Time-Warp–Invariant Neuronal Processing

Fluctuations in the temporal durations of sensory signals constitute a major source of variability within natural stimulus ensembles. The neuronal mechanisms through which sensory systems can stabilize perception against such fluctuations are largely unknown. An intriguing instantiation of such robustness occurs in human speech perception, which relies critically on temporal acoustic cues that are embedded in signals with highly variable duration. Across different instances of natural speech, auditory cues can undergo temporal warping that ranges from 2-fold compression to 2-fold dilation without significant perceptual impairment. Here, we report that time-warp–invariant neuronal processing can be subserved by the shunting action of synaptic conductances that automatically rescales the effective integration time of postsynaptic neurons. We propose a novel spike-based learning rule for synaptic conductances that adjusts the degree of synaptic shunting to the temporal processing requirements of a given task. Applying this general biophysical mechanism to the example of speech processing, we propose a neuronal network model for time-warp–invariant word discrimination and demonstrate its excellent performance on a standard benchmark speech-recognition task. Our results demonstrate the important functional role of synaptic conductances in spike-based neuronal information processing and learning. The biophysics of temporal integration at neuronal membranes can endow sensory pathways with powerful time-warp–invariant computational capabilities.     

α-Synuclein and Neuronal Cell Death

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting ～1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of α-synuclein (αSyn). Missense mutations in αSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type αSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of αSyn protein is considered responsible for the DA neuronal death in PD. Normally, αSyn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal αSyn. The extracellular αSyn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of αSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on αSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating αSyn.     

Neuronal pathology in Parkinson’s disease

Parkinsons disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra leading to the major clinical and pharmacological abnormalities of PD. In order to establish causal or protective treatments for PD, it is necessary to identify the cascade of deleterious events that lead to the dysfunction and death of dopaminergic neurons. Based on genetic, neuropathological, and biochemical data in patients and experimental animal models, dysfunction of the ubiquitin-proteasome pathway, protein aggregation, mitochondrial dysfunction, oxidative stress, activation of the c-Jun N-terminal kinase pathway, and inflammation have all been identified as important pathways leading to excitotoxic and apoptotic death of dopaminergic neurons. Toxin-based and genetically engineered animal models allow (1) the study of the significance of these aspects and their interaction with each other and (2) the development of causal treatments to stop disease progression.     

Neuronal activity during development: permissive or instructive?

Experimental studies over the past year have shown that neural activity has a range of effects on the development of neural pathways. Although activity appears unimportant for establishing many aspects of the gross morphology and topology of the brain, there are many cases where the presence of neural activity is essential for the formation of a mature system of neural connections; in some instances, the pattern of neural activity actually orchestrates the final arrangement of neural connections.     

Promotion of Neuronal Plasticity by (−)-Epigallocatechin-3-Gallate

The consumption of (−)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound found in green tea, has been associated with various neurological benefits including cognitive improvement. The physiological basis for this effect is unknown. In this study, we used synaptic transmission between the CA3 and CA1 regions (Schaffer collateral) of the mouse hippocampus to examine the effects of EGCG on neuronal plasticity. We found that the level of high frequency stimulation-evoked long-term potentiation (LTP) was significantly enhanced when hippocampal slices were pre-incubated with 10 μM EGCG for 1 h prior to the experiment. EGCG incubation also enabled hippocampal slices prepared from Ts65Dn mice, a Down syndrome mouse model deficient in LTP, to express LTP to a level comparable to the normal controls. EGCG treatment did not alter the degree of pair-pulse inhibition; therefore, the enhancement effect of EGCG is unlikely to involve the attenuation of this inhibitory mechanism.     

Neuronal glucose sensing: still a physiological orphan?

Although hypothalamic glucose sensing is a long-established phenomenon, its physiological role remains unclear. New studies (Parton et al., 2007; Claret et al., 2007) disrupting glucose sensing in pro-opiomelanocortin neurons via differing methods have yielded disparate energy and glucose homeostasis phenotypes, suggesting that neuronal glucose sensing is not critical for these processes.     

Is There a Molecular Logic That Sustains Neuronal Functional Integrity and Survival? Lipid Signaling Is Necessary for Neuroprotective Neuronal Transcriptional Programs

A challenge to civilization is the growing incidence in the loss of sight and cognition due to increased life expectancy. Therefore, we are confronted with a rise in the occurrence of photoreceptor- and neuronal-survival failure, as reflected mainly by age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Nervous system development is driven by neuronal apoptotic cell death, and thereafter, for the entire lifespan of an organism, neurons are postmitotic cells. In neurodegenerative diseases, apoptosis and other forms of cells death lead to selective neuronal loss. Although age is the main risk factor, not everyone develops these diseases during aging. Despite decades of important findings about neuronal cell death, the specific mechanisms that regulate neuronal survival remain incompletely understood.     

Neuronal Death: Is There a Role for Astrocytes?

