Gavan Mcnally

• UNSW Sydney

Individuals differ in sensitivity to the adverse consequences of their actions. We have shown that these differences can be linked to differences in correctly learning causal relationships between actions and their negative consequences. To further assess this, here we used a conditioned punishment task in 195 participants. Explicit punishment cont...

Some individuals persist in behaviors that incur harm to themselves or others. While adaptive decision-making requires integrating such punishment feedback to update action selection, the mechanisms driving individual differences in this capacity remain unclear. Here, in a sample spanning 24 countries, we used a conditioned punishment task to ident...

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone known to suppress alcohol consumption in mice and non-human primates. However, the role of FGF21 in modulating environmental and behavioural factors driving alcohol consumption—such as cue-driven responses and effortful actions to obtain alcohol—and its effects on neural activity relate...

The presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibil...

The nucleus of the solitary tract (NTS) receives direct viscerosensory vagal afferent input that drives autonomic reflexes, neuroendocrine function and modulates behaviour. A subpopulation of NTS neurons project to the nucleus accumbens (NAc); however, the function of this NTS‐NAc pathway remains unknown. A combination of neuroanatomical tracing, s...

Reward-seeking involves the engagement and computation of multiple physiological and motivational parameters. The lateral hypothalamus (LH) is a necessary node in the circuits that control food-seeking and motivation. One group of cells that plays an important yet incompletely understood role in these processes are the orexin/hypocretin (OX/HT) neu...

Reward-seeking involves the engagement and computation of multiple physiological and motivational parameters. The lateral hypothalamus (LH) is a necessary node in the circuits that control food-seeking and motivation. One group of cells that plays an important yet incompletely understood role in these processes are the orexin/hypocretin (OX/HT) neu...

Background: Correctly recognising that alcohol or other substances are causing problems is a necessary condition for those problems to spur beneficial behaviour change. Yet such recognition is neither immediate nor straightforward. Recognition that one's alcohol or drug use is causing negative consequences often occurs gradually. Contemporary addi...

The presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibil...

Drugs of abuse alter neuronal signaling

Punishment learning is learning of the causal relationship between responses and their adverse or undesirable consequences. Here, we review our translational approach for understanding whether, when, and how individuals differ in what they learn during punishment, and how these differences in learning may drive persistent poor or maladaptive decisi...

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocri...

Fiber photometry is a powerful tool to measure a wide variety of dynamics from targeted cell populations and circuits in freely-behaving animals. However, measured biosensor signals are contaminated by various artifacts (photobleaching, movement-related, noise) that undermine analysis and interpretation. Here, we consider existing approaches for ob...

Fiber photometry is a powerful tool to measure a wide variety of brain dynamics from targeted cells and circuits in freely-behaving animals. However, measured biosensor signals are contaminated by various artifacts (photobleaching, movement-related, noise) that undermine analysis and interpretation. Here, we consider existing approaches for obtaini...

Background Theoretical models of alcohol use posit that individuals consume alcohol to ameliorate negative affect or to heighten positive affect. It is important, however, to consider the influence of factors that may determine an individual's tendency to consume excessive amounts of alcohol under positive and negative circumstances. Thus, the curr...

The Rescorla-Wagner model remains one of the most important and influential theoretical accounts of the conditions under which Pavlovian learning occurs. Moreover, the experimental approaches that inspired the model continue to provide powerful behavioral tools to advance mechanistic understanding of how we and other animals learn to fear and learn...

Individuals differ in their sensitivity to the adverse consequences of their actions, leading some to persist in maladaptive behaviors. Two pathways have been identified for this insensitivity: a motivational pathway based on excessive reward valuation and a behavioral pathway based on autonomous stimulus-response mechanisms. Here, we identify a th...

The persistence of drug taking despite its adverse consequences plays a central role in the presentation, diagnosis, and impacts of addiction. Eventual recognition and appraisal of these adverse consequences is central to decisions to reduce or cease use. However, the most appropriate ways of conceptualizing persistence in the face of adverse conse...

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocri...

Individuals differ in sensitivity to the adverse consequences of their actions, leading some to persist in maladaptive behaviours. Two pathways have been identified for this insensitivity: a motivational pathway based on reward valuation and a behavioural pathway based on stimulus–response mechanisms. Here we identify a third, cognitive pathway bas...

Hindbrain NTS neurons are highly attuned to internal physiological and external environmental factors that contribute to the control of food intake but the relevant neural phenotypes and pathways remain elusive. Here, we investigated the role of NTS A2 neurons and their projections in the control of feeding behaviors. In male TH Cre rats, we first...

