Biology subjects

Wanat, M. J.

Publications and source records attributed to Wanat, M. J..

8 recordsLinked to original sources

bioRxiv2026

Ventral tegmental area astrocytes regulate drug-cue associations and drug intake

Cocaine use disorder remains a critical public health concern with limited treatment options. Astrocytes are increasingly recognized as active regulators of neurotransmission and are emerging as important contributors to addiction neurobiology. Here, we examined how chemogenetic activation of astrocytic Gq signaling within the ventral tegmental area (VTA) influences cocaine-associated behaviors in drug-naive and cocaine-experienced rats. Using a subthreshold dose of cocaine in a conditioned place preference (CPP) paradigm, we found that VTA astrocyte Gq activation facilitated the acquisition of cocaine CPP in drug-naive rats but suppressed the development of cocaine CPP in cocaine-experienced rats. Additionally, chemogenetic activation of VTA astrocyte Gq signaling suppressed voluntary cocaine intake in a self-administration paradigm. Together, these findings demonstrate that VTA astrocyte Gq signaling shapes cocaine-associated behaviors in a drug history-dependent manner, highlighting VTA astrocytes as a potential therapeutic target in cocaine use disorder.

neuroscience↗

bioRxiv2025

Estrous cycle stage gates the effect of stress on reward learning

Stress produces transient physiological responses that lead to long-lasting changes in cue-driven behavior. In particular, a single exposure to stress facilitates reward learning in male rats. Since stress can produce distinct behavioral phenotypes between males and females, it is critical to additionally determine how stress impacts reward learning in females. To address this, female rats were exposed to restraint stress immediately prior to training on an appetitive Pavlovian conditioning task with food rewards. Females were categorized based on their estrous cycle stage on the first day of Pavlovian conditioning. A single exposure to stress enhanced conditioned responding in non-estrus females but suppressed conditioned responding in estrus females. Therefore, a single stress experience produced opposing effects on cue-driven behavior depending upon the estrous cycle stage. In contrast, both estrus and non-estrus rats exposed to repeated prior stress exhibited an increase in conditioned responding relative to animals that underwent a single stress exposure. We further examined if the distal stress experience subsequently impacted extinction and the ability to learn a new cue-reward association. Prior stress did not affect extinction, though estrus and non-estrus rats exposed to repeated prior stress exhibited higher levels of conditioned responding to the novel cue-reward pairing. Taken together, our data demonstrate that the influence of stress on reward learning is impacted acutely by the estrous cycle as well as by ones prior history with stress.

neuroscience↗

bioRxiv2021

Sex differences in behavioral responding and dopamine release during early Pavlovian learning

Learning associations between cues and rewards requires the mesolimbic dopamine system. The dopamine response to cues signals differences in reward value in well-trained animals. However, these value-related dopamine responses are absent during early training sessions when cues signal differences in the reward rate. These findings suggest cue-evoked dopamine release conveys differences between outcomes only after extensive training, though it is unclear if this is unique to when cues signal differences in reward rate, or if this is also evident when cues signal differences in other value-related parameters such as reward size. To address this, we utilized a Pavlovian conditioning task in which one audio cue was associated with a small reward (one pellet) and another audio cue was associated with a large reward (three pellets). We performed fast-scan cyclic voltammetry to record changes in dopamine release in the nucleus accumbens of male and female rats throughout learning. While female rats exhibited higher levels of conditioned responding, a faster latency to respond, and elevated post-reward head entries relative to male rats, there were no sex differences in the dopamine response to cues. Multiple training sessions were required before cue-evoked dopamine release signaled differences in reward size. Reward-evoked dopamine release scaled with reward size, though females displayed lower reward-evoked dopamine responses relative to males. Conditioned responding related to the decrease in the peak reward-evoked dopamine response and not to cue-evoked dopamine release. Collectively these data illustrate sex differences in behavioral responding as well as in reward-evoked dopamine release during Pavlovian learning.

neuroscience↗

bioRxiv2020

Dopamine release and its control over early Pavlovian learning differs between the NAc core and medial NAc shell

