Stress deficits in reward behaviour are associated with and replicated by dysregulated amygdala-nucleus accumbens pathway function in mice

Abstract

Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) leads to reduced discriminative reward learning (DRL) associated with decreased BA-NAc activity, and to reduced reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc activity. Chronic tetanus toxin BA-NAc inhibition replicates the CSS-DRL effect and causes a mild REV reduction, whilst chronic DREADDs BA-NAc activation replicates the CSS effect on REV without affecting DRL. This study provides evidence that stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate opposite activity changes in reward (learning) neurons and aversion (effort) neurons in the BA-NAc pathway following chronic stress.

Engagement of basal amygdala‐nucleus accumbens glutamate neurons in the processing of rewarding or aversive social stimuli

“…Social events were manually time stamped onto the optical signal data. The time of each social event that resulted in the onset of a social episode, for example, approach, approach + mount, approach + copulation, was designated as t = 0 s. The fibre photometry data were analysed with custom-written MATLAB programmes (Ineichen et al, 2022;Madur et al, 2023). Optical signal data were demodulated at 970 Hz, down-sampled to a sampling frequency of 20 Hz and smoothed using an exponential smoothing function with damping factor 0.5, thereby excluding some of the broad-spectrum signal noise.…”

“…Recombinant AAV vectors (Viral Vector Facility, Zurich Neuroscience Center, ETHZ/UZH) were used for pathway specific expression. For calcium-dependent fluorescent GCaMP6 expression in BA-NAc neurons, a vector encoding GCaMP6 incorporated into a construct with FLEX, ssAAV-9/2-hSyn1-chI-dlox-GCaMP6m-dlox-WPRE-SV40p(A) (rAAV-FLEX-GCaMP6; 4.2 Â 10 12 vg/mL, 300 nL) (Grewe et al, 2017;Madur et al, 2023), was injected unilaterally in the BA (see Stereotactic surgery for retrograde tracing and fibre photometry). For Ca 2+independent EGFP expression, as a control to determine whether certain social behaviours generated movementrelated artefacts in the fibre photometry signal, a vector encoding EGFP incorporated into a construct with FLEX, ssAAV-9/2-hSyn1-dlox-EGFP (rev)-dlox-WPRE-hGHp(A) (rAAV-FLEX-EGFP; 8.2 Â 10 12 vg/mL, 300 nL; Grewe et al, 2017) was injected unilaterally in the BA.…”

“…As described in detail elsewhere (Ineichen et al, 2022;Madur et al, 2023), the optic fibre implant was removed, and the brain sectioned coronally at 100 μm using a vibratome (Leica). Sections underwent Nissl staining (NeuroTrace 640/660 Deep-Red Fluorescent Nissl Stain, Thermo Fisher), followed by washing in PBS, mounting on microscope slides, addition of Dako/DAPI fluorescence mounting medium (Sigma Aldrich) and coverslipping.…”

“…After BA vector injection, a fibre-optic probe (Ø = 200 nm) was implanted directly above the injection site (bregma AP À1.8 mm, ML ± 3.2 mm, DV À4.9 mm). Stable adhesion of the fibre-optic probe onto the cranium was achieved as described previously (Ineichen et al, 2022;Madur et al, 2023). Mice were distributed equally in terms of whether the left or right hemisphere was studied.…”

Mouse Model of Chronic Social Stress‐Induced Excessive Pavlovian Aversion Learning‐Memory

“…We have established a refined resident‐intruder paradigm in male mice, referred to as chronic social stress (CSS) (Azzinnari et al., 2014; Pryce & Fuchs, 2017). This 15‐day paradigm minimizes wounding and the chronic social threat exposure results in a number of changes in the behavioral responses to emotionally salient stimuli of relevance to major symptoms in stress‐related psychiatric disorders, both rewarding (Bergamini et al., 2016, 2018; Kukelova et al., 2018; Madur et al., 2023; Münster et al., 2022) and aversive (Adamcyzk et al., 2022; Azzinnari et al., 2014; Cathomas et al., 2019; Fuertig et al., 2016; Just et al., 2018). One of these aversion‐directed responses is increased PALM, such that male mouse CSS‐PALM constitutes a model of sustained psychosocial threat‐induced generalized hyper‐responsiveness to aversion.…”