Yihe received her Ph.D. degree in Physiology in 2020 from University of Wisconsin-Madison. Her thesis work focused on interrogating hippocampal microcircuits with a hybrid genetically-encoded voltage indicator. In 2021, Yihe joined the Giardino lab as a postdoctoral scholar under the co-mentorship of Dr. William Giardino and Dr. Julie Kauer. At the Giardino lab, Yihe aims to leverage imaging techniques and slice electrophysiology to investigate the underlying mechanism of addiction and sleep disorders in BNST neuropeptide circuits.
Honors & Awards
Biological Sciences Scholar Award, University of Wisconsin-Madison (2012)
Bachelor of Science, Peking University (2012)
Doctor of Philosophy, University of Wisconsin Madison (2020)
Current Research and Scholarly Interests
Systems & Circuits Neuroscience, Addiction, Stress, Sleep, Plasticity, Imaging
Imaging Voltage Globally and in Isofrequency Lamina in Slices of Mouse Ventral Cochlear Nucleus.
The cochlear nuclei (CN) receive sensory information from the ear and perform fundamental computations before relaying this information to higher processing centers. These computations are performed by distinct types of neurons interconnected in circuits dedicated to the specialized roles of the auditory system. In the present study we explored the use of voltage imaging to investigate CN circuitry. We tested two approaches based on fundamentally different voltage sensing technologies. Using a voltage-sensitive dye we recorded glutamate receptor-independent signals arising predominantly from axons. The mean conduction velocity of these fibers of 0.27 m/sec was rapid but in range with other unmyelinated axons. We then used a genetically-encoded hybrid voltage sensor (hVOS) to image voltage from a specific population of neurons. Probe expression was controlled using Cre recombinase linked to c-fos activation. This activity-induced gene enabled targeting of neurons that are activated when a mouse hears a pure 15 kHz tone. In CN slices from these animals auditory nerve fiber stimulation elicited a glutamate receptor-dependent depolarization in hVOS probe-labeled neurons. These cells resided within a band corresponding to an isofrequency lamina, and responded with a high degree of synchrony. In contrast to the axonal origin of voltage-sensitive dye signals, hVOS signals represent predominantly post-synaptic responses. The introduction of voltage imaging to the CN creates the opportunity to investigate auditory processing circuitry in populations of neurons targeted on the basis of their genetic identity and their roles in sensory processing.Significance StatementThe cochlear nucleus uses dedicated circuitry to process and interpret information from the ear. This circuitry is organized tonotopically into laminae, each containing cells with an optimal sensitivity to a specific sound frequency. By targeting a genetically-encoded hybrid voltage sensor (hVOS) to identify neurons activated during the presentation of sound, the properties and function of these neurons become accessible to study in slices of mouse ventral cochlear nucleus. Imaging hVOS signals in these slices recapitulated the tonotopic organization. Imaging with a voltage sensitive dye provided a contrasting global view of signals arising predominantly from unmyelinated axons creating a potential method for studying type II auditory nerve or DCN parallel fibers.
View details for DOI 10.1523/ENEURO.0465-22.2023
View details for PubMedID 36792362
Neural circuit mechanisms of the cholecystokinin (CCK) neuropeptide system in addiction.
Given historical focus on the roles for cholecystokinin (CCK) as a peripheral hormone controlling gastrointestinal processes and a brainstem peptide regulating food intake, the study of CCK as a limbic neuromodulator coordinating reward-seeking and emotional behavior remains underappreciated. Furthermore, localization of CCK to specialized interneurons throughout the hippocampus and cortex relegated CCK to being examined primarily as a static cell type marker rather than a dynamic functional neuromodulator. Yet, over three decades of literature have been generated by efforts to delineate the central mechanisms of addiction-related behaviors mediated by the CCK system across the striatum, amygdala, hypothalamus, and midbrain. Here, we cover fundamental findings that implicate CCK neuron activity and CCK receptor signaling in modulating drug intake and drug-seeking (focusing on psychostimulants, opioids, and alcohol). In doing so, we highlight the few studies that indicate sex differences in CCK expression and corresponding drug effects, emphasizing the importance of examining hormonal influences and sex as a biological variable in translating basic science discoveries to effective treatments for substance use disorders in human patients. Finally, we point toward understudied subcortical sources of endogenous CCK and describe how continued neurotechnology advancements can be leveraged to modernize understanding of the neural circuit mechanisms underlying CCK release and signaling in addiction-relevant behaviors.
View details for DOI 10.1016/j.addicn.2022.100024
View details for PubMedID 35983578
Direct synaptic excitation between hilar mossy cells revealed with a targeted voltage sensor.
The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of excitatory neuron strategically located in the hilus of the dentate gyrus where they can contribute to this processing through networks of synapses with inhibitory neurons and dentate granule cells. Some prior work has suggested that MCs can form excitatory synapses with other MCs, but the role of these synapses in the network activity of the dentate gyrus has received little attention. Here, we investigated synaptic inputs to MCs in mouse hippocampal slices using a genetically encoded hybrid voltage sensor (hVOS) targeted to MCs by Cre-lox technology. This enabled optical recording of voltage changes from multiple MCs simultaneously. Stimulating granule cells and CA3 pyramidal cells activated well-established inputs to MCs and elicited synaptic responses as expected. However, the weak blockade of MC responses to granule cell layer stimulation by DCG-IV raised the possibility of another source of excitation. To evaluate synapses between MCs as this source, single MCs were stimulated focally. Stimulation of one MC above its action potential threshold evoked depolarizing responses in neighboring MCs that depended on glutamate receptors. Short latency responses of MCs to other MCs did not depend on release from granule cell axons. However, granule cells did contribute to the longer latency responses of MCs to stimulation of other MCs. Thus, MCs transmit their activity to other MCs both through direct synaptic coupling and through polysynaptic coupling with dentate granule cells. MC-MC synapses can redistribute information entering the dentate gyrus and thus shape and modulate the electrical activity underlying hippocampal functions such as navigation and memory, as well as excessive excitation during seizures.
View details for DOI 10.1002/hipo.23386
View details for PubMedID 34478219
Optical Studies of Action Potential Dynamics with hVOS probes.
Current opinion in biomedical engineering
2019; 12: 51-58
The detection of action potentials and the characterization of their waveform represent basic benchmarks for evaluating optical sensors of voltage. The effectiveness of a voltage sensor in reporting action potentials will determine its usefulness in voltage imaging experiments designed for the study of neural circuitry. The hybrid voltage sensor (hVOS) technique is based on a sensing mechanism with a rapid response to voltage changes. hVOS imaging is thus well suited for optical studies of action potentials. This technique detects action potentials in intact brain slices with an excellent signal-to-noise ratio. These optical action potentials recapitulate voltage recordings with high temporal fidelity. In different genetically-defined types of neurons targeted by cre-lox technology, hVOS recordings of action potentials recapitulate the expected differences in duration. Furthermore, by targeting an hVOS probe to axons, imaging experiments can follow action potential propagation and document dynamic changes in waveform resulting from use-dependent plasticity.
View details for DOI 10.1016/j.cobme.2019.09.007
View details for PubMedID 32864524
View details for PubMedCentralID PMC7449517
Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor
JOURNAL OF NEUROSCIENCE
2017; 37 (38): 9305–19
Genetically encoded voltage indicators create an opportunity to monitor electrical activity in defined sets of neurons as they participate in the complex patterns of coordinated electrical activity that underlie nervous system function. Taking full advantage of genetically encoded voltage indicators requires a generalized strategy for targeting the probe to genetically defined populations of cells. To this end, we have generated a mouse line with an optimized hybrid voltage sensor (hVOS) probe within a locus designed for efficient Cre recombinase-dependent expression. Crossing this mouse with Cre drivers generated double transgenics expressing hVOS probe in GABAergic, parvalbumin, and calretinin interneurons, as well as hilar mossy cells, new adult-born neurons, and recently active neurons. In each case, imaging in brain slices from male or female animals revealed electrically evoked optical signals from multiple individual neurons in single trials. These imaging experiments revealed action potentials, dynamic aspects of dendritic integration, and trial-to-trial fluctuations in response latency. The rapid time response of hVOS imaging revealed action potentials with high temporal fidelity, and enabled accurate measurements of spike half-widths characteristic of each cell type. Simultaneous recording of rapid voltage changes in multiple neurons with a common genetic signature offers a powerful approach to the study of neural circuit function and the investigation of how neural networks encode, process, and store information.SIGNIFICANCE STATEMENT Genetically encoded voltage indicators hold great promise in the study of neural circuitry, but realizing their full potential depends on targeting the sensor to distinct cell types. Here we present a new mouse line that expresses a hybrid optical voltage sensor under the control of Cre recombinase. Crossing this line with Cre drivers generated double-transgenic mice, which express this sensor in targeted cell types. In brain slices from these animals, single-trial hybrid optical voltage sensor recordings revealed voltage changes with submillisecond resolution in multiple neurons simultaneously. This imaging tool will allow for the study of the emergent properties of neural circuits and permit experimental tests of the roles of specific types of neurons in complex circuit activity.
View details for DOI 10.1523/JNEUROSCI.1363-17.2017
View details for Web of Science ID 000411231700016
View details for PubMedID 28842412
View details for PubMedCentralID PMC5607471
Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor
2017; 4 (4)
The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.
View details for DOI 10.1523/ENEURO.0146-17.2017
View details for Web of Science ID 000407416400013
View details for PubMedID 28785728
View details for PubMedCentralID PMC5526655
Single-trial imaging of spikes and synaptic potentials in single neurons in brain slices with genetically encoded hybrid voltage sensor
JOURNAL OF NEUROPHYSIOLOGY
2015; 113 (4): 1249–59
Genetically encoded voltage sensors expand the optogenetics toolkit into the important realm of electrical recording, enabling researchers to study the dynamic activity of complex neural circuits in real time. However, these probes have thus far performed poorly when tested in intact neural circuits. Hybrid voltage sensors (hVOS) enable the imaging of voltage by harnessing the resonant energy transfer that occurs between a genetically encoded component, a membrane-tethered fluorescent protein that serves as a donor, and a small charged molecule, dipicrylamine, which serves as an acceptor. hVOS generates optical signals as a result of voltage-induced changes in donor-acceptor distance. We expressed the hVOS probe in mouse brain by in utero electroporation and in transgenic mice with a neuronal promoter. Under conditions favoring sparse labeling we could visualize single-labeled neurons. hVOS imaging reported electrically evoked fluorescence changes from individual neurons in slices from entorhinal cortex, somatosensory cortex, and hippocampus. These fluorescence signals tracked action potentials in individual neurons in a single trial with excellent temporal fidelity, producing changes that exceeded background noise by as much as 16-fold. Subthreshold synaptic potentials were detected in single trials in multiple distinct cells simultaneously. We followed signal propagation between different cells within one field of view and between dendrites and somata of the same cell. hVOS imaging thus provides a tool for high-resolution recording of electrical activity from genetically targeted cells in intact neuronal circuits.
View details for DOI 10.1152/jn.00691.2014
View details for Web of Science ID 000349720600019
View details for PubMedID 25411462
View details for PubMedCentralID PMC4329433