Structural Plasticity Research Articles

Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility.

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2 mgkg-1 (±)-DOI. We then demonstrate lasting effects of (±)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2 mgkg-1 (±)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (±)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (±)-DOI's effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (±)-DOI's facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.

Loss of synaptopodin impairs mGluR5 and protein synthesis-dependent mGluR-LTD at CA3-CA1 synapses.

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is an important form of synaptic plasticity that occurs in many regions of the central nervous system and is the underlying mechanism for several learning paradigms. In the hippocampus, mGluR-LTD is manifested by the weakening of synaptic transmission and elimination of dendritic spines. Interestingly, not all spines respond or undergo plasticity equally in response to mGluR-LTD. A subset of dendritic spines containing synaptopodin (SP), an actin-associated protein is critical for mGluR-LTD and protects spines from elimination through mGluR1 activity. The precise cellular function of SP is still enigmatic and it is still unclear how SP contributes to the functional aspect of mGluR-LTD despite its modulation of the structural plasticity. In this study, we show that the lack of SP impairs mGluR-LTD by negatively affecting the mGluR5-dependent activity. Such impairment of mGluR5 activity is accompanied by a significant decrease of surface mGluR5 level in SP knockout (SPKO) mice. Intriguingly, the remaining mGluR-LTD becomes a protein synthesis-independent process in the SPKO and is mediated instead by endocannabinoid signaling. These data indicate that the postsynaptic protein SP can regulate the locus of expression of mGluR-LTD and provide insight into our understanding of spine/synapse-specific plasticity.

Another ghost of Gondwana—Progradungula barringtonensis Michalik & Smith, sp. nov., a new species of the relict spider genus Progradungula (Araneae: Gradungulidae) from a temperate rainforest in eastern Australia

AbstractOdd‐clawed spiders (Gradungulinae), which are considered to be ‘living fossils’, are a faunal element of the mesic forests of eastern Australia and the South Island of New Zealand. To date, 16 species in seven genera are known, with most being highly endemic and hard to find, explaining their scarcity in collections worldwide. Particularly noteworthy is the Australian genus Progradungula that includes only two relict species from eastern Australia (Progradungula carraiensis from the Carrai limestone caves in northern New South Wales and Progradungula otwayensis from Nothofagus rainforests in the Otway Range, southern Victoria) and are known from only a handful of adult specimens. Both species are large nocturnal predators with a rather cryptic lifestyle, which construct unique ladder‐like catching webs composed of non‐combed and combed cribellate silk with exceptional properties. Here, we describe a new relict species, Progradungula barringtonensis Michalik & Smith, sp. nov., from isolated Nothofagus forest patches in Barrington Tops National Park (NSW, Australia). The male of this species is significantly larger than those of P. carraiensis and P. otwayensis and exhibits characteristics of the male genitalia of both species. The webs are similar to those of the other Progradungula species. Field observations revealed that the catching ladder had few looping segments, similar to P. otwayensis, but an immature in captivity constructed webs with more looping segments, similar to P. carraiensis, supporting the previously proposed hypothesis that food availability may explain the plasticity of the catching ladder structure.

Long-term olfactory enrichment promotes non-olfactory cognition, noradrenergic plasticity and remodeling of brain functional connectivity in older mice

Brain functional and structural changes lead to cognitive decline during aging, but a high level of cognitive stimulation during life can improve cognitive performances in the older adults, forming the cognitive reserve. Noradrenaline has been proposed as a molecular link between environmental stimulation and constitution of the cognitive reserve. Taking advantage of the ability of olfactory stimulation to activate noradrenergic neurons of the locus coeruleus, we used repeated olfactory enrichment sessions over the mouse lifespan to enable the cognitive reserve buildup. Mice submitted to olfactory enrichment, whether started in early or late adulthood, displayed improved olfactory discrimination at late ages and interestingly, improved spatial memory and cognitive flexibility. Moreover, olfactory and non-olfactory cognitive performances correlated with increased noradrenergic innervation in the olfactory bulb and dorsal hippocampus. Finally, c-Fos mapping and connectivity analysis revealed task-specific remodeling of functional neural networks in enriched older mice. Long-term olfactory enrichment thus triggers structural noradrenergic plasticity and network remodeling associated with better cognitive aging and thereby forms a promising mouse model of the cognitive reserve buildup.

