Molecular Mechanisms Of Plasticity Research Articles

The molecular mechanisms of plasticity in crystal forms of theophylline

Plastic and elastic behaviors of organic crystals have profound influence on the processability of pharmaceutical substances. Analogous to metals, the identifications of molecular slip planes in organic crystals are regarded as a strategy for harnessing plasticity. In this work, we experimentally characterized the form II anhydrous theophylline (THPa) and its monohydrate (THPm) for their distinct plastic and elastic behaviors. Extensive DFT calculations were performed to model the effects of increasing lattice strains on molecular packing. We discovered that the energy barrier associated with the strain-induced molecular rearrangement would link to the plasticity of THPa, and possibly other simple aromatic compounds. Meanwhile, water molecules in THPm disrupt the stacking architecture from THPm and effectively undermine the general mechanism for plasticity. Hydrate formation would therefore be an alternative strategy to engineer the mechanical property of organic crystalline materials.

Torpor versus interbout arousal: what is more important for protein metabolism and regeneration?

Hibernation is used by specie as diverse as ground squirrels, snakes and bats to cope with reduced food availability and lowered temperatures and is a unique model for studying the molecular mechanisms of plasticity in striated muscles. Important questions in modern muscle biology are why some skeletal muscles atrophy and other muscles such as the diaphragm and the heart hypertrophy during hibernation, and why, despite the atrophy, skeletal muscle strength and fatigue resistance are maintained after arousal. The molecular mechanisms responsible are of interest both from a fundamental biological viewpoint and as a potential therapy for patients in critical care units. In this issue of Experimental Physiology, Yan et al. (2021) shed light on the distinctive features of the molecular mechanisms involved in the development of the hypertrophic response in the diaphragm and the atrophic response in the gastrocnemius muscle in hibernating Daurian ground squirrels. In particular, the authors showed that a decrease in protein synthesis, an increase in protein degradation and a decrease in muscle regeneration potential contributed to the atrophy of the gastrocnemius muscles during torpor, while an increase in protein synthesis, a decrease in protein degradation and an increase in muscle regeneration potential contributed to diaphragm muscle hypertrophy. In discussing these new and interesting results, it can be assumed, however, that a significant contribution to the formation of hypertrophic or atrophic muscle phenotype could have been made by changes in anabolic and catabolic processes occurring in interbout arousals, as indicated by the results of recent studies (Chang et al., 2020; Popova et al., 2020 ). Further research is needed to show how important interbout arousals are in the regulation of protein turnover and regeneration in different striated muscles in hibernating animals. Understanding these and other molecular mechanisms is important for choosing strategies and methods for treatment of skeletal muscle pathologies and diseases of the cardiovascular system, as well as for avoiding injurious interventions in cases of energy deficits in critical illness (Stanzani et al., 2020). None declared.

Expression of brain‐derived neurotrophic factor and structural plasticity in the dentate gyrus and CA2 region correlate with epileptiform activity

Hippocampal sclerosis is a hallmark of mesial temporal lobe epilepsy (MTLE), comprising gliosis and neuronal loss in the hippocampus. However, dentate granule cells and CA2 pyramidal cells (PCs) survive, as they share physiological characteristics that may render them less sensitive to hyperexcitation in MTLE. Here, we asked whether both engage similar molecular plasticity mechanisms to support their resilience in MTLE. We chose brain-derived neurotrophic factor (BDNF), correlated the expression with activity, and used neuropeptide Y (NPY) and principal cell dispersion as plasticity readout. Adult male mice received a unilateral intrahippocampal kainate injection to induce status epilepticus (SE) and bilateral electrodes into the dentate gyrus and CA2 for in vivo recordings and quantification of epileptiform activity. To assess the time course of Bdnf mRNA expression in these regions, we performed fluorescence in situ hybridization, complemented by immunohistochemistry for NPY and quantification of principal cell dispersion. We show that Bdnf expression was transiently up-regulated during SE in the granule cell layer (GCL) and CA2 and, after a slight reduction at 2 days, increased persistently in both regions ipsilaterally. Intrahippocampal recordings revealed a threshold for the duration of SE to induce these changes. Recurrent epileptiform activity developed in the ipsilateral dentate gyrus and CA2 over time and was correlated with Bdnf mRNA levels, although more pronounced in the dentate gyrus. The dispersion of the GCL and CA2 correlated with Bdnf mRNA expression. NPY protein expression was only increased in granule cells and mossy fibers, remaining unchanged in CA2. Our study reveals differential molecular plasticity changes in granule cells and CA2 PCs despite many similarities (epileptiform activity, somatic mossy fiber input, dispersion). These findings contribute to the understanding of common as well as individual characteristics of the cell populations underlying the epileptic hippocampal network.

