543 research outputs found

    Basic mechanisms of DBS for Parkinson’s disease: computational and experimental studies on neural dynamics

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    Deep Brain Stimulation (DBS) has become an accepted therapy of last resort for Parkinson’s disease (PD). The acceptance of DBS for the management of PD motor symptoms is based on its success rate and contrasts sharply with ones understanding of the pathophysiology underlying the disease state and mechanism of DBS. Theoretical and experimental studies at a neuronal and population level continue to shed light on the mechanism of DBS. In this thesis, we employ computational models in order to test certain hypothesis put forward in the field regarding the mechanism of DBS and efficacy of high frequency stimulation. Moreover, we make use of cellular recordings in order to test the validity of observations made using computational models. We incorporate population level recordings, obtained from PD patients, into a theoretical population level model in order to infer possible neuronal mechanisms underlying the differences observed in the recordings, arising from different experimental conditions. Last but not least, we analyze experimental recordings obtained from PD patients and assess which signal properties are selective to certain brain regions of interest

    Dynamics of synaptically coupled integrate-and-fire-or-burst neurons

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    The minimal integrate-and-fire-or-burst (IFB) neuron model reproduces the salient features of experimentally observed thalamocortical (TC) relay neuron response properties, including the tem- poral tuning of both tonic spiking (i.e., conventional action potentials) and post-inhibitory rebound bursting mediated by a low-threshold calcium current. In this paper we consider networks of IFB neurons with slow synaptic interactions and show how the dynamics may be described with a smooth firing rate model. When the firing rate of the IFB model is dominated by a refractory process the equations of motion simplify and may be solved exactly. Numerical simulations are used to show that a pair of reciprocally interacting inhibitory spiking IFB TC neurons supports an alternating rhythm of the type predicted from the firing rate theory. A change in a single parameter of the IFB neuron allows it to fire a burst of spikes in response to a depolarizing signal, so that it mimics the behavior of a reticular (RE) cell. Within a continuum model we show that a network of RE cells with on-center excitation can support a fast traveling pulse. In contrast a network of inhibitory TC cells is found to support a slowly propagating lurching pulse

    Global neural rhythm control by local neuromodulation

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    Neural oscillations are a ubiquitous form of neural activity seen across scales and modalities. These neural rhythms correlate with diverse cognitive functions and brain states. One mechanism for changing the oscillatory dynamics of large neuronal populations is through neuromodulator activity. An intriguing phenomenon explored here is when local neuromodulation of a distinct neuron type within a single brain nucleus exerts a powerful influence on global cortical rhythms. One approach to investigate the impact of local circuits on global rhythms is through optogenetic techniques. My first project involves the statistical analysis of electrophysiological recordings of an optogenetically-mediated Parkinsonian phenotype. Empirical studies demonstrate that Parkinsonian motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the cortico-basal ganglia-thalamic network. However, the mechanism of these aberrant oscillatory dynamics is not well understood. A previous modeling study predicted that cholinergic neuromodulation of medium spiny neurons in the striatum of the basal ganglia may mediate the pathologic beta rhythm. Here, this hypothesis was tested using selective optogenetic stimulation of striatal cholinergic interneurons in normal mice; stimulation robustly and reversibly amplified beta oscillations and Parkinsonian motor symptoms. The modulation of global rhythms by local networks was further studied using computational modeling in the context of intrathalamic neuromodulation. While intrathalamic vasoactive intestinal peptide (VIP) is known to cause long-lasting excitation in vitro, its in vivo dynamical effects have not been reported. Here, biophysical computational models were used to elucidate the impact of VIP on thalamocortical dynamics during sleep and propofol general anesthesia. The modeling results suggest that VIP can form robust sleep spindle oscillations and control aspects of sleep architecture through a novel homeostatic mechanism. This homeostatic mechanism would be inhibited by general anesthesia, representing a new mechanism contributing to anesthetic-induced loss of consciousness. While the previous two projects differed in their use of empirical versus theoretical methods, a challenge common to both domains is the difficulty in visualizing and analyzing large multi-dimensional datasets. A tool to mitigate these issues is introduced here: GIMBL-Vis is a Graphical Interactive Multi-dimensional extensiBLe Visualization toolbox for Matlab. This toolbox simplifies the process of exploring multi-dimensional data in Matlab by providing a graphical interface for visualization and analysis. Furthermore, it provides an extensible open platform for distributed development by the community

