Forms Of Neuronal Plasticity Research Articles

The molecular diversity of plasticity mechanisms underlying memory: An evolutionary perspective.

Experience triggers molecular cascades in organisms (learning) that lead to alterations (memory) to allow the organism to change its behavior based on experience. Understanding the molecular mechanisms underlying memory, particularly in the nervous system of animals, has been an exciting scientific challenge for neuroscience. We review what is known about forms of neuronal plasticity that underlie memory highlighting important issues in the field: (1) the importance of being able to measure how neurons are activated during learning to identify the form of plasticity that underlies memory, (2) the many distinct forms of plasticity important for memories that naturally decay both within and between organisms, and (3) unifying principles underlying the formation and maintenance of long-term memories. Overall, the diversity of molecular mechanisms underlying memories that naturally decay contrasts with more unified molecular mechanisms implicated in long-lasting changes. Despite many advances, important questions remain as to which mechanisms of neuronal plasticity underlie memory.

The pivotal role of pituitary adenylate cyclase-activating polypeptide for lactate production and secretion in astrocytes during fear memory.

Pituitary adenylate cyclase-activating polypeptide (PACAP) plays an essential role in the modulation of astrocyte functions. Although lactate secretion from astrocytes contributes to many forms of neuronal plasticity in the central nervous system, including fear learning and memory, the role of PACAP in lactate secretion from astrocytes is unclear. The amygdala and hippocampus of PACAP (+ / +) and PACAP (-/-) mice were acquired 1 h after memory acquisition and recall in the passive avoidance test. The concentration of glycogen and lactate in these regions was measured. The concentration of lactate in the hippocampus's extracellular fluid was also measured by microdialysis during memory acquisition or intracerebroventricular administration of PACAP. We observed that memory acquisition caused a significant decrease in glycogen concentration and increased lactate concentration in the PACAP (+ / +) mice's hippocampus. However, memory acquisition did not increase in the lactate concentration in PACAP (-/-) mice's hippocampus. Further, memory retrieval evoked lactate production in the amygdala and the hippocampus of PACAP (+ / +) mice. Still, there was no significant increase in lactate concentration in the same regions of PACAP (-/-) mice. In vivo microdialysis in rats revealed that the hippocampus's extracellular lactate concentration increased after a single PACAP intracerebroventricular injection. Additionally, the hippocampus's extracellular lactate concentration increased with the memory acquisition in PACAP (+ / +) mice, but not in PACAP (-/-) mice. PACAP may enhance lactate production and secretion in astrocytes during the acquisition and recall of fear memories.

Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala

To study the effects of chronic FLX treatment we combine an automated assessment of motivation and learning in mice with an investigation of various forms of neuronal plasticity in the central (CeA) and basolateral amygdala (BLA). We use immunohistochemistry to visualize neuronal types and perineuronal nets (PNN), and DI-staining to assess dendritic spine morphology. Gel zymography is used to test FLX's impact on matrix metalloproteinase-9 (MMP-9), an enzyme involved in synaptic plasticity. We show that chronic FLX treatment in non-stressed mice increases PNN-dependent plasticity in the BLA, while simultaneously impairing MMP-9-dependent plasticity in the CeA. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioral impairments are accompanied by alterations in morphology of dendritic spines in the CeA towards a more immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of FLX and its influence on MMP-9 by showing that behavior of MMP-9 knock-out animals remains unaffected by the drug. In conclusion, chronic FLX treatment differentially affects various forms of neuronal plasticity, which may explain its contradicting effects on the brain and behavior. Presented findings are of immediate clinical relevance since reported side effects of FLX pose a potential threat to patients.

Modulation of intrinsic excitability as a function of learning within the fear conditioning circuit.

Experience-dependent neuronal plasticity is a fundamental substrate of learning and memory. Intrinsic excitability is a form of neuronal plasticity that can be altered by learning and indicates the pattern of neuronal responding to external stimuli (e.g. a learning or synaptic event). Associative fear conditioning is one form of learning that alters intrinsic excitability, reflecting an experience-dependent change in neuronal function. After fear conditioning, intrinsic excitability changes are evident in brain regions that are a critical part of the fear circuit, including the amygdala, hippocampus, retrosplenial cortex, and prefrontal cortex. Some of these changes are transient and/or reversed by extinction as well as learning-specific (i.e. they are not observed in neurons from control animals). This review will explore how intrinsic neuronal excitability changes within brain structures that are critical for fear learning, and it will also discuss evidence promoting intrinsic excitability as a vital mechanism of associative fear memories. This work has raised interesting questions regarding the role of fear learning in changes of intrinsic excitability within specific subpopulations of neurons, including those that express immediate early genes and thus demonstrate experience-dependent activity, as well as in neurons classified as having a specific firing type (e.g. burst-spiking vs. regular-spiking). These findings have interesting implications for how intrinsic excitability can serve as a neural substrate of learning and memory, and suggest that intrinsic plasticity within specific subpopulations of neurons may promote consolidation of the memory trace in a flexible and efficient manner.

