Multimodal encoding in a simplified model of intracellular calcium signaling

Many cells use calcium signaling to carry information from the extracellular side of the plasma membrane to targets in their interior. Since virtually all cells employ a network of biochemical reactions for Ca²⁺ signaling, much effort has been devoted to understand the functional role of Ca²⁺ responses and to decipher how their complex dynamics is regulated by the biochemical network of Ca²⁺-related signal transduction pathways. Experimental observations show that Ca²⁺ signals in response to external stimuli encode information via frequency modulation (FM) or alternatively via amplitude modulation (AM). Although minimal models can capture separately both types of dynamics, they fail to exhibit different and more advanced encoding modes. By arguments of bifurcation theory, we propose instead that under some biophysical conditions more complex modes of information encoding can also be manifested by minimal models. We consider the minimal model of Li and Rinzel and show that information encoding can occur by AM of Ca²⁺ oscillations, by FM or by both modes (AFM). Our work is motivated by calcium signaling in astrocytes, the predominant type of cortical glial cells that is nowadays recognized to play a crucial role in the regulation of neuronal activity and information processing of the brain. We explain that our results can be crucial for a better understanding of synaptic information transfer. Furthermore, our results might also be important for better insight on other examples of physiological processes regulated by Ca²⁺ signaling.     

Subcellular interactions between parallel fibre and climbing fibre signals in purkinje cells predict sensitivity of classical conditioning to interstimulus interval

Classical conditioning of the nictitating membrane response requires a specific temporal interval between conditioned stimulus and unconditioned stimulus, and produces an incrase in Protein Kinase C (PKC) activation in Purkinje cells. To evaluate whether biochemical interactions within the Purkinje cell may explain the temporal sensitivity, a model of PKC activation byCa ²⁺, diacylglycerol (DAG), and arachidonic acid (AA) is developed.Ca ²⁺ elevation is due to CF stimulation and IP3 inducedCa ²⁺ release (IICR). DAG andIP ₃ result from PF stimulation, while AA results from phospholipase A2 (PLA ₂). Simulations predict increased PKC activation when PF stimulation precedes CF stimulation by 0.1 to 3 s. The sensitivity of IICR to the temporal relation between PF and CF stimulation, together with the buffering system of Purkinje cells, significantly contribute to the temporal sensitivity.     

Insights into a molecular switch that gates sensory neuron synapses during habituation in Aplysia

This review focuses on synaptic depression at sensory neuron-to-motor neuron synapses in the defensive withdrawal circuit of Aplysia as a model system for analysis of molecular mechanisms of sensory gating and habituation. We address the following topics:1. Of various possible mechanisms that might underlie depression at these sensory neuron-to-motor neuron synapses in Aplysia, historically the most widely-accepted explanation has been depletion of the readily releasable pool of vesicles. Depletion is also believed to account for synaptic depression at long interstimulus intervals in a variety of other systems.2. Multiple lines of evidence now indicate that vesicle depletion is not an important contributing mechanism to synaptic depression at Aplysia sensory neuron-to-motor neuron synapses. More generally, it appears that vesicle depletion does not contribute substantially to depression that occurs with those stimulus patterns that are typically used in studying behavioral habituation.3. Recent evidence suggests that at these sensory neuron-to-motor neuron synapses in Aplysia, synaptic depression is mediated by an activity-dependent, but release-independent, switching of individual release sites to a silent state. This switching off of release sites is initiated by Ca²⁺ influx during individual action potentials. We discuss signaling proteins that may be regulated by Ca²⁺ during the silencing of release sites that underlies synaptic depression.4. Bursts of 2–4 action potentials in presynaptic sensory neurons in Aplysia prevent the switching off of release sites via a mechanism called “burst-dependent protection” from synaptic depression.5. This molecular switch may explain the sensory gating that allows animals to discriminate which stimuli are innocuous and appropriate to ignore and which stimuli are more important and should continue to elicit responses.     

