Publications by authors named "Andrew J Weitz"

8 Publications

  • Page 1 of 1

Thalamic Input to Orbitofrontal Cortex Drives Brain-wide, Frequency-Dependent Inhibition Mediated by GABA and Zona Incerta.

Neuron 2019 12 23;104(6):1153-1167.e4. Epub 2019 Oct 23.

Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, CA 94305, USA. Electronic address:

Anatomical and behavioral data suggest that the ventrolateral orbitofrontal cortex (VLO), which exhibits extensive connectivity and supports diverse sensory and cognitive processes, may exert global influence over brain activity. However, this hypothesis has never been tested directly. We applied optogenetic fMRI to drive various elements of VLO circuitry while visualizing the whole-brain response. Surprisingly, driving excitatory thalamocortical projections to VLO at low frequencies (5-10 Hz) evoked widespread, bilateral decreases in brain activity spanning multiple cortical and subcortical structures. This pattern was unique to thalamocortical projections, with direct stimulations of neither VLO nor thalamus eliciting such a response. High-frequency stimulations (25-40 Hz) of thalamocortical projections evoked dramatically different-though still far-reaching-responses, in the form of widespread ipsilateral activation. Importantly, decreases in brain activity evoked by low-frequency thalamocortical input were mediated by GABA and activity in zona incerta. These findings identify specific circuit mechanisms underlying VLO control of brain-wide neural activities.
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http://dx.doi.org/10.1016/j.neuron.2019.09.023DOI Listing
December 2019

Studying Brain Circuit Function with Dynamic Causal Modeling for Optogenetic fMRI.

Neuron 2017 Feb 26;93(3):522-532.e5. Epub 2017 Jan 26.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address:

Defining the large-scale behavior of brain circuits with cell type specificity is a major goal of neuroscience. However, neuronal circuit diagrams typically draw upon anatomical and electrophysiological measurements acquired in isolation. Consequently, a dynamic and cell-type-specific connectivity map has never been constructed from simultaneous measurements across the brain. Here, we introduce dynamic causal modeling (DCM) for optogenetic fMRI experiments-which uniquely allow cell-type-specific, brain-wide functional measurements-to parameterize the causal relationships among regions of a distributed brain network with cell type specificity. Strikingly, when applied to the brain-wide basal ganglia-thalamocortical network, DCM accurately reproduced the empirically observed time series, and the strongest connections were key connections of optogenetically stimulated pathways. We predict that quantitative and cell-type-specific descriptions of dynamic connectivity, as illustrated here, will empower novel systems-level understanding of neuronal circuit dynamics and facilitate the design of more effective neuromodulation therapies.
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http://dx.doi.org/10.1016/j.neuron.2016.12.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472443PMC
February 2017

Activation of Direct and Indirect Pathway Medium Spiny Neurons Drives Distinct Brain-wide Responses.

Neuron 2016 07 30;91(2):412-24. Epub 2016 Jun 30.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address:

A central theory of basal ganglia function is that striatal neurons expressing the D1 and D2 dopamine receptors exert opposing brain-wide influences. However, the causal influence of each population has never been measured at the whole-brain scale. Here, we selectively stimulated D1 or D2 receptor-expressing neurons while visualizing whole-brain activity with fMRI. Excitation of either inhibitory population evoked robust positive BOLD signals within striatum, while downstream regions exhibited significantly different and generally opposing responses consistent with-though not easily predicted from-contemporary models of basal ganglia function. Importantly, positive and negative signals within the striatum, thalamus, GPi, and STN were all associated with increases and decreases in single-unit activity, respectively. These findings provide direct evidence for the opposing influence of D1 and D2 receptor-expressing striatal neurons on brain-wide circuitry and extend the interpretability of fMRI studies by defining cell-type-specific contributions to the BOLD signal.
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http://dx.doi.org/10.1016/j.neuron.2016.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528162PMC
July 2016

Probing Neural Transplant Networks In Vivo with Optogenetics and Optogenetic fMRI.

Stem Cells Int 2016 12;2016:8612751. Epub 2016 May 12.

Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, CA 94305, USA.

