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.
Highlights
Females are more affected by psychiatric illnesses including eating disorders, depression, posttraumatic stress disorder and other anxiety disorders than males [1,2,3,4,5]
We evaluated a total of 6 conditions: (1) acute Boost1 (AB), (2) acute lithium chloride (LiCl) (AL), (3) NaCl injection only (AN), (4) Boost1 previously paired with NaCl (“Boost® only task (BOT)), (5) Boost1 previously paired with LiCl (BLT), and (6) context only task (COT)
We evaluated the supraoptic and paraventricular nuclei of the hypothalamus (SON, PVN), which respond to LiCl and have been implicated in inhibition of food intake [34,35,36,37,38,39,40,41].We evaluated the Central nucleus of the Amygdala (CeA) [42], which responds both to LiCl and Boost1, and has been shown to contribute to the establishment of either positive or negative affective valence of food stimuli, but is not required for acquisition of expression of Conditioned taste aversion (CTA) [37, 38, 42, 43]
Summary
Females are more affected by psychiatric illnesses including eating disorders, depression, posttraumatic stress disorder and other anxiety disorders than males [1,2,3,4,5]. Unlike many other classical conditioning paradigms, in which an aversive stimulus is paired with a neutral cue, the use of a palatable substance in CTA requires the animal to process the affective valence of the reward versus the aversion [14,15,16]. This provides an opportunity to understand neural processes by which this decision-making occurs. While this seems to be discordant with the human situation, careful reviews of sex differences in varying models of classical conditioning suggest that in situations involving stress, fear, or aversive stimulation, including conditioned taste aversion, males and females do not show quantitative differences in responding but utilize different strategies [12, 18, 19]
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