Modeling of Substance P and 5-HT Induced Synaptic Plasticity in the Lamprey Spinal CPG: Consequences for Network Pattern Generation

Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed by means of simulations. This is motivated by the effects substance P (a tachykinin) and serotonin (5-hydroxytryptamin; 5-HT) have on synaptic transmission in the locomotor network. Activity-dependent synaptic depression and potentiation have recently been shown experimentally using paired intracellular recordings. Although normally activity-dependent plasticity presumably does not contribute to the patterning of network activity, this changes in the presence of the neuromodulators substance P and 5-HT, which evoke significant plasticity. Substance P can induce a faster and larger depression of inhibitory connections but potentiation of excitatory inputs, whereas 5-HT induces facilitation of both inhibitory and excitatory inputs. Changes in the amplitude of the first postsynaptic potential are also seen. These changes could thus be a potential mechanism underlying the modulatory role these substances have on the rhythmic network activity.The aim of the present study has been to implement the activity dependent synaptic depression and facilitation induced by substance P and 5-HT into two alternative models of the lamprey spinal locomotor network, one relying on reciprocal inhibition for bursting and one in which each hemicord is capable of oscillations. The consequences of the plasticity of inhibitory and excitatory connections are then explored on the network level.In the intact spinal cord, tachykinins and 5-HT, which can be endogenously released, increase and decrease the frequency of the alternating left-right burst pattern, respectively. The frequency decreasing effect of 5-HT has previously been explained based on its conductance decreasing effect on K _Ca underlying the postspike afterhyperpolarization (AHP). The present simulations show that short-term synaptic plasticity may have strong effects on frequency regulation in the lamprey spinal CPG. In the network model relying on reciprocal inhibition, the observed effects substance P and 5-HT have on network behavior (i.e., a frequency increase and decrease respectively) can to a substantial part be explained by their effects on the total extent and time dynamics of synaptic depression and facilitation. The cellular effects of these substances will in the 5-HT case further contribute to its network effect.     

Manipulations of spinal cord excitability evoke developmentally-dependent compensatory changes in the lamprey spinal cord

We have examined homeostatic or compensatory plasticity evoked by tonic changes in spinal cord excitability in the lamprey, a model system for investigating spinal cord function. In larval animals, reducing excitability by incubating in tetrodotoxin or the glutamate receptor antagonists CNQX or CNQX/AP5 for 20–48 h resulted in a diverse set of cellular and synaptic changes that together were consistent with an increase in spinal cord excitability. Similar changes occurred to a tonic increase in excitation evoked by incubating in high potassium physiological solution (i.e. responses were unidirectional). We also examined developmental influences on these effects. In animals developing from the larval to adult form effects were reduced or absent, suggesting that at this stage the spinal cord was more tolerant of changes in activity levels. Responses had returned in adult animals, but they were now bi-directional (i.e. opposite effects were evoked by an increase or decrease in excitability). The spinal cord can thus monitor and adapt cellular and synaptic properties to tonic changes in excitability levels. This should be considered in analyses of spinal cord plasticity and injury.     

哺乳动物大脑中神经活动如何改变突触

大脑最基本性质是快速适应周围环境改变的能力,这主要是通过改变各个神经细胞之间的连接来实现的。有多种不同机制可以调节突触的强度,包括突触效率的稳态调节、突触增强和减弱的形态学表现以及钙在其中的作用。当开始了解这些突触改变的细胞生物学机制的时候,也应该考虑这种突触可塑性在完整大脑中的功能意义。因此,应用最新的成像手段来研究经验如何影响皮层环路中突触的改变,尤其是在体双光子显微技术可以在新皮层的单个神经元水平上研究形态和功能可塑性。这些实验将逐渐填补传统的细胞水平和系统水平研究之间的空白,并将有助于更全面充分地理解突触可塑性这种现象及其在皮层功能乃至动物行为中所起的作用。     

Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors: IMPLICATIONS FOR PAIN HYPERSENSITIVITY*

