Brainstem networks construct threat probability and prediction error from neuronal building blocks

When faced with potential threat we must estimate its probability, respond advantageously, and leverage experience to update future estimates. Threat estimation is the proposed domain of the forebrain, while behaviour is elicited by the brainstem. Yet, the brainstem is also a source of prediction error, a learning signal to acquire and update threat estimates. Neuropixels probes allowed us to record single-unit activity across a 21-region brainstem axis in rats receiving probabilistic fear discrimination with foot shock outcome. Against a backdrop of diffuse behaviour signaling, a brainstem network with a dorsal hub signaled threat probability. Neuronal function remapping during the outcome period gave rise to brainstem networks signaling prediction error and shock on multiple timescales. The results reveal brainstem networks construct threat probability, behaviour, and prediction error signals from neuronal building blocks

Human-In-the-Loop for Bayesian Autonomous Materials Phase Mapping

Autonomous experimentation (AE) combines machine learning and research hardware automation in a closed loop, guiding subsequent experiments toward user goals. As applied to materials research, AE can accelerate materials exploration, reducing time and cost compared to traditional Edisonian studies. Additionally, integrating knowledge from diverse sources including theory, simulations, literature, and domain experts can boost AE performance. Domain experts may provide unique knowledge addressing tasks that are difficult to automate. Here, we present a set of methods for integrating human input into an autonomous materials exploration campaign for composition-structure phase mapping. The methods are demonstrated on x-ray diffraction data collected from a thin film ternary combinatorial library. At any point during the campaign, the user can choose to provide input by indicating regions-of-interest, likely phase regions, and likely phase boundaries based on their prior knowledge (e.g., knowledge of the phase map of a similar material system), along with quantifying their certainty. The human input is integrated by defining a set of probabilistic priors over the phase map. Algorithm output is a probabilistic distribution over potential phase maps, given the data, model, and human input. We demonstrate a significant improvement in phase mapping performance given appropriate human input

Normal Aging does Not Impair Orbitofrontal-Dependent Reinforcer Devaluation Effects

Normal aging is associated with deficits in cognitive flexibility thought to depend on prefrontal regions such as the orbitofrontal cortex (OFC). Here, we used Pavlovian reinforcer devaluation to test whether normal aging might also affect the ability to use outcome expectancies to guide appropriate behavioral responding, which is also known to depend on the OFC. Both young and aged rats were trained to associate a 10-s conditioned stimulus (CS+) with delivery of a sucrose pellet. After training, half of the rats in each age group received the sucrose pellets paired with illness induced by LiCl injections; the remaining rats received sucrose and illness explicitly unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Although aged rats displayed lower responding levels overall, both young and aged rats conditioned to the CS+ and developed a conditioned taste aversion following reinforcer devaluation. Furthermore, during the extinction probe test, both young and aged rats spontaneously attenuated conditioned responding to the cue as a result of reinforcer devaluation. These data show that normal aging does not affect the ability to use expected outcome value to appropriately guide Pavlovian responding. This result indicates that deficits in cognitive flexibility are dissociable from other known functions of prefrontal – and particularly orbitofrontal – cortex

Nucleus Accumbens Core and Shell are Necessary for Reinforcer Devaluation Effects on Pavlovian Conditioned Responding

The nucleus accumbens (NA) has been hypothesized to be part of a circuit in which cue-evoked information about expected outcomes is mobilized to guide behavior. Here we tested this hypothesis using a Pavlovian reinforcer devaluation task, previously applied to assess outcome-guided behavior after damage to regions such as the orbitofrontal cortex and amygdala that send projections to NA. Rats with sham lesions or neurotoxic lesions of either the core or shell subdivision of NA were trained to associate a 10-s CS+ with delivery of three food pellets. After training, half of the rats in each lesion group received food paired with illness induced by LiCl injections; the remaining rats received food and illness unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Both sham and lesioned rats conditioned to the CS+ and formed a conditioned taste aversion. However only sham rats reduced their conditioned responding as a result of reinforcer devaluation; devalued rats with lesions of either core or shell showed levels of responding that were similar to lesioned, non-devalued rats. This impairment was not due to the loss of motivational salience conferred to the CS+ in lesioned rats as both groups responded similarly for the cue in conditioned reinforcement testing. These data suggest that NA core and shell are part of a circuit necessary for the use of cue-evoked information about expected outcomes to guide behavior

