Da-Ting Lin, Ph.D.

@article{pmid34921779,

title = {Detailed mapping of behavior reveals the formation of prelimbic neural ensembles across operant learning},

author = {Yan Zhang and Alexander J Denman and Bo Liang and Craig T Werner and Nicholas J Beacher and Rong Chen and Yun Li and Yavin Shaham and Giovanni Barbera and Da-Ting Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/34921779/},

doi = {10.1016/j.neuron.2021.11.022},

issn = {1097-4199},

year  = {2021},

date = {2021-12-01},

urldate = {2021-12-01},

journal = {Neuron},

abstract = {The prelimbic cortex (PrL) is involved in the organization of operant behaviors, but the relationship between longitudinal PrL neural activity and operant learning and performance is unknown. Here, we developed deep behavior mapping (DBM) to identify behavioral microstates in video recordings. We combined DBM with longitudinal calcium imaging to quantify behavioral tuning in PrL neurons as mice learned an operant task. We found that a subset of PrL neurons were strongly tuned to highly specific behavioral microstates, both task and non-task related. Overlapping neural ensembles were tiled across consecutive microstates in the response-reinforcer sequence, forming a continuous map. As mice learned the operant task, weakly tuned neurons were recruited into new ensembles, with a bias toward behaviors similar to their initial tuning. In summary, our data suggest that the PrL contains neural ensembles that jointly encode a map of behavioral states that is fine grained, is continuous, and grows during operant learning.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{BARBERA2020101024,

title = {An open-source capacitive touch sensing device for three chamber social behavior test},

author = {Giovanni Barbera and Bo Liang and Yan Zhang and Casey Moffitt and Yun Li and Da-Ting Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/32939346/},

doi = {https://doi.org/10.1016/j.mex.2020.101024},

issn = {2215-0161},

year  = {2020},

date = {2020-01-01},

journal = {MethodsX},

volume = {7},

pages = {101024},

abstract = {A common feature of many neuropsychiatric disorders is deficit in social behavior. In order to study mouse models for such disorders, several behavioral tests involving social interaction with other mice have been developed. While a precise annotation of rodent behavioral state is necessary for these types of experiments, manual annotation of rodent social behavior is time-consuming and subjective. Therefore, an automated system that can instantly and independently quantify the animal's social exploration is desirable. We developed a capacitive touch device for automated detection of direct social-exploration in a modified three-chamber social behavior test. In this device, capacitive sensors can readily detect nose-pokes and other direct physical touches from the rodent under investigation. In addition, a conductive barrier makes mouse behavioral output immediately available for real-time use, by sending data to a host computer via a custom Field-Programmable Gate Array (FPGA) platform. Our capacitive touch sensing device produced similar results to the manually annotated data, demonstrating the ability to instantly and independently analyze direct social-exploration of animals in a social behavior test. Compared to the manual annotation method, this capacitive touch sensing system can be used to instantaneously quantify direct social-exploration, saving significant amount of time of post-hoc video scoring. Furthermore, this low-cost method enhances the objectivity of data by reducing experimenter involvement in analysis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{BARBERA201956,

title = {A wireless miniScope for deep brain imaging in freely moving mice},

author = {Giovanni Barbera and Bo Liang and Lifeng Zhang and Yun Li and Da-Ting Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/31116963/},

doi = {https://doi.org/10.1016/j.jneumeth.2019.05.008},

issn = {0165-0270},

year  = {2019},

date = {2019-01-01},

journal = {Journal of Neuroscience Methods},

volume = {323},

pages = {56 - 60},

abstract = {Background 

The increasing interest in the study of neuronal activities at the microcircuit level is motivating neuroscientists and engineers to push the limits in developing miniature in vivo imaging systems. This inter-disciplinary effort led to an increasingly widespread use of wearable miniature microscopes, constantly improving in size, cost, spatial and temporal resolutions, and signal to noise ratio. 

New method 

Here we developed a miniature wireless fluorescence microscope (miniScope) that allows recording of brain neural activities at single cell resolution. The wireless miniScope has onboard field-programmable gate array (FPGA) and Micro SD Card storage, and is powered by a battery backpack. 

Results 

Using this wireless miniScope, we simultaneously recorded activities from hundreds of medium spiny neurons (MSNs) in the dorsal striatum of two freely moving mice interacting with each other in an open field, with excellent spatial and temporal resolutions. 

Comparison with existing methods 

Existing miniaturized microscope systems have connecting cables between the microscope sensor and the data acquisition system, consequently limiting the recording to one animal at a time. The wireless miniScope allows simultaneous recording of multiple mice in a group, and could also be applied to freely behaving small primates in the future. 

