Microglia morphology in the developing primate amygdala and effects of early life stress.

A unique pool of immature glutamatergic neurons in the primate amygdala, known as the paralaminar nucleus (PL), are maturing between infancy and adolescence. The PL is a potential substrate for the steep growth curve of amygdala volume during this developmental period. A microglial component is also embedded among the PL neurons, and likely supports local neuronal maturation and emerging synaptogenesis. Microglia may alter neuronal growth following environmental perturbations such as stress. Using multiple measures, we first found that microglia in the infant primate PL had relatively large somas, and a small arbor size. In contrast, microglia in the adolescent PL had a smaller soma, and a larger dendritic arbor. We then examined microglial morphology in the PL after a novel maternal separation protocol, to examine the effects of early life stress. After maternal separation, the microglia had increased soma size, arbor size and complexity. Surprisingly, strong effects were seen not only in the infant PL, but also in the adolescent PL from subjects who had experienced the separation many years earlier. We conclude that under maternal-rearing conditions, PL microglia morphology tracks PL neuronal growth, progressing to a more 'mature' phenotype by adolescence. Maternal separation has long-lasting effects on microglia, altering their normal developmental trajectory, and resulting in a 'hyper-ramified' phenotype that persists for years. We speculate that these changes have consequences for neuronal development in young primates. Significance Statement: The paralaminar (PL) nucleus of the amygdala is an important source of plasticity, due to its unique repository of immature glutamatergic neurons. PL immature neurons mature between birth and adolescence. This process is likely supported by synaptogenesis, which requires microglia. Between infancy and adolescence in macaques, PL microglia became more dense, and shifted to a 'ramified' phenotype, consistent with increased synaptic pruning functions. Early life stress in the form of maternal separation, however, blunted this normal trajectory, leading to persistent 'parainflammatory' microglial morphologies. We speculate that early life stress may alter PL neuronal maturation and synapse formation through microglia.

Rhythmic temporal coordination of neural activity prevents representational conflict during working memory.

Selective attention1 is characterized by alternating states associated with either attentional sampling or attentional shifting, helping to prevent functional conflicts by isolating function-specific neural activity in time.2,3,4,5 We hypothesized that such rhythmic temporal coordination might also help to prevent representational conflicts during working memory.6 Multiple items can be simultaneously held in working memory, and these items can be represented by overlapping neural populations.7,8,9 Traditional theories propose that the short-term storage of to-be-remembered items occurs through persistent neural activity,10,11,12 but when neurons are simultaneously representing multiple items, persistent activity creates a potential for representational conflicts. In comparison, more recent, "activity-silent" theories of working memory propose that synaptic changes also contribute to short-term storage of to-be-remembered items.13,14,15,16 Transient bursts in neural activity,17 rather than persistent activity, could serve to occasionally refresh these synaptic changes. Here, we used EEG and response times to test whether rhythmic temporal coordination helps to isolate neural activity associated with different to-be-remembered items, thereby helping to prevent representational conflicts. Consistent with this hypothesis, we report that the relative strength of different item representations alternates over time as a function of the frequency-specific phase. Although RTs were linked to theta (∼6 Hz) and beta (∼25 Hz) phases during a memory delay, the relative strength of item representations only alternated as a function of the beta phase. The present findings (1) are consistent with rhythmic temporal coordination being a general mechanism for preventing functional or representational conflicts during cognitive processes and (2) inform models describing the role of oscillatory dynamics in organizing working memory.13,18,19,20,21.