Liza J Wills, Bailey Adams, Britta Schwartz, Eric Beaumont, Justin T Gass
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引用次数: 0
Abstract
Rationale: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur, leading to significant impairments in learning and memory. Despite the prevalence of these disorders, existing treatment strategies remain inadequate, necessitating novel approaches targeting underlying neural circuits.
Objectives: This study investigated whether optogenetic stimulation of medial prefrontal cortex subregions could rescue fear extinction deficits in a preclinical model of comorbid PTSD/AUD. We examined the differential roles of the infralimbic (IL) and prelimbic (PL) cortices in modulating extinction learning following combined stress and chronic alcohol exposure.
Methods: Male and female Wistar rats underwent restraint stress (RS) and chronic intermittent ethanol exposure (CIE), followed by fear conditioning and extinction training. Animals received optogenetic stimulation (ChR2 or eYFP control) targeting either IL or PL cortex immediately prior to each extinction session. Extinction learning rates, days to criterion, and long-term memory retention (21-day spontaneous recovery) were assessed.
Results: Combined stress and alcohol exposure significantly impaired extinction learning compared to controls. IL-ChR2 stimulation recovered these extinction deficits in the RS + CIE group, accelerating extinction rates and reducing spontaneous recovery. Conversely, PL-ChR2 stimulation impaired extinction learning in control animals but produced no additional deficits in the already-impaired RS + CIE group, suggesting a ceiling effect.
Conclusions: This study identifies the IL cortex as a critical regulator of fear extinction learning following stress and alcohol exposure, demonstrating that targeted circuit activation can overcome extinction deficits characteristic of comorbid PTSD and AUD. These region-specific effects provide important insights into the prefrontal mechanisms governing fear memory processes in pathological states.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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