Superoxide generation via the NR2B-NMDAR/RasGRF1/NOX2 pathway promotes dendritogenesis.

N-methyl-D-aspartate receptors (NMDARs) that contain the NR2A and NR2B subunits play a critical role in neuronal plasticity and dendritogenesis. Gain-and-loss-of function studies indicate that NR2B, but not NR2A, promotes dendritic branching. Accumulating evidence indicates that stimulation of NMDARs activates NADPH oxidase (NOX2), thereby generating superoxide. However, the molecular underpinnings of this process are not understood. RasGRF1, a guanine nucleotide exchange factor, is key for several forms of neuronal plasticity and interacts directly with the tail of NR2B. We investigated whether the NR2B-NMDAR/RasGRF1 pathway regulates the activity of NOX2 and whether superoxide production is required for dendritogenesis. We measured superoxide production in developing primary cultures of hippocampal neurons from 3 to 25 days in vitro (DIV) with the probe dihydroethidium (dHE). We found the highest dHE levels at early and intermediate developmental stages (3-15 DIV), when the NR2B-NMDAR expression is abundant. During these early/intermediate developmental stages, but not in mature neurons (>15 DIV), NMDAR activity is required for superoxide production. We also found that disrupting the NR2B-RasGRF1 interaction led to reduced dHE fluorescence intensity and moreover inhibited dendritic branching in hippocampal neurons. Together, our data indicate that superoxide production is induced by the NR2B-NMDARs/RasGRF1/NOX2 pathway and promotes dendritogenesis.

Subthreshold Fear Conditioning Produces a Rapidly Developing Neural Mechanism that Primes Subsequent Learning.

Learning results in various forms of neuronal plasticity that provide a lasting representation of past events, and understanding the mechanisms supporting lasting memories has been a primary pursuit of the neurobiological study of memory. However, learning also alters the capacity for future learning, an observation that likely reflects its adaptive significance. In the laboratory, we can study this essential property of memory by assessing how prior experience alters the capacity for subsequent learning. Previous studies have indicated that while a single weak fear conditioning trial is insufficient to support long-term memory (LTM), it can facilitate future learning such that another trial delivered within a protracted time window results in a robust memory. Here, we sought to determine whether or not manipulating neural activity in the basolateral amygdala (BLA) using designer receptors exclusively activated by designer drugs (DREADDs) during or after the initial learning trial would affect the ability of the initial trial to facilitate subsequent learning. Our results show that inhibiting the BLA in rats prior to the first trial prevented the ability of that trial to facilitate learning when a second trial was presented the next day. Inhibition of the BLA immediately after the first trial using DREADDs was not effective, nor was pharmacological inhibition of protein kinase A (PKA) or the mitogen-activated protein kinase (MAPK). These findings indicate that the neural mechanisms that permit an initial subthreshold fear conditioning trial to alter later learning develop rapidly and do not appear to require a typical post-learning consolidation period.

A-Kinase Anchoring Protein 150 (AKAP150) Promotes Cocaine Reinstatement by Increasing AMPA Receptor Transmission in the Accumbens Shell.

Previous work indicated that activation of D1-like dopamine receptors (D1DRs) in the nucleus accumbens shell promoted cocaine seeking through a process involving the activation of PKA and GluA1-containing AMPA receptors (AMPARs). A-kinase anchoring proteins (AKAPs) localize PKA to AMPARs leading to enhanced phosphorylation of GluA1. AKAP150, the most well-characterized isoform, plays an important role in several forms of neuronal plasticity. However, its involvement in drug addiction has been minimally explored. Here we examine the role of AKAP150 in cocaine reinstatement, an animal model of relapse. We show that blockade of PKA binding to AKAPs in the nucleus accumbens shell of Sprague-Dawley rats attenuates reinstatement induced by either cocaine or a D1DR agonist. Moreover, this effect is specific to AKAP150, as viral overexpression of a PKA-binding deficient mutant of AKAP150 also impairs cocaine reinstatement. This viral-mediated attenuation of cocaine reinstatement was accompanied by decreased phosphorylation of GluA1-containing AMPARs and attenuated AMPAR eEPSCs. Collectively, these results suggest that AKAP150 facilitates the reinstatement of cocaine-seeking behavior by amplifying D1DR/PKA-dependent AMPA transmission in the nucleus accumbens.

