Examination of a locus coeruleus to dentate gyrus noradrenergic circuit in aversive contextual processing

Abstract

Dysregulation in aversive contextual processing is believed to affect several forms of psychopathology, including post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a subregion of the hippocampus, is thought to be an important brain region for disambiguating new experiences from prior memories. Noradrenergic (NE) neurons in the locus coeruleus (LC) are more tonically active during stressful events and send dense projections to the DG, yet an understanding of their function in DG-dependent contextual discrimination has not been established. In this thesis, I isolate a key function of the LC-DG noradrenergic circuit in contextual aversive processing using selective manipulations and in vivo calcium imaging. In Chapter 1, we review the current understanding of LC-DG noradrenergic circuitry in aversive contextual processing, and its role in post-traumatic stress disorder. Next, we explore how activation of LC-NE neurons and terminal activity results in contextual generalization, while inhibition of this circuit results in facilitation of contextual disambiguation (Chapter 2). Additionally, we uncover how neural ensemble shifts in the DG granule cell layer (GCL) observed during contextual processing using in vivo 1-photon calcium imaging are involved in successful contextual discrimination, while failure in contextual discrimination is associated with a lack of neural ensemble shift in the DG (Chapter 3). In Chapter 4, we elucidate the effect of β-adrenergic receptor-mediated modulation of DG hilar interneurons to ultimately promote aversive generalization. Then, using in vivo fiber photometry, we demonstrate that prolonged NE release in the DG during aversive contextual processing results in successful contextual discrimination, even in the absence of an aversive stimulus, suggesting that norepinephrine dynamics in the DG serve an important role in driving contextual discrimination (Chapter 5). Altogether, the findings of this thesis suggest that modulation of LC-DG noradrenergic circuitry may serve as an important avenue for treating stress-induced disorders. Lastly, in Chapter 6, we outline our conclusions and future work to further build upon the findings of this thesis.