Abstract
Stress perception, response, adaptation, and coping strategies are individually distinct, and the sequel of stress and/or glucocorticoids (GCs) is also distinct between subjects. In the last years, it has become clear that early life stress is a powerful modulator of neuroendocrine stress-responsive circuits, programing intrinsic susceptibility to stress, and potentiating the appearance of stress-related disorders such as depression, anxiety, and addiction. Herein we were interested in understanding how early life experiences reset the normal processing of negative stimuli, leading to emotional dysfunction. Animals prenatally exposed to GCs (in utero glucocorticoid exposure, iuGC) present hyperanxiety, increased fear behavior, and hyper-reactivity to negative stimuli. In parallel, we found a remarkable increase in the number of aversive 22 kHz ultrasonic vocalizations in response to an aversive cue. Considering the suggested role of the mesopontine tegmentum cholinergic pathway, arising from the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT), in the initiation of 22 kHz vocalizations and hypothetically in the control of emotional arousal and tone, we decided to evaluate the condition of this circuit in iuGC animals. Notably, in a basal situation, iuGC animals present increased choline acetyltransferase (ChAT) expression in the LDT and PPT, but not in other cholinergic nuclei, namely in the nucleus basalis of Meynert. In addition, and in accordance with the amplified response to an adverse stimulus of iuGC animals, we found marked changes in the cholinergic activation pattern of LDT and PPT regions. Altogether, our results suggest a specific cholinergic pathway programing by prenatal GC, and hint that this may be of relevance in setting individual stress vulnerability threshold.
Highlights
Exposure to stressful events or synthetic glucocorticoids (GCs), such as dexamethasone, early in life, are a risk factors for the development of different neuropsychiatric disorders in adulthood, namely depression and anxiety [1]
IN UTERO GLUCOCORTICOID EXPOSURE IMPAIRS EMOTIONAL BEHAVIOR Animals were exposed to a battery of behavioral tests that consisted of paradigms studying spontaneous exploratory behavior (OF), tasks of innate anxiety (EPM, light/dark box (L/D) test, confined cage), and reactivity to adverse stimulus
In the open field (OF), iuGC animals presented a decrease in the number of ambulatory counts (Figure 1A, t = 2.197, p = 0.037) and total distance traveled (Figure 1B, t = 3.002, p = 0.006) when compared with control animals
Summary
Exposure to stressful events or synthetic glucocorticoids (GCs), such as dexamethasone, early in life, are a risk factors for the development of different neuropsychiatric disorders in adulthood, namely depression and anxiety [1] Such effects are partially mediated by de-regulation of the hypothalamic-pituitaryadrenal (HPA) axis, leading to altered GC secretion [2, 3], which can induce long-term molecular and functional changes in GCsensitive nuclei. We have shown that animals prenatally exposed to GC present marked hypodopaminergia and D2 epigenetic/expression changes, responsible for their anhedonia and motivational deficits, since administration of a dopamine precursor, l-DOPA, fully reverted the molecular and behavioral impairments [14, 15] This dopaminergic de-regulation may occur indirectly through modulation of upstream neurotransmitter systems. Relevant is to note that the ascending cholinergic system is implicated in the control of the stress response by modulating hypothalamic pituitary adrenal (HPA) axis function [26,27,28] and in mediating the anxiogenic effects of stress [29,30,31]
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