Effects of developmental hyperserotonemia on juvenile play behavior, oxytocin and serotonin receptor expression in the hypothalamus are age and sex dependent

Madden, Amanda M. K.; Zup, Susan L.

doi:10.1016/j.physbeh.2014.01.036

Cited by 24 publications

(30 citation statements)

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“…Changes in 5-HT bioavailability not only impact on hypothalamic circuitry formation during development but also have been shown to influence appetite and body weight in the adult (Porto et al, 2009;Berg et al, 2013;Madden and Zup 2014). 5-HT primarily regulates energy balance via activity at the Gq-coupled receptor, 5-HT2CR.…”

Section: Discussionmentioning

confidence: 99%

“…Increased anxiety-like behaviour in nonhuman primate offspring of dams fed high fat diet was associated with perturbations in 5-HT system during fetal life (Sullivan et al, 2010). Early hyperserotonemia, in particular, has been identified as a potential factor in the pathogenesis of Autism Spectrum Disorder and Schizophrenia (Chugani, 2004;Madden and Zup, 2014). In addition, both 5-HT2AR and 5-HT2CR that are expressed throughout the brain have been implicated in the pathophysiology of psychiatric disorders (Abramowski et al, 1995;Hoyer et al, 1986;Heisler et al, 2007;Mestre et al, 2013;Lyddon et al, 2013].…”

Section: -Ht2armentioning

confidence: 99%

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5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

et al. 2016

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List of abbreviations5As the prevalence of obesity increases across the globe major efforts are directed at studying the mechanisms involved. Growing evidence suggests that susceptibility to obesity can be programmed by maternal and neonatal nutrition. In particular, individuals with low birth weight that undergo rapid postnatal growth are at higher risk of developing increased adiposity in later life. The molecular mechanisms mediating the interaction between early nutrition and obesity risk are, however, still largely unknown. Currently, there are no pharmacological therapies to prevent the increase in adiposity in individuals that underwent nutritional challenge in early life. Serotonin (5-HT) system is widely recognized as one of the key regulators of food intake and body weight. During fetal life serotonin also acts as a trophic factor that regulates brain development. As compounds targeting endogenous serotonin bioavailability have been among the most clinically effective treatments for obesity (e.g. d-fenfluramine), treatment targeting serotonin system may prevent the development of obesity in at risk individuals. Results:The study has shown that maternal protein restriction increased levels of serotonin in the blood of pregnant rat mums and in the placenta and the fetal brain. In adulthood the offspring had a reduced ability to sense serotonin, which was associated with a reduced hypothalamic expression of 5-HT2Creceptors -the primary serotonin receptor influencing appetite. As expected, reduced 5-HT2Creceptor expression was associated with impaired sensitivity to serotonin-mediated appetite suppression and hence could lead to increases in food intake. On the other hand offspring of low protein dams had a programmed increase in 5-HT2A receptors, which are positioned, just like 5-HT2C receptors, in the arcuate nucleus of the hypothalamus -a key area of the brain, involved in the control of food intake. Moreover, these animals were more sensitive to 5-HT2A receptor agonistinduced appetite suppression. Implications and future directions:This study identified a molecular mechanism that is involved in mediating the effects of suboptimal maternal diet on the regulation of food intake in the offspring. In addition, the authors showed that a treatment with 5-HT2A receptor agonist may potentially prevent the development of obesity in individuals that were exposed in utero to suboptimal nutrition and then underwent rapid postnatal growth. Non-hallucinogenic 5-HT2A receptor agonist should be used for such treatment. Combining the 5-HT2A receptor agonist with 5-HT2CR and 5-HT1BR agonists could potentially further increase the anorectic therapeutic effect. Disease Models & Mechanisms • DMM • Advance article AbstractThough obesity is a global epidemic, the physiological mechanisms involved are little understood.Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid...

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Section: Discussionmentioning

confidence: 99%

Section: -Ht2armentioning

confidence: 99%

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

et al. 2016

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“…Conversely, when a non-selective 5-HT agonist was given to rats or voles prenatally, beginning from gestational day 12, fewer OT cells were evident in the paraventricular nucleus of the hypothalamus in adulthood, and time spent in typical affiliative social behaviors was lower than in saline-treated animals (McNamara et al, 2008, Martin et al, 2012). A similar treatment given to male and female rats pre- and postnatally revealed that the effects on the number of OT or 5-HT receptor positive cells were age- and sex-dependent, and effects on juvenile play behavior were only seen in females, not males (Madden and Zup, 2014). One area for further research includes development of multisensory integration, with evidence that both 5-HT and OT play critical roles in cross-modal plasticity within the sensory cortex (Jitsuki et al, 2011, Zheng et al, 2014).…”

Section: Interplay Between the Serotonin And Oxytocin Systemsmentioning

confidence: 91%

The serotonin system in autism spectrum disorder: From biomarker to animal models

2016

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Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker.

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“…For instance, Paul and coworkers found a positive correlation between social play and vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) of male but not female rats (Paul et al, 2014). Furthermore, Madden and Zup (2014) reported that the reduction in social play behaviour induced by perinatal hyperserotonemia was associated with alterations in the number of oxytocinergic cells in the PVN of the female offspring only. Together, these studies indicate that neuropeptides in the PVN regulate the development of social play in a sexually dimorphic manner.…”

Section: Neural Modulation Of Social Playmentioning

confidence: 99%

The neurobiology of social play and its rewarding value in rats

Vanderschuren

Achterberg

Trezza

2016

Neuroscience & Biobehavioral Reviews

247

202

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In the young of many mammalian species, including humans, a vigorous and highly rewarding social activity is abundantly expressed, known as social play behaviour. Social play is thought to be important for the development of social, cognitive and emotional processes and their neural underpinnings, and it is disrupted in pediatric psychiatric disorders. Here, we summarize recent progress in our understanding of the brain mechanisms of social play behaviour, with a focus on its rewarding properties. Opioid, endocannabinoid, dopamine and noradrenaline systems play a prominent role in the modulation of social play. Of these, dopamine is particularly important for the motivational properties of social play. The nucleus accumbens has been identified as a key site for opioid and dopamine modulation of social play. Endocannabinoid influences on social play rely on the basolateral amygdala, whereas noradrenaline modulates social play through the basolateral amygdala, habenula and prefrontal cortex. In sum, social play behaviour is the result of coordinated activity in a network of corticolimbic structures, and its monoamine, opioid and endocannabinoid innervation.

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Effects of developmental hyperserotonemia on juvenile play behavior, oxytocin and serotonin receptor expression in the hypothalamus are age and sex dependent

Cited by 24 publications

References 81 publications

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

The serotonin system in autism spectrum disorder: From biomarker to animal models

The neurobiology of social play and its rewarding value in rats

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