Conclusion 

The wireless miniScope expands the realm of possible behavioral experiments, both by minimizing the repercussions of the cable from the imaging device on the rodent's behavior and by enabling simultaneous in vivo imaging from multiple animals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yang:2019aa,

title = {A Two-Step GRIN Lens Coating for In Vivo Brain Imaging},

author = {Yupeng Yang and Lifeng Zhang and Zhenni Wang and Bo Liang and Giovanni Barbera and Casey Moffitt and Yun Li and Da-Ting Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/30852804/},

doi = {10.1007/s12264-019-00356-x},

isbn = {1995-8218},

year  = {2019},

date = {2019-01-01},

journal = {Neuroscience Bulletin},

volume = {35},

number = {3},

pages = {419--424},

abstract = {The complex spatial and temporal organization of neural activity in the brain is important for information-processing that guides behavior. Hence, revealing the real-time neural dynamics in freely-moving animals is fundamental to elucidating brain function. Miniature fluorescence microscopes have been developed to fulfil this requirement. With the help of GRadient INdex (GRIN) lenses that relay optical images from deep brain regions to the surface, investigators can visualize neural activity during behavioral tasks in freely-moving animals. However, the application of GRIN lenses to deep brain imaging is severely limited by their availability. Here, we describe a protocol for GRIN lens coating that ensures successful long-term intravital imaging with commercially-available GRIN lenses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{LIANG201983,

title = {An open-source automated surgical instrument for microendoscope implantation},

author = {Bo Liang and Lifeng Zhang and Casey Moffitt and Yun Li and Da-Ting Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/30326202/},

doi = {https://doi.org/10.1016/j.jneumeth.2018.10.013},

issn = {0165-0270},

year  = {2019},

date = {2019-01-01},

journal = {Journal of Neuroscience Methods},

volume = {311},

pages = {83 - 88},

abstract = {Background 

Gradient index (GRIN) lenses can be used to image deep brain regions otherwise inaccessible via standard optical imaging methods. Brain tissue aspiration before GRIN lens implantation is a widely adopted approach. However, typical brain tissue aspiration methods still rely on a handheld vacuum needle, which is subject to human error and low reproducibility. Therefore, a high-precision automated surgical instrument for brain tissue aspiration is desirable. 

New Method 

We developed a robotic surgical instrument that utilizes robotic control of a needle connected to a vacuum pump to aspirate brain tissue. The system was based on a commercial stereotaxic instrument, and the additional parts can be purchased off-the-shelf or Computer Numerical Control (CNC) machined. A MATLAB-based user-friendly graphical user interface (GUI) was developed to control the instrument. 

Results 

We demonstrated the GRIN lens implantation procedure in the dorsal striatum utilizing our proposed surgical instrument and confirmed the surgical results by microscope after the implantation. 

Compare with Existing Method(s) 

Compared to the traditional handheld method, the automatic tissue aspiration can be performed by interacting with GUI. The instrument was designed specifically for microendoscope implantation, but it can also be easily adapted for robotic craniotomy. This robotic surgical instrument can minimize human error, reduce training time, and greatly increase surgical precision. 

Conclusions 

Our robotic surgical instrument is an ideal solution for brain tissue aspiration prior to GRIN lens implantation. It will be useful for neuroscientists performing in vivo deep brain imaging using miniature microscope or two-photon microscope combined with microendoscopes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1002/cpns.56,

title = {Miniscope GRIN Lens System for Calcium Imaging of Neuronal Activity from Deep Brain Structures in Behaving Animals},

author = {Lifeng Zhang and Bo Liang and Giovanni Barbera and Sarah Hawes and Yan Zhang and Kyle Stump and Ira Baum and Yupeng Yang and Yun Li and Da-Ting Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/30315730/},

doi = {10.1002/cpns.56},

year  = {2019},

date = {2019-01-01},

journal = {Current Protocols in Neuroscience},

volume = {86},

number = {1},

pages = {e56},

abstract = {Abstract Visualizing neural activity from deep brain regions in freely behaving animals through miniature fluorescent microscope (miniscope) systems is becoming more important for understanding neural encoding mechanisms underlying cognitive functions. Here we present our custom-designed miniscope GRadient INdex (GRIN) lens system that enables simultaneously recording from hundreds of neurons for months. This article includes miniscope design, the surgical procedure for GRIN lens implantation, miniscope mounting on the head of a mouse, and data acquisition and analysis. First, a target brain region is labeled with virus expressing GCaMP6; second, a GRIN lens is implanted above the target brain region; third, following mouse surgical recovery, a miniscope is mounted on the head of the mouse above the GRIN lens; and finally, neural activity is recorded from the freely behaving mouse. This system can be applied to recording the same population of neurons longitudinally, enabling the elucidation of neural mechanisms underlying behavioral control. copyright 2018 by John Wiley & Sons, Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Liang:2018aa,

title = {Distinct and Dynamic ON and OFF Neural Ensembles in the Prefrontal Cortex Code Social Exploration.},

author = {Bo Liang and Lifeng Zhang and Giovanni Barbera and Wenting Fang and Jing Zhang and Xiaochun Chen and Rong Chen and Yun Li and Da-Ting Lin},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30269987},

doi = {10.1016/j.neuron.2018.08.043},

issn = {1097-4199 (Electronic); 0896-6273 (Linking)},

year  = {2018},

date = {2018-09-13},

journal = {Neuron},

address = {Intramural Research Program, National Institute on Drug Abuse, NIH, 333 Cassell Drive, Baltimore, MD 21224, USA.},

