Enhanced brain performance in mice following postnatal stress

Abstract

The double postnatal stress model (brief maternal separation plus sham injection daily applied from birth to weaning) induces metabolic alterations similar to type 2 diabetes in young-adult male mice. We verify whether 1) the stress also induces brain metabolic-functional alterations connected to diabetes and 2) different alterations are modulated selectively by two stress-damaged endogenous systems (opioid-and/or ACTH-corticosteroid-linked). Here, diabetes-like metabolic plus neurophysiologicneurometabolic parameters are studied in adult mice following postnatal stress and drug treatment. Surprisingly, together with 'classic' diabetes-like alterations, the stress model induces in young-adult mice significantly enhanced brain neurometabolic-neurophysiologic performances, consisting of decreased latency to flash-visual evoked potentials (Kw8%); increased level (Cw40%) and reduced latency (Kw30%) of NAD(P)H autofluorescence postsynaptic signals following electric stimuli; enhanced passive avoidance learning (Cw135% latency); and enhanced brain-derived neurotrophic factor level (Cw70%). Postnatal treatment with the opioid receptor antagonist naloxone prevents some alterations, moreover the treatment with antisense (AS; AS vs proopiomelanocortin mRNA) draws all parameters to control levels, thus showing that some alterations are bound to endogenous opioid-system hyper-functioning, while others depend on ACTHcorticosterone system hyper-functioning. Our stress model induces diabetes-like metabolic alterations coupled to enhanced brain neurometabolic-neurophysiologic performances. Taken all together, these findings are compatible with an 'enduring acute-stress' reaction, which puts mice in favorable survival situations vs controls. However, prolonged hormonal-metabolic imbalances are expected to also produce diabetes-like complications at later ages in stressed mice.

Etiopathogenesis and Pharmacological Prevention of a Type-2 Diabetes Model in Male Mice

“…4C) (Loizzo et al, 2010a). Antiociceptive effects induced by stress on prepuberal/puberal mice (up to about 45 PND), and enhanced performance of visual evoked potentials in adults were prevented by naloxone and also by AS-POMC (Loizzo et al, 2012b), whereas decreased sensitivity of ex vivo aorta isolated rings to noradrenaline contracting effects in stressed mice was prevented by AS-POMC but not by naloxone (Loizzo et al, 2015).…”

“…Alteration of several parameters described in adult mice, following postnatal double stressful procedures (presumably, also travel stress of pregnant mother may have induced a certain sensitization of HPA in mice fetuses; see Hiroi et al, 2016), were prevented by administering to our mice the opioid receptor-antagonist naloxone during the nursing period. Therefore, these alterations can be defined as prevalently opioid sensitive, and include metabolic parameters such as increase of body weight and abdominal fat weight (d'Amore et al, 1996;Loizzo et al, 2010a); increase of food caloric efficiency (Loizzo et al, 2012a); and increase of some brain mitochondrial parameter efficiencies including reduced latency of NAD(P)H fluorescence imaging evoked to cortical pathway inputs in ex vivo brain slices (Loizzo et al, 2012b), alteration of immunological parameters (increase of some cytokines of the Th-1-type released by splenocytes, decrease of some cytokines of the Th-2-type, increase of natural killer cell activity, increase of splenocyte proliferative activity (Loizzo et al, 2002), alteration of behavioral parameters (increased efficiency of passive avoidance test; see Loizzo et al, 2012a), and alteration of neurophysiologic parameters (reduced latency of visual evoked responses and oscillatory responses; see Loizzo et al, 2012b, and others) (see also Supplemental Material).…”

“…Therefore, a series of experiments was performed to identify those diabeteslike parameters induced by the stress model that were not (or only in part) prevented by naloxone treatment in stressed mice, but were efficaciously and dose-dependently prevented in adult mice by daily treatment with AS-POMC administered during the nursing period. These parameters were identified as prevalently ACTH-corticosterone sensitive, and included metabolic parameters (enhanced fasting glycemia; see Loizzo et al, 2010a); some brain mitochondrial parameter efficiencies, such as increased amplitude of NAD(P)H fluorescence imaging evoked to cortical pathway inputs in ex vivo brain slices (Loizzo et al, 2012b); neuroendocrine parameters, such as reduced CRH and ACTH at hypothalamic level, enhanced ACTH at pituitary and plasmatic levels, and enhanced corticosterone at plasmatic levels Loizzo et al, 2010a); and some vascular parameters, such as reduced contracting response to noradrenaline in isolated ex vivo aorta rings and enhanced relaxing response to acetylcholine (Loizzo et al, 2015). There was also a certain amount of interference exerted by naloxone on some endocrine parameters.…”

“…Besides the previously described parameters, another series of parameters was modified in adult mice following postnatal stress; however, prior to this current study we could not demonstrate with reasonable certainty the mechanisms through which these alterations were produced. This is in reference to some metabolic alterations, such as an increase in plasma insulin, leptin, and triglycerides ; some behavioral alterations, such as reduced immobility time in the Porsolt test (Franconi et al, 2004); some neurophysiologic alterations, such as enhanced long-term Stress-Derived Type-2 Diabetes Model potentiation in the hippocampus (Franconi et al, 2004), enhanced electroencephalogram total power, and enhanced power of very fast frequency bands in electroencephalograms (90-400 Hz) recorded during active wakefulness (Loizzo et al, 2012b); and some gene findings alterations, such as enhanced brain mRNA expression of 11b-hydroxysteroid dehydrogenase type 1 (HSD11B1), reduced brain mRNA expression of 11bhydroxysteroid dehydrogenase type 2 (HSD11B2) (Loizzo et al, 2010c), and others. Some effects listed here are depicted in Fig.…”

Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life

“…Detailed methods were described in previous papers [13,15,18]. Multiparous outbreed CD1 pregnant mice (Charles River Italia, Calco, Como) were transferred on the 14th conceptual day to our laboratory.…”