Department of Neurosurgery, and Department of Neurology and Neurological Sciences, by courtesy, Stanford University School of Medicine (2012 - Present)
Honors & Awards
Postdoctoral Fellowship, Parkinsons Disease Foundation (2011)
K99/R00 Pathway to Independence Award, NIH/NINDS (2011)
Klingenstein Fellowship Awards in Neuroscience, Klingenstein Foundation (2013)
Ph.D., Interdepartmental Neuroscience PhD Program , Department of Physiology, Northwestern University, Neuroscience (2007)
Current Research and Scholarly Interests
The interplay between motor cortex, sensory cortex, thalamus and basal ganglia is essential for neural computations involved in generating voluntary movements. Our goal is to dissect the functional organization of motor circuits, particularly cortico-thalamo-basal ganglia networks, using electrophysiology, 2-photon microscopy, optogenetics, and genetic tools. The long-term scientific goal of the lab is to construct functional circuit diagrams and establish causal relationships between activity in specific groups of neurons, circuit function, animal motor behavior and motor learning, and thereby to decipher how the basal ganglia process information and guide motor behavior. We will achieve this by investigating the synaptic organization and function that involve the cortex, thalamus and basal ganglia at the molecular, cellular and circuit level. Currently, we are focusing on several questions:
How are excitatory and inhibitory inputs integrated in the striatum?
How do feed-forward and recurrent local inhibitions balance the excitation in the striatum?
How are functional maps modulated in motor behavior and motor learning?
Our goal is to bridge the gap between molecular or cellular events and the circuit mechanisms that underlie motor behavior. In addition, we aim to further help construct the details of psychomotor disorder circuit diagrams, such as the pathophysiological changes in Parkinsons disease.
Graduate and Fellowship Programs
Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons
2015; 350 (6256): 102-106
Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.
View details for DOI 10.1126/science.aac4690
View details for Web of Science ID 000362098300055
View details for PubMedID 26430123
Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease.
2015; 18 (9): 1299-1309
Dynamic adaptations in synaptic plasticity are critical for learning new motor skills and maintaining memory throughout life, which rapidly decline with Parkinson's disease (PD). Plasticity in the motor cortex is important for acquisition and maintenance of motor skills, but how the loss of dopamine in PD leads to disrupted structural and functional plasticity in the motor cortex is not well understood. Here we used mouse models of PD and two-photon imaging to show that dopamine depletion resulted in structural changes in the motor cortex. We further discovered that dopamine D1 and D2 receptor signaling selectively and distinctly regulated these aberrant changes in structural and functional plasticity. Our findings suggest that both D1 and D2 receptor signaling regulate motor cortex plasticity, and loss of dopamine results in atypical synaptic adaptations that may contribute to the impairment of motor performance and motor memory observed in PD.
View details for DOI 10.1038/nn.4082
View details for PubMedID 26237365
Input- and Cell-Type-Specific Endocannabinoid-Dependent LTD in the Striatum
2015; 10 (1): 75-87
Changes in basal ganglia plasticity at the corticostriatal and thalamostriatal levels are required for motor learning. Endocannabinoid-dependent long-term depression (eCB-LTD) is known to be a dominant form of synaptic plasticity expressed at these glutamatergic inputs; however, whether eCB-LTD can be induced at all inputs on all striatal neurons is still debatable. Using region-specific Cre mouse lines combined with optogenetic techniques, we directly investigated and distinguished between corticostriatal and thalamostriatal projections. We found that eCB-LTD was successfully induced at corticostriatal synapses, independent of postsynaptic striatal spiny projection neuron (SPN) subtype. Conversely, eCB-LTD was only nominally present at thalamostriatal synapses. This dichotomy was attributable to the minimal expression of cannabinoid type 1 (CB1) receptors on thalamostriatal terminals. Furthermore, coactivation of dopamine receptors on SPNs during LTD induction re-established SPN-subtype-dependent eCB-LTD. Altogether, our findings lay the groundwork for understanding corticostriatal and thalamostriatal synaptic plasticity and for striatal eCB-LTD in motor learning.
