Biology subjects

Fraser, K. M.

Publications and source records attributed to Fraser, K. M..

9 recordsLinked to original sources

bioRxiv2026

Ventral tegmental area acetylcholine generates appetitive and aversive incentive motivation

Ventral tegmental area neurons participate in reward learning, motivation, and movement but also have an emerging role in the regulation of aversive behaviors. While these diverse contributions have been attributed to distinct projections of ventral tegmental area neurons, it remains unresolved how these neurons inherit their array of behavioral functions. The ventral tegmental area is rich with acetylcholine receptors and receives dense cholinergic input from the mesopontine tegmentum. While it is known that acetylcholine release in the ventral tegmental area can increase dopamine output we lack an understanding of the scenarios which necessitate ventral tegmental area acetylcholine release. We sought to provide a comprehensive overview of the participation of ventral tegmental area acetylcholine signaling across valence to motivated behavior. Rats were trained on a diverse array of tasks that allowed for the isolation of the contribution of acetylcholine release in the ventral tegmental area to cue- and context-driven behavior. We used intracranial pharmacology to determine the receptor mechanisms that contribute to acetylcholines effects. Ultimately, we found that acetylcholine release in the ventral tegmental area is necessary for appetitive and aversive states to become motivationally relevant and spur reward-seeking and threat-avoidance. We propose that this state-dependent contribution allows ventral tegmental area acetylcholine to act as a motivational gate for behavior across valence. This work expands our view of the interaction between neuromodulatory systems in the brain and opens new directions to the understanding of ventral tegmental area neurons in health and disease.

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bioRxiv2023

Contexts facilitate dynamic value encoding in the mesolimbic dopamine system

Adaptive behavior in a dynamic environment often requires rapid revaluation of stimuli that deviates from well-learned associations. The divergence between stable value-encoding and appropriate behavioral output remains a critical test to theories of dopamines function in learning, motivation, and motor control. Yet how dopamine neurons are involved in the revaluation of cues when the world changes to alter our behavior remains unclear. Here we make use of pharmacology, in vivo electrophysiology, fiber photometry, and optogenetics to resolve the contributions of the mesolimbic dopamine system to the dynamic reorganization of reward-seeking. Male and female rats were trained to discriminate when a conditioned stimulus would be followed by sucrose reward by exploiting the prior, non-overlapping presentation of a separate discrete cue - an occasion setter. Only when the occasion setters presentation preceded the conditioned stimulus did the conditioned stimulus predict sucrose delivery. As a result, in this task we were able to dissociate the average value of the conditioned stimulus from its immediate expected value on a trial-to-trial basis. Both the activity of ventral tegmental area dopamine neurons and dopamine signaling in the nucleus accumbens were essential for rats to successfully update behavioral responding in response to the occasion setter. Moreover, dopamine release in the nucleus accumbens following the conditioned stimulus only occurred when the occasion setter indicated it would predict reward. Downstream of dopamine release, we found that single neurons in the nucleus accumbens dynamically tracked the value of the conditioned stimulus. Together these results reveal a novel mechanism within the mesolimbic dopamine system for the rapid revaluation of motivation.

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bioRxiv2023

Encoding and context-dependent control of reward consumption within the central nucleus of the amygdala

The ability to evaluate and select a preferred option among a variety of available offers is an essential aspect of goal-directed behavior. Dysregulation of this valuation process is characteristic of alcohol use disorder, with the central amygdala being implicated in persistent alcohol pursuit. However, the mechanism by which the central amygdala encodes and promotes the motivation to seek and consume alcohol remains unclear. We recorded single-unit activity in male Long-Evans rats as they consumed 10% ethanol or 14.2% sucrose. We observed significant activity at the time of approach to alcohol or sucrose, as well as lick-entrained activity during the ongoing consumption of both alcohol and sucrose. We then evaluated the ability of central amygdala optogenetic manipulation time-locked to consumption to alter ongoing intake of alcohol or sucrose, a preferred non-drug reward. In closed two-choice scenarios where rats could drink only sucrose, alcohol, or quinine-adulterated alcohol with or without central amygdala stimulation, rats drank more of stimulation-paired options. Microstructural analysis of licking patterns suggests these effects were mediated by changes in motivation, not palatability. Given a choice among different options, central amygdala stimulation enhanced consumption if the stimulation was associated with the preferred reward while closed-loop inhibition only decreased consumption if the options were equally valued. However, optogenetic stimulation during consumption of the less-preferred option, alcohol, was unable to enhance overall alcohol intake while sucrose was available. Collectively, these findings indicate that the central amygdala processes the motivational value of available offers to promote pursuit of the most preferred available option.