Cortico-hippocampal Schemas Enable NMDAR-Independent Fear Conditioning in Rats

The neurobiology of memory formation has been studied primarily in experimentally naive animals, but the majority of learning unfolds on a background of prior experience. Considerable evidence now indicates that the brain processes initial and subsequent learning differently. In rodents, a first instance of contextual fear conditioning requires NMDA receptor (NMDAR) activation in the dorsal hippocampus, but subsequent conditioning to another context does not. This shift may result from a change in molecular plasticity mechanisms or in the information required to learn the second task. To clarify how related events are encoded, it is critical to identify which aspect of a first task engages NMDAR-independent learning and the brain regions that maintain this state. Here, we show in rats that the requirement for NMDARs in hippocampus depends neither on prior exposure to context nor footshock alone but rather on the procedural similarity between two conditioning tasks. Importantly, NMDAR-independent learning requires the memory of the first task to remain hippocampus dependent. Furthermore, disrupting memory maintenance in the anterior cingulate cortex after the first task also reinstates NMDAR dependency. These results reveal cortico-hippocampal interactions supporting experience-dependent learning.

Electroconvulsive seizures influence dendritic spine morphology and BDNF expression in a neuroendocrine model of depression

BackgroundElectroconvulsive therapy (ECT) is a rapid and effective treatment for major depressive disorder. Chronic stress-induced depression causes dendrite atrophy and deficiencies in brain-derived neurotrophic factor (BDNF), which are reversed by anti-depressant drugs. Electroconvulsive seizures (ECS), an animal model of ECT, robustly increase BDNF expression and stimulate dendritic outgrowth. ObjectiveThe present study aims to understand cellular and molecular plasticity mechanisms contributing to the efficacy of ECS following chronic stress-induced depression. MethodsWe quantify Bdnf transcript levels and dendritic spine density and morphology on cortical pyramidal neurons in mice exposed to vehicle or corticosterone and receiving either Sham or ECS treatment. ResultsECS rescues corticosterone-induced defects in spine morphology and elevates Bdnf exon 1 and exon 4-containing transcripts in cortex. ConclusionsDendritic spine remodeling and induction of activity-induced BDNF in the cortex represent important cellular and molecular plasticity mechanisms underlying the efficacy of ECS for treatment of chronic stress-induced depression.

Introduction to the special section on new ideas about cerebellar function.

Richard Thompson's seminal contributions to neuroscience include the discovery of the cerebellar interpositus nucleus as the site of essential plasticity in the formation of the conditioned eyeblink response. In this section, context for this body of research is provided, as well as new findings on cerebellar function using a range of procedures. Current work on the role of the cerebellum in learning and memory include studies of the cellular and molecular mechanisms of plasticity in cortex and deep nuclei, as well as functional magnetic resonance imaging studies in humans. Together, these papers provide a glimpse into new directions in the study of cerebellum and cognition. (PsycINFO Database Record

Molecular and neuronal plasticity mechanisms in the amygdala-prefrontal cortical circuit: implications for opiate addiction memory formation.