Astrocytes are ubiquitous in the brain and have multiple functions. It is becoming increasingly clear that they play an important role in monitoring the neuromicroenvironment in CNS and in information processing or signaling in the nervous system in normal conditions and respond to CNS injuries in a gradual and varied way. It is still debated whether such reactions are beneficial or detrimental. It was believed that reactive astrogliosis observed in most neurological disorders may regulate the removal of toxic compounds produced by damaged neurons and support neuronal growth by releasing trophic factors. However it was also suggested that astrocytes contribute to a decline of neurologic function, for example by accumulation and release of excitotoxic aminoacids after ischemia and oxidative stress, formation of epileptogenic scars in response to CNS injury and metabolism of protoxins to potent toxins. In a number of metabolic diseases astrocytes, not neurons, may be the primary target. The astrocyte's role in normal and pathological conditions will be discussed in the light of recent information about their metabolism, receptor distribution and release.     

The Caenorhabditis elegans Elongator Complex Regulates Neuronal α-tubulin Acetylation

Although acetylated α-tubulin is known to be a marker of stable microtubules in neurons, precise factors that regulate α-tubulin acetylation are, to date, largely unknown. Therefore, a genetic screen was employed in the nematode Caenorhabditis elegans that identified the Elongator complex as a possible regulator of α-tubulin acetylation. Detailed characterization of mutant animals revealed that the acetyltransferase activity of the Elongator is indeed required for correct acetylation of microtubules and for neuronal development. Moreover, the velocity of vesicles on microtubules was affected by mutations in Elongator. Elongator mutants also displayed defects in neurotransmitter levels. Furthermore, acetylation of α-tubulin was shown to act as a novel signal for the fine-tuning of microtubules dynamics by modulating α-tubulin turnover, which in turn affected neuronal shape. Given that mutations in the acetyltransferase subunit of the Elongator (Elp3) and in a scaffold subunit (Elp1) have previously been linked to human neurodegenerative diseases, namely Amyotrophic Lateral Sclerosis and Familial Dysautonomia respectively highlights the importance of this work and offers new insights to understand their etiology.     

Neuronal variability: noise or part of the signal?

Sensory, motor and cortical neurons fire impulses or spikes at a regular, but slowly declining, rate in response to a constant current stimulus. Yet, the intervals between spikes often vary randomly during behaviour. Is this variation an unavoidable effect of generating spikes by sensory or synaptic processes ('neural noise') or is it an important part of the 'signal' that is transmitted to other neurons? Here, we mainly discuss this question in relation to sensory and motor processes, as the signals are best identified in such systems, although we also touch on central processes.     

Neurotrophic Factor Effects on Oxidative Stress–Induced Neuronal Death

Neurotrophic factors have been shown to potentiate necrotic neuronal death in cortical cultures. In this study we characterized the death induced by various oxidative insults and tested the effects of neurotrophic factors on that death. Treatment with fibroblast growth factor-2, neurotrophin-4, or insulin-like growth factor-1 potentiated neuronal cell death induced by iron-citrate (Fe) or buthionine sulfoximine (BSO), but not ethacrynic acid (EA). Neuronal death induced by each insult was blocked by the free radical scavenger, trolox. An analysis of the death indicated that Fe and BSO induced necrotic cell death, while EA induced apoptotic cell death. BSO and EA caused decreased cellular glutathione levels, whereas Fe had no effect on glutathione levels. Neurotrophic factors had no effect on the changes in glutathione. The results indicate that oxidative insults can induce either apoptotic or necrotic death and that the effects of neurotrophic factors are dependent on the type of cell death.     

Neuronal Cyclooxygenase-2 Activity and Prostaglandins PGE2, PGD2, and PGF2α Exacerbate Hypoxic Neuronal Injury in Neuron-enriched Primary Culture

Cyclooxygenase-2 (COX-2) activity has been implicated in the pathogenesis of cerebral ischemia. To determine whether COX-2 activity within the neuron itself exacerbates hypoxic neuronal injury, neuron-enriched cultures were subjected to anoxia. Treatment with COX-2 selective antagonists decreased cell death. Neurons cultured from homozygous COX-2 gene disrupted mice were resistant to hypoxia compared to those of heterozygotes. Infection of primary neurons with AAV expressing COX-2 exacerbated cell death compared to neurons infected with enhanced green fluorescent protein (EGFP) control vector. Addition of PGE2, PGD2 or PGF2α to the medium exacerbated injury, suggesting that the deleterious effects of COX-2 overexpression in hypoxia could be mediated by direct receptor mediated effects of prostaglandins. Overexpression of COX-2 did not increase expression of cyclin D1 or phosphoretinoblastoma protein (pRb), or cleavage of caspase 3 suggesting that this cell cycle mechanism does not mediate COX-2 toxicity in this model.     

