Journal Articles

@article{LM2024b,

title = {Neuromodulation in Small Animal fMRI},

author = {Hsu LM, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/39279265/},

doi = {10.1002/jmri.29575},

year  = {2024},

date = {2024-09-15},

urldate = {2024-09-15},

journal = {Journal of magnetic resonance imaging},

abstract = {The integration of functional magnetic resonance imaging (fMRI) with advanced neuroscience technologies in experimental small animal models offers a unique path to interrogate the causal relationships between regional brain activity and brain-wide network measures-a goal challenging to accomplish in human subjects. This review traces the historical development of the neuromodulation techniques commonly used in rodents, such as electrical deep brain stimulation, optogenetics, and chemogenetics, and focuses on their application with fMRI. We discuss their advantageousness roles in uncovering the signaling architecture within the brain and the methodological considerations necessary when conducting these experiments. By presenting several rodent-based case studies, we aim to demonstrate the potential of the multimodal neuromodulation approach in shedding light on neurovascular coupling, the neural basis of brain network functions, and their connections to behaviors. Key findings highlight the cell-type and circuit-specific modulation of brain-wide activity patterns and their behavioral correlates. We also discuss several future directions and feature the use of mediation and moderation analytical models beyond the intuitive evoked response mapping, to better leverage the rich information available in fMRI data with neuromodulation. Using fMRI alongside neuromodulation techniques provide insights into the mesoscopic (relating to the intermediate scale between single neurons and large-scale brain networks) and macroscopic fMRI measures that correlate with specific neuronal events. This integration bridges the gap between different scales of neuroscience research, facilitating the exploration and testing of novel therapeutic strategies aimed at altering network-mediated behaviors. In conclusion, the combination of fMRI with neuromodulation techniques provides crucial insights into mesoscopic and macroscopic brain dynamics, advancing our understanding of brain function in health and disease. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Optogenetic fMRI reveals therapeutic circuits of subthalamic nucleus deep brain stimulation},

author = {Li Y, Lee SH, Yu C, Hsu LM, Wang TW, Do K, Kim HJ, Shih YY, Grill WM},

url = {https://pubmed.ncbi.nlm.nih.gov/39096961/},

doi = {/10.1101/2024.02.22.581627},

year  = {2024},

date = {2024-08-01},

urldate = {2024-08-01},

journal = {Brain Stimulation},

abstract = {While deep brain stimulation (DBS) is widely employed for managing motor symptoms in Parkinson’s disease (PD), its exact circuit mechanisms remain controversial. To identify the neural targets affected by therapeutic DBS in PD, we analyzed DBS-evoked whole brain activity in female hemi-parkinsonian rats using function magnetic resonance imaging (fMRI). We delivered subthalamic nucleus (STN) DBS at various stimulation pulse repetition rates using optogenetics, allowing unbiased examinations of cell-type specific STN feed-forward neural activity. Unilateral STN optogenetic stimulation elicited pulse repetition rate-dependent alterations of blood-oxygenation-level-dependent (BOLD) signals in SNr (substantia nigra pars reticulata), GP (globus pallidus), and CPu (caudate putamen). Notably, these manipulations effectively ameliorated pathological circling behavior in animals expressing the kinetically faster Chronos opsin, but not in animals expressing ChR2. Furthermore, mediation analysis revealed that the pulse repetition rate-dependent behavioral rescue was significantly mediated by optogenetically induced activity changes in GP and CPu, but not in SNr. This suggests that the activation of GP and CPu are critically involved in the therapeutic mechanisms of STN DBS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TE2024b,

title = { Space wandering in the rodent default mode network},

author = {Nghiem TE, Lee B, Chao TH, Branigan NK, Mistry PK, Shih YY, Menon V},

url = {https://pubmed.ncbi.nlm.nih.gov/38557177/},

doi = {10.1073/pnas.2315167121},

year  = {2024},

date = {2024-04-01},

urldate = {2024-04-01},

journal = {Proceedings of the National Academy of Sciences},

volume = {121},

issue = {15},

abstract = {The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here we use multisite GCaMP fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats. We examined neural dynamics in three core DMN nodes- the retrosplenial cortex, cingulate cortex, and prelimbic cortex- as well as the anterior insula node of the salience network, and their association with the rats' spatial exploration behaviors. We found that DMN nodes displayed a hierarchical functional organization during spatial exploration, characterized by stronger coupling with each other than with the anterior insula. Crucially, these DMN nodes encoded the kinematics of spatial exploration, including linear and angular velocity. Additionally, we identified latent brain states that encoded distinct patterns of time-varying exploration behaviors and discovered that higher linear velocity was associated with enhanced DMN activity, heightened synchronization among DMN nodes, and increased anticorrelation between the DMN and anterior insula. Our findings highlight the involvement of the DMN in collectively and dynamically encoding spatial exploration in a real-world setting. Our findings challenge the notion that the DMN is primarily a "task-negative" network disengaged from the external world. By illuminating the DMN's role in naturalistic behaviors, our study underscores the importance of investigating brain network function in ecologically valid contexts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{DH2023,

title = {Distinct neurochemical influences on fMRI response polarity in the striatum},

author = {Cerri DH, Albaugh DL, Walton LR, Katz B, Wang TW, Chao TH, Zhang WT, Nonneman RJ, Jiang J, Lee SH, Etkin A, Hall CN, Stuber GD, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/38429266/},

doi = {10.1038/s41467-024-46088-z},

year  = {2024},

date = {2024-03-01},

urldate = {2024-03-01},

journal = {Nature Communications},

volume = {15},

abstract = {The striatum, known as the input nucleus of the basal ganglia, is extensively studied for its diverse behavioral roles. However, the relationship between its neuronal and vascular activity, vital for interpreting functional magnetic resonance imaging (fMRI) signals, has not received comprehensive examination within the striatum. Here, we demonstrate that optogenetic stimulation of dorsal striatal neurons or their afferents from various cortical and subcortical regions induces negative striatal fMRI responses in rats, manifesting as vasoconstriction. These responses occur even with heightened striatal neuronal activity, confirmed by electrophysiology and fiber-photometry. In parallel, midbrain dopaminergic neuron optogenetic modulation, coupled with electrochemical measurements, establishes a link between striatal vasodilation and dopamine release. Intriguingly, in vivo intra-striatal pharmacological manipulations during optogenetic stimulation highlight a critical role of opioidergic signaling in generating striatal vasoconstriction. This observation is substantiated by detecting striatal vasoconstriction in brain slices after synthetic opioid application. In humans, manipulations aimed at increasing striatal neuronal activity likewise elicit negative striatal fMRI responses. Our results emphasize the necessity of considering vasoactive neurotransmission alongside neuronal activity when interpreting fMRI signal.},

note = {https://www.eurekalert.org/news-releases/1038135},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Intrinsic functional connectivity between the anterior insular and retrosplenial cortex as a moderator and consequence of cocaine self-administration in rats},

author = {Hsu LM, Cerri DH, Lee SH, Shnitko TA, Carelli RM, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/38233216/},

doi = {10.1523/JNEUROSCI.1452-23.2023},

year  = {2024},

date = {2024-01-17},

urldate = {2024-01-17},

journal = {Journal of Neuroscience},

abstract = {While functional brain imaging studies in humans suggest that chronic cocaine use alters functional connectivity within and between key large-scale brain networks, including the default mode network (DMN), the salience network (SN), and the central executive network (CEN), cross-sectional studies in humans are challenging to obtain brain functional connectivity prior to cocaine use. Such information is critical to reveal the relationship between individual's brain functional connectivity and the subsequent development of cocaine dependence and brain changes during abstinence. Here, we performed a longitudinal study examining functional magnetic resonance imaging (fMRI) data in male rats (n = 7), acquired before cocaine self-administration (baseline), on 1 day of abstinence following 10 days of cocaine self-administration, and again after 30 days of experimenter-imposed abstinence. Using repeated measures analysis of variance (ANOVA) with network-based statistics (NBS), significant connectivity changes were found between anterior insular cortex (AI) of the SN, retrosplenial cortex (RSC) of the DMN, somatosensory cortex, and caudate putamen (CPu), with AI-RSC functional connectivity showing the most robust changes between baseline and 1 day of abstinence. Additionally, the level of escalated cocaine intake is associated with AI-RSC and AI-CPu functional connectivity changes between 1 day and 30 days of abstinence; further, the subjects' AI-RSC functional connectivity prior to cocaine intake is a significant moderator for the AI-RSC changes during abstinence. These results provide novel insights into the roles of AI-RSC functional connectivity before and after cocaine intake and suggest this circuit to be a potential target to modulate large-scale network and associated behavioral changes in cocaine use disorders.Significance Statement This study examines the impact of chronic cocaine self-administration on brain network-level interactions involving the default mode network (DMN; retro-splenial cortex, RSC), salience network (SN; anterior insular, AI), and caudate putamen (CPu). These brain regions have been associated with self-referential functions, emotion, memory, and coordination between internal and external stimuli and align with the "triple network model" of psychopathology and addiction. By identifying relationships between the escalated cocaine self-administration and the changes of functional connectivity across longitudinal measures, this study contributes to the future development of circuit-based treatment strategies and suggests AI and RSC connectivity to be an imaging circuit marker for cocaine use disorders.},

note = {:::|||https://www.jneurosci.org/content/44/7/e4472024:::[This Week In The Journal]},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Topiramate suppresses peri-infarct spreading depolarization and improves outcomes in a rat model of photothrombotic stroke},

