Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis

Studies suggest that frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN), surviving neurons, enlarged neurons (EN), and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: 1) pathological variation in FTLD-TDP is best described as a ‘continuum’ without clearly distinct subtypes, 2) vacuolation was the single greatest source of variation and reflects the ‘stage’ of the disease, and 3) within the FTLD-TDP ‘continuum’ cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.

Evaluating the potential neurotoxicity of hexanedione isomers:an in vitro approach

2,5-hexanedione (2,5HD) is the neurotoxic metabolite of the aliphatic hydrocarbon n-Hexane. The isomers, 2,3-hexanedione (2,3HD) and 3,4-hexanedione (3,4HD) are used as food additives. Although the neurotoxicity of 2,5HD is well established, there are no human data of the possible toxicity of the 2,3- and 3,4- isomers. MTT and flow cytometry were utilised to determine the cytotoxicity of hexanedione isomers in neuroblastoma cells. The neuroblastoma cell lines SK-N-SH and SH-SY5Y are sufficiently neuron-like to provide preliminary assessment of the neurotoxic potential of these isomers, in comparison with toxicity towards human non-neuronal cells. Initial studies showed that 2,5HD was the least toxic in all cell lines at all times (4, 24 and 48h). Although considerably lower than for 2,5HD, in general the IC50s for the α isomers were not significantly different from each other and, besides 4h exposure, the SH-SY5Y cells were significantly more sensitive to 2,3HD and 3,4HD than the SK-N-SH cells. All three isomers caused varying degrees of apoptosis in the neuroblastoma lines, with 3,4HD more potent than 2,3HD. Flow cytometry highlighted cell cycle arrest indicative of DNA damage with 2,3- and 3,4HD. The toxicity of the isomers towards 3 non-neuronal cell lines (MCF7, HepG2 and CaCo-2) was assessed by MTT assay. All 3 hexanedione isomers proved to be cytotoxic in all non-neuronal cell lines at all time points. These data suggest cytotoxicity of 2,3- and 3,4HD (mM range), but it is difficult to define this as specific neurotoxicity in the absence of specific neurotoxic endpoints. However, the neuroblastomas were significantly more susceptible to the cytotoxic effects of the α hexanedione isomers at exposures of 4 and 24 hours, compared to non-neuronal lines. Finally, a mechanism of toxicity is suggested for the α HD isomers whereby inhibition of the oxoglutarate carrier (OGC) releases apoptosis inducing factor (AIF), causing apoptosis-like cell death.

Experiments and observations on the behaviour and brain of the aging female mouse with special reference to dementia of the Alzheimer type

The objective of this research was to investigate the effects of normal aging and the additional effects of chronic exposure to two experimental diets, one enriched in aluminium, the other enriched in lecithin, on aspects of the behaviour and brain histology of the female mouse. The aluminium diet was administered in an attempt to develop a rodent model of Dementia of the Alzheimer Type (DAT). With normal aging, almost all assessed aspects of behaviour were found to be impaired. As regards cognition, selective impairments of single-trial passive avoidance and Morris place learning were observed. While all aspects of open-field behaviour were impaired, the degree of impairment was directly related to the degree of motoric complexity. Deficits were also observed on non-visual sensorimotor coordination tasks and in olfactory discrimination. Histologically, neuron loss, gliosis, vacuolation and congophilic angiopathy were observed in several of the brain regions/fibre tracts believed to contribute to the control of some of the assessed behaviours. The aluminium treatment had very selective effects on both behaviour and brain histology, inducing several features observed in DAT. Behaviourally, the treatment induced impaired spatial reference memory; reduced ambulation; disturbed olfactory function and induced the premature development of the senile pattern of swimming. Histologically, significant neuron loss and gliosis were observed in the hippocampus, entorhinal cortex, amygdala, medial septum, pyriform and pr-frontal cortex. In addition, the brain distribution of congophilic angiopathy was significantly increased by the treatment. The lecithin treatment had effects on both non-cognitive and cognitive aspects of behaviour. The effects of aging on open-field ambulation and rearing were partially ameliorated by the treatment. A similar effect was observed for single-trial passive avoidance performance. Age-dependent improvements in acquisition/retention were observed in 17-23 month mice and Morris place task performance was improved in 11 and 17 month mice. Histologically, a partial sparing of neurons in the cerebellum, hippocampus, entorhinal cortex and subiculum was observed.

Beauty in the brain of the beholder

Facial beauty is an honest signal of the genotypic and phenotypic quality of the bearer. Beautiful people are thus regarded as high-value mates who maximize reproductive success by producing viable offspring. Here, the functional neuroanatomy of facial beauty is reviewed and placed into the context of the distributed model for human face perception. A proposed extension of the distributed model is provided, which takes into account the neuroanatomy of beautiful face perception.