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bioRxiv2023

Nucleus accumbens and dorsal medial striatal dopamine and neural activity are essential for action sequence performance

Separable striatal circuits have unique functions in Pavlovian and instrumental behaviors but how these roles relate to performance of sequences of actions with and without associated cues is less clear. Here we tested whether dopamine release and neural activity more generally in three striatal subdomains are necessary for performance of an action chain leading to reward delivery. Male and female Long-Evans rats were trained to press a series of three spatially-distinct levers to receive reward. We assessed the contribution of neural activity or dopamine release within each striatal subdomain when progression through the action sequence was explicitly cued and in the absence of cues. Behavior in both task variations was substantially impacted following microinfusion of the dopamine antagonist, flupenthixol, into nucleus accumbens core (NAc) or dorsomedial striatum (DMS), with impairments in sequence timing and a strong impact on motivation after NAc flupenthixol. In contrast, after pharmacological inactivation to suppress overall activity, there was minimal impact on motivation, except within the uncued task after DMS inactivation. Inactivation of both NAc and DMS impaired sequence timing and led to sequence errors in the uncued, but not cued task. There was virtually no impact of dopamine antagonism or reversible inactivation of dorsolateral striatum on either cued or uncued action sequence completion. These results highlight an essential contribution of NAc and DMS dopamine systems in motivational and performance aspects of chains of actions, whether cued or internally generated, as well as the impact of intact NAc and DMS function for correct sequence performance.

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bioRxiv2022

From Prediction to Action: Dissociable Roles of Ventral Tegmental Area and Substantia Nigra Dopamine Neurons in Instrumental Reinforcement

Reward-seeking requires the coordination of motor programs to achieve goals. Midbrain dopamine neurons are critical for reinforcement and their activation is sufficient for learning about cues, actions, and outcomes. Here we examine in detail the mechanisms underlying the ability of ventral tegmental area (VTA) and substantia nigra (SNc) dopamine neurons to support instrumental learning. By exploiting numerous behavioral tasks in combination with time-limited optogenetic manipulations, we reveal that VTA and SNc dopamine neurons generate reinforcement through separable psychological processes. VTA dopamine neurons imbue actions and their associated cues with motivational value that allows flexible and persistent pursuit whereas SNc dopamine neurons support time-limited, precise, action-specific learning that is non-scalable and inflexible. This architecture is reminiscent of actor-critic reinforcement learning models with VTA and SNc instructing the critic and actor, respectively. Our findings indicate that heterogeneous dopamine systems support unique forms of instrumental learning that ultimately result in disparate reward-seeking strategies.

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bioRxiv2022

Basolateral amygdala and orbitofrontal cortex, but not dorsal hippocampus, are necessary for the control of reward-seeking by occasion setters

Reward-seeking in the world is driven by cues that can have ambiguous predictive and motivational value. To produce adaptive, flexible reward-seeking it is necessary to exploit occasion setters, other distinct features in the environment, to resolve the ambiguity of Pavlovian reward-paired cues. Despite this, very little research has investigated the neurobiological underpinnings of occasion setting and as a result little is known about which brain regions are critical for occasion setting. To address this, we exploited a recently developed task that was amenable to neurobiological inquiry where a conditioned stimulus is only predictive of reward delivery if preceded in time by the non-overlapping presentation of a separate cue - an occasion setter. This task required male rats to maintain and link cue-triggered expectations across time to produce adaptive reward-seeking. We interrogated the contributions of the basolateral amygdala and orbitofrontal cortex to occasion setting as these regions are thought to be critical for the computation and exploitation of state value, respectively. Reversible inactivation of either structure prior to the occasion-setting task resulted in a profound inability of rats to use the occasion setter to guide reward seeking. In contrast, inactivation of the dorsal hippocampus, a region fundamental for context-specific responding was without effect nor did inactivation of the basolateral amygdala or orbitofrontal cortex in a standard Pavlovian conditioning preparation affect conditioned responding. We conclude that neural activity within the orbitofrontal cortex and basolateral amygdala circuit is necessary to update and resolve ambiguity in the environment to promote cue-driven reward-seeking.