We studied the role of dopamine [tyrosine hydroxylase (TH)] neurons in the rat ventral tegmental area (VTA) in safety learning. First, we used an AX +/BX-discrimination procedure to establish conditioned stimulus (CS) B as a learned safety signal that passed both summation and retardation tests of conditioned inhibition. Then, we combined this proc...

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach-avoidance decis...

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach-avoidance decis...

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, t...

Punishment involves learning the relationship between actions and their adverse consequences. Both the acquisition and expression of punishment learning depend on the basolateral amygdala (BLA), but how BLA supports punishment remains poorly understood. To address this, we measured calcium (Ca ²⁺ ) transients in BLA principal neurons during punishm...

Punishment involves learning the relationship between actions and their adverse consequences. Both the acquisition and expression of punishment learning depend on the basolateral amygdala (BLA), but how BLA supports punishment remains poorly understood. To address this, we measured calcium (Ca2+) transients in BLA principal neurons during punishmen...

Punishment maximises the probability of our individual survival by reducing behaviours that cause us harm, and also sustains trust and fairness in groups essential for social cohesion. However, some individuals are more sensitive to punishment than others and these differences in punishment sensitivity have been linked to a variety of decision-maki...

It is well established that the activity of VTA dopamine neurons is sufficient to serve as a Pavlovian reinforcer but whether this activity can also serve as instrumental reinforcer is less well understood. Here we studied the effects of optogenetic inhibition of VTA dopamine neurons in instrumental conditioning preparations. We show that optogenet...

Punishment maximises the probability of our individual survival by reducing behaviours that cause us harm, and also sustains trust and fairness in groups essential for social cohesion. However, some individuals are more sensitive to punishment than others and these differences in punishment sensitivity have been linked to a variety of decision-maki...

The actions of dopamine are essential to relapse to drug seeking but we still lack a precise understanding of how dopamine achieves these effects. Here we review recent advances from animal models in understanding how dopamine controls relapse to drug seeking. These advances have been enabled by important developments in understanding about the bas...

Although significant progress has been made in understanding the behavioral and brain mechanisms for motivational systems, much less is known about competition between motivational states or motivational conflict (e,g. approach – avoidance conflict). Despite being produced under diverse conditions, behavior during motivational competition has two s...

It is well established that the activity of VTA dopamine neurons is sufficient to serve as a Pavlovian reinforcer but whether this activity can also serve as instrumental reinforcer is less well understood. Here we studied the effects of optogenetic inhibition of VTA dopamine neurons in instrumental conditioning preparations. We show that optogenet...

Animals, including humans, use prediction error to guide learning about danger in the environment. The basolateral amygdala (BLA) is obligatory for this learning and BLA excitatory projection neurons are instructed by aversive prediction error to form fear associations. Complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expr...

Background The misuse and abuse of alcohol is a major public health issue. However, available treatments are limited with variable efficacy. Recently, preclinical studies show that glucagon‐like‐peptide‐1 (GLP‐1) and its analogue Exendin‐4 (Ex4) potently reduce a range of alcohol intake behaviors, thus highlighting its potential as a treatment for...

The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking in male rats are assembled from activity acr...

Alcohol‐use disorders are chronically relapsing conditions characterized by cycles of use, abstinence and relapse. The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to alcohol seeking and a key target of pharmacotherapies for relapse prevention. There has been a significant increase in our understanding of the molec...

Cocaine amphetamine related transcript (CART) is a neuropeptide first isolated and sequenced from ovine hypothalamus and later shown to have functions related to drug taking, drug seeking, and energy balance. Here we review the molecular features of CART, its anatomical distribution and provide an update on CART function in energy balance control a...

The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking are assembled from activity across the ventr...

Feeding is at once both a basic biological need and a function set in a complex system of competing motivational drivers. Orexin/hypocretin neurons are located exclusively within the lateral hypothalamus (LH) and are commonly implicated in feeding, arousal, and motivated behavior, although largely based on studies employing long-term systemic manip...

Fiber photometry has enabled neuroscientists to easily measure targeted brain activity patterns in awake, freely behaving animal. A focus of this technique is to identify functionally-relevant changes in activity around particular environmental and/or behavioral events, i.e., event-related activity transients (ERT). A simple and popular approach to...

The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking. How this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH...

Although significant progress has been made in understanding how learning controls the operation of motivational systems, much less is known about how motivational systems control behavior to achieve motivational stability and resolve motivational conflict. Here we provide an overview of the basic characteristics of motivational conflict as well as...

Our behaviour is shaped by its consequences – we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation...

Our behaviour is shaped by its consequences – we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation...

The infralimbic prefrontal cortex serves complex roles in controlling drug-seeking behavior. In this issue of Neuron, Cameron et al. (2019) provide new insights into engagement and function of the infralimbic cortex → nucleus accumbens corticostriatal pathway in the incubation of cocaine craving.

