Abstract
Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories.
Highlights
Life stress (ELS) exposure enhances susceptibility to neurodevelopmental disorders
To determine the optimal dose of Tumor Necrosis Factor (TNF) to use in the study, we performed a pilot experiment in which mouse pups were injected with TNF doses ranging from 0.25 to 20 μg/Kg (Figure 1A)
For pups injected with higher doses, 5 and 20 μg/Kg, there was a dose-dependent increase in serum TNF levels at P5, respectively (Figure 1C)
Summary
Life stress (ELS) exposure enhances susceptibility to neurodevelopmental disorders. Immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life (Cattane et al, 2020). Tumor Necrosis Factor (TNF) is a pro-inflammatory cytokine historically known as a chief orchestrator of the innate immune response (Holbrook et al, 2019), via signaling through two membrane receptors, TNFR1 and TNFR2. TNF is expressed as a 27 kDa transmembrane form (mTNF) that can be cleaved into a soluble 17 kDa form (sTNF) released in tissues and blood (Kriegler et al, 1988). TNF and its receptors are expressed outside the immune compartment, and notably in the brain (Probert, 2015). Cells of the brain parenchyma (neural stem cells, neuronal progenitors, neurons, oligodendrocytes, astrocytes and microglia), as well as endothelial cells of the blood-brain-barrier (BBB) express TNF and its receptors (Probert, 2015)
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