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Review
. 2018 Jun 2:9:271-285.
doi: 10.1016/j.ynstr.2018.05.004. eCollection 2018 Nov.

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

Jayme R McReynolds  1 , John P Christianson  2 , Jordan M Blacktop  1 , John R Mantsch  1
Affiliations
Review

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

Jayme R McReynolds et al. Neurobiol Stress. .

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.

Keywords: Addiction; Fos; Reinstatement; Relapse; Stress; cfos.

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Figures

Fig. 1
Fig. 1
Basic neurocircuitry of stressor-induced reinstatement. Stressor-induced reinstatement requires corticotropin-releasing factor (CRF), via activation of CRFR1, and noradrenergic signaling, via activation of β2-adrenergic receptors, in the bed nucleus of the stria terminalis (BNST). CRF in the BNST may arise from the local release of CRF or CRF-containing afferent projections from the central nucleus of the amygdala (CeA). The BNST then sends CRF-containing efferent projections to the ventral tegmental area (VTA) where activation of CRFR1 is critical for stressor-induced reinstatement. The VTA is further regulated by afferent GABAergic projections from the nucleus accumbens (NAc) shell and sends important dopaminergic projections to the medial prefrontal cortex (mPFC). The mPFC then sends a glutamatergic projection to the nucleus accumbens core that is necessary for stressor-, drug-, and drug-associated cue-induced reinstatement.
Fig. 2
Fig. 2
Utility of Fos imaging approaches. There are multiple approaches to using Fos as an activity marker and each approach provides different levels of information as detailed below. A) Fos protein expression is predominantly localized to the nucleus (red circles). Fos is expressed in multiple cell types, including GABAergic and glutamatergic neurons, and examination of Fos expression alone will identify multiple cell types and multiple projection targets. B) One method to identify unique patterns of neuronal activation is to co-localize the Fos signal (red) with a cell type-specific marker (green), such as a marker for glutamatergic neurons. Therefore, it is possible to identify neuronal activation of a particular cell type via comparison of the number of neurons that express both Fos and the cell-type specific marker. However, this method still does not provide information about selective activation of efferent projections. C) To identify activation of specific pathways, a retrograde tracer can be used. The retrograde tracer is micro-infused into a specific projection target, is taken up by the axon terminals and is transported back to the cell body. It is possible to then to quantify the co-localization of the retrograde tracer signal (blue) and Fos expression (red) to analyze the pattern of pathway activation. It should be noted that in regions where projection neurons are comprised of multiple cell-types, this method only identifies activation of the specific pathway independent of cell type. To obtain information about cell type- and pathway-specific neuronal activation, it would be necessary to use both a retrograde tracer and a cell type-specific marker in combination with Fos expression. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Stressor-induced reinstatement of cocaine seeking is positively correlated with activation of ventral tegmental area (VTA) dopamine neurons. A) Electric footshock induces significant reinstatement of cocaine seeking, as defined by an increase in the number of lever responses during the reinstatement test as compared to extinction responding, in rats with a variable history of self-administration (2/hr or 6/hr access/day; t (19) = −3.67, p < .05). Data are presented as mean ± SEM. B) Representative image depicting the area within which immunoreactive cells were counted (at −6.0 mm from Bregma). C) The number of cells that were positive for both tyrosine hydroxylase (TH) and Fos expression in the VTA is positively correlated with the magnitude of stress-induced reinstatement (p < .05). D) Representative image of a TH-positive neuron in the VTA. E) Representative image of a Fos-positive neuron in the VTA. F) Representative image of a TH/Fos-positive neuron in the VTA.
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