Decision-making often involves motivational conflict due to the competing demands of approach and avoidance for a common resource: behavior. This conflict must be resolved as a necessary precursor for adaptive behavior. Here we show a role for the paraventricular thalamus (PVT) in behavioral control during motivational conflict. We used Pavlovian c...

Associative and reinforcement learning rules describe how animals, including humans, predict events in the world. In aversive learning, these rules describe how we predict danger. Here we outline major associative and reinforcement rules for aversive learning as well as behavioural approaches to study them. We identify key findings from the emergin...

Current pharmacotherapies for smoking have only modest efficacy with failure rates of up to 90%. One potential target for new pharmacotherapies is the orexin/hypocretin system, a hypothalamic neuropeptide system involved in arousal, appetite, and reward. The orexin system has been suggested as a potential therapeutic target for nicotine addiction b...

Ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking but how this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH)...

The ventral pallidum (VP) is a critical regulator of alcohol consumption and relapse to alcohol seeking. Recent advances in basic science encourage a fundamental shift in understanding the VP function in alcohol addiction. Rather than a passive integrator of nucleus accumbens inputs, increased recognition of its heterogeneous organization, cellular...

A key insight of associative learning theory is that learning depends on the actions of prediction error: a discrepancy between the actual and expected outcomes of a conditioning trial. This view of learning has inspired, and in turn been supported by, work in the neurosciences ranging from single unit recording and neuroimaging studies to pharmaco...

The contexts where drugs are self‐administered have important control over relapse and extinction of drug seeking behavior. The nucleus accumbens shell (AcbSh) is essential to this contextual control over drug‐seeking behaviour. It has been consistently implicated in both the expression of context‐induced reinstatement and the expression of extinct...

Adolescent humans and rodents are impaired in extinguishing learned fear relative to younger and older groups. This impairment could be due to differences in recruitment of medial prefrontal cortex (PFC), orbitofrontal cortex (OFC), or amygdala during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-in...

I was honoured to be selected for that issue's cover. I didn't immediately realise that I was expected to produce it myself. I would've thought the journal would entrust their cover to a designer who specialised in that sort of thing, over a scientist who's more used to working with animals, chemicals and spreadsheets. And then I cynically wonder...

After some back and forth of comedic proportions, I gave up on getting the table I envisioned into the manuscript. It is here for posterity.

Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context. However, the specific cell t...

Punishment involves learning about the relationship between behavior and its adverse consequences. Punishment is fundamental to reinforcement learning, decision-making and choice, and is disrupted in psychiatric disorders such as addiction, depression, and psychopathy. However, little is known about the brain mechanisms of punishment and much of wh...

The midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in the expression of defensive behavior is well understood, the relationship between the activity of PAG neurons and fear learning, the exact ti...

BLA neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in male rats. We show that brief optogenetic inhibition...

The midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in expression of defensive behavior is well understood, the relationship between activity of PAG neurons and fear learning, the exact timing of...

Basolateral amygdala (BLA) glutamatergic neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in rats. We show th...

Sodium pentobarbital is a commonly used agent for euthanizing laboratory rats, however its high pH can cause abdominal discomfort after intraperitoneal injection. Previous studies suggest that the addition of a local anaesthetic may alleviate this discomfort, but the practice has not been widely adopted. We examined the effect of combining lidocain...

The midbrain periaqueductal gray (PAG) has been implicated in the generation and transmission of a prediction error signal that instructs amygdala-based fear and extinction learning. However, the PAG also plays a key role in the expression of conditioned fear responses. The evidence for a role of the PAG in fear learning and extinction learning has...

The orexins are widely regarded potential therapeutic targets for a range of disorders of appetitive motivation, including obesity. The motivational activator theory, the first coherent account of the orexin system's role in appetitive motivation, predicts that orexin release motivates appetitive behaviour when the reinforcer is highly salient, ava...

The orexin/hypocretin system is important for appetitive motivation towards multiple drugs of abuse, including nicotine. Both OX1 and OX2 receptors individually have been shown to influence nicotine self-administration and reinstatement. Due to the increasing clinical use of dual orexin receptor antagonists in the treatment of disorders such as ins...

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Foraging animals balance the need to seek food and energy against the accompanying dangers of injury and predation. To do so, they rely on learning systems encoding reward and danger. Whereas much is known about these separate learning systems, little is known about how they interact to shape and guide behavior. Here we show a key role for the rat...

This chapter reviews the anatomical and functional evidence demonstrating the contribution of the paraventricular thalamic nucleus (PVT) to appetitive motivation, food intake control, and drug-seeking behaviors. We first consider the anatomical properties of the PVT to highlight its relevance in the control of appetitive motivation, feeding, and dr...

