Neuromodulation of Thalamic Synaptic Transmission---Cellular Mechanisms and Alterations in Output Signals

Except for olfaction, environmental information collected from sensory receptors converges in the subcortical thalamus before passing onto the cerebral cortex in mammals. The thalamus thus plays a central role in the sensory gating and processing. For example, the information processed by the thalamus and relayed to the cortex is very different in awake and in asleep states of the individual, indicative of fast dynamic changes in information processing in the thalamus. Many factors contribute to this dynamic process, from the molecular to the network level. These factors can be intrinsic and extrinsic to the thalamic circuit. In this regard, the neuromodulators from both remote and local sources would constitute the majority of the extrinsic factors and potentially affect the intrinsic membrane properties of a thalamocortical neuron. Thalamic synaptic transmission and the information encoded by action potential firing patterns of the thalamus are thus altered. Despite the abundant evidences underscoring the roles of several neuromodulators in shaping the information relay through thalamic synaptic connections, the cellular and molecular mechanisms underlying these processes as well as their physiological consequences remain obscure. This proposal addresses the hypothesis that the coexistence of two or more neuromodulators, conditions conceivably occurring in physiological circumstances, should contribute significantly to the sensory information processing in the thalamus. We have obtained preliminary data showing that the combination of two physiological neuromodulators may exert very intriguing effect, which would not have imagined based on the action of each single modulator, on the synaptic transmission between the retinal ganglion cells and the lateral geniculate nucleus (LGN), the retinogeniculate synapse. The altered properties of synaptic transmission include synaptic strength, short-term synaptic plasticity, and discharge patterns. Most intriguingly, short-term depression is transformed to facilitation, a novel phenomenon that has never been reported before. The retinogenicualte synapse shares many common principles of information processing with other thalamic synapses and is one of the few optimal model systems for study of the synaptic transmission as well as its functional consequences. We would therefore propose to study neuromodulation of presynaptic neurotransmitter release, synaptic plasticity, and network activities at the retinogeniculate synapses by combinations of different neuromodulators mimicking physiological conditions with electrophysiological, anatomical, and optical techniques. We will examine the synaptic response to pairs of retinal fiber stimuli and stimulation patterns that also mimic physiological retinal ganglion cell activity. Both the characteristics of the presynaptic retinal input and the response of postsynaptic thalamic relay neurons will be monitored. Mechanisms that underlie neuromodulation of short-term synaptic plasticity will be identified and characterized with comprehensive pharmacological agents, biological toxins, as well as optical tools. Also, the effects of synaptic plasticity on the firing patterns of postsynaptic thalamic relay neurons will be documented. Thalamic switch between different discharge patterns is closely related to the sleep-wakefulness cycle. Also, short-term synaptic plasticity, which determines how the presynaptic spiking pattern ultimately influences the firing of its target cell, may act as a “filter” (e.g. a high-pass filter or a low-pass filter) that screens the visual signals relayed to the cortex and can be modulated by neuromodulators. Therefore, these studies will not only enhance our understanding of the contributions of neuromodulators and synaptic mechanisms to information processing in the central nervous system, but also shed light on the regulation of the sleep-wakefulness cycle and visual information processing in mammals.

Project ID:PA9712-0681
External Project ID:NSC97-2311-B182-005-MY2