author = {Wang Y, Yen S, Shih YY, Lai CW, Chen YL, Chen LT, Chen H, Liao LD},

url = {https://pubmed.ncbi.nlm.nih.gov/38947531/},

doi = {10.1016/j.isci.2024.110033},

year  = {2024},

date = {2024-01-02},

journal = {iScience},

volume = {27},

number = {110033},

issue = {6},

abstract = {Ischemic stroke can cause depolarized brain waves, termed peri-infarct depolarization (PID). Here, we evaluated whether topiramate, a neuroprotective drug used to treat epilepsy and alleviate migraine, has the potential to reduce PID. We employed a rat model of photothrombotic ischemia that can reliably and reproducibly induce PID and developed a combined electrocorticography-laser speckle contrast imaging (ECoG-LSCI) platform to monitor neuronal activity and cerebral blood flow (CBF) simultaneously. Topiramate administration after photothrombotic ischemia did not rescue CBF but significantly restored somatosensory evoked potentials in the forelimb area of the primary somatosensory cortex. Moreover, infarct volume was investigated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and neuronal survival was evaluated by Nissl staining. Mechanistically, the levels of inflammatory markers, such as ED1 (CD68), Iba-1, and GFAP, decreased significantly after topiramate administration, as did BDNF expression, while the expression of NeuN and Bcl-2/Bax increased, which is indicative of reduced inflammation and improved neuroprotection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{AV2024,

title = {Acute and chronic alcohol modulation of extended amygdala calcium dynamics},

author = {Roland AV, Chao TH, Hon OJ, Machinski SN, Sides TR, Lee SI, Shih YY, Kash TL},

url = {https://pubmed.ncbi.nlm.nih.gov/37873188/},

doi = {10.1016/j.alcohol.2024.02.004},

year  = {2024},

date = {2024-01-01},

urldate = {2024-05-01},

journal = {Alcohol},

volume = {116},

pages = {53-64},

abstract = {The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while increased stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{V2023,

title = {Optogenetic stimulation of anterior insular cortex neurons in male rats reveals causal mechanisms underlying suppression of the default mode network by the salience network},

author = {Menon V, Cerri DH, Lee BW, Yuan R, Lee SH, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/36797303/},

doi = {10.1038/s41467-023-36616-8},

year  = {2023},

date = {2023-12-31},

urldate = {2023-02-16},

journal = {Nature Communications},

abstract = {The salience network (SN) and default mode network (DMN) play a crucial role in cognitive function. The SN, anchored in the anterior insular cortex (AI), has been hypothesized to modulate DMN activity during stimulus-driven cognition. However, the causal neural mechanisms underlying changes in DMN activity and its functional connectivity with the SN are poorly understood. Here we combine feedforward optogenetic stimulation with fMRI and computational modeling to dissect the causal role of AI neurons in dynamic functional interactions between SN and DMN nodes in the male rat brain. Optogenetic stimulation of Chronos-expressing AI neurons suppressed DMN activity, and decreased AI-DMN and intra-DMN functional connectivity. Our findings demonstrate that feedforward optogenetic stimulation of AI neurons induces dynamic suppression and decoupling of the DMN and elucidates previously unknown features of rodent brain network organization. Our study advances foundational knowledge of causal mechanisms underlying dynamic cross-network interactions and brain network switching.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TH2023,

title = {Neuronal dynamics of the default mode network and anterior insular cortex: Intrinsic properties and modulation by salient stimuli},

author = {Chao TH, Lee BW, Hsu LM, Cerri DH, Zhang WT, Wang TW, Ryali S, Menon V, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/36791185/},

doi = {10.1126/sciadv.ade5732},

year  = {2023},

date = {2023-12-30},

urldate = {2023-02-15},

journal = {Science Advances},

volume = {9},

issue = {7},

abstract = {The default mode network (DMN) is critical for self-referential mental processes, and its dysfunction is implicated in many neuropsychiatric disorders. However, the neurophysiological properties and task-based functional organization of the rodent DMN are poorly understood, limiting its translational utility. Here, we combine fiber photometry with functional magnetic resonance imaging (fMRI) and computational modeling to characterize dynamics of putative rat DMN nodes and their interactions with the anterior insular cortex (AI) of the salience network. Our analysis revealed neuronal activity changes in AI and DMN nodes preceding fMRI-derived DMN activations and cyclical transitions between brain network states. Furthermore, we demonstrate that salient oddball stimuli suppress the DMN and enhance AI neuronal activity and that the AI causally inhibits the retrosplenial cortex, a prominent DMN node. These findings elucidate the neurophysiological foundations of the rodent DMN, its spatiotemporal dynamical properties, and modulation by salient stimuli, paving the way for future translational studies.},

note = {https://www.eurekalert.org/news-releases/979893:::[Press release]|||https://physicsworld.com/a/novel-imaging-platform-reveals-the-neuronal-basis-of-a-drifting-mind/:::[Physics world]|||https://www.youtube.com/watch?v=s9RZpK19RU4&t=173s:::[News video]},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{J2023b,

title = {Cardiomyocyte Alpha-1A Adrenergic Receptors Mitigate Postinfarct Remodeling and Mortality by Constraining Necroptosis},

author = {Zhang J, Sandroni PB, Huang W, Gao X, Oswalt L, Schroder MA, Lee SH, Shih YY, Huang HYS, Swigart PM, Myagmar BE, Simpson PC, Rossi JS, Schisler JC, Jensen BC},

url = {https://pubmed.ncbi.nlm.nih.gov/38362342/},

doi = {/10.1016/j.jacbts.2023.08.013},

year  = {2023},

date = {2023-11-15},

urldate = {2023-11-15},

journal = {JACC: Basic to Translational Science},

abstract = {Clinical studies have shown that α1-adrenergic receptor antagonists (α-blockers) are associated with increased heart failure risk. The mechanism underlying that hazard and whether it arises from direct inhibition of cardiomyocyte α1-ARs or from systemic effects remain unclear. To address these issues, we created a mouse with cardiomyocyte-specific deletion of the α1A-AR subtype and found that it experienced 70% mortality within 7 days of myocardial infarction driven, in part, by excessive activation of necroptosis. We also found that patients taking α-blockers at our center were at increased risk of death after myocardial infarction, providing clinical correlation for our translational animal models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Y2023,

title = {Translational landscape of direct cardiac reprogramming reveals a role of Ybx1 in repressing cardiac fate acquisition},

author = {Xie Y, Wang Q, Yang Y, Near D, Wang H, Colon M, Nguyen C, Slattery C, Keepers B, Farber G, Wang TW, Lee SH, Shih YY, Liu J, Qian L},

url = {https://pubmed.ncbi.nlm.nih.gov/38524149/},

doi = {10.1038/s44161-023-00344-5},

year  = {2023},

date = {2023-10-16},

urldate = {2023-10-16},

journal = {Nature Cardiovascular Research},

abstract = {Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise for heart regeneration. Although considerable progress has been made in understanding the transcriptional and epigenetic mechanisms of iCM reprogramming, its translational regulation remains largely unexplored. Here, we characterized the translational landscape of iCM reprogramming through integrative ribosome and transcriptomic profiling, and found extensive translatome repatterning during this process. Loss-of-function screening for translational regulators uncovered Y-box binding protein 1 (Ybx1) as a critical barrier to iCM induction. In a mouse model of myocardial infarction, removing Ybx1 enhanced in vivo reprogramming, resulting in improved heart function and reduced scar size. Mechanistically, Ybx1 depletion de-repressed the translation of its direct targets Srf and Baf60c, both of which mediated the effect of Ybx1 depletion on iCM generation. Furthermore, removal of Ybx1 allowed single-factor, Tbx5-mediated iCM conversion. In summary, the findings reveal a new layer of regulatory mechanism that controls cardiac reprogramming at the translational level.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Q2023,

title = {Complement receptor 3-mediated neurotoxic glial activation contributes to rotenone-induced cognitive decline in mice},

author = {Wang Q, Ruan Z, Jing L, Guo Z, Zhang X, Liu J, Tian L, Sun W, Song S, Hong JS, Shih YY, Hou L, Wang Q},

url = {https://pubmed.ncbi.nlm.nih.gov/37832486/},

doi = {10.1016/j.ecoenv.2023.115550},

year  = {2023},

date = {2023-10-11},

urldate = {2023-10-11},

journal = {Ecotoxicology and Environmental Safety},

volume = {266},

issue = {115550},

abstract = {Microglia-mediated chronic neuroinflammation has been associated with cognitive decline induced by rotenone, a well-known neurotoxic pesticide used in agriculture. However, the mechanisms remain unclear. This work aimed to elucidate the role of complement receptor 3 (CR3), a highly expressed receptor in microglia, in cognitive deficits induced by rotenone. Rotenone up-regulated the expression of CR3 in the hippocampus and cortex area of mice. CR3 deficiency markedly ameliorated rotenone-induced cognitive impairments, neurodegeneration and phosphorylation (Ser129) of α-synuclein in mice. CR3 deficiency also attenuated rotenone-stimulated microglial M1 activation. In microglial cells, siRNA-mediated knockdown of CR3 impeded, while CR3 activation induced by LL-37 exacerbated, rotenone-induced microglial M1 activation. Mechanistically, CR3 deficiency blocked rotenone-induced activation of nuclear factor κB (NF-κB), signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathways. Pharmacological inhibition of NF-κB or STAT3 but not STAT1 was confirmed to suppress microglial M1 activation elicited by rotenone. Further study revealed that CR3 deficiency or knockdown also reduced rotenone-induced expression of C3, an A1 astrocyte marker, and production of microglial C1q, TNFα and IL-1α, a cocktail for activated microglia to induce neurotoxic A1 astrocytes, via NF-κB and STAT3 pathways. Finally, a small molecule modulator of CR3 efficiently mitigated rotenone-elicited cognitive deficits in mice even administered after the establishment of cognitive dysfunction. Taken together, our findings demonstrated that CR3 is a key factor in mediating neurotoxic glial activation and subsequent cognitive impairments in rotenone-treated mice, giving novel insights into the immunopathogenesis of cognitive impairments in pesticide-related Parkinsonism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SH2023,

title = {Acute alcohol induces greater dose-dependent increase in the lateral cortical network functional connectivity in adult than adolescent rats},

author = {Lee SH, Shnitko TA, Hsu LM, Broadwater MA, Sardinas M, Wang TW, Robinson DL, Vetreno RP, Crews FT, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/37576436/},

doi = {10.1016/j.addicn.2023.100105},

year  = {2023},

date = {2023-09-01},

urldate = {2023-09-01},

journal = {Addiction Neuroscience},

volume = {7},

abstract = {Alcohol misuse and, particularly adolescent drinking, is a major public health concern. While evidence suggests that adolescent alcohol use affects frontal brain regions that are important for cognitive control over behavior, little is known about how acute alcohol exposure alters large-scale brain networks and how sex and age may moderate such effects. Here, we employ a recently developed functional magnetic resonance imaging (fMRI) protocol to acquire rat brain functional connectivity data and use an established analytical pipeline to examine the effect of sex, age, and alcohol dose on connectivity within and between three major rodent brain networks: default mode, salience, and lateral cortical network. We identify the intra- and inter-network connectivity differences and establish moderation models to reveal significant influences of age on acute alcohol-induced lateral cortical network connectivity. Through this work, we make brain-wide isotropic fMRI data with acute alcohol challenge publicly available, with the hope to facilitate future discovery of brain regions/circuits that are causally relevant to the impact of acute alcohol use.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{CM2023,

title = {Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer’s mouse model},

author = {Wander CM, Li YD, Bao H, Asrican B, Luo YJ, Sullivan HA, Chao TH, Zhang WT, Chéry SL, Tart DS, Chen ZK, Shih YY, Wickersham IR, Cohen TJ, Song J},

url = {https://pubmed.ncbi.nlm.nih.gov/37061718/},

doi = {10.1186/s12967-023-04078-7},

year  = {2023},

date = {2023-04-15},

urldate = {2023-04-15},

journal = {Journal of Translational Medicine},

volume = {21},

number = {258},

abstract = {Background

Alzheimer’s disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined.