Leaf drought adaptive response in winter oilseed rape is altered at the onset of senescence: a study combining NMR relaxometry, multi-omics and microscopy.

Climate change is bringing more frequent and intense droughts, reducing overall water availability and adversely affecting crops. There is a need to improve our understanding of the tissular and cellular adaptation mechanisms that are critical for plant water conservation strategies. Here, we have used NMR relaxometry in combination with microscopy and multi-omic analysis to study the effects of progressive soil drought on winter oilseed rape (WOSR, Brassica napus L., cv. Aviso) leaves. This study reveals the structural and metabolic adjustments these leaves operate to maintain cell homeostasis. Our results are original in showing that the adaptive responses are altered in leaves at the onset of senescence, associated with changes in metabolic plasticity and mesophyll structures. Thus, long-term responses in young leaves involving osmotic adjustment were combined with the maintenance of tissue hydration and cell growth, contributing to high survival and recovery capacity. For the first time, short-term responses observed in early senescent-old leaves were associated with early drought-induced dehydration of the spongy layer. However, this dehydration was not followed by osmotic adjustment and did not allow maintenance of leaf tissue turgor. These findings open further studies on the genetic variability of drought responses related to identified short- and long-term structural and metabolic plasticity traits in Brassica species.

Neuroadaptive Tracking Control of Affine Nonlinear Systems Using Echo State Networks Embedded With Multiclustered Structure and Intrinsic Plasticity.

In this article, we present an echo state network (ESN)-based tracking control approach for a class of affine nonlinear systems. Different from the most existing neural-network (NN)-based control methods that are focused on the feedforward NN, the proposed method adopts a bioinspired recurrent NN fusing with multiple cluster and intrinsic plasticity (IP) to deal with modeling uncertainties and coupling nonlinearities in the systems. The key features of this work can be summarized as follows: 1) the proposed control is built upon the ESN embedded with multiclustered reservoir inspired from the hierarchically clustered organizations of cortical connections in mammalian brains; 2) the developed neuroadaptive control scheme utilizes unsupervised learning rules inspired from the neural plasticity mechanism of the individual neuron in nervous systems, called IP; 3) a multiclustered reservoir with IP is integrated into the algorithm to enhance the approximation performance of NN; and 4) the multiclustered reservoir is constructed offline and is task-independent, rendering the proposed method less expensive in computation. The effectiveness of the method is also confirmed by comparison with the existing neuroadaptive methods via numerical simulations, demonstrating that better tracking precision is achieved by the proposed method.

Bilingual Spatial Cognition: Spatial Cue Use in Bilinguals and Monolinguals.

Structural plasticity changes and functional differences in executive control tasks have been reported in bilinguals compared to monolinguals, supporting a proposed bilingual 'advantage' in executive control functions (e.g., task switching) due to continual usage of control mechanisms that inhibit one of the coexisting languages. However, it remains unknown whether these differences are also apparent in the spatial domain. The present fMRI study explores the use of spatial cues in 15 bilinguals and 14 monolinguals while navigating in an open-field virtual environment. In each trial, participants had to navigate towards a target object that was visible during encoding but hidden in retrieval. An extensive network was activated in bilinguals compared to monolinguals in the encoding and retrieval phase. During encoding, bilinguals activated the right temporal and left parietal regions (object trials) and left inferior frontal, precentral, and lingual regions more than monolinguals. During retrieval, the same contrasts activated the left caudate nucleus and the right dorsolateral prefrontal cortex (DLPFC), the left parahippocampal gyrus, as well as caudate regions. These results suggest that bilinguals may recruit neural networks known to subserve not only executive control processes but also spatial strategies.

