Biology subjects

Gerfen, C. R.

Publications and source records attributed to Gerfen, C. R..

At least 19 recordsLinked to original sources

bioRxiv2025

Hybrid Solid-Liquid Optics Enable Scalable, High-Resolution, Multi-Immersion Light-Sheet Microscopy

Modern biology increasingly depends on data-driven discovery, requiring scalable and affordable high-content 3D imaging across molecular to organ scales. Although tissue clearing, expansion microscopy, and light-sheet microscopy (LSM) enable subcellular-resolution imaging of intact specimens, their scalability remains fundamentally limited by detection optics: immersion objectives deliver high-resolution, aberration-free imaging but with short working distances, high cost, and multi-immersion incompatibility, while air objectives offer long working distances and portability at lower cost but suffer from severe aberrations and reduced photon collection when imaging immersed samples. We introduce the Hybrid Solid-Liquid Immersion Lens (HySIL) framework, which pairs an off-the-shelf solid optical component with a refractive index-matched liquid to precompensate aberrations and enhance resolution. Building on HySIL, we developed SCOPE and Super-SCOPE, objective-agnostic imaging devices achieving submicron lateral resolution (<0.75 {micro}m) across centimeter-scale samples using inexpensive air objectives with >30 mm working distances. Integration with a low-cost LSM platform yielded a compact, scalable system demonstrated for multi-immersion, multi-color, subcellular-resolution mapping of cleared or expanded mouse, salamander, and cavefish brains, human iPSC-derived organoids, and 3D histopathology of breast tissue. HySIL and SCOPE establish an accessible foundation for scalable, high-resolution volumetric imaging, advancing data-driven biological discovery.

bioengineering↗

bioRxiv2025

Cholinergic-dependent dopamine signals in mouse dorsal striatum are regulated by frontal but not sensory cortices

Everyday decisions depend on linking sensory stimuli with actions and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Thus, the timing and magnitude of dopamine release is critical for learning. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via acetylcholine activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine responses in the dorsomedial striatum through this cholinergic-dependent mechanism. Using anatomical and functional methods to identify which pathways elicit these signals, we found that visual and auditory cortices that project to the dorsomedial striatum lack robust connectivity to CINs and were unable to drive cholinergic-dependent dopamine release. In contrast, frontal cortical regions, including the prelimbic and anterior cingulate cortices, strongly recruited CINs and acetylcholine, producing robust dopamine release both ex vivo and in vivo. These frontal corticostriatal projections are activated by visual stimuli, representing a possible pathway by which visual information reaches the dorsomedial striatum to evoke dopamine. These findings reveal a fundamental distinction between sensory and frontal cortical inputs to the striatum, demonstrating that only the latter evoke cholinergic-dependent dopamine signaling. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

neuroscience↗

bioRxiv2025

Cocaine-induced immediate-early gene expression in the nucleus accumbens: roles of separate cAMP sensors

Immediate-early gene (IEG) induction after administration of amphetamine or cocaine has been used to trace the signaling pathways that mediate neuronal plasticity required for the short- and long-term behavioral effects of these psychostimulants. We recently reported that a novel cyclic AMP (cAMP)-dependent Rap guanine nucleotide exchange factor-2 (RapGEF2)-ERK signaling pathway is required for Egr-1 induction in D1 medium-spiny neurons (MSNs) of the nucleus accumbens (NAc) after cocaine treatment, and that its deletion from the NAc neurons attenuates cocaine-induced locomotor sensitization and conditioned place preference (CPP). However, the cell type-specific neuronal mechanisms underlying this effect remain unclear. In this study, we used Cre-LoxP technology and a novel Cre-amplifier transgene to generate conditional RapGEF2 knockout mice targeting D1-MSNs and investigated the functional role of RapGEF2 in cocaine reward. Deletion of RapGEF2 in D1-MSNs blocked cocaine-induced ERK phosphorylation (p-ERK) and Egr-1 induction. D1-MSN-specific RapGEF2 deletion did not affect intravenous cocaine self-administration, nor did it affect Fos induction by cocaine, prompting us to examine more closely the role of metabotropic (cAMP-dependent) signaling to IEGs after cocaine administration. We used a battery of D1-MSN-specific genetic interventions targeting cAMP signaling, including Drd1-Cre::Rap1A/Bfl/fl mice, and AAV injection of a Cre-dependent catalytically active phosphodiesterase (PDE4D3-cat) or a Cre-dependent protein kinase A-inhibitor (PKI) in the NAc of Drd1-Cre mice, to explore further the underlying cAMP dependence of IEG induction by acute and chronic cocaine administration, and the cAMP sensors required. Rap1 is reported as a necessary component for both RapGEF2- and PKA-dependent ERK activation, but a requirement for Rap in Fos induction by cocaine has not been examined. Deletion of Rap1A/B in D1-MSNs blocked cocaine-induced p-ERK and Egr-1 expression, but not c-Fos, supporting the idea that the RapGEF2-Rap1-ERK pathway specifically regulates Egr-1, not c-Fos, expression. D1-specific expression of the PDE4D3-cat ablated up-regulation of both Egr-1 and Fos in NAc after cocaine administration, demonstrating that induction of both IEGs requires cAMP elevation in D1-MSNs. Notably, inhibition of PKA activity via AAV-mediated expression of PKI-alpha in D1-MSNs blocked both c-Fos and Egr-1 induction. Thus, acute or chronic cocaine administration activates at least two cAMP-dependent signaling pathways in D1-MSNs: a PKA-Fos pathway and a RapGEF2-ERK-Egr-1 pathway. The finding that PKA also activates the ERK-Egr-1 signaling pathway by convergence on Rap1, and concomitantly activates c-Fos independently of Rap1, may underlie selective effects of metabotropic activation of RapGEF2 and PKA activation by cAMP on cocaine-dependent behaviors in mice.

neuroscience↗

bioRxiv2024

Patch and matrix striatonigral neurons differentially regulate locomotion

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs--and optical activation of striatonigral neurons in particular--reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

neuroscience↗

bioRxiv2023

Cell-type-specific plasticity shapes neocortical dynamics for motor learning

Neocortical spiking dynamics control aspects of behavior, yet how these dynamics emerge during motor learning remains elusive. Activity-dependent synaptic plasticity is likely a key mechanism, as it reconfigures network architectures that govern neural dynamics. Here, we examined how the mouse premotor cortex acquires its well-characterized neural dynamics that control movement timing, specifically lick timing. To probe the role of synaptic plasticity, we have genetically manipulated proteins essential for major forms of synaptic plasticity, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Cofilin, in a region and cell-type-specific manner. Transient inactivation of CaMKII in the premotor cortex blocked learning of new lick timing without affecting the execution of learned action or ongoing spiking activity. Furthermore, among the major glutamatergic neurons in the premotor cortex, CaMKII and Cofilin activity in pyramidal tract (PT) neurons, but not intratelencephalic (IT) neurons, is necessary for learning. High-density electrophysiology in the premotor cortex uncovered that neural dynamics anticipating licks are progressively shaped during learning, which explains the change in lick timing. Such reconfiguration in behaviorally relevant dynamics is impeded by CaMKII manipulation in PT neurons. Altogether, the activity of plasticity-related proteins in PT neurons plays a central role in sculpting neocortical dynamics to learn new behavior.

neuroscience↗

bioRxiv2023

Symmetry in frontal but not motor and somatosensory corticocortical and corticostriatal circuitry

Neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision making, where lateralization of function may be less important. This study contrasted the topographic precision of cell type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. Motor cortex had somewhat stronger projections, but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision making. Significance StatementEach cerebral hemisphere is responsible for sensation and movement of the opposite side of the body. Many axonal projections cross the midline to target contralateral areas. Crossed corticocortical, corticostriatal, and corticothalamic projections originate from much of neocortex, but how these projections vary across cortical regions and cell types is unknown. We quantify differences in the strength and targeting of ipsilateral and contralateral projections from frontal, motor, and somatosensory areas. The contralateral corticocortical and corticostriatal projections are proposed to play a larger role in frontal areas than in sensory or motor ones as a circuit basis for unifying computation across hemispheres in motor planning, while contralateral connectivity plays a smaller role in sensory and motor processing.

neuroscience↗

bioRxiv2023

Distinct brain-wide presynaptic networks underlie the functional identity of individual cortical neurons

Neuronal connections provide the scaffolding for neuronal function. Revealing the connectivity of functionally identified individual neurons is necessary to understand how activity patterns emerge and support behavior. Yet, the brain-wide presynaptic wiring rules that lay the foundation for the functional selectivity of individual neurons remain largely unexplored. Cortical neurons, even in primary sensory cortex, are heterogeneous in their selectivity, not only to sensory stimuli but also to multiple aspects of behavior. Here, to investigate presynaptic connectivity rules underlying the selectivity of pyramidal neurons to behavioral state1-12 in primary somatosensory cortex (S1), we used two-photon calcium imaging, neuropharmacology, single-cell based monosynaptic input tracing, and optogenetics. We show that behavioral state-dependent neuronal activity patterns are stable over time. These are minimally affected by neuromodulatory inputs and are instead driven by glutamatergic inputs. Analysis of brain-wide presynaptic networks of individual neurons with distinct behavioral state-dependent activity profiles revealed characteristic patterns of anatomical input. While both behavioral state-related and unrelated neurons had a similar pattern of local inputs within S1, their long-range glutamatergic inputs differed. Individual cortical neurons, irrespective of their functional properties, received converging inputs from the main S1-projecting areas. Yet, neurons that tracked behavioral state received a smaller proportion of motor cortical inputs and a larger proportion of thalamic inputs. Optogenetic suppression of thalamic inputs reduced behavioral state-dependent activity in S1, but this activity was not externally driven. Our results revealed distinct long-range glutamatergic inputs as a substrate for preconfigured network dynamics associated with behavioral state.

neuroscience↗

bioRxiv2023

Superior colliculus cell types bidirectionally modulate choice activity in frontal cortex

Action selection occurs through competition between potential choice options. Neural correlates of choice competition are observed across frontal cortex and downstream superior colliculus (SC) during decision-making, yet how these regions interact to mediate choice competition remains unresolved. Here we report that cell types within SC can bidirectionally modulate choice competition and drive choice activity in frontal cortex. In the mouse, topographically matched regions of frontal cortex and SC formed a descending motor pathway for directional licking and a re-entrant loop via the thalamus. During decision-making, distinct neuronal populations in both frontal cortex and SC encoded opposing lick directions and exhibited push-pull dynamics. SC GABAergic neurons encoded ipsilateral choice and glutamatergic neurons encoded contralateral choice, and activating or suppressing these cell types could bidirectionally drive push-pull choice activity in frontal cortex. These results thus identify SC as a major locus to modulate choice competition within the broader action selection network.

neuroscience↗

bioRxiv2022

Excessive Firing of Dyskinesia-Associated Striatal Direct Pathway Neurons is Gated By Dopamine and Excitatory Synaptic Input

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions, but the precise mechanisms remain unclear. One way to study action selection is when it breaks down. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinsons disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. This activation is likely to be driven by two cellular mechanisms we identified through ex vivo electrophysiology: higher sensitivity to dopamine and stronger excitatory input from the motor cortex and thalamus. Together, these findings suggest how intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.

neuroscience↗

bioRxiv2021

Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions.

Fronto-striatal circuits have been extensively implicated in the cognitive control of behavioral output for both social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output strongly mediated by connectivity to the dorsal striatum. Despite evidence for functional diversity along the anterior-posterior axis of the dorsomedial striatum (DMS), it is unclear how distinct fronto- striatal sub-circuits support neural computations essential for action selection. Here we identify prefrontal populations targeting distinct DMS subregions and characterize their functional roles. We first performed neural circuit tracing to reveal segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. We then probed the functional relevance of these parallel circuits via in vivo calcium imaging and temporally precise causal manipulations during a feedback-based 2-alternative choice task. Single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A- DMS) uniquely encoded choices and responses to negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and behavioral control in response to negative outcomes while perturbation of PL::P-DMS signals impaired task engagement and strategies following positive outcomes. Di-synaptic retrograde tracing uncovered differences in afferent connectivity that may underlie these pathways functional divergence. Together our data uncover novel PL populations engaged in distributed processing for action control. SUMMARYO_LIPrelimbic cortex engages A- and P-DMS via distinct circuits C_LIO_LIPL::A-DMS and PL::P-DMS pathways encode divergent aspects of a simple goal-directed task C_LIO_LIPL::A-DMS pathways shape responding to negative outcomes via multiple mechanisms C_LIO_LIPL::P-DMS pathways guide engagement and choices in response to positive outcomes C_LIO_LIAfferent connectomes of PL neurons defined by A-P DMS target are distinct C_LI

neuroscience↗

bioRxiv2021

Organization of cortical and thalamic input to inhibitory neurons in mouse motor cortex

Intracortical inhibition in motor cortex (M1) regulates movement and motor learning. If inhibitory cell types and cortical laminae targeted by cortical and thalamic afferents differ, then these afferents play different roles in regulating M1 output. We quantified input to two classes of M1 interneurons, parvalbumin+ (PV) fast-spiking cells and somatostatin+ (SOM) low-threshold-spiking cells, using monosynaptic rabies tracing. We then compared anatomical connectivity and functional connectivity based on synaptic strength from sensory cortex and thalamus. Functionally, each input innervated M1 interneurons with a unique laminar profile. Different interneuron types were excited in a distinct, complementary manner, suggesting feedforward inhibition proceeds selectively via distinct circuits. Specifically, somatosensory cortex (S1) inputs primarily targeted PV+ neurons in upper layers (L2/3) but SOM+ neurons in middle layers (L5). Somatosensory thalamus (PO) inputs targeted PV+ neurons in middle layers (L5). In contrast to sensory cortical areas, thalamic input to SOM+ neurons was equivalent to PV+ neurons. Thus, long-range excitatory inputs target inhibitory neurons in an area and cell type-specific manner which contrasts with input to neighboring pyramidal cells. In contrast to feedforward inhibition providing generic inhibitory tone in cortex, circuits are selectively organized to recruit inhibition matched to incoming excitatory circuits.

neuroscience↗

bioRxiv2020

A midbrain - thalamus - cortex circuit reorganizes cortical dynamics to initiate planned movement

Motor behaviors are often planned long before execution, but only released after specific sensory events. Planning and execution are each associated with distinct patterns of motor cortex activity. Key questions are how these dynamic activity patterns are generated and how they relate to behavior. Here we investigate the multi-regional neural circuits that link an auditory go cue and the transition from planning to execution of directional licking. Ascending glutamatergic neurons in the midbrain reticular and pedunculopontine nuclei show short-latency and phasic changes in spike rate that are selective for the go cue. This signal is transmitted via the thalamus to the motor cortex, where it triggers a rapid reorganization of motor cortex state from planning-related activity to a motor command, which in turn drives appropriate movement. Our studies show how brainstem structures can control cortical dynamics via the thalamus for rapid and precise motor behavior.

neuroscience↗

bioRxiv2020

Behavioral role of PACAP signaling reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations

The neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAPs role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.

neuroscience↗

bioRxiv2020

Cocaine-dependent acquisition of locomotor sensitization and conditioned place preference requires D1 dopaminergic signaling through a cyclic AMP, NCS-Rapgef2, ERK and Egr-1/Zif268 pathway

Elucidation of the underlying mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor expressingneurons leadingto acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK[->]Egr-1/zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons (MSNs) of nucleus accumbens slices; and in mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the nucleus accumbens (NAc) in adult mice, using AAV-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-MSNs and cocaine-induced behaviors including locomotor sensitization and conditioned place preference (CPP). Abrogation of NCS-Rapgef2 gene expression in medium prefrontal cortex and basolateral amygdala, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase II promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1-receptor expressing neurons in the NAc, butnotin corticolimbic areas, contributes to cocaine-induced locomotor sensitization and CPP. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling. SIGNIFICANCE STATEMENTERK phosphorylation in dopamine D1 receptor expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioraladaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the nucleus accumbens is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequentenhanced locomotor response anddrugseeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-MSNs encode the experience of psychomotor stimulant exposure.

neuroscience↗

bioRxiv2019

A causal role for mouse superior colliculus in visual perceptual decision-making

The superior colliculus (SC) is arguably the most important visual structure in the mouse brain and is well-known for its involvement in innate responses to visual threats and prey items. In other species, the SC plays a central role in voluntary as well as innate visual functions, including crucial contributions to selective attention and perceptual decision-making. In the mouse, the possible role of the SC in voluntary visual choice behaviors has not been established. Here, we demonstrate that the mouse SC plays a causal role in visual perceptual decision-making by transiently inhibiting SC activity during an orientation-change detection task. First, unilateral SC inhibition induced spatially specific deficits in detection. Hit rates were reduced and reaction times increased for orientation changes in the contralateral but not ipsilateral visual field. Second, the deficits caused by SC inhibition were specific to a temporal epoch coincident with early visual burst responses in the SC. Inhibiting SC during this 100-ms period caused a contralateral detection deficit, whereas inhibition immediately before or after did not. Third, SC inhibition reduced visual detection sensitivity. Psychometric analysis revealed that inhibiting SC visual activity significantly increased detection thresholds for contralateral orientation changes. In addition, effects on detection thresholds and lapse rates caused by SC inhibition were larger in the presence of a competing visual stimulus, indicating a role for the mouse SC in visual target selection. Together, our results demonstrate that the mouse SC plays a crucial role in voluntary visual choice behaviors. Significance statementThe mouse superior colliculus has become a popular model for studying the circuit organization and development of the visual system. Although the SC is a fundamental component of the visual pathways in mice, its role in visual perceptual decision-making is not clear. By investigating how temporally precise SC inhibition influenced behavioral performance during a visually guided orientation change detection task, we identified a 100-ms temporal epoch of SC visual activity that is crucial for the ability of mice to detect behaviorally relevant visual changes. In addition, we found that SC inhibition also caused deficits in visual target selection. Thus, our findings highlight the importance of the SC for visual perceptual choice behavior in the mouse.

animal behavior and cognition↗

bioRxiv2019

An amygdala circuit mediates experience-dependent momentary exploratory arrests

Exploration of novel environments ensures survival and evolutionary fitness. This behavior is expressed through exploratory bouts and arrests, which change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase of momentary arrests in visited locations where animals previously arrested. Quantitative analyses of neuronal calcium activity in freely-exploring mice revealed that a large neuronal ensemble in basolateral amygdala is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests. Additionally, we found that neurons in the basolateral amygdala projecting to central amygdala mediate these momentary arrests. These findings uncover an amygdala circuit that mediates momentary exploratory arrests in familiar places, without changing place preference or anxiety/fear-like behaviors.

neuroscience↗

bioRxiv2019

Reconstruction of 1,000 projection neurons reveals new cell types and organization of long-range connectivity in the mouse brain

Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neurons in the mouse brain have been reconstructed in their entirety. Here we present a robust and efficient platform for imaging and reconstructing complete neuronal morphologies, including axonal arbors that span substantial portions of the brain. We used this platform to reconstruct more than 1,000 projection neurons in the motor cortex, thalamus, subiculum, and hypothalamus. Together, the reconstructed neurons comprise more than 75 meters of axonal length and are available in a searchable online database. Axonal shapes revealed previously unknown subtypes of projection neurons and suggest organizational principles of long-range connectivity.

neuroscience↗

bioRxiv2018

Automatic navigation system for the mouse brain

Identification and delineation of brain regions in histologic mouse brain sections is especially pivotal for many neurogenomics, transcriptomics, proteomics and connectomics studies, yet this process is prone to observer error and bias. Here we present a novel brain navigation system, named NeuroInfo, whose general principle is similar to that of a global positioning system (GPS) in a car. NeuroInfo automatically navigates an investigator through the complex microscopic anatomy of histologic sections of mouse brains (thereafter: \"experimental mouse brain sections\"). This is achieved by automatically registering a digital image of an experimental mouse brain section with a three-dimensional (3D) digital mouse brain atlas that is essentially based on the third version of the Allen Mouse Brain Common Coordinate Framework (CCF v3), retrieving graphical region delineations and annotations from the 3D digital mouse brain atlas, and superimposing this information onto the digital image of the experimental mouse brain section on a computer screen. By doing so, NeuroInfo helps in solving the long-standing problem faced by researchers investigating experimental mouse brain sections under a light microscope--that of correctly identifying the distinct brain regions contained within the experimental mouse brain sections. Specifically, NeuroInfo provides an intuitive, readily-available computer microscopy tool to enhance researchers ability to correctly identify specific brain regions in experimental mouse brain sections. Extensive validation studies of NeuroInfo demonstrated that this novel technology performs remarkably well in accurately delineating regions that are large and/or located in the dorsal parts of mouse brains, independent on whether the sections were imaged with fluorescence or brightfield microscopy. This novel navigation system provides a highly efficient way for registering a digital image of an experimental mouse brain section with the 3D digital mouse brain atlas in a minute and accurate delineation of the image in real-time.

neuroscience↗