Neuronal adaptation effects in decision making

Recently, there has been an increased interest on the neural mechanisms underlying perceptual decision making. However, the effect of neuronal adaptation in this context has not yet been studied. We begin our study by investigating how adaptation can bias perceptual decisions. We considered behavioral data from an experiment on high-level adaptation-related aftereffects in a perceptual decision task with ambiguous stimuli on humans. To understand the driving force behind the perceptual decision process, a biologically inspired cortical network model was used. Two theoretical scenarios arose for explaining the perceptual switch from the category of the adaptor stimulus to the opposite, nonadapted one. One is noise-driven transition due to the probabilistic spike times of neurons and the other is adaptation-driven transition due to afterhyperpolarization currents. With increasing levels of neural adaptation, the system shifts from a noise-driven to an adaptation-driven modus. The behavioral results show that the underlying model is not just a bistable model, as usual in the decision-making modeling literature, but that neuronal adaptation is high and therefore the working point of the model is in the oscillatory regime. Using the same model parameters, we studied the effect of neural adaptation in a perceptual decision-making task where the same ambiguous stimulus was presented with and without a preceding adaptor stimulus. We find that for different levels of sensory evidence favoring one of the two interpretations of the ambiguous stimulus, higher levels of neural adaptation lead to quicker decisions contributing to a speed–accuracy trade off.

The neuronal basis of attention: rate versus synchronization modulation

Extensive theoretical and experimental work on the neuronal correlates of visual attention raises two hypotheses about the underlying mechanisms. The first hypothesis, named biased competition, originates from experimental single-cell recordings that have shown that attention upmodulates the firing rates of the neurons encoding the attended features and downregulates the firing rates of the neurons encoding the unattended features. Furthermore, attentional modulation of firing rates increases along the visual pathway. The other, newer hypothesis assigns synchronization a crucial role in the attentional process. It stems from experiments that have shown that attention modulates gamma-frequency synchronization. In this paper, we study the coexistence of the two phenomena using a theoretical framework. We find that the two effects can vary independently of each other and across layers. Therefore, the two phenomena are not concomitant. However, we show that there is an advantage in the processing of information if rate modulation is accompanied by gamma modulation, namely that reaction times are shorter, implying behavioral relevance for gamma synchronization.

Development of neuronal markers in aggregating fetal rat telencephalon cells cultured in the presence of triiodothyronine.

The concentrations of the general neuronal markers D2-protein (N-CAM), D3-protein and neuron specific enolase (NSE) in reaggregating cultures of fetal rat telencephalon cells were affected by the presence of 30 nM triiodothyronine in the defined culture medium. The extent of normal developmental changes were enhanced by triiodothyronine, as demonstrated by crossed immunoelectrophoresis. From 13 to 19 days in culture, the concentration of D2-protein decreased, and the concentrations of both D3-protein and NSE increased. Nerve growth factor (NGF) was without effect on the development of these general neuronal markers. However, as shown previously both triiodothyronine and NGF increased the activity of choline acetyltransferase, a marker for cholinergic neurons. The results suggest an enhanced overall differentiation of several types of telencephalon neurons in the presence of triiodothyronine, and a specific stimulation of cholinergic telencephalon neurons by NGF.

Altered expression of the transcription factor Mef2c during retinal degeneration in Rpe65-/- mice.

Purpose. To investigate the role of the myocyte enhancer factor 2 (Mef2) transcription factor family in retinal diseases, Mef2c expression was assessed during retinal degeneration in the Rpe65(-/-) mouse model of Leber's congenital amaurosis (LCA). Mef2c-dependent expression of photoreceptor-specific genes was further addressed. Methods. Expression of Mef2 members was analyzed by oligonucleotide microarray, quantitative PCR (qPCR) and in situ hybridization. Mef2c-dependent transcriptional activity was assayed by luciferase assay in HEK293T cells. Results. Mef2c was the only Mef2 member markedly downregulated during retinal degeneration in Rpe65(-/-) mice. Mef2c mRNA level was decreased by more than 2 fold at 2 and 4 months and by 3.5 fold at 6 months in retinas of Rpe65(-/-) mice. Downregulation of Mef2c at the protein level was confirmed in Rpe65(-/-) retinas. The decrease in Mef2c mRNA levels in the developing Rpe65(-/-) retinas, from post-natal day (P)13 onward, was concomitant with the decreased expression of the rod-specific transcription factors Nrl and Nr2e3. Nrl was further shown to drive Mef2c transcriptional activity, supporting a physiological role for Mef2c in the retina. In addition, Mef2c appeared to act as a transcriptional repressor of its own expression, as well as those of the retina-specific retinal G-protein coupled receptor (Rgr), rhodopsin and M-opsin genes. Conclusions. These findings highlight the early altered regulation of the rod-specific transcriptional network in Rpe65-related disease. They further indicate that Mef2c may act as a novel transcription factor involved in the development and the maintenance of photoreceptor cells.

