NeuroInfo Case Studies Archives - MBF Bioscience

How Certain Movement Control Cells Go Into Overdrive and Cause Unwanted Movements in Parkinson’s

Pasang — Sun, 15 Oct 2006 14:14:05 +0000

Ryan MB, Girasole AE, Flores AJ, Twedell EL, McGregor MM, Brakaj R, Paletzki RF, Hnasko TS, Gerfen CR, Nelson AB. Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input. Cell Rep 2024;43(8):114483. doi: 10.1016/j.celrep.2024.114483.

Background: Levodopa-induced dyskinesia (LID) is a common side effect of long-term dopamine replacement therapy in Parkinson’s disease, producing involuntary movements. The striatum integrates dopaminergic and glutamatergic input to control movement, but the cellular mechanisms that lead to the abnormal activation of specific neuronal subtypes during LID remain unclear.

Hypothesis: This study hypothesized that striatal direct pathway medium spiny neurons (dMSNs) activated during dyskinesia possess heightened dopamine sensitivity and excitatory synaptic drive, resulting in excessive levodopa-evoked firing that contributes to abnormal motor activity.

Methods: The authors used a FosTRAP mouse model of LID to label neurons activated during dyskinesia and applied electrophysiological, optogenetic and tracing methods to characterize them. Monosynaptic rabies tracing was performed to map presynaptic inputs, and brain sections were reconstructed and registered to the CCF v3 using NeuroInfo for automated cell detection and quantification. Whole-cell recordings were conducted to assess excitability and synaptic strength, and fluorescent in situ hybridization quantified dopamine receptor and prodynorphin expression.

Results: TRAPed dMSNs exhibited markedly higher firing rates after levodopa administration compared with other striatal neurons. They showed increased frequency of miniature excitatory postsynaptic currents, decreased paired-pulse ratios and stronger excitatory inputs from motor cortex and thalamus. These neurons also displayed elevated excitability in response to D1 receptor stimulation and higher D1 receptor and prodynorphin mRNA levels.

Conclusions: TRAPed dMSNs represent a dyskinesia-associated subpopulation with enhanced dopamine signaling and excitatory input, which together drive excessive firing and underlie the pathophysiology of levodopa-induced dyskinesia.

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Quantitative Brain-Wide Neuronal Mapping Through Three-Dimensional Reconstruction and Atlas Alignment of Serial Tissue Sections

Pasang — Thu, 12 Oct 2006 14:10:16 +0000

Eastwood BS, Hooks BM, Paletzki RF, O’Connor NJ, Glaser JR, Gerfen CR. Whole mouse brain reconstruction and registration to a reference atlas with standard histochemical processing of coronal sections. J Comp Neurol 2019;527(13):2170-2178. doi: 10.1002/cne.24602.

Background: Understanding neural circuits requires whole-brain mapping of specific neuronal connections within a standardized framework. Although modern genetic and viral tools allow precise labeling of neurons, integrating these data into complete brain reconstructions using conventional histological methods has been difficult.

Hypothesis: This study hypothesized that whole mouse brain reconstructions from conventionally sectioned and processed tissue can be accurately registered to a common reference atlas, enabling quantitative analysis of labeled neurons and axons throughout the brain.

Methods: The authors sectioned mouse brains labeled via modified rabies transsynaptic tracing and immunohistochemistry, imaged them using a fluorescence microscope equipped with Neurolucida software, and reconstructed serial coronal sections into a three-dimensional brain volume using BrainMaker software. Labeled cells were automatically detected through a Laplacian of Gaussian–based algorithm implemented in NeuroInfo, and whole-brain images were registered to the CCF v3 through a multistage registration pipeline.

Results: Registration accuracy tests showed mean landmark errors of approximately 63 µm in three-dimensional space and about 21 µm within imaging planes. Quantitative analysis of registered datasets generated spreadsheets of cell counts across atlas-defined structures, allowing comparisons between cases. Reconstructions revealed distinct distributions of neurons projecting to different cortical areas, demonstrating consistent alignment and reproducibility across brains.