NT2 derived neuronal and astrocytic network signalling

A major focus of stem cell research is the generation of neurons that may then be implanted to treat neurodegenerative diseases. However, a picture is emerging where astrocytes are partners to neurons in sustaining and modulating brain function. We therefore investigated the functional properties of NT2 derived astrocytes and neurons using electrophysiological and calcium imaging approaches. NT2 neurons (NT2Ns) expressed sodium dependent action potentials, as well as responses to depolarisation and the neurotransmitter glutamate. NT2Ns exhibited spontaneous and coordinated calcium elevations in clusters and in extended processes, indicating local and long distance signalling. Tetrodotoxin sensitive network activity could also be evoked by electrical stimulation. Similarly, NT2 astrocytes (NT2As) exhibited morphology and functional properties consistent with this glial cell type. NT2As responded to neuronal activity and to exogenously applied neurotransmitters with calcium elevations, and in contrast to neurons, also exhibited spontaneous rhythmic calcium oscillations. NT2As also generated propagating calcium waves that were gap junction and purinergic signalling dependent. Our results show that NT2 derived astrocytes exhibit appropriate functionality and that NT2N networks interact with NT2A networks in co-culture. These findings underline the utility of such cultures to investigate human brain cell type signalling under controlled conditions. Furthermore, since stem cell derived neuron function and survival is of great importance therapeutically, our findings suggest that the presence of complementary astrocytes may be valuable in supporting stem cell derived neuronal networks. Indeed, this also supports the intriguing possibility of selective therapeutic replacement of astrocytes in diseases where these cells are either lost or lose functionality.

Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets δ-subunit-containing GABA(A) receptors

The rodent ventrobasal (VB) thalamus contains a relatively uniform population of thalamocortical (TC) neurons that receive glutamatergic input from the vibrissae and the somatosensory cortex, and inhibitory input from the nucleus reticularis thalami (nRT). In this study we describe ?-aminobutyric acid (GABA)(A) receptor-dependent slow outward currents (SOCs) in TC neurons that are distinct from fast inhibitory postsynaptic currents (IPSCs) and tonic currents. SOCs occurred spontaneously or could be evoked by hypo-osmotic stimulus, and were not blocked by tetrodotoxin, removal of extracellular Ca(2+) or bafilomycin A1, indicating a non-synaptic, non-vesicular GABA origin. SOCs were more common in TC neurons of the VB compared with the dorsal lateral geniculate nucleus, and were rarely observed in nRT neurons, whilst SOC frequency in the VB increased with age. Application of THIP, a selective agonist at d-subunit-containing GABA(A) receptors, occluded SOCs, whereas the benzodiazepine site inverse agonist ß-CCB had no effect, but did inhibit spontaneous and evoked IPSCs. In addition, the occurrence of SOCs was reduced in mice lacking the d-subunit, and their kinetics were also altered. The anti-epileptic drug vigabatrin increased SOC frequency in a time-dependent manner, but this effect was not due to reversal of GABA transporters. Together, these data indicate that SOCs in TC neurons arise from astrocytic GABA release, and are mediated by d-subunit-containing GABA(A) receptors. Furthermore, these findings suggest that the therapeutic action of vigabatrin may occur through the augmentation of this astrocyte-neuron interaction, and highlight the importance of glial cells in CNS (patho) physiology.

Contradiction in universal and particular reasoning

A wide range of essential reasoning tasks rely on contradiction identification, a cornerstone of human rationality, communication and debate founded on the inversion of the logical operators "Every" and "Some." A high-density electroencephalographic (EEG) study was performed in 11 normal young adults. The cerebral network involved in the identification of contradiction included the orbito-frontal and anterior-cingulate cortices and the temporo-polar cortices. The event-related dynamic of this network showed an early negative deflection lasting 500 ms after sentence presentation. This was followed by a positive deflection lasting 1.5 s, which was different for the two logical operators. A lesser degree of network activation (either in neuron number or their level of phase locking or both) occurred while processing statements with "Some," suggesting that this was a relatively simpler scenario with one example to be figured out, instead of the many examples or the absence of a counterexample searched for while processing statements with "Every." A self-generated reward system seemed to resonate the recruited circuitry when the contradictory task is successfully completed.

