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“Three important kinds of enzymes that are activated by stress and radiation are phospholipases (that release fatty acids), tryptophan hydroxylase (that controls the conversion of tryptophan to serotonin), and aromatase (estrogen synthetase, that converts androgens to estrogen). The products of these enzymes stimulate cell division, and produce features ofthe inflammatory process, including the leakiness of capillaries.” -Ray Peat, PhD
Since estrogen promotes serotonin, progesterone is likely to be the protective factor (Donner & Handa, 2009; Hiroi, et al., 2006; Berman, et al., 2006; Bethea, et al., 2000). -Ray Peat, PhD
Biol Psychiatry. 2006 Aug 1;60(3):288-95. Epub 2006 Feb 3.
Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field.
Hiroi R, McDevitt RA, Neumaier JF.
BACKGROUND:
Ovarian steroids modulate anxiety behavior, perhaps by regulating the serotonergic neurons in the midbrain raphe nucleus. The regulation of the brain-specific isoform of rat tryptophan hydroxylase (TPH2) by ovarian hormones has not yet been investigated. Therefore, we examined the effects of estrogen and progesterone on TPH2 mRNA in the rat dorsal and median raphe nuclei (DRN and MRN, respectively) and whether TPH2 mRNA levels correlated with anxiety behavior.
METHODS:
Ovariectomized rats were treated for two weeks with placebo, estrogen or estrogen plus progesterone, exposed to the open field test, and TPH2 mRNA was quantified by in situ hybridization histochemistry.
RESULTS:
Estrogen increased TPH2 mRNA in the mid-ventromedial and caudal subregions of the DRN and the caudal MRN. Combined estrogen and progesterone treatment did not change TPH2 mRNA relative to ovariectomized controls. TPH2 mRNA in caudal DRN was associated with lower anxiety-like behavior, whereas TPH2 mRNA in rostral dorsomedial DRN was associated with increased anxiety-like behavior.
CONCLUSIONS:
These results suggest that estrogen may increase the capacity for serotonin synthesis in discrete subgroups of raphe neurons, and reinforce previous observations that different subregions of DRN contribute to distinct components of anxiety behavior.
Int J Dev Neurosci. 1996 Aug;14(5):641-8.
Nutritional recovery does not reverse the activation of brain serotonin synthesis in the ontogenetically malnourished rat.
Manjarrez GG, Magdaleno VM, Chagoya G, Hernández J.
In the present work we confirm that gestational malnutrition effects body and brain composition and results in an activation of the synthesis of the brain neurotransmitter 5-hydroxytryptamine. These results also demonstrate more activity of the rate-limiting enzyme tryptophan hydroxylase in the malnourished fetal and postnatal brain. However, the activity of this enzyme remains increased in the brain of nutritionally recovered animals accompanied by an increase in the synthesis of 5-hydroxytryptamine. We therefore suggest that, in the nutritionally recovered animal, the mechanism of activation of this biosynthetic path in the brain may be not dependent on the increased availability of free L-tryptophan observed in malnourished animals, but might be due to a specific change in the enzyme complex itself. This hypothesis is supported by the fact that plasma free and brain L-tryptophan return to normal in the recovered animal.
“An excess of tryptophan in the diet, especially with deficiencies of other nutrients, can combine with inflammation to increase serotonin. Polyunsaturated fatty acids promote the absorption of tryptophan by the brain, and its conversion to serotonin. A “deficiency” of polyunsaturated fat decreases the expression of the enzyme that synthesizes serotonin (McNamara, et al., 2009). -Ray Peat, PhD
J Psychiatr Res. 2009 Mar;43(6):656-63. Epub 2008 Nov 4.
Omega-3 fatty acid deficiency during perinatal development increases serotonin turnover in the prefrontal cortex and decreases midbrain tryptophan hydroxylase-2 expression in adult female rats: dissociation from estrogenic effects.
McNamara RK, Able J, Liu Y, Jandacek R, Rider T, Tso P, Lipton JW.
A dysregulation in central serotonin neurotransmission and omega-3 fatty acid deficiency have been implicated in the pathophysiology of major depression. To determine the effects of omega-3 fatty acid deficiency on indices of serotonin neurotransmission in the adult rat brain, female rats were fed diets with or without the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during perinatal (E0-P90), post-weaning (P21-P90), and post-pubescent (P60-130) development. Ovariectomized (OVX) rats and OVX rats with cyclic estrogen treatment were also examined. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content, and fatty acid composition were determined in the prefrontal cortex (PFC), and tryptophan hydroxylase-2 (TPH-2), serotonin transporter, and 5-HT(1A) autoreceptor mRNA expression were determined in the midbrain. ALA deficiency during perinatal (-62%, p=0.0001), post-weaning (-34%, p=0.0001), and post-pubertal (-10%, p=0.0001) development resulted in a graded reduction in adult PFC docosahexaenoic acid (DHA, 22:6n-3) composition. Relative to controls, perinatal DHA-deficient rats exhibited significantly lower PFC 5-HT content (-65%, p=0.001), significant greater 5-HIAA content (+15%, p=0.046), and a significant greater 5-HIAA/5-HT ratio (+73%, p=0.001). Conversely, post-weaning DHA-deficient rats exhibited significantly greater PFC 5-HT content (+12%, p=0.03), no change in 5-HIAA content, and a significantly smaller 5-HIAA/5-HT ratio (-9%, p=0.01). Post-pubertal DHA-deficient and OXV rats did not exhibit significant alterations in PFC 5-HT or 5-HIAA content. Only perinatal DHA-deficient rats exhibited a significant reduction in midbrain TPH-2 mRNA expression (-29%, p=0.03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen.
