I am interested in the neural circuits for motor control and how it is affected under the progression of Parkinson’s disease (PD). Currently I focus on dissecting the role of the striatal spiny projection neurons on integrating information from other brain areas, which are highly altered in PD. By incorporating various tools and state-of-the-art approaches, such as two-photon imaging/uncaging, patch-clamp electrophysiology, optogenetic manipulation of neural circuit and computational simulation, I aim to provide a comprehensive view, in the neuronal circuitry level, of how motor control is achieved and what goes wrong during the pathophysiological changes in PD, so that potential new therapeutic targets will be discovered to help PD patients.
My past training has quipped me with various research skills including:
1.Brain slice electrophysiology for studying ion channel physiology and synaptic transmission.
2.Two-photon calcium imaging for monitor subcellular neuronal activity in brain slices and in vivo.
3.Optics and microscopy development.
4.Computer programming for image processing, data analysis, and instrumental control.
5.Optogenetic techniques for controlling targeted neuronal circuits with transgenic mice and AAV viral injection.
6.Immunohistochemistry and biochemical essays.
These skills enable me not only to design and perform bench works independently but also capable to have a working model and a big picture in mind. I have a solid background in biology and neurophysiology, and my broad research skills further facilitate collaboration with experts from multidisciplinary. In summary, I have demonstrated a record for successfully completing research projects, and my strong motivation and substantial research skills have prepared me well to achieve my goal.
Honors & Awards
Postdoctoral Research Fellowship, Parkinson’s Disease Foundation, USA (2015-2016)
Special Travel Award for Annual Meeting for Society for Neuroscience, Society for Neuroscience, USA The Japan Neuroscience Society, Japan (2011)
Travel Award for FENS Forum, Federation of European Neurosciences, EU (2010)
The Scholarship for Studying Abroad, The Ministry of Education, Taiwan (2007-2010)
Travel Award for IBRO APRC/RIKEN BSI Advanced School, IBRO APRC, Japan (2007)
Travel Award for SfN meeting, The Ministry of Education, Taiwan (2007)
Dr. De-qui Chie and Dr. Song-yen Fong Memorial Scholarship, College of Life Science, NTU (2006)
Boards, Advisory Committees, Professional Organizations
Member, Society for Neuroscience, USA (2006 - Present)
Member, The Japan Neuroscience Society, Japan (2011 - Present)
Member, Neuroscience Society of Taiwan, Taiwan (2006 - Present)
Bachelor of Science, National Taiwan University (2003)
Master of Science, National Taiwan University (2007)
Doctor of Philosophy, University College London (2012)
Jun Ding, Postdoctoral Research Mentor
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
Denoising of two-photon fluorescence images with Block-Matching 3D filtering
2014; 68 (2): 308-316
Two-photon florescence imaging is widely used to perform morphological analysis of subcellular structures such as neuronal dendrites and spines, astrocytic processes etc. This method is also indispensable for functional analysis of cellular activity such as Ca2+ dynamics. Although spatial resolution of laser scanning two-photon system is greater than that of confocal or wide field microscope, it is still diffraction limited. In practice, the resolution of the system is more affected by its signal-to-noise ratio (SNR) than the diffraction limit. Thus, various approaches aiming to increase the SNR in two-photon imaging are desirable and can potentially save on building costly super-resolution imaging system. Here we analyze the statistics of noise in the two-photon florescence images of hippocampal astrocytes expressing genetically encoded Ca2+ sensor GCaMP2 and show that it can be reasonably well approximated using the same models which are used for describing noise in images acquired with digital cameras. This allows to use denoising methods available for wide field imaging on two-photon images. Particularly we demonstrate that the Block-Matching 3D (BM3D) filter can significantly improve the quality of two-photon fluorescence images so small details such as astrocytic processes can be easier identified. Moreover, denoising of the images with BM3D yields less noisy Ca2+ signals in astrocytes when denoising of the images with Gaussian filter.
