Development by environment interactions controlling tryptophan hydroxylase expression

Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, USA.
Journal of chemical neuroanatomy (Impact Factor: 1.5). 05/2011; 41(4):219-26. DOI: 10.1016/j.jchemneu.2011.05.002
Source: PubMed


Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin (5-hydroxytryptamine; 5-HT). Two isoforms of tryptophan hydroxylase, derived from different genes, tph1 and tph2, have been identified. The tph1 isoform is expressed in peripheral tissues, whereas tph2 is brain and neuron-specific. Recent studies suggest that tph2 expression and brain serotonin turnover are upregulated in depressed suicide patients, and drug-free depressed patients, respectively. Increased tph2 expression could result from genetic influences, early life developmental influences, adverse experience during adulthood, or interactions among these factors. Studies in rodents support the hypothesis that interactions between early life developmental influences and adverse experience during adulthood play an important role in determining tph2 expression. In this review, we highlight the evidence for the effects of adverse early life experience and stressful experience during adulthood on both tph1 and tph2 expression.

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Available from: Christopher Alan Lowry, Oct 13, 2015
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    • "Lastly, we determined if there was a relationship between within-litter differences in the frequency of licking that females received and later tryptophan hydroxylase-2 (TPH2) in their medial prefrontal cortex (mPFC). TPH2 is found in all serotonergic somata and proximal axons (Donner and Handa, 2009; Hale, Shekhar, and Lowry, 2011; Walther and Bader, 2003) and its levels are highly correlated with the amount of serotonin that the cells produce and their rate of activity (Calcagno et al., 2007; Cervo et al., 2005; Gutknecht et al., 2012; Patel et al., 2004; Zhang et al., 2004). TPH2 mRNA and protein also exist in the cytoplasm of serotonergic terminals, including the prefrontal cortex (Carkaci-Salli et al., 2011; Sakowski et al., 2006; Perroud et al., 2010; Zill et al., 2007). "
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    ABSTRACT: The effects of differential maternal care received on offspring phenotype in rodents has been extensively studied between litters, but the consequences of differential mothering within litters on offspring neurobehavioral development have been rarely examined. We here investigated how variability in maternal care received among female rat siblings (measured four times daily on postnatal days 4, 6, 8, and 10) relates to the siblings' later emotional and maternal behaviors. As previously reported, we found that some female pups received up to three times more maternal licking bouts compared to their sisters; this difference was positively correlated with the pups' body weights. The number of maternal licking bouts females received was negatively correlated with their later neophobic behaviors in an open field during periadolescence, but positively correlated with their anxiety-related behavior in an elevated plus maze during adulthood. Licking received was also positively correlated with females' later likelihood to retrieve pups in a maternal sensitization paradigm. In addition, females' neophobia during adolescence and anxiety-related behavior during adulthood predicted some aspects of both postpartum and sensitized maternal responsiveness. Medial prefrontal cortex expression of tryptophan hydroxylase-2 (TPH2; enzyme necessary for serotonin synthesis) was negatively associated with early maternal licking received. Interestingly, cortical TPH2 was positively associated with the maternal responsiveness of sensitized virgins but negatively associated with it in postpartum females. These results indicate that within-litter differences in maternal care received is an often neglected, but important, contributor to individual differences in offspring socioemotional behaviors and the cortical serotonin neurochemistry that may influence these behaviors. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 07/2015; DOI:10.1016/j.yhbeh.2015.07.017 · 4.63 Impact Factor
