Biology subjects

McNally, G.

Publications and source records attributed to McNally, G..

8 recordsLinked to original sources

bioRxiv2026

Dual GLP-1/FGF21 agonism suppresses voluntary alcohol consumption, alcohol choice, and nucleus accumbens dopamine modulation

Excessive alcohol consumption remains a major public health challenge with limited therapeutic options. Both glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) independently regulate alcohol intake through complementary metabolic and reward pathways, but their combined potential has not been explored. Here, we report that a long-acting dual agonist, GLP1-ELP-FGF21 modulates behavioural, neurophysiological, and cognitive components of alcohol seeking in mice. A single GLP1-ELP-FGF21 dose reversibly reduces voluntary alcohol intake for at least 72 hours in male mice, has sustained effects in female mice, and markedly blunts nucleus accumbens dopamine transients aligned to the initiation and termination of lick bouts during alcohol consumption. To assess its effects on decision-making, we used a novel two-choice (alcohol versus food) decision task modelled with evidence-accumulation frameworks. Alcohol choice behaviour conformed to evidence accumulation decision models: Linear Ballistic Accumulator (LBM) and Racing diffusion models (RDM). Critically, GLP1-ELP-FGF21 selectively reduces choices for alcohol and slows the latent accumulation rate for alcohol options, without affecting food-directed choice or non-decision processes. Sensory-specific satiety devaluation confirms that reductions in reward value are explained by reductions in accumulation rates. Together, these results highlight GLP1-ELP-FGF21 as a therapeutic strategy for alcohol use disorder via modulation of central reward pathways and decision-making when confronted with alcohol reward

animal behavior and cognition↗

bioRxiv2025

The brain architecture of punishment learning

Learning which actions cause harm is essential for survival, yet how the brain transforms this knowledge into adaptive control of behavior remains unclear. We combined whole-brain analysis, multisite chemogenetic silencing, spatial transcriptomics, and longitudinal calcium imaging to map how punishment learning reorganizes brain networks across scales. Learning reshaped mesoscale community organization into a network anchored by the amygdala, subthalamic-hypothalamic zone, and ventral midbrain tegmentum. These regions contributed distinct components of adaptive avoidance and engaged diverse transcriptional programs across multiple neuronal subclasses. Within this network, the amygdala acted as a hub, partitioning action and outcome information and remapping neural geometry to segregate punished from safe actions. Together, these results identify a multiscale neural architecture through which aversive experience can be transformed into flexible behavioral control.

neuroscience↗

bioRxiv2025

Instrumental Punishment Learning Enhances the Intrinsic Excitability of Basolateral Amygdala Neurons

The basolateral amygdala (BLA) is a structure that is critical for forming Pavlovian and instrumental emotional associations. Previous studies have established that Pavlovian fear conditioning increases the intrinsic excitability of BLA projection neurons. Learning-associated increases in excitability are hypothesised to facilitate the induction of synaptic plasticity and integration of neurons into functional learning circuits. Here, we examined whether instrumental learning produces similar changes in intrinsic excitability. Male and Female Long Evans rats were trained to lever press for a food reward and subsequently split into 3 behavioural groups; punished, yoked, and reward. Punished rats received response-contingent footshocks, yoked rats received response-independent footshocks, and reward rats received no shock. Intrinsic excitability was measured as the number of action potentials (APs) evoked by a series of depolarising current injections during whole-cell patch clamp recordings. Reward learning increased the intrinsic excitability of BLA projection neurons compared to naive controls. Punishment training maintained excitability and excitability was correlated with performance on the punishment task. Response-independent footshocks arrested reward-associated increases in excitability, reverting the BLA neurons to a naive state. Group differences were observed in AP half-width and the current underlying the post-burst AHP. Together, these findings show that instrumental reward learning enhances the intrinsic excitability of BLA projection neurons, potentially supporting action-outcome encoding by promoting synaptic plasticity and circuit integration. The results also suggest that different forms of learning engage distinct biophysical adaptations. A mechanistic understanding of the neurobiology underlying instrumental association learning may help inform the development of treatments for psychiatric disorders characterized by deficits in this process, such as major depressive disorder and conduct disorder.

neuroscience↗

bioRxiv2021

A corticothalamic circuit trades off speed for safety during decision-making under motivational conflict