The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related “trigger” memories that may persist for lengthy periods of time, even during abstinence, in both humans, and other animals. Furthermore, the transitional switch from the drug-naïve, non-dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall, and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway's ventral tegmental area (VTA) and nucleus accumbens (NAc) and can modulate dopamine (DA) transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modeling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory-related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK) and the Ca2+/calmodulin-dependent protein kinases (CaMK). Evidence will be reviewed that points to the importance of critical molecular memory switches within the mammalian brain that might mediate the neuropathological adaptations resulting from chronic opiate exposure, dependence, and withdrawal.

Brain structural and functional development: genetics andexperience.

Brain development is the result of the combined work of genes and environment. In this paper we first briefly discuss how, in terms of cellular and molecular plasticity mechanisms, the richness of early environment can control developmental trajectories and can induce long-term changes in neural circuits that underlie enduring changes in brain structure and function. We then see that experience most effectively moulds neural circuit development during specific time windows called critical periods. After the closure of these privileged windows for plasticity, it is very difficult to promote repair from 'errors' in brain development. As an example, congenital cataracts, refractive defects, or strabismus, if not precociously corrected during development, cause permanent deficit in visual acuity of the affected eye, a condition known as amblyopia. Little or no recovery from amblyopia is possible in the adult. However, recent results show that by using protocols of enriched environment it is possible to design interventions, which, by acting on specific plasticity factors, enhance adult cortical plasticity and allow recovery from amblyopia. This suggests that a better knowledge of how experience and environment engage endogenous plasticity factors could help to design interventions aimed at promoting recovery from neurodevelopmental defects, even after the end of critical periods.

Linking conceptual mechanisms and transcriptomic evidence of plasticity‐driven diversification

The East African cichlid fishes provide text book examples of adaptive radiation. Diversification and speciation of cichlids associate with variation in diet and trophic morphologies among other ecological, behavioural and morphological phenotypes (Kocher 2004). Numerous case studies in cichlids reveal a role of developmental plasticity in generating jaw ecomorphs in response to variation in feeding ecology that can facilitate niche exploitation and subsequent diversification (e.g. Meyer 1987). Specifically, genetic divergence among such environmentally induced morphs can occur via reproductive isolation due to divergence in habitat and resource use in combination with genetic assimilation of environmentally induced phenotypes (West-Eberhard 2003; Pfennig et al. 2010). Expansion of this conceptual model has been hampered in part by the limited knowledge of the molecular mechanisms of plasticity in nonstandard model systems and the associated lack of evidence linking the molecular mechanisms of plasticity to those that generate phenotypic divergence among populations and taxa. In this issue of Molecular Ecology, Gunter et al. (2013) identify the transcriptional mechanisms of diet-induced lower pharyngeal jaw (LPJ) plasticity in the cichlid fish Astatoreochromis alluaudi. Natural populations of A. alluaudi exhibit variation in jaw morphology in relation to diet hardness. Among the plastic responses to diet are adjustments to the LPJ ranging from a robust molariform morph in response to a hard diet to a more gracile papilliform morph in response to a soft diet (Fig. 1). Gunter and colleagues induced developmental plasticity of the A. alluaudi jaw using diet manipulations and compared LPJ transcriptomic profiles of the resulting morphs. In this foundational work, the authors identify 187 differentially expressed genes that underlie the development and maintenance of diet-induced LPJ morphologies. This list includes a wide range of genes spanning from broad-acting transcription factors to signalling molecules and structural genes. Here, I examine the ontogeny of the molecular response to mechanical strain imposed by diet hardness and discuss the role of the stages of this response in the evolution of plasticity and plasticity-driven diversification.