Significance statement: Ventral pallidum (VP) serves important roles in reward and motivation and is a critical node in the neural circuitry for reinstatement of drug seeking. Despite being a common locus for different forms of reinstatement, fundamental aspects of neural circuitry for these VP contributions to reinstatement of drug seeking remain...

Aversive outcomes punish behaviors that cause their occurrence. The prefrontal cortex (PFC) has been implicated in punishment learning and behavior, although the exact roles for different PFC regions in instrumental aversive learning and decision- making remain poorly understood. Here, we assessed the role of the orbitofrontal (OFC), rostral agranu...

The contexts where drugs are self-administered play an important role in regulating persistent drug-taking and in relapse to such taking after periods of abstinence. Here we review the behavioral and brain mechanisms enabling contexts to promote and prevent relapse to drug seeking. We review the key brain structures, their neuropharmacology, and th...

Rodents display characteristic defense responses to predators that are influenced by predatory imminence. The midbrain periaqueductal gray (PAG) serves an important role controlling these responses. The most influential model states that variations in defensive topography are due to distinct PAG regions: ventrolateral PAG (VLPAG) controls postencou...

Unlabelled: Basolateral amygdala (BLA) is critical for fear learning, and its heightened activation is widely thought to underpin a variety of anxiety disorders. Here we used chemogenetic techniques in rats to study the consequences of heightened BLA activation for fear learning and memory, and to specifically identify a mechanism linking increase...

Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear-conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stag...

Conditioned stimuli (CSs) vary in their reliability as predictors of danger. Animals must therefore select among CSs those that are appropriate to enter into an association with the aversive unconditioned stimulus (US). The actions of prediction error instruct this stimulus selection so that when prediction error is large, attention to the CS is ma...

Aversive stimuli not only support fear conditioning to their environmental antecedents, they also punish behaviors that cause their occurrence. The amygdala, especially the basolateral nucleus (BLA), has been critically implicated in Pavlovian fear learning but its role in punishment remains poorly understood. Here, we used a within-subjects punish...

The ventral pallidum (VP) is a key component of the neural circuitry mediating relapse to drug seeking, but the critical afferent pathways to VP recruited during relapse remain poorly understood. We studied the role of the nucleus accumbens core (AcbC) → VP pathway in ABA renewal and reacquisition of alcohol seeking. Rats received application of ad...

Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex (dmPFC) neurons an...

The lateral habenula (LHb) is a small epithalamic structure that projects via the fasciculus retroflexus to the midbrain. The LHb is known to modulate midbrain dopamine (DA) neurons, including inhibition of ventral tegmental area (VTA) neurons via glutamatergic excitation of the GABAergic rostromedial tegmental nucleus (RMTg). A variety of lines of...

Two experiments used vivo morpholinos to assess the role of orexin/hypocretin in ABA renewal of extinguished alcohol seeking. Rats were trained to respond for alcoholic beer in a distinctive context, A, and then extinguished in a second distinctive context, B. When rats were tested in the extinction context, ABB, responding was low but when they we...

Fear learning occurs in response to positive prediction error, when the expected outcome of a conditioning trial exceeds that predicted by the conditioned stimuli present. This role for error in Pavlovian association formation is best exemplified by the phenomenon of associative blocking, whereby prior fear conditioning of conditioned stimulus (CS)...

Endogenous opioids play an important role in prediction error during fear learning. However, the evidence for this role has been obtained almost exclusively using the species-specific defense response of freezing as the measure of learned fear. It is unknown whether opioid receptors regulate predictive fear learning when other measures of learned f...

The retrieval of extinction memories is dependent on contextual cues associated with extinction training. Various forms of response restoration after extinction, such as renewal, reinstatement, and spontaneous recovery, can be viewed as failures to retrieve an extinction memory. It follows that provision of a cue to aid retrieval of the extinction...

Adolescent rats exhibit impaired extinction retention compared to pre-adolescent and adult rats. A single nonreinforced exposure to the conditioned stimulus (CS; a retrieval trial) given shortly before extinction has been shown in some circumstances to reduce the recovery of fear after extinction in adult animals. This study investigated whether a...

Opioid antagonists reduce the rate of relapse to drinking in clinical trials and reduce reinstatement in animal models of drug seeking. However, the neuroanatomical locus for this effect remains poorly understood. We examined the role of nucleus accumbens shell (AcbSh) μ-opioid receptors in two different forms of recovery of alcoholic beer seeking....

The ventral pallidum (VP) is a major target of projections from the nucleus accumbens, and has been implicated in the reinstatement of psychostimulant seeking as part of a cortical-striatal-pallidal 'final common pathway' for relapse. Here, we studied the role of the VP in context-induced and primed reinstatement of alcoholic beer seeking, using a...