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.
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.
This is the first of two papers on the electrosensory lobe (ELL) of mormyrid electric fish. The ELL is the first stage in the central processing of electrosensory information from electroreceptors. Cells of the mormyrid ELL are affected at the time of the electric organ discharge (EOD) by two different inputs, EOD-evoked reafferent input from electroreceptors and corollary discharge input associated with the motor command that elicits the EOD. This first paper examines the intracellular responses of ELL cells to these two different inputs in the region of ELL that receives primary afferent fibers from mormyromast electroreceptors. Mormyromast electroreceptors are responsible for active electrolocation. The paper extends previous studies of the mormyrid ELL by describing the physiological responses of cell types, which had been previously identified only morphologically, including: the two types of Purkinje-like medium ganglionic cells, MG1 and MG2; the thick smooth dendrite cells; and the medium fusiform cells. In addition, two previously unrecognized cell types, the large thick smooth dendrite cell and the interzonal cell, are described both morphologically and physiologically for the first time. Finally, new information is provided on the two types of ELL efferent cells, the large ganglionic and large fusiform cells. All cell types, except for the medium fusiform cell, show nonlinear interactions between electrosensory and corollary discharge inputs. All cell types, except for the medium fusiform cell and the interzonal cell, also show plasticity of the corollary discharge response after pairing with electrosensory stimuli.
IntroductionA substantial number of therapeutic drugs for Alzheimer's 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 Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) results on acetylcholinesterase inhibitors and 5-HT6 antagonists to improve the model's 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.
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