Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer’s disease, traumatic brain and spinal cord injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior.

Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male-typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period.

Microglia, the innate immune cells of the central nervous system, regulate brain development by promoting cell genesis, pruning synapses, and removing dying, newly-born or progenitor cells. However, the role of microglia in the early life programming of behavior under normal conditions is not well characterized. We used central infusion of liposomal clodronate to selectively deplete microglia from the neonatal rat brain and subsequently assessed the impact of microglial depletion on programming of juvenile and adult motivated behaviors. Liposomal clodronate treatment on postnatal days one and four led to greater than 70% loss of forebrain microglia by postnatal day 6 that lasted for approximately ten days. Neonatal microglia depletion led to reduced juvenile and adult anxiety behavior on the elevated plus maze and open field test, and increased locomotor activity. On a test of juvenile social play, microglial depletion led to decreased chase behaviors relative to control animals. There was no change in active social behavior in adults on a reciprocal social interaction test, but there was decreased passive interaction time and an increased number of social avoidance behaviors in clodronate treated rats relative to controls. There was an overall decrease in behavioral despair on the forced swim test in adult rats treated neonatally with clodronate. Females, but not males, treated neonatally with clodronate showed a blunted corticosterone response after acute stress in adulthood. These results show that microglia are important for the early life programming of juvenile and adult motivated behavior.

Visual recognition memory is subserved by a distributed set of neural circuits, which include structures of the temporal lobe. Conflicting experimental results regarding the role of the hippocampus in nonspatial forms of such memories have been attributed to species, task, and lesion discrepancies. We have overcome obstacles that have prevented a direct evaluation of the role of the hippocampus in this type of memory by developing for rats a nonspatial, picture-based, trial-unique, delayed matching-to-sample task that is a procedural analogue of standard visual recognition memory tasks used in primates. With this task, we demonstrate that rats have a visual memory profile, which is analogous to that in primates and depends on the function of perirhinal cortex. We also find that selective lesions of hippocampus impair delay-dependent visual memory with a profile different from that produced by damage to the perirhinal cortex. These data demonstrate that rats have a visual recognition memory system fundamentally similar to primates that depends on the function of the hippocampus.M ost theories of medial temporal lobe function are in agreement that the hippocampus and perirhinal cortex are important for learning and memory. The specific processes that depend on the hippocampus, however, have been the subject of intense debate: in general, agreement exists that hippocampal function is essential for spatial memory, but wide disagreement occurs on the role of the hippocampus in nonspatial, visual recognition memory, or more generally, in explicit or episodic memory (1-5).The hallmark of this type of memory is retrieval of specific information from a single event (or episode) (6, 7). Trial-unique, delayed, matching-to-sample (DMTS) and delayed, nonmatching-to-sample (DNMTS) tasks, in which the participant must choose between two or more items, one of which is an item seen only once previously, have become the standard for measuring recognition memory in humans and nonhuman primates. Studies in primates have clearly shown that damage to perirhinal cortex disrupts performance on these tasks (8). The role of the hippocampus in this form of memory, on the other hand, cannot be as clearly inferred from existing data. For example, hippocampal damage in humans impairs performance on nonverbal recognition tasks, but the results in nonhuman primates are conflicting as to whether selective hippocampal damage impairs performance on visual recognition memory tasks (9-12).Visual recognition memory tasks have had limited application in rodents, but in general, recognition memory has been found to be unaffected by hippocampal damage unless the memory task includes a spatial component (13)(14)(15). A striking example of the apparent spatial dependence of hippocampal function is found in a study by Dudchenko and colleagues (16), in which memory for places or odors was measured in DNMTS procedures. The memory for places, but not odors, was disrupted by selective damage to the hippocampus. Attempts to measure nonspatial visual recognitio...