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Basic neurobiology studies

Hippocampal regulation of social cognition, aggression, and learning and memory

We recently reported a role for the dentate gyrus (DG) in the regulation of aggressive behaviors in mice (Lewis et al., 2018). Specifically, these studies showed an association between DG activation and aggressive behaviors. We also demonstrated that alpha-7 nicotinic acetylcholine receptor (nAChR) agonists reduced aggressive behavior and reduced DG activation (Lewis et al., 2015 and 2018). In the DG, alpha-7 nAChRs are located on non-granule cells, specifically certain subtypes of GABAergic interneurons and mossy cells, and thus we hypothesize that these cell types may play a regulatory role in aggressive behaviors. We are thus interested in testing the role of these cells in regulating aggressive and social behaviors by optical recording from these cell subtypes, as well as performing activation and inhibition experiments to identify behavioral effects.

More broadly, we are interested in how the DG communicates with other hippocampal and non-hippocampal brain regions to regulate these behaviors, as well as further investigate the potential of nAChR-agents to modulate these circuits.

Mossy cells

Mossy cells are a remarkably interesting glutamatergic neuron subtype located in the hilus of the dentate gyrus throughout the hippocampal dorsoventral axis. They receive input from granule cells and pyramidal neurons and project locally to inhibitory interneurons and distantly to granule cell proximal dendrites in the inner molecular layer. These cells are vulnerable to cell death in a number of important neuropsychiatric disorders as well. We are currently studying the role of mossy cells in the caudal hippocampus on regulation of aggressive behaviors as well as learning and memory.

 

Understanding how autism-specific genetic variation may contribute to development of challenging behaviors and aggression

Aggression and other challenging behaviors can present a major barrier to optimal functioning in neurodevelopmental disorders such as autism spectrum disorder (ASD). While there has been an explosion in understanding the genetic underpinnings of ASD, exactly how these alterations may specifically result in aggressive behavior is largely unknown. Through collaborations with Tom Fernandez, MD, at the Yale Child Study Center, we will use a variety of in vitro and in vivo animal model techniques to test the functional effects of specific genetic variants enriched in protein degradation pathways in multiple brain regions and neuron subtypes.