Methods

Circuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression.



Results

We identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons.



Conclusion

We report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{J2023,

title = {A consensus protocol for functional connectivity analysis in the rat brain},

author = {Grandjean J, Desrosiers-Gregoire G, Anckaerts C, Angeles-Valdez D, Ayad F, Barrière DA, Blockx I, Bortel A, Broadwater M, Cardoso BM, Célestine M, Chavez-Negrete JE, Choi S, Christiaen E, Clavijo P, Colon-Perez L, Cramer S, Daniele T, Dempsey E, Diao Y, Doelemeyer A, Dopfel D, Dvořáková L, Falfán-Melgoza C, Fernandes FF, Fowler CF, Fuentes-Ibañez A, Garin C, Gelderman E, Golden CEM, Guo CCG, Henckens MJAG, Hennessy LA, Herman P, Hofwijks N, Horien C, Ionescu TM, Jones J, Kaesser J, Kim E, Lambers H, Lazari A, Lee SH, Lillywhite A, Liu Y, Liu YY, López-Castro A, López-Gil X, Ma Z, MacNicol E, Madularu D, Mandino F, Marciano S, McAuslan MJ, McCunn P, McIntosh A, Meng X, Meyer-Baese L, Missault S, Moro F, Naessens DMP, Nava-Gomez LJ, Nonaka H, Ortiz JJ, Paasonen J, Peeters LM, Pereira M, Perez PD, Pompilus M, Prior M, Rakhmatullin R, Reimann HM, Reinwald J, Rio RTD, Rivera-Olvera A, Ruiz-Pérez D, Russo G, Rutten TJ, Ryoke R, Sack M, Salvan P, Sanganahalli BG, Schroeter A, Seewoo BJ, Selingue E, Seuwen A, Shi B, Sirmpilatze N, Smith J, Smith C, Sobczak F, Stenroos PJ, Straathof M, Strobelt S, Sumiyoshi A, Takahashi K, Torres-García ME, Tudela R, Berg MVD, Marel KVD, Hout ATBV, Vertullo R, Vidal B, Vrooman RM, Wang VX, Wank I, Watson DJG, Yin T, Zhang Y, Zurbruegg S, Achard S, Alcauter S, Auer DP, Barbier EL, Baudewig J, Beckmann CF, Beckmann N, Becq GJPC, Blezer ELA, Bolbos R, Boretius S, Bouvard S, Budinger E, Buxbaum JD, Cash D, Chapman VX, Chuang K, Ciobanu L, Coolen BF, Dalley JW, Dhenain M, Dijkhuizen RM, Esteban O, Faber C, Febo M, Feindel KW, Forloni GJPC, Fouquet J, Garza-Villarreal EA, Gass N, Glennon JC, Gozzi A, Gröhn O, Harkin A, Heerschap A, Helluy X, Herfert K, Heuser A, Homberg JR, Houwing DJG, Hyder F, Ielacqua GD, Jelescu IO, Johansen-Berg H, Kaneko G, Kawashima R, Keilholz SD, Keliris GA, Kelly C, Kerskens C, Khokhar JY, Kind PC, Langlois J, Lerch JP, López-Hidalgo MA, Manahan-Vaughan D, Marchand F, Mars RB, Marsella G, Micotti E, Muñoz-Moreno E, Near J, Niendorf T, Otte WM, Pais-Roldán PC, Pan W, Prado-Alcalá RA, Quirarte GL, Rodger J, Rosenow T, Sampaio-Baptista C, Sartorius A, Sawiak SJ, Scheenen TWJ, Shemesh N, Shih YY, Shmuel A, Soria G, Stoop R, Thompson GJPC, Till SM, Todd N, Linden AVD, Toorn AVD, Tilborg GAF, Vanhove C, Veltien A, Verhoye M, Wachsmuth L, Weber-Fahr W, Wenk PC, Yu X, Zerbi V, Zhang N, Zhang BB, Zimmer L, Devenyi GA, Chakravarty MM, Hess A},

url = {https://pubmed.ncbi.nlm.nih.gov/36973511/},

doi = {10.1038/s41593-023-01286-8},

year  = {2023},

date = {2023-04-01},

urldate = {2023-04-01},

journal = {Nature Neuroscience},

volume = {26},

issue = {4},

pages = {673-681},

abstract = {Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{BM2023,

title = {Putative neurochemical and cell type contributions to hemodynamic activity in the rodent caudate putamen},

author = {Katz BM, Walton LR, Houston KM, Cerri DH, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/36448509/},

doi = {10.1177/0271678X221142533},

year  = {2023},

date = {2023-01-09},

urldate = {2023-01-09},

journal = {Journal of Cerebral Blood Flow and Metabolism},

abstract = {Functional magnetic resonance imaging (fMRI) is widely used by researchers to noninvasively monitor brain-wide activity. The traditional assumption of a uniform relationship between neuronal and hemodynamic activity throughout the brain has been increasingly challenged. This relationship is now believed to be impacted by heterogeneously distributed cell types and neurochemical signaling. To date, most cell-type- and neurotransmitter-specific influences on hemodynamics have been examined within the cortex and hippocampus of rodent models, where glutamatergic signaling is prominent. However, neurochemical influences on hemodynamics are relatively unknown in largely GABAergic brain regions such as the rodent caudate putamen (CPu). Given the extensive contribution of CPu function and dysfunction to behavior, and the increasing focus on this region in fMRI studies, improved understanding of CPu hemodynamics could have broad impacts. Here we discuss existing findings on neurochemical contributions to hemodynamics as they may relate to the CPu with special consideration for how these contributions could originate from various cell types and circuits. We hope this review can help inform the direction of future studies as well as interpretation of fMRI findings in the CPu.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{MJ2023,

title = {Mouse Brain MRI: Including In Vivo, Ex Vivo, and fcMRI for the Study of Microcephaly},

author = {MacKinnon MJ, Wang TW, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/36418731/},

doi = {10.1007/978-1-0716-2752-5_12},

year  = {2023},

date = {2023-01-02},

urldate = {2023-01-02},

journal = {Methods in Molecular Biology},

volume = {2583},

pages = {129-148},

abstract = {With its sensitivity to soft tissue, MRI is a powerful tool for the study of the neuroanatomical manifestations of a variety of conditions, such as microcephaly-related morbidities that are not easily visualized by other imaging techniques, such as CT. In addition to structural imaging, more recently, researchers have found changes in brain function in a wide range of neurological conditions—highlighting the utility of MRI for the study of microcephaly.



In this methods chapter, basic mouse preparation and the acquisition of data for in vivo anatomical MRI will be discussed. Additionally, we will provide our protocol for the perfusion and fixation of brain tissue with gadolinium contrast agent. Following that, the process of optimization of system parameters will be shown for anatomical imaging of in vivo and ex vivo brain tissue. Lastly, the chapter will detail a protocol for fcMRI along with a discussion of considerations specific to functional imaging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Song2023,

title = {Dysfunction of the noradrenergic system drives inflammation, α-synucleinopathy, and neuronal loss in mouse colon},

author = {S Song, Tu D, Meng C, Liu J, Wilson B, Wang Q, Shih YY, Gao HM, Hong JS},

url = {https://pubmed.ncbi.nlm.nih.gov/36845109/},

doi = {/10.17615/cx6h-sv72},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Frontiers in Immunology},

volume = {14},

issue = {1083513},

abstract = {Clinical and pathological evidence revealed that α-synuclein (α-syn) pathology seen in PD patients starts in the gut and spreads via anatomically connected structures from the gut to the brain. Our previous study demonstrated that depletion of central norepinephrine (NE) disrupted brain immune homeostasis, producing a spatiotemporal order of neurodegeneration in the mouse brain. The purpose of this study was 1) to determine the role of peripheral noradrenergic system in the maintenance of gut immune homeostasis and in the pathogenesis of PD and 2) to investigate whether NE-depletion induced PD-like α-syn pathological changes starts from the gut. For these purposes, we investigated time-dependent changes of α-synucleinopathy and neuronal loss in the gut following a single injection of DSP-4 (a selective noradrenergic neurotoxin) to A53T-SNCA (human mutant α-syn) over-expression mice. We found DPS-4 significantly reduced the tissue level of NE and increased immune activities in gut, characterized by increased number of phagocytes and proinflammatory gene expression. Furthermore, a rapid-onset of α-syn pathology was observed in enteric neurons after 2 weeks and delayed dopaminergic neurodegeneration in the substantia nigra was detected after 3-5 months, associated with the appearance of constipation and impaired motor function, respectively. The increased α-syn pathology was only observed in large, but not in the small, intestine, which is similar to what was observed in PD patients. Mechanistic studies reveal that DSP-4-elicited upregulation of NADPH oxidase (NOX2) initially occurred only in immune cells during the acute intestinal inflammation stage, and then spread to enteric neurons and mucosal epithelial cells during the chronic inflammation stage. The upregulation of neuronal NOX2 correlated well with the extent of α-syn aggregation and subsequent enteric neuronal loss, suggesting that NOX2-generated reactive oxygen species play a key role in α-synucleinopathy. Moreover, inhibiting NOX2 by diphenyleneiodonium or restoring NE function by salmeterol (a β2-receptor agonist) significantly attenuated colon inflammation, α-syn aggregation/propagation, and enteric neurodegeneration in the colon and ameliorated subsequent behavioral deficits. Taken together, our model of PD shows a progressive pattern of pathological changes from the gut to the brain and suggests a potential role of the noradrenergic dysfunction in the pathogenesis of PD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{EA2022b,