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.

Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Paradoxical Effect of NMDA Receptor Blockade in Chicks on Learning and Memory in Passive Avoidance Model.

Activity of NMDA receptors is a prerequisite for numerous but not all forms of neuronal plasticity and learning. The present study examined the role of NMDA receptors in standard, weak, and repeated passive avoidance training in young chicks. Injection of MK-801, an antagonist of NMDA receptor, prior to strong training episode impaired subsequent memory recall. Moreover, repeated training did not restore the lost memory. In the double weak training protocol, the impairing effect of MK-801 was observed only when it was injected prior to the second but not to the first training episode. These results suggest that activation of NMDA receptors is not a necessary stage for memory acquisition in the weak training task. In contrast, the mechanisms of strong training depending on activation of NMDA receptors can be probably involved into the second training episode performed against the background of existing NMDA receptor-independent memory about the first training episode.

Autocrine BDNF-TrkB signalling within a single dendritic spine.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), which is a correlate of an animal's learning. However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy, we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl-d-aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin. We demonstrate that this postsynaptic BDNF-TrkB signalling pathway is necessary for both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR-CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.

Neural circuit rewiring: insights from DD synapse remodeling.

Nervous systems exhibit many forms of neuronal plasticity during growth, learning and memory consolidation, as well as in response to injury. Such plasticity can occur across entire nervous systems as with the case of insect metamorphosis, in individual classes of neurons, or even at the level of a single neuron. A striking example of neuronal plasticity in C. elegans is the synaptic rewiring of the GABAergic Dorsal D-type motor neurons during larval development, termed DD remodeling. DD remodeling entails multi-step coordination to concurrently eliminate pre-existing synapses and form new synapses on different neurites, without changing the overall morphology of the neuron. This mini-review focuses on recent advances in understanding the cellular and molecular mechanisms driving DD remodeling.

Temporal integration of cholinergic and GABAergic inputs in isolated insect mushroom body neurons exposes pairing-specific signal processing.

GABAergic modulation of neuronal activity plays a crucial role in physiological processes including learning and memory in both insects and mammals. During olfactory learning in honeybees (Apis mellifera) and Drosophila melanogaster the temporal relation between excitatory cholinergic and inhibitory GABAergic inputs critically affects learning. However, the cellular mechanisms of temporal integration of these antagonistic inputs are unknown. To address this question, we use calcium imaging of isolated honeybee and Drosophila Kenyon cells (KCs), which are targets of cholinergic and GABAergic inputs during olfactory learning. In the whole population of honeybee KCs we find that pairing of acetylcholine (ACh) and γ-aminobutyric acid (GABA) Comment: Please use the greek letter for gamma reduces the ACh-induced calcium influx, and depending on their temporal sequence, induces different forms of neuronal plasticity. After ACh-GABA pairing the calcium influx of a subsequent excitatory stimulus is increased, while GABA-ACh pairing affects the decay time leading to elevated calcium levels during the late phase of a subsequent excitatory stimulus. In an exactly defined subset of Drosophila KCs implicated in learning we find similar pairing-specific differences. Specifically the GABA-ACh pairing splits the KCs in two functional subgroups: one is only weakly inhibited by GABA and shows no neuronal plasticity and the other subgroup is strongly inhibited by GABA and shows elevated calcium levels during the late phase of a subsequent excitatory stimulus. Our findings provide evidence that insect KCs are capable of contributing to temporal processing of cholinergic and GABAergic inputs, which provides a neuronal mechanism of the differential temporal role of GABAergic inhibition during learning.

Hippocampal neurogenesis and antidepressive therapy: shocking relations.

Speculations on the involvement of hippocampal neurogenesis, a form of neuronal plasticity, in the aetiology of depression and the mode of action of antidepressive therapies, started to arise more than a decade ago. But still, conclusive evidence that adult neurogenesis contributes to antidepressive effects of pharmacological and physical therapies has not been generated yet. This review revisits recent findings on the close relation between the mode(s) of action of electroconvulsive therapy (ECT), a powerful intervention used as second-line treatment of major depression disorders, and the neurogenic response to ECT. Following application of electroconvulsive shocks, intricate interactions between neurogenesis, angiogenesis, and microglia activation, the hypothalamic-pituitary-adrenal axis and the secretion of neurotrophic factors have been documented. Furthermore, considering the fact that neurogenesis strongly diminishes along aging, we investigated the response to electroconvulsive shocks in young as well as in aged cohorts of mice.