Understanding how stem cell-derived neurons functionally integrate into the brain upon transplantation has been a long sought-after goal of regenerative medicine. However, methodological limitations have stood as a barrier, preventing key insight into this fundamental problem. A recently developed technology, termed optogenetic functional magnetic resonance imaging (ofMRI), offers a possible solution. By combining targeted activation of transplanted neurons with large-scale, noninvasive measurements of brain activity, ofMRI can directly visualize the effect of engrafted neurons firing on downstream regions. Importantly, this tool can be used to identify not only whether transplanted neurons have functionally integrated into the brain, but also which regions they influence and how. Furthermore, the precise control afforded over activation enables the input-output properties of engrafted neurons to be systematically studied. This review summarizes the efforts in stem cell biology and neuroimaging that made this development possible and outlines its potential applications for improving and optimizing stem cell-based therapies in the future.
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http://dx.doi.org/10.1155/2016/8612751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880717PMC
June 2016

Frequency-selective control of cortical and subcortical networks by central thalamus.

Elife 2015 Dec 10;4:e09215. Epub 2015 Dec 10.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, United States.

Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, 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.
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http://dx.doi.org/10.7554/eLife.09215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721962PMC
December 2015

Direct in vivo assessment of human stem cell graft-host neural circuits.

Neuroimage 2015 Jul 25;114:328-37. Epub 2015 Apr 25.

Department of Bioengineering, Stanford University, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, CA 94305, USA; Department of Psychiatry and Biobehavioral Sciences, Neuroscience Interdepartmental Program, University of California, Los Angeles, CA 90095, USA; Department of Neurosurgery, Stanford University, CA 94305, USA; Department of Electrical Engineering, Stanford University, CA 94305, USA. Electronic address:

Despite the potential of stem cell-derived neural transplants for treating intractable neurological diseases, the global effects of a transplant's electrical activity on host circuitry have never been measured directly, preventing the systematic optimization of such therapies. Here, we overcome this problem by combining optogenetics, stem cell biology, and neuroimaging to directly map stem cell-driven neural circuit formation in vivo. We engineered human induced pluripotent stem cells (iPSCs) to express channelrhodopsin-2 and transplanted resulting neurons to striatum of rats. To non-invasively visualize the function of newly formed circuits, we performed high-field functional magnetic resonance imaging (fMRI) during selective stimulation of transplanted cells. fMRI successfully detected local and remote neural activity, enabling the global graft-host neural circuit function to be assessed. These results demonstrate the potential of a novel neuroimaging-based platform that can be used to identify how a graft's electrical activity influences the brain network in vivo.
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http://dx.doi.org/10.1016/j.neuroimage.2015.03.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573170PMC
July 2015

Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

Neuroimage 2015 Feb 22;107:229-241. Epub 2014 Oct 22.

Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford, CA 94305, USA. Electronic address:

Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.
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http://dx.doi.org/10.1016/j.neuroimage.2014.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409430PMC
February 2015

In vivo imaging of transplanted stem cells in the central nervous system.

Curr Opin Genet Dev 2014 Oct 5;28:83-8. Epub 2014 Nov 5.

Department of Neurology & Neurological Sciences, Stanford University, CA 94305, USA; Department of Bioengineering, Stanford University, CA 94305, USA; Department of Neurosurgery, Stanford University, CA 94305, USA; Department of Electrical Engineering, Stanford University, CA 94305, USA. Electronic address:

In vivo imaging is increasingly being utilized in studies investigating stem cell-based treatments for neurological disorders. Direct labeling is used in preclinical and clinical studies to track the fate of transplanted cells. To further determine cell viability, experimental studies are able to take advantage of reporter gene technologies. Structural and functional brain imaging can also be used alongside cell imaging as biomarkers of treatment efficacy. Furthermore, it is possible that new imaging techniques could be used to monitor functional integration of stem cell-derived cells with the host nervous system. In this review, we examine recent developments in these areas and identify promising directions for future research at the interface of stem cell therapies and neuroimaging.
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http://dx.doi.org/10.1016/j.gde.2014.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621007PMC
October 2014