Biology subjects

Dalley, J. W.

Publications and source records attributed to Dalley, J. W..

6 recordsLinked to original sources

bioRxiv2025

Dopamine Dynamics in the Nucleus Accumbens Reflect Confidence in Detecting the Occurrence and Non-Occurrence of Visual Signals in Perceptual Decision-Making

Dopamine (DA) is critically involved in processes such as reward anticipation, attention, and decision - making. The present study examined the temporal dynamics of phasic DA transients in the nucleus accumbens core (NAcC) during a visual decisional task based on signal detection theory, using the fluorescent DA sensor dLight1.3b. During the decision-making phase, DA transients in the NAcC encoded real-time outcome expectancy, apparently reflecting the confidence of rats in their choices. Reward prediction errors (RPEs) emerged following reward delivery and omission and were amplified under conditions of increased uncertainty, produced either by degrading the visual target or introducing interfering distraction. Moreover, DA transients were elicited on both visual signal and no-signal trials. These findings demonstrate that DA fluctuations in the NAcC reflect the RPE that incorporates confidence and levels of uncertainty, emphasizing an involvement of nucleus accumbens DA in adaptive decision-making.

neuroscience↗

bioRxiv2024

Development and early life stress sensitivity of the rat cortical microstructural similarity network

Understanding how early life experiences shape brain network development is a key challenge in the neuroscience of mental health disorders. To address this, we used magnetic resonance imaging (MRI) similarity network analysis to study the effects of stress in the rat, an important animal model in neuropsychiatry. We measured magnetization transfer ratio (MTR) at each of 53 distinct cortical areas and estimated a cortical similarity network for each individual scan, in two independent experimental datasets. We first characterized normative network development in rats scanned repeatedly between postnatal days 20 (weanling) and 290 (mid-adulthood) (N=47), and then contrasted these findings with a cohort exposed to early life stress in the form of repeated maternal separation (RMS, N=40). The normative rat cortical similarity network exhibited biologically meaningful organization, aligning with prior cytoarchitectonic and tract-tracing data, and displayed complex topological features, including rich club organization. During postnatal and adolescent development, brain regions became more similar, including an early phase of fronto-hippocampal convergence. Early increases in inter-areal similarity were reversed in a later phase of fronto-hippocampal divergence in mid-adulthood. RMS exposure altered inter-areal similarity, especially between frontal and parahippocampal regions, that were also most active developmentally and in aging. Our results reveal how normative cortical network changes in the developing brain are influenced by early life stress. These findings suggest a new translational framework for elucidating how environmental risk factors lead to atypical development of cortical networks.

neuroscience↗

bioRxiv2024

Modelling determinants of region-specific dopamine dynamics in the striatum

Striatal dopamine (DA) release regulates reward-related learning and motivation and is believed to consist of a short-lived phasic and continuous tonic component. Here, we build a large-scale three-dimensional model of extracellular DA dynamics in dorsal (DS) and ventral striatum (VS). The model predicts rapid dynamics in DS with little-to-no basal DA, and slower dynamics in the VS enabling build-up of tonic DA levels. These regional differences do not reflect release-related phenomena but rather differential dopamine transporter (DAT) activity. Interestingly, our simulations posit DAT nanoclustering as a possible regulator of this activity. Receptor binding simulations show that D1 receptor occupancy follows extracellular DA concentration with milliseconds delay, while D2 receptors do not respond to brief pauses in firing but rather integrate DA signal over seconds. Summarized, our model distills recent experimental observations into a computational framework that challenge prevailing paradigms of striatal DA signalling.

neuroscience↗

bioRxiv2024

Mesencephalic projections to the nucleus accumbens shell modulate value updating during probabilistic reversal learning

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including substance use disorder and Parkinsons disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesised to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%:20% basis, that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcbS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). Moreover, the exploitation-exploration parameter, {beta}, was increased (indicating greater exploitation of information) when this pathway was optogenetically stimulated after a spurious loss (i.e. an incorrect (20%) response at the 80% reinforrced location) compared to after a spurious win (i.e. a correct (20%) response at the 20% reinforced location). VTA [->] NAcbS stimulation during other phases of the behavioural task was without effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no effect on reversal learning. These findings are consistent with the notion that enhanced activity in VTA [->] NAcbS projections leads to maladaptive perseveration as a consequence of an inappropriate bias to exploitation via positive reinforcement.

animal behavior and cognition↗

bioRxiv2023

5-HT 2A and 5-HT 2C receptor antagonism differentially modulates reinforcement learning and cognitive flexibility: behavioral and computational evidence

Cognitive flexibility, the ability to adapt behavior in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Evidence suggests that flexibility, which can be operationalized using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behavior and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on cognitive flexibility and underlying RL mechanisms. Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning performance and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task. 5-HT2AR antagonism impaired reversal learning during certain phases. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate at high and low doses. The low dose also increased exploration (beta) and increased stimulus and side stickiness (kappa). 5-HT2CR antagonism also increased beta, but reduced side stickiness. These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback and 5-HT2cRs for learning from positive feedback.

animal behavior and cognition↗

bioRxiv2023

Computational modeling of reinforcement learning and functional neuroimaging of probabilistic reversal dissociates compulsive behaviors in Gambling and Cocaine Use Disorders

Cognitive flexibility refers to the ability to adjust to changes in the environment and is essential for adaptive behavior. It can be investigated using laboratory tests such as probabilistic reversal learning (PRL). In individuals with both Cocaine Use Disorder (CUD) and Gambling Disorder (GD), overall impairments in PRL flexibility are observed. However, it is poorly understood whether this impairment depends on the same brain mechanisms in cocaine and gambling addictions. Reinforcement learning (RL) is the process by which rewarding or punishing feedback from the environment is used to adjust behavior, to maximise reward and minimise punishment. Using RL models, a deeper mechanistic explanation of the latent processes underlying cognitive flexibility can be gained. Here, we report results from a re-analysis of PRL data from control participants (n=18) and individuals with either GD (n=18) or CUD (n=20) using a hierarchical Bayesian RL approach. We observed significantly reduced stimulus stickiness (i.e., stimulus-bound perseveration) in GD, which may reflect increased exploratory behavior that is insensitive to outcomes. RL parameters were unaffected in CUD. We relate the behavioral findings to their underlying neural substrates through an analysis of task-based fMRI data. We report differences in tracking reward and punishment expected values (EV) in individuals with GD compared to controls, with greater activity during reward EV tracking in the cingulate gyrus and amygdala. In CUD, we observed reduced responses to positive punishment prediction errors (PPE) and increased activity following negative PPEs in the superior frontal gyrus compared to controls. Thus, an RL framework serves to differentiate behavior in a probabilistic learning paradigm in two compulsive disorders, GD and CUD.

neuroscience↗