Recent evidence suggests that estrogen is synthesized in the spinal dorsal horn and plays a role in nociceptive processes. However, the cellular and molecular mechanisms underlying these effects remain unclear. Using electrophysiological, biochemical, and morphological techniques, we here demonstrate that 17β-estradiol (E2), a major form of estrogen, can directly modulate spinal cord synaptic transmission by 1) enhancing NMDA receptor-mediated synaptic transmission in dorsal horn neurons, 2) increasing glutamate release from primary afferent terminals, 3) increasing dendritic spine density in cultured spinal cord dorsal horn neurons, and 4) potentiating spinal cord long term potentiation (LTP) evoked by high frequency stimulation (HFS) of Lissauer''s tract. Notably, E2-BSA, a ligand that acts only on membrane estrogen receptors, can mimic E2-induced facilitation of HFS-LTP, suggesting a nongenomic action of this neurosteroid. Consistently, cell surface biotinylation demonstrated that three types of ERs (ERα, ERβ, and GPER1) are localized on the plasma membrane of dorsal horn neurons. Furthermore, the ERα and ERβ antagonist ICI 182,780 completely abrogates the E2-induced facilitation of LTP. ERβ (but not ERα) activation can recapitulate E2-induced persistent increases in synaptic transmission (NMDA-dependent) and dendritic spine density, indicating a critical role of ERβ in spinal synaptic plasticity. E2 also increases the phosphorylation of ERK, PKA, and NR2B, and spinal HFS-LTP is prevented by blockade of PKA, ERK, or NR2B activation. Finally, HFS increases E2 release in spinal cord slices, which can be prevented by aromatase inhibitor androstatrienedione, suggesting activity-dependent local synthesis and release of endogenous E2.     

Invited review: Neural network plasticity in respiratory control.

Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.     

Functional MRI of long-term potentiation: imaging network plasticity

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.     

Progress in neural plasticity

The year 2009 marks the tenth anniversary of the founding of Institute of Neuroscience (ION) in the Shanghai campus of Chinese Academy of Sciences.     

Neuroplasticity in respiratory motor control.

Although recent evidence demonstrates considerable neuroplasticity in the respiratory control system, a comprehensive conceptual framework is lacking. Our goals in this review are to define plasticity (and related neural properties) as it pertains to respiratory control and to discuss potential sites, mechanisms, and known categories of respiratory plasticity. Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. Respiratory neuroplasticity is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, the balance between opposing modulatory systems, age, gender, and genetics. Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury, stress, and pharmacological interventions or conditioning and occurs during development as well as in adults. Developmental plasticity is induced by experiences (e.g., altered respiratory gases) during sensitive developmental periods, thereby altering mature respiratory control. The same experience later in life has little or no effect. In adults, neuromodulation plays a prominent role in several forms of respiratory plasticity. For example, serotonergic modulation is thought to initiate and/or maintain respiratory plasticity following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory denervation, spinal cord injury, and at least some conditioned reflexes. Considerable work is necessary before we fully appreciate the biological significance of respiratory plasticity, its underlying cellular/molecular and network mechanisms, and the potential to harness respiratory plasticity as a therapeutic tool.     

Neuronal cytoskeleton in synaptic plasticity and regeneration

During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo‐dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre‐ and post‐synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system.     

热性癫痫发作大鼠海马齿状回外侧支的可塑性和再可塑性

热性癫痫发作是儿童常见病,能损害认知功能,而突触可塑性和再可塑性(metaplasticity)是维系大脑认知功能的重要神经基础.本文通过脑片灌流和细胞外场电位记录术研究了热性癫痫发作大鼠海马齿状回外侧支的突触可塑性和再可塑性.制作对照组和热性癫痫发作组大鼠的脑切片后,记录电极置于齿状回外侧支的外分子层获取兴奋性突触后...     

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the 'synaptic plasticity and memory (SPM)' hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.     

Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity

Recent data suggest that tissue plasminogen activator (tPA) influences long-term plasticity at hippocampal synapses by converting plasminogen into plasmin, which then generates mature brain-derived neurotrophic factor (mBDNF) from its precursor, proBDNF. Motivated by this hypothesis, we used fluorescent chimeras, expressed in hippocampal neurons, to elucidate (1) mechanisms underlying plasminogen secretion from hippocampal neurons, (2) if tPA, plasminogen, and proBDNF are copackaged and cotransported in hippocampal neurons, especially within dendritic spines, and (3) mechanisms mediating the transport of these neuromodulators to sites of release. We find that plasminogen chimeras traffic through the regulated secretory pathway of hippocampal neurons in dense-core granules (DCGs) and that tPA, plasminogen, and proBDNF chimeras are extensively copackaged in DCGs throughout hippocampal neurons. We also find that 80% of spines that contain DCGs contain chimeras of these neuromodulators in the same DCG. Finally, we demonstrate, for the first time, that neuromodulators undergo cotransport along dendrites in rapidly mobile DCGs, indicating that neuromodulators can be efficiently recruited into active spines. These results support the hypothesis that tPA mediates synaptic activation of BDNF by demonstrating that tPA, plasminogen, and proBDNF colocalize in DCGs in spines, where these neuromodulators can undergo activity-dependent release and then interact and/or mediate changes that influence synaptic efficacy. The results also raise the possibility that frequency-dependent changes in extents of neuromodulator release from DCGs influence the direction of plasticity at hippocampal synapses by altering the relative proportions of two proteins, mBDNF and proBDNF, that exert opposing effects on synaptic efficacy.     