Inhibition of mGluR1 and IP3Rs impairs long-term memory formation in young chicks

Calcium (Ca²⁺) is involved in a myriad of cellular functions in the brain including synaptic plasticity. However, the role of intracellular Ca²⁺ stores in memory processing remains poorly defined. The current study explored a role for glutamate-dependent intracellular Ca²⁺ release in memory processing via blockade of metabotropic glutamate receptor subtype 1 (mGluR1) and inositol (1,4,5)-trisphosphate receptors (IP₃Rs). Using a single-trial discrimination avoidance task developed for the young chick, administration of the specific and potent mGluR1 antagonist JNJ16259685 (500 nM, immediately post-training, ic), or the IP₃R antagonist Xestospongin C (5 μM, immediately post-training, ic), impaired retention from 90 min post-training. These findings are consistent with mGluR1 activating IP₃Rs to release intracellular Ca²⁺ required for long-term memory formation and have been interpreted within an LTP2 model. The consequences of different patterns of retention loss following ryanodine receptor (RyR) and IP₃R inhibition are discussed.     

Detection of amplitude modulation and frequency modulation in tactual gratings: a critical bandwidth for active touch

Since most natural surfaces are complex and vary in amplitude and spatial frequency, it might be interesting to consider gratings not in the spatial domain, but in the spatial-frequency domain. Detection thresholds for amplitude modulation (AM) and frequency modulation (FM) in sinusoidal gratings were measured for seven participants. Participants moved their fingers actively across the gratings. Although the two types of modulation are quite different in the spatial domain, they have many features in common in the frequency domain. In previous research (Nefs et al 2001 Perception 30 1263-1274) we measured the discrimination thresholds for amplitude and frequency for sinusoidal gratings. We hypothesised then that these thresholds could be used to predict the discriminability of other types of gratings. In the present study, we did indeed find that the FM and AM detection thresholds can be understood quite well by these discrimination thresholds. The results indicate that the tactual system contains parallel psychophysical channels that filter and integrate the power of stimuli within critical bands. With these results, we are also able to calculate the critical bandwidth for active dynamic touch. We estimated the critical bandwidth surrounding the spatial frequency of 2 cycles cm(-1) to be about 125% of that spatial frequency. This value for the critical band for spatial frequency is incompatible with previous findings for temporal frequencies in vibrotactile research. This indicates that dynamic spatial-frequency discrimination is not likely to be done by temporal frequency.     

Across-channel masking of changes in modulation depth for amplitude- and frequency-modulated signals

This study examines a form of masking that can take place when the signal and masker are widely separated in frequency and cannot be explained in terms of the traditional concept of the auditory filter or critical band. We refer to this as across-channel masking. The task of the subject was to detect an increment in modulation depth of a 1000-Hz sinusoidal carrier. The carrier could either be sinusoidally amplitude modulated or sinusoidally frequency modulated at a 10-Hz rate. Modulation increment thresholds of this “target” signal were measured for the target alone, and in the presence of two interfering sounds with carrier frequencies of 230 and 3300 Hz. When the interfering sounds were unmodulated, they had no effect on modulation increment thresholds. When the interfering sounds were either amplitude or frequency modulated, thresholds increased. Amplitude modulation (AM) increment thresholds were affected by both amplitude-modulated and frequency-modulated interference. Similarly, frequency modulation (FM) increment thresholds were affected by both amplitude-modulated and frequency-modulated interference. For both types of signal, the interference was tuned for modulation rate; across-channel masking was greatest when the interfering sounds were modulated at rates close to 10 Hz, and declined for higher or lower rates. However, the tuning was rather broad. When the target and interfering sounds were modulated at the same rate, there was no effect of the relative phase of the modulators. Two possible explanations for the results are discussed. One is based on the idea that carriers that are modulated in a similar way tend to be perceptually “grouped”. The other is based on the idea that there are “channels” in the auditory system tuned for AM and FM rate. Neither explanation appears completely satisfactory.     

A study of the spin-Hamiltonian parameters for Cr5+ at the rhombically-distorted tetrahedral P5+ site of Ca2PO4Cl crystal using a two-mechanism model

The complete high-order perturbation formulae of spin-Hamiltonian (SH) parameters (g factors g_i and hyperfine structure constants A_i , where i = x, y, z) containing contributions from both the crystal-field (CF) and charge-transfer (CT) mechanisms (the latter mechanism is neglected in the widely-used CF theory) are established for d¹ ions in rhombic tetrahedra. From these formulae, the SH parameters of Cr⁵⁺ ion at the rhombically-distorted tetrahedral P⁵⁺ site of Ca₂PO₄Cl crystal are calculated. The CF and CT energy levels used in the calculation are obtained from the optical spectra of the studied Ca₂PO₄Cl : Cr⁵⁺ crystal. The calculated results showed reasonable agreement with the experimental values. The signs of the hyperfine structure constants A_i and the relative importance of the CT mechanism to SH parameters are acquired from the calculations.     

Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse

The endogenous cannabinoid system has been shown recently to play a crucial role in the extinction of aversive memories. As the amygdala is presumably involved in this process, we investigated the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN-2) on synaptic transmission in the lateral amygdala (LA) of wild-type and cannabinoid receptor type 1 (CB1)-deficient mice. Extracellular field potential recordings and patch-clamp experiments were performed in an in vitro slice preparation. We found that WIN-2 reduces basal synaptic transmission and pharmacologically isolated AMPA receptor- and GABA_A receptor-mediated postsynaptic currents in wild-type, but not in CB1-deficient mice. These results indicate that, in the LA, cannabinoids modulate both excitatory and inhibitory synaptic transmission via CB1. WIN-2-induced changes of paired-pulse ratio and of spontaneous and miniature postsynaptic currents suggest a presynaptic site of action. Inhibition of G_i/o proteins and blockade of voltage-dependent and G protein-gated inwardly rectifying K⁺ channels inhibited WIN-2 action on basal synaptic transmission. In contrast, modulation of the adenylyl cyclase-protein kinase A pathway, and blockade of presynaptic N- and P/Q- or of postsynaptic L- and R/T-type voltage-gated Ca²⁺ channels did not affect WIN-2 effects. Our results indicate that the mechanisms underlying cannabinoid action in the LA partly resemble those observed in the nucleus accumbens and differ from those described for the hippocampus.     

Serum calcium levels in Alzheimer's disease: A finding and an aetiological hypothesis

We report that lower serum Ca²⁺ levels are found in severely demented patients when compared with mildly affected individuals (P < 0.001) and we formulate an aetiological hypothesis of Alzheimer's disease based on the disruption of intraneuronal microtubular networks by low calcium levels and other forms of intraneuronal mechanical disruption. The findings are discussed in relation to Hendrickson's theory of the biological basis of psychometric intelligence.     

Habituation in Aplysia: The Cheshire Cat of neurobiology

The marine snail, Aplysia californica, is a valuable model system for cell biological studies of learning and memory. Aplysia exhibits a reflexive withdrawal of its gill and siphon in response to weak or moderate tactile stimulation of its skin. Repeated tactile stimulation causes this defensive withdrawal reflex to habituate. Both short-term habituation, lasting <30 min, and long-term habituation, which can last >24 h, have been reported in Aplysia. Habituation of the withdrawal reflex correlates with, and is in part due to, depression of transmission at the monosynaptic connection between mechanoreceptive sensory neurons and motor neurons within the abdominal ganglion. Habituation-related short-term depression of the sensorimotor synapse appears to be due exclusively to presynaptic changes. However, changes within the sensory neuron, by themselves, do not account for more persistent depression of the sensorimotor synapse. Recent behavioral work suggests that long-term habituation in Aplysia critically involves postsynaptic processes, specifically, activation of AMPA- and NMDA-type receptors. In addition, long-term habituation requires activity of protein phosphatases, including protein phosphatases 1, 2A, and 2B, as well as activity of voltage-dependent Ca²⁺ channels. Cellular work has succeeded in demonstrating long-term, homosynaptic depression (LTD) of the sensorimotor synapse in dissociated cell culture and, more recently, LTD of the glutamate response of isolated motor neurons in culture (“hemisynaptic” LTD). These in vitro forms of LTD have mechanistic parallels to long-term habituation. In particular, homosynaptic LTD of the sensorimotor synapse requires elevated intracellular Ca²⁺ within the motor neuron, and hemisynaptic LTD requires activity of AMPA- and NMDA-type receptors. In addition, activation of group I and II metabotropic glutamate receptors (mGluRs) can induce hemisynaptic LTD. The demonstration of LTD in vitro opens up a promising new avenue for attempts to relate long-term habituation to cellular changes within the nervous system of Aplysia.     

The effect of variable rest intervals and chronic ankle instability on triplanar ankle motion during performance of the Star Excursion Balance Test

Inadequate rest intervals may contribute to impaired performance during functional tests. However, the effect of different rest intervals on performance of the SEBT in individuals with and without CAI is not known. Our purposes were to determine whether different rest intervals impact ankle kinematics during the SEBT and whether there differences between those two populations. 24 controls and 24 CAI completed 3 trials in 3 reach directions (anteromedial; AM, medial; M, posteromedial; PM). The order of rest intervals and reach distance were randomized and counterbalanced. Three visits were required to complete the 3 rest interval conditions (10, 20, 40 s). Rest interval did not impact ankle kinematics between controls and CAI during the SEBT. Dorsiflexion (DF) (AM:partial η² = 0.18; M:partial η² = 0.23; PM:partial η² = 0.23) for all directions and tibial internal rotation (TIR) excursions (AM:partial η² = 0.20) for AM direction were greater in individuals with CAI regardless of rest interval length. Rest intervals ranging from 10 to 40 s did not influence ankle kinematics. Differences exist in DF and TIR between controls and CAI during the SEBT. These findings suggest that clinicians can use any rest interval between 10 and 40 s when administrating the SEBT. However, triplanar motion differs during a complex functional movement in controls compared to CAI.     

Detection of spatial cues in linear and logarithmic frequency-modulated sweeps

Frequency- and amplitude-modulated (FM and AM) sounds are the building blocks of complex sounds. In the present study, we investigated the ability of human observers to process spatial information in an important class of FM sounds: broadband directional sweeps common in natural communication signals such as speech. The stimuli consisted of linear or logarithmic unidirectional FM pulses that swept either up or down in frequency at various rates. Spatial localization thresholds monotonically improved as sweep duration decreased and as sweep rate increased, but no difference in performance was observed between logarithmic and linear or between upand down-frequency sweeps. Counterintuitive reversals in localization were observed which suggested that the localization of high-frequency sweeps may be strongly dominated by amplitude information even in situations in which one might consider timing cues to be critical. Implications of these findings for the localization of complex sounds are discussed.     

Co-induction of long-term potentiation and long-term depression at a central synapse in the leech

Most studies of long-term potentiation (LTP) have focused on potentiation induced by the activation of postsynaptic NMDA receptors (NMDARs). However, it is now apparent that NMDAR-dependent signaling processes are not the only form of LTP operating in the brain [Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: An embarrassment of riches. Neuron, 44, 5–21]. Previously, we have observed that LTP in leech central synapses made by the touch mechanosensory neurons onto the S interneuron was NMDAR-independent [Burrell, B. D., & Sahley, C. L. (2004). Multiple forms of long-term potentiation and long-term depression converge on a single interneuron in the leech CNS. Journal of Neuroscience, 24, 4011–4019]. Here we examine the cellular mechanisms mediating T-to-S (T → S) LTP and find that its induction requires activation of metabotropic glutamate receptors (mGluRs), voltage-dependent Ca²⁺ channels (VDCCs) and protein kinase C (PKC). Surprisingly, whenever LTP was pharmacologically inhibited, long-term depression (LTD) was observed at the tetanized synapse, indicating that LTP and LTD were activated at the same time in the same synaptic pathway. This co-induction of LTP and LTD likely plays an important role in activity-dependent regulation of synaptic transmission.     

Differential Effect of TEA on Long-Term Synaptic Modification in Hippocampal CA1 and Dentate Gyrus in vitro

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni²⁺ (50 μM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni²⁺ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 μM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni²⁺. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni²⁺. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Dissociative effects of true and false recall as a function of different encoding strategies

Goodwin, Meissner, and Ericsson (2001 Goodwin, K. A., Meissner, C. A. and Ericsson, K. A. 2001. Toward a model of false recall: Experimental manipulation of encoding context and the collection of verbal reports. Memory & Cognition, 29: 806–819. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) proposed a path model in which elaborative encoding predicted the likelihood of verbalisation of critical, nonpresented words at encoding, which in turn predicted the likelihood of false recall. The present study tested this model of false recall experimentally with a manipulation of encoding strategy and the implementation of the process-tracing technique of protocol analysis. Findings indicated that elaborative encoding led to more verbalisations of critical items during encoding than rote rehearsal of list items, but false recall rates were reduced under elaboration conditions (Experiment 2). Interestingly, false recall was more likely to occur when items were verbalised during encoding than not verbalised (Experiment 1), and participants tended to reinstate their encoding strategies during recall, particularly after elaborative encoding (Experiment 1). Theoretical implications for the interplay of encoding and retrieval processes of false recall are discussed.     

