Biology subjects

Willuhn, I.

Publications and source records attributed to Willuhn, I..

11 recordsLinked to original sources

bioRxiv2025

Ventromedial striatal dopamine dynamically integrates motivated action and reward proximity

Dopamine release in the ventromedial striatum (VMS) both invigorates actions and encodes reward-related information, yet how these functions are integrated remains under active debate. To investigate this further, we designed four different versions of a rat Go/No-go task, where we systematically manipulated response requirements, temporal task demands, and controllability of reward pursuit. Dopamine release increased reliably during action initiation (Go) but was delayed during action suppression (No-go), and this difference was insensitive to augmented response demands or controllability. Following response completion, dopamine rose gradually until animals arrived at the reward location, irrespective of reward-delivery timing, prior action demands, or controllability. This proximity dopamine-signal was exaggerated after animals exhibited Pavlovian consummatory behavior during No-go trials, revealing a motivational signal component. Together, these findings indicate that in reward contexts, VMS-dopamine signals successively integrate the invigoration of action initiation with the continuous tracking of spatial - but not temporal - proximity to rewards.

neuroscience↗

bioRxiv2024

Rescuing behavioral flexibility in a mouse model for OCD by enhancing reward-cue salience

Deficits in cognitive flexibility are a frequent symptom of obsessive-compulsive disorder (OCD) and have been hypothesized to underlie compulsive behavior. Sign- and goal-tracking behaviors are thought to be related to cognitive flexibility, yet have not been studied in this context. To investigate the relationship between sign- and goal-tracking behavior and cognitive flexibility, we tested SAPAP3 knockout mice (SAPAP3-/-) and wild-type littermate controls in a Pavlovian reversal-learning task with two conditioned stimuli, one predicting reward delivery and the other reward omission. SAPAP3-/- displayed a heterogenous reversal-learning performance: Half of the population failed to acquire the reversed cue-reward contingencies, whereas the other half reversed their approach behavior similar to control mice. Surprisingly, such behavioral inflexibility and compulsive-like grooming were unrelated, suggesting a non-causal relationship between these traits. Importantly, compromised reversal learning in impaired mice was associated with diminished sign-tracking behavior (and therefore presumably with an overreliance on goal-tracking behavior). Administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the first-line pharmacological OCD treatment, ameliorated both anxiety-like behavior and compulsive-like grooming, but did not improve behavioral flexibility in SAPAP3-/-. In contrast, enhancing reward-cue salience by altering conditioned stimuli brightness improved behavioral flexibility through augmenting sign-tracking behavior. These findings suggest that deficits in behavioral flexibility are associated with imbalanced sign- and goal-tracking behaviors in SAPAP3-/-, and enhancing reward-cue salience can rescue behavioral flexibility by restoring the balance. Thus, sign- and goal-tracking behavior might be an underexplored cognitive mechanism that could potentially be exploited to improve cognitive flexibility in OCD patients.

neuroscience↗

bioRxiv2023

Cocaine Seeking And Taking Are Oppositely Regulated By Dopamine

In some individuals, drug-associated cues subsume potent control of behavior, such as the elicitation of drug craving1-3 and automatized drug use4. The intensity of this cue reactivity is highly predictive of relapse and other clinical outcomes in substance use disorders5, 6. It has been postulated that this cue reactivity is driven by augmentation of dopamine release over the course of chronic drug use7. Here we carried out longitudinal recording and manipulation of cue-evoked dopamine signaling across phases of substance-use related behavior in rats. We observed a subset of individuals that exhibited increased cue reactivity and escalated drug consumption, two cardinal features of substance use disorders. In these individuals, cue-evoked phasic dopamine release underwent diametrically opposed changes in amplitude, determined by the context in which the cue is presented. Dopamine evoked by non-contingent cue presentation increased over drug use, producing greater cue reactivity; whereas dopamine evoked by contingent cue presentation decreased over drug use, producing escalation of drug consumption. Therefore, despite being in opposite directions, these dopamine trajectories each promote core symptoms of substance use disorders.

neuroscience↗

bioRxiv2022

Unraveling the therapeutic mechanism of deep-brain stimulation

Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while compulsive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

neuroscience↗

bioRxiv2022

The direct and indirect pathways of the basal ganglia antagonistically influence cortical activity and perceptual decisions

