Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress
Introduction
Approximately one in five Americans will experience a depressive disorder within their lifetime (Kessler et al., 2005), and only about 50% of those will fully respond to available treatments (Culpepper, 2010). In recent decades, it has become increasingly clear that the variability in depressive disorders and in the response to existing treatments stems, at least in part, from individual differences in both genetics (Flint and Kendler, 2014) and gene expression (Vialou et al., 2013). Our group and many others suggest that chronic stress or exposure to antidepressants causes induction and altered function of transcription factors which, in turn, modulate gene expression to alter mood and behavior (Vialou et al., 2013). We therefore propose that determining: 1) the specific brain regions, 2) the specific transcription factors, and 3) the specific target genes involved in these processes could potentially lead to the development of novel therapeutic approaches for the treatment and prevention of depressive disorders. Previous studies indicate that the transcription factor ΔFosB is induced by both chronic stress and chronic antidepressant treatment, and that it plays an essential role in mouse models of depression and antidepressant action (Perrotti et al., 2004, Vialou et al., 2010, Ohnishi et al., 2011, Lobo et al., 2013, Robison et al., 2014, Vialou et al., 2014).
The brain's reward circuitry centers on dopaminergic neurons in the ventral tegmental area (VTA) and their mesolimbic projections to nucleus accumbens (NAc), dorsal striatum, amygdala, and hippocampus, as well as their mesocortical projections, in particular to the prefrontal cortex (PFC). Previous studies of the role of ΔFosB in stress responses and antidepressant action have focused on discrete brain regions within the reward circuitry, namely the NAc (Vialou et al., 2010, Robison et al., 2014) and the PFC (Vialou et al., 2014). However, other forms of stimulation, such as chronic exposure to various drugs of abuse, are known to induce ΔFosB in many additional brain regions, both within and outside the reward circuitry (Perrotti et al., 2008). Moreover, the FosB message undergoes complex splicing resulting in multiple proteins, the most prominent of which have apparent molecular weights of 50 kDa (full-length FosB), 35–37 kDa (ΔFosB), and 25 kDa (Δ2ΔFosB) that may have distinct transcriptional target genes and may play distinct roles in behavioral responses (Ohnishi et al., 2011). For instance, ΔFosB appears to drive spontaneous locomotor activity and accumulation of E-cadherin and phospho-Akt, while full-length FosB is essential for stress tolerance (Ohnishi et al., 2011). Though the expression of the distinct gene products in response to stress and various drugs has been examined extensively in NAc and to some degree in PFC (Perrotti et al., 2004), expression of the different FosB gene products outside the NAc in mouse models of depression and antidepressant action has not been reported in detail. Here, we demonstrate that chronic treatment with the antidepressant fluoxetine induces FosB gene products in more than 25 distinct regions of the mouse brain, and that the presence of specific FosB splice products varies in select regions of the reward circuitry under both stress and antidepressant conditions. We chose to focus on NAc and PFC because our previous studies demonstrate the behavioral importance of FosB in these regions (Vialou et al., 2010, Vialou et al., 2014), and we chose hippocampus because is both modulates the function of the mesolimbic and mesocortical dopamine system and has been directly implicated in many studies of depression, both in humans and in pre-clinical models (Duman and Aghajanian, 2012, Eisch and Petrik, 2012).
Section snippets
Animals
C57BL/6J male mice (The Jackson Laboratory), 7–8 weeks old and weighing 25–30 g, were habituated to the animal facility one week before use and maintained at 22–25 °C on a 12 h light/dark cycle. All animals had access to food and water ad libitum. All experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committees at Icahn School of Medicine at Mount Sinai and Michigan State University. All efforts were made to minimize animal suffering, to
Fluoxetine induction of FosB-like immunoreactivity throughout the brain
Previous studies indicate that FosB gene products are induced in the mouse NAc by chronic exposure to fluoxetine, and that induction of NAc ΔFosB is essential for fluoxetine's behavioral effects in the mouse chronic social defeat stress (CSDS) model of depression (Vialou et al., 2010). In order to determine whether fluoxetine also induces FosB gene products in other brain regions, we used immunohistochemistry to assess levels of FosB gene products after chronic exposure to fluoxetine. As
Discussion
Here, we show that FosB gene products are induced throughout the brain by chronic exposure to fluoxetine, and that the specific gene products expressed vary by brain region and between chronic stress and antidepressant treatment. Because antidepressants are administered systemically, they potentially affect signaling throughout the brain. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could thus directly affect any brain region in which serotonin signaling occurs. The serotonin
Conflict of interest
The authors declare no competing financial interests.
Acknowledgments
The research was supported by the Whitehall Foundation (AJR; 2013-08-43), and the National Institute of Mental Health (NIMH) (E.J.N.), the Multidisciplinary Training in Environmental Toxicology grant (ALE; T32-ES007255), and a 2014 NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (ALE; 22774). The authors would like to thank Kenneth Moon for outstanding technical support.
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