Conclusions: This study established that whole-brain reconstructions from standard histological sections can be precisely registered to a reference atlas, enabling automated detection and quantitative comparison of labeled neurons across experiments. This approach facilitates high-resolution mapping of brain-wide connectivity using widely available laboratory techniques.

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Molecular Taxonomy Links Transcriptional Identity to Functional Specialization in Brain-Wide Spinal Projecting Neurons

Pasang — Tue, 10 Oct 2006 14:17:20 +0000

Winter CC, Jacobi A, Su J, Chung L, van Velthoven CTJ, Yao Z, Lee C, Zhang Z, Yu S, Gao K, Duque Salazar G, Kegeles E, Zhang Y, Tomihiro MC, Zhang Y, Yang Z, Zhu J, Tang J, Song X, Donahue RJ, Wang Q, McMillen D, Kunst M, Wang N, Smith KA, Romero GE, Frank MM, Krol A, Kawaguchi R, Geschwind DH, Feng G, Goodrich LV, Liu Y, Tasic B, Zeng H, He Z. A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons. Nature 2023;624(7991):403-414. doi: 10.1038/s41586-023-06817-8.

Background: Spinal projecting neurons (SPNs) transmit descending motor, sensory and autonomic commands from the brain to the spinal cord. Although their importance in voluntary movement and homeostatic regulation is well established, the molecular diversity and organization of SPNs across the entire brain have remained poorly characterized.

Hypothesis: This study hypothesized that distinct transcriptional signatures define discrete classes of SPNs, whose molecular identities correspond to their anatomical origins and functional specializations in motor and autonomic control.

Methods: The authors combined single-nucleus RNA sequencing using the 10x Genomics Chromium platform and SMART-Seq v4 with high-resolution spatial transcriptomics and anatomical mapping. Whole-brain reconstructions of retrogradely labeled neurons were acquired using the TissueCyte serial two-photon tomography platform. Image segmentation, registration and three-dimensional reconstruction of labeled nuclei were conducted with NeuroInfo. Quantification of labeled neurons and fluorescence intensity was performed using QuPath image analysis software.

Results: Sequencing of 65,002 SPN nuclei identified 76 molecularly distinct neuron types across three principal divisions: cortical, midbrain–hindbrain and modulatory. Reticulospinal neurons were organized by a LIM homeobox transcription factor “code” into five spatially distinct subclasses, and Spp1-positive rubrospinal neurons displayed larger soma size and fast-firing electrophysiological properties.

Conclusions: This study establishes a comprehensive molecular taxonomy of brain-wide SPNs, linking transcriptional identity to anatomical distribution and functional specialization in descending motor pathways.

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Automated Brain Mapping Tool Helps Scientists Accurately Identify Where They’re Looking in the Brain

Pasang — Wed, 20 Sep 2006 14:07:33 +0000

Tappan SJ, Eastwood BS, O’Connor N, Wang Q, Ng L, Feng D, Hooks BM, Gerfen CR, Hof PR, Schmitz C, Glaser JR. Automatic navigation system for the mouse brain. J Comp Neurol 2019;527(13):2200-2211. doi: 10.1002/cne.24635.

Background: Reliable identification of brain regions in histologic mouse brain sections is essential for neuroanatomical, genomic and connectomic analyses but is often limited by human error and variability when using traditional atlases. Manual matching of experimental sections to reference atlases is particularly challenging when sectioning planes differ, highlighting the need for an automated and objective solution.

Hypothesis: This study hypothesized that an automated system, NeuroInfo, could accurately register experimental mouse brain sections to the Allen Mouse Brain Common Coordinate Framework version 3 (CCF v3) and delineate brain regions with accuracy comparable to expert manual annotations.