The striatum, input nucleus of the basal ganglia, receives topographically organized input from the cortex and gives rise to the direct and indirect pathways with antagonistic effects on the output of the basal ganglia. We optogenetically stimulated the direct and indirect pathways in mice and measured their influence on perceptual decisions and neuronal activity in the cortex. In a task in which mice had to detect a visual stimulus, unilateral direct-pathway stimulation increased the probability of lick responses to the non-stimulated side and increased cortical activity globally. In contrast, indirect-pathway stimulation increased the probability of licks to the stimulated side and decreased activity in visual cortical areas. To probe the possible role of the two pathways in working memory, we trained the mice to report the location of a stimulus with licking one of two spouts, after a memory delay. Direct-pathway stimulation prior to and during the memory delay enhanced both the neural representation of a contralateral visual stimulus and the number of contraversive choices, whereas indirect-pathway stimulation had the opposite effects, in accordance with an antagonistic influence of the direct and indirect pathways on licking direction. Our results demonstrate how these two pathways influence perceptual decisions and working memories, and modify activity in the cerebral cortex. One sentence summaryVisuomotor transformations are influenced antagonistically by the direct and indirect pathways of the basal ganglia during visual detection and working memory tasks

neuroscience↗

bioRxiv2022

Anticipation of appetitive operant action induces sustained dopamine release in the nucleus accumbens

The mesolimbic dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. These implications are commonly investigated in either Pavlovian or operant reinforcement paradigms, where only the latter requires instrumental action. To parse contributions of reward- and action-related information to dopamine signals, we directly compared the two paradigms: rats underwent either Pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. Task conditions were identical with the exception of the operant-lever response requirement. Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire five-second cue presentation (preceding the required action). This dopamine "ramp" was unaffected by probabilistic reward delivery, occurred exclusively prior to operant actions, and was not related to task performance or task acquisition, as it persisted throughout the two-week daily behavioral training. Instead, the ramp flexibly increased in duration with longer cue presentation, seemingly modulating the initial cue-onset triggered dopamine release (i.e., the reward-prediction error (RPE) signal), as both signal amplitude and sustain diminished when reward timing was made more predictable. Thus, our findings suggest that RPE and action components of dopamine release can be differentiated temporally into phasic and ramping/sustained signals, respectively, where the latter depends on the former and presumably reflects the anticipation or incentivization of appetitive action, conceptually akin to motivation. Significance StatementIt is unclear whether the components of dopamine signals that are related to reward-associated information and reward-driven approach behavior can be separated. Most studies investigating the dopamine system utilize either Pavlovian or operant conditioning, which both involve the delivery of reward and necessitate appetitive approach behavior. Thus, used exclusively, neither paradigm can disentangle the contributions of these components to dopamine release. However, by combining both paradigms in the same study, we find that anticipation of a reward-driven operant action induces a modulation of reward-prediction-associated dopamine release, producing so-called "dopamine ramps". Therefore, our findings provide new insight into dopamine ramps, and suggest that dopamine signals integrate reward and appetitive action in a temporally distinguishable, yet dependent, manner.

neuroscience↗

bioRxiv2021

A novel automated approach for improving standardization of the marble burying test enables quantification of burying bouts and activity characteristics

The marble burying test is a commonly used paradigm to screen phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies solely on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), rather than the behavior itself (burying bouts), many important characteristics regarding the temporal aspect of this assay are lost. Here we introduce a novel, automated method to quantify mouse behavior throughout the duration of the marble burying test with the focus on the burying bouts. Using open-source software packages, we trained a supervised machine learning algorithm (the "classifier") to distinguish burying behavior in freely moving mice. In order to confirm the classifiers accuracy and uncover the behavioral meaning of the marble burying test, we performed marble burying test in three mouse models: Ube3am-/p+ (Angelman Syndrome model), Shank2-/- (autism model), and Sapap3-/- (obsessive-compulsive disorder model) mice. The classifier scored burying behavior accurately and consistent with the literature in the Ube3am-/p+ mice, which showed decreased levels of burying compared to controls. Shank2-/- mice showed a similar pattern of decreased burying behavior, which was not found in Sapap3-/- mice. Tracking mouse behavior throughout the test enabled us to quantify activity characteristics, revealing hypoactivity in Ube3am-/p+ and hyperactivity in the Shank2-/- mice, indicating that mouse activity is unrelated to burying behavior. Together, we demonstrate that our classifier is an accurate method for the analysis of the marble burying test, providing more information than the currently used methods. Significance StatementThe marble burying test is widely used in phenotyping neurodevelopmental and neuropsychiatric disorder mouse models. Currently, its analysis consists of manually scoring the number of buried marbles upon the completion of the assay. This approach is not standardized across laboratories, and leaves out important variables such as movement characteristics and information about the burying bouts. This leads to divergent interpretations of the marble burying test, ranging from anxiety to cognitive impairment. We introduce a method that reliably tracks mouse behavior throughout the experiment, classifies the duration and number of the burying bouts, and is generalizable across laboratories. Using machine learning for measuring the actual burying behavior standardizes this method, and provides rich information about the burying characteristics.

