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Bentzley, B. S.

Publications and source records attributed to Bentzley, B. S..

7 recordsLinked to original sources

Striatal integration of inverse dopamine and serotonin signals gates learning

The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT) are powerful regulators of associative learning1-9. Similarities in the activity and connectivity of these neuromodulatory systems have inspired competing models of how DA and 5HT interact to drive the formation of new associations10-13. However, these hypotheses have yet to be tested directly because it has not been possible to precisely interrogate and manipulate multiple neuromodulatory systems in a single subject. Here, we establish a double transgenic mouse model enabling simultaneous genetic access to the brains DA and 5HT systems. Anterograde axon tracing revealed the nucleus accumbens (NAc) to be a putative hotspot for the integration of convergent DA and 5HT signals. Simultaneous recordings of DA and 5HT input activity in the NAc posterior medial shell revealed that DA axons are excited by rewards while 5HT axons are inhibited. Optogenetically blunting DA and 5HT reward responses simultaneously blocked learning about a reward-predictive cue. Optogenetically reproducing both DA and 5HT responses to reward, but not either one alone, was sufficient to drive the acquisition of new associations. Altogether, these results demonstrate that striatal integration of inverse DA and 5HT signals is a crucial mechanism gating associative learning.

neuroscience↗

Striatal dopamine integrates cost, benefit and motivation

Dopamine (DA) release in the ventral and dorsal striatum has been linked to reward processing and motivation, but there are longstanding controversies about whether DA release in these key target structures primarily reflects costs or benefits, and how these signals vary with motivation. Here we apply behavioral economic principles to generate demand curves for rewards while directly measuring DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) via a genetically-encoded sensor. By independently varying costs and benefits, we reveal that DA release in both structures incorporates reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release; the higher the motivation for rewards the lower the reward-evoked DA release. These relationships between DA release, cost and motivation remained identical when we used optogenetic activation of striatal DA inputs as a reward. Our results reconcile previous disparate findings by demonstrating that during operant tasks, striatal DA release simultaneously encodes cost, benefit and motivation but in distinct manners over different time scales.

neuroscience↗

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

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. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

animal behavior and cognition↗

On the origins of a selective vulnerability to opioid addiction.

The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early-life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function and cause opioid addiction vulnerability is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

neuroscience↗

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD).

BackgroundCurrent treatments for depression are limited by suboptimal efficacy, delayed response, and frequent side effects. Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation treatment that is FDA-approved for treatment-resistant depression (TRD). Recent methodological advancements suggest iTBS could be improved through 1) treating with multiple sessions per day at optimally-spaced intervals, 2) applying a higher overall pulse-dose of stimulation and 3) precision targeting of the left dorsolateral prefrontal cortex (L-DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. We examined the feasibility, tolerability, and preliminary efficacy of an accelerated, high-dose, resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for TRD termed Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). MethodsTwenty-one participants with TRD received open-label SAINT. FcMRI was used to individually target the region of L-DLPFC most anticorrelated with sgACC. Fifty iTBS sessions (1800 pulses per session, 50-minute inter-session interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. ResultsNineteen of 21 participants (90.48%) met criteria for remission ([≤]10 on the Montgomery-[A]sberg Depression Rating Scale) immediately after SAINT. Neuropsychological testing demonstrated no negative cognitive side-effects. There were no seizures or other severe adverse events. DiscussionOur accelerated, high-dose, iTBS protocol with fcMRI-guided targeting (SAINT) was well tolerated and safe. Efficacy was strikingly high, especially for this treatment-resistant population. Double-blinded sham-controlled trials are required to confirm the high remission rate found in this initial study. Trial registrationClinicalTrials.gov NCT03240692

clinical trials↗

The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to vary with behavioral state and can be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as BE-experienced animals after a two-week period of abstinence to relate the number of LH orexin cells to economic demand for cocaine. We also unilaterally knocked down LH orexin expression prior to BE with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. Animals with greater motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a two-week abstinence from BE, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual demand for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.

neuroscience↗

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaines reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.\n\nSignificance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamines complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

neuroscience↗