Nat Med. 2015 Feb 5;21(2):114-6. doi: 10.1038/nm.3797.
Reducing peripheral serotonin turns up the heat in brown fat.
Carey AL1, Kingwell BA1.
Obesity is a major risk factor for chronic disease. A new study in mice reveals that lowering levels of the signaling molecule serotonin outside of the brain reduces obesity and its complications by increasing brown adipose tissue (BAT) energy expenditure.
“Serotonin and its derivative, melatonin, are both involved in the biology of torpor and hibernation.” -Ray Peat, PhD
“When an animal such as a squirrel approaches hibernation and is producing less carbon dioxide, the decrease in carbon dioxide releases serotonin, which slows respiration, lowers temperature, suppresses appetite, and produces torpor.
But in energy-deprived humans, increases of adrenalin oppose the hibernation reaction, alter energy production and the ability to relax, and to sleep deeply and with restorative effect.”-Ray Peat, PhD
“In squirrels, hibernation is brought on by the accumulation of unsaturated fats in the tissues, suppressing respiration and stimulating increased serotonin production. In humans, winter sickness is intensified by those same antithyroid substances, so it’s important to limit consumption of unsaturated fats and tryptophan (which is the source of serotonin). When a person is using a thyroid supplement, it’s common to need four times as much in December as in July.” -Ray Peat, PhD
“Although it is common to speak of sleep and hibernation as variations on the theme of economizing on energy expenditure, I suspect that nocturnal sleep has the special function of minimizing the stress of darkness itself, and that it has subsidiary functions, including its now well confirmed role in the consolidation and organization of memory. This view of sleep is consistent with observations that disturbed sleep is associated with obesity, and that the torpor-hibernation chemical, serotonin, powerfully interferes with learning.” -Ray Peat, PhD
Pharmacol Biochem Behav. 1993 Sep;46(1):9-13.
Involvement of brain tryptophan hydroxylase in the mechanism of hibernation.
Popova NK, Voronova IP, Kulikov AV.
Marked changes were revealed in the activity of the key enzyme in serotonin biosynthesis, tryptophan hydroxylase (TPH), during entry into hibernation, hibernation, and arousal in ground squirrels (Citellus erythrogenys). An increase in TPH activity was found in the midbrain, hippocampus, and striatum during the prehibernation period in euthermic ground squirrels. A further increase in TPH activity was observed during the entry into hibernation. Significant elevation was found not only in potential TPH activity measured at the incubation temperature of 37 degrees C but also at incubation temperature of 7 degrees C, approximating the body temperature in hibernation. Vmax in the midbrain of hibernating animals was about 50% higher than in active ones without significant changes in Km. Thus, brain TPH maintains functionality during torpidity and is activated before the entry into hibernation. The results support the idea that brain serotonin is crucially involved in the transition to and the maintenance of the hibernation state.
Pharmacol Biochem Behav. 1981 Jun;14(6):773-7.
Brain serotonin metabolism in hibernation.
Popova NK, Voitenko NN.
It has been shown that notwithstanding 2-fold decreased monoamine oxidase (MAO) activity in brain of hibernating ground squirrels (Citellus erythrogenys major, Brandt), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in most of the brain areas studied were not significantly different from the ones in active ground squirrels. However, marked changes were revealed in 5-HT and 5-HIAA brain level in entering hibernation (body temperature 11-9 degrees C) and arousing (body temperature 22 degrees C) animals. In entry into hibernation an increase in brain 5-HT, decrease in 5-HIAA level and lowered MAO activity was found. In arousal from hibernation 5-HT was decreased, 5-HIAA was increased and MAO activity was found to be increased to the level of the active ground squirrels.
The Journal of Neuroscience, 1 June 2016, 36(22): 6041-6049; doi: 10.1523/JNEUROSCI.2534-15.2016
Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain
Nick Goeden1, Juan Velasquez, Kathryn A. Arnold, Yen Chan, Brett T. Lund, George M. Anderson6, and Alexandre Bonnin
Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternal L-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment.
SIGNIFICANCE STATEMENT The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.
