David Gozal, MD - US grants

sleep apnea; respiratory airflow disorder; neuropsychology; sleep disorders; child behavior; attention deficit disorder; middle childhood (6-11); epidemiology; academic achievement; cognition; polysomnography; neuropsychological tests; questionnaires; human subject; behavioral /social science research tag; clinical research;

Obstructive sleep apnea syndrome (OSAS) is a frequent condition affecting up to 5 percent of the population, and is characterized by repeated episodes of hypoxia and recurrent EEG/behavioral arousal, particularly during REM sleep. When untreated, OSAS is associated with significant neurocognitive morbidities such as excessive daytime sleepiness and diminished intellectual performance, attention span, learning and vigilance. However, the relative contributions of REM sleep deprivation (REMSD) and episodic hypoxia to OSAS-associated neurocognitive dysfunction remain unclear. To test the hypothesis that REM sleep deprivation and episodic hypoxia affect learning and memory in an additive fashion, four major specific aims will be examined in a young adult rat model as follows: (1) The acquisition and retention of Morris water maze task paradigms will be assessed in conscious 55-60-day old male rats after either 4-day REMSD using the inverted flower pot technique, 14-day episodic daytime hypoxia (EHYP), or the combination thereof (REMSD-EHYP); (2) The effect of such exposure paradigms on long-term potentiation (LTP) within the CA1 region of the hippocampus will be examined using neurophysiological extracellular recordings of the in vitro hippocampal slice preparation; (3) Changes in ionotropic glutamate receptor distribution and in apoptosis within the hippocampal formation and neocortex will be determined using immunohistochemical and wester blot approaches in naive and maze trained animals following REMSD, EHYP, or both; (4) Alterations in early gene induction (c-fos) elicited by maze learning procedures will be further assessed in the hippocampus of REMSD, EHYP, and REMSD-EHYP by immunohistochemistry and AP-1 electromobility shift assays. These e xperiments will extend our understanding on potential mechanisms and interactions underlying the decreased performance that occurs in particular neurocognitive functions of untreated OSAS patients. In this context, REMSD, EHYP, or both would lead to either up-regulation or down-regulation of specific ionotropic glutamate receptor complexes, induce apoptosis, and thereby modify early gene activation patterns associated with learning or retention of newly learned tasks. Such alterations in receptor-signal transduction pathways could also lead to both short- and long- term changes in neuronal excitability and synaptic transmission within brain regions with important and defined roles in memory formation and learning such as the hippocampus.

DESCRIPTION (provided by applicant): Obstructive sleep apnea syndrome (OSA) is a frequent condition affecting up to 2 percent of the pediatric population at ages that are characteristically associated with dynamic brain development and acquisition of important neurocognitive functions. OSA is characterized by repeated episodes of hypoxia during sleep, and when untreated it is associated with significant neurocognitive morbidities such as excessive restlessness and irritability, diminished intellectual performance, attention span, learning and vigilance. However, the relative contributions of chronic intermittent hypoxia (CIH) to OSA-associated neurocognitive dysfunction in children remain unclear. In adult rats, a CIII profile that mimics the intermittent hypoxia observed in patients with OSA during sleep leads to substantial reductions in spatial learning and retention as well as diminished ability to induce long-term potentiation in the CA1 region of the hippocampus. These neurobehavioral and physiological alterations correlate with anatomical changes developing in cortico-hippocampal regions., and we have found that such anatomical changes are particularly prominent in developing rat pups at post-natal ages that coincide with the peak prevalence of USA in children, suggesting that this period of brain maturation is uniquely vulnerable to CIH. We therefore hypothesized that the detrimental effects of CIH on memory and learning performances during this highly vulnerable developmental period are long-lasting, and will be manifest even during adulthood, long after the CIH exposure has ceased. Furthermore, these neurocognitive deficits will be associated and correlated with parallel electrophysiological alterations in the characteristics of long-term potentiation (LTP) of the CAl region of the hippocampus, as well as with disruption of normal ionotropic glutamate receptor expression and binding characteristics within the cortex and hippocampus. We propose to: (1) examine the short-term and long-term consequences of CIH on behavioral patterning and on water maze task acquisition and retention. (2) To assess the short-term and long-lasting effects of CIH on LTP characteristics of the CA1 region of the hippocampus.; (3) To establish changes in NMDA glutamate receptor expression and binding characteristics in neocortical and hippocampal regions associated with CIH, and following long-term recovery; (4) To determine whether exposure to CIH during a critically-vulnerable period of development will elicit time-dependent glial and neuronal stem cell proliferation within cortical and hippocampal regions. These studies will characterize concomitant structural and phenotypic changes induced by CIH in a developmental rodent model of OSA, and provide initial insights into the role of CIH in short-term and long-term neurobehavioral morbidity of USA in children.