Methods: The authors developed NeuroInfo as a Windows-based C++ desktop application. The software uses a multi-stage, intensity-based 3D image registration algorithm to align two-dimensional experimental sections with the 3D CCF v3 reference atlas. Validation was performed on 60 coronal sections from 12 mouse brains prepared in two laboratories and imaged using fluorescence or bright-field microscopy. Section images were acquired using Neurolucida. Automatic delineations were compared with manual ones drawn using Stereo Investigator, using Dice coefficients, centroid distances and area overlap metrics.

Results: NeuroInfo achieved strong agreement with manual delineations for large or dorsal regions (Dice >0.7), moderate alignment for small or ventrolateral regions (0.5–0.7), and weak performance for small midline or non-neuronal areas (<0.5). Mean registration time per section was approximately 77 seconds, and imaging modality had no effect on accuracy.

Conclusions: NeuroInfo accurately and efficiently identifies most major mouse brain regions, providing an objective, automated tool for histologic image registration and region delineation that enhances reproducibility in mouse brain mapping.

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Different Brain Cells Use Different Strategies to Communicate with Movement Control Centers

Pasang — Sat, 16 Sep 2006 14:13:02 +0000

Hooks BM, Papale AE, Paletzki RF, Feroze MW, Eastwood BS, Couey JJ, Winnubst J, Chandrashekar J, Gerfen CR. Topographic precision in sensory and motor corticostriatal projections varies across cell type and cortical area. Nat Commun 2018;9(1):3549. doi: 10.1038/s41467-018-05780-7.

Background: The cerebral cortex communicates with the striatum through two major classes of layer 5 pyramidal neurons: intratelencephalic-type (IT-type) and pyramidal tract-type (PT-type). While both contribute to topographically organized corticostriatal circuits, how their projection patterns differ across cortical areas remains unclear. Clarifying these differences is essential to understanding how sensory and motor information are integrated in the basal ganglia.

Hypothesis: This study hypothesized that IT-type and PT-type cortical neurons exhibit distinct corticostriatal projection patterns, with IT-type neurons showing greater topographic precision and stereotypy than PT-type neurons, and that these differences vary across sensory, motor and frontal cortical areas.

Methods: The authors used Cre-driver mice specific for IT-type (Tlx3_PL56) and PT-type (Sim1_KJ18) neurons. Cre-dependent viral tracers expressing fluorescent reporters were injected into sensory, motor and frontal cortices. Brain sections were imaged and analyzed in three dimensions using Neurolucida for neuronal annotation and the BrainMaker module of NeuroInfo for whole-brain alignment to the CCF v3, enabling voxel-based quantification of corticostriatal projections.

Results: IT-type neurons projected bilaterally to cortex and striatum, while PT-type neurons projected ipsilaterally and to subcortical structures. IT-type projections displayed higher inter-animal consistency and greater overlap between interconnected cortical regions. PT-type projections were more focal, less stereotyped and exhibited reduced correlation across animals. Striatal clusters received distinct sensory and motor inputs organized along the anterior–posterior axis.

Conclusions: This study concluded that corticostriatal topography differs by cortical area and cell type. IT-type neurons provide broad, consistent mapping across interconnected cortical networks, whereas PT-type neurons convey more localized and variable projections, reflecting distinct roles in striatal information processing.

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Neuron-Specific Thalamic Connectivity Patterns Encode Spontaneous Movement in Sensory Cortex

Pasang — Sun, 26 Feb 2006 15:06:48 +0000

Inácio AR, Lam KC, Zhao Y, Pereira F, Gerfen CR, Lee S. Brain-wide presynaptic networks of functionally distinct cortical neurons. Nature 2025;641(8061):162-172. doi: 10.1038/s41586-025-08631-w.

Background: Neuronal activity in the primary somatosensory cortex (wS1) is influenced by both sensory stimuli and spontaneous movements, yet the organization of circuits that support this functional diversity remains unclear. Prior studies have shown that neuromodulators and thalamic activity correlate with behavioral state, but how these inputs contribute to movement-related cortical activity at the level of single neurons is poorly understood.