Seismic Performance of U-Shaped Connection for Prefabricated Steel Plate Shear Wall

In this investigation, a U-shaped connection (U-C) was introduced for a prefabricated steel plate shear wall with beam-only connections. This design replaces a portion of shear bolts with tension bolts to enhance bolt efficiency and reduce the overall bolt count, and it is suitable for a prefabricated high-rise steel structure. Four 1/3 scale specimens were designed, and an array of performance aspects including failure modes, hysteretic behavior, skeleton curves, energy dissipation capacity, stiffness degradation, and key performance indicators were systematically investigated through a combination of quasi-static tests and finite element analyses. The results showed that the combination arrangement of tensile and shear bolts in U-C effectively reduced the usage of bolts used and reduced installation costs; under low cycle reciprocating loads, the ultimate bearing capacity and energy dissipation capacity of a beam-only-connected prefabricated steel plate shear wall with U-shaped connection (BPSW-U) had slightly decreased compared with the prefabricated steel plate shear wall with discontinuous cover-plate connection (DCPC). Nevertheless, the BPSW-U excelled in preserving the integrity of the frame beams, channeling structural plastic deformations primarily into the infilled steel plate. This design feature ensures that post-earthquake functionality recovery can be achieved by simply replacing the infilled steel plate.

Divergent Learning-Related Transcriptional States of Cortical Glutamatergic Neurons.

Experience-dependent gene expression reshapes neural circuits, permitting the learning of knowledge and skills. Most learning involves repetitive experiences during which neurons undergo multiple stages of functional and structural plasticity. Currently, the diversity of transcriptional responses underlying dynamic plasticity during repetition-based learning is poorly understood. To close this gap, we analyzed single-nucleus transcriptomes of L2/3 glutamatergic neurons of the primary motor cortex after 3 d motor skill training or home cage control in water-restricted male mice. "Train" and "control" neurons could be discriminated with high accuracy based on expression patterns of many genes, indicating that recent experience leaves a widespread transcriptional signature across L2/3 neurons. These discriminating genes exhibited divergent modes of coregulation, differentiating neurons into discrete clusters of transcriptional states. Several states showed gene expressions associated with activity-dependent plasticity. Some of these states were also prominent in the previously published reference, suggesting that they represent both spontaneous and task-related plasticity events. Markedly, however, two states were unique to our dataset. The first state, further enriched by motor training, showed gene expression suggestive of late-stage plasticity with repeated activation, which is suitable for expected emergent neuronal ensembles that stably retain motor learning. The second state, equally found in both train and control mice, showed elevated levels of metabolic pathways and norepinephrine sensitivity, suggesting a response to common experiences specific to our experimental conditions, such as water restriction or circadian rhythm. Together, we uncovered divergent transcriptional responses across L2/3 neurons, each potentially linked with distinct features of repetition-based motor learning such as plasticity, memory, and motivation.

Static magnetic stimulation induces structural plasticity at the axon initial segment of inhibitory cortical neurons

Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that alters neural activity and induces neural plasticity that outlasts the period of stimulation. This can modify corticospinal excitability or motor behaviours, suggesting that SMS may alter the intrinsic excitability of neurons. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity (changes in length and position from the soma) as a homeostatic mechanism to counteract chronic changes in neuronal activity. We investigated whether the chronic application of SMS (6 and 48 h, 0.5 T) induces structural AIS plasticity in postnatally derived primary cortical neurons. Following 6 h of SMS, we observed a shortening in mean AIS length compared to control, that persisted 24 h post stimulation. In contrast, 48 h of SMS induced an immediate distal shift that persisted 24 h post-stimulation. Pharmacological blockade of voltage gated L/T-type calcium channels during stimulation did not prevent SMS-induced AIS structural plasticity. Our findings provide the foundation to expand the use of chronic SMS as a non-invasive method to promote AIS plasticity.

Experience shapes chandelier cell function and structure in the visual cortex

Detailed characterization of interneuron types in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells (ChCs) in visual processing remains poorly characterized. Using viral tracing we found that V1 ChCs predominantly receive monosynaptic input from local layer 5 pyramidal cells and higher-order cortical regions. Two-photon calcium imaging and convolutional neural network modeling revealed that ChCs are visually responsive but weakly selective for stimulus content. In mice running in a virtual tunnel, ChCs respond strongly to events known to elicit arousal, including locomotion and visuomotor mismatch. Repeated exposure of the mice to the virtual tunnel was accompanied by reduced visual responses of ChCs and structural plasticity of ChC boutons and axon initial segment length. Finally, ChCs only weakly inhibited pyramidal cells. These findings suggest that ChCs provide an arousal-related signal to layer 2/3 pyramidal cells that may modulate their activity and/or gate plasticity of their axon initial segments during behaviorally relevant events.

