Investigating The Role of Hippocampal Dopamine in Early Life Adversity Effects on Fear Generalization

About This Grant

PROJECT SUMMARY: Fear generalization is an adaptive process by which a learned fear response to an aversive context is extended to a novel similar context. However, heightened fear generalization in the absence of persistent threat can lead to excessive fearfulness. Such overgeneralization of fear is observed in psychiatric disorders, such as generalized anxiety, PTSD, or depression. Early Life Adversity (ELA) is a major risk factor for these disorders, and generalization has indeed been proposed as a mechanism by which ELA increases risk for developing psychopathology. Understanding the neural mechanisms underlying fear generalization, and how they are affected by ELA, will thus be important to identify neural circuits regulating generalization during normal brain function, and how these circuits are affected in disease-relevant conditions. In this proposal, we will investigate how dopamine (DA) and norepinephrine (NE) release from locus coeruleus (LC) projections to the ventral dentate gyrus (vDG) of the hippocampus dynamically control and coordinate real-time neural responses during generalization, and how this regulation is disrupted by ELA. The vDG receives its main DA input from the LC. Our data show that ELA dampens DA signaling in the vDG, increases granule cell (GC) activity, and increases fear generalization. In Aim 1, we will now use in vivo imaging of DA biosensors and GC Ca2+ activity to study how ELA alters DA release in the vDG during fear generalization and how these temporal changes in DA release are associated with GC activity and freezing behavior. Because the predominant LC neurotransmitter is NE in addition to DA, we will also image NE release in combination with GC activity to compare how temporal dynamics of DA vs NE release in the vDG are associated with GC activity and freezing. In Aim 2, we will test whether LC-vDG projections increase fear generalization via NE, and whether they reduce fear generalization in ELA-exposed mice via DA. We will test these hypotheses using optogenetic stimulation of LC-vDG projections with simultaneous infusions of DA receptor antagonists or NE receptor antagonists into the vDG. In Aim 3, we will test the hypothesis that overlapping neural representations of an aversive and a novel context in the vDG are a neural correlate of generalization. We will use single cell in vivo Ca2+ imaging with head- mounted miniature microscopes to test whether GCs that encode an aversive context are reactivated more in a similar, but novel context in ELA-reared mice. We will then test whether DA release from LC projections disambiguates GC ensemble coding of fear and neutral contexts, and whether NE release from LC projections enhances overlap between GC ensembles for the two contexts. We will use machine learning techniques to predict how GC activity dynamics regulate freezing vs non-freezing behavior, and how they are affected by ELA and by DA vs NE. Overall, our study will use innovative neuroscience techniques to test a novel conceptual framework for how fear generalization is regulated at the neural circuit level, and how individual components of this circuit are modulated by ELA and by DA vs NE release from LC projections to the vDG.