View details for DOI 10.1016/j.ymeth.2014.03.010
View details for Web of Science ID 000338180700005
View details for PubMedID 24657185
Spatiotemporal calcium dynamics in single astrocytes and its modulation by neuronal activity
2014; 55 (2): 119-129
Astrocytes produce a complex repertoire of Ca2+ events that coordinate their major functions. The principle of Ca2+ events integration in astrocytes, however, is unknown. Here we analyze whole Ca2+ events, which were defined as spatiotemporally interconnected transient Ca2+ increases. Using such analysis in single hippocampal astrocytes in culture and in slices we found that spreads and durations of Ca2+ events follow power law distributions, a fingerprint of scale-free systems. A mathematical model demonstrated that such Ca2+ dynamics can arise from intracellular inositol-3-phosphate diffusion. The power law exponent (α) was decreased by activation of metabotropic glutamate receptors (mGluRs) either by specific receptor agonist or by low frequency stimulation of glutamatergic fibers in hippocampal slices. Decrease in α indicated an increase in proportion of large Ca2+ events. Notably, mGluRs activation did not increase the frequency of whole Ca2+ events. This result suggests that neuronal activity does not trigger new Ca2+ events in astrocytes (detectable by our methods), but modulates the properties of existing ones. Thus, our results provide a new perspective on how astrocyte responds to neuronal activity by changing its Ca2+ dynamics, which might further affect local network by triggering release of gliotransmitters and by modulating local blood flow.
View details for DOI 10.1016/j.ceca.2013.12.006
View details for Web of Science ID 000332911400005
View details for PubMedID 24484772
Tonic GABA(A) conductance decreases membrane time constant and increases EPSP-spike precision in hippocampal pyramidal neurons
FRONTIERS IN NEURAL CIRCUITS
Because of a complex dendritic structure, pyramidal neurons have a large membrane surface relative to other cells and so a large electrical capacitance and a large membrane time constant (τm). This results in slow depolarizations in response to excitatory synaptic inputs, and consequently increased and variable action potential latencies, which may be computationally undesirable. Tonic activation of GABAA receptors increases membrane conductance and thus regulates neuronal excitability by shunting inhibition. In addition, tonic increases in membrane conductance decrease the membrane time constant (τm), and improve the temporal fidelity of neuronal firing. Here we performed whole-cell current clamp recordings from hippocampal CA1 pyramidal neurons and found that bath application of 10μM GABA indeed decreases τm in these cells. GABA also decreased first spike latency and jitter (standard deviation of the latency) produced by current injection of 2 rheobases (500 ms). However, when larger current injections (3-6 rheobases) were used, GABA produced no significant effect on spike jitter, which was low. Using mathematical modeling we demonstrate that the tonic GABAA conductance decreases rise time, decay time and half-width of EPSPs in pyramidal neurons. A similar effect was observed on EPSP/IPSP pairs produced by stimulation of Schaffer collaterals: the EPSP part of the response became shorter after application of GABA. Consistent with the current injection data, a significant decrease in spike latency and jitter was obtained in cell attached recordings only at near-threshold stimulation (50% success rate, S50). When stimulation was increased to 2- or 3- times S50, GABA significantly affected neither spike latency nor spike jitter. Our results suggest that a decrease in τm associated with elevations in ambient GABA can improve EPSP-spike precision at near-threshold synaptic inputs.
View details for DOI 10.3389/fncir.2013.00205
View details for Web of Science ID 000328958000001
View details for PubMedID 24399937
Backpropagating Action Potentials Enable Detection of Extrasynaptic Glutamate by NMDA Receptors
2012; 1 (5): 495-505
Synaptic NMDA receptors (NMDARs) are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, back-propagating action potentials (bAPs) recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are "protected," under baseline conditions, from such glutamate influences by peri-synaptic transporters: we detect bAP-evoked Ca(2+) entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca(2+) entry either downregulates or upregulates an h-channel conductance (G(h)) of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of G(h) plasticity. G(h) plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation.
View details for DOI 10.1016/j.celrep.2012.03.007
View details for Web of Science ID 000309712600011
View details for PubMedID 22832274
ROLES OF A-TYPE POTASSIUM CURRENTS IN TUNING SPIKE FREQUENCY AND INTEGRATING SYNAPTIC TRANSMISSION IN NORADRENERGIC NEURONS OF THE A7 CATECHOLAMINE CELL GROUP IN RATS
2010; 168 (3): 633-645
We investigated voltage-dependent K(+) currents (I(K)) in noradrenergic (NAergic) A7 neurons. The I(K) evoked consisted of A-type I(K) (I(A)), which had the characteristics of a low threshold for activation (approximately -50 mV), fast activation/inactivation, and rapid recovery from inactivation. Since the I(A) were blocked by heteropodatoxin-2 (Hptx-2), a specific Kv4 channel blocker, and the NAergic A7 neurons were shown to be reactive with antibodies against Kv4.1/Kv4.3 channel proteins, we conclude that the I(A) evoked in NAergic neurons are mediated by Kv4.1/Kv4.3 channels. I(A) were also evoked using voltage commands of a single action potential (AP), a subthreshold voltage change between two consecutive APs, or excitatory postsynaptic potential (EPSP) activity recorded in current-clamp mode (CCM). Blockade of the I(A) by 4-AP, a broad spectrum I(A) blocker, or by Hptx-2 increased the half-width and spontaneous firing of APs and reduced the amount of synaptic drive needed to elicit APs in CCM, showing that the I(A) play important roles in regulating the shape and firing frequency of APs and in synaptic integration in NAergic A7 neurons. Since these neurons are the principal projection neurons to the dorsal horn of the spinal cord, these results also suggest roles for Kv4.1/4.3 channels in descending NAergic pain regulation.
