Safety learning in anxiety, Pavlovian conditioned inhibition and Covid concerns

Experimental studies of fear conditioning have identified the effectiveness of safety signals in inhibiting fear and maintaining fear-motivated behaviours. In fear conditioning procedures, the presence of safety signals means that the otherwise expected feared outcome will not now occur. Differences in the inhibitory learning processes needed to learn safety are being identified in various psychological and psychiatric conditions. However, despite early theoretical interest, the role of conditioned inhibitors as safety signals in anxiety has been under-investigated to date, in part because of the stringent test procedures required to confirm the demonstration of conditioned inhibition as such. Nonetheless, the theoretical implications of an inhibitory learning perspective continue to influence clinical practice. Moreover, our understanding of safety signals is of additional importance in the context of the increased health anxiety and safety behaviours generated by the Covid-19 pandemic.

Fear Conditioning Deficits in Children and Adolescents with Psychopathic Traits: a Study in a Clinical Population

Deficits in fear conditioning related to psychopathy have been widely studied in adults. However, evidence in children and adolescents is scarce and inconsistent. This research aimed to expand knowledge about fear conditioning in psychopathy and its dimensions in child and early adolescent clinical populations. Participants were 45 boys (outpatients) aged 6–14 years (M = 10.59, SD = 2.04). They were assessed with the parents’ and teachers’ versions of the Child Problematic Traits Inventory (CPTI). A fear conditioning paradigm (Neumann et al., in Biological Psychology, 79(3), 337–342, 2008) for children and adolescents was used. Conditioned stimuli (CS+ and CS-) were geometric shapes and the unconditioned stimulus (US) was an unpleasant sound of metal scraping on slate (83 dB). Difference scores (CS+ minus CS-) in skin conductance responses (SCR) and self-reported cognitive and affective measures were considered as indices of fear conditioning. Results showed that: a) deficits in fear conditioning were related to some psychopathy dimensions but not to psychopathy as a unitary construct; b) the Impulsivity-Need for Stimulation dimension was a predictor of impaired fear conditioning at a cognitive level; c) the interaction of Callous-Unemotional and Impulsivity-Need for Stimulation dimensions was a significant predictor of impaired electrodermal fear conditioning; d) by contrast, the Grandiose-Deceitful dimension, was marginally associated with a greater electrodermal fear conditioning. In conclusion, psychopathy dimensions and their interactions, but not psychopathy as a whole, predicted deficits in fear conditioning as measured by SCR and cognitive indices. These findings confirm the notion that psychopathic traits are associated with deficits in fear conditioning in child and adolescent clinical populations and provide support for a multidimensional approach to youth psychopathy.

Morris Water Maze and Contextual Fear Conditioning Tasks to Evaluate Cognitive Functions Associated With Adult Hippocampal Neurogenesis

New neurons are continuously generated and functionally integrated into the dentate gyrus (DG) network during the adult lifespan of most mammals. The hippocampus is a crucial structure for spatial learning and memory, and the addition of new neurons into the DG circuitry of rodents seems to be a key element for these processes to occur. The Morris water maze (MWM) and contextual fear conditioning (CFC) are among the most commonly used hippocampus-dependent behavioral tasks to study episodic-like learning and memory in rodents. While the functional contribution of adult hippocampal neurogenesis (AHN) through these paradigms has been widely addressed, results have generated controversial findings. In this review, we analyze and discuss possible factors in the experimental methods that could explain the inconsistent results among AHN studies; moreover, we provide specific suggestions for the design of more sensitive protocols to assess AHN-mediated learning and memory functions.

Fear in the theater of the mind: Mental imagery of conditioned stimuli undergo the acquisition and generalization of differential fear conditioning

Many symptoms of anxiety and post-traumatic stress disorder are elicited by mental imagery of a conditioned stimulus (CS). Yet, little is known about how visual imagery of CSs interacts with the acquisition of differential fear conditioning. Across three experiments (n1=33, n2=27, n3=26), we observed that healthy human participants acquired differential fear conditioning to both viewed and imagined percepts serving as the conditioned stimuli as measured via self-reported fear and the skin conductance response (SCR). Additionally, this differential conditioning generalized across CS percept modalities, such that differential conditioning acquired to visual percepts generalized to the corresponding imagined percepts and vice versa. This is novel evidence that perceived and imagined stimuli engage learning processes in very similar ways and is consistent with theory that mental imagery is depictive and recruits neural resources shared with visual perception. Our findings also provide new insight into the mechanisms of anxiety and related disorders.

