Subcallosal area 25: Its responsivity to the stress hormone cortisol and its opposing effects on appetitive motivation in marmosets

Abstract

Aberrant activity in caudal subcallosal anterior cingulate cortex (scACC) is implicated in depression and anxiety symptomatology, with its normalisation a putative biomarker of successful treatment response. The function of scACC in emotion processing and mental health is not fully understood despite its known influence on stress-mediated processes through its rich expression of mineralocorticoid and glucocorticoid receptors. Here we examine the causal interaction between area 25 within scACC (scACC-25) and the stress hormone, cortisol, in the context of anhedonia and anxiety-like behaviour. In addition, the overall role of scACC-25 in hedonic capacity and motivation is investigated under transient pharmacological inactivation and overactivation. The results suggest that a local increase of cortisol in scACC-25 shows a rapid induction of anticipatory anhedonia and increased responsiveness to uncertain threat. Separate inactivation and overactivation of scACC-25 increased and decreased motivation and hedonic capacity, respectively, likely through different underlying mechanisms. Together, these data show that area scACC-25 has a causal role in consummatory and motivational behaviour and produces rapid responses to the stress hormone cortisol, that mediates anhedonia and anxiety-like behaviour.

Keywords: Anhedonia; Anxiety; Area 25; Depression; Stress; Subcallosal anterior cingulate cortex.

Fig. 1

Human intruder behavioural paradigm. A. Human intruder test carried out in home cage illustrating zone categorisation. B. The factor loading of each measure used in the EFA score which is derived from an exploratory factor analysis from a cohort of 171 subjects (Quah et al., 2020).

Fig. 2

Appetitive Pavlovian paradigm. A. Schematic illustration of appetitive Pavlovian test apparatus with B. a timeline of a two-trial session used for all infusions.

Fig. 3

Progressive ratio behavioural paradigm. A. Schematic illustration of touchscreen-based test apparatus for progressive ratio test. B. Graph illustrating the progressive ratio schedule.

Fig. 4

Flow chart demonstrating the order of experiments carried out in A. Experiment 1 and B. Experiment 2. In Experiment 1 (n = 4), half the marmosets (subjects 1 and 2) were tested on appetitive Pavlovian discrimination before the human intruder and vice versa for the other half (subjects 3 and 4). All subjects then proceeded to appetitive Pavlovian test and peripheral cortisol manipulation. In experiment 2, seven out of eight marmosets were tested on progressive ratio, four of which were also tested on sucrose preference. One animal was only tested on sucrose preference.

Fig. 5

Histological verification of scACC-25 cannulation. A. Example of a cresyl stained coronal section with infusion site indicated by black arrows. B and C depict schematics indicating the confirmed infusion placements of subjects in experiments 1 and 2 respectively, within scACC-25 (light grey shading) at AP +13.80 (Paxinos et al., 2012). The range of infusion placements lay between AP 13.00–13.80.

Fig. 6

The effects of scACC-25 cortisol infusion on responsivity to uncertain threat and anticipatory arousal. A. Responsivity to an uncertain threat in the form of a human intruder was increased by scACC-25 infusion of Cort5 with an increase in the EFA score, whilst Cort1.5 had no effect. The factors contributing to this EFA increase were B. the time spent at the back of the cage (TSB%) and C. average height. Data are displayed as mean ± SEM error, *p < 0.05. D. Infusion of cortisol into scACC-25 decreased CS + directed head jerk behaviour at 1.5 ng/μl (Cort1.5) but not 5 ng/μl (Cort5) relative to saline. Peripheral injection of 20 mg/kg cortisol also decreased this behaviour (P-Cort20). E. Neither central or peripheral administration of cortisol impacted anticipatory cardiovascular arousal, with CS-directed MAP being unaffected. Female marmosets: diamond and square.

Fig. 7

The effect of scACC-25 interventions on appetitive motivation in the progressive ratio test. A. Inactivation (MB) and overactivation (DHK) of scACC-25 led to increases and decreases in overall responses, respectively. B. DHK infusion into scACC-25 reduced overall response rate compared to saline and MB. C. Average response rate per trial was decreased by DHK compared to saline. D. DHK increased the post reinforcement pause (PRP) compared to saline. E. Inactivation of scACC-25 led to an increase in the amount of time spent licking the spout outside of reward delivery when compared to saline and DHK. F. Water restriction increased the time spent licking outside reward delivery regardless of the effect of drug manipulation. Data are displayed as mean ± SEM error, *p < 0.05, **p < 0.01 and ***p < 0.001. Female marmosets: filled triangle, filled square, open circle, open diamond.

Fig. 8

The effect of scACC-25 interventions on consummatory behaviour. A. Inactivation and overactivation of scACC-25 had no effect on sucrose preference. B. Inactivation of scACC-25 increased consumption of sucrose solution compared to saline whereas DHK decreased it. C. Neither drug manipulation had any effect on water consumption. Data are displayed as mean ± SEM error, *p < 0.05. Female marmosets: triangle and square.