No abstract

Anxiety-like behavior of rodents is frequently accompanied by reduced exploration. Here, we identify dissociable components of anxiety, fear, and exploratory drive of sated and foraging mice. With the help of behavioral assays, including the open field task, elevated plus maze, dark–light transition task, and beetle mania task, we demonstrate a general increase in exploration by food restriction. Food-restricted mice bred for high anxiety behavior (HAB) showed ameliorated anxiety- but not fear-related behavior. By means of principal component analysis, we identified three independent components, which resemble the behavioral dimensions proposed by Gray’s Reinforcement Sensitivity Theory (approach behavior, avoidance behavior, and decision making). Taken together, we demonstrate anxiolytic consequences of food restriction in a mouse model of anxiety disorders that can be dissociated from a general increase in foraging behavior.

The diameter of the human pupil tracks working memory processing and is associated with activity in the frontoparietal network. At the same time, recent neuroimaging research has linked human pupil fluctuations to activity in the salience network. In this combined functional magnetic resonance imaging (fMRI)/pupillometry study, we recorded the pupil size of healthy human participants while they performed a blockwise organized working memory task (N‐back) inside an MRI scanner in order to monitor the pupil fluctuations associated neural activity during working memory processing. We first confirmed that mean pupil size closely followed working memory load. Combining this with fMRI data, we focused on blood oxygen level dependent (BOLD) correlates of mean pupil size modeled onto the task blocks as a parametric modulation. Interrogating this modulated task regressor, we were able to retrieve the frontoparietal network. Next, to fully exploit the within‐block dynamics, we divided the blocks into 1 s time bins and filled these with corresponding pupil change values (first‐order derivative of pupil size). We found that pupil change within N‐back blocks was positively correlated with BOLD amplitudes in the areas of the salience network (namely bilateral insula, and anterior cingulate cortex). Taken together, fMRI with simultaneous measurement of pupil parameters constitutes a valuable tool to dissect working memory subprocesses related to both working memory load and salience of the presented stimuli.

Avoidance behavior is a key symptom of most anxiety disorders and a central readout in animal research. However, the quantification of real-life avoidance behavior in humans is typically restricted to clinical populations, who show actual avoidance of phobic objects. In experimental approaches for healthy participants, many avoidance tasks utilize button responses or a joystick navigation on the screen as indicators of avoidance behavior. To allow the ecologically valid assessment of avoidance behavior in healthy participants, we developed a new automated immersive Virtual Reality paradigm, where participants could freely navigate in virtual 3-dimensional, 360-degrees scenes by real naturalistic body movements. A differential fear conditioning procedure was followed by three newly developed behavioral tasks to assess participants' avoidance behavior of the conditioned stimuli: an approach, a forced-choice, and a search task. They varied in instructions, degrees of freedom, and high or low task-related relevance of the stimuli. We initially examined the tasks in a quasi-experiment (N = 55), with four consecutive runs and various experimental adaptations. Here, although we observed avoidance behavior in all three tasks after additional reinforcement, we only detected fear-conditioned avoidance behavior in the behavioral forced-choice and search tasks. These findings were largely replicated in a confirmatory experiment (N = 72) with randomized group allocation, except that fear-conditioned avoidance behavior was only manifest in the behavioral search task. This supports the notion that the behavioral search task is sensitive to detect avoidance behavior after fear conditioning only, whereas the behavioral approach and forced-choice tasks are still able to detect "strong" avoidance behavior after fear conditioning and additional reinforcement.

Obsessive-compulsive disorder (OCD) is characterized by recurrent, persistent thoughts and repetitive behaviors causing stress and anxiety. In the associative learning model of OCD, mechanisms of fear extinction are supposed to partly underlie symptom development, maintenance and treatment of OCD, proposing that OCD patients suffer from rigid memory associations and inhibitory learning deficits. To test these assumptions, previous studies have used skin conductance and subjective ratings as readouts in fear conditioning paradigms, finding impaired fear extinction learning, impaired fear extinction recall or no differences between individuals with OCD and healthy controls. Against this heterogeneous background, we tested fear acquisition and extinction in 37 OCD patients and 56 healthy controls, employing skin conductance as well as pupillometry and startle electromyography. Extinction recall was also included in a subsample. We did not observe differences between groups in any of the task phases, except a trend toward higher startle amplitudes during extinction for OCD. Overall, sensitive readouts such as pupillometry and startle responses did not provide evidence for moderate-to-large inhibitory learning deficits using classical fear conditioning, challenging the assumption of generically impaired extinction learning and memory in OCD.