Differential Contributions of Dopamine and Serotonin to Orbitofrontal Cortex Function in the Marmoset

We have shown previously that the inhibitory control functions of the orbitofrontal cortex (OFC) are disrupted by serotonin, but not dopamine depletions. However, both dopamine and serotonin terminals and receptors are present within the OFC and thus the aim of the present study was to determine the differential contributions of these neurotransmitters to orbitofrontal function. OFC and dopamine are involved in the process by which neutral stimuli take on reinforcing properties, by virtue of their prior association with reward, and guide behavior. Thus, we compared the performance of marmosets with dopaminergic or serotoninergic OFC depletions on a test of conditioned reinforcement. To further our understanding of serotonin in behavioral flexibility, the effect of these depletions was also compared on the extinction of a visual discrimination. Monkeys with serotonin depletions of the OFC displayed stimulus-bound responding on both tests of conditioned reinforcement and discrimination extinction suggesting that orbitofrontal serotonin plays a specific role in preventing competing, task irrelevant, salient stimuli from biasing responding. In contrast, monkeys with dopamine depletion were insensitive to conditioned reinforcers and displayed persistent responding in the absence of reward in extinction, a pattern of deficits that may reflect basic deficits in the associative processing of reward

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.This study was funded by the WT fellowship grant for VV (093705/Z/ 10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. YW is supported by the Fyssen Fondation and MRC Studentships. PD is supported by the Gatsby Charitable Foundation. JEG has received grants from the National Institute of Drug Abuse and the National Center for Responsible Gaming. TWR and BJS are supported on a WT Programme Grant (089589/Z/09/Z). The BCNI is supported by a WT and MRC grant.This is the final published version. It's also available from Molecular Psychiatry at http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201444a.html

Lateral orbitofrontal cortex partitions mechanisms for fear regulation and alcohol consumption.

Anxiety disorders and alcohol use disorder are highly comorbid, yet identifying neural dysfunction driving comorbidity has been challenging. Lateral orbitofrontal cortex (lOFC) dysfunction has been independently observed in each disorder. Here we tested the hypothesis that the lOFC is essential to partition mechanisms for fear regulation and alcohol consumption. Specifically, the capacity to regulate fear and the propensity to consume alcohol are unrelated when lOFC is intact, but become linked through lOFC dysfunction. Male Long Evans rats received bilateral, neurotoxic lOFC lesions or sham surgery. Fear regulation was determined by establishing discrimination to danger, uncertainty, and safety cues then shifting the shock probability of the uncertainty cue. Alcohol consumption was assessed through voluntary, intermittent access to 20% ethanol. The neurotoxic lesion approach ensured lOFC dysfunction spanned testing in fear regulation and alcohol consumption. LOFC-lesioned rats demonstrated maladaptive fear generalization during probability shifts, inverting normal prediction error assignment, and subsequently consumed more alcohol. Most novel, fear regulation and alcohol consumption were inextricably linked only in lOFC-lesioned rats: extreme fear regulation predicted excessive alcohol consumption. The results reveal the lOFC is essential to partition mechanisms for fear regulation and alcohol consumption and uncover a plausible source of neural dysfunction contributing to comorbid anxiety disorders and alcohol use disorder

Early adversity disrupts the adult use of aversive prediction errors to reduce fear in uncertainty

Early life adversity increases anxiety in adult rodents and primates, and increases the risk for developing post-traumatic disorder (PTSD) in humans. We hypothesized that early adversity impairs the use of learning signals – negative, aversive prediction errors – to reduce fear in uncertainty. To test this hypothesis, we gave adolescent rats a battery of adverse experiences then assessed adult performance in probabilistic Pavlovian fear conditioning and fear extinction. Rats were confronted with three cues associated with different probabilities of foot shock: one cue never predicted shock, another cue predicted shock with uncertainty, and a final cue always predicted shock. Control rats initially acquired fear to all cues, but rapidly reduced fear to the non-predictive and uncertain cues. Early adversity rats were slower to reduce fear to the non-predictive cue and never fully reduced fear to the uncertain cue. In extinction, all cues were presented in the absence of shock. Fear to the uncertain cue in discrimination, but not early adversity itself, predicted the reduction of fear in extinction. These results demonstrate early adversity impairs the use of negative, aversive prediction errors to reduce fear, especially in situations of uncertainty