View details for DOI 10.1016/j.celrep.2014.12.005
View details for Web of Science ID 000347465600008
View details for PubMedID 25543142
Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum.
2012; 15 (2): 215-223
The proper formation of synaptic connectivity in the mammalian brain is critical for complex behavior. In the striatum, balanced excitatory synaptic transmission from multiple sources onto two classes of principal neurons is required for coordinated and voluntary motor control. Here we show that the interaction between the secreted semaphorin 3E (Sema3E) and its receptor Plexin-D1 is a critical determinant of synaptic specificity in cortico-thalamo-striatal circuits in mice. We find that Sema3e (encoding Sema3E) is highly expressed in thalamostriatal projection neurons, whereas in the striatum Plxnd1 (encoding Plexin-D1) is selectively expressed in direct-pathway medium spiny neurons (MSNs). Despite physical intermingling of the MSNs, genetic ablation of Plxnd1 or Sema3e results in functional and anatomical rearrangement of thalamostriatal synapses specifically in direct-pathway MSNs without effects on corticostriatal synapses. Thus, our results demonstrate that Sema3E and Plexin-D1 specify the degree of glutamatergic connectivity between a specific source and target in the complex circuitry of the basal ganglia.
View details for DOI 10.1038/nn.3003
View details for PubMedID 22179111
Thalamic Gating of Corticostriatal Signaling by Cholinergic Interneurons
2010; 67 (2): 294-307
Salient stimuli redirect attention and suppress ongoing motor activity. This attentional shift is thought to rely upon thalamic signals to the striatum to shift cortically driven action selection, but the network mechanisms underlying this interaction are unclear. Using a brain slice preparation that preserved cortico- and thalamostriatal connectivity, it was found that activation of thalamostriatal axons in a way that mimicked the response to salient stimuli induced a burst of spikes in striatal cholinergic interneurons that was followed by a pause lasting more than half a second. This patterned interneuron activity triggered a transient, presynaptic suppression of cortical input to both major classes of principal medium spiny neuron (MSN) that gave way to a prolonged enhancement of postsynaptic responsiveness in striatopallidal MSNs controlling motor suppression. This differential regulation of the corticostriatal circuitry provides a neural substrate for attentional shifts and cessation of ongoing motor activity with the appearance of salient environmental stimuli.
View details for DOI 10.1016/j.neuron.2010.06.017
View details for Web of Science ID 000280461500013
View details for PubMedID 20670836
Live-Cell Superresolution Imaging by Pulsed STED Two-Photon Excitation Microscopy
2013; 104 (4): 770-777
Two-photon laser scanning microscopy (2PLSM) allows fluorescence imaging in thick biological samples where absorption and scattering typically degrade resolution and signal collection of one-photon imaging approaches. The spatial resolution of conventional 2PLSM is limited by diffraction, and the near-infrared wavelengths used for excitation in 2PLSM preclude the accurate imaging of many small subcellular compartments of neurons. Stimulated emission depletion (STED) microscopy is a superresolution imaging modality that overcomes the resolution limit imposed by diffraction and allows fluorescence imaging of nanoscale features. Here, we describe the design and operation of a superresolution two-photon microscope using pulsed excitation and STED lasers. We examine the depth dependence of STED imaging in acute tissue slices and find enhancement of 2P resolution ranging from approximately fivefold at 20 ?m to approximately twofold at 90-?m deep. The depth dependence of resolution is found to be consistent with the depth dependence of depletion efficiency, suggesting resolution is limited by STED laser propagation through turbid tissue. Finally, we achieve live imaging of dendritic spines with 60-nm resolution and demonstrate that our technique allows accurate quantification of neuronal morphology up to 30-?m deep in living brain tissue.
View details for DOI 10.1016/j.bpj.2012.12.053
View details for Web of Science ID 000315320200007
View details for PubMedID 23442955
Dopaminergic neurons inhibit striatal output through non-canonical release of GABA
2012; 490 (7419): 262-?