Effect of Sensory Deprivation of Nasal Respiratory on Behavior of C57BL/6J Mice

Nasal breathing is a dynamic cortical organizer involved in various behaviors and states, such as locomotion, exploration, memory, emotion, introspection. However, the effect of sensory deprivation of nasal respiratory breath (NRD) on behavior remain poorly understood. Herein, general locomotor activity, emotion, learning and memory, social interaction, and mechanical pain were evaluated using a zinc sulfate nasal irrigation induced nasal respiratory sensory deprivation animal model (ZnSO4-induced mouse model). In the open field test, the elevated O-maze test, and forced swim test, NRD mice exhibited depressive and anxiety-like behaviors. In memory-associated tests, NRD mice showed cognitive impairments in the hippocampal-dependent memory (Y maze, object recognition task, and contextual fear conditioning (CFC)) and amygdala-dependent memory (the tone-cued fear conditioning test (TFC)). Surprisingly, NRD mice did not display deficits in the acquisition of conditional fear in both CFC and TFC tests. Still, they showed significant memory retrieval impairment in TFC and enhanced memory retrieval in CFC. At the same time, in the social novelty test using a three-chamber setting, NRD mice showed impaired social and social novelty behavior. Lastly, in the von Frey filaments test, we found that the pain sensitivity of NRD mice was reduced. In conclusion, this NRD mouse model showed a variety of behavioral phenotypic changes, which could offer an important insight into the behavioral impacts of patients with anosmia or those with an impaired olfactory bulb (OB) (e.g., in COVID-19, Alzheimer’s disease, Parkinson’s disease, etc.).

The Opioid Receptor Antagonist Naloxone Enhances First-Order Fear Conditioning, Second-Order Fear Conditioning and Sensory Preconditioning in Rats

The opioid receptor antagonist naloxone enhances Pavlovian fear conditioning when rats are exposed to pairings of an initially neutral stimulus, such as a tone, and a painful foot shock unconditioned stimulus (US; so-called first-order fear conditioning; Pavlov, 1927). The present series of experiments examined whether naloxone has the same effect when conditioning occurs in the absence of US exposure. In Experiments 1a and 1b, rats were exposed to tone-shock pairings in stage 1 (one trial per day for 4 days) and then to pairings of an initially neutral light with the already conditioned tone in stage 2 (one trial per day for 4 days). Experiment 1a confirmed that this training results in second-order fear of the light; and Experiment 1b showed that naloxone enhances this conditioning: rats injected with naloxone in stage 2 froze more than vehicle-injected controls when tested with the light alone (drug-free). In Experiments 2a and 2b, rats were exposed to light-tone pairings in stage 1 (one trial per day for 4 days) and then to tone-shock pairings in stage 2 (one trial per day for 2 days). Experiment 2a confirmed that this training results in sensory preconditioned fear of the light; and Experiment 2b showed that naloxone enhances sensory preconditioning when injected prior to each of the light-tone pairings: rats injected with naloxone in stage 1 froze more than vehicle-injected controls when tested with the light alone (drug-free). These results were taken to mean that naloxone enhances fear conditioning independently of its effect on US processing; and more generally, that opioids regulate the error-correction mechanisms that underlie associative formation.

Conditional Freezing, Flight and Darting?

Fear conditioning is one of the most frequently used laboratory procedures for modeling learning and memory generally, and anxiety disorders in particular. The conditional response (CR) used in the majority of fear conditioning studies in rodents is freezing. Recently, it has been reported that under certain conditions, running, jumping or darting replaces freezing as the dominant CR. These findings raise both a critical methodological problem and an important theoretical issue. If only freezing is measured but rodents express their learning with a different response, then significant instances of learning, memory, or fear may be missed. In terms of theory, whatever conditions lead to these different behaviors may be a key to how animals transition between different defensive responses and different emotional states. We replicated these past results but along with several novel control conditions. Contrary to the prior conclusions, running and darting were entirely a result of nonassociative processes and were actually suppressed by associative learning. Darting and flight were taken to be analogous to nonassociative startle or alpha responses that are potentiated by fear. On the other hand, freezing was the purest reflection of associative learning. We also uncovered a rule that describes when these movements replace freezing: When afraid, freeze until there is a sudden novel change in stimulation, then burst into vigorous flight attempts. This rule may also govern the change from fear to panic.

Dopamine and fear memory formation in the human amygdala

Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.