Experience shapes chandelier cell function and structure in the visual cortex.

Detailed characterization of interneuron types in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells (ChCs) in visual processing remains poorly characterized. Using viral tracing we found that V1 ChCs predominantly receive monosynaptic input from local layer 5 pyramidal cells and higher-order cortical regions. Two-photon calcium imaging and convolutional neural network modeling revealed that ChCs are visually responsive but weakly selective for stimulus content. In mice running in a virtual tunnel, ChCs respond strongly to events known to elicit arousal, including locomotion and visuomotor mismatch. Repeated exposure of the mice to the virtual tunnel was accompanied by reduced visual responses of ChCs and structural plasticity of ChC boutons and axon initial segment length. Finally, ChCs only weakly inhibited pyramidal cells. These findings suggest that ChCs provide an arousal-related signal to layer 2/3 pyramidal cells that may modulate their activity and/or gate plasticity of their axon initial segments during behaviorally relevant events.

Interaction modes of human orexin 2 receptor with selective and nonselective antagonists studied by NMR spectroscopy

Orexin neuropeptides have many physiological roles in the sleep-wake cycle, feeding behavior, reward demands, and stress responses by activating cognitive receptors, the orexin receptors (OX1R and OX2R), distributed in the brain. There are only subtle differences between OX1R and OX2R in the orthosteric site, which has hindered the rational development of subtype-selective antagonists. In this study, we utilized solution-state NMR to capture the structural plasticity of OX2R labeled with 13CH3-ε-methionine in complex with antagonists. Mutations in the orthosteric site allosterically affected the intracellular tip of TM6. Ligand exchange experiments with the subtype-selective EMPA and the nonselective suvorexant identified three methionine residues that were substantially perturbed. The NMR spectra suggested that the suvorexant-bound state exhibited more structural plasticity than the EMPA-bound state, which has not been foreseen from the close similarity of their crystal structures, providing insights into dynamic features to be considered in understanding the ligand recognition mode.

Real-time visualization of structural dynamics of synapses in live cells in vivo.

The structural plasticity of synapses is crucial for regulating brain functions. However, currently available methods for studying synapse organization based on split fluorescent proteins (FPs) have been limited in assessing synaptic dynamics in vivo due to the irreversible binding of split FPs. Here, we develop 'SynapShot', a method for visualizing the structural dynamics of intact synapses by combining dimerization-dependent FPs (ddFPs) with engineered synaptic adhesion molecules. SynapShot allows real-time monitoring of reversible and bidirectional changes of synaptic contacts under physiological stimulation. The application of green and red ddFPs in SynapShot enables simultaneous visualization of two distinct populations of synapses. Notably, the red-shifted SynapShot is highly compatible with blue light-based optogenetic techniques, allowing for visualization of synaptic dynamics while precisely controlling specific signaling pathways. Furthermore, we demonstrate that SynapShot enables real-time monitoring of structural changes in synaptic contacts in the mouse brain during both primitive and higher-order behaviors.

Altered Protein Dynamics and a More Reactive Catalytic Cysteine in a Neurodegeneration-associated UCHL1 Mutant

