Effects of maternal separation on serotonergic systems in the dorsal and median raphe nuclei of adult male Tph2-deficient mice

Lieb, Margaret W.; Weidner, Magdalena; Arnold, Mathew R.; Loupy, Kelsey M.; Nguyen, Kadi T.; Hassell, James E.; Schnabel, K’Loni S.; Kern, Raphael; Day, Heidi E.W.; Lesch, Klaus‐Peter; Waider, Jonas; Lowry, Christopher A.

doi:10.1016/j.bbr.2019.112086

Cited by 15 publications

(19 citation statements)

References 107 publications

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“…A slightly altered expression of Maoa in amygdala and hippocampus may point to specific compensatory mechanisms due to MS 53 . Furthermore, MS exposed mice showed altered expression of Htr1a and Htr2a in the raphe independent of Tph2 icKO, which is in line with previous MS studies 76 , 77 . Alterations in 5-HT receptors in target regions of 5-HT neurons have previously been associated with altered anxiety and exploratory behavior 78 .…”

Section: Discussionsupporting

confidence: 91%

Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

Aboagye

Weber

Merdian

et al. 2021

Sci Rep

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Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.

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Section: Discussionsupporting

confidence: 91%

Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

Aboagye

Weber

Merdian

et al. 2021

Sci Rep

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“…Further, maternally-separated rats have increased detectable serotonin in the spinal cord and colon and an increase in intestinal EC density following induced colonic distension. Further, serotonergic neurons in the dorsal raphe nucleus responsible for top-down pain inhibition are highly-activated in these rats [ 38 , 39 , 40 , 41 , 42 ].…”

Section: Tryptophan Metabolitesmentioning

confidence: 99%

Tryptophan Metabolism and Gut-Brain Homeostasis

Roth

Zadeh

Vekariya

et al. 2021

IJMS

221

142

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Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.

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“…Previously published methods were used for in situ hybridization histochemistry (Day and Akil, 1996;Lieb et al, 2019). Briefly, brains were dissected then frozen on dry ice immediately after euthanasia.…”

Section: In Situ Hybridization Histochemistrymentioning

confidence: 99%

Effects of Immunization With the Soil-Derived Bacterium Mycobacterium vaccae on Stress Coping Behaviors and Cognitive Performance in a “Two Hit” Stressor Model

et al. 2021

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Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a “two hit” stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day –28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days –21, –14, –7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0–56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days –1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience.

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Effects of maternal separation on serotonergic systems in the dorsal and median raphe nuclei of adult male Tph2-deficient mice

Cited by 15 publications

References 107 publications

Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

Tryptophan Metabolism and Gut-Brain Homeostasis

Effects of Immunization With the Soil-Derived Bacterium Mycobacterium vaccae on Stress Coping Behaviors and Cognitive Performance in a “Two Hit” Stressor Model

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