Neuromodulation of Thalamic and Subthalamic Responses to Cortical Activities

In human and most mammals, brain activity and thus behavior patterns alternate among different vigilance stages. Wake-promoting monoaminergic and cholinergic innervations from the brainstem and local somnogens such as adenosine provide vigilance state-dependent impacts on the thalamocortical network, the oscillatory activity of which has long been assumed to underlie the switch between different vigilance states. Although homeostatic regulation of sleep has been linked to global synaptic rescaling in the brain, the synaptic substrates for the neuromodulator control of vigilance remain unclear. Most importantly, physiologically-relevant interactions of different modulators on synaptic transmission are not known. Recently at the retinogeniculate synapse, we found for the first time that different modulators selectively released in different vigilance states would interact to have dramatic synaptic effects that cannot be achieved by one modulator alone even in very high concentrations. Most interestingly, these combined synaptic modulations reasonably match the electrophysiological characteristics expected for each vigilance state based on the behavioral attributes. In addition to the retinal input, thalamic relay neurons in the dorsal lateral geniculate nucleus (dLGN) receive another important glutamatergic input, namely massive feedback projection from layer VI cells of the visual cortex. Both retinothalamic and corticothalamic synapses could significantly contribute to the firing frequency and pattern of the relay neuron. The corticothalamic synapses presumably constitute the cardinal pathway for cortical modulation of peripheral sensory input at the level of thalamus, and thus may play a critical role in the cortico-subcortical neural computation and integration. Different neuromodulators that provide vigilance state-dependent impacts on the thalamic networks could also affect corticothalamic synapses, but how these modulators could interact to influence corticothalamic synaptic transmission remains essentially unexplored. On the other hand, the extended thalamocortical networks shall include the cortico-subcortical re-entrant loops involving the basal ganglia. In terms of both anatomical and electrophysiological attributes, the cortico-subthalamic network is very much reminiscent of the cortico-thalamic network. It is desirable to determine whether the properties and principles obtained from the cortico-thalamic pathways are also applicable to the cortico-subthalamic circuits. We would therefore propose to study the effect of individual neuromodulators such as adenosine, dopamine, monoamines and acetylcholine in synaptic transmission, short-term plasticity, and network activities in the cortico-thalamic and the cortico-subthalamic pathways, which bear close structural and electrophysiological similarities to each other. We will also investigate the effect of agonists or antagonists of the neuromodulators, singly or in different combinations mimicking different physiological (e.g. sleep-wakefulness) and pathophysiological (e.g. Parkinsonian) states on short-term synaptic plasticity and accumulation of synaptic charges, which should play a crucial role in the firing patterns of the postsynaptic neuron. In view of the different characteristics of synapse-modulation effects at different synapses, we shall also endeavor to dissect the possible underlying mechanisms, paying particular attention to primary role and modulation of presynaptic Ca2+ which is the key determinant of neurotransmitter release at most synapses. With the execution of this proposal, hopefully we shall have more in-depth and comprehensive understandings of the context-dependent neuromodulation of synaptic transmission in the corticothalamic and cortico-subthalamic pathways, and thus would be able to elucidate more fundamental physiological rationales underlying the operation of cortico-subcortical networks.

Project ID:PA10207-0701
External Project ID:NSC102-2311-B182-003