Neuronal Activity at Synapse Resolution:Reporters and Effectors for Synaptic Neuroscience

The development of methods for the activity-dependent tagging of neurons enabled a new way to tackle the problem of engram identification at the cellular level, giving rise to groundbreaking findings in the field of memory studies. However, the resolution of activity-dependent tagging remains limited to the whole-cell level. Notably, events taking place at the synapse level play a critical role in the establishment of new memories, and strong experimental evidence shows that learning and synaptic plasticity are tightly linked. Here, we provide a comprehensive review of the currently available techniques that enable to identify and track the neuronal activity with synaptic spatial resolution. We also present recent technologies that allow to selectively interfere with specific subsets of synapses. Lastly, we discuss how these technologies can be applied to the study of learning and memory

Abstinence-Induced Nicotine Seeking Relays on a Persistent Hypoglutamatergic State within the Amygdalo-Striatal Neurocircuitry

Nicotine robustly sustains smoking behavior by acting as a primary reinforcer and by enhancing the incentive salience of the nicotine-associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood. In here we used a contingent nicotine and saline control self-administration model to disentangle the contribution of cue-elicited seeking responding for nicotine after drug abstinence in male Wistar rats. Using ex vivo electrophysiological recordings and a network analysis approach, we defined temporal and brain-region specific amygdalo-striatal glutamatergic alterations that occur during nicotine abstinence. The results from this study provide critical evidence indicating a persistent hypoglutamatergic state within the amygdalo-striatal neurocircuitry over protracted nicotine abstinence. During abstinence-induced nicotine seeking, electrophysiological recordings showed progressive neuroadaptations in dorsal and ventral striatum already at 14-d abstinence while neuroadaptations in subregions of the amygdala emerged only after 28-d abstinence. The observed neuroadaptations pointed to a brain network involving the amygdala and the dorsolateral striatum (DLS) to be implied in cue-induced reinstatement of nicotine seeking. Together these data suggest long-lasting neuroadaptations that might reflect neuroplastic changes responsible to abstinence-induced nicotine craving. Neurophysiological transformations were detected within a time window that allows therapeutic intervention advancing clinical development of preventive strategies in nicotine addiction. </p

Distance education based on learning outcomes: designing a course in higher education

Il lavoro presenta un caso di progettazione didattica di un insegnamento universitario per learning outcome (LO) e la sua attuazione in modalità a distanza dovuta alla situazione sanitaria del 2020. I LO si configurano come risultati di apprendimento coerenti con gli sbocchi professionali prefigurati al momento della scelta universitaria. Il design del corso in modalità a distanza è stato guidato, nella sua progettazione e nella successiva realizzazione, da un approccio centrato su learning outcome, connessi agli obiettivi formativi declinati secondo i cinque descrittori di Dublino. L’articolo presenta inizialmente gli obiettivi del corso e le teorie pedagogiche e didattiche che hanno maggiormente orientato la scelta di metodi e strumenti utilizzati. Sono poi descritte le fasi di progettazione e attuazione del corso con particolare attenzione rivolta agli strumenti di verifica. Future piste di ricerca e di analisi sono discusse nelle conclusioni

Neuronal signature of spatial decision-making during navigation by freely moving rats using calcium imaging

A challenge in spatial memory is understanding how place cell firing contributes to decision-making in navigation. A spatial recency task was created in which freely moving rats first became familiar with a spatial context over several days and thereafter were required to encode and then selectively recall one of three specific locations within it that was chosen to be rewarded that day. Calcium imaging was used to record from more than 1,000 cells in area CA1 of the hippocampus of five rats during the exploration, sample, and choice phases of the daily task. The key finding was that neural activity in the startbox rose steadily in the short period prior to entry to the arena and that this selective population cell firing was predictive of the daily changing goal on correct trials but not on trials in which the animals made errors. Single-cell and population activity measures converged on the idea that prospective coding of neural activity can be involved in navigational decision-making

“Does isometric exercise improve leg stiffness and hop pain in subjects with Achilles tendinopathy? A feasibility study"

