Arie Kaffman, MD, PhD

Roughly 1.5 million children are abused or neglected each year in the US and this alarming trend has been documented for over 30 years. In the absence of effective interventions, maltreated children often develop a range of behavioral, emotional, cognitive, and medical consequences that can be chronic and refractory to treatment. The total economic burden associated with early life adversity (ELA) is estimated to be $247 billion annually, which is equivalent to the combined costs of all cancers. ELA causes similar behavioral abnormalities in many mammalian species, including nonhuman primates and rodents. This suggests that animal models may elucidate the molecular and cellular changes that underlie these developmental changes in children. We currently have four interrelated projects in the lab.

Project 1- Role of microglia

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.

Project 2- Sex differences

A key question in the lab is why the development of certain circuits is differentially affected in males and females exposed to ELA, 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.

Project 3- Agrp/POMC neurons and 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 ELA. 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 ELA leads to impairment in the ability of maternal cues to activate POMC neurons. This in turn leads to inappropriate and sustained activation of Agrp neurons early in development resulting the development of insecure attachment, emotional dysregulation, and abnormal threat detection.

Project 4- Effects of ELA on myelination

ELA 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.