Axon initial segment structural plasticity in animal models of genetic and acquired epilepsy

A novel form of neuronal plasticity, occurring at the axon initial segment (AIS), has recently been described. Lengthening of the AIS and movement away from the soma are consequences of changes in neuronal input and result in alterations in neuronal excitability. We hypothesised that AIS plasticity may play a role in epilepsy, due to chronic changes in neuronal activity. Immunohistochemistry and confocal microscopy were used to analyse AIS length and position in pyramidal neurons in deep layer 5 of the somatosensory cortex from 5 mice with genetic epilepsy and 4 controls, and from 3 rats subjected to amygdala kindling and 3 controls. The effect of a subtle alteration of AIS position was modelled computationally. We identified a difference in the position of the AIS in animals with seizures: in mice the AIS was positioned 0.2 μm further away from the soma, and in rats the AIS was positioned 0.6 μm closer to the soma compared with controls. Computational modelling indicated that a subtle alteration in AIS position could result in a change in action potential firing threshold. The identification of AIS plasticity in animal models of epilepsy is significant in furthering our understanding of the pathophysiological mechanisms involved in this disorder.

MSK1 regulates environmental enrichment-induced hippocampal plasticity and cognitive enhancement

Environmental enrichment (EE) has marked beneficial effects on cognitive capacity. Given the possibility that this form of neuronal plasticity could function via the actuation of the same cellular signaling pathways that underlie learning/memory formation, we examined whether the MAPK cascade effector, mitogen/stress-activated kinase 1 (MSK1), could play a role in this process. MSK1 functions as a key signaling intermediate that couples changes in neuronal activity into inducible gene expression, neuronal plasticity, and learning/memory. Here, we show that MSK1 is expressed in excitatory cell layers of the hippocampus, progenitor cells of the subgranular zone (SGZ), and adult-born immature neurons. MSK1(-/-) mice exhibit reduced spinogenesis and decreased dendritic branching complexity in hippocampal neurons, compared with WT mice. Further, in MSK1(-/-) mice, progenitor cell proliferation within the SGZ was significantly reduced and, correspondingly, the number of immature neurons within the dentate gyrus was significantly reduced. Consistent with prior work, MSK1(-/-) mice displayed deficits in both spatial and recognition memory tasks. Strikingly, cognitive enhancement resulting from a 40-d period of EE was markedly reduced in MSK1(-/-) animals. MSK1(-/-) mice exhibited reduced levels of EE-induced spinogenesis and SGZ progenitor proliferation. Taken together, these data reveal that MSK1 serves as a critical regulator of hippocampal physiology and function and that MSK1 serves as a key conduit by which enriching stimuli augment cellular plasticity and cognition.

Cell-specific expression of calcineurin immunoreactivity within the rat basolateral amygdala complex and colocalization with the neuropeptide Y Y1 receptor

Neuropeptide Y (NPY) produces potent anxiolytic effects via activation of NPY Y1 receptors (Y1r) within the basolateral amygdaloid complex (BLA). The role of NPY in the BLA was recently expanded to include the ability to produce stress resilience and long-lasting reductions in anxiety-like behavior. These persistent behavioral effects are dependent upon activity of the protein phosphatase, calcineurin (CaN), which has long been associated with shaping long-term synaptic signaling. Furthermore, NPY-induced reductions in anxiety-like behavior persist months after intra-BLA delivery, which together indicate a form of neuronal plasticity had likely occurred. To define a site of action for NPY-induced CaN signaling within the BLA, we employed multi-label immunohistochemistry to determine which cell types express CaN and if CaN colocalizes with the Y1r. We have previously reported that both major neuronal cell populations in the BLA, pyramidal projection neurons and GABAergic interneurons, express the Y1r. Therefore, this current study evaluated CaN immunoreactivity in these cell types, along with Y1r immunoreactivity. Antibodies against calcium-calmodulin kinase II (CaMKII) and GABA were used to identify pyramidal neurons and GABAergic interneurons, respectively. A large population of CaN immunoreactive cells displayed Y1r immunoreactivity (90%). Nearly all (98%) pyramidal neurons displayed CaN immunoreactivity, while only a small percentage of interneurons (10%) contained CaN immunoreactivity. Overall, these anatomical findings provide a model whereby NPY could directly regulate CaN activity in the BLA via activation of the Y1r on CaN-expressing, pyramidal neurons. Importantly, they support BLA pyramidal neurons as prime targets for neuronal plasticity associated with the long-term reductions in anxiety-like behavior produced by NPY injections into the BLA.

