Adolescence alcohol exposure impairs fear extinction and alters medial prefrontal cortex plasticity.

After experiencing a traumatic event people often turn to alcohol to cope with symptoms. In those with post-traumatic stress disorder (PTSD) and a co-occurring alcohol use disorder (AUD), PTSD symptoms can worsen, suggesting that alcohol changes how traumatic memory is expressed. The objective of this series of experiments is to identify how alcohol drinking (EtOH), following cued fear conditioning and extinction, impacts fear expression in mice. Molecular (activity-regulated cytoskeleton-associated protein, Arc/arg3.1) and structural (dendrite and spine morphometry) markers of neuronal plasticity were measured following remote extinction retrieval. Mouse age (adolescent and adult) and sex were included as interacting variables in a full factorial design. Females drank more EtOH than males and adolescents drank more EtOH than adults. Adolescent females escalated EtOH intake across drinking days. Adolescent drinkers exhibited more conditioned freezing during extinction retrieval, an effect that persisted for at least 20 days. Heightened cued freezing in the adolescent group was associated with greater Arc/arg3.1 expression in layer (L) 2/3 prelimbic (PL) cortex, greater spine density, and reduced basal dendrite complexity. In adults, drinking was associated with reduced L2/3 infralimbic (IL) Arc expression but no behavioral differences. Few sex interactions were uncovered throughout. Overall, these data identify prolonged age-related differences in alcohol-induced fear extinction impairment and medial prefrontal cortex neuroadaptations.

Cingulate circuits are associated with escalation of heroin use and naloxone-induced increases in heroin self-administration.

Opioid use disorder (OUD) is defined as a compulsion to seek and take opioids, loss of control over intake and the development of a negative emotional state when access to opioids is denied. Using functional magnetic resonance imaging (fMRI) data in a rat model of OUD, we demonstrate that the escalation of heroin self-administration (SA) and the increased heroin SA following an injection of an opioid receptor antagonist (naloxone) are associated with changes in distinct brain circuits, centered on the cingulate cortex (Cg). Here, SA escalation score was negatively associated with changes in resting state functional connectivity (rsFC) between the Cg and the dorsal striatum. Conversely, increased heroin SA following naloxone injection, was associated with increased connectivity between the Cg and the extended amygdala and hypothalamus. Naloxone-induced increased SA was also positively associated with changes in the amplitude of low frequency fluctuations within the Cg, a measure of spontaneous neuronal activity. Characterizing the distinct brain circuit and behavior changes associated with different facets of addiction increases our understanding of OUD and may provide insight into addiction prevention and treatment.

Nicotine addiction: Translational insights from circuit neuroscience.

Contemporary neuroscience aims to understand how neuronal activity produces internal processes and observable behavioral states. This aim crucially depends on systems-level, circuit-based analyses of the working brain, as behavioral states arise from information flow and connectivity within and between discrete and overlapping brain regions, forming circuits and networks. Functional magnetic resonance imaging (fMRI), offers a key to advance circuit neuroscience; fMRI measures inter and intra- regional circuits at behaviorally relevant spatial-temporal resolution. Herein, we argue that cross-sectional observations in human populations can be best understood via mechanistic and causal insights derived from brain circuitry obtained from preclinical fMRI models. Using nicotine addiction as an exemplar of a circuit-based substance use disorder, we review fMRI-based observations of a circuit that was first shown to be disrupted among human smokers and was recently replicated in rodent models of nicotine dependence. Next, we discuss circuits that predispose to nicotine dependence severity and their interaction with circuits that change as a result of chronic nicotine administration using a rodent model of dependence. Data from both clinical and preclinical fMRI experiments argue for the utility of fMRI studies in translation and reverse translation of a circuit-based understanding of brain disease states. We conclude by discussing the future of circuit neuroscience and functional neuroimaging as an essential bridge between animal models and human populations to the understanding of brain function in health and disease.

Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6 N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.