title = {Chemogenetic Stimulation of Tonic Locus Coeruleus Activity Strengthens the Default Mode Network},

author = {Oyarzabal EA, Hsu LM, Das M, Chao TH, Zhou J, Song S, Zhang WT, Smith KG, Sciolino NR, Evsyukova IY, Yuan H, Lee SH, Cui G, Jensen P, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/35486721/},

doi = {10.1126/sciadv.abm9898},

year  = {2022},

date = {2022-12-31},

urldate = {2022-12-31},

journal = {Science Advances},

volume = {8},

issue = {17},

abstract = {The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.},

note = {https://www.eurekalert.org/news-releases/951200},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{FA2022,

title = {Whole-Brain Single-Cell Imaging and Analysis of Intact Neonatal Mouse Brains Using MRI, Tissue Clearing, and Light-Sheet Microscopy},

author = {Kyere FA, Curtin I, Krupa O, McCormick CM, Dere M, Khan S, Kim M, Wang TW, He Q, Wu G, Shih YY, Stein JL},

url = {https://pubmed.ncbi.nlm.nih.gov/35969091/},

doi = {10.3791/64096},

year  = {2022},

date = {2022-08-01},

urldate = {2022-08-01},

journal = {Journal of Visualized Experiments},

volume = {186},

abstract = {Tissue clearing followed by light-sheet microscopy (LSFM) enables cellular-resolution imaging of intact brain structure, allowing quantitative analysis of structural changes caused by genetic or environmental perturbations. Whole-brain imaging results in more accurate quantification of cells and the study of region-specific differences that may be missed with commonly used microscopy of physically sectioned tissue. Using light-sheet microscopy to image cleared brains greatly increases acquisition speed as compared to confocal microscopy. Although these images produce very large amounts of brain structural data, most computational tools that perform feature quantification in images of cleared tissue are limited to counting sparse cell populations, rather than all nuclei. Here, we demonstrate NuMorph (Nuclear-Based Morphometry), a group of analysis tools, to quantify all nuclei and nuclear markers within annotated regions of a postnatal day 4 (P4) mouse brain after clearing and imaging on a light-sheet microscope. We describe magnetic resonance imaging (MRI) to measure brain volume prior to shrinkage caused by tissue clearing dehydration steps, tissue clearing using the iDISCO+ method, including immunolabeling, followed by light-sheet microscopy using a commercially available platform to image mouse brains at cellular resolution. We then demonstrate this image analysis pipeline using NuMorph, which is used to correct intensity differences, stitch image tiles, align multiple channels, count nuclei, and annotate brain regions through registration to publicly available atlases. We designed this approach using publicly available protocols and software, allowing any researcher with the necessary microscope and computational resources to perform these techniques. These tissue clearing, imaging, and computational tools allow measurement and quantification of the three-dimensional (3D) organization of cell-types in the cortex and should be widely applicable to any wild-type/knockout mouse study design.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{WT2022,

title = {Spectral fiber photometry derives hemoglobin concentration changes for accurate measurement of fluorescent sensor activity},

author = {Zhang WT, Chao TH, Yang Y, Wang TW, Lee SH, Oyarzabal EA, Zhou J, Nonneman R, Pegard NC, Zhu H, Cui G, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/35880016/},

doi = {10.1016/j.crmeth.2022.100243},

year  = {2022},

date = {2022-06-29},

urldate = {2022-06-29},

journal = {Cell Reports Methods},

volume = {2},

number = {100243},

issue = {7},

abstract = {Fiber photometry is an emerging technique for recording fluorescent sensor activity in the brain. However, significant hemoglobin absorption artifacts in fiber photometry data may be misinterpreted as sensor activity changes. Because hemoglobin exists widely in the brain, and its concentration varies temporally, such artifacts could impede the accuracy of photometry recordings. Here we present use of spectral photometry and computational methods to quantify photon absorption effects by using activity-independent fluorescence signals, which can be used to derive oxy- and deoxy-hemoglobin concentration changes. Although these changes are often temporally delayed compared with the fast-responding fluorescence spikes, we found that erroneous interpretation may occur when examining pharmacology-induced sustained changes and that sometimes hemoglobin absorption could flip the GCaMP signal polarity. We provide hemoglobin-based correction methods to restore fluorescence signals and compare our results with other commonly used approaches. We also demonstrated the utility of spectral fiber photometry for delineating regional differences in hemodynamic response functions.},

note = {https://news.unchealthcare.org/2022/08/scientists-develop-new-method-for-improved-fiber-optic-measurement-of-brain-activity-changes/:::[Press release]|||https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308156/:::[Preview]|||https://www.cell.com/cell-reports-methods/collections/best-of-2022:::[Cell Reports Methods Best of 2022]},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{WT2022b,

title = {Simultaneous recording of neuronal and vascular activity in the rodent brain using fiber-photometry},

author = {Zhang WT, Chao TH, Cui G, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/35776651/},

doi = {10.1016/j.xpro.2022.101497},

year  = {2022},

date = {2022-06-22},

urldate = {2022-06-22},

journal = {STAR protocols},

volume = {3},

number = {101497},

issue = {3},

abstract = {Coupling of hemodynamic responses to neuronal activity is the foundation of several functional neuroimaging techniques. Here, we provide three fiber-photometry approaches to simultaneously measure neuronal and vascular signals in the rodent brain using a spectrometer-based system. Two out of these three approaches allow the removal of hemoglobin (Hb)-absorption artifacts and restore the underlying neuronal activity. This technique is applicable to different fluorescent sensors and provides a more accurate measurement of hemodynamic response function in any location of the rodent brain. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2022).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{THH2022,

title = {Computing hemodynamic response functions from concurrent spectral fiber-photometry and fMRI data},

author = {Chao THH, Zhang WT, Hsu LM, Cerri DH, Wang TW, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/35005057/},

doi = {10.1117/1.NPh.9.3.032205},

year  = {2022},

date = {2022-01-05},

urldate = {2022-07-01},

journal = {Neurophotonics},

volume = {9},

number = {3},

pages = {032205},

abstract = {Significance: Although emerging evidence suggests that the hemodynamic response function (HRF) can vary by brain region and species, a single, canonical, human-based HRF is widely used in animal studies. Therefore, the development of flexible, accessible, brain-region specific HRF calculation approaches is paramount as hemodynamic animal studies become increasingly popular. Aim: To establish an fMRI-compatible, spectral, fiber-photometry platform for HRF calculation and validation in any rat brain region. Approach: We used our platform to simultaneously measure (a) neuronal activity via genetically encoded calcium indicators (GCaMP6f), (b) local cerebral blood volume (CBV) from intravenous Rhodamine B dye, and (c) whole brain CBV via fMRI with the Feraheme contrast agent. Empirical HRFs were calculated with GCaMP6f and Rhodamine B recordings from rat brain regions during resting-state and task-based paradigms. Results: We calculated empirical HRFs for the rat primary somatosensory, anterior cingulate, prelimbic, retrosplenial, and anterior insular cortical areas. Each HRF was faster and narrower than the canonical HRF and no significant difference was observed between these cortical regions. When used in general linear model analyses of corresponding fMRI data, the empirical HRFs showed better detection performance than the canonical HRF. Conclusions: Our findings demonstrate the viability and utility of fiber-photometry-based HRF calculations. This platform is readily scalable to multiple simultaneous recording sites, and adaptable to study transfer functions between stimulation events, neuronal activity, neurotransmitter release, and hemodynamic responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{LM2021,

title = {3D U-Net Improves Automatic Brain Extraction for Isotropic Rat Brain Magnetic Resonance Imaging Data},

author = {Hsu LM, Wang S, Walton L, Wang TWW, Lee SH, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/34975392/},

doi = {10.3389/fnins.2021.801008},

year  = {2021},

date = {2021-12-16},

urldate = {2021-12-16},

journal = {Frontiers in Neuroscience},

volume = {15},

pages = {801008},

abstract = {Brain extraction is a critical pre-processing step in brain magnetic resonance imaging (MRI) analytical pipelines. In rodents, this is often achieved by manually editing brain masks slice-by-slice, a time-consuming task where workloads increase with higher spatial resolution datasets. We recently demonstrated successful automatic brain extraction via a deep-learning-based framework, U-Net, using 2D convolutions. However, such an approach cannot make use of the rich 3D spatial-context information from volumetric MRI data. In this study, we advanced our previously proposed U-Net architecture by replacing all 2D operations with their 3D counterparts and created a 3D U-Net framework. We trained and validated our model using a recently released CAMRI rat brain database acquired at isotropic spatial resolution, including T2-weighted turbo-spin-echo structural MRI and T2*-weighted echo-planar-imaging functional MRI. The performance of our 3D U-Net model was compared with existing rodent brain extraction tools, including Rapid Automatic Tissue Segmentation, Pulse-Coupled Neural Network, SHape descriptor selected External Regions after Morphologically filtering, and our previously proposed 2D U-Net model. 3D U-Net demonstrated superior performance in Dice, Jaccard, center-of-mass distance, Hausdorff distance, and sensitivity. Additionally, we demonstrated the reliability of 3D U-Net under various noise levels, evaluated the optimal training sample sizes, and disseminated all source codes publicly, with a hope that this approach will benefit rodent MRI research community. Significant Methodological Contribution: We proposed a deep-learning-based framework to automatically identify the rodent brain boundaries in MRI. With a fully 3D convolutional network model, 3D U-Net, our proposed method demonstrated improved performance compared to current automatic brain extraction methods, as shown in several qualitative metrics (Dice, Jaccard, PPV, SEN, and Hausdorff). We trust that this tool will avoid human bias and streamline pre-processing steps during 3D high resolution rodent brain MRI data analysis. The software developed herein has been disseminated freely to the community.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{A2021,