    Towards building a more complex view of the lateral geniculate nucleus: Recent advances in understanding its role

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    The lateral geniculate nucleus (LGN) has often been treated in the past as a linear filter that adds little to retinal processing of visual inputs. Here we review anatomical, neurophysiological, brain imaging, and modeling studies that have in recent years built up a much more complex view of LGN . These include effects related to nonlinear dendritic processing, cortical feedback, synchrony and oscillations across LGN populations, as well as involvement of LGN in higher level cognitive processing. Although recent studies have provided valuable insights into early visual processing including the role of LGN, a unified model of LGN responses to real-world objects has not yet been developed. In the light of recent data, we suggest that the role of LGN deserves more careful consideration in developing models of high-level visual processing

    The augmentation of retinogeniculate communication during thalamic burst mode

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    Retinal signals are transmitted to cortex via neurons in the lateral geniculate nucleus (LGN), where they are processed in burst or tonic response mode. Burst mode occurs when LGN neurons are sufficiently hyperpolarized for T-Type Ca(2+) channels to de-inactivate, allowing them to open in response to depolarization which can trigger a high-frequency sequence of Na(+)-based spikes (i.e. burst). In contrast, T-type channels are inactivated during tonic mode and do not contribute to spiking. Although burst mode is commonly associated with sleep and the disruption of retinogeniculate communication, bursts can also be triggered by visual stimulation, thereby transforming the retinal signals relayed to the cortex.To determine how burst mode affects retinogeniculate communication, we made recordings from monosynaptically connected retinal ganglion cells and LGN neurons in male/female cats during visual stimulation. Our results reveal a robust augmentation of retinal signals within the LGN during burst mode. Specifically, retinal spikes were more effective and often triggered multiple LGN spikes during periods likely to have increased T-Type Ca(2+) channel activity. Consistent with the biophysical properties of T-Type Ca(2+) channels, analysis revealed that effect magnitude was correlated with the duration of the preceding thalamic interspike interval and occurred even in the absence of classically defined bursts. Importantly, the augmentation of geniculate responses to retinal input was not associated with a degradation of visual signals. Together, these results indicate a graded nature of response mode and suggest that, under certain conditions, bursts facilitate the transmission of visual information to the cortex by amplifying retinal signals.SIGNIFICANCE STATEMENTThe thalamus is the gateway for retinal information traveling to the cortex. The lateral geniculate nucleus (LGN), like all thalamic nuclei, has two classically defined categories of spikes-tonic and burst-that differ in their underlying cellular mechanisms. Here we compare retinogeniculate communication during burst and tonic response modes. Our results show that retinogeniculate communication is enhanced during burst mode and visually evoked thalamic bursts, thereby augmenting retinal signals transmitted to cortex. Further, our results demonstrate that the influence of burst mode on retinogeniculate communication is graded and can be measured even in the absence of classically defined thalamic bursts

    Brain State Dependent Activity in the Lateral Geniculate Nucleus

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    Brain state dependent thalamocortical (TC) activity plays and important role in sensory coding, oscillations and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state dependent spontaneous and visually evoked activity of LGN neurons in awake behaving animals remains controversial. In awake head-restrained mice, using a combination of pupillometry, extracellular and intracellular recordings from morphologically and physiologically identified LGN neurons we show that TC neurons and putative local interneurons are inversely related to arousal forming two complementary coalitions with TC cells being positively correlates with wakefulness, while local interneuron activity is negatively correlated. Additionally, the orientation tuning of visually evoked thalamic cell responses is altered during various brain states. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback by GABAA agonist muscimol applied on the dural surface significantly diminishes the correlation between brain states and thalamic neuronal activity. Additional investigations show that by photostimulating GABAergic axons (expressing Channelrhodopsin-2 in a Cre-dependent manner) that project from the lateral hypothalamus (LH) to the dorsal raphe nucleus (DRN), neurons in the DRN increase their action potential output, presumably through disinhibition. Taken together our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal dependent brain states in awake mice and this fact might have important functional implications
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