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Eshel, N.

Publications and source records attributed to Eshel, N..

9 recordsLinked to original sources

Local control of dopamine release in nucleus accumbens gates opioid withdrawal aversion

The opioid crisis has emphasized the need for more effective treatments for opioid use disorder (OUD)1-3, which is characterized by habitual opioid use to avoid withdrawal symptoms4,5. Both physical and affective symptoms contribute to opioid withdrawal yet whether different neural mechanisms mediate these different symptom domains and contribute distinctly to opioid relapse is unknown. While neurons expressing mu opioid receptors (MORs) gate opioids reinforcing effects6-8 by increasing dopamine (DA) release in nucleus accumbens (NAc), sharp decreases in NAc DA release are associated with withdrawal9-11, the cellular and circuit mechanisms of which are unknown. Here we describe an unusual population of evolutionarily-conserved MOR+ neurons in the NAc expressing the transcription factor Tshz1. Increased activity in these neurons is required for withdrawal aversion learning. Deletion of MORs in Tshz1 neurons prevented withdrawal-induced decreases in DA release and affective aversion, but not physical symptoms associated with withdrawal. Pharmacological activation of mGluR8, which is preferentially expressed in Tshz1 neurons, reduced withdrawal aversion. Thus, by dissociating the circuit mechanisms contributing to the physical and affective components of opioid withdrawal focusing on the critical role of Tshz1 neurons, we have identified a novel druggable target with therapeutic potential for treating key OUD withdrawal symptoms.

neuroscience↗

Serotonin modulates nucleus accumbens circuits to suppress aggression

Serotonin (5-hydroxytryptamine; 5HT) has long been considered anti-aggressive, but the mechanisms by which 5HT regulates downstream circuits to control aggression remain unclear. Combining fiber photometry, optogenetics, and miniaturized microscope recordings in double-transgenic mice, we find that 5HT levels ramp up in the nucleus accumbens during aggression, inhibiting a subset of D1 medium spiny neurons to suppress attacks. Our results reveal a novel 5HT-mediated neuromodulatory mechanism for limiting aggressive behavior.

neuroscience↗

Cholinergic modulation of dopamine release drives effortful behavior

Effort is costly: given a choice, we tend to avoid it1. But in many cases, effort adds value to the ensuing rewards2. From ants3 to humans4, individuals prefer rewards that had been harder to achieve. This counterintuitive process may promote reward-seeking even in resource-poor environments, thus enhancing evolutionary fitness5. Despite its ubiquity, the neural mechanisms supporting this behavioral effect are poorly understood. Here we show that effort amplifies the dopamine response to an otherwise identical reward, and this amplification depends on local modulation of dopamine axons by acetylcholine. High-effort rewards evoke rapid acetylcholine release from local interneurons in the nucleus accumbens. Acetylcholine then binds to nicotinic receptors on dopamine axon terminals to augment dopamine release when reward is delivered. Blocking the cholinergic modulation blunts dopamine release selectively in high-effort contexts, impairing effortful behavior while leaving low-effort reward consumption intact. These results reconcile in vitro studies, which have long demonstrated that acetylcholine can trigger dopamine release directly through dopamine axons6-11; with in vivo studies that failed to observe such modulation12-14, but did not examine high-effort contexts. Our findings uncover a mechanism that drives effortful behavior through context-dependent local interactions between acetylcholine and dopamine axons.

neuroscience↗

Opponent regulation of striatal output pathways by dopamine and serotonin

Classic theories propose opponent functions for striatal dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT), with DA promoting approach and 5HT promoting patience or avoidance. How these neuromodulators regulate downstream circuits to achieve such antagonistic effects remains mysterious. Here, we mapped striatal 5HT receptor expression and recorded from genetically-identified striatal neurons to demonstrate that DA and 5HT selectively activate distinct populations of striatal neurons to exert opponent control over striatal output.

neuroscience↗

5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.

neuroscience↗

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↗

A Comparison of Pruning During Multi-Step Planning in Depressed and Healthy Individuals

BackgroundReal-life decisions are often complex because they involve making sequential choices that constrain future options. We have previously shown that to render such multi-step decisions manageable, people "prune" (i.e. selectively disregard) branches of decision trees that contain negative outcomes. We have theorized that sub-optimal pruning contributes to depression by promoting an oversampling of branches that result in unsavoury outcomes, which results in a negatively-biased valuation of the world. However, no study has tested this theory in depressed individuals. MethodsThirty unmedicated depressed and 31 healthy participants were administered a sequential reinforcement-based decision-making task to determine pruning behaviours, and completed measures of depression and anxiety. Computational, Bayesian and frequentist analyses examined group differences in task performance and relationships between pruning and depressive symptoms. ResultsConsistent with prior findings, participants robustly pruned branches of decision trees that began with large losses, regardless of the potential utility of those branches. However, there was no group difference in pruning behaviours. Further, there was no relationship between pruning and levels of depression/anxiety. LimitationsThe relatively small sample size limited the examination of individual differences. The use of other heuristics that are used to render complex decisions feasible, such as memoization and fragmentation, were not examined. ConclusionsWe found no evidence that sub-optimal pruning is evident in depression. Future research could determine whether maladaptive pruning behaviours are observable in specific sub-groups of depressed patients (e.g. in treatment-resistant individuals), or whether misuse of other heuristics may contribute to depression.

systems biology↗

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↗