Brain Plasticity

From early description by Charcot, the classification of the Amyotrophic Lateral Sclerosis (ALS) is evolving from a subtype of Motor Neuron (MN) Disease to be considered rather a multi-systemic, non-cell autonomous and complex neurodegenerative disease. In the last decade, the huge amount of knowledge acquired has shed new insights on the pathological mechanisms underlying ALS from different perspectives. However, a whole vision on the multiple dysfunctional pathways is needed with the inclusion of information often excluded in other published revisions. We propose an integrative view of ALS pathology, although centered on the synaptic failure as a converging and crucial player to the etiology of the disease. Homeostasis of input and output synaptic activity of MNs has been proved to be severely and early disrupted and to definitively contribute to microcircuitry alterations at the spinal cord. Several cells play roles in synaptic communication across the MNs network system such as interneurons, astrocytes, microglia, Schwann and skeletal muscle cells. Microglia are described as highly dynamic surveying cells of the nervous system but also as determinant contributors to the synaptic plasticity linked to neuronal activity. Several signaling axis such as TNFα/TNFR1 and CX3CR1/CX3CL1 that characterize MN-microglia cross talk contribute to synaptic scaling and maintenance, have been found altered in ALS. The presence of dystrophic and atypical microglia in late stages of ALS, with a decline in their dynamic motility and phagocytic ability, together with less synaptic and neuronal contacts disrupts the MN-microglia dialogue, decreases homeostatic regulation of neuronal activity, perturbs “on/off” signals and accelerates disease progression associated to impaired synaptic function and regeneration. Other hotspot in the ALS affected network system is the unstable neuromuscular junction (NMJ) leading to distal axonal degeneration. Reduced neuromuscular spontaneous synaptic activity in ALS mice models was also suggested to account for the selective vulnerability of MNs and decreased regenerative capability. Synaptic destabilization may as well derive from increased release of molecules by muscle cells (e.g. NogoA) and by terminal Schwann cells (e.g. semaphorin 3A) conceivably causing nerve terminal retraction and denervation, as well as inhibition of re-connection to muscle fibers. Indeed, we have overviewed the alterations on the metabolic pathways and self-regenerative capacity presented in skeletal muscle cells that contribute to muscle wasting in ALS. Finally, a detailed footpath of pathologic changes on MNs and associated dysfunctional and synaptic alterations is provided. The oriented motivation in future ALS studies as outlined in the present article will help in fruitful novel achievements on the mechanisms involved and in developing more target-driven therapies that will bring new hope in halting or delaying disease progression in ALS patients.

Alcohol addiction is a debilitating disorder producing maladaptive changes in the brain, leading drinkers to become more sensitive to stress and anxiety. These changes are key factors contributing to alcohol craving and maintaining a persistent vulnerability to relapse.

Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter widely expressed in the central nervous system where it plays an important role in the regulation of mood. The serotonin system has been extensively implicated in the regulation of stress and anxiety, as well as the reinforcing properties of all of the major classes of drugs of abuse, including alcohol. Dysregulation within the 5-HT system has been postulated to underlie the negative mood states associated with alcohol use disorders.

This review will describe the serotonergic (5-HTergic) neuroplastic changes observed in animal models throughout the alcohol addiction cycle, from prenatal to adulthood exposure. The first section will focus on alcohol-induced 5-HTergic neuroadaptations in offspring prenatally exposed to alcohol and the consequences on the regulation of stress/anxiety. The second section will compare alterations in 5-HT signalling induced by acute or chronic alcohol exposure during adulthood and following alcohol withdrawal, highlighting the impact on the regulation of stress/anxiety signalling pathways. The third section will outline 5-HTergic neuroadaptations observed in various genetically-selected ethanol preferring rat lines. Finally, we will discuss the pharmacological manipulation of the 5-HTergic system on ethanol- and anxiety/stress-related behaviours demonstrated by clinical trials, with an emphasis on current and potential treatments.

Inhibitory synapses on Purkinje cell somata in organotypic cerebellar cultures derived from newborn mice were increased after chronic exposure post explantation to agents that enhance neuronal activity. Inhibitory synaptogenesis was reduced in similar cultures after continuous blockade of spontaneous neuronal discharges. By contrast, excitatory synapses developed fully in the absence of neuronal activity. The reduction of inhibitory synaptogenesis was prevented by the simultaneous application of activity blocking agents and neurotrophins BDNF or NT-4, which are TrkB receptor ligands, but not with NT-3, a TrkC receptor ligand. The effect of endogenous neurotrophins was evaluated by continuously exposing cerebellar cultures to antibodies to BDNF and NT-4, which caused a significant reduction in the development of inhibitory Purkinje cell axosomatic synapses. These combined results indicated a role for TrkB receptors in activity-dependent inhibitory synaptogenesis. This concept was supported by the promotion of inhibitory synaptogenesis by specific antibody activation of TrkB receptors.

Adult hippocampal neurogenesis is modulated by physiological and pathological stimuli, including seizures and inflammation. Here, we describe stable interactions between microglia and newborn neurons using two-photon and confocal microscopy. On 3 weeks-old neurons, these interactions exhibit preferences for distal dendrites under physiological conditions. Conversely, after status epilepticus, ramified microglia, in particular, interact more with the proximal dendrites of new neurons. No such differences were found on 6 weeks-old neurons. Our study demonstrates regional and temporal specificity of the interactions between newborn neurons and microglia during a critical period for homeostasis and synaptic integration.

Background: The muscle representations in non-primary motor area (NPMA) are located in the dorsal premotor area (PMd) and in the border region between the premotor area and the supplementary motor area (SMA).

Objective: We characterized the plasticity of intracortical inhibitory and excitatory circuits in muscle representations in primary motor cortex (M1) and in NPMA related to acquired fine motor skills. We compared local cortical inhibition and facilitation balance in M1 and in NPMA between control subjects (n = 6) and right-handed string-instrument players (n = 5).

Methods: Navigated transcranial magnetic stimulation (TMS) was used to compare motor thresholds (MTs), motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in non-dominant hand muscle representations in M1 and NPMA.

Results: String-instrument players showed reduced SICI in M1 in the actively used left hand abductor digiti minimi (ADM) muscle representation at 3 ms inter-stimulus interval (ISI) with a conditioning stimulus (CS) intensity of 80% of MT and increased SICI in NPMA in ADM representation at 2 ms ISI and CS intensity of 50% of MT in comparison with controls. No differences between string-instrument players and controls were found for the SICI in the left hand opponens pollicis (OP) muscle representation, which is a muscle not intensively trained in string-instrument players.

Conclusions: These preliminary results indicate that the stronger inhibition in motor representations outside M1 in string-instrument players may be crucial when accurate movements of single muscles must be performed. In contrast, weaker inhibition in M1 in string-instrument players may benefit the performance of fast finger movements.