What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders

Abstract

Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fos-based approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stress-related drug use.

Variability in nicotine conditioned place preference and stress‐induced reinstatement in mice: Effects of sex, initial chamber preference, and guanfacine

“…These experiments did not test the effects of nicotine, stress, or abstinence per se on the expression of immediate early genes, which have been examined in previous studies. [90][91][92][93][94][95][96] In the BLA we did not find a significant effect of nicotine on Arc immunoreactivity ( Figure 6A,B), although chemogenetic inactivation of BLA CaMKIIα neurons has been shown to induce reinstatement of nicotine CPP in mice. 37 There was a near-significant decrease in BLA Arc immunoreactivity after guanfacine, which is consistent with previous research using in vivo electrophysiology and clonidine in the BLA.…”

“…The Arc experiments are conducted in independent cohorts of mice from the behavioral studies, and thus rather than correlating with behavior, these findings represent an initial survey of brain regions with potential sex‐specific responses to guanfacine in the context of nicotine CPP and stress following nicotine abstinence. These experiments did not test the effects of nicotine, stress, or abstinence per se on the expression of immediate early genes, which have been examined in previous studies …”

Pattern of neural activation following yohimbine‐induced reinstatement of alcohol seeking in rats

“…Considerably higher doses of yohimbine (2.5–5 mg/kg) induce Fos in the Cg1, Cg2, LPO, LH, DMH, DR and LC (Funk, Li & Le, ; Singewald & Sharp, ; Singewald et al., ; Tsujino et al., ), but not at 1 mg/kg. However, rat strain, prior ethanol experience and mode or timing of Fos/ c‐fos detection may contribute to discrepancies between studies (McReynolds, Christianson, Blacktop & Mantsch, ).…”

Raising overlapping litters: Differential activation of rat maternal neural circuitry after interacting with newborn or juvenile pups

“…Also, even though c-Fos is a good indicator of neural activation, 42,43 not all activated neurones express Fos proteins, 44,45 and therefore other neural activation markers or approaches may be necessary to reveal the state of activation of this region.…”

“…It would be interesting to explore the influence of previous maternal experience on the activity of the different subregions of mPFC after mother‐litter interaction. Also, even though c‐Fos is a good indicator of neural activation, not all activated neurones express Fos proteins, and therefore other neural activation markers or approaches may be necessary to reveal the state of activation of this region.…”