Rapid changes in plasticity across generations within an expanding cedar forest

We investigated the inter‐individual variation of phenotypic plasticity and its evolution across three generations within an expanding forest. Plasticity was assessed in situ from dendrochronological data as the response of radial growth to summer rainfall. A linear mixed model was used to account for spatial effects (environment and stand structure), temporal factors (stand dynamics) and the variation with age. Beyond these effects, our results reveal a significant inter‐individual variance of growth and plasticity within each generation. We also show that the mean values and variances of growth and plasticity changed significantly across generations, with different patterns for both traits. The possible environmental and genetic drivers of these changes are discussed. Contrasting with the trade‐off between stress tolerance and plasticity generally observed among populations, we detected a positive covariance at the individual level, which does not support the cost of plasticity hypothesis in this case.     

Common pathways for growth and for plasticity

Cell growth and differentiation in developing tissues are, at first impression, quite different endeavors from readjusting synaptic strength during activity-dependent synaptic plasticity in mature neurons. Nevertheless, it is becoming increasingly clear that these two distinct processes share multiple intracellular signaling events. How these common pathways result in cell division (during proliferation), large-scale cellular remodeling (during differentiation) or synapse-specific changes (during synaptic plasticity) is only starting to be elucidated. Here we review the latest findings on two prototypical examples of these shared mechanisms: the Ras-PI3K pathway and the intracellular signaling elicited by neural cell adhesion molecules interacting with growth factor receptors.     

Plasticity of GABAergic synapses in the neonatal rat hippocampus

While the development and plasticity of excitatory synaptic connections have been studied into detail, little is known about the development of inhibitory synapses. As proposed for excitatory synapses, recent studies have indicated that activity-dependent forms of synaptic plasticity, such as long-term potentiation and long-term depression, may play a role in the establishment of functional inhibitory synaptic connections. Here, I review these different forms of plasticity and focus on their possible role in the developing neuronal network.     

Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity

Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns.     

Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.     

Effects of Q-switched Nd:YAG laser irradiation on neural impulse propagation: I. Spinal cord.

We studied the effect of irradiation with Q-switched Nd:YAG laser light (1064 nm) on spinal cord dorsal column and dorsolateral white matter in anesthetized rats. To evoke a synchronous sensory input, the sciatic nerve was stimulated electrically and the resulting evoked spinal cord potential (SCP) recorded from the dorsal columns of the ipsilateral side. The waveshape of the SCP showed three components: an early positive peak (P1), representing the responses of the most rapidly conducting fibers, followed by two negative peaks (N1 and N2), which are mainly due to synaptic effects of the volley on dorsal horn cells located in dorsal grey matter. Laser irradiation at 50 mJ/pulse and above resulted in severe reduction in the amplitudes of N1 and N2. In contrast, there was either no reduction at all or only a slight decrease in the amplitude of P1. The selective loss of the synaptic field might be mediated by impairment of synaptic transmission or by loss of high threshold fiber input to dorsal horn neurones. In either event it is likely that the mechanism of the differential effects of laser irradiation on the components of the electrically evoked SCP is at least in part photothermally mediated, since intracord temperatures during laser application greatly exceeded the physiological range.     

Proteolytic activity,synapse elimination,and the Hebb synapse

The Hebb synapse has been postulated to serve as a mechanism subserving both regulation of synaptic strength in the adult nervous system (long-term potentiation and depression) and developmental activity-dependent plasticity. According to this model, pre- and postsynaptic temporal concordance of activity results in strengthening of connections, while discordant activity results in synapse weakening. Evidence is presented that proteases and protease inhibitors may be involved in modification of synaptic strength. This leads to a modification of the Hebb assumptions, namely that postsynaptic activity results in protease elaboration with a consequent general reduction of synaptic connections to the active postsynaptic element. Further, presynaptic activity, if strong enough, induces local release of a protease inhibitor, such as protease nexin I, which neutralizes proteolytic activity and produces a relative preservation of the active input. This formulation produces many of the effects of the classical Hebbian construction, but the protease/inhibitor model suggests additional specific mechanistic features for activity-dependent plasticity. 1994 John Wiley & Sons, Inc.     

Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain

Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor-dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.