abstract = {The medial prefrontal cortex (mPFC) is important for social behavior, but the mechanisms by which mPFC neurons code real-time social exploration remain largely unknown. Here we utilized miniScopes to record calcium activities from hundreds of excitatory neurons in the mPFC while mice freely explored restrained social targets in the absence or presence of the psychedelic drug phencyclidine (PCP). We identified distinct and dynamic ON and OFF neural ensembles that displayed opposing activities to code real-time behavioral information. We further illustrated that ON and OFF ensembles tuned to social exploration carried information of salience and novelty for social targets. Finally, we showed that dysfunctions in these ensembles were associated with abnormal social exploration elicited by PCP. Our findings underscore the importance of mPFC ON and OFF neural ensembles for proper exploratory behavior, including social exploration, and pave the way for future studies elucidating neural circuit dysfunctions in psychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zhang0201,

title = {BDNF rescues prefrontal dysfunction elicited by pyramidal neuron-specific DTNBP1 deletion in vivo.},

author = {Wen Zhang and Kathryn M Daly and Bo Liang and Lifeng Zhang and Xuan Li and Yun Li and Da-Ting Lin},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27330059},

doi = {10.1093/jmcb/mjw029},

issn = {1759-4685 (Electronic); 1759-4685 (Linking)},

year  = {2017},

date = {2017-04-01},

journal = {J Mol Cell Biol},

volume = {9},

number = {2},

pages = {117--131},

address = {Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.},

abstract = {Dystrobrevin-binding protein 1 (Dtnbp1) is one of the earliest identified schizophrenia susceptibility genes. Reduced expression of DTNBP1 is commonly found in brain areas of schizophrenic patients. Dtnbp1-null mutant mice exhibit abnormalities in behaviors and impairments in neuronal activities. However, how diminished DTNBP1 expression contributes to clinical relevant features of schizophrenia remains to be illustrated. Here, using a conditional Dtnbp1 knockout mouse line, we identified an in vivo schizophrenia-relevant function of DTNBP1 in pyramidal neurons of the medial prefrontal cortex (mPFC). We demonstrated that DTNBP1 elimination specifically in pyramidal neurons of the mPFC impaired mouse pre-pulse inhibition (PPI) behavior and reduced perisomatic GABAergic synapses. We further revealed that loss of DTNBP1 in pyramidal neurons diminished activity-dependent secretion of brain-derived neurotrophic factor (BDNF). Finally, we showed that chronic BDNF infusion in the mPFC fully rescued both GABAergic synaptic dysfunction and PPI behavioral deficit induced by DTNBP1 elimination from pyramidal neurons. Our findings highlight brain region- and cell type-specific functions of DTNBP1 in the pathogenesis of schizophrenia, and underscore BDNF restoration as a potential therapeutic strategy for schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Barbera2016,

title = {Spatially Compact Neural Clusters in the Dorsal Striatum Encode Locomotion Relevant Information.},

author = {Giovanni Barbera and Bo Liang and Lifeng Zhang and Charles R Gerfen and Eugenio Culurciello and Rong Chen and Yun Li and Da-Ting Lin},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27667003},

doi = {10.1016/j.neuron.2016.08.037},

issn = {1097-4199 (Electronic); 0896-6273 (Linking)},

year  = {2016},

date = {2016-10-05},

journal = {Neuron},

volume = {92},

number = {1},

pages = {202--213},

address = {Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA; Weldon School of Biomedical Engineering, Purdue University, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, USA.},

abstract = {An influential striatal model postulates that neural activities in the striatal direct and indirect pathways promote and inhibit movement, respectively. Normal behavior requires coordinated activity in the direct pathway to facilitate intended locomotion and indirect pathway to inhibit unwanted locomotion. In this striatal model, neuronal population activity is assumed to encode locomotion relevant information. Here, we propose a novel encoding mechanism for the dorsal striatum. We identified spatially compact neural clusters in both the direct and indirect pathways. Detailed characterization revealed similar cluster organization between the direct and indirect pathways, and cluster activities from both pathways were correlated with mouse locomotion velocities. Using machine-learning algorithms, cluster activities could be used to decode locomotion relevant behavioral states and locomotion velocity. We propose that neural clusters in the dorsal striatum encode locomotion relevant information and that coordinated activities of direct and indirect pathway neural clusters are required for normal striatal controlled behavior. VIDEO ABSTRACT.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zhang2016,

title = {Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders.},

author = {Wen Zhang and Lifeng Zhang and Bo Liang and David Schroeder and Zhong-Wei Zhang and Gregory A Cox and Yun Li and Da-Ting Lin},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26900927},

doi = {10.1038/nn.4257},

issn = {1546-1726 (Electronic); 1097-6256 (Linking)},

year  = {2016},

date = {2016-04-01},

journal = {Nat Neurosci},

volume = {19},

number = {4},

pages = {557--559},

address = {Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.},

abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Using TDP-43(A315T) mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PNs and alleviated neurodegeneration, suggesting a new therapeutic target for ALS and FTD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}