General Neuroscience

A Molecular Approach to Addiction: ΔFosB

Deniz Kirca


Introduction

Ravaging communities, tearing apart families, and ruining livelihoods, addiction is undoubtedly one of the most costly afflictions-- both socially and financially-- in the United States today. In 2013, the U.S. Substance Abuse and Mental Health Services Administration estimated that 24.6 million Americans aged 12 or older were illicit drug users at the time of the survey {1].  For reference, that is more than the populations of New York, Los Angeles, and Chicago combined.

As more information is amassed, the possible solution to this national epidemic becomes all the more elusive. While addiction is ultimately a complex social, political, and economic issue, the focus of this article is one aspect of the biological component of the problem: the impact of the molecule ΔFosB on the molecules that ultimately translate into the expression of an addictive phenotype.

The purpose of this article is to provide a brief summary of current research regarding the ΔFosB molecule, its mechanism of action, impact on behavior, and further research directions.

 

The Molecule-- What is ΔFosB?

     ΔFosB is a member of the FOS family of proteins, which are a group of proteins that can dimerize, or form, bonds, with another group of proteins via leucine zippers-- JUN family proteins. The complex formed is called an AP1 Transcription Complex {2]. A diagram of the components of AP1 can be found in Figure 1 below:

 

Adapted AP1.png

Figure 1:  Interactions between AP-1 proteins and other transcription factors, adapted {3].

 

    ΔFosB is a truncated splice variant of FosB, meaning that after mRNA translation, the protein is cut after its 237th amino acid. (the full length FosB protein in most species is 338 amino acids long) This is important because after truncation, the protein lacks two c-terminal degron domains, which are areas in the protein that signal protein destruction and degradation when activated by kinases and other cellular mechanisms {4]. This leads to ΔFosB having a half-life of up to 7 days, making it a prime candidate for molecular studies relating to transcriptional changes associated with addiction {5] {6] {7]. One more factor that contributes to this increased stability has been found to be a phosphorylation of the amino acid serine 27 by CAMKII (a kinase in the cell) in ΔFosB {7]{8].

 

The Molecule- What does ΔFosB do?

    ΔFosB,  being a splice variant of an Immediate Early Gene (IEG), or a gene that is found to be expressed rapidly in response to various cellular stimuli including drug abuse, has the capability to act on other such genes when in the AP1 transcription factor complex, which is proposed to lead to the various morphological and cellular changes associated with addiction {9] {10] {11].

     As described in a subsequent section, more research is warranted in order to determine the exact biological mechanisms and gene targets through which ΔFosB acts.

 

The Molecule-- How is ΔFosB expressed?

    There are many separate mechanisms of induction for ΔFosB and other similar transcription factors, many of which involve activation of receptors on the cell membrane as a switch for induction. The diagram below depicts four key mechanisms of this nature:


C:\Users\kirca_g7fyfva\AppData\Local\Microsoft\Windows\INetCache\Content.Word\Figure-2-Common-signaling-cascades-leading-to-activity-dependent-TF-activation.png

Figure 2: Common signaling cascades leading to activity-dependent TF activation {12].

    A: GPCR-mediated pathway

    B: NMDAR-mediated pathway

   C: VGCC-mediated pathway

   D: RTK-mediated pathway

 

     As is visible in the diagram, all four of the listed mechanisms involve one key modality: a stimulus signals the opening of a receptor, which leads to a phosphorylation cascade of different kinases. This in turn leads to the activation of certain transcription factors which alter DNA directly inside of the nucleus. This is the basic mechanism through which the production of ΔFosB, as well as of a plethora of other transcription factors, can be increased or decreased. However, it is important to note that this mechanism is not necessarily specific to ΔFosB, and the mechanism of ΔFosB induction still remains unknown in the hippocampus. Whereas in the Nucleus Accumbens the aforementioned systems (CREB/SRF) have been shown to directly increase fosb gene expression [14].

     Current research has shown that antidepressants [14] , ischemia [15],  stress [14] [16], maternal separation [17], spatial learning [18] and nearly all drugs of abuse [19] can cause ΔFosB induction in the hippocampus. Additionally, drugs of abuse cause robust ΔFosB expression in Medium Spiny Neurons (MSNs) that feature Type-1 Dopamine receptors in the Nucleus Accumbens and dorsal striatum [20].
 

The Impacts of ΔFosB

     Perhaps one of the most relevant impacts of ΔFosB for the purposes of this article is the well documented increase in locomotor sensitivity and Conditioned Place Preference -- hallmarks of addictive behavior--  that Cocaine induces in ΔFosB overexpressed mice [21] [22]. This means that when mice are exposed to unnaturally elevated levels of ΔFosB , they have enhanced receptiveness to cocaine coupled with an increased preference for stimuli that they have learned to associate with the cocaine.