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    • "For IHC, one third of the sections were taken through a series of rinses and sequential incubations on an orbital shaker using a rabbit anti-c-Fos antibody that has been previously characterized [27], [28] (1∶200, SC-253, Santa Cruz Biotechnology), a biotinylated donkey anti-rabbit secondary antibody (711-065-152, Jackson ImmunoResearch Laboratories), a validated avidin-biotin complex (NeutrAvidin, A2666, Life Technologies; Peroxidase-biotinamidocaproyl conjugate, P-9568, Sigma-Aldrich), and reacted with nickel enhanced 3,3′-diaminobenzidine tetrahydrochloride (DAB; D5637, Sigma-Aldrich) for color detection [23], [29]–[31]. This was immediately followed by a second IHC using a sheep anti-tryptophan hydroxylase antibody that has been previously characterized and shown to bind specifically to both isoforms of Tph [30], [31] (1∶800, T8575, Sigma-Aldrich), a biotinylated donkey anti-sheep secondary antibody (713-065-147, Jackson ImmunoResearch Laboratories), and reacted with DAB for color detection as previously described [23], [29]–[31]. After the color reaction, sections were rinsed, mounted on gelatin-coated slides, dehydrated through increasing concentrations of ethanol (70–100%), cleared in Histo-Clear (National Diagnostics), and coverslipped with Permount (Fisher Scientific). "
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    ABSTRACT: Functionally heterogeneous populations of serotonergic neurons, located within the dorsal raphe nucleus (DR), play a role in stress-related behaviors and neuropsychiatric illnesses such as anxiety and depression. Abnormal development of these neurons may permanently alter their structure and connections, making the organism more susceptible to anxiety-related disorders. A factor that critically regulates the development of serotonergic neurons is fibroblast growth factor 8 (Fgf8). In this study, we used acute restraint stress followed by behavioral testing to examine whether Fgf8 signaling during development is important for establishing functional stress- and anxiety-related DR neurocircuits in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8 were exposed to acute restraint stress and then tested for anxiety-like behavior on the elevated plus-maze. Further, we measured c-Fos immunostaining as a marker of serotonergic neuronal activation and tissue 5-hydroxyindoleacetic acid concentrations as a marker of serotonin functional output. Results showed that Fgf8 hypomorphs exhibited 1) an exaggerated response of DR anxiety-promoting circuits and 2) a blunted response of a DR panic-inhibiting circuit to stress, effects that together were associated with increased baseline anxiety-like behavior. Overall, our results provide a neural substrate upon which Fgf8 deficiency could affect stress response and support the hypothesis that developmental disruptions of serotonergic neurons affect their postnatal functional integrity.
    PLoS ONE 07/2014; 9(7):e101420. DOI:10.1371/journal.pone.0101420 · 3.23 Impact Factor
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    • "The IHC used tryptophan hydroxylase (Tph; the rate-limiting enzyme for serotonin biosynthesis) as a marker of serotonergic neurons. Briefly, one third of the sections were taken through a series of rinses and sequential incubations on an orbital shaker with a sheep antitryptophan hydroxylase antibody that has been previously characterized and has been shown to bind specifically to both isoforms of Tph [37] [38] (T8575, "
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    ABSTRACT: Serotonergic neurons in the dorsal raphe nucleus (DR) are organized in anatomically distinct subregions that form connections with specific brain structures to modulate diverse behaviors, including anxiety-like behavior. It is unclear if the functional heterogeneity of these neurons is coupled to their developmental heterogeneity, and if abnormal development of specific DR serotonergic subregions can permanently impact anxiety circuits and behavior. The goal of this study was to examine if deficiencies in different components of fibroblast growth factor (Fgf) signaling could preferentially impact the development of specific populations of DR serotonergic neurons to alter anxiety-like behavior in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8, Fgfr1, or both (Fgfr1/Fgf8) were tested in an anxiety-related behavioral battery. Both Fgf8- and Fgfr1/Fgf8-deficient mice display increased anxiety-like behavior as measured in the elevated plus-maze and the open-field tests. Immunohistochemical staining of a serotonergic marker, tryptophan hydroxylase (Tph), revealed reductions in specific populations of serotonergic neurons in the ventral, interfascicular, and ventrolateral/ventrolateral periaqueductal gray subregions of the DR in all Fgf-deficient mice, suggesting a neuroanatomical basis for increased anxiety-like behavior. Overall, this study suggests Fgf signaling selectively modulates the development of different serotonergic neuron subpopulations. Further, it suggests anxiety-like behavior may stem from developmental disruption of these neurons, and individuals with inactivating mutations in Fgf signaling genes may be predisposed to anxiety disorders.
    Behavioural brain research 02/2014; 264. DOI:10.1016/j.bbr.2014.01.053 · 3.03 Impact Factor
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