Behavioral flexibility—that is, the ability to deviate from established behavioral sequences—is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors. However, the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory remain elusive. Here we demonstrate in mice that basolateral amygdala (BLA)→OFC projections bidirectionally control memory formation when familiar behaviors are unexpectedly not rewarded, whereas OFC→dorsomedial striatum (DMS) projections facilitate memory retrieval. OFC neuronal ensembles store a memory trace for newly learned information, which appears to be facilitated by circuit-specific dendritic spine plasticity and neurotrophin signaling within defined BLA–OFC–DMS connections and obstructed by cocaine. Thus, we describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time, whereby novel memories are encoded by BLA→OFC inputs, represented within OFC ensembles and retrieved via OFC→DMS outputs during future choice.
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Individual data points are represented throughout. More detailed datasets are available from the corresponding author upon reasonable request.
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We thank R. A. Davies for technical assistance and laboratory members for feedback on the manuscript. This work was supported by National Institutes of Health grants F30MH117873 (D.C.L.), R01MH117103 (S.L.G.) and R01DA044297 (S.L.G.). The Emory Viral Vector Core is supported by National Institute of Neurological Disorders and Stroke Core Facilities grant P30NS055077. The Emory National Primate Research Center is supported by Office of Research Infrastructure Programs grant P51OD011132. Research reported in this publication was also supported, in part, by the Emory University Integrated Cellular Imaging Core and Children’s Healthcare of Atlanta.
The authors declare no competing interests.
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Response side bias (responses on aperture to be non-reinforced / total responses) during training sessions. (a) BLA→OFC inactivation: memory encoding (session: F14,378 = 1.22, 0.256; session × CNO: F28,378 < 1), (b) delayed memory encoding (session: F10,80 = 3.18, p = 0.002; session × CNO: F10,80 < 1), or (c) memory retrieval (session: F8,128 = 4.86, p < 0.001; session × CNO: F8,128 < 1). (d) BLA→OFC stimulation (session: F14,392 < 1; session × cocaine: F14,392 < 1; session × CNO: F14,392 = 1.30, p = 0.205; session × cocaine × CNO: F14,392 < 1). (e) OFC→DMS inactivation (session: F8,144 = 1.05, p = 0.404; session× CNO: F8,144 = 1.21, p = 0.295). (f) OFC→BLA inactivation (session: F8,112 = 1.04, p = 0.205; session × CNO: F8,112 < 1). (g) OFC memory trace inactivation: novel (session: F6,96 = 1.03, p = 0.414; session × 4OHT: F6,96 = 1.73, p = 0.122) or (h) familiar reinforcement conditions (session: F6,108 < 1; session × 4OHT: F6,108 < 1). (i) BDNF-dependent circuit function: BLA-OFC (session: F6,204 = 1.10 p = 0.365; session × lateralization: F12,204 < 1) or (j) OFC-DMS disconnections (session: F6,138 = 1.44, p = 0.204; session × lateralization: F12,138 < 1). Data presented as individual points (semi-transparent) and group means (solid). Correspondence to main figures noted.
(a,e) Behavioral procedure used to assess sensitivity to instrumental omission for nose-poking or lever-pressing. (b, c) Nose-poke responses across training (F6,42 = 10.1, p < 0.001) and during omission session (F5,35 = 16.9, p < 0.001). (d) Raster plot of nose-poking responses for each animal throughout the omission session. (f, g) Lever-pressing across training (F3,21 = 29.1, p < 0.001) and during omission session (F5,35 = 35.0, p < 0.001). (h) Raster plot of lever-pressing responses for each animal throughout the omission session. Data presented as individual points (semi-transparent) and group means (solid). Repeating measures ANOVA was applied, 2-sided, with no adjustment for multiple comparisons required.
(a) Left. Chemogenetic receptor expression in the anterior ventrolateral OFC from experiments described in Figs.1–3 of main text. Right. Extent of inhibitory chemogenetic receptor expression in the posterolateral OFC. Anterior-posterior (A-P) distance from bregma noted. (b) Timing of CNO administration for posterolateral OFC inactivation during memory encoding. (c) Responses across training (session: F6,84 = 73.9, p < 0.001; session × virus: F6,84 < 1). (d, e) Responses during first (reinforcement: F1,14 = 8.49, p = 0.011; reinforcement × virus: F1,14 = 1.59, p = 0.228) and second choice tests (reinforcement: F1,14 = 26.9, p < 0.001; reinforcement × virus: F1,14 < 1). Choice tests were performed on sequential days. Data presented as individual points or mean ± S.E.M. *p < 0.05 (main effect). n = 8 GFP, 8 hM4Di mice. Correspondence to main figures noted. Analyses were performed by ANOVA (2-sided) with repeating measures when appropriate; no adjustments for multiple comparisons required.
Extended Data Fig. 4 Responding during non-reinforced sessions did not differ between groups prior to choice tests.