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bioRxiv2019

A history-derived reward prediction error signal in ventral pallidum

Learning from past interactions with the environment is critical for adaptive behavior. Within the framework of reinforcement learning, the nervous system builds expectations about future reward by computing reward prediction errors (RPEs), the difference between actual and predicted rewards. Correlates of RPEs have been observed in the midbrain dopamine system, which is thought to locally compute this important variable in service of learning. However, the extent to which RPE signals may be computed upstream of the dopamine system is largely unknown. Here, we quantify history-based RPE signals in the ventral pallidum (VP), an input region to the midbrain dopamine system implicated in reward-seeking behavior. We trained rats to associate cues with future delivery of reward and fit computational models to predict individual neuron firing rates at the time of reward delivery. We found that a subset of VP neurons encoded RPEs and did so more robustly than nucleus accumbens, an input to VP. VP RPEs predicted trial-by-trial task engagement, and optogenetic inhibition of VP reduced subsequent task-related reward seeking. Consistent with reinforcement learning, activity of VP RPE cells adapted when rewards were delivered in blocks. We further found that history- and cue-based RPEs were largely separate across the VP neural population. The presence of behaviorally-instructive RPE signals in the VP suggests a pivotal role for this region in value-based computations.

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bioRxiv2018

Setting the occasion for incentive motivation: implications for addiction

The context in which reward-paired cues are encountered sets the occasion for appropriate reward-seeking but may also spur inappropriate behaviors such as the renewal of drug-seeking. The psychological processes underlying occasion setting remain unclear as contexts are diffuse and difficult to isolate from other stimuli. To overcome this, we modeled a context as a phasic and discrete event - an occasion setter - which allowed for control over its presentation and influence on cue-driven reward-seeking. This allowed us to directly assess how occasion setters, like contexts, regulate the predictive and motivational significance of Pavlovian cues. Male rats (n=50) were trained in a Pavlovian paradigm where the presentation of an ambiguous conditioned stimulus was reinforced only if preceded by an occasion setting cue. We assessed the motivational value of the occasion setter and conditioned stimulus alone or in combination using conditioned reinforcement. Rats showed enhanced conditioned approach to the reward port during the reward-adjacent conditioned stimulus when it was preceded by the occasion setter. When allowed the opportunity, rats responded more to obtain presentations of the conditioned stimulus in combination with the occasion setter than the conditioned stimulus alone. Critically, rats also worked to obtain presentations of the occasion setter alone more than the conditioned stimulus, and this was resistant to manipulations of the value of the occasion setter. We conclude that occasion setting can act via incentive motivational mechanisms and that, apart from resolving predictive information about ambiguous reward-paired cues, occasion setters themselves generate states of appetitive motivation that can facilitate reward-seeking.

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bioRxiv2017

Long-Lasting Contribution Of Dopamine In The Nucleus Accumbens Core, But Not Dorsal Lateral Striatum, To Sign-Tracking

The attribution of incentive salience to reward-paired cues is dependent on dopamine release in the nucleus accumbens core. These dopamine signals conform to traditional reward-prediction error signals and have been shown to diminish with time. Here we examined if the diminishing dopamine signal in the nucleus accumbens core has functional implications for the expression of sign-tracking, a Pavlovian conditioned response indicative of the attribution of incentive salience to reward-paired cues. Food-restricted male Sprague-Dawley rats were trained in a Pavlovian paradigm in which an insertable lever predicted delivery of food reward in a nearby food cup. After 7 or 14 training sessions, rats received infusions of saline, the dopamine antagonist flupenthixol (100 mM), or the GABA agonists baclofen and muscimol (0.5 mM baclofen/0.05 mM muscimol) into the nucleus accumbens core or the dorsal lateral striatum. Dopamine antagonism within the nucleus accumbens core attenuated sign-tracking, whereas reversible inactivation did not affect sign-tracking but increased non-specific food cup checking behaviors. Neither drug in the dorsal lateral striatum affected sign-tracking behavior. Critically, extended training did not alter these effects. Though extended experience with an incentive stimulus may reduce cue-evoked dopamine in the nucleus accumbens core, this does not alter the function of dopamine in this region to promote Pavlovian cue approach nor result in the recruitment of dorsal lateral striatal systems for this behavior. These data support the notion that dopamine within the mesoaccumbal system, but not the nigrostriatal system, contributes critically to incentive motivational processes independent of the length of training.\n\nAbbreviations

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