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Author ORCID Identifier

https://orcid.org/0009-0003-9134-8669

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Neuroscience and Behavior

Year Degree Awarded

2023

Month Degree Awarded

September

First Advisor

Karine Fénelon

Second Advisor

Luke Remage-Healey

Third Advisor

Rolf O. Karlstrom

Fourth Advisor

Mariana Pereira

Subject Categories

Neuroscience and Neurobiology

Abstract

Sensorimotor gating is a fundamental pre-attentive process, which can be operationally measured through prepulse inhibition (PPI) of the startle response. PPI describes the suppression of the startle response when a non-startling stimulus (“prepulse”) precedes the startling stimulus (“pulse”). As a hallmark of schizophrenia, PPI deficits are also found in other neuropsychiatric disorders and are associated with cognitive overload and attention impairments (Braff et al., 2001). However, currently-used dopaminergic antipsychotics exhibit inconsistent effects on PPI in affected individuals (Geyer et al., 2001; Frau et al., 2014; Lally et al., 2016). Therefore, it’s critical to investigate the precise cellular and synaptic mechanisms behind PPI, both under physiological and pathological conditions. The brainstem structure, caudal pontine reticular nucleus (PnC), is at the core of the startle and PPI circuitry. The PnC mainly comprises startle-mediating giant neurons and inhibitory glycinergic neurons (Koch and Friauf, 1995; Zeilhofer et al., 2005). Recent findings from our lab have indicated that the central nucleus of the amygdala (CeA) contributes to PPI by sending glutamatergic inputs to the PnC (Cano et al., 2021). Moreover, these CeA glutamatergic neurons form synapses with PnC glycinergic neurons, suggesting a potential role of PnC glycinergic neurons in PPI. Therefore, this dissertation aims to investigate the contribution of the CeA-PnC connection to PPI by 1) determining the role of PnC glycinergic neurons in PPI 2) using Cal-Light to identify PPI-related neurons with high spatiotemporal resolution in the CeA and PnC 3) examining the CeA-PnC connection in Prodh-/- mice relevant to schizophrenia. We used multiple transgenic mouse models combined with optogenetics, tract tracing, and immunohistological assays in the study. Our results suggest that the projection from CeA glutamatergic neurons to PnC glycinergic neurons plays an important role in PPI, which is further supported by the specific labeling of neurons active during PPI in both regions. Additionally, an altered CeA-PnC connection may underlie PPI deficits in Prodh-/- mice, which can be rescued through photo-activation of this connection. Taken together, these findings expand our understanding of the PPI circuitry and provide critical insights toward identifying potential therapeutic targets for addressing sensorimotor gating deficits.

DOI

https://doi.org/10.7275/36001852

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