Sensitive Periods Of Development
The prenatal period and adolescence are two phases of development consistently linked with adult psychiatric illness. For example, when a woman experiences extreme stress during pregnancy, her offspring have an increased risk for psychiatric problems such as anxiety, depression, and schizophrenia[1-3]. In contrast, adolescence is the time when many psychiatric illnesses tend to emerge. However, the relationship between adolescent development and psychiatric illness remains poorly understood. Therefore, an overarching goal of our laboratory is to understand how the timing of stress exposure across development determines brain and behavioral development.
Nicotinic Acetylcholine Receptors (nAChRs) and Mental Illness
Nicotinic receptor dysfunction is common across many mental illnesses[5, 6]. Nicotine activates nicotinic acetylcholine receptors in the same way as the endogenous neurotransmitter acetylcholine. Rates of smoking are significantly higher amongst depressed, anxious, and schizophrenic individuals compared to the general population, suggesting individuals may be “self-medicating” to alleviate some of their symptoms. In support of this possibility, nicotine has anxiolytic actions in humans, and nicotine also ameliorates sensory gating attentional deficits in schizophrenia patients. There are several nicotinic receptor subtypes, and the two most widely found in the brain and implicated in psychiatric disorders are the high affinity nicotinic alpha4 beta2 receptors and the low affinity nicotinic alpha7 receptors. Animal studies demonstrate that alpha7 or alpha4 beta2 nicotinic receptor activation facilitates memory performance in a variety of testing paradigms[10, 11]. There is also evidence to suggest that disrupting the balance of hippocampal alpha7 and alpha4 beta2 receptor activity alters memory function in rats[10, 11]. In addition, both alpha7 and alpha4 beta2 hippocampal receptors have been shown to influence anxiety and depressive-like behaviors in rodents. Taken together, these data suggest that alpha7 and alpha4 beta2 nicotinic receptors in the hippocampus play a key role in both cognitive and affective behavioral function.
Prenatal Stress, Behavior, and nAChRs
Behavioral effects of prenatal stress
Prenatal stress has wide-ranging effects on the behavior of rodents. Dozens of published papers demonstrate that prenatal stress increases anxiety and depressive-related behaviors, and decrease memory function. Interestingly, these effects tend to be sexually dimorphic in nature. In our laboratory, we observe prenatal stress-induced increases in anxiety-related behaviors in females but not in males, and decreased memory function in males but not in females.
Effects of prenatal stress on nAChRs
The mechanisms by which prenatal stress alters emotional and memory function appear to be complex and to involve a number of neurotransmitter systems. However, the effects of prenatal stress on the brain cholinergic system has received very little attention, despite the importance of this system for both emotional and memory function. We recently demonstrated that prenatal stress significantly increases hippocampal alpha4 beta2 receptor levels in adulthood, suggesting that prenatal stress disrupts normal cholinergic signaling.In contrast, the effects of prenatal stress on alpha7 receptors were more subtle. Specifically, prenatal stress increased alpha7 nAChRs in the dentate gyrus of females. These sex-specific effects of prenatal stress may contribute to the sex-specific nature of behavioral impairments caused by prenatal stress.
Choline as a Stress Intervention
Choline is an essential nutrient and an important structural component of all cell membranes. Therefore, a women's need for choline increases during pregnacy because the fetus requires high choline levels to build new cells. Although choline is abundant in protein-rich foods such as eggs, meats, and beans, about 25% of women do not meet the recommended levels of choline during pregnancy, and are consequently at a 4-fold greater risk of having a child with neural tube defects. Interestingly, choline is also a neurotransmitter in the brain and acts directly on the nAChRs that are altered by prenatal stress. As such, we tested whether perinatal dietary choline supplementation counteracts the detrimental effects of prenatal stress. Specifically, we fed stressed and nonstressed dams a choline-supplemented or control diet during pregnancy and lactation, and measured anxiety-related behaviors in adulthood.
Effects of prenatal stress on hypothalamic nAChRs
Prenatal stress is associated with reproductive dysfunctions in offspring including mating behavior, sexual orientation, female fertility, and female fecundity. Nicotinic acetylcholine receptors (nAChR) in the hypothalamus regulate these same processes, but whether the effects of prenatal stress on reproductive function are mediated by altered nicotinic acetylcholine receptors is not known. Given that prenatal stress alters levels of nAChRs in other brain regions, we are testing the hypothesis that maternal stress alters the development of hypothalamic alpha7 nicotinic acetylcholine receptor levels in offspring.
Effects of prenatal stress on basolateral amygdala nAChRs
Both human and animal studies demstrate that prenatal stress impacts basolateral amygdala (BLA) development. For example, higher maternal cortisol concentrations in early gestation are associated with larger right amygdala volumes in girls at 7 years of age. Furthermore, early gestational cortisol levels are associated with affective problems in girls, suggesting that this association might be mediated, in part, by the larger right amygdala volume . In rodents, the offspring of prenatally stressed Sprague-Dawley dams have smaller BLA nuclei volumes, smaller BLA anterior/posterior lengths, and decreased numbers of neurons and glial cells in the brain. Given that PS impacts overall BLA development, and nicotinic receptors in the BLA are important for many of the behaviors impaired by PS, we hypothesize that PS will also alter levels of nAChRs in the BLA.
Prenatal programming of the effects of adolescent stress?
From the standpoint of sensitive periods of brain development, and individual’s previous stressful experiences may alter the course of brain development in a manner that confers increased risk, or even resilience, to the impact of subsequent stressors. Although both prenatal and adolescent stress are associated with increased risk of mental illness[1-3], whether prenatal stress exposure increases sensitivity to stress during adolescence is not known. Preclinical rodent models have enormous potential for elucidating the relationships between the timing of stress exposure across development and dysfunction. Therefore, we are currently testing the hypothesis that early stress exposure modifies the behavioral impact of stress during adolescence. This hypothesis predicts that the combined effects of prenatal and adolescent stress on behavioral function will be greater than the isolated effects of stress during either time period.
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