title = {Altered Cortico-Subcortical Network After Adolescent Alcohol Exposure Mediates Behavioral Deficits in Flexible Decision-Making},

author = {Gómez-A A, Dannenhoffer CA, Elton A, Lee SH, Ban W, Shih YY, Boettiger CA, Robinson DL},

url = {https://pubmed.ncbi.nlm.nih.gov/34912227/},

doi = {10.3389/fphar.2021.778884},

year  = {2021},

date = {2021-12-01},

urldate = {2021-12-01},

journal = {Frontiers in Pharmacology},

volume = {12},

abstract = {Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and resting-state functional connectivity MRI in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions statistically mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SH2021,

title = {An isotropic EPI database and analytical pipelines for rat brain resting-state fMRI},

author = {Lee SH, Broadwater MA, Ban W, Wang TW, Kim HJ, Dumas JS, Vetreno RP, Herman MA, Morrow AL, Besheer J, Kash TL, Boettiger CA, Robinson DL, Crews FT, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/34478824/},

doi = {10.1016/j.neuroimage.2021.118541},

year  = {2021},

date = {2021-11-01},

urldate = {2021-11-01},

journal = {NeuroImage},

volume = {243},

pages = {118541},

abstract = {Resting-state functional magnetic resonance imaging (fMRI) has drastically expanded the scope of brain research by advancing our knowledge about the topologies, dynamics, and interspecies translatability of functional brain networks. Several databases have been developed and shared in accordance with recent key initiatives in the rodent fMRI community to enhance the transparency, reproducibility, and interpretability of data acquired at various sites. Despite these pioneering efforts, one notable challenge preventing efficient standardization in the field is the customary choice of anisotropic echo planar imaging (EPI) schemes with limited spatial coverage. Imaging with anisotropic resolution and/or reduced brain coverage has significant shortcomings including reduced registration accuracy and increased deviation in brain feature detection. Here we proposed a high-spatial-resolution (0.4 mm), isotropic, whole-brain EPI protocol for the rat brain using a horizontal slicing scheme that can maintain a functionally relevant repetition time (TR), avoid high gradient duty cycles, and offer unequivocal whole-brain coverage. Using this protocol, we acquired resting-state EPI fMRI data from 87 healthy rats under the widely used dexmedetomidine sedation supplemented with low-dose isoflurane on a 9.4 T MRI system. We developed an EPI template that closely approximates the Paxinos and Watson's rat brain coordinate system and demonstrated its ability to improve the accuracy of group-level approaches and streamline fMRI data pre-processing. Using this database, we employed a multi-scale dictionary-learning approach to identify reliable spatiotemporal features representing rat brain intrinsic activity. Subsequently, we performed k-means clustering on those features to obtain spatially discrete, functional regions of interest (ROIs). Using Euclidean-based hierarchical clustering and modularity-based partitioning, we identified the topological organizations of the rat brain. Additionally, the identified group-level FC network appeared robust across strains and sexes. The "triple-network" commonly adapted in human fMRI were resembled in the rat brain. Through this work, we disseminate raw and pre-processed isotropic EPI data, a rat brain EPI template, as well as identified functional ROIs and networks in standardized rat brain coordinates. We also make our analytical pipelines and scripts publicly available, with the hope of facilitating rat brain resting-state fMRI study standardization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{LR2021,

title = {Simultaneous fMRI and fast-scan cyclic voltammetry bridges evoked oxygen and neurotransmitter dynamics across spatiotemporal scales},

author = {Walton LR, Verber M, Lee SH, Chao TH, Wightman RM, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/34624504/},

doi = {10.1016/j.neuroimage.2021.118634},

year  = {2021},

date = {2021-10-05},

urldate = {2021-10-05},

journal = {NeuroImage},

volume = {244},

pages = {118634},

abstract = {The vascular contributions of neurotransmitters to the hemodynamic response are gaining more attention in neuroimaging studies, as many neurotransmitters are vasomodulatory. To date, well-established electrochemical techniques that detect neurotransmission in high magnetic field environments are limited. Here, we propose an experimental setting enabling simultaneous fast-scan cyclic voltammetry (FSCV) and blood oxygenation level-dependent functional magnetic imaging (BOLD fMRI) to measure both local tissue oxygen and dopamine responses, and global BOLD changes, respectively. By using MR-compatible materials and the proposed data acquisition schemes, FSCV detected physiological analyte concentrations with high temporal resolution and spatial specificity inside of a 9.4 T MRI bore. We found that tissue oxygen and BOLD correlate strongly, and brain regions that encode dopamine amplitude differences can be identified via modeling simultaneously acquired dopamine FSCV and BOLD fMRI time-courses. This technique provides complementary neurochemical and hemodynamic information and expands the scope of studying the influence of local neurotransmitter release over the entire brain.},

key = {(NeuroImage Paper of the Year)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{M2021,

title = {One-pot synthesis of carboxymethyl-dextran coated iron oxide nanoparticles (CION) for preclinical fMRI and MRA applications},

author = {Das M, Oyarzabal EA, Chen L, Lee SH, Shah N, Gerlach G, Zhang WT, Chao TH, Van Den Berge N, Liu C, Donley C, Montgomery SA, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/34116153/},

doi = {10.1016/j.neuroimage.2021.118213},

year  = {2021},

date = {2021-09-01},

urldate = {2021-09-01},

journal = {NeuroImage},

volume = {238},

pages = {118213},

abstract = {Superparamagnetic iron-oxide nanoparticles are robust contrast agents for magnetic resonance imaging (MRI) used for sensitive structural and functional mapping of the cerebral blood volume (CBV) when administered intravenously. To date, many CBV-MRI studies are conducted with Feraheme, manufactured for the clinical treatment of iron-deficiency. Unfortunately, Feraheme is currently not available outside the United States due to commercial and regulatory constraints, making CBV-MRI methods either inaccessible or very costly to achieve. To address this barrier, we developed a simple, one-pot recipe to synthesize Carboxymethyl-dextran coated Iron Oxide Nanoparticles, namely, "CION", suitable for preclinical CBV-MRI applications. Here we disseminate a step-by-step instruction of our one-pot synthesis protocol, which allows CION to be produced in laboratories with minimal cost. We also characterized different CION-conjugations by manipulating polymer to metal stoichiometric ratio in terms of their size, surface chemistry, and chemical composition, and shifts in MR relaxivity and pharmacokinetics. We performed several proof-of-concept experiments in vivo, demonstrating the utility of CION for functional and structural MRI applications, including hypercapnic CO2 challenge, visual stimulation, targeted optogenetic stimulation, and microangiography. We also present evidence that CION can serve as a cross-modality research platform by showing concurrent in vivo optical and MRI measurement of CBV using fluorescent-labeled CION. The simplicity and cost-effectiveness of our one-pot synthesis method should allow researchers to reproduce CION and tailor the relaxivity and pharmacokinetics according to their imaging needs. It is our hope that this work makes CBV-MRI more openly available and affordable for a variety of research applications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Y2021b,

title = {Vibration-Assisted Insertion of Flexible Neural Microelectrodes With Bio-Dissolvable Guides for Medical Implantation},

author = {Wang Y, Shih YY, Lee YS},

doi = {10.1115/MSEC2021-63952},

year  = {2021},

date = {2021-08-04},

urldate = {2021-08-04},

journal = {American Society of Mechanical Engineers},

abstract = {This paper presents vibration-assisted insertion of flexible neural electrodes with bio-dissolvable guides to deliver accurate microprobe insertion with minimized tissue damage. Invasive flexible neural microprobe is an important new tool for neuromodulation and recording research for medical neurology treatment applications. Flexible neural electrode probes are susceptible to bending and buckling during surgical implantation due to the thin and flexible soft substrates. Inspired by insects in nature, a vibration-assisted insertion technique is developed for flexible neural electrode insertion to deliver accurate microprobe insertion with minimized tissue damage. A three-dimensional combined longitudinal-twisting (L&T) vibration is used to reduce the insertion friction force, and thus reducing soft tissue damage. To reduce the flexible microelectrode buckling during surgical insertion, a bio-dissolvable Polyethylene glycol (PEG) guide is developed for the enhancement of flexible neural probe stiffness. Combining these two methods, the insertion performance of the flexible neural probe is significantly improved. Both the in vitro and the in vivo experiments were conducted to validate the proposed techniques.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{MJ2021,

title = {Superoxide free radical spin‐lattice relaxivity: A quench‐assisted MR study},

author = {MacKinnon MJ, Berkowitz BA, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/33755248/},

doi = {10.1002/mrm.28722},

year  = {2021},

date = {2021-03-23},

urldate = {2021-03-23},

journal = {Magnetic Resonance in Medicine},

volume = {86},

number = {2},

pages = {1058-1066},

abstract = {Purpose

QuEnch‐assiSTed (QUEST) MRI provides a unique biomarker of excessive production of paramagnetic free radicals (oxidative stress) in vivo. The contribution from superoxide, a common upstream species found in oxidative stress‐based disease, to the QUEST metric is unclear. Here, we begin to address this question by measuring superoxide spin‐lattice relaxivity (r1) in phantoms.



Methods

Stable superoxide free radicals were generated in water phantoms of potassium superoxide (KO₂). To measure r1, 1/T₁ of different concentration solutions of KO₂ in the presence and absence of the antioxidant superoxide dismutase were measured. The 1/T₁ confounding factors including acquisition sequence, pH, and water source were also evaluated.



Results

The T₁‐weighted signal intensity increased with KO₂ concentration. No contribution from pH, or reaction products other than superoxide, noted on 1/T₁. Superoxide r1 was measured to be 0.29 mM⁻¹ s⁻¹, in agreement with that reported for paramagnetic molecular oxygen and nitroxide free radicals.



Conclusion

Our first‐in‐kind measurement of superoxide free radical r1 suggests a detection sensitivity of QUEST MRI on the order of tens of μM, within the reported level of free radical production during oxidative stress in vivo. Similar studies for other common free radicals are needed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{LM2020,

title = {Automatic Skull Stripping of Rat and Mouse Brain MRI Data Using U-Net},

author = {Hsu LM, Wang Shuai, Ranadive P, Ban W, Chao TH, Song S, Cerri DH, Walton LR, Broadwater MA, Lee SH, Shen D, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/33117118/},

doi = {10.3389/fnins.2020.568614},

year  = {2020},

date = {2020-10-07},

urldate = {2020-10-07},

journal = {Frontiers in Neuroscience},

volume = {14},

pages = {568614},

abstract = {Accurate removal of magnetic resonance imaging (MRI) signal outside the brain, a.k.a., skull stripping, is a key step in the brain image pre-processing pipelines. In rodents, this is mostly achieved by manually editing a brain mask, which is time-consuming and operator dependent. Automating this step is particularly challenging in rodents as compared to humans, because of differences in brain/scalp tissue geometry, image resolution with respect to brain-scalp distance, and tissue contrast around the skull. In this study, we proposed a deep-learning-based framework, U-Net, to automatically identify the rodent brain boundaries in MR images. The U-Net method is robust against inter-subject variability and eliminates operator dependence. To benchmark the efficiency of this method, we trained and validated our model using both in-house collected and publicly available datasets. In comparison to current state-of-the-art methods, our approach achieved superior averaged Dice similarity coefficient to ground truth T2-weighted rapid acquisition with relaxation enhancement and T2-weighted echo planar imaging data in both rats and mice (all p < 0.05), demonstrating robust performance of our approach across various MRI protocols.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{H2020,

title = {Mitochondriotropic lanthanide nanorods: implications for multimodal imaging},

author = {Singh H, Sreedharan S, Oyarzabal E , Mahapatra TS, Green N, Shih YY, Das M, Thomas JA, Pramanik SK, Das A},

url = {https://pubmed.ncbi.nlm.nih.gov/32531009/},

doi = {10.1039/d0cc02698k},

year  = {2020},

date = {2020-07-21},

urldate = {2020-07-21},

journal = {Chemical communications},

volume = {56},

number = {57},

pages = {7945-7948},

abstract = {Two-photon active mitochondriotropic lanthanide nanorods for high resolution fluorescence imaging. The presence of Gd in the nanorods also enabled us to utilize this material as a T1-T2 dual-mode contrast reagent for recording magnetic resonance images of the mouse brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Y2020,

title = {Supramammillary nucleus synchronizes with dentate gyrus to regulate spatial memory retrieval through glutamate release},

author = {Li Y, Bao H, Luo Y, Yoan C, Sullivan HA, Quintanilla L, Wickersham I, Lazarus M, Shih YY, Song J},

url = {https://pubmed.ncbi.nlm.nih.gov/32167473/},

doi = {10.7554/eLife.53129},

year  = {2020},

date = {2020-02-26},

urldate = {2020-02-26},

journal = {eLife},

volume = {9},

pages = {e53129},

abstract = {The supramammillary nucleus (SuM) provides substantial innervation to the dentate gyrus (DG). It remains unknown how the SuM and DG coordinate their activities at the circuit level to regulate spatial memory. Additionally, SuM co-releases GABA and glutamate to the DG, but the relative role of GABA versus glutamate in regulating spatial memory remains unknown. Here we report that SuM-DG Ca2+ activities are highly correlated during spatial memory retrieval as compared to the moderate correlation during memory encoding when mice are performing a location discrimination task. Supporting this evidence, we demonstrate that the activity of SuM neurons or SuM-DG projections is required for spatial memory retrieval. Furthermore, we show that SuM glutamate transmission is necessary for both spatial memory retrieval and highly-correlated SuM-DG activities during spatial memory retrieval. Our studies identify a long-range SuM-DG circuit linking two highly correlated subcortical regions to regulate spatial memory retrieval through SuM glutamate release.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{CM2020,

title = {The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging},

author = {Wander CM, Tseng JH, Song S, Housseiny HAA, Tart DS, Ajit A, Shih YY, Lobrovich R, Song J, Meeker RB, Irwin DJ, Cohen TJ},

url = {https://pubmed.ncbi.nlm.nih.gov/32585593/},

doi = {10.1016/j.isci.2020.101255},

year  = {2020},

date = {2020-02-24},

urldate = {2020-07-24},

journal = {iScience},

volume = {23},

number = {7},

pages = {101255},

abstract = {The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{F2020,

title = {Animal functional magnetic resonance imaging: Trends and path toward standardization},

author = {Mandino F, Cerri DH, Garin CM, Straathof M, Tilborg GA, Chakravarty MM, Dhenain M, Dijkhuizen R, Gozzi A, Hess A, Keilholz SD, Lerch JP, Shih YY, Grandjean J},

url = {https://pubmed.ncbi.nlm.nih.gov/32038217/},

doi = {10.3389/fninf.2019.00078},

year  = {2020},

date = {2020-01-06},

urldate = {2020-01-06},

journal = {Frontiers in Neuroinformatics},

volume = {13},

number = {78},

abstract = {Animal whole-brain functional magnetic resonance imaging (fMRI) provides a non-invasive window into brain activity. A collection of associated methods aims to replicate observations made in humans and to identify the mechanisms underlying the distributed neuronal activity in the healthy and disordered brain. Animal fMRI studies have developed rapidly over the past years, fueled by the development of resting-state fMRI connectivity and genetically encoded neuromodulatory tools. Yet, comparisons between sites remain hampered by lack of standardization. Recently, we highlighted that mouse resting-state functional connectivity converges across centers, although large discrepancies in sensitivity and specificity remained. Here, we explore past and present trends within the animal fMRI community and highlight critical aspects in study design, data acquisition, and post-processing operations, that may affect the results and influence the comparability between studies. We also suggest practices aimed to promote the adoption of standards within the community and improve between-lab reproducibility. The implementation of standardized animal neuroimaging protocols will facilitate animal population imaging efforts as well as meta-analysis and replication studies, the gold standards in evidence-based science.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{S2019,

title = {Noradrenergic dysfunction accelerates LPS-elicited inflammation-related ascending sequential neurodegeneration and deficits in non-motor/motor functions},

author = {Song S, Wang Q, Jiang L, Oyarzabal E, Riddick NV, Wilson B, Moy SS, Shih YY, Hong JS},

url = {https://pubmed.ncbi.nlm.nih.gov/31247288/},

doi = {10.1016/j.bbi.2019.06.034},

year  = {2019},

date = {2019-10-02},

urldate = {2019-10-02},

journal = {Brain, Behavior, and Immunity},

volume = {81},

pages = {374-387},

abstract = {The loss of central norepinephrine (NE) released by neurons of the locus coeruleus (LC) occurs with aging, and is thought to be an important factor in producing the many of the nonmotor symptoms and exacerbating the degenerative process in animal models of Parkinson's disease (PD). We hypothesize that selectively depleting noradrenergic LC neurons prior to the induction of chronic neuroinflammation may not only accelerate the rate of progressive neurodegeneration throughout the brain, but may exacerbate nonmotor and motor behavioral phenotypes that recapitulate symptoms of PD. For this reason, we used a "two-hit" mouse model whereby brain NE were initially depleted by DSP-4 one week prior to exposing mice to LPS. We found that pretreatment with DSP-4 potentiated LPS-induced sequential neurodegeneration in SNpc, hippocampus, and motor cortex, but not in VTA and caudate/putamen. Mechanistic study revealed that DSP-4 enhanced LPS-induced microglial activation and subsequently elevated neuronal oxidative stress in affected brain regions in a time-dependent pattern. To further characterize the effects of DSP-4 on non-motor and motor symptoms in the LPS model, physiological and behavioral tests were performed at different time points following injection. Consistent with the enhanced neurodegeneration, DSP-4 accelerated the progressive deficits of non-motor symptoms including hyposmia, constipation, anxiety, sociability, exaggerated startle response and impaired learning. Furthermore, notable decreases of motor functions, including decreased rotarod activity, grip strength, and gait disturbance, were observed in treated mice. In summary, our studies provided not only an accelerated "two-hit" PD model that recapitulates the features of sequential neuron loss and the progression of motor/non-motor symptoms of PD, but also revealed the critical role of early LC noradrenergic neuron damage in the pathogenesis of PD-like symptoms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TC2019,

title = {MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat},

author = {Lin TC, Lo YC, Lin HC, Li SJ, Lin SH, Wu HF, Chu MC, Lee CW, Lin IC, Chang CW, Liu YC, Chen TC, Lin YJ, Shih YY, Chen YY},

url = {https://pubmed.ncbi.nlm.nih.gov/31324604/},

doi = {10.1016/j.brs.2019.07.004},

year  = {2019},

date = {2019-07-06},

urldate = {2019-07-06},

journal = {Brain Stimulation},

volume = {12},

number = {6},

pages = {1410-1420},

abstract = {Background

Social deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders.



Objective

We first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model.



Methods

Brain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model.



Results

The DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits.



