Repeated, intense, cutaneous stimulation results in the gradual development of inhibition of spinal interneurones. This change in neuronal activity could not be demonstrated in rats whose spinal cords had been transected, and was considered to be the consequence of supraspinal mechanisms. . Experiments sere carried out to determine which areas of the brain were involved. Unitary recordings from neurones situated in nucleus reticularis pontis-caudalis, nucleus reticularis giganto-cellularis, nucleus reticularis parvocellularis and nucleus medulla oblongata pars ventralis demonstrated a progressively increasing excitatory response to repeated intense cutaneous stimulation. These areas were shown to have direct projections to the spinal cord, by retrograde transport of horseradish peroxidase. Cells in nucleus reticularis gigantocellularis, which demonstrated a progressively increasing excitatory response, could also be antidromically activated from the spinal cord. Repeated stimulation of some of these areas produced a progressive inhibition of spinal interneurones which was similar to that resulting from cutaneous stimulation. It would appear that nucleus reticularis gigantocellularis and nucleus reticularis pontis-caudalis are involved in the development of a progressive inhibition of spinal interneurones. A similar role for other reticular and raphe nuclei can not be excluded on the basis of evidence presently available. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

The brain is a complex system which consists of billions of neuron cells and gives rise to diverse neural dynamics spatially and temporally. Spontaneous neural activities construct the foundation for various cognitive processing. However, caused by the limitation spatiotemporal resolution and coverage of recording methods in experiments, the organization of spatiotemporal dynamics of the self-organized brain activity remains largely unknown. Current experimental technique can optically image population voltage transients generated by pyramidal neurons across cortical layer 2/3 of the mouse dorsally with a genetically encoded voltage indicator. Such data provided unique opportunities to investigate the structure- dynamics relationship to elucidate the mechanisms of spontaneous brain activity. The aim of this thesis is to develop a systematic understanding of spatiotemporal mechanism in the mouse cortex by analyzing voltage imaging data, in collaboration with neuroscientist Dr. Knöpfel from the Imperial College London. Local oscillation properties such as duration, amplitude and oscillation forms were studies on the cortex-wide scale and be compared among brain states. Wakefulness modulated the excitability of the neural activity which influenced the duration of the oscillation and the transition of different half wave types. Relatively larger amplitude of parietal cortex reflected stronger neural activity determined by structural hierarchy. Motifs of the oscillations showed consistency in different brain states which indicated typical pathways of the wave propagations. Dynamical properties of various waves and their interactions in sedated mice were investigated. Based on phase velocity fields, there were only a small number of large-scale, cortex-wide plane wave and synchrony (standing wave) patterns during Up-Down states. Interactions of local sources and sinks can generate saddles, and interactions of local wave patterns with large plane waves can induce a change of their wave propagating direction. Local wave patterns emerged at preferred spatial locations. Specifically, sources were predominantly found in cortical regions with high cumulative input through the underlying connectome. The findings revealed the principled spatiotemporal dynamics of Up-Down states and associated them with the large-scale cortical connectome. Waking from deep anesthesia to consciousness increased the number of local wave patterns and made the spatiotemporal dynamics more complex. Although the active state increased the wave propagation speeds, the average speed decreased because of the interaction and collapse of wave patterns. Not affected by the brain states, the two principal modes with the highest variance remained stable. The first mode represented the large waves spreading across the cortex forward or backward while the second mode corresponded to the waves propagating in opposite direction in the frontal and parietal cortex. An infra-slow frequency of the wave number might reflect the bold flow and oxygenation. The characterizations presented in this thesis can be used to predict and guide measurement and analysis of large-scale brain activity. The analysis of cortex-wide neural dynamical patterns builds foundation for further investigation of their functional implications.

