Angelo Di Garbo

Environmental enrichment strengthens corticocortical interactions and reduces amyloid-β oligomers in aged mice

Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes.

Botulinum neurotoxin E (BoNT/E) reduces CA1 neuron loss and granule cell dispersion, with no effects on chronic seizures, in a mouse model of temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is often the result of an early insult that induces a reorganization in hippocampal circuitry leading, after a latent period, to chronic epilepsy. Hippocampal rearrangements during the latent phase include neuronal loss, axonal and dendritic plasticity, neurogenesis, and cell repositioning, but the role of these changes in epilepsy development is unclear. Here we have tested whether administration of the synaptic blocker botulinum neurotoxin E (BoNT/E) interferes with development of spontaneous seizures and histopathological changes following an episode of status epilepticus (SE). SE was induced by unilateral intrahippocampal injection of kainic acid in mice and BoNT/E was delivered to the same hippocampus 3 h later. We found that treatment with BoNT/E prolonged the duration of the latent period but did not block the occurrence of spontaneous seizures. At the histopathological level, BoNT/E reduced loss of CA1 pyramidal neurons and dispersion of dentate granule cells. Downregulation of reelin expression along the hippocampal fissure was also suppressed by BoNT/E treatment. Our findings indicate that administration of BoNT/E after SE inhibits specific morphological changes in hippocampal circuitry but not the development of spontaneous seizures. This indicates a dissociation between certain anatomical modifications and establishment of chronic epilepsy in MTLE.

Synchronization in a network of fast-spiking interneurons.

Experimental results revealed that in neocortex inhibitory fast-spiking (FS) interneurons interact also by electrical synapses (gap-junctions). They receive sensory information from thalamus and transfer it to principal cells by feedforward inhibition. Moreover, their synchronous discharge enhances their inhibitory control of pyramidal neurons. By using a biophysical model of FS interneurons the synchronization properties of a network of two synaptically coupled units are investigated. In the case they interact only by inhibitory synapses, well defined regions exist in the parameters space described by the strength and duration of the synaptic current, where synchronous regimes occur. Then an empirical protocol is proposed to determine approximately the borders of the synchronization manifold (SM). When electrical synapses are included, the region of synchronous discharge of the two interneurons becomes larger. In both cases, the coherent states are characterized by discharge frequencies in the gamma range. Lastly, the effects of heterogeneity, either obtained by using different stimulation currents or unidirectional inhibitory coupling, are studied.

Environmental Enrichment Modulates Cortico-Cortical Interactions in the Mouse

Environmental enrichment (EE) is an experimental protocol based on a complex sensorimotor stimulation that dramatically affects brain development. While it is widely believed that the effects of EE result from the unique combination of different sensory and motor stimuli, it is not known whether and how cortico-cortical interactions are shaped by EE. Since the primary visual cortex (V1) is one of the best characterized targets of EE, we looked for direct cortico-cortical projections impinging on V1, and we identified a direct monosynaptic connection between motor cortex and V1 in the mouse brain. To measure the interactions between these areas under standard and EE rearing conditions, we used simultaneous recordings of local field potentials (LFPs) in awake, freely moving animals. LFP signals were analyzed by using different methods of linear and nonlinear analysis of time series (cross-correlation, mutual information, phase synchronization). We found that EE decreases the level of coupling between the electrical activities of the two cortical regions with respect to the control group. From a functional point of view, our results indicate, for the first time, that an enhanced sensorimotor experience impacts on the brain by affecting the functional crosstalk between different cortical areas.

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration.

The synchronization properties of a network of inhibitory interneurons depend on the biophysical model

The synchronization properties of a pair of coupled fast spiking interneurons are studied by using the theory of weakly coupled oscillators. Four different biophysical models of the single fast spiking interneuron are used and the corresponding results are compared. It is shown that for a pair of identical coupled cells, the synchronization properties are model-dependent. In particular, the firing coherence of the network is strongly affected by the reversal potential, the kinetics of the inhibitory postsynaptic current and the electrical coupling; the activation properties of the sodium and potassium currents play a significant role too.

Evidence for two conductive pathways in P2X7 receptor: differences in modulation and selectivity

J. Neurochem. (2010) 113, 796–806.

The leaky integrate-and-fire with noise: a useful tool to investigate SR

Abstract The behaviour of a relaxation-like neural model, driven by noise and underthreshold sinusoidal signal, is analysed by computer simulation. The histograms of interspike intervals and the cycle histograms (CHs) are computed as well as the power spectral densities (PSDs) of the point process generated. The system is shown to exhibit bona fide stochastic resonance (SR).

DYNAMICAL BEHAVIOR OF THE LINEARIZED VERSION OF THE FITZHUGH NAGUMO NEURAL MODEL

For a linearized version of the FitzHugh–Nagumo model, firing and resetting conditions are defined by analogy with the Integrate and Fire model. The dynamical behavior of the model, subject to periodic synaptic inputs, is investigated both theoretically and numerically, with particular emphasis on the synchronization properties. The study is then extended to a network of two synaptically coupled units.

Rescaling prescriptions: On the conflict between Hurst's analysis and the second moment prediction

Abstract The numerical treatment of anomalous diffusion shows that in some cases Hursts analysis and the second moment technique express the long-range properties by means of distinctly different rescaling coefficients. With theoretical arguments we show this effect to be determined by the finite speed of the propagation front.