Extracellular Signal-regulated Kinase and Glycogen Synthase Kinase 3β Regulate Gephyrin Postsynaptic Aggregation and GABAergic Synaptic Function in a Calpain-dependent Mechanism

Molecular mechanisms of plasticity at GABAergic synapses are currently poorly understood. To identify signaling cascades that converge onto GABAergic postsynaptic density proteins, we performed MS analysis using gephyrin isolated from rat brain and identified multiple novel phosphorylation and acetylation residues on gephyrin. Here, we report the characterization of one of these phosphoresidues, Ser-268, which when dephosphorylated leads to the formation of larger postsynaptic scaffolds. Using a combination of mutagenesis, pharmacological treatment, and biochemical assays, we identify ERK as the kinase phosphorylating Ser-268 and describe a functional interaction between residues Ser-268 and Ser-270. We further demonstrate that alterations in gephyrin clustering via ERK modulation are reflected by amplitude and frequency changes in miniature GABAergic postsynaptic currents. We unravel novel mechanisms for activity- and ERK-dependent calpain action on gephyrin, which are likely relevant in the context of cellular signaling affecting GABAergic transmission and homeostatic synaptic plasticity in pathology.

Neuroplasticity: An Appreciation From Synapse to System

Gillick BT, Zirpel L. Neuroplasticity: an appreciation from synapse to system. ObjectiveTo integrate our functional knowledge in neurorehabilitation with a greater understanding of commonly held theories and current research in neuroplasticity. DesignLiterature review. SettingNot applicable. ParticipantsAnimal and human research. InterventionsInterventions specific to application in humans: constraint-induced movement therapy, transcranial magnetic stimulation, and transcranial direct current stimulation. Main Outcome MeasuresCortical excitability, blood oxygen level–dependent signal, and functional outcomes. ResultsThere is increasing evidence elucidating the cellular and molecular mechanisms of plasticity of the nervous system including growth, modification, degradation, and even death of neurons. Some of these mechanisms directly correlate with therapy-induced behavioral changes, and all provide an understanding of the response of the nervous system to altered inputs. The understanding of neural correlates of behavior can then form the foundation for more productive, comprehensive interventions. ConclusionsThe focus of recent research surrounds translational projects aimed at enhancing clinical outcomes. Knowledge of mechanisms underlying this adaptability is the foundation for our treatments, diagnoses, and prognoses. The increasing understanding of the mechanisms underlying neuroplasticity can guide, direct, and focus the practice of current and future therapies to greater efficacy and better functional outcomes in clinical rehabilitation.

Recovery from Retinal Lesions: Molecular Plasticity Mechanisms in Visual Cortex Far beyond the Deprived Zone

In cats with central retinal lesions, deprivation of the lesion projection zone (LPZ) in primary visual cortex (area 17) induces remapping of the cortical topography. Recovery of visually driven cortical activity in the LPZ involves distinct changes in protein expression. Recent observations, about molecular activity changes throughout area 17, challenge the view that its remote nondeprived parts would not be involved in this recovery process. We here investigated the dynamics of the protein expression pattern of remote nondeprived area 17 triggered by central retinal lesions to explore to what extent far peripheral area 17 would contribute to the topographic map reorganization inside the visual cortex. Using functional proteomics, we identified 40 proteins specifically differentially expressed between far peripheral area 17 of control and experimental animals 14 days to 8 months postlesion. Our results demonstrate that far peripheral area 17 is implicated in the functional adaptation to the visual deprivation, involving a meshwork of interacting proteins, operating in diverse pathways. In particular, endocytosis/exocytosis processes appeared to be essential via their intimate correlation with long-term potentiation and neurite outgrowth mechanisms.

Presynaptic development at L4 to l2/3 excitatory synapses follows different time courses in visual and somatosensory cortex.

Visual and somatosensory cortices exhibit profound experience-dependent plasticity during development and adulthood and are common model systems for probing the synaptic and molecular mechanisms of plasticity. However, comparisons between the two areas may be confounded by a lack of accurate information on their relative rates of development. In this study, we used whole-cell recording in acute brain slices to study synaptic development in mouse barrel and visual cortex. We found that short-term plasticity (STP) switched from strong depression at postnatal day (P)12 to weaker depression and facilitation in mature cortex. However, presynaptic maturation was delayed by ∼2 weeks at layer (L)4 to L2/3 excitatory synapses in visual cortex relative to barrel cortex. This developmental delay was pathway-specific; maturation of L2/3 to L2/3 synapses occurred over similar timescales in barrel and visual cortex. The developmental increase in the paired-pulse ratio to values greater than unity was mirrored by a developmental decrease in presynaptic release probability. Therefore, L4 to L2/3 excitatory synapses had lower release probabilities and showed greater short-term facilitation in barrel cortex than in visual cortex at P28. Postsynaptic mechanisms could not account for the delayed maturation of STP in visual cortex. These findings indicate that synaptic development is delayed in the L4 to L2/3 pathway in visual cortex, and emphasize the need to take into account the changes in synaptic properties that occur during development when comparing plasticity mechanisms in different cortical areas.

