Modulation Of Synaptic Plasticity Research Articles

Caprylic acid promotes synaptic plasticity potentially through enhancing Leptin/NM2B signaling

Synaptic plasticity is crucial for memory formation and can be impaired in metabolic diseases. Insulin and insulin-like growth factors play important roles in synaptic plasticity, while leptin protects neurons and stimulates growth. Diets can affect synaptic plasticity through macronutrients and appetite signals, highlighting the need for deeper research and interventions for synaptic dysfunction in metabolic diseases. Recent research suggests that while saturated fatty acids (SFA) have been viewed as unhealthy for cognition, they may benefit memory and learning in certain conditions. High levels of SFA were found to improve recollection in young people. In specific, low-level intake of caprylic acid may reduce neuroinflammation and protect against neural degeneration. This anti-neuroinflammatory effect of caprylic acid may be mediated through the JAK2/STAT3 signaling pathway, which is a crucial part in the modulation of synaptic plasticity by leptin/NM2B signaling. Therefore, this work hypothesized that caprylic acid can enhance leptin/NM2B signaling pathway by increasing the expression of JAK2/STAT3 signaling pathway. In this proposal, a 12-week mice experiment is proposed with fEPSP measurements, immunoblotting, and immunoprecipitation to test the long-term potentiation (LTP) and the expression level as well as regions of the signaling molecules. This work may offer another perspective on the complex role of SFA in brain health.

The dose-dependent effect of the D2R agonist quinpirole microinjected into the ventral pallidum on information flow in the limbic system

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals.The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus.Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP.Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation.Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation.These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D2Rs in the regulation of limbic information flow.

Astrocyte modulation of synaptic plasticity mediated by activity-dependent Sonic hedgehog signaling.

The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which they accomplish this have remained largely unknown. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte derived molecules that modify synapses. Whisker stimulation and chemogenetic activation both increase Shh activity in deep layers of the somatosensory cortex, where neuron-astrocyte Shh signaling is predominantly found. Experience-dependent Hevin and SPARC require intact Shh signaling and selective loss of pathway activity in astrocytes occludes experience-dependent structural plasticity. Taken together, these data identify Shh signaling as an activity-dependent, neuronal derived cue that stimulates astrocyte interactions with synapses and promotes synaptic plasticity.

Bidirectional modulation of synaptic transmission by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) at layer 2/3 pyramidal neurons (PNs) of the mouse barrel cortex is favored or prevented by IGF-I (10 nM) or IGF-I (7 nM), respectively, when IGF-I is applied 1 h before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10 nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing long-term depression (LTD) of the inhibitory post-synaptic currents (IPSCs), 7 nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain.

Study on the Role of Physical Fields in TMAS to Modulate Synaptic Plasticity in Mice.

Transcranial magneto-acoustic stimulation (TMAS) is a composite technique combining static magnetic and coupled electric fields with transcranial ultrasound stimulation (TUS) and has shown advantages in neuromodulation. However, the role of these physical fields in neuromodulation is unclear. Synaptic plasticity is the cellular basis for learning and memory. In this paper, we varied the intensity of static magnetic, electric and ultrasonic fields respectively to investigate the modulation of synaptic plasticity by these physical fields. There are control, static magnetic field (0.1 T/0.2 T), TUS (0.15/0.3 MPa), and TMAS (0.15 MPa + 0.2 V/m, 0.3 MPa + 0.2 V/m, 0.3 MPa + 0.4 V/m) groups. Hippocampal areas were stimulated at 5 min daily for 7 days and in vivo electrophysiological experiments were performed. TMAS induced greater LTP, LTD, and paired-pulse ratio (PPR) than TUS, reflecting that TMAS has a more significant modulation in both long- and short- term synaptic plasticity. In TMAS, a doubling of the electric field amplitude increases LTP, LTD and PPR to a greater extent than a doubling of the acoustic pressure. Increasing the static magnetic field intensity has no significant effect on the modulation of synaptic plasticity. This paper argues that electric fields should be the main reason for the difference in modulation between TMAS and TUS and that changing the amplitude of the electric field affected the modulation of TMAS more than changing the acoustic pressure. This study elucidates the roles of the physical fields in TMAS and provides a parameterisation way to guide TMAS applications based on the dominant roles of the physical fields.