The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (?-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons.
View details for DOI 10.1038/nature11466
View details for Web of Science ID 000309733300050
View details for PubMedID 23034651
Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone
2012; 73 (3): 511-522
AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.
View details for DOI 10.1016/j.neuron.2011.11.027
View details for Web of Science ID 000300140600012
View details for PubMedID 22325203
Muscarinic modulation of striatal function and circuitry.
Handbook of experimental pharmacology
Striatal cholinergic interneurons are pivotal modulators of the striatal circuitry involved in action selection and decision making. Although nicotinic receptors are important transducers of acetylcholine release in the striatum, muscarinic receptors are more pervasive and have been more thoroughly studied. In this review, the effects of muscarinic receptor signaling on the principal cell types in the striatum and its canonical circuits will be discussed, highlighting new insights into their role in synaptic integration and plasticity. These studies, and those that have identified new circuit elements driven by activation of nicotinic receptors, make it clear that temporally patterned activity in cholinergic interneurons must play an important role in determining the effects on striatal circuitry. These effects could be critical to the response to salient environmental stimuli that serve to direct behavior.
View details for DOI 10.1007/978-3-642-23274-9_10
View details for PubMedID 22222701
Cholinergic modulation of synaptic integration and dendritic excitability in the striatum
CURRENT OPINION IN NEUROBIOLOGY
2011; 21 (3): 425-432
Modulatory interneurons such as, the cholinergic interneuron, are always a perplexing subject to study. Far from clear-cut distinctions such as excitatory or inhibitory, modulating interneurons can have many, often contradictory effects. The striatum is one of the most densely expressing brain areas for cholinergic markers, and actylcholine (ACh) plays an important role in regulating synaptic transmission and cellular excitability. Every cell type in the striatum has receptors for ACh. Yet even for a given cell type, ACh affecting different receptors can have seemingly opposing roles. This review highlights relevant effects of ACh on medium spiny neurons (MSNs) of the striatum and suggests how its many effects may work in concert to modulate MSN firing properties.
View details for DOI 10.1016/j.conb.2011.04.004
View details for Web of Science ID 000294097100010
View details for PubMedID 21550798
Supraresolution Imaging in Brain Slices using Stimulated-Emission Depletion Two-Photon Laser Scanning Microscopy
2009; 63 (4): 429-437
Two-photon laser scanning microscopy (2PLSM) has allowed unprecedented fluorescence imaging of neuronal structure and function within neural tissue. However, the resolution of this approach is poor compared to that of conventional confocal microscopy. Here, we demonstrate supraresolution 2PLSM within brain slices. Imaging beyond the diffraction limit is accomplished by using near-infrared (NIR) lasers for both pulsed two-photon excitation and continuous wave stimulated emission depletion (STED). Furthermore, we demonstrate that Alexa Fluor 594, a bright fluorophore commonly used for both live cell and fixed tissue fluorescence imaging, is suitable for STED 2PLSM. STED 2PLSM supraresolution microscopy achieves approximately 3-fold improvement in resolution in the radial direction over conventional 2PLSM, revealing greater detail in the structure of dendritic spines located approximately 100 microns below the surface of brain slices. Further improvements in resolution are theoretically achievable, suggesting that STED 2PLSM will permit nanoscale imaging of neuronal structures located in relatively intact brain tissue.
View details for DOI 10.1016/j.neuron.2009.07.011
View details for Web of Science ID 000269570400004
View details for PubMedID 19709626
Corticostriatal and thalamostriatal synapses have distinctive properties
JOURNAL OF NEUROSCIENCE
2008; 28 (25): 6483-6492
The two principal excitatory glutamatergic inputs to striatal medium spiny neurons (MSNs) arise from neurons in the cerebral cortex and thalamus. Although there have been many electrophysiological studies of MSN glutamatergic synapses, little is known about how corticostriatal and thalamostriatal synapses differ. Using mouse brain slices that allowed each type of synapse to be selectively activated, electrophysiological approaches were used to characterize their properties in identified striatopallidal and striatonigral MSNs. At corticostriatal synapses, a single afferent volley increased the glutamate released by a subsequent volley, leading to enhanced postsynaptic depolarization with repetitive stimulation. This was true for both striatonigral and striatopallidal MSNs. In contrast, at thalamostriatal synapses, a single afferent volley decreased glutamate released by a subsequent volley, leading to a depressed postsynaptic depolarization with repetitive stimulation. Again, this response pattern was the same in striatonigral and striatopallidal MSNs. These differences in release probability and short-term synaptic plasticity suggest that corticostriatal and thalamostriatal projection systems code information in temporally distinct ways, constraining how they regulate striatal circuitry.
