Sleep and Brain Development: The Critical Role of Sleep in Fetal and Early Neonatal Brain Development

In paper citation (Graven & Browne, 2008)

Note: Human infants are born around 40 gestational weeks.

Normal Sleep in Development

• Sleep & sleep cycles are essential for sensory system development in the fetus and young infant. 
• As early as the end of the first trimester, fetuses begin to show circadian rhythms, periods or rest and activity, and rhythmic hormone production. These circadian rhythms are regulated by the mother's hormones (Rivkees & Hao, 2000)
• Between 20 and 28 weeks' gestation, the human fetus shows irregular and immature brain activity. As the preterm infant approaches 28 weeks' gestation, cell firing becomes regular and starts to occur as synchronous waves. This is organized by the ganglion cell firing. (Lai, et al., 1999).
• By 30 weeks gestation, the EEG patterns of REM and nREM occur, but not continuously. The EEG patterns become continuous between 36 and 38 gestational weeks (Davis, et al., 1999).
• In the fetus and young infant the brain is more active during REM than during wakefulness (Mizhari, et al, 2004).
• At 28 weeks gestation, the sleep cycle is mostly REM sleep. 
• By term at 40 weeks, the sleep cycles are about equal REM and NREM.
• By 8 or 9 months, the sleep cycle is about 80% NREM, 20% REM. This is reflective of adult sleeping patterns (Mizhari, et al., 2004)
• Rapid eye movement deprivation between 30 weeks' gestational age and 4-5 months postterm results in delayed or disordered development. 

Preservation of Brain Plasticity

• 3 cellular components of plasticity:
• nerve growth factor
• BDNF
• ubiquitin
• All three components repond to the stimulation and activation of CREB ( cyclic AMP responsive element binding protein) that regulates gene transcription.

Theory of memory consolidation

• Short term memory circuits in the neocortex.
• Consolidation phase during NREM for novel information.
• Neocortex communicates with hippocampus via theta waves in NREM.
• Hippocampus organizes the information and sends it back to the neocortex using different theta waves in REM. Continued theta waves solidify this memory connection. 
• Stickgold et al., 2008; Yoo, et al., 2007 

Sleep Development in the NICU

• Better sleep organization correlated with improved outcomes in the NICU (Lehtonen & Martin, 2004)
• NICU babies have historically been handled constantly with an average of 100 interventions in 24 hours. 
• NICU babies follow the developmental pattern of their gestational age in terms of sleeping patterns unless they have chronic lung disease (Scher, et al., 1992).
• Kangaroo mother care and breast feeding seem best in establishing sleep-wake patterns in pre-term infants. 

Remaining questions:

What are the established effects of REM deprivation and sleep deprivation?

If SSRIs decrease REM, how does this affect neonatal development? Is there a causal relationship between sleep and cognitive ability or is the correlation deeper?

New Perspectives on the Neurodevelopmental effects of SSRIs

In paper citation: (Homberg, Schubert, & Gaspar, 2009)

This paper is a review article and therefore is mostly just a collection of useful facts. I will leave citations to be looked up using the paper.

Introduction

• Selective serotonin reuptake inhibitors inhibit the function of the serotonin transporter (5HTT), which is responsible for the high affinity reuptake of serotonin.
• The 5HTT has only one gene and is an identical protein in the peripheral and central nervous system, making it hard to target.
• 10-16% of pregnant women are depressed; 25% of these women continue SSRI use through their pregnancy and another .5% of these women start taking SSRIs while pregnant.
• The SSRIs reach the fetus through the placenta and the newborn through breastmilk. 
• Perinatal administration of SSRIs causes anxiety and depression-like behaviors in rodents (the SSRI paradox)

The SSRI paradox

• In adults the chronic use of SSRIs:
• decrease anxiety/depression
• decrease REM sleep
• cause cardiodepression and vasodilation
• In contrast, perinatal exposure to SSRIs:
• increases anxiety/depression
• increases REM sleep
• blunts pain responses
• improves spatial learning
• increases cocaine-induced conditioned place preference
• causes dilated cardiomyopathy

It is important to note that functional brain maturity at postnatal day 12&13 in rodents are most similar to the day of birth in primates. 

Cellular Targets of SSRIs during development

• At mid gestation (E11) the 5HTT gene is first expressed in the raphe nucleus.
• At birth, the 5HTT gene is expressed in many regions of the frontal cortex.
• 5HTT expression in non-serotonergic neurons ends rapidly during during the second postnatal week.
• Repression of 5HTT expression is controlled by circulating hormones, such as thyroid, that peak in postnatal life.

Signalling Pathways of 5HT

• 5HT1B receptors are similar to the 5HTT and regulate activity dependent axon-remodelling by controlling glutamate release and cyclic AMP production. This in turn is involved in the production of netrins and ephrins. This could result in an altered brain topography.
• 5HTT regulates 5HT levels and thus determine the activation of pre and post synaptic 5HT receptors. 

Lessons from rodent behavioral studies

Embryonic exposure to SSRIs:

• increased neonatal mortality
• reduced body weight
• reduced the receptor density of 5HT2A/2C 
• reduced expression of 5HT and 5HTT
• resulted in depression-like symptoms during adulthood
• reduced exploratory behavior and increased anxiety-related phenotype
• reduced aggression
• reduced sexual behavior
• increased REM sleep and anhedonia
• blunted thermal and tactile responses
• delayed motor development
• improved spatial learning
• reduced impulsivity
• kept the rats from swimming on a forced swim test
• increased sensitivity to cocaine-seeking behaviors

Genetic vs. Pharmacological models of 5HTT downregulation

• 5HT1A affected in knockout mice, but not in mice treated with SSRIs neonatally
• Cognitive effects seem similar, but not enough testing has been done to be sure.

Neuroanatomical differences in rodents with perinatal SSRI exposure:

• Somatosensory cortex:
• treated rats have thinned terminal clusters and altered dendritic organization in the spiny stellate neurons in layer 4 barrel cortex
• rats have impaired transmission of tactile information in the somatosensory cortex, but do not lose their tactile skills completely
• structural organization of thalamocortical innervations perturbed
• Corticolimbic circuit
• The dorsal raphe nucleus, mPFC and amygdala make up this serotonergic circuit
• in knockout rodents, the PFC and amygdala have pyramidal cells with abnormally increased branching and  abnormally increased dendritic spine density

In humans

• Humans carrying the short allelic variant of the 5HTT promoter have reduced circulating 5HTT in their blood. These people show increased stress responsivity as newborns, and increased amygdala activity as adults.
• This allele also modulates the antidepressant effects of SSRIs.