Spatial relationships between diffuse prion protein deposits and neuronal perikarya in variant Creutzfeldt-Jakob disease

Two morphological types of prion protein (PrPsc) deposit occur in the cerebral cortex of cases of variant Creutzfeldt-Jakob disease (vCJD), viz., diffuse and florid deposits. The objective of this study was to determine whether diffuse-type PrPsc deposits in areas of the cerebral cortex in six cases of the variant form of CJD (vCJD) were spatially correlated with neurons and whether diffuse deposit size was related to the number of adjacent neurons contributing PrPsc. In cortical gyri, density of surviving neurons was 5.38-12.15 per 50 × 200 µm sample field, neurons being distributed randomly, regularly or were clustered relative to the pia mater. Density of neurons embedded within diffuse deposits, however, was three to eight times their overall density in the section. In addition, diffuse deposit area was positively correlated with the number of embedded neurons. The frequency distribution of diffuse deposits with 0, 1, 2, 3, …, n, embedded neurons did not deviate from a Poisson distribution. These results suggest: (1) diffuse deposits in vCJD develop in situ as a result of the formation of PrPsc in relation to clusters of neurons, (2) size of a diffuse deposit is determined by the number of adjacent neurons which develop PrPsc, and (3) the probability that PrPsc is formed in relation to one neuron is independent of that of its neighbour.

Reflecting on mirror mechanisms:motor resonance effects during action observation only present with low-intensity transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) studies indicate that the observation of other people's actions influences the excitability of the observer's motor system. Motor evoked potential (MEP) amplitudes typically increase in muscles which would be active during the execution of the observed action. This 'motor resonance' effect is thought to result from activity in mirror neuron regions, which enhance the excitability of the primary motor cortex (M1) via cortico-cortical pathways. The importance of TMS intensity has not yet been recognised in this area of research. Low-intensity TMS predominately activates corticospinal neurons indirectly, whereas high-intensity TMS can directly activate corticospinal axons. This indicates that motor resonance effects should be more prominent when using low-intensity TMS. A related issue is that TMS is typically applied over a single optimal scalp position (OSP) to simultaneously elicit MEPs from several muscles. Whether this confounds results, due to differences in the manner that TMS activates spatially separate cortical representations, has not yet been explored. In the current study, MEP amplitudes, resulting from single-pulse TMS applied over M1, were recorded from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles during the observation of simple finger abductions. We tested if the TMS intensity (110% vs. 130% resting motor threshold) or stimulating position (FDI-OSP vs. ADM-OSP) influenced the magnitude of the motor resonance effects. Results showed that the MEP facilitation recorded in the FDI muscle during the observation of index-finger abductions was only detected using low-intensity TMS. In contrast, changes in the OSP had a negligible effect on the presence of motor resonance effects in either the FDI or ADM muscles. These findings support the hypothesis that MN activity enhances M1 excitability via cortico-cortical pathways and highlight a methodological framework by which the neural underpinnings of action observation can be further explored. © 2013 Loporto et al.

Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures

An enhanced tonic GABA-A inhibition in the thalamus plays a crucial role in experimental absence seizures, and has been attributed, on the basis of indirect evidence, to a dysfunction of the astrocytic GABA transporter-1 (GAT-1). Here, the GABA transporter current was directly investigated in thalamic astrocytes from a well-established genetic model of absence seizures, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and its non-epileptic control (NEC) strain. We also characterized the novel form of GABAergic and glutamatergic astrocyte-to-neuron signalling by recording slow outward currents (SOCs) and slow inward currents (SICs), respectively, in thalamocortical (TC) neurons of both strains. In patch-clamped astrocytes, the GABA transporter current was abolished by combined application of the selective GAT-1 and GAT-3 blocker, NO711 (30µM) and SNAP5114 (60µM), respectively, to GAERS and NEC thalamic slices. NO711 alone significantly reduced (41%) the transporter current in NEC, but had no effect in GAERS. SNAP5114 alone reduced by half the GABA transporter current in NEC, whilst it abolished it in GAERS. SIC properties did not differ between GAERS and NEC TC neurons, whilst moderate changes in SOC amplitude and kinetics were observed. These data provide the first direct demonstration of a malfunction of the astrocytic thalamic GAT-1 transporter in absence epilepsy and support an abnormal astrocytic modulation of thalamic ambient GABA levels. Moreover, while the glutamatergic astrocyte-neuron signalling is unaltered in the GAERS thalamus, the changes in some properties of the GABAergic astrocyte-neuron signaling in this epileptic strain may contribute to the generation of absence seizures.

