Whole-brain investigation of thalamocortical and basal ganglia circuitry with optogenetic fMRI
- Understanding how neuronal populations interact in the nervous system is a central goal of neuroscience. However, characterizing these interactions represents a significant technical challenge. Over the last decade, optogenetic fMRI has been established as a powerful technique to overcome this problem and interrogate the brain-wide influence of specific neuronal populations defined by location, connectivity, and genetic makeup. In this work, we used optogenetic fMRI to study the effects of stimulating specific populations and projections within the basal ganglia and thalamocortical systems. Three studies are presented. In the first, we compared the brain-wide effects of stimulating medium spiny neurons in the basal ganglia that make up the direct and indirect pathways. A central theory of basal ganglia function is that striatal neurons making up these two pathways exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. We found that excitation of either inhibitory population evoked robust positive BOLD signals locally, while downstream regions exhibited significantly different and generally opposing responses consistent with - though not easily predicted from - contemporary models of basal ganglia function. Positive and negative fMRI signals throughout the basal ganglia were also associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of the direct and indirect pathways on brain-wide circuitry. They also extend the interpretability of fMRI studies by defining cell type-specific contributions to the fMRI BOLD signal. We next investigated the dynamic influence of central thalamus relay neurons on brain-wide activity. Central thalamus plays a critical role in forebrain arousal and organized behavior, but the network-level mechanisms that link its activity to brain state remain enigmatic. We combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation. Finally, we show that thalamic input to the orbitofrontal cortex (OFC) can selectively drive remote, bilateral cortical inhibition that is mediated by GABA and zona incerta. While inhibition driven by thalamocortical input is a ubiquitous circuit motif in the brain, measurements of thalamically driven inhibition are typically restricted to the thalamocortical projection field. By using whole-brain imaging, we found that optogenetically stimulating thalamic input to OFC at low frequencies (5-10 Hz) caused widespread negative fMRI signals throughout cortex and striatum that were associated with underlying decreases in neuronal firing rate. Downstream from the stimulated projections, stimulus-evoked decreases in firing rate were reduced after local infusion of a GABA antagonist and inactivation of the GABAergic zona incerta. High-frequency (25-40 Hz) stimulations of the same OFC afferents led to widespread activation of the ipsilateral forebrain, but minimal inhibition. These findings reveal a novel, frequency-dependent inhibitory network that allows thalamocortical input to dynamically shape activity throughout neocortex. Collectively, these three studies offer important insight into the dynamic function of thalamocortical and basal ganglia networks and their contributions to large-scale activity in the brain.
|Type of resource
|electronic resource; remote; computer; online resource
|1 online resource.
|Weitz, Andrew James
|Lee, Jin Hyung
|Lee, Jin Hyung
|Degree committee member
|Degree committee member
|Stanford University, Department of Bioengineering.
|Statement of responsibility
|Andrew James Weitz.
|Submitted to the Department of Bioengineering.
|Thesis Ph.D. Stanford University 2018.
- © 2018 by Andrew James Weitz
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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