Neuromodulatory systems, such as the locus coeruleus (LC) - norepinephrine (NE) system, are integral in the modulation of behavioral state, which in turn exerts a heavy influence on sensory processing, perception, and behavior. LC neurons project diffusely through the forebrain as the sole source of NE. LC tonic firing rate has been shown to correlate with arousal level and behavioral performance. As the LC-NE system innervates sensory pathways and NE has been shown to affect neuronal response, the LC-NE system could potentially allow for state-dependent modulation of sensory processing. However, the precise link between LC activation and sensory processing in the various stages of the sensory pathway that underly perception remained elusive. It is well established that thalamic relay nuclei play an essential role in gating the flow of sensory information to the neocortex, serving to establish cortical representation of sensory environment. Thalamocortical information transmission has been proposed to be strongly modulated by the dynamic interplay between the thalamic relay nuclei and the thalamic reticular nucleus (TRN). Neurons in the early stages of sensory pathways selectively respond to specific features of sensory stimuli. In the rodent vibrissa pathway, thalamocortical neurons in the ventral posteromedial nucleus (VPm) encode kinetic features of whisker movement, allowing stimuli to be encoded by distinctive, temporally precise firing patterns. Therefore, understanding feature selectivity is crucial to understanding sensory processing and perception. However, whether LC activation modulates this feature selectivity, and if it does, the mechanisms through which this modulation occurs, remained largely unknown. This work investigates LC modulation of thalamic feature selectivity through reverse correlation analysis of single-unit recordings from different stages of the rat vibrissa pathway. LC activation increased feature selectivity, drastically improving thalamic information transmission. This improvement was dependent on both local activation of α-adrenergic receptors and modulation of T-type calcium channels in the thalamus and was not due to LC modulation of trigeminothalamic feedforward or corticothalamic feedback inputs. LC activation reduced thalamic bursting, but this change in thalamic firing mode was not the primary cause of the improved information transmission as tonic spikes with LC stimulation carried three-times the information than tonic spikes without LC stimulation. Modelling confirmed NE regulation of intrathalamic circuit dynamics led to the improved information transmission as LC-NE modulation of either relay or reticular nucleus alone cannot account for the improvement. These results suggest a new sub-dimension within the tonic mode in which brain state can optimize thalamic sensory processing through modulation of intrathalamic circuit dynamics. Subsequent computational work was then performed to determine exactly how the encoding of sensory information by thalamic relay neurons was altered to allow for an increase in both information transmission efficiency and rate. The results show that LC-NE induced improvements in feature selectivity are not simply due to an increased signal-to-noise ratio, a shift from bursting to tonic firing, or improvements in reliability or precision. Rather, LC-NE-induced modulation of intrathalamic dynamics changed the temporal response structure thalamic neurons used to encode the same stimuli to a new structure that increased the information carried by both tonic and burst spikes. The shift in events times favors optimal encoding, as more events occur at ideal positions, i.e. when the stimulus most closely matches the neuron’s feature selectivity. Further, this work analyzed the ability to reconstruct the original stimulus using the evoked spike trains of multiple neurons and their recovered feature selectivity from an ideal observer point-of-view. The results showed that LC-activation improved the accuracy of this reconstruction, indicating it may improve the accuracy of perception of whisker stimuli. Finally, to make this work translatable, the use of vagus nerve stimulation (VNS) was investigated as a potential method for minimally invasive enhancement of thalamic sensory processing. The vagus nerve, which runs through the side of the neck, has long been known to have profound effects on brain-state and VNS has been shown to evoke LC firing. This work elucidates the previously uninvestigated short-term effects of VNS on thalamic sensory processing. Similar to direct LC stimulation, VNS enhanced the feature selectivity of thalamic neurons, resulting in a significant increase in the efficiency and rate of stimulus-related information conveyed by thalamic spikes. VNS-induced improvement in thalamic sensory processing also coincided with a decrease in thalamic burst firing, suggesting the same underlying mechanism as the improvements induced with direct LC stimulation.

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In this thesis the various characteristics of a neuron are discussed at some length. Particular attention is given to the more important features which determine the input and output characteristics and the responses of a neuron. Included are both of the major inhibition characteristics: presynaptic inhibition (depolarization), and postsynaptic inhibition (hyperpolarization). The simulation presented uses a single 12 volt power supply, operates on pulses which swing in the negative direction, has a high input impedance and a low output impedance, may be easily modified to adjust the response characteristics to individual system needs, and uses only 132 milliwatts power. Input pulses are weighted and transmitted to the summation circuit by a common collector stage which provides isolation of the inputs from the summation circuitry. A hyperpolarization input raises the resting voltage at the summation circuit, requiring more stimulation to lower the summation voltage to the threshold value. This inhibition follows a predetermined time course, The simulation will produce output pulses as long as the voltage at the summation circuit is below the threshold value. These pulses have a duration of 0.7 ms. and are followed by a refractory period of about one millisecond. A depolarization input lowers the amplitude of the output pulse by a predetermined time course. / Master of Science

In the stochastic modeling of neurons, the first passage time problem arises as a natural object of study when considering the inter spike interval distribution. In this report, we study some aspects of this problem as it arises in the context of neuroscience. In the first chapter we describe the basic neurophysiology required to model the neuron. In the second, we study the Poisson model, Stein’s model, and some diffusion models, calculating or indicating methods to compute the density of the first passage time random variable or its moments. In the third and fourth chapters, we study the Fokker-Planck equation, and use it to compute the first passage time in the discrete and continuous time random walk cases. In the final chapter, we study sequences of neurons and the change in the density of the waiting time distributions, and hence in the inter spike intervals, as the output spike train from one neuron is considered as the input in the subsequent neuron.

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The purpose of this study was to test the hypothesis that early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiac function. After 2 wk of rapid ventricular pacing in nine anesthetized canines, cardiac and right atrial neuronal function were evaluated in situ in response to enhanced cardiac sensory inputs, stimulation of extracardiac autonomic efferent neuronal inputs, and close coronary arterial administration of neurochemicals that included nicotine. Right atrial neuronal intracellular electrophysiological properties were then evaluated in vitro in response to synaptic activation and nicotine. Intrinsic cardiac nicotine-sensitive, neuronally induced cardiac responses were also evaluated in eight sham-operated, unpaced animals. Two weeks of rapid ventricular pacing reduced the cardiac index by 54%. Intrinsic cardiac neurons of paced hearts maintained their cardiac mechano- and chemosensory transduction properties in vivo. They also responded normally to sympathetic and parasympathetic preganglionic efferent neuronal inputs, as well as to locally administered α- or β-adrenergic agonists or angiotensin II. The dose of nicotine needed to modify intrinsic cardiac neurons was 50 times greater in failure compared with normal preparations. That dose failed to alter monitored cardiovascular indexes in failing preparations. Phasic and accommodating neurons identified in vitro displayed altered intracellular membrane properties compared with control, including decreased membrane resistance, indicative of reduced excitability. Early-stage heart failure differentially affects the intrinsic cardiac nervous system's capacity to regulate cardiodynamics. While maintaining its capacity to transduce cardiac mechano- and chemosensory inputs, as well as inputs from extracardiac autonomic efferent neurons, intrinsic cardiac nicotine-sensitive, local-circuit neurons differentially remodel such that their capacity to influence cardiodynamics becomes obtunded.