Distribution of neuronal and metabolic markers in the human auditory cortex

SUMMARY The human auditory cortex, located on the supratemporal plane of the temporal lobe, is divided in a primary auditory area and several non-primary areas surrounding it. These different areas show anatomical and functional differences. Many studies have focussed on auditory areas in non-human primates, using investigation techniques such as electrophysiological recordings, tracing of neural connections, or immunohistochemical and histochemical staining. Some of these studies have suggested parallel and hierarchical organization of the cortical auditory areas as well as subcortical auditory relays. In humans, only few studies have investigated these regions immunohistochemically, but activation and lesion studies speak in favour of parallel and hierarchical organization, very similar to that of non-human primates. Calcium-binding proteins and metabolic markers were used to investigate possible correlates of hierarchical and parallel organization in man. Calcium-binding proteins, parvalbumin, calretinin and calbindin, modulate the concentration of intracellular free calcium ions and were found in distinct subpopulations of GABAergic neurons in non-human primates species. In our study, their distribution showed several differences between auditory areas: the primary auditory area was darkly stained for both parvalbumin and calbindin, and their expression rapidly decreased while moving away from the primary area. This staining pattern suggests a hierarchical organization of the areas, in which the more darkly stained areas could correspond to an earlier integration level and the areas showing light staining may correspond to higher level integration areas. Parallel organization of primary and non-primary auditory areas was suggested by the complementarity, within a given area, between parvalbumin and calbindin expression across layers. To investigate the possible differences in the energetic metabolism of the cortical auditory areas, several metabolic markers were used: cytochrome oxidase and LDH1 were used as oxidative metabolism markers and LDH5 was used as glycolytic metabolism marker. The results obtained show a difference in the expression of enzymes involved in oxidative metabolism between areas. In the primary auditory area the oxidative metabolism markers were maximally expressed in layer IV. In contrast, higher order areas showed maximal staining in supragranular layers. The expression of LDH5 varied in patches, but did not differ between the different hierarchical auditory areas. The distribution of the two LDH enzymes isoforms also provides information about cellular aspects of metabolic organization, since neurons expressed the LDH1 isoform whereas astrocytes express primarily LDH5, but some astrocytes also contained the LDH1 isoform. This cellular distribution pattern supports the hypothesis of the existence of an astrocyte-neuron lactate shuttle, previously suggested in rodent studies, and in particular of lactate transfer from astrocytes, which produce lactate from the glucose obtained from the circulation, to neurons that use lactate as energy substrate. In conclusion, the hypothesis of parallel and hierarchical organization of the auditory areas can be supported by CaBPs, cytochrome oxidase and LDH1 distribution. Moreover, the two LDHs cellular distribution pattern support the hypothesis of an astrocyte-neuron lactate shuttle in human cortex.

Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders.

Autophagy is a cellular mechanism for degrading proteins and organelles. It was first described as a physiological process essential for cellular health and survival, and this is its role in most cells. However, it can also be a mediator of cell death, either by the triggering of apoptosis or by an independent "autophagic" cell death mechanism. This duality is important in the central nervous system, where the activation of autophagy has recently been shown to be protective in certain chronic neurodegenerative diseases but deleterious in acute neural disorders such as stroke and hypoxic/ischemic injury. The authors here discuss these distinct roles of autophagy in the nervous system with a focus on the role of autophagy in mediating neuronal death. The development of new therapeutic strategies based on the manipulation of autophagy will need to take into account these opposing roles of autophagy.