Conclusions

Applying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{S2019b,

title = {Loss of Brain Norepinephrine Elicits Neuroinflammation-Mediated Oxidative Injury and Selective Caudo-Rostral Neurodegeneration},

author = {Song S, Jiang L, Oyarzabal EA, Wilson B, Li Z, Shih YY, Wang Q, Hong JS},

url = {https://pubmed.ncbi.nlm.nih.gov/30051353/},

doi = {10.1007/s12035-018-1235-1},

year  = {2019},

date = {2019-04-01},

urldate = {2019-04-01},

journal = {Molecular Neurobiology},

volume = {56},

number = {4},

pages = {2653-2669},

abstract = {Environmental toxicant exposure has been strongly implicated in the pathogenesis of Parkinson's disease (PD). Clinical manifestations of non-motor and motor symptoms in PD stem from decades of progressive neurodegeneration selectively afflicting discrete neuronal populations along a caudo-rostral axis. However, recapitulating this spatiotemporal neurodegenerative pattern in rodents has been unsuccessful. The purpose of this study was to generate such animal PD models and delineate mechanism underlying the ascending neurodegeneration. Neuroinflammation, oxidative stress, and neuronal death in mice brains were measured at different times following a single systemic injection of lipopolysaccharide (LPS). We demonstrate that LPS produced an ascending neurodegeneration that temporally afflicted neurons initially in the locus coeruleus (LC), followed by substantia nigra, and lastly the primary motor cortex and hippocampus. To test the hypothesis that LPS-elicited early loss of noradrenergic LC neurons may underlie this ascending pattern, we used a neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to deplete brain norepinephrine. DSP-4 injection resulted in a time-dependent ascending degenerative pattern similar to that generated by the LPS model. Mechanistic studies revealed that increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX2)-dependent superoxide/reactive oxygen species (ROS) production plays a key role in both LPS- and DSP-4-elicited neurotoxicity. We found that toxin-elicited chronic neuroinflammation, oxidative neuronal injuries, and neurodegeneration were greatly suppressed in mice deficient in NOX2 gene or treated with NOX2-specific inhibitor. Our studies document the first rodent PD model recapturing the ascending neurodegenerative pattern of PD patients and provide convincing evidence that the loss of brain norepinephrine is critical in initiating and maintaining chronic neuroinflammation and the discrete neurodegeneration in PD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{X2018,

title = {IL-11 antagonist suppresses Th17 cell-mediated neuroinflammation and demyelination in a mouse model of relapsing-remitting multiple sclerosis},

author = {Zhang X, Kiapour N, Kapoor S, Merrill JR, Xia Y, Ban W, Cohen SM, Midkiff BR, Jewells V, Shih YY, Markovic-Plese S},

url = {https://pubmed.ncbi.nlm.nih.gov/30149119/},

doi = {10.1016/j.clim.2018.08.006},

year  = {2018},

date = {2018-08-24},

urldate = {2018-08-24},

journal = {Clinical Immunology},

volume = {197},

pages = {45-53},

abstract = {IL-11 induced differentiation and expansion of Th17 cells in patients with early relapsing-remitting multiple sclerosis (RRMS). In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RREAE), IL-11 exacerbated disease, induced demyelination in the central nervous system (CNS), increased the percentage of IL-17A+CD4+ Th17 cells in the CNS in the early acute phase, and up-regulated serum IL-17A levels and the percentage of IL-17A+CD4+ Th17 cells in lymph nodes, and IFN-γ+CD4+ T cells in spinal cord in the RR phase. IL-11 antagonist suppressed RREAE disease activities, inhibited IL-17A+CD4+ cell infiltration and demyelination in the CNS, and decreased the percentage of IL-17A+CD4+ T cells in peripheral blood mononuclear cells and ICAM1+CD4+ T cells in brain and SC. Diffusion Tensor Imaging indicated that IL-11 antagonist inhibited demyelination in several brain regions. We conclude that by suppressing Th17 cell-mediated neuroinflammation and demyelination, IL-11 antagonist can be further studied as a potential selective and early therapy for RRMS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{YW2018,

title = {Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses},

author = {Chen YW, Das M, Oyarzabal EA, Cheng Q, Pulmmer N, Smith K, Jones G, Malawsky D, Yakel J, Shih YY, Jensen P},

url = {https://pubmed.ncbi.nlm.nih.gov/30214043/},

doi = {10.1038/s41380-018-0245-8},

year  = {2018},

date = {2018-08-13},

urldate = {2018-08-13},

journal = {Molecular Psychiatry},

volume = {24},

number = {5},

pages = {710-725},

abstract = {Noradrenergic signaling plays a well-established role in promoting the stress response. Here we identify a subpopulation of noradrenergic neurons, defined by developmental expression of Hoxb1, that has a unique role in modulating stress-related behavior. Using an intersectional chemogenetic strategy, in combination with behavioral and physiological analyses, we show that activation of Hoxb1-noradrenergic (Hoxb1-NE) neurons decreases anxiety-like behavior and promotes an active coping strategy in response to acute stressors. In addition, we use cerebral blood volume-weighted functional magnetic resonance imaging to show that chemoactivation of Hoxb1-NE neurons results in reduced activity in stress-related brain regions, including the bed nucleus of the stria terminalis, amygdala, and locus coeruleus. Thus, the actions of Hoxb1-NE neurons are distinct from the well-documented functions of the locus coeruleus in promoting the stress response, demonstrating that the noradrenergic system contains multiple functionally distinct subpopulations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{AJ2018,

title = {An Adeno-Associated Virus-Based Toolkit for Preferential Targeting and Manipulating Quiescent Neural Stem Cells in the Adult Hippocampus},

author = {Crowther AJ, Lim SA, Asrican B, Albright BH, Wooten J, Yeh CY, Bao H, Cerri DH, Hu J, Ian Shih YY, Asokan A, Song J

},

url = {https://pubmed.ncbi.nlm.nih.gov/29478897/},

doi = {10.1016/j.stemcr.2018.01.018},

year  = {2018},

date = {2018-07-31},

urldate = {2018-07-31},

journal = {Stem Cell Reports},

volume = {10},

number = {3},

pages = {1146-1159},

abstract = {Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need. Here, we report a recombinant adeno-associated virus serotype 4 (rAAV4)-based toolkit that preferentially targets hippocampal qNSCs and allows for lineage tracing, functional analyses, and activity manipulation of adult qNSCs. Importantly, targeting qNSCs in a non-Cre-dependent fashion opens the possibility for studying qNSCs in less genetically tractable animal species and may have translational impact in gene therapy by preferentially targeting qNSCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{MA2017,

title = {Adolescent alcohol exposure decreases frontostriatal resting-state functional connectivity in adulthood},

author = {Broadwater MA, Lee SH, Yu Y, Zhu H, Crews FT, Robinson DL, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/28691248/},

doi = {10.1111/adb.12530},

year  = {2018},

date = {2018-03-23},

urldate = {2018-03-23},

journal = {Addiction Biology},

volume = {23},

number = {2},

pages = {810-823},

abstract = {Connectivity of the prefrontal cortex (PFC) matures through adolescence, coinciding with emergence of adult executive function and top-down inhibitory control over behavior. Alcohol exposure during this critical period of brain maturation may affect development of PFC and frontolimbic connectivity. Adult rats exposed to adolescent intermittent ethanol (AIE; 5 g/kg ethanol, 25 percent v/v in water, intragastrically, 2-day-on, 2-day-off, postnatal day 25–54) or water control underwent resting-state functional MRI to test the hypothesis that AIE induces persistent changes in frontolimbic functional connectivity under baseline and acute alcohol conditions (2 g/kg ethanol or saline, intraperitoneally administered during scanning). Data were acquired on a Bruker 9.4-T MR scanner with rats under dexmedetomidine sedation in combination with isoflurane. Frontolimbic network regions-of-interest for data analysis included PFC [prelimbic (PrL), infralimbic (IL), and orbitofrontal cortex (OFC) portions], nucleus accumbens (NAc), caudate putamen (CPu), dorsal hippocampus, ventral tegmental area, amygdala, and somatosensory forelimb used as a control region. AIE decreased baseline resting-state connectivity between PFC subregions (PrL-IL and IL-OFC) and between PFC-striatal regions (PrL-NAc, IL-CPu, IL-NAc, OFC-CPu, and OFC-NAc). Acute ethanol induced negative blood-oxygen-level-dependent changes within all regions of interest examined, along with significant increases in functional connectivity in control, but not AIE animals. Together, these data support the hypothesis that binge-like adolescent alcohol exposure causes persistent decreases in baseline frontolimbic (particularly frontostriatal) connectivity and alters sensitivity to acute ethanol-induced increases in functional connectivity in adulthood.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{A2017,

title = {Simultaneous functional photoacoustic microscopy and electrocorticography reveal the impact of rtPA on dynamic neurovascular functions after cerebral ischemia},

author = {Bandla A, Liao LD, Chan SJ, Ling JM, Liu YH, Shih YY, Pan HC, Wong PT, Lai HY, King NKK, Chen YY, Ng WH, Thakor NV},

url = {https://pubmed.ncbi.nlm.nih.gov/28685662/},

doi = {10.1177/0271678X17712399},

year  = {2017},

date = {2017-07-07},

urldate = {2017-07-07},

journal = {Journal of Cerebral Blood Flow and Metabolism},

volume = {38},

number = {6},

pages = {980-995},

abstract = {The advance of thrombolytic therapy has been hampered by the lack of optimization of the therapy during the hyperacute phase of focal ischemia. Here, we investigate neurovascular dynamics using a custom-designed hybrid electrocorticography (ECoG)-functional photoacoustic microscopy (fPAM) imaging system during the hyperacute phase (first 6 h) of photothrombotic ischemia (PTI) in male Wistar rats following recombinant tissue plasminogen activator (rtPA)-mediated thrombolysis. We reported, for the first time, the changes in neural activity and cerebral hemodynamic responses following rtPA infusion at different time points post PTI. Interestingly, very early administration of rtPA (< 1 h post PTI) resulted in only partial recovery of neurovascular dynamics (specifically, neural activity recovered to 71 ± 3.5% of baseline and hemodynamics to only 52 ± 2.6% of baseline) and late administration of rtPA (> 4 h post PTI) resulted in the deterioration of neurovascular function. A therapeutic window between 1 and 3 h post PTI was found to improve recovery of neurovascular function (i.e. significant restoration of neural activity to 93 ± 4.2% of baseline and hemodynamics to 81 ± 2.1% of baseline, respectively). The novel combination of fPAM and ECoG enables direct mapping of neurovascular dynamics and serves as a platform to evaluate potential interventions for stroke.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{YC2016,

title = {The Role of Genetic Variation in Collateral Circulation in the Evolution of Acute Stroke: A Multimodal MRI Study},

author = {Kao YC, Oyarzabal EA, Zhang H, Faber JE, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/28188261/},

doi = {10.1161/STROKEAHA.116.015878},

year  = {2017},

date = {2017-02-10},

journal = {Stroke},

volume = {48},

number = {3},

abstract = {Background and Purpose—No studies have determined the effect of differences in pial collateral extent (number and diameter), independent of differences in environmental factors and unknown genetic factors, on severity of stroke. We examined ischemic tissue evolution during acute stroke, as measured by magnetic resonance imaging and histology, by comparing 2 congenic mouse strains with otherwise identical genetic backgrounds but with different alleles of the Determinant of collateral extent-1 (Dce1) genetic locus. We also optimized magnetic resonance perfusion and diffusion–deficit thresholds by using histological measures of ischemic tissue.