View details for DOI 10.1016/j.neuroscience.2010.03.063
View details for Web of Science ID 000278611500005
View details for PubMedID 20381592
Neurokinin 1 receptor activates transient receptor potential-like currents in noradrenergic A7 neurons in rats
MOLECULAR AND CELLULAR NEUROSCIENCE
2009; 42 (1): 56-65
Noradrenergic (NAergic) A7 neurons are involved in modulating nociception by releasing noradrenaline in the dorsal spinal cord. Since NAergic A7 neurons receive dense Substance P (Sub-P) releasing terminals from ventromedial medulla, here we tested the effect of Sub-P on them. Bath application of Sub-P induced an inward current (I(Sub-P)) in NAergic neurons, which was significantly blocked by Neurokinin 1 (NK1) receptor antagonist. The I(Sub-P) was reversed at approximately -20 mV, blocked by several TRP channel blockers, enhanced by OAG and negatively regulated by PKC. Immunohistochemistry staining showed that NAergic A7 neurons express high level of TRPC6 channel proteins, which is consistent with pharmacological properties of I(Sub-P) shown above, as TRPC6 channel is shown to be augmented by OAG and inhibited by PKC. In conclusion, the above results provide mechanism underlying postsynaptic action of Sub-P on NAergic A7 neurons and a role for TRPC6 channel in NAergic pain modulation.
View details for DOI 10.1016/j.mcn.2009.05.006
View details for Web of Science ID 000268735300006
View details for PubMedID 19463951
Physiological and morphological properties of, and effect of substance P on, neurons in the A7 catecholamine cell group in rats
2008; 153 (4): 1020-1033
The A7 catecholamine cell group consists of noradrenergic (NAergic) neurons that project to the dorsal horn of the spinal cord. Here, we characterized their morphology and physiology properties and tested the effect of substance P (Sub-P) on them, since the results of many morphological studies suggest that A7 neurons are densely innervated by Sub-P-releasing terminals from nuclei involved in the descending inhibitory system, such as the lateral hypothalamus and periaqueductal gray area. Whole cell recordings were made from neurons located approximately 200 microm rostral to the trigeminal motor nucleus (the presumed A7 area) in sagittal brainstem slices from rats aged 7-10 days. After recording, the neurons were injected with biocytin and immunostained with antibody against dopamine-beta-hydroxylase (DBH). DBH-immunoreactive (ir) cells were presumed to be NAergic neurons. They had a large somata diameter ( approximately 20 microm) and relatively simple dendritic branching patterns. They fired action potentials (AP) spontaneously with or without blockade of synaptic inputs, and had similar properties to those of NAergic neurons in other areas, including the existence of calcium channel-mediated APs and a voltage-dependent delay in initiation of the AP (an indicator of the existence of A-type potassium currents) and an ability to be hyperpolarized by norepinephrine. Furthermore, in all DBH-ir neurons tested, Sub-P caused depolarization of the membrane potential and an increase in neuronal firing rate by acting on neurokinin-1 receptors. Non-DBH-ir neurons with a smaller somata size were also found in the A7 area. These showed great diversity in firing patterns and about half were depolarized by Sub-P. Morphological examination suggested that the non-DBH-ir neurons form contacts with DBH-ir neurons. These results provide the first description of the intrinsic regulation of membrane properties of, and the excitatory effect of Sub-P on, A7 area neurons, which play an important role in pain regulation.
View details for DOI 10.1016/j.neuroscience.2008.03.011
View details for Web of Science ID 000256742200013
View details for PubMedID 18440151