Reduced left ventricular dimension and function following early life stress: A thrifty phenotype hypothesis engendering risk for mood and anxiety disorders

Abstract

BackgroundEarly life stress (ELS) in macaques in the form of insecure maternal attachment putatively induces epigenetic adaptations resulting in a “thrifty phenotype” throughout the life cycle. For instance, ELS induces persistent increases in insulin resistance, hippocampal and corpus callosum atrophy and reduced “behavioral plasticity”, which, taken together, engenders an increased risk for mood and anxiety disorders in humans but also a putative sparing of calories. Herein, we test the hypothesis whether a thrifty phenotype induced by ELS is peripherally evident as hypotrophy of cardiac structure and function, raising the possibility that certain mood disorders may represent maladaptive physiological and central thrift adaptations.Methods14 adult bonnet macaques (6 males) exposed to the maternal variable foraging demand (VFD) model of ELS were compared to 20 non-VFD adult subjects (6 males). Left ventricle end-diastolic dimension (LVEDD), Left ventricle end-systolic dimension (LVESD) and stroke volume (SV) were calculated using echocardiography. Blood pressure and heart rate were measured only in females. Previously obtained neurobehavioral correlates available only in males were analyzed in the context of cardiac parameters.ResultsReduced LVESD (p < 0.05) was observed when controlled for age, sex, body weight and crown-rump length whereas ejection fraction (EF) (p = 0.037) was greater in VFD-reared versus non-VFD subjects. Pulse pressure was lower in VFD versus non-VFD females (p < 0.05). Male timidity in response to a human intruder was associated with reduced LVEDD (p < 0.05).ConclusionsELS is associated with both structural and functional reductions of left ventricular measures, potentially implying a body-wide thrifty phenotype. Parallel “thrift” adaptations may occur in key brain areas following ELS and may play an unexplored role in mood and anxiety disorder susceptibility.

Association of Childhood Adversity With Differential Susceptibility of Transdiagnostic Psychopathology to Environmental Stress in Adulthood

“…Studies of stress-related epigenetic changes support this hypothesis that early adversity alters the expression of stress hormone factors implicated in the development of stress-related psychopathology. 21 , 22 , 23 For example, Klengel and colleagues 6 , 24 showed that childhood trauma-dependent demethylation of a glucocorticoid response element ( FKBP5 [OMIM 602623 ] codes for a nuclear receptor involved in terminating the stress response to threat) resulted in increased risk for the development of posttraumatic stress disorder in adulthood. Thus, the association between childhood adversity and mental health disorders in adulthood is consistent with increased vulnerability to negative environmental influences in particular.…”

Lifelong reductions of PKMζ in ventral hippocampus of nonhuman primates exposed to early-life adversity due to unpredictable maternal care

“…We speculate that attenuation of a neural substrate critical to emotional navigation and affective memory maintenance may ensue. An adversity-induced reduction in PKMζ-maintained LTP in the afferent and efferent projections of the ventral hippocampus could, in turn, impair neocortical function in certain areas or circuitries, in line with a caloric “thrift” hypothesis that we have proposed for depression ( Coplan et al 2018 ). The reduction in the molecular mechanism of LTP maintenance within the ventral hippocampus may therefore be relevant to the underlying mechanisms of mood disorders and posttraumatic disorders.…”

“…Affective memory potentially underlies components of personal identity ( Karavanta 2013 ) and might modulate risk for the development of psychiatric disease, including posttraumatic stress disorder (PTSD) and depression ( Bryant et al 2007 ; van Vugt et al 2012 ). An impairment of affective memory through reduction of PKMζ expression might also serve a protective or defensive role through reduction of the putative caloric demand required for the maintenance of memories of uncertainty and stress, including those formed early in infancy in the context of adversity ( Coplan et al 2018 ). Although we are unaware of published work on PKMζ in human depression or PTSD, studies on PKMζ in PTSD are ongoing (Coplan and Sacktor), and the results will be of interest in relation to these NHP data.…”

Injectable Nanocomposite Implants Reduce ROS Accumulation and Improve Heart Function after Infarction

“…Overall, such reduced damage and preservation of LV wall dimensions may assist in preservation of heart function. [ 51 , 52 , 53 , 54 , 55 , 56 ]…”

“…Overall, such reduced damage and preservation of LV wall dimensions may assist in preservation of heart function. [51][52][53][54][55][56] To determine whether the ability to absorb ROS in the LV after injury contributes to protection of the cells, we analyzed the integrity of the LV tissue downstream of the injury site. As shown, compared to the control groups, cardiomyocytes within the LV of animals treated with the composite hydrogel were elongated and aligned, as evidenced by the massive, organized troponin T expression (Figure 5e,f; and Figure S7, Supporting Information).…”