Methods—Perfusion, diffusion, and T2-weighted magnetic resonance imaging were performed on collateral-poor (congenic-Bc) and collateral-rich (congenic-B6) mice at 1, 5, and 24 hours after permanent middle cerebral artery occlusion. Magnetic resonance imaging–derived penumbra and ischemic core volumes were confirmed by histology in a subset of mice at 5 and 24 hours after permanent middle cerebral artery occlusion.



Results—Although perfusion-deficit volumes were similar between strains 1 hour after permanent middle cerebral artery occlusion, diffusion-deficit volumes were 32% smaller in collateral-rich mice. At 5 hours, collateral-rich mice had markedly restored perfusion patterns showing reduced perfusion-deficit volumes, smaller infarct volumes, and smaller perfusion–diffusion mismatch volumes compared with the collateral-poor mice (P<0.05). At 24 hours, collateral-rich mice had 45% smaller T2-weighted lesion volumes (P<0.005) than collateral-poor mice, with no difference in perfusion–diffusion mismatch volumes because of penumbral death occurring 5 to 24 hours after permanent middle cerebral artery occlusion in collateral-poor mice.



Conclusions—Variation in collateral extent significantly alters infarct volume expansion, transiently affects perfusion and diffusion magnetic resonance imaging signatures, and impacts salvage of ischemic penumbra after stroke onset.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Albaugh2016,

title = {Functional Circuit Mapping of Striatal Output Nuclei using Simultaneous DBS-fMRI},

author = {Van Den Berge N, Albaugh DL, Salzwedel A, Vanhove C, Van Holen R, Gao W, Stuber GD, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/27825979/},

doi = {10.1016/j.neuroimage.2016.10.049},

year  = {2017},

date = {2017-02-02},

journal = {NeuroImage},

volume = {146},

pages = {1050–1061},

abstract = {The substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) constitute the two major output targets of the rodent striatum. Both the SNr and GPe converge upon thalamic relay nuclei (directly or indirectly, respectively), and are traditionally modeled as functionally antagonistic relay inputs. However, recent anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe, demonstrating their potential as far more than relay nuclei. In the present study, we employed simultaneous deep brain stimulation and functional magnetic resonance imaging (DBS-fMRI) with cerebral blood volume (CBV) measurements to functionally and unbiasedly map the circuit- and network level connectivity of the SNr and GPe. Sprague-Dawley rats were implanted with a custom-made MR-compatible stimulating electrode in the right SNr (n=6) or GPe (n=7). SNr- and GPe-DBS, conducted across a wide range of stimulation frequencies, revealed a number of surprising evoked responses, including unexpected CBV decreases within the striatum during DBS at either target, as well as GPe-DBS-evoked positive modulation of frontal cortex. Functional connectivity MRI revealed global modulation of neural networks during DBS at either target, sensitive to stimulation frequency and readily reversed following cessation of stimulation. This work thus contributes to a growing literature demonstrating extensive and unanticipated functional connectivity among basal ganglia nuclei.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{EA2016b,

title = {Aging and Microglial Activation in Neurodegenerative Diseases},

author = {Oyarzabal EA, Shih YY, Hong JS},

doi = {10.1007/978-3-319-33486-8_7},

year  = {2016},

date = {2016-12-15},

journal = {Inflammation, Aging, and Oxidative Stress},

pages = {107-131},

abstract = {Biological aging describes the gradual degradation of physiological function which is a consequence of accumulating spontaneous and environmentally derived mutations and adducts. Aging lowers cellular fitness and drives senescence in the later years of life. Some hallmarks associated with aging include genomic instability; increased protein aggregates with reduced proteolytic capabilities; hypometabolism; and primed inflammatory responses—together increasing the vulnerability of aged cells to insults, disease and death. According to the World Health Organization, better living and working conditions, improved access to healthcare, and trends to reduce harmful habits (e.g. improper hygiene, poor nutrition, smoking and sedentary lifestyles) have contributed to shifting the world average life expectancy from 31 to 71.5 years of age within the century. Consequently, with greater longevity the prevalence of late-onset neurodegenerative disorders is on the rise—particularly among developed countries. As population trends project the world average life expectancy to reach 87 years by 2030 with an elderly population (>65 years of age) growing from 6 to 12 % of the total population, understanding how aging increases the risk of developing a late-onset neurodegenerative disorder is paramount. This chapter will describe the current state of research regarding the risk of aging-related oxidative stress and neuroinflammation on the development of neurodegenerative diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{F2016,

title = {Functional magnetic resonance imaging of electrical and optogenetic deep brain stimulation at the rat nucleus accumbens},

author = {Albaugh DL, Salzwedel A, Van Den Berge N, Gao W, Stuber GD, Shih YY},

url = {https://pubmed.ncbi.nlm.nih.gov/27601003/},

doi = {10.1038/srep31613},

year  = {2016},

date = {2016-08-12},

urldate = {2016-08-12},

journal = {Scientific Reports},

volume = {6},

number = {31613},

abstract = {Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{F2016b,

title = {Coordination of brain wide activity dynamics by dopaminergic neurons},

author = {Decot H, Namboodiri VMK, Gao W, McHenry J, Jennings J, Lee SH, Kantak P, Kao YC, Das M, Witten I, Disseroth K, Shih YY, Stuber GD},

url = {https://pubmed.ncbi.nlm.nih.gov/27515791/},

doi = {10.1038/npp.2016.151},

year  = {2016},

date = {2016-08-11},

journal = {Neuropsychopharmacology},

volume = {42},

number = {3},

pages = {615–627},

abstract = {Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (THVTA) neurons, as well as from more global maladaptation in neurocircuit function. However, whether THVTA activity affects large-scale brain-wide function remains unknown. Here we selectively activated THVTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of THVTA neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of THVTA neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of THVTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct THVTA input.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ZC2016,

title = {Resting state network topology of the ferret brain},

author = {Zhou ZC, Salzwedel AP, Radtke-Schuller S, Li Y, Sellers KK, Gilmore JH, Shih YY, Frohlich F, Gao W},

url = {https://pubmed.ncbi.nlm.nih.gov/27596024/},

doi = {10.1016/j.neuroimage.2016.09.003},

year  = {2016},

date = {2016-08-01},

urldate = {2016-08-01},

journal = {NeuroImage},

volume = {143},

pages = {70-81},

abstract = {Resting state functional magnetic resonance imaging (rsfMRI) has emerged as a versatile tool for non-invasive measurement of functional connectivity patterns in the brain. RsfMRI brain dynamics in rodents, non-human primates, and humans share similar properties; however, little is known about the resting state functional connectivity patterns in the ferret, an animal model with high potential for developmental and cognitive translational study. To address this knowledge-gap, we performed rsfMRI on anesthetized ferrets using a 9.4T MRI scanner, and subsequently performed group-level independent component analysis (gICA) to identify functionally connected brain networks. Group-level ICA analysis revealed distributed sensory, motor, and higher-order networks in the ferret brain. Subsequent connectivity analysis showed interconnected higher-order networks that constituted a putative default mode network (DMN), a network that exhibits altered connectivity in neuropsychiatric disorders. Finally, we assessed ferret brain topological efficiency using graph theory analysis and found that the ferret brain exhibits small-world properties. Overall, these results provide additional evidence for pan-species resting-state networks, further supporting ferret-based studies of sensory and cognitive function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{S2016,

title = {Combining optogenetic stimulation and fMRI to validate a multivariate dynamical systems model for estimating causal brain interactions},

author = {Ryali S, Shih YY, Chen T, Kochalka J, Albaugh D, Fang Z, Supekar K, Lee JH, Menon V.},

url = {https://pubmed.ncbi.nlm.nih.gov/26934644/},

doi = {10.1016/j.neuroimage.2016.02.067},

year  = {2016},

date = {2016-05-15},

urldate = {2016-05-15},

journal = {NeuroImage},

volume = {132},

pages = {398-405},

abstract = {State-space multivariate dynamical systems (MDS) (Ryali et al. 2011) and other causal estimation models are being increasingly used to identify directed functional interactions between brain regions. However, the validity and accuracy of such methods are poorly understood. Performance evaluation based on computer simulations of small artificial causal networks can address this problem to some extent, but they often involve simplifying assumptions that reduce biological validity of the resulting data. Here, we use a novel approach taking advantage of recently developed optogenetic fMRI (ofMRI) techniques to selectively stimulate brain regions while simultaneously recording high-resolution whole-brain fMRI data. ofMRI allows for a more direct investigation of causal influences from the stimulated site to brain regions activated downstream and is therefore ideal for evaluating causal estimation methods in vivo. We used ofMRI to investigate whether MDS models for fMRI can accurately estimate causal functional interactions between brain regions. Two cohorts of ofMRI data were acquired, one at Stanford University and the University of California Los Angeles (Cohort 1) and the other at the University of North Carolina Chapel Hill (Cohort 2). In each cohort, optical stimulation was delivered to the right primary motor cortex (M1). General linear model analysis revealed prominent downstream thalamic activation in Cohort 1, and caudate-putamen (CPu) activation in Cohort 2. MDS accurately estimated causal interactions from M1 to thalamus and from M1 to CPu in Cohort 1 and Cohort 2, respectively. As predicted, no causal influences were found in the reverse direction. Additional control analyses demonstrated the specificity of causal interactions between stimulated and target sites. Our findings suggest that MDS state-space models can accurately and reliably estimate causal interactions in ofMRI data and further validate their use for estimating causal interactions in fMRI. More generally, our study demonstrates that the combined use of optogenetics and fMRI provides a powerful new tool for evaluating computational methods designed to estimate causal interactions between distributed brain regions.},

key = {(NeuroImage Paper of the Year)},

keywords = {},

pubstate = {published},

tppubtype = {article}

}