Neuronal responses in mouse barrel cortex:Comparison of two signal discriminators

Barrels are discrete cytoarchitectonic neurons cluster located in the layer IV of the somatosensory¦cortex in mice brain. Each barrel is related to a specific whisker located on the mouse snout. The¦whisker-to-barrel pathway is a part of the somatosensory system that is intensively used to explore¦sensory activation induced plasticity in the cerebral cortex.¦Different recording methods exist to explore the cortical response induced by whisker deflection in¦the cortex of anesthetized mice. In this work, we used a method called the Single-Unit Analysis by¦which we recorded the extracellular electric signals of a single barrel neuron using a microelectrode.¦After recording the signal was processed by discriminators to isolate specific neuronal shape (action¦potentials).¦The objective of this thesis was to familiarize with the barrel cortex recording during whisker¦deflection and its theoretical background and to compare two different ways of discriminating and¦sorting cortical signal, the Waveform Window Discriminator (WWD) or the Spike Shape Discriminator (SSD).¦WWD is an electric module allowing the selection of specific electric signal shape. A trigger and a¦window potential level are set manually. During measurements, every time the electric signal passes¦through the two levels a dot is generated on time line. It was the method used in previous¦extracellular recording study in the Département de Biologie Cellulaire et de Morphologie (DBCM) in¦Lausanne.¦SSD is a function provided by the signal analysis software Spike2 (Cambridge Electronic Design). The¦neuronal signal is discriminated by a complex algorithm allowing the creation of specific templates.¦Each of these templates is supposed to correspond to a cell response profile. The templates are saved¦as a number of points (62 in this study) and are set for each new cortical location. During¦measurements, every time the cortical recorded signal corresponds to a defined number of templates¦points (60% in this study) a dot is generated on time line. The advantage of the SSD is that multiple¦templates can be used during a single stimulation, allowing a simultaneous recording of multiple¦signals.¦It exists different ways to represent data after discrimination and sorting. The most commonly used¦in the Single-Unit Analysis of the barrel cortex are the representation of the time between stimulation¦and the first cell response (the latency), the representation of the Response Magnitude (RM) after¦whisker deflection corrected for spontaneous activity and the representation of the time distribution¦of neuronal spikes on time axis after whisker stimulation (Peri-Stimulus Time Histogram, PSTH).¦The results show that the RMs and the latencies in layer IV were significantly different between the¦WWD and the SSD discriminated signal. The temporal distribution of the latencies shows that the¦different values were included between 6 and 60ms with no peak value for SSD while the WWD¦data were all gathered around a peak of 11ms (corresponding to previous studies). The scattered¦distribution of the latencies recorded with the SSD did not correspond to a cell response.¦The SSD appears to be a powerful tool for signal sorting but we do not succeed to use it for the¦Single-Unit Analysis extracellular recordings. Further recordings with different SSD templates settings¦and larger sample size may help to show the utility of this tool in Single-Unit Analysis studies.

Reducing the clinical burden of ranibizumab treatment for neovascular age-related macular degeneration using an individually planned regimen.

AIMS: The purpose of this study was to clinically validate an individually planned treatment regimen for neovascular age-related macular degeneration (nAMD), termed, observe and plan. This regimen was based on the predictability of an individual's need for retreatment and aimed to reduce the clinical burden, while obtaining good functional results. METHODS: This was a prospective case series that included 104 patients (115 eyes) with treatment-naive nAMD. Following three loading doses of ranibizumab, monthly observation visits allowed the disease recurrence interval to be determined. The recurrence interval was reduced by 2 weeks to give the retreatment interval for the next three injections. Periodical control visits (at least every 6 months) allowed the effectiveness of the treatment to be assessed and individual intervals adjusted. RESULTS: Mean visual acuity (VA) improved by 8.7 and 9.8 letters in months 3 and 12, respectively. The mean number of injections during the 12-month study was 7.8, while the mean number of ophthalmic examinations between months 3 and 12 was 3.97. The mean treatment interval after the loading doses was 1.97 months. CONCLUSIONS: The observe-and-plan regimen significantly improved VA. This was obtained with fewer clinic visits compared with other regimens, which could ease the burden of nAMD treatment. TRIAL REGISTRATION NUMBER: Commission cantonale (VD) d'éthique de la recherché Clinique, Université de Lausanne, Protocole 351/11.

Neocortical maturation during adolescence: change in neuronal soma dimension.

