Effect of developmental stress on the in vivo neuronal circuits related to excitation-inhibition balance and mood in adulthood

Abstract

Introduction: Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET).

Methods: To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats.

Results: The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male.

Conclusion: Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.

Keywords: early life stress; neurotransmission; positron emission tomography; sex; trauma.

FIGURE 1

Schematic of the study protocol.

FIGURE 2

Comparison of the body weights in control, MS, and MRS group [(A) male and (B) female]. Data are presented as means ± SD (n = 6).

FIGURE 3

Comparison of immobility time in the forced swim test [(A) male and (B) female] and % time spent in open arms in the elevated plus-maze [(C) male and (D) female]. Data are presented as means ± SD (n = 6). Statistical significance was defined as a p-value less than 0.05 (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

FIGURE 4

Concentration of corticosterone (A), T3 (B), and T4 (C) levels form blood serum. Data are presented as means ± SD (n = 6). Statistical significance was defined as a p-value less than 0.05 (*p < 0.05, **p < 0.01).

FIGURE 5

Comparison of the neuroreceptor PET images of glutamate (A), GABA (B), and serotonin. (C) The mean PET images were obtained from 40 to 60 min and categorized as male and female.

FIGURE 6

Quantification of the radioactivities for the glutamate (A,B), GABA (C,D), and serotonin PET (E,F) in the specific brain regions in male (left) and female (right). Data are presented as the mean ± the SD (n = 6). Statistical significance was defined as a p-value less than 0.05 (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

FIGURE 7

Immunohistochemical staining of NeuN in the brain of male (A) and female (B) rats in the control, MS, and MRS groups. The NeuN immunoreactive (brown color) revealed on all hippocampus region (GCL, granule cell layer; ML, molecular layer; PL, polymorphic layer; SO, stratum oriens; SP, stratum pyramidale; and SR, stratum radiatum) [a–c: hippocampus (HC), d–f: CA1, g–i: CA3, j–l: dentate gyrus (DG) (count area: 100 × 100 μm, a,b: ×100, c–h: ×400)]; (C) Comparison of % relative number of NeuN staining cells in the CA1, CA3, and DG region; data are presented as means ± SD (n = 6). Statistical significance was defined as a p-value less than 0.05 (*p < 0.05, **p < 0.01, ****p < 0.0001).