Hypothesis: This study hypothesized that functionally distinct neurons in wS1 receive inputs from anatomically distinct presynaptic networks, and that this organization underlies the stable encoding of spontaneous movement-related activity.

Methods: The authors used two-photon calcium imaging to record layer 2/3 pyramidal neuron activity in awake mice during spontaneous whisker and locomotor movements. Functionally identified neurons were electroporated with constructs encoding TVA, glycoprotein and a fluorescent marker, followed by injection of a glycoprotein-deleted rabies virus expressing red fluorescence. Whole-brain reconstructions identified monosynaptic presynaptic neurons, which were mapped and quantified using Neurolucida for three-dimensional reconstruction and NeuroInfo for anatomical registration with the CCF v3.

Results: In wS1, movement-correlated neurons increased activity during spontaneous movements, while uncorrelated neurons did not. Glutamate receptor blockade disrupted this activity, but neuromodulatory receptor blockade did not, showing glutamatergic dependence. Tracing revealed that movement-correlated neurons received fewer motor cortical and more thalamic inputs. Optogenetic suppression confirmed that only thalamic input reductions decreased movement-related activity.

Conclusions: These findings indicate that stable representations of spontaneous movement in wS1 arise from neuron-specific anatomical biases in presynaptic connectivity, primarily mediated by thalamic glutamatergic inputs rather than direct neuromodulatory control.

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Ventral Tegmental Dopamine Initiates Fear Extinction by Activating Reward-Processing Circuits in the Amygdala

Pasang — Tue, 17 Jan 2006 15:47:31 +0000

Zhang X, Flick K, Rizzo M, Pignatelli M, Tonegawa S. Dopamine induces fear extinction by activating the reward-responding amygdala neurons. Proc Natl Acad Sci USA 2025;122(18):e2501331122. doi: 10.1073/pnas.2501331122.

Background: Extinguishing conditioned fear responses is vital for adaptive behavior, and its failure contributes to anxiety disorders such as PTSD. The basolateral amygdala (BLA) contains anterior Rspo2⁺ neurons driving fear and posterior Ppp1r1b⁺ neurons encoding reward and extinction. Although extinction memory forms in the Ppp1r1b⁺ neurons, the signal that initiates this process was unknown. Dopaminergic activity from the ventral tegmental area (VTA) has been proposed to provide such a teaching signal.

Hypothesis: This study hypothesized that the omission of expected aversive stimuli during fear extinction increases dopaminergic activity from the VTA onto Ppp1r1b⁺ BLA neurons, thereby initiating extinction learning.

Methods: The authors used viral circuit tracing, optogenetics and in vivo fiber photometry in genetically defined mouse lines to examine dopamine signaling between the VTA and BLA. Fluorescence and cell-count analyses were performed with NeuroInfo and Stereo Investigator for brain mapping and quantification, respectively, and fiber photometry data were acquired using a single-site recording system.

Results: Anterograde and retrograde tracing showed topographically distinct VTA dopamine projections to Rspo2⁺ and Ppp1r1b⁺ neurons. Dopamine receptor mapping revealed stronger D1 receptor expression in Ppp1r1b⁺ neurons. Fiber photometry demonstrated that dopamine activity in Ppp1r1b⁺ neurons, but not Rspo2⁺ neurons, increased following freezing cessation and correlated with extinction learning strength. Optogenetic activation of VTA terminals in the posterior BLA accelerated extinction, whereas inhibition impaired it. Manipulating D1 receptor expression bidirectionally modulated extinction behavior.

Conclusions: Dopaminergic input from the VTA to BLA Ppp1r1b⁺ neurons acts as a teaching signal that drives fear extinction learning through D1 receptor–mediated excitation, identifying a circuit mechanism by which dopamine promotes the transition from fear to safety.

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