fine strands of the sural nerve proximal to the nerve lesion. Using a laser-Doppler device cutaneous blood flow was measured in the hairless skin of the hindpaw that was now reinnervated by the sural nerve. The results show a qualitative change of the reflex organization of sympathetic neurones following cross-union of these nerves. 3. Stimulation of arterial chemoreceptors by ventilating the animals with a hypoxic gas mixture (8% O2 in N2 for 3-8 min) increased the activity in twelve out of thirteen strands containing postganglionic sympathetic fibres. The increase of sympathetic activity contrasts with results from normal animals where systemic hypoxia causes a reflex decrease of activity in postganglionic fibres of the sural nerve. 4. Reflex changes of sympathetic activity were closely followed by corresponding changes of cutaneous blood flow. Systemic hypoxia produced vasoconstriction in operated animals in contrast to the vasodilatation observed in normal animals. 5. We conclude that the reflex organization of sympathetic neurones can change qualitatively following nerve lesion when sympathetic neurones regenerate and supply inappropriate target tissues. This long-lasting change reflects the plasticity of the autonomic nervous system and can produce a sustained abnormal control of reinnervated autonomic effector organs.

Animals↗
PubMed2006

A biophysically based neural model of matching law behavior: melioration by stochastic synapses.

In experiments designed to uncover the neural basis of adaptive decision making in a foraging environment, neuroscientists have reported single-cell activities in the lateral intraparietal cortex (LIP) that are correlated with choice options and their subjective values. To investigate the underlying synaptic mechanism, we considered a spiking neuron model of decision making endowed with synaptic plasticity that follows a reward-dependent stochastic Hebbian learning rule. This general model is tested in a matching task in which rewards on two targets are scheduled randomly with different rates. Our main results are threefold. First, we show that plastic synapses provide a natural way to integrate past rewards and estimate the local (in time) "return" of a choice. Second, our model reproduces the matching behavior (i.e., the proportional allocation of choices matches the relative reinforcement obtained on those choices, which is achieved through melioration in individual trials). Our model also explains the observed "undermatching" phenomenon and points to biophysical constraints (such as finite learning rate and stochastic neuronal firing) that set the limits to matching behavior. Third, although our decision model is an attractor network exhibiting winner-take-all competition, it captures graded neural spiking activities observed in LIP, when the latter were sorted according to the choices and the difference in the returns for the two targets. These results suggest that neurons in LIP are involved in selecting the oculomotor responses, whereas rewards are integrated and stored elsewhere, possibly by plastic synapses and in the form of the return rather than income of choice options.

Action Potentials↗
PubMed2002

Dendritic BC1 RNA: functional role in regulation of translation initiation.

In neurons, local protein synthesis in synaptodendritic microdomains has been implicated in the growth and plasticity of synapses. Prerequisites for local translation are the targeted transport of RNAs to distal sites of synthesis in dendrites and translational control mechanisms to limit synthesis to times of demand. Here we identify dendritic BC1 RNA as a specific repressor of translation. Experimental use of internal ribosome entry mechanisms and sucrose density gradient centrifugation showed that BC1-mediated repression targets translation at the level of initiation. Specifically, BC1 RNA inhibited formation of the 48S preinitiation complex, i.e., recruitment of the small ribosomal subunit to the messenger RNA (mRNA). However, 48S complex formation that is independent of the eukaryotic initiation factor 4 (eIF4) family of initiation factors was found to be refractory to inhibition by BC1 RNA, a result that implicates at least one of these factors in the BC1 repression pathway. Biochemical experiments indicated a specific interaction of BC1 RNA with eIF4A, an RNA unwinding factor, and with poly(A)-binding protein. Both proteins were found enriched in synaptodendritic microdomains. Significantly, BC1-mediated repression was shown to be effective not only in cap-dependent translation initiation but also in eIF4-dependent internal initiation. The results suggest a functional role of BC1 RNA as a mediator of translational control in local protein synthesis in nerve cells.

Animals↗