Differential Susceptibility to Extinction-Induced Despair and Age-Dependent Alterations in the Hypothalamic-Pituitary-Adrenal Axis and Neurochemical Parameters

Abstract

Clinical studies point to structural differences in the neurobiological mechanisms underlying early versus late onset of depression. However, studies examining the neuropathology of depressive-like behavior induced in the aged rodent are sparse. Extinction of learned behavior induces be- havioral ‘despair’, and is held to provide a conceptual and empirical model of human depression resulting from the withdrawal of reinforcement. We tested whether the neuroendocrinological and chemical concomitants of susceptibility to extinction-induced despair in aged animals differed from adult ones. Following the withholding of reinforcement (extinction of escape from a water maze), a number of aged and adult rats are prone to develop depressive-like behavior, i.e. immobility. Analysis of hypothalamus-pituitary-adrenal (HPA) axis markers revealed an increase in the mineralocorticoid/glucocorticoid receptor (MR/GR) mRNA ratio in the CA1 region of the hippocampus in aged and adult despair animals; however, in dependence on age, divergent changes contributed to the enhanced ratio. While aged despair rats had less GR mRNA, adult despair rats had more MR mRNA. Furthermore, age- and despair-related interactions with hippocampal and cortical steroid receptor co-activators and neurotransmitter contents in diverse brain areas were found. For instance, adult despair rats had an increased, and aged despair rats a decreased, DOPAC/dopamine turnover compared to the respective non-despair group. These results show that neurobiological underpinnings of depression in the aged differ from those of adults, and underline the importance of investigating age-related alterations in HPA axis dynamics in conjunction with neurotransmitter systems to advance our knowledge about neuronal mechanisms of late-life and/or late-onset depression.

A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

“…MR expression is highly dynamic, showing changes during development, aging and after physical or psychological stress. 30, 31, 32, 33, 34, 35 Context-dependent changes in MR expression can be established by distinct 5′ MR mRNA transcripts (MRα and MRβ), each having its own promoter containing regulatory elements and showing differential expression depending on tissue, time and availability of steroids and stress. 6, 30, 36, 37, 38 SNPs may result in differential expression of MRα vs MRβ by affecting TF binding or splicing.…”

Distance from source of reward as a marker for extinction-induced “despair”: Modulation by the antidepressants clomipramine and citalopram

“…In aged rats, the extent of immobility and, thereby, hypothetically, ''despair'', was correlated with different measures of anxiety in the open field, black-white box and the elevated-plus maze (Schulz et al, 2007b). Animals that had undergone extinction of water-maze escape also showed significant changes in the density of the mineralocorticoid/glucocorticoid receptors in the hippocampus (Topic et al, 2008b) and in the levels of brain-derived neurotrophic factor (BDNF) and nervegrowth factor (NGF; Topic et al, 2008a), all supporting the hypothesis that extinction can lead to a depressivelike state.…”

Diferencias individuales en modelos animales: un enfoque para el estudio de factores neurobiológicos relacionados con depresión

“…Lo anterior sugiere que las diferencias conductuales podrían estar relacionadas al menos en una parte, con diferencias en la neurotransmisión monoaminérgica asociadas con la edad; esto ha sido ha sido propuesto también por otros autores (Topic, Oitzl, Meijer, Huston & de Souza Silva, 2008;Arrant, Jemal & Kuhn, 2013). La comparación entre altos y bajos también arrojó datos interesantes al tomar en cuenta el factor edad.…”