Upregulation of hippocampal TrkB and synaptotagmin is involved in treadmill exercise-enhanced aversive memory in mice

Cognitive functions usually involve various synaptic proteins and neurotrophic factors in the hippocampus. However, whether treadmill exercise can improve learning and memory by upregulating some of these molecules remain unraveled. To address this question, male BALB/c mice were divided into control and exercise groups, the latter group went through 4 weeks of treadmill exercise training. At the end of exercise training period, they were either tested for passive avoidance (PA) performance or sacrificed for quantifying the hippocampal levels of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB, the BDNF receptor), synaptotagmin (a Ca²⁺-dependent synaptic vesicle protein), and SNAP-25 (a presynaptic vesicular fusion protein). Our results showed that treadmill exercise training (1) increased the retention latency without affecting the fear acquisition in the PA test, (2) transiently increased the hippocampal BDNF level at 1, 2, and 4 h after the completion of exercise training, and (3) persistently increased the hippocampal protein levels of full-length TrkB, phosphorylated TrkB and synaptotagmin, but not truncated TrkB or SNAP-25. Moreover, the protein expression level of full-length TrkB or synaptotagmin was positively correlated with PA performance in mice. Finally, inhibition of TrkB signaling by K252a abolished the exercise-facilitated PA performance and upregulation of TrkB and synaptotagmin. Taken together, these data suggest that the upregulation of TrkB and synaptotagmin in the hippocampus contributes to the exercise-facilitated aversive memory.     

大脑视知觉调控的神经机制

大脑的知觉加工并非单纯由外部刺激驱动,而是存在自上而下的知觉调控。尽管这一现象被大量实验研究证实,但其神经机制仍然是认知神经科学研究的重要问题。本研究系统介绍了知觉调控的神经基础、实现形式、研究范式,及其理论模型,分析指出了当前研究面临的主要问题,并对未来的研究进行了展望,以期促进该问题研究的进一步开展。     

Difficulties in auditory organization as a cause of reading backwardness? An auditory neuroscience perspective

Over 30 years ago, it was suggested that difficulties in the ‘auditory organization’ of word forms in the mental lexicon might cause reading difficulties. It was proposed that children used parameters such as rhyme and alliteration to organize word forms in the mental lexicon by acoustic similarity, and that such organization was impaired in developmental dyslexia. This literature was based on an ‘oddity’ measure of children's sensitivity to rhyme (e.g. wood, book, good) and alliteration (e.g. sun, sock, rag). The ‘oddity’ task revealed that children with dyslexia were significantly poorer at identifying the ‘odd word out’ than younger children without reading difficulties. Here we apply a novel modelling approach drawn from auditory neuroscience to study the possible sensory basis of the auditory organization of rhyming and non‐rhyming words by children. We utilize a novel Spectral‐Amplitude Modulation Phase Hierarchy (S‐AMPH) approach to analysing the spectro‐temporal structure of rhyming and non‐rhyming words, aiming to illuminate the potential acoustic cues used by children as a basis for phonological organization. The S‐AMPH model assumes that speech encoding depends on neuronal oscillatory entrainment to the amplitude modulation (AM) hierarchy in speech. Our results suggest that phonological similarity between rhyming words in the oddity task depends crucially on slow (delta band) modulations in the speech envelope. Contrary to linguistic assumptions, therefore, auditory organization by children may not depend on phonemic information for this task. Linguistically, it is assumed that ‘book’ does not rhyme with ‘wood’ and ‘good’ because the final phoneme differs. However, our auditory analysis suggests that the acoustic cues to this phonological dissimilarity depend primarily on the slower amplitude modulations in the speech envelope, thought to carry prosodic information. Therefore, the oddity task may help in detecting reading difficulties because phonological similarity judgements about rhyme reflect sensitivity to slow amplitude modulation patterns. Slower amplitude modulations are known to be detected less efficiently by children with dyslexia.