Inducible molecular switches for the study of long-term potentiation.

This article reviews technical and conceptual advances in unravelling the molecular bases of long-term potentiation (LTP), learning and memory using genetic approaches. We focus on studies aimed at testing a model suggesting that protein kinases and protein phosphatases balance each other to control synaptic strength and plasticity. We describe how gene 'knock-out' technology was initially exploited to disrupt the Ca(2+)/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) gene and how refined knock-in techniques later allowed an analysis of the role of distinct phosphorylation sites in CaMKII. Further to gene recombination, regulated gene expression using the tetracycline-controlled transactivator and reverse tetracycline-controlled transactivator systems, a powerful new means for modulating the activity of specific molecules, has been applied to CaMKIIalpha and the opposing protein phosphatase calcineurin. Together with electro-physiological and behavioural evaluation of the engineered mutant animals, these genetic methodologies have helped gain insight into the molecular mechanisms of plasticity and memory. Further technical developments are, however, awaited for an even higher level of finesse.

In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus.

Long-term synaptic plasticity is thought to underlie many forms of long-lasting memory. Long-lasting plasticity has been most extensively studied in the marine snail Aplysia and in the mammalian hippocampus, where Bliss and Lømo first described long-term potentiation 30 years ago. The molecular mechanisms of plasticity in these two systems have proven to have many similarities. Here, we briefly describe some of these areas of overlap. We then summarize recent advances in our understanding of the mechanisms of long-lasting synaptic facilitation in Aplysia and suggest that these may prove fruitful areas for future investigation in the mammalian hippocampus and at other synapses in the mammalian brain.

Noses That Learn

Synaptic plasticity leads to long-term changes in neuronal responsiveness, and the molecular mechanisms of plasticity are beginning to be elucidated for the central nervous system (CNS). Watt and Storm show that olfactory neurons activate the extracellular signal-regulated, mitogen-activated protein kinase cascade (ERK) in response to odorant stimuli. This pathway has been implicated in CNS plasticity. Activation of the ERK cascade in olfactory neurons leads to phosphorylation and activation of the cyclic AMP response element binding protein (CREB) through the activation of the CREB kinase pp 90 Rsk. Inhibition of this pathway did not affect primary olfactory signaling measured by electroolfactograms, supporting the hypothesis that the ERK pathway is involved in adaptation to odorant stimulation. In CRE/LacZ transgenic mice, exposure of the mice to the odorant citralva stimulated expression of the reporter gene in a specific layer and zone of the olfactory epithelium. These results provide a molecular mechanism for other physiological and behavioral data that suggest that smells can be learned. W. C. Watt, D. R. Storm, Odorants stimulate the ERK/mitogen-activated protein kinase pathway and activate cAMP-response element-mediated transcription in olfactory sensory neurons. J. Biol. Chem. 276 , 2047-2052 (2001). [Abstract] [Full Text]

