Prolonged maternal separation disturbs the serotonergic system during early brain development

Abstract

Early life stress interrupts brain development through the disturbance of various neurotransmitter and neurotrophic factor activities, but the details remain unclear. In the current study, we focused on the serotonergic system, which plays a critical role in brain development, and examined the time-dependent influence of prolonged maternal separation on male Sprague-Dawley rats. The rats were separated from their dams for 3h twice-daily during postnatal days (PDs) 2-20. The influence of prolonged maternal separation was analyzed on PDs 7, 14, 21, and 28 using HPLC to assess concentrations of serotonin and 5-hydroxyindoleacetic acid and using real-time RT-PCR to measure mRNA expression of the serotonin 1A and 2A receptors in various brain regions. HPLC revealed imbalance between serotonin and 5-hydroxyindoleacetic acid in midbrain raphe nuclei, the amygdala, the hippocampus, and the medial prefrontal cortex (mPFC) on PDs 7 and 14. Furthermore, real-time RT-PCR showed attenuation of mRNA expression of the serotonin 1A receptor in the hippocampus and the mPFC and of the serotonin 2A receptor only in the mPFC on PDs 7 and 14. The observed alterations returned to control levels after maternal separation ended. These findings suggest that the early life stress of prolonged maternal separation disturbs the serotonergic system during a crucial period of brain development, which might in part be responsible for emotional abnormalities later in life.

Mapping the connectivity of serotonin transporter immunoreactive axons to excitatory and inhibitory neurochemical synapses in the mouse limbic brain

“…For example, changes in serotonin neuronal innervation and function have been observed in rodents or monkeys following prenatal exposure to stress (Miyagawa et al 2011), alcohol (for review, see Belmer et al 2016) or cocaine (Snyder-Keller and Keller 1993). Early life or adulthood exposure to stress (Kuramochi and Nakamura 2009; Xue et al 2013; Ohta et al 2014), MDMA (Hatzidimitriou et al 1999) or selective serotonin reuptake inhibitors (Zhou et al 2006) also facilitate changes in 5-HTergic signaling. This high-throughput screening method provides a valuable tool for determining how 5-HTergic neuron plasticity is modulated following chronic exposure to anxious stimuli, stressors or drugs of abuse which can be investigated using behavioral paradigms in rodents.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Monoamine-sensitive developmental periods D Suri et al Ohta et al, 2014;Raftogianni et al, 2012;Rentesi et al, 2013), and reduces dorsal raphe HTR1A expression and 5-HT 1A receptor levels (Leventopoulos et al, 2009;Ohta et al, 2014), together strongly indicative of a postnatal hyper-5-HTergic phenotype. Furthermore, maternal separation increases prefrontal 5-HT 2A/2C receptor function during the second postnatal week (Benekareddy et al, 2010) and blockade of 5-HT 2A/2C function during maternal separation prevents the emergence of the adverse early stress-evoked behavioral and molecular sequelae (Benekareddy et al, 2011).…”

Effects of Neonatal Methamphetamine and Stress on Brain Monoamines and Corticosterone in Preweanling Rats

“…In rodent models of early life stress, activation of the HPA axis increases corticosterone (CORT) levels, as well as monoamine concentrations (Champagne et al 2004; Zhang et al 2005; Barbosa Neto et al 2012; Masis-Calvo et al 2013; Ohta et al 2014). Although adrenal output of the HPA axis is normally blunted during the stress hyporesponsive period (Schoenfeld et al 1980), this attenuation may only compensate up to a certain level of stress.…”

“…This impoverished environment induces significant maternal stress, and this stress is associated with aberrant nurturing behaviors, such as decreased licking and grooming and shortened nursing bouts (Baram et al 2012; Ivy et al 2008). These early life stress situations also alter dopamine (DA) and serotonin (5-HT) concentrations (Masis-Calvo et al 2013; Ohta et al 2014). When dams and pups are returned to normal bedding conditions, maternal behavior and monoamine levels rapidly returns to normal (Champagne et al 2004; Ivy et al 2008; Ohta et al 2014).…”