Patrick D. Roberts

Spike timing dependent synaptic plasticity in biological systems

Abstract. Association of a presynaptic spike with a postsynaptic spike can lead to changes in synaptic efficacy that are highly dependent on the relative timing of the pre- and postsynaptic spikes. Different synapses show varying forms of such spike-timing dependent learning rules. This review describes these different rules, the cellular mechanisms that may be responsible for them, and the computational consequences of these rules for information processing and storage in the nervous system.

Computational Consequences of Temporally Asymmetric Learning Rules: I. Differential Hebbian Learning

Temporally asymetric learning rules governing plastic changes in synaptic efficacy have recently been identified in physiological studies. In these rules, the exact timing of pre- and postsynaptic spikes is critical to the induced change of synaptic efficacy. The temporal learning rules treated in this article are approximately antisymmetric; the synaptic efficacy is enhanced if the postsynaptic spike follows the presynaptic spike by a few milliseconds, but the efficacy is depressed if the postsynaptic spike precedes the presynaptic spike. The learning dynamics of this rule are studied using a stochastic model neuron receiving a set of serially delayed inputs. The average change of synaptic efficacy due to the temporally antisymmetric learning rule is shown to yield differential Hebbian learning. These results are demonstrated with both mathematical analyses and computer simulations, and connections with theories of classical conditioning are discussed.

Computational Consequences of Temporally Asymmetric Learning Rules: II. Sensory Image Cancellation

The electrosensory lateral line lobe (ELL) of mormyrid electric fish is a cerebellum-like structure that receives primary afferent input from electroreceptors in the skin. Purkinje-like cells in ELL store and retrieve a temporally precise negative image of prior sensory input. The stored image is derived from the association of centrally originating predictive signals with peripherally originating sensory input. The predictive signals are probably conveyed by parallel fibers. Recent in vitro experiments have demonstrated that pairing parallel fiber-evoked excitatory postsynaptic potentials (epsps) with postsynaptic spikes in Purkinje-like cells depresses the strength of these synapses. The depression has a tight dependence on the temporal order of pre- and postsynaptic events. The postsynaptic spike must follow the onset of the epsp within a window of about 60 msec for the depression to occur and pairings at other delays yield a nonassociative enhancement of the epsp. Mathematical analyses and computer simulations are used here to test the hypothesis that synaptic plasticity of the type established in vitro could be responsible for the storage of temporal patterns that is observed in vivo. This hypothesis is confirmed. The temporally asymmetric learning rule established in vitro results in the storage of activity patterns as observed in vivo and does so with significantly greater fidelity than other types of learning rules. The results demonstrate the importance of precise timing in pre- and postsynaptic activity for accurate storage of temporal information.

Efficient Encoding of Vocalizations in the Auditory Midbrain

An important question in sensory neuroscience is what coding strategies and mechanisms are used by the brain to detect and discriminate among behaviorally relevant stimuli. There is evidence that sensory systems migrate from a distributed and redundant encoding strategy at the periphery to a more heterogeneous encoding in cortical structures. It has been hypothesized that heterogeneity is an efficient encoding strategy that minimizes the redundancy of the neural code and maximizes information throughput. Evidence of this mechanism has been documented in cortical structures. In this study, we examined whether heterogeneous encoding of complex sounds contributes to efficient encoding in the auditory midbrain by characterizing neural responses to behaviorally relevant vocalizations in the mouse inferior colliculus (IC). We independently manipulated the frequency, amplitude, duration, and harmonic structure of the vocalizations to create a suite of modified vocalizations. Based on measures of both spike rate and timing, we characterized the heterogeneity of neural responses to the natural vocalizations and their perturbed variants. Using information theoretic measures, we found that heterogeneous response properties of IC neurons contribute to efficient encoding of behaviorally relevant vocalizations.

Dynamics of the sit-to-stand movement

The strategies of the sit-to-stand movement are investigated by describing the movement in terms of the topology of an associated phase diagram. Kinematic constraints are applied to describe movement sequences, thus reducing the dimension of the phase space. This dimensional reduction allows us to apply theorems of topological dynamics for two-dimensional systems to arrive at a classification of six possible movement strategies, distinguished by the topology of their corresponding phase portrait. Since movement is treated in terms of topological structure rather than specific trajectories, individual variations are automatically included, and the approach is by nature model independent. Pathological movement is investigated, and this method clarifies how subtle abnormalities in movement lead to difficulties in achieving a stable stance upon rising from a seated position.

Slow glycinergic transmission mediated by transmitter pooling

Most fast-acting neurotransmitters are rapidly cleared from synaptic regions. This feature isolates synaptic sites, rendering the time course of synaptic responses independent of the number of active synapses. We found an exception at glycinergic synapses on granule cells of the rat dorsal cochlear nucleus. Here the duration of inhibitory postsynaptic currents (IPSCs) was dependent on the number of presynaptic axons that were stimulated and on the number of vesicles that were released from each axon. Increasing the stimulus number or frequency, or blocking glycine uptake, slowed synaptic decays, whereas a low-affinity competitive antagonist of glycine receptors (GlyRs) accelerated IPSC decay. These effects could be explained by unique features of GlyRs that are activated by pooling of glycine across synapses. Functionally, increasing the number of IPSPs markedly lengthened the period of spike inhibition following the cessation of presynaptic stimulation. Thus, temporal properties of inhibition can be controlled by activity levels in multiple presynaptic cells or by adjusting release probability at individual synapses.