During adolescence, cognitive abilities increase robustly. To search for possible related structural alterations of the cerebral cortex, we measured neuronal soma dimension (NSD = width times height), cortical thickness and neuronal densities in different types of neocortex in post-mortem brains of five 12-16 and five 17-24 year-olds (each 2F, 3M). Using a generalized mixed model analysis, mean normalized NSD comparing the age groups shows layer-specific change for layer 2 (p < .0001) and age-related differences between categorized type of cortex: primary/primary association cortex (BA 1, 3, 4, and 44) shows a generalized increase; higher-order regions (BA 9, 21, 39, and 45) also show increase in layers 2 and 5 but decrease in layers 3, 4, and 6 while limbic/orbital cortex (BA 23, 24, and 47) undergoes minor decrease (BA 1, 3, 4, and 44 vs. BA 9, 21, 39, and 45: p = .036 and BA 1, 3, 4, and 44 vs. BA 23, 24, and 47: p = .004). These data imply the operation of cortical layer- and type-specific processes of growth and regression adding new evidence that the human brain matures during adolescence not only functionally but also structurally.

Maturation-dependent effects of chlorpyrifos and parathion and their oxygen analogs on acetylcholinesterase and neuronal and glial markers in aggregating brain cell cultures.

An in vitro model, the aggregating brain cell culture of fetal rat telencephalon, has been used to study the maturation-dependent sensitivity of brain cells to two organophosphorus pesticides (OPs), chlorpyrifos and parathion, and to their oxon derivatives. Immature (DIV 5-15) or differentiated (DIV 25-35) brain cells were treated continuously for 10 days. Acetylcholinesterase (AChE) inhibitory potency for the OPs was compared to that of eserine (physostigmine), a reversible AChE inhibitor. Oxon derivatives were more potent AChE inhibitors than the parent compounds, and parathion was more potent than chlorpyrifos. No maturation-dependent differences for AChE inhibition were found for chlorpyrifos and eserine, whereas for parathion and paraoxon there was a tendency to be more effective in immature cultures, while the opposite was true for chlorpyrifos-oxon. Toxic effects, assessed by measuring protein content as an index of general cytotoxicity, and various enzyme activities as cell-type-specific neuronal and glial markers (ChAT and GAD, for cholinergic and GABAergic neurons, respectively, and GS and CNP, for astrocytes and oligodendrocytes, respectively) were only found at more than 70% of AChE inhibition. Immature compared to differentiated cholinergic neurons appeared to be more sensitive to OP treatments. The oxon derivates were found to be more toxic on neurons than the parent compounds, and chlorpyrifos was more toxic than parathion. Eserine was not neurotoxic. These results indicate that inhibition of AChE remains the most sensitive macromolecular target of OP exposure, since toxic effects were found at concentrations in which AChE was inhibited. Furthermore, the compound-specific reactions, the differential pattern of toxicity of OPs compared to eserine, and the higher sensitivity of immature brain cells suggest that the toxic effects and inhibition of AChE are unrelated.

ERK1/2 pathway is activated in degenerated Rpe65-deficient mice.

The MAPK family is composed of three majors kinases, JNK, p38 and ERK1/2, and is implicated in many degenerative processes, including retinal cell death. The purpose of our study was to evaluate the activation of ERK1/2 kinase, and its potential role in Müller cell gliosis, during photoreceptor cell death in Rpe65(-/-) mice. We assayed ERK1/2 mRNA and protein levels, and evaluated ERK1/2 phosphorylation involved in kinase activation, in 2, 4 and 6 month-old Rpe65(-/-) mice and in age-matched wild-type controls. No differences in ERK1/2 expression were detected between Rpe65(-/-) and wild-type mice, however, ERK1/2 phosphorylation was dramatically increased in the knock out mice at 4 and 6 months-of-age. Phosphorylated ERK1/2 co-localized with GFAP in the ganglion cell layer, and correlated with an increase in GFAP protein expression and retinal cell death. Accumulation of cFOS protein in the ganglion cell layer occurred concomitant with pERK1/2 activation. Müller cell proliferation was not observed. ERK1/2 activation did not occur in 2 month-old Rpe65(-/-) or in the Rpe65(-/-)/Gnat1(-/-) mice, in which no degeneration was evident. The observed activation ERK1/2 and GFAP, both markers of Müller cell gliosis, in the absence of Müller cell proliferation, is consistent with the activation of atypical gliosis occurring during the slow process of degeneration in Rpe65(-/-) mice. As Müller cell gliosis is activated in many neuronal and retinal degenerative diseases, further studies will be needed to determine whether atypical gliosis in Rpe65(-/-) mice contributes to, or protects against, the pathogenesis occurring in this model of Leber congenital amaurosis.

Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.

The AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS.