The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System

Berger, Anthony L.; Henricks, Angela M.; Lugo, Janelle M.; Wright, Hayden R.; Warrick, Collin R.; Sticht, Martin A.; Morena, Maria; Bonilla, Itziar; Laredo, Sarah A.; Craft, Rebecca M.; Parsons, Loren H.; Grandes, Pedro; Hillard, Cecilia J.; Hill, Matthew N.; McLaughlin, Ryan J.

doi:10.1016/j.biopsych.2018.04.018

Cited by 58 publications

(67 citation statements)

References 99 publications

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“…Membranes (10μg protein/sample) were incubated in TME buffer with [3H]CP55,940 (0.25, 0.5, 1.25, or 2.5 nM) in the absence or presence of AM251 (10 µM) to assess total and nonspecific binding, respectively. Bmax (maximal binding site density) and Kd (binding affinity) were calculated by nonlinear curve fitting to the single site Michaelis-Menten equation using GraphPad Prism as described previously [29,30].…”

Section: Cb1r Radioligand Binding Assaymentioning

confidence: 99%

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Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Freels

Baxter-Potter

Lugo

et al. 2019

Preprint

Self Cite

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Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug employed and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized ∆9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) complete cannabis extracts. Male Sprague Dawley rats were trained to nosepoke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily one-hour sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared to CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors. Cannabis vapor self-administration

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Section: Cb1r Radioligand Binding Assaymentioning

confidence: 99%

“…Anxiety-like behavior was assessed in another cohort of rats (N=37) 24 hours after the final selfadministration session using the elevated plus maze (EPM) test as described previously [30,31]…”

Section: Elevated Plus Maze Testmentioning

confidence: 99%

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Freels

Baxter-Potter

Lugo

et al. 2019

Preprint

Self Cite

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“…The intruder was a black coat-coloured C57BL/6J mouse (Jackson Labs, #000664), and the resident was a white coat-coloured CD-1 mouse (Charles River, #022). For the rat resident-intruder protocol, we recorded resident-intruder dyadic encounters between a male intruder Sprague Dawley rat (Simonsen Laboratories) and male resident Long-Evans rat (Simonsen Laboratories) in clear polycarbonate cages with fresh bedding (cage size: 33x46x19cm) using a previously detailed protocol 51 .…”

Section: Simba Workflow Overviewmentioning

confidence: 99%

Simple Behavioral Analysis (SimBA) – an open source toolkit for computer classification of complex social behaviors in experimental animals

Nilsson

Goodwin

Choong

et al. 2020

Preprint

193

191

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Aberrant social behavior is a core feature of many neuropsychiatric disorders, yet the study of complex social behavior in freely moving rodents is relatively infrequently incorporated into preclinical models. This likely contributes to limited translational impact. A major bottleneck for the adoption of socially complex, ethology-rich, preclinical procedures are the technical limitations for consistently annotating detailed behavioral repertoires of rodent social behavior. Manual annotation is subjective, prone to observer drift, and extremely time-intensive. Commercial approaches are expensive and inferior to manual annotation. Open-source alternatives often require significant investments in specialized hardware and significant computational and programming knowledge. By combining recent computational advances in convolutional neural networks and pose-estimation with further machine learning analysis, complex rodent social behavior is primed for inclusion under the umbrella of computational neuroethology.Here we present an open-source package with graphical interface and workflow (Simple Behavioral Analysis, SimBA) that uses pose-estimation to create supervised machine learning predictive classifiers of rodent social behavior, with millisecond resolution and accuracies that can out-perform human observers. SimBA does not require specialized video acquisition hardware nor extensive computational background. Standard descriptive statistical analysis, along with graphical region of interest annotation, are provided in addition to predictive classifier generation. To increase ease-of-use for behavioural neuroscientists, we designed SimBA with accessible menus for pre-processing videos, annotating behavioural training datasets, selecting advanced machine learning options, robust classifier validation functions and flexible visualizations tools. This allows for predictive classifier transparency, explainability and tunability prior to, and during, experimental use. We demonstrate that this approach is flexible and robust in both mice and rats by classifying social behaviors that are commonly central to the study of brain function and social motivation. Finally, we provide a library of poseestimation weights and behavioral predictive classifiers for resident-intruder behaviors in mice and rats. All code and data, together with detailed tutorials and documentation, are available on the SimBA GitHub repository.Graphical abstractSimBA graphical interface (GUI) for creating supervised machine learning classifiers of rodent social behavior.(a) Pre-process videos. SimBA supports common video pre-processing functions (e.g., cropping, clipping, sampling, format conversion, etc.) that can be performed either on single videos, or as a batch.(b) Managing poseestimation data and creating classification projects. Pose-estimation tracking projects in DeepLabCut and DeepPoseKit can be either imported or created and managed within the SimBA graphical user interface, and the tracking results are imported into SimBA classification projects.SimBA also supports userdrawn region-of-interests (ROIs) for descriptive statistics of animal movements, or as features in machine learning classification projects.(c) Create classifiers, perform classifications, and analyze classification data. SimBA has graphical tools for correcting poseestimation tracking inaccuracies when multiple subjects are within a single frame, annotating behavioral events from videos, and optimizing machine learning hyperparameters and discrimination thresholds. A number of validation checkpoints and logs are included for increased classifier explainability and tunability prior to, and during, experimental use. Both detailed and summary data are provided at the end of classifier analysis. SimBA accepts behavioral annotations generated elsewhere (such as through JWatcher) that can be imported into SimBA classification projects.(d) Visualize classification results. SimBA has several options for visualizing machine learning classifications, animal movements and ROI data, and analyzing the durations and frequencies of classified behaviors.See the SimBA GitHub repository for a comprehensive documentation and user tutorials.

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“…A unilateral guide cannula was implanted into hippocampal CA1 regions (anteroposterior, −2.0 mm; mediolateral, ±1.5 mm; dorsoventral, −1.5 mm) of Cdk5 f/f and Cdh5-Cre;Cdk5 f/f mice as described previously (Berger et al, 2018). After 7 d of recovery, a microdialysis probe (AZ-2-01) was inserted and secured to the guide cannula for dialysate collection.…”

Section: In Vivo Microdialysis Experimentsmentioning

confidence: 99%

Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis

Liu

Yang

Shao

et al. 2019

Journal of Experimental Medicine

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Blood–brain barrier (BBB) dysfunction has been suggested to play an important role in epilepsy. However, the mechanism mediating the transition from cerebrovascular damage to epilepsy remains unknown. Here, we report that endothelial cyclin-dependent kinase 5 (CDK5) is a central regulator of neuronal excitability. Endothelial-specific Cdk5 knockout led to spontaneous seizures in mice. Knockout mice showed increased endothelial chemokine (C-X-C motif) ligand 1 (Cxcl1) expression, decreased astrocytic glutamate reuptake through the glutamate transporter 1 (GLT1), and increased glutamate synaptic function. Ceftriaxone restored astrocytic GLT1 function and inhibited seizures in endothelial Cdk5-deficient mice, and these effects were also reversed after silencing Cxcl1 in endothelial cells and its receptor chemokine (C-X-C motif) receptor 2 (Cxcr2) in astrocytes, respectively, in the CA1 by AAV transfection. These results reveal a previously unknown link between cerebrovascular factors and epileptogenesis and provide a rationale for targeting endothelial signaling as a potential treatment for epilepsy.

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The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System

Abstract: Alterations in LHb ECB signaling may be relevant for development of stress-related pathologies in which LHb dysfunction and stress-coping impairments are hallmark symptoms.

Cited by 58 publications

References 99 publications

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Simple Behavioral Analysis (SimBA) – an open source toolkit for computer classification of complex social behaviors in experimental animals

Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis

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