Behavior and Fos activation reveal that male and female rats differentially assess affective valence during CTA learning and expression

Abstract

Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.

Chemogenetic activation of CRF neurons as a model of chronic stress produces sex-specific physiological and behavioral effects

“…This suggested that males learned the negative association faster or were more sensitive to the negative effects of CRF activation. Interestingly, this mirrors findings from conditioned taste aversion studies where male rodents developed an aversion to lithium chloride-containing saccharin faster than females and were slower to extinguish this aversion [ 88 – 92 ].…”

Hearing, touching, and multisensory integration during mate choice

“…Like in mice, female rats emit more 50 kHz calls when sexually receptive (Thomas and Barfield, 1985 ; Matochik and Barfield, 1994 ; Bernanke et al, 2021 ; Lenell and Johnson, 2021 ) and males increase their calling rate in the presence of a receptive female (McGinnis and Vakulenko, 2003 ; Portfors, 2007 ) indicating the potential of USVs to modulate female mate choice. However, there has been controversy regarding the importance of male calls in female mate choice; while some studies support the importance of male calls (Thomas and Barfield, 1985 ; Gerson et al, 2019 ) eliciting female approach behavior (Seffer et al, 2014 ; Willadsen et al, 2014 ; Berg et al, 2018 , 2021 ; Kisko et al, 2018 , 2020 ), others found that females choose vocalizing vs. non-vocalizing males equally often (Snoeren et al, 2014 ).…”

Chemogenetic activation or inhibition of histaminergic neurons bidirectionally modulates recognition memory formation and retrieval in male and female mice

“…Our object recognition results clearly indicate a sex-dependent effect of stimulation of TMN HA neurons on memory. Sex differences in cognitive functions have been documented in humans 30 and experimental animals 31,32 . For instance, robust sexual dimorphism was also described in the recruitment of circuits underlying fear memory and in the evolution of whole-brain networks over time 33 .…”