Design principles of sensory processing in cerebellum-like structures: Early stage processing of electrosensory and auditory objects

Cerebellum-like structures are compared for two sensory systems: electrosensory and auditory. The electrosensory lateral line lobe of mormyrid electric fish is reviewed and the neural representation of electrosensory objects in this structure is modeled and discussed. The dorsal cochlear nucleus in the auditory brainstem of mammals is reviewed and new data are presented that characterize the responses of neurons in this structure in the mouse. Similarities between the electrosensory and auditory cerebellum-like structures are shown, in particular adaptive processes that may reduce responses to predictable stimuli. We suggest that the differences in the types of sensory objects may drive the differences in the anatomical and physiological characteristics of these two cerebellum-like structures.

Inhibition shapes selectivity to vocalizations in the inferior colliculus of awake mice.

The inferior colliculus (IC) is a major center for integration of auditory information as it receives ascending projections from a variety of brainstem nuclei as well as descending projections from the thalamus and auditory cortex. The ascending projections are both excitatory and inhibitory and their convergence at the IC results in a microcircuitry that is important for shaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined the role inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearing adult mice (CBA/CaJ strain). Neurons in the IC of mice show selectivity in their responses to vocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitry in the IC. We compared single unit responses in the IC to pure tones and a variety of ultrasonic mouse vocalizations before and after iontophoretic application of GABAA receptor (GABAAR) and glycine receptor (GlyR) antagonists. The most pronounced effects of blocking GABAAR and GlyR on IC neurons were to increase spike rates and broaden excitatory frequency tuning curves in response to pure tone stimuli, and to decrease selectivity to vocalizations. Thus, inhibition plays an important role in creating selectivity to vocalizations in the IC.

Simulations of symptomatic treatments for Alzheimer's disease: computational analysis of pathology and mechanisms of drug action

IntroductionA substantial number of therapeutic drugs for Alzheimers disease (AD) have failed in late-stage trials, highlighting the translational disconnect with pathology-based animal models.MethodsTo bridge the gap between preclinical animal models and clinical outcomes, we implemented a conductance-based computational model of cortical circuitry to simulate working memory as a measure for cognitive function. The model was initially calibrated using preclinical data on receptor pharmacology of catecholamine and cholinergic neurotransmitters. The pathology of AD was subsequently implemented as synaptic and neuronal loss and a decrease in cholinergic tone. The model was further calibrated with clinical Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-Cog) results on acetylcholinesterase inhibitors and 5-HT6 antagonists to improve the models prediction of clinical outcomes.ResultsAs an independent validation, we reproduced clinical data for apolipoprotein E (APOE) genotypes showing that the ApoE4 genotype reduces the network performance much more in mild cognitive impairment conditions than at later stages of AD pathology. We then demonstrated the differential effect of memantine, an N-Methyl-D-aspartic acid (NMDA) subunit selective weak inhibitor, in early and late AD pathology, and show that inhibition of the NMDA receptor NR2C/NR2D subunits located on inhibitory interneurons compensates for the greater excitatory decline observed with pathology.ConclusionsThis quantitative systems pharmacology approach is shown to be complementary to traditional animal models, with the potential to assess potential off-target effects, the consequences of pharmacologically active human metabolites, the effect of comedications, and the impact of a small number of well described genotypes.

Spatial organization of receptive fields in the auditory midbrain of awake mouse

Efficient encoding of sensory information can be implemented by heterogeneous response properties of neurons within sensory pathways. In the auditory system, neurons in the main auditory midbrain nucleus, the inferior colliculus (IC), show heterogeneous response properties to various types of acoustic stimuli including behaviorally relevant sounds. The receptive fields of these neurons, and their spatial organization, may reveal mechanisms that underlie response heterogeneity in the IC. The mouse is becoming an increasingly popular system for auditory studies and although some studies have examined spectral characteristics in the IC, most of these have been conducted in anesthetized animals. There were two goals of this study. The first goal was to examine the frequency representation of awake mouse IC in fine spatial resolution. The second goal was to determine whether there is a spatial organization of excitatory frequency tuning curves in the IC of awake mice. We achieved these goals by histologically reconstructing locations of single and multiunit recordings throughout the IC in a mouse strain with normal hearing (CBA/CaJ). We found that the tonotopic progression is discontinuous in mouse IC, and we found that there is no clear spatial organization of frequency tuning curve types. Rather, there is heterogeneity of receptive fields in the bulk of the IC such that frequency tuning characteristics and hence the structure of excitatory and inhibitory inputs does not depend on location in the IC. This heterogeneity likely provides a mechanism for efficient encoding of auditory stimuli throughout the extent of the mouse IC.