Broadband Artificial Tetrachromatic Synaptic Devices Composed of 2D/3D Integrated WSe2‐GaN‐based Dual‐Channel Floating Gate Transistors

AbstractThe development of artificial tetrachromatic vision holds great potential to enhance human color perception and discrimination, thereby enabling more effective navigation in diverse environments. Herein, an artificial tetrachromatic synaptic device is presented built upon 2D‐3D vertically stacked semiconductors composed of tungsten diselenide (WSe2)‐gallium nitride (GaN) configuration, forming a dual‐channel floating gate transistor (FGT). Under the concerted influence of electrical and optical stimulation, the device successfully mimics fundamental tetrachromatic synaptic behaviors, including short‐term potentiation (STP), weak long‐term potentiation (wLTP), long‐term potentiation (LTP), paired‐pulse facilitation (PPF), spike number‐dependent plasticity (SNDP), and spike rate‐dependent plasticity (SRDP). Notably, the plasticity of the device can be further modulated under ultraviolet (UV) stimulation, providing insights into the modulation of synaptic plasticity through the photogenerated carrier dynamics in the GaN channel. These results imply that WSe2‐GaN‐based FGT architecture with dual‐channel characteristics seamlessly integrates optical sensing and synaptic simulation functionalities, representing a promising avenue for the development of next‐generation artificial visual perception systems (AVPS), with a particular advantage for the pursuit of high‐performance artificial tetrachromatic neuromorphic computing applications of the future.

Synaptic Plasticity Modulation of Neuromorphic Transistors through Phosphorus Concentration in Phosphosilicate Glass Electrolyte Gate.

This study proposes a phosphosilicate glass (PSG)-based electrolyte gate synaptic transistor with varying phosphorus (P) concentrations. A metal oxide semiconductor capacitor structure device was employed to measure the frequency-dependent (C-f) capacitance curve, demonstrating that the PSG electric double-layer capacitance increased at 103 Hz with rising P concentration. Fourier transform infrared spectroscopy spectra analysis facilitated a theoretical understanding of the C-f curve results, examining peak differences in the P-OH structure based on P concentration. Using the proposed synaptic transistors with different P concentrations, changes in the hysteresis window were investigated by measuring the double-sweep transfer curves. Subsequently, alterations in proton movement within the PSG and charge characteristics at the channel/PSG electrolyte interface were observed through excitatory post-synaptic currents, paired-pulse facilitation, signal-filtering functions, resting current levels, and potentiation and depression characteristics. Finally, we demonstrated the proposed neuromorphic system's feasibility based on P concentration using the Modified National Institute of Standards and Technology learning simulations. The study findings suggest that, by adjusting the PSG film's P concentration for the same electrical stimulus, it is possible to selectively mimic the synaptic signal strength of human synapses. Therefore, this approach can positively contribute to the implementation of various neuromorphic systems.

Astrocyte ryanodine receptors facilitate gliotransmission and astroglial modulation of synaptic plasticity.

Intracellular Ca2+-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca2+ level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca2+-sensitive ryanodine receptors (RyRs). While the physiological role for glial IP3 became a focus of intensive research and debate, ryanodine receptors received much less attention. We explored the role for ryanodine receptors in the modulation of cytosolic Ca2+-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data show that RyR-mediated Ca2+-induced Ca2+-release from ER brings substantial contribution into signaling in the functional microdomains hippocampal and neocortical astrocytes. Furthermore, RyR-mediated CICR activated the release of ATP and glutamate from hippocampal and neocortical astrocytes which, in turn, elicited transient purinergic and tonic glutamatergic currents in the neighboring pyramidal neurons. The CICR-facilitated release of ATP and glutamate was inhibited after intracellular perfusion of astrocytes with ryanodine and BAPTA and in the transgenic dnSNARE mice with impaired astroglial exocytosis. We also found out that RyR-mediated amplification of astrocytic Ca2+-signaling enhanced the long-term synaptic potentiation in the hippocampus and neocortex of aged mice. Combined, our data demonstrate that ryanodine receptors are essential for astrocytic Ca2+-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.