     Tying into this, a 2009 article chronicles a similar response in positive sexual reward as a stimulus in hamsters, with increased Conditioned Place Preference (cPP) for sexual activity in sexually mature female hamsters [23]. Conversely, the overexpression of ΔJunD, which has a similar effect as the silencing of ΔFosB, has been documented in a separate study to have nearly the opposite effect on hamsters [24].

     Additionally, ΔFosB  overexpression has been shown to significantly increase patterns of behavior associated with anxiety in mice, as well as to increase immature dendritic spine formation in the hippocampus in mice. The same study also showed that this overexpression impaired learning and memory, in a pattern similar to the effects observed in ΔFosB silencing or inhibition [18].

     Studies conducted postmortem on humans revealed that individuals with a history of depression coupled with antidepressant treatment had decreases in ΔFosB as well as other FosB isoforms in the hippocampus, whereas patients who suffered from depression without antidepressant medication did not express this finding, suggesting that antidepressant medication impacts FosB expression not only on an acute level as described earlier, but on a long-term level as well [25].

 

Further Research

      Currently, there is much ground to be made with regards to discovering both novel ΔFosB  gene targets and its exact molecular mechanism of induction, particularly in certain brain regions such as the hippocampus, through comparative mRNA sequencing before and after stimulus or other tests [26]. Advancement in bioinformatics technology in order to actually analyze the data from these tests is also necessary for further research. Finding these gene targets or mechanisms may ultimately allow researchers to identify sites for therapeutic or pharmacological treatment of depression and addiction [27]. However, in order to achieve the aforementioned goal, more research must also be done regarding the other factors that dictate how and why a particular transcription factor binds to its target gene [27].

     Ultimately, the burgeoning field of ΔFosB  and addiction research is one that has the potential to become extremely influential in our understanding of addiction and mental illness as a whole. By being able to understand the exact molecular mechanisms that underlie the pathology of addiction and mental illness--in other words, what happens when things go wrong--we will be able to take one step closer to understanding what goes on when things go right, including the processes, substances, and molecules that collectively make us who we are.


References


  1. Robison, Alfred, Nestler, Eric. (12/10/2011). Transcriptional and epigenetic mechanisms of addiction. Nature Reviews Neuroscience. 623-637. Retrieved; (15/09/2017).

  2. Eagle, Andrew, Gajewski, Paula, Robison, Alfred. (26/03/2016). Role of hippocampal activity-induced transcription in memory consolidation. Reviews in the Neuroscience. 559-573. Retrieved; (15/09/2017).

  3. Gajewski, Paula, Turecki, Gustavo, Robison, Alfred. (05/08/2016). Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients. PLoS ONE. https://doi.org/10.1371 /journal.pone.0160355. Retrieved; (15/09/2017).

  4. Been, Laura, Hedges, Valerie, Vialou, Vincent, Nestler, Eric, Meisel, Robert. (08/2013). Delta JunD overexpression in the nucleus accumbens prevents sexual reward in female Syrian hamsters. Genes Brain and Behavior. 666-672. Retrieved; (15/09/2017).

  5. Hedges, VL, Chakravarty, S, Nestler, EJ, Meisel, RL. (06/2009). ΔFosB overexpression in the nucleus accumbens enhances sexual reward in female Syrian hamsters. Genes Brain and Behavior. 442-449. Retrieved; (15/09/2017).

  6. Zachariou, V, Bolanos, CA, Selley, DE, Theobald, D, Cassidy, MP, Kelz, MB, Shaw-Lutchman, T, Berton, O, Sim-Selley, LJ, Dileone, RJ, Kumar, A, Nestler, EJ. (02/2006). An essential role for DeltaFosB in the nucleus accumbens in morphine action. Nature Neuroscience. 205–211. Retrieved; (15/09/2017).

  7. Kelz, MB, Chen, J, Carlezon, WA Jr, Whisler, K, Gilden, L, Beckmann, AM, Steffen, C, Zhang, YJ, Marotti, L, Self, DW, Tkatch, T, Baranauskas, G, Surmeier, DJ, Neve, RL, Duman, RS, Picciotto, MR, Nestler, EJ. (16/09/1999). Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature. 272–276. Retrieved; (15/09/2017).

  8. Lobo, MK, Covington, HE, 3rd, Chaudhury, D, Friedman, AK, Sun, H, Damez-Werno, D, Dietz, DM, Zaman, S, Koo, JW, Kennedy, PJ, Mouzon, E, Mogri, M, Neve, RL, Deisseroth, K, Han, MH, Nestler, EJ. (15/10/2010). Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science. 385-390. Retrieved; (15/09/2017).

  9. Perrotti, LI, Weaver, RR, Robison, B, Renthal, W, Maze, I, Yazdani, S, Elmore, RG, Knapp, DJ, Selley, DE, Martin, BR, et al. (05/2008). Distinct patterns of ΔFosB induction in brain by drugs of abuse. Synapse. 358–369. Retrieved; (15/09/2017).

