Neuroplasticity Mediated by Altered Gene Expression

Department of Psychiatry and Center for Basic Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 02/2008; 33(1):3-17. DOI: 10.1038/sj.npp.1301544
Source: PubMed


Plasticity in the brain is important for learning and memory, and allows us to respond to changes in the environment. Furthermore, long periods of stress can lead to structural and excitatory changes associated with anxiety and depression that can be reversed by pharmacological treatment. Drugs of abuse can also cause long-lasting changes in reward-related circuits, resulting in addiction. Each of these forms of long-term plasticity in the brain requires changes in gene expression. Upon stimulation, second messenger pathways are activated that lead to an enhancement in transcription factor activity at gene promoters. This stimulation results in the expression of new growth factors, ion channels, structural molecules, and other proteins necessary to alter the neuronal circuit. With repeated stimulation, more permanent modifications to transcription factors and chromatin structure are made that result in either sensitization or desensitization of a circuit. Studies are beginning to uncover the molecular mechanisms that lead to these types of long-term changes in the brain. This review summarizes some of the major transcriptional mechanisms that are thought to underlie neuronal and behavioral plasticity.

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Available from: Colleen A Mcclung, Sep 30, 2015
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    • "Moreover, although the neuroadaptations that underlie locomotor sensitization to cocaine are thought to play an important role in the development of addiction (Robinson & Berridge, 1993; McClung & Nestler, 2008; Steketee & Kalivas, 2011), the impact of consuming a diet high in fat and/or sugar on drug-taking is less clear with remote histories of sugar or fat consumption having no effect, or enhancing cocaine self-administration, respectively (Vendruscolo , Gueye, Darnaudery, Ahmed, & Cador, 2010; Puhl, Cason, Wojnicki, Corwin, & Grigson, 2011). Future studies will be expanded to include drugs from diverse pharmacologic classes and to investigate the degree to which sex and dietary history (e.g., current vs. past, or continuous vs. intermittent consumption) impact the reinforcing effectiveness of drugs using intravenous selfadministration assays. "
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    ABSTRACT: Drug abuse and obesity are serious public health problems. Dopamine plays a central role in mediating the reinforcing effects of drugs and food. Prolonged use of drugs is known to alter the function and/or sensitivity of many neurotransmitter systems, including dopamine; however, the impact of consuming foods high in fat and/or sugar is less clear. These studies characterized the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice consuming 1 of 4 diets: (a) standard chow + water; (b) standard chow + 10% sucrose solution; (c) high-fat chow + water; or (d) high-fat chow + 10% sucrose solution. The acute locomotor effects of cocaine (3.2-32.0 mg/kg) were evaluated 4 weeks after initiating dietary conditions; the effects of repeated cocaine administration were evaluated after 5, 6, 7, and 12 weeks. During acute tests, mice consuming a diet high in fat and/or sucrose exhibited greater locomotor responses to cocaine than mice consuming standard chow and water, regardless of sex. Although diet-induced enhancements persisted across repeated cocaine testing, locomotor sensitization developed more rapidly in females drinking sucrose (and consuming either standard or high-fat chow) than in females consuming standard chow and water. In addition to providing evidence that consuming a diet high in fat and/or sugar enhances abuse-related effects of cocaine in ways that might increase vulnerability to abuse cocaine, these studies identified a potentially important sex-related difference in the interaction between nutrition and cocaine effects, with the impacts of sucrose consumption being greater in females than in males. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
    Experimental and Clinical Psychopharmacology 08/2015; 23(4):228-237. DOI:10.1037/pha0000019 · 2.71 Impact Factor
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    • "addiction (Freeman et al. 2010; McClung and Nestler 2008 "
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    ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD), the most commonly diagnosed neurobehavioral disorder of childhood, is usually treated with psychostimulants (e.g., amphetamine). Little is known about the neuronal and behavioral consequences of chronic amphetamine use or abuse in individuals with ADHD. Of all ADHD animal models, the spontaneously hypertensive rat (SHR) is the most validated and widely used. Here, we analyzed striatal transcriptomes in amphetamine-pretreated SHRs (5 mg/kg, i.p. for 7 days [twice daily]), which showed a conditioned place preference to and self-administration of amphetamine. Microarray analyses revealed increased mRNA expression of 55 genes (>1.65-fold increase), while 17 genes were downregulated (<0.6-fold) in the striatum of SHRs. The main functional categories overrepresented among the differentially expressed genes in the striatum include those involved in transcription (e.g., Cebpb, Per2), genes associated with angiogenesis (e.g., Kdr, Klf5), cell adhesion (e.g., Col11a1, Ctgf), apoptosis (e.g., Nfkbia, Perp) and neuronal development (e.g., Egr2, Nr4a3). In conclusion, we dissected the striatal transcriptional responses to the reinforcing effects of repeated amphetamine treatment in the SHR model of ADHD. Future studies should determine the influence of these altered transcripts on amphetamine reinforcement in amphetamine-treated SHRs, and the clinical relevance of the present findings with regard to amphetamine use/abuse in ADHD individuals.
    Archives of Pharmacal Research 08/2014; 38(5). DOI:10.1007/s12272-014-0470-x · 2.05 Impact Factor
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    • "Importantly, among the predicted targets of these miRNAs are genes of the MAP kinase pathway (eg, Map2k1; Map3k1), calcium-signaling-related genes (eg, Calml4, Camkk2), and Rho-signaling-related genes (eg, RhoGef, Rnd2) (Lewis et al, 2005). This finding is interesting in light of the role of miRNAs in neuronal development and neuroplasticity (McClung and Nestler, 2008) and their potential for serving as new therapeutic targets (Hansen and Obrietan, 2013). Indeed, several recent studies have demonstrated that miRNAs are both targets not only for disruption in mental illness (Kohen et al, 2014) but also for AD treatment action (Baudry et al, 2010; O&apos;Connor et al, 2013). "
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    ABSTRACT: Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine which activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.Neuropsychopharmacology accepted article preview online, 18 July 2014; doi:10.1038/npp.2014.176.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.176 · 7.05 Impact Factor
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