Background In Achilles tendinopathy (AT) the ability to store and recycle elastic energy during ground contact phase is often altered. A measure of this function is represented by leg stiffness (LS). Immediate responses in LS following therapeutic intervention have not been examined. Objective The aim of this paper was to examine the feasibility of the protocol in participants with AT. Design Single cohort feasibility study. Participants Adults with persistent AT pain, symptoms on palpation and less than 80 points on the Visa-A questionnaire. Intervention heavy isometric exercise sequence in plantarflexion Outcome Measures Feasibility was assessed by evaluating: the willingness of participants to enroll into the study, the number of eligible participants, the recruitment rate, adherence to the intervention, the drop-out rate, the tolerability of the protocol. LS, reactive strength index, pain and rate of perceived effort were secondary outcomes. Results 22 AT were eligible for data collection and 19 entered the statistical analysis. The intervention was well tolerated, no withdrawals. Pain scores were low during both the intervention and the assessment. Immediate improvements in LS and pain were recorded. Conclusions The isometric exercise protocol was feasible. Future research should investigate its effectiveness

Defining the Characteristics of Story Production of Autistic Children: A Multilevel Analysis

Several studies suggest that a valuable tool to examine linguistic skills in communication disorders is offered by procedures of narrative discourse assessment. Following this line of research, we present an exploratory study aimed to investigate storytelling abilities of autistic children to better define the characteristics of their story production. Participants included 41 autistic children and 41 children with typical development aged between 7.02 and 11.03 years matched on age, gender, level of formal education, intelligence quotient, working memory, attention skills, theory of mind, and phonological short-term memory. Narrative production was assessed by analysing the language samples obtained through the “Nest Story” description task. A multilevel analysis including micro- and macro-linguistic variables was adopted for narrative assessment. Group differences emerged on both micro- and macro-linguistic dimensions: autistic children produced narratives with more phonological errors and semantic paraphasias (microlinguistic variables) as well as more errors of global coherence and a fewer number of visible events and inferred events (macrolinguistic variables) than the control group.This study shows that even autistic children with adequate cognitive skills display several limitations in their narrative competence and that such weaknesses affect both micro- and macrolinguistic aspects of story production

Cell-type-specific optogenetic stimulation of the locus coeruleus induces slow-onset potentiation and enhances everyday memory in rats

Memory formation is typically divided into phases associated with encoding, storage, consolidation, and retrieval. The neural determinants of these phases are thought to differ. This study first investigated the impact of the experience of novelty in rats incurred at a different time, before or after, the precise moment of memory encoding. Memory retention was enhanced. Optogenetic activation of the locus coeruleus mimicked this enhancement induced by novelty, both when given before and after the moment of encoding. Optogenetic activation of the locus coeruleus also induced a slow-onset potentiation of field potentials in area CA1 of the hippocampus evoked by CA3 stimulation. Despite the locus coeruleus being considered a primarily noradrenergic area, both effects of such stimulation were blocked by the dopamine D1/D5 receptor antagonist SCH 23390. These findings substantiate and enrich the evidence implicating the locus coeruleus in cellular aspects of memory consolidation in hippocampus.</p

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo-electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase

Fast diffusing p75NTR monomers support apoptosis and growth cone collapse by neurotrophin ligands

The p75 neurotrophin (NT) receptor (p75NTR) plays a crucial role in balancing survival-versus-death decisions in the nervous system. Yet, despite 2 decades of structural and biochemical studies, a comprehensive, accepted model for p75NTR activation by NT ligands is still missing. Here, we present a single-molecule study of membrane p75NTR in living cells, demonstrating that the vast majority of receptors are monomers before and after NT activation. Interestingly, the stoichiometry and diffusion properties of the wild-type (wt) p75NTR are almost identical to those of a receptor mutant lacking residues previously believed to induce oligomerization. The wt p75NTR and mutated (mut) p75NTR differ in their partitioning in cholesterol-rich membrane regions upon nerve growth factor (NGF) stimulation: We argue that this is the origin of the ability of wt p75NTR , but not of mut p75NTR, to mediate immature NT (proNT)-induced apoptosis. Both p75NTR forms support proNT-induced growth cone retraction: We show that receptor surface accumulation is the driving force for cone collapse. Overall, our data unveil the multifaceted activity of the p75NTR monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature