Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

Abstract

Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10-and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits. OSA is a highly prevalent condition that affects 2-3% of all children (1-3). It is characterized by the repetitive development of either complete or partial upper airway occlusion that leads to periodic hypoxemia and hypercapnia and to recurring arousals. In recent years, it has become apparent that OSA imposes substantial neurobehavioral morbidity (4 -6), particularly of functions pertaining to the PFC (7), and that such alterations in attention, executive, and intellectual function may not be completely reversible (8). The recent development of a rodent model, whereby IH is applied during sleep, has allowed for improved delineation of some of the potential mechanisms underlying the morbid consequences of OSA (8 -17). Furthermore, a unique period of neuronal susceptibility emerged, such that developing rats exposed to IH displayed reduced apoptosis during the immediate postnatal period but markedly enhanced neuronal cell loss between 10 and 25 d of age, compared with adult animals (18). Furthermore, exposure to IH during this period was associated with marked reductions in the ability to acquire a spatial task in the water maze and with locomotor hyperactivity in males but not in females (9). The potential irreversibility of the IH-induced effects was further suggested by Decker and colleagues (19), who reported altered dopaminergic transmission in rats exposed perinatally

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

“…Although cell counts have not been performed in other brain regions to examine neurodegeneration, there is evidence of apoptosis in this model of sleep apnea oxygenation in the hippocampus and cortex (Goldbart et al, 2003;Xu et al, 2004;Kheirandish et al, 2005). The present study findings support exploration of neural injury in humans with severe obstructive sleep apnea, including the catecholaminergic wake neurons and other catecholaminergic groups.…”

“…LTIH is an established model of sleep apnea oxygenation patterns (Gozal et al, 2001;Decker et al, 2003;Li et al, 2004;Row et al, 2004;Kheirandish et al, 2005;Zhan et al, 2005;Polotsky et al, 2006). The LTIH protocol details were published recently (Veasey et al, 2004a).…”

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

“…They established that exposure to IH during sleep cycle of adult rats is associated with significant spatial learning deficits as well as increased neuronal loss within susceptible brain regions such as the hippocampus and cortex. Subsequent studies have confirmed that chronic IH treatment, as well as sleep fragmentation, as models of OSA, could impair spatial memory functions of rodents to different degrees, as measured by the conventional water maze tests [16][17][18][19][20][21][22] .…”

Obstructive Sleep Apnea in Children: Implications for the Developing Central Nervous System

“…The latter could represent either the presence of a "learning debt", i.e., the decreased learning capacity during OSA may have led to such a delay in learned skills that recuperation is only possible with additional teaching assistance, or alternatively could be indicative that OSA may have irreversibly altered the performance characteristics of the neuronal circuitry responsible for learning particular skills. Support for both these possibilities has emerged from our rodent models of OSA developed in our laboratory (94).…”