Right hemisphere contributions to imitation tasks

Humans imitate biological movements faster than non-biological movements. The faster response has been attributed to an activation of the human mirror neuron system, which is thought to match observation and execution of actions. However, it is unclear which cortical areas are responsible for this behavioural advantage. Also, little is known about the timing of activations. Using whole-head magnetoencephalography we recorded neuronal responses to single biological finger movements and non-biological dot movements while the subjects were required to perform an imitation task or an observation task, respectively. Previous imaging studies on the human mirror neurone system suggested that activation in response to biological movements would be stronger in ventral premotor, parietal and superior temporal regions. In accordance with previous studies, reaction times to biological movements were faster than those to dot movements in all subjects. The analysis of evoked magnetic fields revealed that the reaction time benefit was paralleled by stronger and earlier activation of the left temporo-occipital cortex, right superior temporal area and right ventral motor/premotor area. The activity patterns suggest that the latter areas mediate the observed behavioural advantage of biological movements and indicate a predominant contribution of the right temporo-frontal hemisphere to action observation–execution matching processes in intransitive movements, which has not been reported previously.

Observing repetitive finger movements modulates response times of auditorily cued finger movements

Our motor and perceptual representations of actions seem to be intimately linked and the human mirror neuron system (MNS) has been proposed as the mediator. In two experiments, we presented biological or non-biological movement stimuli that were either congruent or incongruent to a required response prompted by a tone. When the tone occurred with the onset of the last movement in a series, i.e., it was perceived during the movement presentation, congruent biological stimuli resulted in faster reaction times than congruent non-biological stimuli. The opposite was observed for incongruent stimuli. When the tone was presented after visual movement stimulation, however, no such interaction was present. This implies that biological movement stimuli only affect motor behaviour during visual processing but not thereafter. These data suggest that the MNS is an “online” system; longstanding repetitive visual stimulation (Experiment 1) has no benefit in comparison to only one or two repetitions (Experiment 2).

Synchronized oscillations at α and θ frequencies in the lateral geniculate nucleus

In relaxed wakefulness, the EEG exhibits robust rhythms in the alpha band (8-13 Hz), which decelerate to theta (approximately 2-7 Hz) frequencies during early sleep. In animal models, these rhythms occur coherently with synchronized activity in the thalamus. However, the mechanisms of this thalamic activity are unknown. Here we show that, in slices of the lateral geniculate nucleus maintained in vitro, activation of the metabotropic glutamate receptor (mGluR) mGluR1a induces synchronized oscillations at alpha and theta frequencies that share similarities with thalamic alpha and theta rhythms recorded in vivo. These in vitro oscillations are driven by an unusual form of burst firing that is present in a subset of thalamocortical neurons and are synchronized by gap junctions. We propose that mGluR1a-induced oscillations are a potential mechanism whereby the thalamus promotes EEG alpha and theta rhythms in the intact brain.

Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics

In this review, we summarize three sets of findings that have recently been observed in thalamic astrocytes and neurons, and discuss their significance for thalamocortical loop dynamics. (i) A physiologically relevant ‘window’ component of the low–voltage–activated, T–type Ca2+ current (ITwindow) plays an essential part in the slow (less than 1 Hz) sleep oscillation in adult thalamocortical (TC) neurons, indicating that the expression of this fundamental sleep rhythm in these neurons is not a simple reflection of cortical network activity. It is also likely that ITwindow underlies one of the cellular mechanisms enabling TC neurons to produce burst firing in response to novel sensory stimuli. (ii) Both electrophysiological and dye–injection experiments support the existence of gap junction–mediated coupling among young and adult TC neurons. This finding indicates that electrical coupling–mediated synchronization might be implicated in the high and low frequency oscillatory activities expressed by this type of thalamic neuron. (iii) Spontaneous intracellular Ca2+ ([Ca2+]i) waves propagating among thalamic astrocytes are able to elicit large and long–lasting N–methyl–D–aspartate–mediated currents in TC neurons. The peculiar developmental profile within the first two postnatal weeks of these astrocytic [Ca2+]i transients and the selective activation of these glutamate receptors point to a role for this astrocyte–to–neuron signalling mechanism in the topographic wiring of the thalamocortical loop. As some of these novel cellular and intracellular properties are not restricted to thalamic astrocytes and neurons, their significance may well apply to (patho)physiological functions of glial and neuronal elements in other brain areas.

Generalization by Computation Through Memory

Usually, generalization is considered as a function of learning from a set of examples. In present work on the basis of recent neural network assembly memory model (NNAMM), a biologically plausible 'grandmother' model for vision, where each separate memory unit itself can generalize, has been proposed. For such a generalization by computation through memory, analytical formulae and numerical procedure are found to calculate exactly the perfectly learned memory unit's generalization ability. The model's memory has complex hierarchical structure, can be learned from one example by a one-step process, and may be considered as a semi-representational one. A simple binary neural network for bell-shaped tuning is described.