View details for DOI 10.1523/JNEUROSCI.0435-08.2008
View details for Web of Science ID 000256890000022
View details for PubMedID 18562619
Re-emergence of striatal cholinergic interneurons in movement disorders
TRENDS IN NEUROSCIENCES
2007; 30 (10): 545-553
Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.
View details for DOI 10.1016/j.tins.2007.07.008
View details for Web of Science ID 000250679500009
View details for PubMedID 17904652
D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons
TRENDS IN NEUROSCIENCES
2007; 30 (5): 228-235
Dopamine shapes a wide variety of psychomotor functions. This is mainly accomplished by modulating cortical and thalamic glutamatergic signals impinging upon principal medium spiny neurons (MSNs) of the striatum. Several lines of evidence suggest that dopamine D1 receptor signaling enhances dendritic excitability and glutamatergic signaling in striatonigral MSNs, whereas D2 receptor signaling exerts the opposite effect in striatopallidal MSNs. The functional antagonism between these two major striatal dopamine receptors extends to the regulation of synaptic plasticity. Recent studies, using transgenic mice in which cells express D1 and D2 receptors, have uncovered unappreciated differences between MSNs that shape glutamatergic signaling and the influence of DA on synaptic plasticity. These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function.
View details for DOI 10.1016/j.tins.2007.03.008
View details for Web of Science ID 000246752000007
View details for PubMedID 17408758
RGS4-dependent attenuation of M-4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion
2006; 9 (6): 832-842
Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D(2) dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D(2) dopamine receptor modulation of calcium (Ca(2+)) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M(4) muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.
View details for DOI 10.1038/nn1700
View details for Web of Science ID 000237895200024
View details for PubMedID 16699510
Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons
2006; 50 (3): 443-452
Long-term depression (LTD) of the synapse formed between cortical pyramidal neurons and striatal medium spiny neurons is central to many theories of motor plasticity and associative learning. The induction of LTD at this synapse is thought to depend upon D(2) dopamine receptors localized in the postsynaptic membrane. If this were true, LTD should be inducible in neurons from only one of the two projection systems of the striatum. Using transgenic mice in which neurons that contribute to these two systems are labeled, we show that this is not the case. Rather, in both cell types, the D(2) receptor dependence of LTD induction reflects the need to lower M(1) muscarinic receptor activity-a goal accomplished by D(2) receptors on cholinergic interneurons. In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning.
View details for DOI 10.1016/j.neuron.2006.04.010
View details for Web of Science ID 000237726800013
View details for PubMedID 16675398
Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models
2006; 9 (2): 251-259
Parkinson disease is a common neurodegenerative disorder that leads to difficulty in effectively translating thought into action. Although it is known that dopaminergic neurons that innervate the striatum die in Parkinson disease, it is not clear how this loss leads to symptoms. Recent work has implicated striatopallidal medium spiny neurons (MSNs) in this process, but how and precisely why these neurons change is not clear. Using multiphoton imaging, we show that dopamine depletion leads to a rapid and profound loss of spines and glutamatergic synapses on striatopallidal MSNs but not on neighboring striatonigral MSNs. This loss of connectivity is triggered by a new mechanism-dysregulation of intraspine Cav1.3 L-type Ca(2+) channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease.
View details for DOI 10.1038/nn1632
View details for Web of Science ID 000234990100021
View details for PubMedID 16415865