A mutant of ubiquitin C-terminal hydrolase L1 (UCHL1) detected in early-onset neurodegenerative patients, UCHL1R178Q, showed higher catalytic activity than wild-type UCHL1 (UCHL1WT). Lying within the active-site pocket, the arginine is part of an interaction network that holds the catalytic histidine in an inactive arrangement. However, the structural basis and mechanism of enzymatic activation upon glutamine substitution was not understood. We combined X-ray crystallography, protein nuclear magnetic resonance (NMR) analysis, enzyme kinetics, covalent inhibition analysis, and biophysical measurements to delineate activating factors in the mutant. While the crystal structure of UCHL1R178Q showed nearly the same arrangement of the catalytic residues and active-site pocket, the mutation caused extensive alteration in the chemical environment and dynamics of more than 30 residues, some as far as 15 Å away from the site of mutation. Significant broadening of backbone amide resonances in the HSQC spectra indicates considerable backbone dynamics changes in several residues, in agreement with solution small-angle X-ray scattering (SAXS) analyses which indicate an overall increase in protein flexibility. Enzyme kinetics show the activation is due to a kcat effect despite a slightly weakened substrate affinity. In line with this, the mutant shows a higher second-order rate constant (kinact/Ki) in a reaction with a substrate-derived irreversible inhibitor, Ub-VME, compared to the wild-type enzyme, an observation indicative of a more reactive catalytic cysteine in the mutant. Together, the observations underscore structural plasticity as a factor contributing to enzyme kinetic behavior which can be modulated through mutational effects.

Structural biases in disordered proteins are prevalent in the cell

Intrinsically disordered proteins and protein regions (IDPs) are prevalent in all proteomes and are essential to cellular function. Unlike folded proteins, IDPs exist in an ensemble of dissimilar conformations. Despite this structural plasticity, intramolecular interactions create sequence-specific structural biases that determine an IDP ensemble’s three-dimensional shape. Such structural biases can be key to IDP function and are often measured in vitro, but whether those biases are preserved inside the cell is unclear. Here we show that structural biases in IDP ensembles found in vitro are recapitulated inside human-derived cells. We further reveal that structural biases can change in a sequence-dependent manner due to changes in the intracellular milieu, subcellular localization, and intramolecular interactions with tethered well-folded domains. We propose that the structural sensitivity of IDP ensembles can be leveraged for biological function, can be the underlying cause of IDP-driven pathology or can be used to design disorder-based biosensors and actuators.

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis.

Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines ( Il1β, Tnfα, and Ifnγ) and glial cell markers ( Gfap and Cd68) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

Imaging of Structural Plasticity of Dendritic Spines with Two-Photon Microscopy.

Plasticity of synaptic transmission underlies learning and memory. It is accompanied by changes in the density and size of synapses, collectively called structural plasticity. Therefore, understanding the mechanism of structural plasticity is critical for understanding the mechanism of synaptic plasticity. In this chapter, we describe the procedures and equipment required to image structural plasticity of a single dendritic spine, which hosts excitatory synapses in the central nervous system, and underlying molecular interactions/biochemical reactions using two-photon fluorescence lifetime microscopy (2P-FLIM) in combination with Förster resonance energy transfer (FRET)-based biosensors.

Towards a structural and functional analysis of the immunoglobulin-fold proteome.

The immunoglobulinfold (Igfold) domain is a super-secondary structural motif consisting of a sandwich with two layers of β-sheets that is present in many proteins with very diverse biological functions covering a wide range of physiological processes. This domain presents a modular architecture built with β strands connected by variable length loops that has a highly conserved structural core of four β-strands and quite variable β-sheet extensions in the two sandwich layers that enable both divergent and convergent evolutionary mechanisms in the known Igfold proteome. The central role of this Igfold's structural plasticity in the evolutionary success of antibodies in our immune system is well established. Nature has also utilized this Igfold in all domains of life in many different physiological contexts that go way beyond the immune system. Here we will present a structural and functional overview of the utilization of the Igfold in different biological processes and in different cellular contexts to highlight some of the innumerable ways that this structural motif can interact in multidomain proteins to enable their diversity of functions. This includes shareable specific protein structure visualizations behind those functions that serve as starting points for further explorations of the biomolecular interactions spanning the Igfold proteome. This overview also highlights how this Igfold is being utilized through natural adaptation, engineering, and even building from scratch for a range of biotechnological applications.

Interplay between intrinsic flexibility and sugar coating in Contactin-2 homodimerization

In this issue of Structure, Chataigner etal. reveal that Contactin-2's homotypic interaction, a glycosylation-dependent process, generates a broad conformational landscape. This structural plasticity, driven by conformational equilibria and sugar coating, facilitates adaptation to diverse ligands and environmental conditions, highlighting its dynamic role in neuronal function.