Brain metabolic alterations in mice subjected to postnatal traumatic stress and in their offspring

Abstract

Adverse environmental and social conditions early in life have a strong impact on health. They are major risk factors for mental diseases in adulthood and, in some cases, their effects can be transmitted across generations. The consequences of detrimental stress conditions on brain metabolism across generations are not well known. Using high-field (14.1 T) magnetic resonance spectroscopy, we investigated the neurochemical profile of adult male mice exposed to traumatic stress in early postnatal life and of their offspring, and of undisturbed control mice. We found that, relative to controls, early life stress-exposed mice have metabolic alterations consistent with neuronal dysfunction, including reduced concentration of N-acetylaspartate, glutamate and γ-aminobutyrate, in the prefrontal cortex in basal conditions. Their offspring have normal neurochemical profiles in basal conditions. Remarkably, when challenged by an acute cold swim stress, the offspring has attenuated metabolic responses in the prefrontal cortex, hippocampus and striatum. In particular, the expected stress-induced reduction in the concentration of N-acetylaspartate, a putative marker of neuronal health, was prevented in the cortex and hippocampus. These findings suggest that paternal trauma can confer beneficial brain metabolism adaptations to acute stress in the offspring.

Keywords: Traumatic stress; magnetic resonance spectroscopy; metabolism; neurochemical profile; neurodevelopmental; transgenerational.

Figure 1.

Representative ¹H spectra acquired in vivo at 14.1 T from the mouse prefrontal cortex, dorsal hippocampus and striatum (a). For display, spectra were processed with a shifted Gaussian function (gf = 0.12, gfs = 0.02) prior to Fourier transformation. Peak assignment is as follows: 1, glucose; 2, lactate; 3, alanine; 4, phosphocreatine; 5, creatine; 6, glutamate; 7, glutamine; 8, GABA; 9, N-acetylaspartylglutamate; 10, aspartate; 11, glycine; 12, phosphorylethanolamine; 13, phosphrylcholine; 14, glycerylphosphorylcholine; 15, N-acetylaspartate; 16, glutathione; 17, ascorbate; 18, taurine; 19, myo-inositol. Consecutive mouse brain slices from fast-spin-echo images (6-mm thickness) are displayed below. Typical placement of VOIs in the cortex, striatum and hippocampus is represented in slices A–B, C–E and I–K, respectively. LCModel fit of the top spectrum (prefrontal cortex) is represented in (b). The fit is overlaid on the spectrum and the resulting residual is shown below. Mac: macromolecules; bk: background baseline; see text for metabolites.

Figure 2.

Neurochemical profiles in the hippocampus, prefrontal cortex and striatum of MSUS-exposed mice (F1, n = 11) and non-stressed controls (n = 12) mice. Data are mean ± SEM. *P < 0.05 for MSUS-exposed mice vs. controls. Ala: alanine; Asc: ascorbate; Asp: aspartate; Cr: creatine; GABA: γ-aminobutyrate; Glc: glucose; Gln: glutamine; Glu: glutamate; Gly: glycine; GPC: glycerophosphorylcholine; GSH: glutathione; Ins: myo-inositol; Lac: lactate; NAA: N-acetylaspartate; NAAG: N-acetylaspartylglutamate; PCho: phosphorylcholine; PCr: phosphocreatine; PE: phosphorylethanolamine; Tau: taurine.

Figure 3.

Neurochemical profiles in the hippocampus, prefrontal cortex and striatum of the offspring (F2) of MSUS-exposed (n = 24) and control mice (n = 21). Data are mean ± SEM. Abbreviations are as in Figure 2.

Figure 4.

Acute swim stress-induced variation of metabolite concentrations in the hippocampus, prefrontal cortex and striatum of the offspring (F2) of MSUS-exposed (n = 11) and control (n = 9) mice. Data are mean ± SEM. Multivariate ANOVA results: region F_(36,182) = 101.0, P < 0.001; stress F_(18,90) = 9.524, P < 0.001; MSUS F_(18,90) = 2.725; P = 0.001; region*MSUS F_(36,182) = 0.816, P = 0.773; stress*MSUS F_(18,90) = 1.803; P = 0.032; region*stress F_(36,182) = 2.552; P < 0.001; region*stress*MSUS F_(36,182) = 1.166, P = 0.248. Post-hoc testing significant stress-induced modifications are depicted by ^†P < 0.05 and ^‡P < 0.01 (baseline vs. post-stress); MSUS-exposure effect was tested on concentration differences between post-stress and baseline (*P < 0.05, **P < 0.01). Abbreviations are as in Figure 2.