Neuronal Expression of Splice Variants of “Glial” Glutamate Transporters in Brains Afflicted by Alzheimer’s Disease: Unmasking an Intrinsic Neuronal Property

Anomalies in glutamate homeostasis may contribute to the pathological processes involved in Alzheimer’s disease (AD). Glutamate released from neurons or glial cells is normally rapidly cleared by glutamate transporters, most of which are expressed at the protein level by glial cells. However, in some patho-physiological situations, expression of glutamate transporters that are normally considered to be glial types, appears to be evoked in populations of distressed neurons. This study analysed the expression of exon-skipping forms of the three predominant excitatory amino acid (glutamate) transporters (EAATs1-3) in brains afflicted with AD. We demonstrate by immunocytochemistry in temporal cortex, the expression of these proteins particularly in limited subsets of neurons, some of which appeared to be dys-morphic. Whilst the neuronal expression of the “glial” glutamate transporters EAAT1 and EAAT2 is frequently considered to represent the abnormal and ectopic expression of such transporters, we suggest this may be a misinterpretation, since neurons such as cortical pyramidal cells normally express abundant mRNA for these EAATs (but little if any EAAT protein expression). We hypothesize instead that distressed neurons in the AD brain can turn on the translation of pre-existent mRNA pools, or suppress the degradation of alternately spliced glutamate transporter protein, leading to the “unmasking” of, rather than evoked expression of “glial” glutamate transporters in stressed neurons. Special issue article in honor of Dr. Graham Johnston.     

A Neuronal piRNA Pathway Inhibits Axon Regeneration in C. elegans

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Neuronal markers in the rodent pineal gland — an immunohistochemical investigation

Summary Although some embryological and morphological features speak in favour of a neuronal character of rodent pinealocytes, histochemistry and ultrastructure let this issue appear controversial. Using antibodies to different neurofilaments, the neural adhesion molecule L1, synaptophysin and tubulin as neuronal markers, the pineal glands of rat and guinea-pig were studied by means of immunfluorescence. Neurofilament-immunoreactivity was present in some rat pineal nerve fibers and in the majority of guinea-pig pinealocytes, L1 decorated rat intrapineal nerve fibers, synaptophysin was almost ubiquitously distributed in the pineal of both species, while tubulin-immunofluorescence was seen in nerve fibers of rat and guinea-pig pineal and in some pinealocytes of the latter. These findings speak in favour of the neuronal character of guinea-pig pinealocytes. The lack of neurofilament- and tubulin-immunoreactivity in rat pinealocytes might be attributable to very low concentrations of these proteins or species differences as to their expression. Further studies including in situhybridisation of relevant mRNAs will be necessary to answer these questions definitely.The data presented in this study form part of a thesis presented by A. Bendig in partial fulfillment for the degree of M.D..Supported by the Deutsche Forschungsgemeinschaft, grant Schr 283/2-1     

Can Power-Law Scaling and Neuronal Avalanches Arise from Stochastic Dynamics?

The presence of self-organized criticality in biology is often evidenced by a power-law scaling of event size distributions, which can be measured by linear regression on logarithmic axes. We show here that such a procedure does not necessarily mean that the system exhibits self-organized criticality. We first provide an analysis of multisite local field potential (LFP) recordings of brain activity and show that event size distributions defined as negative LFP peaks can be close to power-law distributions. However, this result is not robust to change in detection threshold, or when tested using more rigorous statistical analyses such as the Kolmogorov–Smirnov test. Similar power-law scaling is observed for surrogate signals, suggesting that power-law scaling may be a generic property of thresholded stochastic processes. We next investigate this problem analytically, and show that, indeed, stochastic processes can produce spurious power-law scaling without the presence of underlying self-organized criticality. However, this power-law is only apparent in logarithmic representations, and does not survive more rigorous analysis such as the Kolmogorov–Smirnov test. The same analysis was also performed on an artificial network known to display self-organized criticality. In this case, both the graphical representations and the rigorous statistical analysis reveal with no ambiguity that the avalanche size is distributed as a power-law. We conclude that logarithmic representations can lead to spurious power-law scaling induced by the stochastic nature of the phenomenon. This apparent power-law scaling does not constitute a proof of self-organized criticality, which should be demonstrated by more stringent statistical tests.     

Protective Effects of Curcumin on Amyloid-β-Induced Neuronal Oxidative Damage

To investigate the protective effects of curcumin against amyloid-β (Aβ)-induced neuronal damage. Primary rat cortical neurons were cultured with different treatments of Aβ and curcumin. Neuronal morphologies, viability and damage were assessed. Neuronal oxidative stress was assessed, including extracellular hydrogen peroxide and intracellular reactive oxygen species. The abilities of curcumin to scavenge free radicals and to inhibit Aβ aggregation and β-sheeted formation are further assessed and discussed. Curcumin preserves cell viability, which is decreased by Aβ. The results of changed morphology, released Lactate dehydrogenases and cell viability assays indicate that curcumin protects Aβ-induced neuronal damage. Curcumin depresses Aβ-induced up-regulation of neuronal oxidative stress. The treatment sequence impacts the protective effect of curcumin on Aβ-induced neuronal damage. Curcumin shows a more protective effect on neuronal oxidative damage when curcumin was added into cultured neurons not later than Aβ, especially prior to Aβ. The abilities of curcumin to scavenge free radicals and to inhibit the formation of β-sheeted aggregation are both beneficial to depress Aβ-induced oxidative damage. Curcumin prevents neurons from Aβ-induced oxidative damage, implying the therapeutic usage for the treatment of Alzheimer's disease patients.