  10. Eagle, Andrew, Gajewski, Paula, Yang, Miyoung, Kechner, Megan, Masraf, Basma, Kennedy, Pamela, Wang, Hongbing, Mazei-Robison, Michelle, Robison, Alfred. (07/10/2015). Experience-Dependent Induction of Hippocampal FosB Controls Learning. The Journal of Neuroscience. 13773–13783. Retrieved; (15/09/2017)

  11. Zhang, L, Hernández, VS, Liu, B, Medina, MP, Nava-Kopp, AT, Irles, C, and Morales, M. (26/07/2012). Hypothalamic vasopressin system regulation by maternal separation: its impact on anxiety in rats. Neuroscience. 135-148. Retrieved; (15/09/2017)

  12. Perrotti, LI, Hadeishi, Y, Ulery, PG, Barrot, M, Monteggia, L, Duman, RS, Nestler, EJ. (24/11/2004). Induction of ΔFosB in reward-related brain structures after chronic stress. Journal of Neuroscience. 10594–10602. Retrieved; (15/09/2017)

  13. McGahan, L, Hakim, AM, Nakabeppu, Y, and Robertson, GS (05/1998). Ischemia-induced CA1 neuronal death is preceded by elevated FosB and Jun expression and reduced NGFI-A and JunB levels. Molecular Brain Research. 146–161. Retrieved; (15/09/2017).

  14. Vialou, V, Thibault, M, Kaska, S, Cooper, S, Gajewski, P, Eagle, A, Mazei-Robison, M, Nestler, E.J, and Robison, A.J. (12/2015). Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress. Neuropharmacology. 28–37. Retrieved; (15/09/2017).

  15. Vialou, V, Feng, J, Robison, AJ, Ku, SM, Ferguson, D, Scobie, KN, Mazei-Robison, MS, Mouzon, E, Nestler, EJ. (22/05/2012). Serum response factor and cAMP response element binding protein are both required for cocaine induction of ΔFosB. Journal of Neuroscience. 7577–7584. Retrieved; (15/09/2017)

  16. Eagle, Andrew, Gajewski, Paula, Robison, AJ . (26/03/2010). Role of hippocampal activity-induced transcription in memory consolidation. Reviews in the Neurosciences. https://www.ncbi.nlm.nih.gov/pubmed/27180338. Retrieved; (11/09/2017).

  17. Kalivas, PW. (08/2010). The glutamate homeostasis hypothesis of addiction. Nature Reviews Neuroscience. 561–572. Retrieved; (11/09/2017).

  18. Robinson, TE. and Kolb, B. (2004). Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology. 33–46 (11/09/2017).

  19. Russo, SJ, Dietz, DM, Dumitriu, D, Morrison, JH, Malenka, RC, and Nestler, Eric. (06/2010) The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends in Neuroscience. 267–276. Retrieved; (11/09/2017).

  20. Robison, AJ, Vialou, V., Mazei-Robison, M, Feng, J, Kourrich, S, Collins, M, Wee, S, Koob, G, Turecki, G, Neve, R, et al. (06/03/2013). Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell. Journal of Neuroscience. 4295–4307. Retrieved; (11/09/2017).

  21. Ulery-Reynolds, PG, Castillo, MA, Vialou, V, Russo, SJ, and Nestler, Eric (2009). Phosphorylation of ΔFosB mediates its stability in vivo. Neuroscience. 369–372. Retrieved; (10/09/2017).

  22. Andersson, M, Westin, JE, and Cenci, MA. (31/01/2003). Time course of striatal ΔFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment. European Journal of Neuroscience. 661-666. Retrieved; (10/09/2017).

  23. Hope, BT, Nye, HE, Kelz, MB, Self, DW, Ladarola, MJ, Nakabeppu, Y, Duman, RS, and Nestler, Eric. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron. 1235-1244. Retrieved; (10/09/2017).

  24. Carle, TL, Ohnishi, YN, Ohnishi, YH, Alibhai, IN, Wilkinson, MB, Kumar, A, and Nestler, Eric. (25/05/2007). Proteasome-dependent and -independent mechanisms for FosB destabilization: identification of FosB degron domains and implications for DeltaFosB stability. European Journal of Neuroscience. 3009-3019. Retrieved; (10/09/2017)

  25. Foletta, Victoria, Segal, David, and Cohen, Donna. (03/1998). Transcriptional regulation in the immune system: all roads lead to AP-1. Journal of Leukocyte Biology. 139-152. Retrieved; (10/09/2017).

  26. Minatohara, Keichiiro, Akiyoshi, Mika, and Okuno, Hiroyuki. (05/01/2015). Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace. Frontiers in Molecular Neuroscience. 78. Retrieved; (10/09/2017).

  27. n.p. (09/2014) Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. Substance Abuse and Mental Health Services Administration. https://www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.htm#3.1.2. Retrieved; (10/09/2017).

Deniz Kirca

Deniz Kirca


This author has not yet uploaded a bio.