Author(s): Massimo Ubaldi aff1 , Eugenia Ricciardelli aff2 aff3 , Lorenza Pasqualini aff2 aff3 aff4 , Giuseppina Sannino aff2 aff3 aff5 , Laura Soverchia aff1 , Barbara Ruggeri aff6 , Silvia Falcinelli aff2 aff3 , Alessandra Renzi aff2 aff3 , Colleen Ludka aff2 , Roberto Ciccocioppo aff1 , Gary Hardiman [*] aff2 aff7
acute; amygdala; chronic; cortex; hippocampus; restraint; stress
Stress occurs when an individual is unable to cope effectively with physical or psychological requests. While acute stress may be beneficial to recruit adaptive responses to cope with the stressful situation, prolonged stress may result in maladaptation that can be a risk factor of numerous affective mental illness [1-3 ]. Moreover stress impacts the cardiovascular system, metabolism, digestion, growth, the immune system and memory [4-6 ]. In the context of the cardiovascular system, chronic stress is related to hypertension, heart disease and atherosclerosis of the coronary arteries. In addition, chronic stress affects blood sugar levels promoting the development of diabetes [4 ].
There are many brain regions affected by stress and that mediate stress-associated responses. Among these the hippocampus is the brain region in which the effects of stress have been extensively studied. The hippocampus is a major component of the brains of humans and other vertebrates. It mediates cognitive functions such as learning and memory and is highly sensitive to both endogenous and exogenous insults, including stress [ 5,7-9 ]. It regulates human stress responses serving as a major feedback site for increased levels of glucocorticoid hormones, which if unchecked are neurotoxic [10,11 ]. In addition, the hippocampus is one of the key brain regions involved in the pathophysiology and management of mood-affective disorders. Animal studies have revealed that a reduction in hippocampal neurons upon exposure to stress [12-14 ]. Similarly in humans psychiatric conditions related to stressful events, including posttraumatic stress disorder, emotional intensity disorder and clinical depression, diminish hippocampal neurons [15-17 ].
Chronic stress is a risk factor for clinical depression in individuals with genetic vulnerability [18,19 ]. Moreover, repetitive stress is often used as a rodent representation of depression because it induces the symptoms, one of which is anhedonia [ 20 ]. Others include alterations in rapid eye movement (REM) sleep [ 21,22 ], reduced sexual activity [23,24 ], increased corticosterone levels [19 ] and disturbed circadian rhythms [25 ]. Clinical studies have shown that individuals with long-term stress exhibit reduced hippocampal volume, in addition to degeneration of other limbic brain regions. Reduced hippocampal volume has been reported in individuals with recurrent depressive disorder and post-traumatic stress disorder [ 25-27 ]. High-resolution magnetic resonance imaging revealed correlation between post-traumatic stress disorder and a smaller mean CA3/dentate gyrus (DG) subfield volume, a finding in line with animal models. This indicates that chronic stress inhibits neurogenesis and dendritic branching in these structures [27 ]. Protraction of stressful stimuli leads to dysregulation of specific neurochemical mechanisms, long-term changes in synaptic plasticity, and alterations in the hippocampal structure and function [28,29 ].
To better elucidate how prolonged stress affects the molecular function of the hippocampus we carried out genome-wide microarray analysis using a well-established...