Impact of (Co–Fe–B)x(LiNbO3)100–x Nanocomposite Memristors Characteristics Dispersion on Dopamine-Like Modulation of Synaptic Plasticity

Impact of (Co–Fe–B)x(LiNbO3)100–x Nanocomposite Memristors Characteristics Dispersion on Dopamine-Like Modulation of Synaptic Plasticity

Piezo-phototronic effect modulated optoelectronic artificial synapse based on a-Ga2O3/ZnO heterojunction

Amorphous gallium oxide (a-Ga2O3) based optoelectronic devices responds to deep ultraviolet (DUV), which triggers their potential applications for simulating biological vision system. However, there is still lack of research on the influence of multiple stimuli on regulating synaptic plasticity in artificial synapse. Herein, we reported a flexible a-Ga2O3/ZnO film heterostructure with tunable DUV photoresponse, serving as a promising platform for artificial optoelectronic synapse. Based on persistent photoconductivity effect under 265 nm illumination, basic synaptic functions have been mimicked. Notably, the strain-induced piezo-phototronic effect of the heterojunction enables the modulation of synaptic plasticity, playing a role analogous to neuromodulator interaction with biological synapse activity. Strain-evoked an additional degree of freedom controls synapse weight-update rate during learning process and synapse weight-decay during forgetting process. The underlying mechanism is attributed to energy band bending tailored by strain-induced piezo-potential that determines carrier separation/transport and the recombination reaction of ionized oxygen vacancy. The recognition accuracy of MNIST images is as high as 92.31% in the artificial neural network constructed by the heterojunction devices. This work not only exhibits the application prospect of ultra-wide bandgap semiconductor-based heterojunction in artificial optoelectronic synapse, but also opens up a new avenue for multiple stimuli modulating synaptic plasticity.

Light-Stimulated IGZO Transistors with Tunable Synaptic Plasticity Based on Casein Electrolyte Electric Double Layer for Neuromorphic Systems.

In this study, optoelectronic synaptic transistors based on indium-gallium-zinc oxide (IGZO) with a casein electrolyte-based electric double layer (EDL) were examined. The casein electrolyte played a crucial role in modulating synaptic plasticity through an internal proton-induced EDL effect. Thus, important synaptic behaviors, such as excitatory post-synaptic current, paired-pulse facilitation, and spike rate-dependent and spike number-dependent plasticity, were successfully implemented by utilizing the persistent photoconductivity effect of the IGZO channel stimulated by light. The synergy between the light stimulation and the EDL effect allowed the effective modulation of synaptic plasticity, enabling the control of memory levels, including the conversion of short-term memory to long-term memory. Furthermore, a Modified National Institute of Standards and Technology digit recognition simulation was performed using a three-layer artificial neural network model, achieving a high recognition rate of 90.5%. These results demonstrated a high application potential of the proposed optoelectronic synaptic transistors in neuromorphic visual systems.

The Importance of α-Klotho in Depression and Cognitive Impairment and Its Connection to Glutamate Neurotransmission-An Up-to-Date Review.

Depression is a serious neuropsychiatric disease affecting an increasing number of people worldwide. Cognitive deficits (including inattention, poor memory, and decision-making difficulties) are common in the clinical picture of depression. Cognitive impairment has been hypothesized to be one of the most important components of major depressive disorder (MDD; referred to as clinical depression), although typical cognitive symptoms are less frequent in people with depression than in people with schizophrenia or bipolar disorder (BD; sometimes referred to as manic-depressive disorder). The importance of α-Klotho in the aging process has been well-documented. Growing evidence points to the role of α-Klotho in regulating other biological functions, including responses to oxidative stress and the modulation of synaptic plasticity. It has been proven that a Klotho deficit may contribute to the development of various nervous system pathologies, such as behavioral disorders or neurodegeneration. Given the growing evidence of the role of α-Klotho in depression and cognitive impairment, it is assumed that this protein may be a molecular link between them. Here, we provide a research review of the role of α-Klotho in depression and cognitive impairment. Furthermore, we propose potential mechanisms (related to oxidative stress and glutamatergic transmission) that may be important in α-Klotho-mediated regulation of mental and cognitive function.

Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity.

Extracellular vesicles (EVs) play an important role in intercellular communication as carriers of signalling molecules such as bioactive miRNAs, proteins and lipids. EVs are key players in the functioning of the central nervous system (CNS) by influencing synaptic events and modulating recipient neurons. However, the specific role of neuron-to-neuron communication via EVs is still not well understood.Here, we provide evidence that primary neurons uptake neuron-derived EVs in the soma, dendrites, and even in the dendritic spines, and carry synaptic proteins. Neuron-derived EVs increased spine density and promoted the phosphorylation of Akt and ribosomal protein S6 (RPS6), via TrkB-signalling, without impairing the neuronal network activity. Strikingly, EVs exerted a trophic effect on challenged nutrient-deprived neurons. Altogether, our results place EVs in the spotlight for synaptic plasticity modulation as well as a possible therapeutic tool to fight neurodegeneration.

Tailoring Neuroplasticity in a Ferroelectric‐Gated Multi‐Terminal Synaptic Transistor by Bi‐Directional Modulation for Improved Pattern Edge Recognition

AbstractThe dynamic modulation of the plasticity of artificial neuromorphic devices facilitates a wide range of neuromorphic functions. However, integrating diverse plasticity modulation techniques into a single device presents a challenge due to limitations in the device structure design. Here, a multiterminal artificial synaptic device capable of bi‐directional modulation on its plasticity is proposed. Significantly, the conversion of inhibitory and excitatory synaptic plasticity can be achieved not only by modifying the polarity of the presynaptic voltage spike but also by exchanging its input terminal between top and bottom gate while maintaining the same presynaptic stimuli. This unique bi‐directional modulation of synaptic plasticity has been attributed to two distinct physical mechanisms: nonvolatile ferroelectric polarization and interface charge trap‐induced memory characteristics. Additionally, the effective dynamic modulation of the synaptic behaviors is quantified under different back‐gate bias and verified in the constructed neural network perceptron. Further, a visual simulation demonstrates the enhanced clarity and precision of edge recognition through the back‐gate modulation in the artificial synapses. This study provides a strategy to fulfill diversified modulation on synaptic plasticity in ferroelectric‐gated transistors, thereby prompting efficient and controllable neuromorphic visual systems.

Insulin-induced long-term potentiation in the dentate gyrus of hippocampal formation

The discovery that brain areas involving in learning and memory express receptors for insulin hormone, led to the idea that insulin signaling may have a role in regulating cognitive function. Although previous studies have shown a role for insulin in regulation of the threshold of plasticity induction, no study has addressed whether insulin can induce a chemical plasticity per se. Young-adult male rats that are fed with standard diets with or without carbohydrate syrup (sucrose or high-fructose corn syrups) were enrolled in this study. Extracellular field potentials were recorded from the dentate gyrus in response to perforant pathway stimulation at 0.033 Hz in anesthetized rats. The slope of field excitatory postsynaptic potentials (fEPSPs) and the amplitude of population spike (PS) were measured 15 min after a 60-min infusion of insulin (500 nM), NT157 (an IRS inhibitor, 6 μM), alone or together, or physiological saline. mRNA expressions of insulin signaling proteins were measured by rt-PCR in the whole hippocampus. We did not observe any appreciable change in the fEPSP slope and the PS amplitude before and after saline infusion. However, intra-hippocampal insulin application results in the induction of LTP of fEPSP and of PS in the dentate gyrus. Insulin infusion together with NT157 inhibited fEPSP-LTP, but not PS-LTP, and rats that are fed with carbohydrate syrup did not express synaptic LTP. In rats that additional carbohydrate syrup is not given, insulin-induced LTP was accompanied with an increase in PI3K-mRNA, AKT-mRNA, and GSK-3β-mRNA which was not observed when co-administered with NT157. The GSK-3β-mRNA and IRS1-mRNA levels were found to be lower in rats that received supplemental carbohydrate and that not express insulin-induced synaptic LTP, compared to the rats expressing synaptic LTP and fed by standard diet. The results obtained provide a mechanistic link between insulin and synaptic plasticity. We concluded that insulin not only functions as a modulator of synaptic plasticity but also acts as a chemical inducer of LTP.

