Network-Dependent Drives of Neuronal Burst Discharges in Normal and Deranged Mammalian Brain

Brain rhythmogenesis has been associated with many physiological (e.g. sleep) and pathophysiological (e.g. seizure) processes. Although these rhythms are in essence grouped electrical activities oscillating among populations of neurons that fire in synchronous burst discharges, the underlying mechanisms remain largely unclear. Central neurons involved in rhythmogenesis could discharge in two distinct modes, namely the relay and burst (oscillatory) modes. The former has firing frequencies roughly correlated with synaptic inputs. In contrast, the functional consequences of neuronal burst discharges have been centered on interruption of neural information relay because of their autonomously repetitive feature which is controlled by intrinsic cell membrane properties. Thus, the conventional view is that the neuronal burst discharges do not rely on, and thus relay, excitatory synaptic inputs. The necessity of fast glutamatergic synaptic input to the generation of physiological and/or pathophysiological burst discharges in a mammalian neuron is not known. Here we aim to explore a novel unifying principle in brain rhythm regulation. We reason that excitatory ligand-gated channels may provide the membrane-depolarizing forces for burst initiation. Inputs from glutamatergic synapses (i.e. nodal points of a neural network) thus may serve as an extrinsic drive of neuronal burst discharges and propel network oscillations. Employing electrophysiological, optogenetic, and pharmacological methods on acutely dissected brain slices and in behaving animal models, we would propose to test the hypothesis in two major rhythmogenic networks: the cortico-thalamic and basolateral amygdalar (BLA) networks. We will elucidate: (1) the contribution of fast glutamatergic synaptic inputs to the generation and/or regulation of spontaneous or evoked neuronal burst discharges in normal and pathophysiological conditions, (2) normal and pathogenic rhythmic burst firings in response to presynaptic glutamatergic neuronal activities over multiple temporal and spatial scales, and (3) the electrophysiological (e.g. oscillatory patterns) and behavioral (e.g. sleep/wakefulness or seizures) consequences in behaving animals. Epileptogenesis with the amygdaloid circuits is a common seizure type in human. We will investigate whether network-dependent reverberating activities between interneurons (INs) and glutamatergic principle neurons (PNs) in BLA contribute to epileptogenesis. The collaboration of BLA PNs and INs in the initiation and propagation of epileptic (burst) discharges correlative to seizure behaviors induced by both chemical and electrical maneuverings will be documented. We will also explore whether network-driven burst discharges are essential for neural synchrony in the reciprocal thalamocortical connections, resulting in a more synchronized slow oscillation with non-rapid-eye-movement sleep. Moreover, the thalamocortical network constitutes an ideal system for recruitment of and spreading of seizure activities via the cortico-subcortical re-entrant loops. We will thus dissect the possible convergent roles of cortical synaptic inputs in thalamic burst discharges and consequent normal and deranged oscillations associated with sleep and seizures in behaving animals. The documented mechanisms and functional consequences will be compared between circuitries. We hope that these approaches would be able to define a previously-unknown unifying principle on which our brain operates, and expand our basic understanding of brain rhythm generation and its perturbations in disease. Accordingly, new avenues could be opened for the development of more effective ways to ameliorate relevant clinical disorders.

Project ID:PC10907-1571
External Project ID:MOST109-2320-B182-006