Dopamine neurons respond to cues to reflect the value of associated outcomes. These cue-evoked dopamine responses can encode the relative rate of reward in rats with extensive Pavlovian training. Specifically, a cue that always follows the previous reward by a short delay (high reward rate) evokes a larger dopamine response in the nucleus accumbens (NAc) core relative to a distinct cue that always follows the prior reward by a long delay (low reward rate). However, it was unclear if these reward rate dopamine signals are evident during early Pavlovian training sessions and across NAc subregions. To address this, we performed fast-scan cyclic voltammetry recordings of dopamine levels to track the pattern of cue- and reward-evoked dopamine signals in the NAc core and medial NAc shell. We identified regional differences in the progression of cue-evoked dopamine signals across training. However, the dopamine response to cues did not reflect the reward rate in either the NAc core or the medial NAc shell during early training sessions. Pharmacological experiments found that dopamine-sensitive conditioned responding emerged in the NAc core before the medial NAc shell. Together, these findings illustrate regional differences in NAc dopamine release and its control over behavior during early Pavlovian learning.

neuroscience↗

bioRxiv2019

Acute stress enhances associative learning via dopamine signaling in the ventral lateral striatum

Acute stress transiently increases vigilance, whereby enhancing the detection of salient stimuli. This increased perceptual sensitivity is thought to promote associating rewarding outcomes with relevant cues. The mesolimbic dopamine system is critical for learning cue-reward associations. Dopamine levels in the ventral striatum are elevated following exposure to stress. Together, this suggests the mesolimbic dopamine system could mediate the influence of acute stress on cue-reward learning. To address this possibility, we examined how a single stressful experience influenced learning in an appetitive Pavlovian conditioning task. Male rats underwent an episode of restraint prior to the first conditioning session. This acute stress treatment augmented conditioned responding in subsequent sessions. Voltammetry recordings of mesolimbic dopamine levels demonstrated that acute stress selectively increased reward-evoked dopamine release in the ventral lateral striatum (VLS), but not in the ventral medial striatum (VMS). Antagonizing dopamine receptors in the VLS blocked the stress-induced enhancement of conditioned responding. Collectively, these findings illustrate that stress engages dopamine signaling in the VLS to facilitate appetitive learning.

neuroscience↗

bioRxiv2019

Changes in subjective preference do not require dopamine signaling or the orbital frontal cortex

Sunk or unrecoverable costs impact proximal reward-based decisions across species. However, it is not known if these incurred costs elicit a long-lasting change in reward value. To address this, we identified the relative preference between different flavored food pellets in rats. Animals were then trained to experience the initially preferred reward after short delays and the initially less preferred reward after long delays. This training regimen enhanced the preference for the initially less desirable food reward. We probed whether this change in subjective preference involved dopamine signaling or the orbital frontal cortex (OFC) given that these neural systems contribute to reward valuation. Systemic dopamine receptor antagonism attenuated anticipatory responding during training sessions but did not prevent the change in reward preference elicited by incurred temporal costs. OFC lesions had no effect on anticipatory responding during training or on the change in reward preference. These findings collectively illustrate that the neural systems involved with economic assessments of reward value are not contributing to changes in subjective preference.

neuroscience↗

bioRxiv2018

Ventral tegmental area astrocytes orchestrate avoidance and approach behavior

The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates approach and avoidance behaviors by integrating activity from numerous afferents. Within neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies in vitro and during behavior we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, VTA astrocytes facilitate excitation of local GABA neurons to increase inhibition of dopamine neurons. The increased inhibition of dopamine neurons elicits real-time and learned avoidance behavior that is sufficient to impede expression of learned preference for reward. Despite the large number of functions performed by astrocytes, loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct learned avoidance circuit that opposes learned approach behavior.

neuroscience↗

bioRxiv2017

A Basal Ganglia Circuit Sufficient to Guide Birdsong Learning

Learning complex vocal behaviors, like speech and birdsong, is thought to rely on continued performance evaluation. Whether candidate performance evaluation circuits in the brain are sufficient to guide vocal learning is not known. Here, we test the sufficiency of VTA projections to the vocal basal ganglia (Area X) in singing zebra finches, a songbird species that learns to produce a complex and stereotyped multi-syllabic courtship song during development. We optogenetically manipulate VTA axon terminals in singing birds contingent on how the pitch of individual song syllables are naturally performed. We find that optical excitation and inhibition of VTA terminals have opponent effects on future performances of targeted song syllables and are each sufficient to reliably guide learned changes in song, consistent with positive and negative reinforcement of performance outcomes. These findings define a central role for reinforcement mechanisms in learning vocalizations and provide the first demonstration of minimal circuit elements for learning vocal behaviors.

neuroscience↗