Research Projects

Role of microglia

Fig 1

Microglia from normally developing mouse brain are large, ramified cells (green) containing large number of synaptic puncta (red dots), Indicating efficient removal of non-functional synapses in the developing hippocampus. In contrast, mice exposed to early life adversity are smaller and contain fewer synaptic puncta. For more details, see Dayanada et.al. 2023, DOI:10.1016/j.bbi.2022.09.014.

Our group has been one of the first to propose that perturbation of microglial function during a critical period of development plays a crucial role in mediating changes in connectivity, cognition, and behavior observed in rodents exposed to early adversity (Johnson and Kaffman, doi: 10.1016/j.bbi.2017.06.008). We recently discovered that exposure to limited bedding (LB), a commonly used model ELA, causes significant impairments in the microglia's ability to phagocytose synaptic material in the hippocampus of 17-day old pups, when synaptic pruning peaks in the hippocampus. We have also shown that these deficits are at least partly mediated by a reduction in the expression of the receptor Trem2 on microglia and are associated with the retention of immature spines that persist into adolescence (Dayanada et.al. 2023, DOI: 10.1016/j.bbi.2022.09.014). We are currently investigating the underlying mechanisms that inhibit microglial-mediated synaptic pruning, aiming to clarify their impact on connectivity and behavior, and to identify strategies to reverse these deficits.

Sex differences

Fig 2

Connectivity between the amygdala (Amy) and the prefrontal cortex (PFC) is increased in male mice, but not female mice, exposed to complex stress abbreviated as UPS. For more details, see White 2020, doi: 10.7554/eLife.58301

A key question in the lab is why the development of certain circuits is differentially affected in males and females exposed to early adversity , while other circuits are similarly altered in both sexes. For example, using diffusion MRI we recently found that mice exposed to complex and unpredictable stress early in life, abbreviated as UPS show several neuroanatomical changes that resemble those seen in humans. These findings were observed in both male and female mice. Interestingly, UPS increases fronto-limbic connectivity in males, but not in female mice (White 2020, doi: 10.7554/eLife.58301). We would like to clarify why UPS increases fronto-limbic connectivity in males and not in females and how these sex-specific changes in connectivity impact behavior later in life.

Agrp/POMC neruons and attachment

Fig 3

Fiber photometry work from the Dietrich lab has shown that Agrp neurons are rapidly activated and inactivated when pups are separated and then reunited with the dam. For additional information see Zimmer 2019, doi 10.1016/j.cell.2019.04.026. In collaboration with the Dietrich lab, we are testing whether this response is altered in pups exposed to early adversity and whether abnormal Agrp activation is responsible for the formation of insecure attachment.

In collaboration with the Dietrich lab at Yale, we are investigating the role that Agrp and POMC neurons in the hypothalamus play in mediating abnormal attachment behavior in mice exposed to early adversity . This is an exciting and highly innovative project that utilizes cutting-edge technologies such as calcium imaging in pups, chemogenetic viral manipulations, and a sophisticated home-cage monitoring system. The project aims to test the hypothesis that normal attachment causes effective activation and the release of beta-endorphin from POMC neurons. This in turn inactivates a distress response mediated by neighboring Agrp-positive neurons in the hypothalamus. Exposure to early adversity leads to impairment in the ability of maternal cues to activate POMC neurons leading to inappropriate and sustained activation of Agrp neurons early in development. Abnormal development of Agrp/POMC circuitry contributes to the development of insecure attachment, emotional dysregulation, and abnormal threat detection.

Early adversity impairs myelination

Fig 4

Pups exposed to limited bedding show reduced myelination in the stratum lacunosum moleculare (SLM), one of the most highly myelinated regions in the developing hippocampus. For additional information see our recent BioRxiv preprint: https://www.biorxiv.org/content/10.1101/2023.08.08.552517v1.

Early adversity has been shown to impair myelination in rodents, non-human primates, and humans (Islam and Kaffman, doi:10.3389/fnins.2021.657693). This project explores the mechanisms by which ELA impairs myelin development and tests whether correcting these deficits in myelination can restore normal connectivity and behavior later in life.