Neuroinflammation, Early-Life Adversity, and Brain Development

Abstract

The overarching objective is to review how early exposure to adversity interacts with inflammation to alter brain maturation. Both adversity and inflammation are significant risk factors for psychopathology. Literature relevant to the effects of adversity in children and adolescents on brain development is reviewed. These studies are supported by research in animals exposed to species-relevant stressors during development. While it is known that exposure to adversity at any age increases inflammation, the effects of inflammation are exacerbated at developmental stages when the immature brain is uniquely sensitive to experiences. Microglia play a vital role in this process, as they scavenge cellular debris and prune synapses to optimize performance. In essence, microglia modify the synapse to match environmental demands, which is necessary for someone with a history of adversity. Overall, by piecing together clinical and preclinical research areas, what emerges is a picture of how adversity uniquely sculpts the brain. Microglia interactions with the inhibitory neurotransmitter GABA (specifically, the subtype expressing parvalbumin) are discussed within contexts of development and adversity. A review of inflammation markers in individuals with a history of abuse is combined with preclinical studies to describe their effects on maturation. Inconsistencies within the literature are discussed, with a call for standardizing methodologies relating to the age of assessing adversity effects, measures to quantify stress and inflammation, and more brain-based measures of biochemistry. Preclinical studies pave the way for interventions using anti-inflammation-based agents (COX-2 inhibitors, CB2 agonists, meditation/yoga) by identifying where, when, and how the developmental trajectory goes awry.

Figure 1.

A simplified model of the interactions of microglia (blue), parvalbumin neurons, and pyramidal neurons (gray) across age. Typically, microglia aid in pruning but will switch to an activated form and increase inflammatory factors. Second, cytokines decrease parvalbumin (PV; red) neurons and shift the balance to more excitation. Third, eventually, the neurons are surrounded by perineuronal nets (blue), and plasticity is limited. (Bottom) Voxel placement on the right in adolescent male rats. MRS data of GABA/tCr versus PV levels from the same animals as assayed by Western immunoblot. We can detect GABA levels with magnetic resonance spectroscopy (MRS) and compare them to PV levels later. Shown are controls animals (black dots), rats with a history of maternal separation (red dots). Levels of PV were quantified with Western Immunoblot, using our standard methods. The spectrograph and the location of the voxel are on the right. Credit to Dr. Dionyssios Mintzopoulos for the MRS data.

Figure 2.

Two different types of signals activate the innate immune system. The first pathway, mediated by the toll receptors (TLRs), recognizes an initiating pro-inflammatory signal. The second is mediated by the inflammasome, which has a well-recognized role in depression. The key protein complex, (Nod)-like receptor family pyrin domain-containing 3 (NLRP3), is a target of novel therapeutics. This complex is modulated by the cannabinoid receptor 2 (CB2), MARCH7 (axotropin). Signal 1 via the TLRs initiates the synthesis of NF-KB, which is involved in the synthesis of a Pro-IL-1b. The NLRP3 activates Caspase-1, which then results in a cleaved and active IL-1b. This simplified diagram suggests that there are two different points of access to regulate inflammation.