neuroscience↗

bioRxiv2021

Nucleus-accumbens dopamine tracks aversive-stimulus duration and prediction but not value or prediction error

There is active debate on the role of dopamine in processing aversive stimuli, where inferred roles range from no involvement at all, to signaling an aversive-prediction error (APE). Here, we systematically investigate dopamine release in the nucleus-accumbens core (NAC), which is closely linked to reward-prediction errors, in rats exposed to white noise (WN, a versatile, underutilized, aversive stimulus) and its predictive cues. Both induced a negative dopamine ramp, followed by slow signal recovery upon stimulus cessation. In contrast to reward conditioning, this dopamine signal was unaffected by WN value, context valence, or probabilistic contingencies, and the WN dopamine-response shifted only partially towards its predictive cue. However, unpredicted WN provoked slower post-stimulus signal recovery than predicted WN. Despite differing signal qualities, dopamine responses to simultaneous presentation of rewarding and aversive stimuli were additive. Together, our findings demonstrate that instead of an APE, NAC dopamine primarily tracks prediction and duration of aversive events.

neuroscience↗

bioRxiv2019

NINscope: a versatile miniscope for multi-region circuit investigations

Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural activity during unrestrained behavior and their open-source versions have helped to distribute them at an affordable cost. Generally, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight, small footprint, open-source miniscope that incorporates a high-sensitivity image sensor, an inertial measurement unit (IMU), and an LED driver for an external optogenetic probe. We highlight the advantages of NINscope by performing the first simultaneous cellular resolution (dual scope) recordings from cerebellum and cerebral cortex in unrestrained mice, revealing that the activity of both regions generally precedes the onset of behavioral acceleration. We further demonstrate the optogenetic stimulation capabilities of NINscope and show that cerebral cortical activity can be driven strongly by cerebellar stimulation. To validate the performance of our miniscope to image from deep-brain regions, we recorded in the dorsal striatum and, using the IMU to assess turning movements, replicate previous studies that show encoding of action space in this subcortical region. Finally, we combine optogenetic stimulation of distinct cortical regions projecting to the dorsal striatum, to probe functional connectivity. In combination with cross-platform control software, NINscope is a versatile addition to the expanding toolbox of open-source miniscopes and will aid multi-region circuit investigations during unrestrained behavior.

neuroscience↗

bioRxiv2018

Behavioral flexibility in an OCD mouse model: Impaired Pavlovian reversal learning in SAPAP3 mutants

Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior, and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3-/-) exhibit compulsive behavior (grooming), anxiety, and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3-/- display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3-/- and wild-type littermates (WT) were trained in a Pavlovian conditioning task pairing the delivery of visual cues with that of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS-), contingencies were reversed (CS+ became CS- and vice versa). Additionally, we assessed grooming, anxiety, and general activity. SAPAP3-/- acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3-/- were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming, and anxiety were unrelated. This study demonstrates that SAPAP3-/- are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3-/- do not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3-/- as a suitable model for OCD. The observation that compulsive-like behavior, anxiety, and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for OCD patients.

animal behavior and cognition↗

bioRxiv2017

A neuronal mechanism underlying decision-making deficits during hyperdopaminergic states

Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision-making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to faulty decision-making in rats. Activation of the VTA-nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTA-prefrontal cortex pathway promotes risky decision-making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision-making, providing a mechanistic understanding of the reckless behaviors seen in substance abuse, mania, and after dopamine replacement therapy in Parkinsons disease.

neuroscience↗