The infralimbic cortex and mGlu5 mediate the effects of chronic intermittent ethanol exposure on fear learning and memory

Abstract

Rationale and Objectives-Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) often occur comorbidly. While the incidence of these disorders is increasing, there is little investigation into the interacting neural mechanisms between these disorders. These studies aim to identify cognitive deficits that occur as a consequence of fear and ethanol exposure, implement a novel pharmaceutical intervention, and determine relevant underlying neurocircuitry. Additionally, due to clinical sex differences in PTSD prevalence and alcohol abuse, these studies examine the nature of this relationship in rodent models.Methods-Animals were exposed to a model of PTSD+AUD using auditory fear conditioning followed by chronic intermittent ethanol exposure (CIE). Then, rats received extinction training consisting of multiple conditioned stimulus presentations in absence of the shock. Extinction recall and context induced freezing were measured in subsequent tests. CDPPB, a metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator, was used to treat these deficits, and region-specific effects were determined using microinjections.Results-These studies determined that CIE exposure led to deficits in fear extinction learning and heightened context induced freezing while sex-differences emerged in fear conditioning and extinction cue recall tests. Further, using CDPPB, these studies found that enhancement of infralimbic (IfL) mGlu5 activity was able to recover CIE induced deficits in both males and females.Conclusions-These studies show that CIE induces deficits in fear-related behaviors and that enhancement of IfL glutamatergic activity can facilitate learning during extinction. Additionally, we identify novel pharmacological targets for the treatment of individuals who suffer from PTSD and AUD.

Adolescent Alcohol Exposure Results in Sex-specific Alterations in Conditioned Fear Learning and Memory in Adulthood

“…We observed that male Air control rats displayed both within-session and between-session reductions in the percentage of time spent freezing in response to CS presentation. This observation is consistent with previous studies that also utilized a protracted extinction protocol ( Elias et al, 2010 ; Smiley et al, 2020 ; Smiley et al, 2021a ). While some within session differences in freezing between the Air control and AIE exposed rats were noted, there was no significant difference in extinction of conditioned freezing when examined across days of extinction training.…”

“…Rats were tested using a fear conditioning, extinction and recovery paradigm that is based on previously published studies ( Smiley et al, 2020 ; Smiley et al, 2021b ). As is depicted in Figure 1B , an “ABBAB” contextual design was used to assess conditioned fear acquisition, cued fear extinction, extinction recall (retention), context-dependent fear renewal, and spontaneous recovery ( Cain et al, 2012 ; Vanelzakker et al, 2013 ).…”

“…Interestingly, it has become clear in recent years that many of the fundamental principles of learning and memory also play a major role in the development and maintenance of deficits associated with addictions and trauma and anxiety-related disorders ( Tipps et al, 2014 ). Previous findings from our lab have shown that pharmacological manipulation of the metabotropic glutamate receptor 5 (mGlu5) can attenuate behavioral deficits associated with chronic alcohol and stress ( Gass et al, 2014a ; Smiley et al, 2020 ; Smiley et al, 2021a ). However, the impact of adolescent alcohol exposure on fear learning in adulthood has not been widely investigated, and even less is known regarding sex-specific differences as most previous studies have been conducted in males.…”

Mechanisms of alcohol influence on fear conditioning: a computational model

“…Stephens shows reduction in fear acquisition for binge drinkers but sees generalization of fear in them. However, fear extinction has been shown to consistently become weaker after chronic alcohol exposure (26,27,30). In this paper, we aim to reproduce the impaired fear extinction by incorporating known alterations produced by alcohol in the amygdala circuitry in a computational model.…”

Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study

“…Indeed, microdialysis analysis showed that alcohol modulates the release of glutamate by parvalbumin-expressing interneurons in the rat medial prefrontal cortex (mPFC) [6]. Other rat studies showed that the glutamatergic signaling in the infralimbic subregion of the PFC facilitated extinction of alcohol-seeking behaviors [7], while activity-dependent ablation of neurons in parts of the PFC induced excessive alcohol seeking in rats [8]. In addition, pharmacological blockade of glutamate receptors in the basolateral amygdala and nucleus accumbens reduced cue-induced reinstatement of alcohol in rats [9].…”