(m-CF3-PhSe)2 benefits against anxiety-like phenotype associated with synaptic plasticity impairment and NMDAR-mediated neurotoxicity in young mice exposed to a lifestyle model

Lifestyle habits including energy-dense foods and ethanol intake are associated with anxiety disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] has been reported to modulate serotonergic and opioidergic systems and elicit an anxiolytic-like phenotype in animal models. This study investigated if the modulation of synaptic plasticity and NMDAR-mediated neurotoxicity contributes to the (m-CF3-PhSe)2 anxiolytic-like effect in young mice exposed to a lifestyle model. Swiss male mice (25-days old) were subjected to a lifestyle model, an energy-dense diet (20:20% lard: corn syrup) from the postnatal day (PND) 25–66 and sporadic ethanol (2 g/kg) (3 x a week, intragastrically, i.g.) from PND 45 to 60. From PND 60 to 66, mice received (m-CF3-PhSe)2 (5 mg/kg/day; i.g). The corresponding vehicle (control) groups were carried out. After, mice performed anxiety-like behavioral tests. Mice exposed only to an energy-dense diet or sporadic ethanol did not show an anxiety-like phenotype. (m-CF3-PhSe)2 abolished the anxiety-like phenotype in young mice exposed to a lifestyle model. Anxious-like mice showed increased levels of cerebral cortical NMDAR2A and 2B, NLRP3 and inflammatory markers, and decreased contents of synaptophysin, PSD95, and TRκB/BDNF/CREB signaling. (m-CF3-PhSe)2 reversed cerebral cortical neurotoxicity, the increased levels of NMDA2A and 2B, and decreased levels of synaptic plasticity-related signaling in the cerebral cortex of young mice exposed to a lifestyle model. In conclusion, the (m-CF3-PhSe)2 anxiolytic-like effect was associated with the modulation of NMDAR-mediated neurotoxicity and synaptic plasticity in the cerebral cortex of young mice exposed to the lifestyle model.

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

Optically modulated ionic conductivity in a hydrogel for emulating synaptic functions.

Ion-conductive hydrogels, with ions as signal carriers, have become promising candidates to construct functional ionotronics for sensing, actuating, and robotics engineering. However, rational modulation of ionic migration to mimic biological information processing, including learning and memory, remains challenging to be realized in hydrogel materials. Here, we develop a hybrid hydrogel with optically modulated ionic conductivity to emulate the functions of a biological synapse. Through a responsive supramolecular approach, optical stimuli can trigger the release of mobile ions for tuning the conductivity of the hydrogel, which is analogous to the modulation of synaptic plasticity. As a proof of concept, this hydrogel can be used as an information processing unit to perceive different optical stimuli and regulate the grasping motion of a robotic hand, performing logical motion feedback with "learning-experience" function. Our ionic hydrogel provides a valuable strategy toward developing bioinspired ionotronic systems and pushes forward the functional applications of hydrogel materials.

Dopaminergic regulation of hippocampal plasticity, learning, and memory.

The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.

Spatiotemporal Modulation of Plasticity in Multi‐Terminal Tactile Synaptic Transistor (Adv. Electron. Mater. 1/2023)

Synaptic Transistors In article number 2200733, Ye Zhou and co-workers design a multi-terminal MoS2 synaptic transistor to mimic the parallel signal transmission behaviors of biological multipolar neurons. With the combination of microstructured pressure sensors, an intelligent tactile recognition system is built up to realize spatiotemporal tactile recognition and modulation of synaptic plasticity.