Understanding Reward Dysfunction in Bipolar Affective Disorder through Behavioural, Cognitive and Neurobiological Changes

Bipolar disorder, like many neuropsychiatric conditions, can be studied from a number of perspectives; from observation of behaviour, to study of cognitive dysfunction, through to changes at the molecular and genetic level. A consequence of this way of working is that there is inadequate communication between different levels of analysis, such that insufficient thought is given to whether a theoretical model derived from behavioural work fits with neurobiological data, and vice versa. Such limitations represent a key limiting factor in successful translation. Therefore, this paper takes a dominant theoretical model of bipolar disorder, based on that by Gray (1994) and developed by Alloy et al., (2015) as a basis to propose that the foundational pathology in bipolar is reward hypersensitivity, and to review how recent diverse neurobiological, cognitive and behavioural findings fit with this understanding. Executive Function deficits, partially derived from heritable structural changes are suggested as a foundation through which reward hypersensitivity develops to disorder, and CANA1C polymorphism-induced hyperactivity, further serves to drive the system towards reward seeking goals, through interaction with dopaminergic systems. This action is supplemented by a genetic predisposition for cognitive regulatory dysfunction, leading to improper modulation of emotive and reward networks. Specifically, deficits in top-down limbic modulation leads to behaviours disproportionally driven by limbic and reward circuitry; this pathology strengths over time through use. This therefore eventually results in substantial regional disconnect, reflected in epigenetic changes to neurotransmitters and observable histological changes.

Competing cognitive pressures on human exploration in the absence of trade-off with exploitation

Exploring novel environments through sequential sampling is essential for efficient decision-making under uncertainty. In the laboratory, human exploration has been studied in situations where exploration is traded against reward maximisation. By design, these ‘explore-exploit’ dilemmas confound the behavioural characteristics of exploration with those of the trade-off itself. Here we designed a sequential sampling task where exploration can be studied and compared in the presence and absence of trade-off with exploitation. Detailed model-based analyses of choice behaviour revealed specific exploration patterns arising in situations where information seeking is not traded against reward seeking. Human choices are directed toward the most uncertain option available, but only after an initial sampling phase consisting of choice streaks from each novel option. These findings outline competing cognitive pressures on information seeking: the repeated sampling of the current option (for hypothesis testing), and the directed sampling of the most uncertain option available (for structure mapping).

Quantifying defensive behavior and threat response through integrated headstage accelerometry

Background Defensive and threat-related behaviors are common targets of investigation, because they model aspects of human mental illness. These behaviors are typically quantified by video recording and post hoc analysis. Those quantifications can be laborious and/or computationally intensive. Depending on the analysis method, the resulting measurements can be noisy or inaccurate. Other defensive behaviors, such as suppression of operant reward seeking, require extensive animal pre-training. New Method We demonstrate a method for quantifying defensive behavior (immobility or freezing) by 3-axis accelerometry integrated with an electrophysiology headstage. We tested multiple pre-processing and smoothing methods, and correlated them against two common methods for quantification: freezing as derived from standard video analysis, and suppression of operantly shaped bar pressing. We assessed these three methods' ability to track defensive behavior during a standard threat conditioning and extinction paradigm. Results The best approach to tracking defensive behavior from accelerometry was Gaussian filter smoothing of the first derivative (change score or jerk). Behavior scores from this method reproduced canonical conditioning and extinction curves at the group level. At the individual level, timepoint-to-timepoint correlations between accelerometry, video, and bar press metrics were statistically significant but modest (largest r=0.53, between accelerometry and bar press). Comparison with existing methods The integration with standard electrophysiology systems and relatively lightweight signal processing may make accelerometry particularly well suited to detect behavior in resource-constrained or real-time applications. At the same time, there were modest cross-correlations between all three methods for quantifying defensive behavior. Conclusions Accelerometry analysis allows researchers already using electrophysiology to assess defensive behaviors without the need for additional behavioral measures or video. The similarities in behavioral tracking and modest correlations between each metric suggest that each measures a distinct aspect of defensive behavior. Accelerometry is a viable alternative to current defensive measurements, and its non-overlap with other metrics may allow a more sophisticated dissection of threat responses in future experiments.

Repetitive Blast Exposure Increases Appetitive Motivation and Behavioral Inflexibility in Male Mice

Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.

Dorsal Bed Nucleus of the Stria Terminalis-Subcortical Output Circuits Encode Positive Bias in Pavlovian Fear and Reward

Opposite emotions like fear and reward states often utilize the same brain regions. The bed nucleus of the stria terminalis (BNST) comprises one hub for processing fear and reward processes. However, it remains unknown how dorsal BNST (dBNST) circuits process these antagonistic behaviors. Here, we exploited a combined Pavlovian fear and reward conditioning task that exposed mice to conditioned tone stimuli (CS)s, either paired with sucrose delivery or footshock unconditioned stimuli (US). Pharmacological inactivation identified the dorsal BNST as a crucial element for both fear and reward behavior. Deep brain calcium imaging revealed opposite roles of two distinct dBNST neuronal output pathways to the periaqueductal gray (PAG) or paraventricular hypothalamus (PVH). dBNST neural activity profiles differentially process valence and Pavlovian behavior components: dBNST-PAG neurons encode fear CS, whereas dBNST-PVH neurons encode reward responding. Optogenetic activation of BNST-PVH neurons increased reward seeking, whereas dBNST-PAG neurons attenuated freezing. Thus, dBNST-PVH or dBNST-PAG circuitry encodes oppositely valenced fear and reward states, while simultaneously triggering an overall positive affective response bias (increased reward seeking while reducing fear responses). We speculate that this mechanism amplifies reward responding and suppresses fear responses linked to BNST dysfunction in stress and addictive behaviors.

Antagonism of D1, but not D2, dopamine receptors inhibits cued sucrose seeking by decreasing arousal

Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis, a novel synthesis that accounts both for our findings and many previous results that have drawn disparate and conflicting conclusions.

Reward-Seeking Behaviors and Behavioral Activation Therapy in Depressed Individuals

The article's abstract is not available.