Stress alters motivated behaviors, such as natural reward seeking and drug craving [1]. In drug self-administration animals, acute stress (e.g., forced swimming, foot shock, restraint stress) exposure following abstinence facilitates cue-induced drug seeking behavior and promotes relapse, as found with cocaine, heroin, nicotine and many other drugs [2], [3]. On the other hand, these stress stimuli lead to suppression of natural reward-seeking behavior in animals [4], which may implicate in prolonged changes in feeding behavior and eating disorders, such as anorexia nervosa [5]. However, the discrete neural circuitry mechanism underlying this suppression as stress coping strategy has not been delineated. Lateral septum (LS) is implicated in integrating cortical inputs and subcortical inputs for emotional, motivational functions, feeding regulation and responses to stress [6], [7], [8]. Early lesion and electrical stimulation studies emphasized its roles in regulating motivational behaviors to fulfill physiological needs such as food and water intake [9]. Recent study showed that the LS-lateral hypothalamus pathway mediates food seeking through gamma oscillation coupling, which is regulated by medial prefrontal cortex inputs [10]. On the other hand, lesion or chemogenetic inhibition of the dorsal hippocampal-septal circuit could prevent context-induced reinstatement of cocaine seeking [11]. In addition, another study reported that the pathway of LS-medial hypothalamus could also mediate aggressive behavior in mice [12]. Despite these evidences, potential LS downstream regions and neural circuitry in the limbic system relate to stress induced reward-seeking suppression remain unclear. In present study, we aim to understand the potential role of LS in regulating stress evoked suppression of natural reward seeking. The mice model of sucrose self-administration was established using a 10 days training paradigm, followed by 21 days of abstinence prior to the seeking test. We then examined the effects of acute stress on sucrose seeking and brain regional activity using c-Fos mapping. We further used chemogenetic tools to manipulate activity of intermediolateral septum (LSi), and two downstream targets relate to natural reward processing, ventral tegmental area (VTA) and Nucleus Accumbens (NAc), respectively, to understand the potential effects on modulation of stress effects. The results shall uncover the neural substrate underlying stress induced suppression of reward seeking and may indicate treatment targets for relevant disorders.

Stress alters motivated behaviors, such as natural reward seeking and drug craving [1]. In drug self-administration animals, acute stress (e.g., forced swimming, foot shock, restraint stress) exposure following abstinence facilitates cue-induced drug seeking behavior and promotes relapse, as found with cocaine, heroin, nicotine and many other drugs [2], [3]. On the other hand, these stress stimuli lead to suppression of natural reward-seeking behavior in animals [4], which may implicate in prolonged changes in feeding behavior and eating disorders, such as anorexia nervosa [5]. However, the discrete neural circuitry mechanism underlying this suppression as stress coping strategy has not been delineated. Lateral septum (LS) is implicated in integrating cortical inputs and subcortical inputs for emotional, motivational functions, feeding regulation and responses to stress [6], [7], [8]. Early lesion and electrical stimulation studies emphasized its roles in regulating motivational behaviors to fulfill physiological needs such as food and water intake [9]. Recent study showed that the LS-lateral hypothalamus pathway mediates food seeking through gamma oscillation coupling, which is regulated by medial prefrontal cortex inputs [10]. On the other hand, lesion or chemogenetic inhibition of the dorsal hippocampal-septal circuit could prevent context-induced reinstatement of cocaine seeking [11]. In addition, another study reported that the pathway of LS-medial hypothalamus could also mediate aggressive behavior in mice [12]. Despite these evidences, potential LS downstream regions and neural circuitry in the limbic system relate to stress induced reward-seeking suppression remain unclear. In present study, we aim to understand the potential role of LS in regulating stress evoked suppression of natural reward seeking. The mice model of sucrose self-administration was established using a 10 days training paradigm, followed by 21 days of abstinence prior to the seeking test. We then examined the effects of acute stress on sucrose seeking and brain regional activity using c-Fos mapping. We further used chemogenetic tools to manipulate activity of intermediolateral septum (LSi), and two downstream targets relate to natural reward processing, ventral tegmental area (VTA) and Nucleus Accumbens (NAc), respectively, to understand the potential effects on modulation of stress effects. The results shall uncover the neural substrate underlying stress induced suppression of reward seeking and may indicate treatment targets for relevant disorders.