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 decisions under motivational conflict. Then we used cognitive modelling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and non-human primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging and functional circuit analyses, we show that this speed-safety trade off occurs because increases in paraventricular thalamus (PVT) activity increase decision caution, thereby increasing approach-avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit involving the PVT and its prefrontal cortical input dynamically adjusts decision caution during motivational conflict, trading off decision speed for decision safety when danger is close. They identify the corticothalamic pathway as central to cognitive control during decision-making under conflict.

neuroscience↗

bioRxiv2021

Rapid appetitive transitions are sculpted by amygdala to accumbens pathways

Foraging, pursuit, and predation rapidly transition into behavioral quiescence during reward capture and consumption. While appetitive-consummatory dissociations are embedded at both psychological and neural levels, the mechanisms controlling switches or transitions between appetitive seeking and consummatory behaviors remain poorly understood. Here we identify the BLA[->]AcbSh pathway as critical to these transitions by showing that this pathway inhibits the appetitive seeking response in the presence of consummatory demands. Using an appetitive cue-discrimination task in male rats, we show that reward delivery is a significant driver of seeking inhibition and that a BLA[->]AcbSh pathway mediates this inhibition. This role in suppressing seeking responses during periods of consumption was not due to a general suppression of behavior because responding to other cues during the same test was unaffected. Moreover, it was specific to the BLA[->]AcbSh pathway, because the contribution of the BLA[->]AcbC pathway to appetitive switching was distinct and modest. State-dependent silencing of BLA[->]AcbSh revealed that the modulation of seeking before and after reward delivery are co-dependent. Finally, we found that BLA terminals in AcbSh have functional connectivity to LH-projecting AcbSh neurons, thereby identifying a BLA[->]AcbSh[->]LH pathway as a putative route for the rapid regulation of appetitive behaviors. Taken together, these findings suggest that the BLA[->]AcbSh pathway is a core component of an appetitive switching system, recruited under conditions requiring rapid or dynamic shifts in appetitive behavior, and that this pathway enables these shifts by actively inhibiting seeking. Significance statementForaging, pursuit, and predation quickly transition into behavioral quiescence during reward capture and consumption. These transitions are critical for flexible and responsive sequences of behavior. Here we show that behavioral transitions are actively controlled at the limbic-striatal interface. We identify reward receipt as a proximal trigger for transition between reward seeking and taking, we identify active inhibition as the functional operation of this transition, and we identify the basolateral amygdala[->]accumbens shell pathway as critical to this functional operation.

neuroscience↗

bioRxiv2020

Phasic inhibition of dopamine neurons is an instrumental punisher

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 optogenetic inhibition of VTA dopamine neurons causes a response-specific, contingency-sensitive suppression of instrumental responding. This suppression was due to instrumental response, not Pavlovian stimulus, learning and could not be attributed to deepened instrumental extinction learning. These effects of optogenetic inhibition of VTA dopamine neurons on instrumental responding are formally similar to the effects of aversive events in instrumental preparations and show that optogenetic inhibition of VTA dopamine neurons is sufficient to serve as an instrumental punisher.

neuroscience↗

bioRxiv2020

Basolateral amygdala parvalbumin neurons report aversive prediction error to constrain fear learning

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) expressing GABAergic neurons, form the intrinsic microcircuitry of the BLA to control projection neuron activity. Whether BLA PV interneurons are also sensitive to prediction error and how they use this error to control fear learning remains unknown. We used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats to address these issues. We show that BLA PV neurons control fear learning about aversive events but not learning about their omission. Furthermore, during fear learning BLA PV neurons express the activity signatures of aversive prediction error: greater activity to unexpected than expected aversive events and greater activity to better rather than poorer predictors of these events. Crucially, we show that BLA PV neurons act to limit fear learning across these variations in prediction error. Together, this demonstrates that prediction error instructs and regulates BLA fear association formation in a cell-type specific manner. Whereas BLA projection neurons use prediction error signals to form and store fear associations, BLA PV interneurons use prediction error signals to constrain fear association formation. Significance StatementThe capacity to predict sources of danger in the environment is essential for survival. This capacity is supported by associative learning mechanisms that are triggered when the danger experienced is greater than the danger expected. Here we show that the activity of parvalbumin positive GABAergic interneurons in the rat basolateral amygdala neurons report this difference between the danger expected and the danger experienced and that they use this difference to limit the amount of fear which is learned.

neuroscience↗

bioRxiv2019

Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance

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 for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48; 18 female) trained in a task permitting concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.

neuroscience↗