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Mental health disorders affect a substantial proportion of the worldwide population, and currently available treatments do not work for all affected individuals. Understanding the psychological and biological mechanisms that underlie mental health disorders will facilitate treatment development, and the use of translational animal models is potentially transformative for this. Structured around the US National Institute of Mental Health's 'Research Domain Criteria' (RDoC) approach, this special issue showcases reviews that consider how animal models can best be used to understand and treat the processes that go awry in mental health disorders.

The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though, that studies reporting no effect of propranolol on memory reconsolidation could be due to a failure to engage the memory destabilisation process, which is necessary for the memory to become susceptible to disruption with amnestic agents. Demonstrating that memory destabilisation has not been engaged is challenging when only using behavioural measures, but there are molecular correlates of memory destabilisation that can be used to determine whether memory lability has been induced. Here, we attempted to replicate the classic finding that systemic administration of propranolol disrupts the reconsolidation of a pavlovian auditory fear memory. Following a failure to replicate, we manipulated the parameters of the memory reactivation session to enhance prediction error in an attempt to overcome the boundary conditions of reconsolidation. On finding no disruption of memory despite these manipulations, we examined the expression of the post-synaptic density protein Shank in the basolateral amygdala. Degradation of Shank has been shown to correlate with the induction of memory lability, but we found no effect on Shank expression, consistent with the lack of observed behavioural effects.

Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. However, maladaptive expression of fear can lead to debilitating stressor-related and anxiety disorders such as post-traumatic stress disorder. Although the neural basis of fear has been extensively researched for several decades, recent technological advances in pharmacogenetics and optogenetics have allowed greater resolution in understanding the neural circuits that underlie fear. Alongside conceptual advances in the understanding of fear memory, this increased knowledge has clarified mechanisms for some currently available therapies for post-traumatic stress disorder and has identified new potential treatment targets.

Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This ‘retrieval-extinction’ procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the ‘retrieval-extinction’ effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.

Extinction—defined as the gradual disappearance of a learned response following the withdrawal of reinforcement—was first described by Pavlov (1927), and has been a subject of great psychological and neurobiological interest for a number of decades. Extinction is a fundamental learning process that has also formed the basis of prolonged exposure treatments for mental health disorders, including post-traumatic stress disorder and phobia, but potentially also for addictions. However, prolonged exposure therapy is not effective for all patients. Advances in understanding the psychopharmacology of extinction, at the whole-organism and circuit levels, are directing us to novel ways for optimising therapy-based around extinction. It is increasingly providing us with novel insights into the basic process itself. Preclinical research is also helping to address the underlying mechanisms and clinical feasibility of interventions such as exploiting memory updating mechanisms by extinguishing a memory within a critical window of reconsolidation.

Alcohol addiction is a problem of great societal concern, for which there is scope to improve current treatments. One potential new treatment for alcohol addiction is based on disrupting the reconsolidation of the maladaptive Pavlovian memories that can precipitate relapse to drug-seeking behavior. In alcohol self-administering rats, we investigated the effects of bidirectionally modulating adrenergic signaling on the strength of a Pavlovian cue-alcohol memory, using a behavioral procedure that isolates the specific contribution of one maladaptive Pavlovian memory to relapse, the acquisition of a new alcohol-seeking response for an alcohol-associated conditioned reinforcer. The β-adrenergic receptor antagonist propranolol, administered in conjunction with memory reactivation, persistently disrupted the memory that underlies the capacity of a previously alcohol-associated cue to act as a conditioned reinforcer. By contrast, enhancement of adrenergic signaling by administration of the adrenergic prodrug dipivefrin at reactivation increased the strength of the cue-alcohol memory and potentiated alcohol seeking. These data demonstrate the importance of adrenergic signaling in alcohol-associated memory reconsolidation, and suggest a pharmacological target for treatments aiming to prevent relapse through the disruption of maladaptive memories.