Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

Abstract

Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.

High Fat Diet Multigenerationally Affects Hippocampal Neural Stem Cell Proliferation via Epigenetic Mechanisms

“…Abnormal neurotrophin activity is a leading etiological hypothesis by which early-life adverse experiences persistently modify brain plasticity [ 41 ]. Therefore, early-life stress increased the gliogenesis in several brain areas including the hippocampus [ 42 ]. Accordingly, alteration of BDNF signaling and astroglial activation play a critical role in the diet-dependent dysregulation of neuroplasticity [ 43 , 44 ].…”

“…ChIP assay revealed a molecular shift of STAT proteins occurring between NeuroD1 and Gfap promoters, in parallel with both epigenetic repression of pro-neurogenic and activation of pro-glial differentiation genes ( Figure 6 B). This epigenetic rearrangement of STAT transcription factors on the regulatory sequences of genes regulating NSPC commitment could be a tentative but ineffective metabolic stress response aimed at fostering and expanding the neurogenic niche [ 42 ]. Moreover, the inhibition of BDNF signaling together with alteration of redox state or cytokine-related signals may lead to the STAT reassembly with chromatin remodeling complexes triggering astrocyte-specific gene expression in NSPCs [ 47 , 48 ].…”

Exercise in Adolescence Enhances Callosal White Matter Refinement in the Female Brain in a Rat Model of Fetal Alcohol Spectrum Disorders

“…AE-induced neuroimmune activation during fetal development disrupts the myelination of early cortical-hippocampal circuits in murine models of FASD [ 11 ]. Such alterations to the white matter milieu during development affect the onset and progression of processes involved in circuit refinement in adolescence, such as synaptic pruning and myelination [ 12 ].…”

Early Life Stress Affects Bdnf Regulation: A Role for Exercise Interventions

“…Over 30 years ago, Dr. David Barker presented the Barker Hypothesis, which stated that the perinatal environment sets off a chain reaction of neural programming that determines cognitive function and emotional health in adulthood [ 1 ]. In line with this idea, the perinatal period is marked by a degree of neural plasticity that is highly sensitive to environmental influences and not seen during any later period of life [ 2 , 3 , 4 ]. During this developmental period, a cascade of neural processes work in tandem to program the brain [ 4 ].…”

“…In line with this idea, the perinatal period is marked by a degree of neural plasticity that is highly sensitive to environmental influences and not seen during any later period of life [ 2 , 3 , 4 ]. During this developmental period, a cascade of neural processes work in tandem to program the brain [ 4 ]. Negative experiences during early development, such as stress, can alter the epigenetic regulation of neurotrophins [ 5 , 6 , 7 , 8 ] and thereby increase an individual’s susceptibility to later development of neuropsychiatric and neurodegenerative disorders [ 6 , 7 , 8 , 9 ].…”