A dual-pathway architecture for stress to disrupt agency and promote habit

Chronic stress can change how we learn and, thus, how we make decisions. Here we investigated the neuronal circuit mechanisms that enable this. Using a multifaceted systems neuroscience approach in male and female mice, we reveal a dual pathway, amygdala-striatal neuronal circuit architecture by which a recent history of chronic stress disrupts the action-outcome learning underlying agency and promotes the formation of inflexible habits. We found that the basolateral amygdala projection to the dorsomedial striatum is activated by rewarding events to support the action-outcome learning needed for flexible, goal-directed decision making. Chronic stress attenuates this to disrupt action-outcome learning and, therefore, agency. Conversely, the central amygdala projection to the dorsomedial striatum mediates habit formation. Following stress this pathway is progressively recruited to learning to promote the premature formation of inflexible habits. Thus, stress exerts opposing effects on two..., Fiber photometry calcium imaging of CeADMS or BLADMS projections during instrumental learning following stress Male and female (BLADMS Control: Final N = 9, 4 male; BLADMS Stress: N = 12, 5 male; CeADMS Control: N = 11, 6 male; CeADMS Stress: N = 11, 4 male) naïve mice were used in this experiment to monitor calcium fluctuations in CeADMS and BLADMS projections during instrumental conditioning after stress. 18 subjects (not included in above N) with off-target viral expression and/or fiber location were excluded from the dataset. 4 subjects were excluded for loss of optic fibers/headcaps. 4 subjects were excluded for missing recording data from one session. 3 subjects that did not complete instrumental conditioning were also excluded. Mice were randomly assigned to Virus and Stress groups. At surgery, mice received unilateral infusion (left/right hemisphere counterbalanced across subjects within each group) of a retrogradely trafficked AAV encoding crerecombinase (AAVrg-Syn-Cre-..., , # A dual-pathway architecture for stress to disrupt agency and promote habit

**Description of the data and file structure**

Fiber photometry data was analyzed using custom-written Matlab codes. Source data for each figure is included in SourceData.xlsx.

**Source Data File**

All data for main and extended data figures is contained in the Source Data file. Data is organized by figure

**Code Files**

**NPM_new_gcamp_minus_isos_pipeline_V4.m** – for processing the data, subtracting the isosbestic channel, and calculating dF/F

**NPM_new_to_old_format_v4.m** – for converting data files from old Neurophotometrics format (v1) to new Neurophotometrics format (v2)

**align_df_F_zBL_medPC.m –** calculates dF with a z-scored baseline aligned to TTLs

**align_gcamp_medPC.m –** calculates dF aligned to TTLs

**align_gcampRaw_isosFit_medPC.m –** calculates dF with fit isosbestic channel

**align_z_df_F_medPC.m –** calculates z-scored df/F

**loadPhotometry_npm_temp.m –** loads photometry files

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