Date of Degree

6-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Nesha Burghardt

Committee Members

Ekaterina Likhtik

Glenn Schafe

Elizabeth Bauer

Mark Ansorge

Subject Categories

Behavioral Neurobiology | Biological Psychology | Neuroscience and Neurobiology

Keywords

serotonin, bed nucleus of the stria terminalis, amygdala, fear learning

Abstract

Post-traumatic stress disorder (PTSD) is a trauma-related disorder characterized by intense fearful memory formation. Women are twice as likely as men to develop PTSD, indicating there may be sex differences in the underlying neural circuits. Given that serotonin (5-HT) dysfunction is implicated in PTSD, and 5-HT modulates fear learning, we investigated whether there are sex differences in the modulation of fear learning by 5-HT. We administered the selective serotonin reuptake inhibitor (SSRI) citalopram (20mg/kg or 10m/kg, i.p.) once to male and female mice prior to auditory fear conditioning and tested the effects on fear memory the next day. We found that elevating extracellular levels of 5-HT with citalopram before learning enhanced fear memory in females at both the low and high dose. In contrast, males only exhibited a modest elevation in fear memory during recall at the high dose, suggesting females may be more sensitive to increases in 5-HT than males. The low dose of citalopram also upregulated learning-induced c-Fos activity in the anterior dorsal bed nucleus of the stria terminalis (adBNST) and central amygdala (CeA) in females, but not males. To further explore the role of the extended amygdala in 5-HT mediated increases in fear learning, we optogenetically stimulated 5-HT terminals in the adBNST during auditory fear conditioning while simultaneously recording local field potentials in the adBNST in CeA. Similar to what we found with pharmacological upregulation of serotonin, this manipulation enhanced fear recall in females but not males, effects that were associated with greater high gamma (90 – 120 Hz) coherence between the adBNST and CeA. In females stimulation of 5-HT in the adBNST during conditioning also upregulated c-Fos in the oval BNST (ovBNST) and CeA, further implicating outputs to the CeA in the underlying circuitry. To determine if adBNST-to-CeA communication is necessary for 5-HT mediated increased in fear learning in females, we chemogenetically inhibited adBNST to CeA projections during conditioning and optogenetic stimulation of 5-HT in the adBNST. We found that inhibition of this projection significantly reduced recall of a cued and contextual fear memory, indicating adBNST-to-CeA communication modulates both auditory and contextual fear learning in females. We may be the first to show that sex differences in the 5-HT system contributes to greater fear learning in females by differentially affecting activity within the BNST-CeA circuit. Our findings may provide insight into why women are at a greater risk of developing PTSD than men and could inform novel treatment options for trauma exposed women.

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