Past events

The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer’s disease, is associated with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated via synergistic pathological interactions with amyloid β (Aβ). We have recently shown that activation of the amyloid cascade by inhibition of the Aβ-degrading enzyme neprilysin in brains of apoE3 and apoE4 mice results in the isoform specific degeneration in apoE4 mice, of hippocampal CA1 neurons and of entorhinal and septal neurons. This is accompanied by the accumulation of intracellular Aβ and apoE and by pronounced cognitive deficits in the ApoE4 mice. We presently investigated the cellular mechanisms underlying the apoE4 dependent Aβ mediated neurodegeneration of CA1 and septal neurons and their neuronal specificity. Confocal microscopy kinetic studies revealed that the accumulated Aβ in CA1 neurons of apoE4 mice co-localizes with lysosomes and is associated with lysosomal activation and subsequent apoptotic neuronal cell death. Furthermore the accumulated Aβ is oligomerized. In contrast the degeneration of septal neurons is not associated with oligomerization of the accumulated Aβ. Instead intracellular Aβ in septal neurons co-localizes with the apoE receptor LRP whose levels are specifically elevated in these cells. These findings suggest that the apoE4 dependent Aβ mediated neurodegeneration is related, in CA1 but not in septal neurons, to oligomerization of the accumulated Aβ. In addition, neurodegeneration of CA1 but not of septal neurons is associated with inflammatory activation suggesting that the brain area specificity of the effects of apoE4 and Aβ are also related to brain area specific non neuronal mechanisms such as inflammation. Neuronal plasticity experiments revealed that apoE4 inhibits synaptogenesis and neurogenesis and stimulates apoptosis in hippocampal neurons of apoE4 mice that have been exposed to an enriched environment. These effects are also associated with the specific accumulation of apoE4 and oligomerized Aβ in the affected neurons. Additional experiments revealed that apoE4 up-regulates the expression of inflammation-related genes following i.c.v injection of LPS and that this effect is also associated with the accumulation of intra neuronal Aβ in hippocampal neurons. These findings suggest that the impaired neuronal plasticity and hyper inflammatory effects of apoE4 may also be mediated via cross talk interactions of apoE4 with the amyloid cascade.

Circadian rhythms in locomotor activity are an example of a well-characterized behavior for which the molecular and neurobiological bases are not yet completely understood. These rhythms are self-sustained 24 hours rhythms that underlie most physiological and behavioral processes. The central circadian clock, which is situated in the brain, is responsible for daily rhythms in locomotor activity that persist even after weeks in constant darkness (DD). Peripheral clocks are spread trough the fly body and regulate a plethora of physiological functions that include: olfaction, detoxification and immunity. All these clocks keep time trough complex transcriptional-translational feedback loops that include the proteins CLK, CYC, PER and TIM. My research focuses on the study of the molecular basis of the circadian clock. In particular, I am interested in the contribution of the different molecular interactions and processes to the generation of robust 24hs rhythms. In this context, I have recently demonstrated that transcriptional speed of the clock gene PER is a determinant of the circadian period and that translational regulation by miRNAs is part of the central circadian clock.

Never before have such intense experimental efforts been focused on neuronal circuits of the size of few hundred thousands neurons whose functions are relatively well defined. The extraordinarily powerful new genetic tools and 3D reconstruction methods, combined with modern multi-electrode arrays, telemetry, two-photon imaging and photo-activation are starting to shed bright light on the intricacies of these circuits, and in particular of the cortical column. But without tools that integrate all this different types of data, one cannot expect to gain a comprehensive understanding on how these circuits perform specific sensory-motor or cognitive functions. As in any other complex system, a modeling study is essential if we are to ever say that we understand how this system works. I will describe several attempts in my group to begin building detailed models of the cortical column, highlighting that, at both circuit level and at the level of individual neurons, models should capture experimental variability and that the building of these models should become automated. I will demonstrate how these models could be used to fruitfully guide new experiments and discuss were all this new integrated "simulation-driven brain research agenda" might lead to.

The view that the brain computes is a working hypothesis in cognitive and brain sciences. But what does it mean to say that a system computes? What distinguishes computing systems, such as brains, from non-computing systems, such as stomachs and tornadoes? I argue that a "structural" approach to computing cannot account for much of the computational work in cognitive neuroscience. Instead, I offer a modeling account, which is a variant of a "semantic" approach. On this modeling account, the key feature of computing is a similarity between the "inner" mathematical relations, defined over the representing states, and "outer" mathematical relations, defined over the represented states.

Performance of OCD patients was compared with that of matched normal individuals who were asked to perform the same task that the patients ascribed to their performance. Sequences of consecutive functional acts were long in controls and short in OCD, whereas sequences of non-functional acts were short in controls and long in OCD. Non-functional acts accumulated as a "tail" after the natural termination of the task, supporting the notion of incompleteness as an underling mechanism in OCD. It is suggested that the identified properties are consistent with a recent hypothesis that the individual's attention in OCD shifts from a normal focus on structured actions to a pathological attraction onto the processing of basic acts, a shift that invariably overtaxes memory. Such characteristics and mechanisms of compulsive rituals may prove useful in objective assessment of psychiatric disorders, behavioral therapy, and OCD nosology.

It is unclear how the complex spatiotemporal organization of ongoing cortical neuronal activity recorded in anesthetized animals relates to the awake animal. We therefore used two-photon population calcium imaging in awake and subsequently anesthetized rats to follow action potential firing in populations of neurons across brain states, and examined how single neurons contributed to population activity. Firing rates and spike bursting in awake rats were higher, and pair-wise correlations were lower, compared with anesthetized rats. Anesthesia modulated population-wide synchronization and the relationship between firing rate and correlation. Overall, brain activity during wakefulness cannot be inferred using anesthesia.

Traditionally, the brain and sensory cortex in particular have been viewed as being primarily driven by external events, but recent studies in anesthetized animals revealed robust spontaneous activity in sensory cortex, highlighting the intrinsic nature of brain processing. Using fMRI we found widespread slow fluctuations occurring spontaneously in the human visual cortex in the absence of external stimuli. These waves exhibited a consistent and specific neuro-anatomical distribution, suggesting that they largely reflect neuronal activity rather than hemodynamic noise sources. In further studies we obtained neurophysiological recordings in neurosurgical patients, and found direct electrophysiological evidence for such slow spontaneous neuronal fluctuation in human sensory cortex. These fluctuations were evident mainly in neuronal firing rates and in LFP gamma power changes, showed unique temporal dynamics following 1/f power laws, and were found to be correlated between corresponding ‘mirror’ sites across hemispheres within specific functional networks. Overall, these results extend previous animal studies of spontaneous activity by revealing and characterizing such activity in human sensory cortex.