NEURODEGENERATION AND PLASTICITY OF THE BRAIN

Aging involves neural circuitry rearrangements that are broadly referred to as synaptic plasticity. This is the result of several events, mainly of synaptic activity. Long-term potentiation (LTP), learning and memory promote plasticity of synapses, notably in the hippocampus. There are also pathological conditions that trigger plasticity. For example, in ischemic stroke, damaged neurons (penumbra), sprout and reestablish connections, partially or wholly recovering function. In epileptogenesis, aberrant synaptic plasticity involve a network of intra- and extracellular messengers that modulate receptors, ion channels, and gene expression. Intracellular pathways of signal transduction modulate neuronal survival. Often, upregulation of certain steps of these pathways leads to neuronal damage or death. An early event is phospholipase A2 activation and the release of arachidonic acid (and subsequent synthesis of prostaglandins and other bioactive derivatives), as well as PAF (platelet-activating factor). PAF is a retrograde messenger in LTP and also, when over-produced, becomes an endogenous neurotoxin by enhancing glutamate release and activating the transcription of the inducible cyclooxygenase (COX)-2 (gene linked to synaptic plasticity and also to the inflammatory response). Molecular events involved in neuronal plasticity to be described involve messenger-activated stress sensitive protein quinces, the subsequent stimulation of transcription factors, and how these DNA-binding proteins modulate gene expression by interacting with consensus sequences in gene promoters. NFK-B (an inflammation-related transcription factor) may be critical in turning on the COX-2 gene in human neocortical samples from Alzheimer's patients. This highlights the potential importance of inflammatory signaling and plasticity in neurodegenerative disease. The identification of the cellular and molecular mechanisms of plasticity of neural circuitry is opening up avenues for novel interventions in aging and in neurodegenerative diseases. (NIH NS23002)

Chapter 11 Mechanisms of neuronal plasticity as analyzed at the single cell level

This chapter has highlighted how correlates of neuronal plasticity such as electrophysiological responsiveness and changes in gene expression may be examined in defined CNS regions as well as in single cells. The ability to simultaneously measure the mRNA levels for hundreds of different genes, to clone novel genes, and to characterize the physiology and morphology of the cell promises to provide insight into molecular mechanisms of plasticity. The importance of understanding how one gene product changes relative to another (coordinated changes) as well as subcellular distribution of mRNAs cannot be overstated. It is only through an analysis of both the molecular and cellular processes associated with plasticity that a thorough understanding of the mechanisms of neuronal plasticity can be gained.

Distributed input to the tail-siphon withdrawal circuit in Aplysia from neurons in the J cluster of the cerebral ganglion

Plasticity in the circuits for the withdrawal reflexes has been correlated with several simple forms of nonassociative and associative learning in Aplysia, and biochemical, biophysical, and molecular mechanisms of plasticity in these circuits have been described. In order to examine network features of this plasticity, we identified and characterized a component of the modulatory circuitry for the tail-siphon withdrawal circuit. Activation of mechanoafferent neurons in the J cluster of the cerebral ganglion produced strong and distributed input to the tail-siphon withdrawal circuit. Stimulation of the J cells led to excitatory and inhibitory effects in the sensory neurons in the pleural ganglion, the tail motor neurons in the pedal ganglion, and several classes of interneurons in the pleural ganglion, including the multifunctional neuron LPI17. Activation of the J cells produced both fast and slow post-synaptic potentials in neurons of the tail-siphon withdrawal circuit. Of particular interest was the ability of the J cells to produce slow EPSPs in the pleural sensory neurons. These slow EPSPs were associated with an increase in the excitability of the sensory neurons, but no effect of the J cells on spike duration in the sensory neurons was observed. The J cells appear to mediate both sensory and modulatory inputs to the circuit for tail withdrawal.

Plastic behaviour under simple shear of thermosetting resins for fibre composite matrices

Simple shear tests have been performed on four different types of resins (cyanate and epoxy-based) which are usually employed for carbon composites. Unexpectedly, all the resins exhibited an intensive plastic response, even at room temperature. Most of the specimens could undergo, at least in their central part, a local shear strain as large as about 0.5. Their constitutive behaviour is very similar to those of glassy thermoplastics — visco-elastic stage, strain softening, shear banding, strain hardening, ultimately homogeneous strain and rupture. It appeared thatτy decreases withTg. The results are discussed in terms of the molecular mechanisms of plasticity. Some consequences on the micromechanics of fibre-reinforced composites are also presented.