The spatio‐temporal characteristics of action potential initiation in layer 5 pyramidal neurons: a voltage imaging study

The spatial pattern of Na(+) channel clustering in the axon initial segment (AIS) plays a critical role in tuning neuronal computations, and changes in Na(+) channel distribution have been shown to mediate novel forms of neuronal plasticity in the axon. However, immunocytochemical data on channel distribution may not directly predict spatio-temporal characteristics of action potential initiation, and prior electrophysiological measures are either indirect (extracellular) or lack sufficient spatial resolution (intracellular) to directly characterize the spike trigger zone (TZ). We took advantage of a critical methodological improvement in the high sensitivity membrane potential imaging (V(m) imaging) technique to directly determine the location and length of the spike TZ as defined in functional terms. The results show that in mature axons of mouse cortical layer 5 pyramidal cells, action potentials initiate in a region ∼20 μm in length centred between 20 and 40 μm from the soma. From this region, the AP depolarizing wave invades initial nodes of Ranvier within a fraction of a millisecond and propagates in a saltatory fashion into axonal collaterals without failure at all physiologically relevant frequencies. We further demonstrate that, in contrast to the saltatory conduction in mature axons, AP propagation is non-saltatory (monotonic) in immature axons prior to myelination.

Somatic Translocation: A Novel Mechanism of Granule Cell Dendritic Dysmorphogenesis and Dispersion

Pronounced neuronal remodeling is a hallmark of temporal lobe epilepsy. Here, we use real-time confocal imaging of tissue from mouse brain to demonstrate that remodeling can involve fully differentiated granule cells following translocation of the soma into an existing apical dendrite. Somatic translocation converts dendritic branches into primary dendrites and shifts adjacent apical dendrites to the basal pole of the cell. Moreover, somatic translocation contributes to the dispersion of the granule cell body layer in vitro, and when granule cell dispersion is induced in vivo, the dispersed cells exhibit virtually identical derangements of their dendritic structures. Together, these findings identify novel forms of neuronal plasticity that contribute to granule cell dysmorphogenesis in the epileptic brain.

Experimental protocols and preparations to study respiratory long term facilitation

Respiratory long-term facilitation is a form of neuronal plasticity that is induced following exposure to intermittent hypoxia. Long-term facilitation is characterized by a progressive increase in respiratory motor output during normoxic periods that separate hypoxic episodes and by a sustained elevation in respiratory activity for up to 90min after exposure to intermittent hypoxia. This phenomenon is associated with increases in phrenic, hypoglossal or carotid sinus nerve inspiratory-modulated discharge. The examination of long-term facilitation has been steadily ongoing for approximately 3 decades. During this period of time a variety of animal models (e.g. cats, rats and humans), experimental preparations and intermittent hypoxia protocols have been used to study long-term facilitation. This review is designed to summarize the strengths and weaknesses of the models, preparations and protocols that have been used to study LTF over the past 30 years. The review is divided into two primary sections. Initially, the models and protocols used to study LTF in animals other than humans will be discussed, followed by a section specifically focused on human studies. Each section will begin with a discussion of various factors that must be considered when selecting an experimental preparation and intermittent hypoxia protocol to examine LTF. Model and protocol design recommendations will follow, with the goal of presenting a prevailing model and protocol that will ultimately ensure standardized comparisons across studies.

Trafficking and Surface Expression of Hyperpolarization-activated Cyclic Nucleotide-gated Channels in Hippocampal Neurons

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate the hyperpolarization-activated current I(h) and thus play important roles in the regulation of brain excitability. The subcellular distribution pattern of the HCN channels influences the effects that they exert on the properties and activity of neurons. However, little is known about the mechanisms that control HCN channel trafficking to subcellular compartments or that regulate their surface expression. Here we studied the dynamics of HCN channel trafficking in hippocampal neurons using dissociated cultures coupled with time lapse imaging of fluorophore-fused HCN channels. HCN1-green fluorescence protein (HCN1-GFP) channels resided in vesicle-like organelles that moved in distinct patterns along neuronal dendrites, and these properties were isoform-specific. HCN1 trafficking required intact actin and tubulin and was rapidly inhibited by activation of either NMDA or AMPA-type ionotropic glutamate receptors in a calcium-dependent manner. Glutamate-induced inhibition of the movement of HCN1-GFP-expressing puncta was associated with increased surface expression of both native and transfected HCN1 channels, and this surface expression was accompanied by augmented I(h). Taken together, the results reveal the highly dynamic nature of HCN1 channel trafficking in hippocampal neurons and provide a novel potential mechanism for rapid regulation of I(h), and hence of neuronal properties, via alterations of HCN1 trafficking and surface expression.