All non-reinforced sessions were performed drug- and manipulation-free. (a) BLA→OFC inactivation (memory encoding): test 1 (time: F4,108 = 16.5, p < 0.001; time × CNO: F8,108 < 1), test 2 (time: F4,108 = 17.9, p < 0.001; time × CNO: F8,108 < 1), or test 3 (time: F4,108 = 16.2, p < 0.001; time × CNO: F8,108 < 1). (b) BLA→OFC inactivation (delayed memory encoding): test 1 (time: F4,56 = 29.9, p < 0.001; time × CNO: F4,56 < 1) or test 2 (time: F4,56 = 35.2, p < 0.001; time × CNO: F4,56 = 1.63, p = 0.179). (c) BLA→OFC inactivation (memory retrieval): test 1 (time: F4,64 = 12.2, p < 0.001; time × CNO: F4,64 < 1) or test 2 (time: F4,64 = 7.17, p < 0.001; time × CNO: F4,64 < 1). (d) BLA→OFC stimulation: test 1 (time: F4,112 = 16.3, p < 0.001; time × cocaine: F4,112 < 1; time × CNO: F4,112 = 1.18, p = 0.324; time × cocaine × CNO: F4,112 < 1), test 2 (time: F4,112 = 47.0, p < 0.001; time × cocaine: F4,112 = 2.61, p = 0.056; time × CNO: F4,112 = 2.19, p = 0.075; time × cocaine × CNO: F4,112 < 1), or test 3 (time: F4,112 = 55.2, p < 0.001; time × cocaine: F4,112 = 1.27, p = 0.284; time × CNO: F4,112 < 1; time × cocaine × CNO: F4,112 = 1.74, p = 0.147). (e) OFC→DMS inactivation: test 1 (time: F4,72 = 8.30, p < 0.001; time × CNO: F4, 72 < 1) or test 2 (time: F4,72 = 40.5, p < 0.001; time × CNO: F4,72 < 1). (f) OFC→BLA inactivation: test 1 (time: F4,56 = 20.8, p < 0.001; time × CNO: F4,56 < 1) or test 2 (time: F4,56 = 27.1, p < 0.001; time × CNO: F4,56 = 1.62, p = 0.183). (g-h) OFC memory trace inactivation: novel (time: F4,84 = 26.1, p < 0.001; time × 4OHT: F4,84 < 1) or familiar reinforcement conditions (time: F4,72 = 19.3, p < 0.001; time × 4OHT: F4,72 < 1). (i-j) BDNF-dependent circuit function: BLA-OFC (time: F4,136 = 61.6, p < 0.001; time × lateralization: F8,136 < 1) or OFC-DMS disconnections (time: F4,92 = 31.7, p < 0.001; time × lateralization: F8,92 < 1). Data presented as mean ± S.E.M. Correspondence to main figures noted.
(a) Responses across training (F14,196 = 16.9, p < 0.001). (b) Choice test responses (t14 < 1). Data presented as individual points or mean ± S.E.M. n = 15 mice. Analyses were performed by ANOVA with repeating measures, and paired t-test (2-sided).
Extended Data Fig. 6 Correlations between choice behavior and relative experience frequency of reinforced vs. non-reinforced nose pokes.
Correlation between individual choice test preference ratios (reinforced / non-reinforced) and the standard contingency measure (ΔP; see Methods) for each 25-minute non-reinforced session. (a) BLA→OFC inactivation: memory encoding (FR1: F1,28 < 1; RI30: F1,28 < 1; RI60: F1,28 = 2.40, p = 0.132), (b) delayed memory encoding (all F1,14 < 1), or (c) memory retrieval (all F1,16 < 1). (d) BLA→OFC stimulation (all F1,30 < 1). (e) OFC→DMS inactivation (all F1,18 < 1). (f) OFC→BLA inactivation (all F1,14 < 1). (g) Correlation coefficients (Pearson’s r) between session ΔP and choice test preference ratios for all experiments in panels a-f (in order). Data presented as individual points or group means. 95% confidence interval (grey shading). Correspondence to main figures noted.
Extended Data Fig. 7 Chemogenetic inactivation of OFC→DMS projections disrupts memory retrieval independent of repeated testing.
(a) Combinatorial viral targeting of OFC→DMS projections. (b) Timing of CNO administration for OFC→DMS projection inactivation during memory retrieval. (c) Responses across training (session: F6,48 = 33.3, p < 0.001; session × CNO: F6,48 < 1). (d) Choice test responses (reinforcement: F1,14 = 15.2, p = 0.002; reinforcement × CNO: F1,14 = 6.74, p = 0.021). Data resented as mean ± S.E.M. *p < 0.05 (post-hoc). n = 8 veh, 8 CNO mice. Experiments were replicated at least once, with concordant results.
Extended Data Fig. 8 Size of chemogenetically inactivated OFC neuronal ensembles does not predict choice behavior.
(a, b) Correlation between number of chemogenetically inactivated OFC neurons and choice test preference ratios (reinforced / non-reinforced) for OFC ensembles labelled following exposure to novel (F1,10 < 1) or familiar reinforcement conditions (F1,8 < 1). Data presented as individual points. 95% confidence interval (shading). Centre lines indicate regression.
(a) Location of all sampled dendrites from trained (T; filled circles) and yoked (∅; open circles) mice by anterior-posterior (A-P) distance from bregma. (b, c) Dendritic spine density across A-P extent of the ventrolateral OFC for yoked (F1,70 < 1) and trained mice (F1,70 < 1). Centre lines indicate regression. (d–f) Left panels. Dendrite diameter (cocaine: F1,20 < 1; training: F1,20 < 1; cocaine × training: F1,20 < 1), dendritic spine length (cocaine: F1,20 = 3.80, p = 0.053; training: F1,20 = 1.47, p = 0.227; cocaine × training: F1,20 < 1) and dendritic spine diameter (cocaine: F1,20 < 1; training: F1,20 < 1; cocaine × training: F1,20 < 1). Right panels. Percent change (trained mouse vs. yoked cage mate) in dendrite diameter (t10 < 1), dendritic spine length (t10 < 1), and dendritic spine diameter (t10 < 1). Data presented as individual points (solid = per animal; transparent=per dendrite). #p = 0.053 (main effect). n = 6 sal ø, 6 coc ø, 6 sal T, 6 coc T mice.
Extended Data Fig. 10 Correlations between BLA→OFC→DMS circuit-defined dendritic spine plasticity and choice behavior.
Correlation between individual choice test preference ratios (reinforced / non-reinforced) and dendritic spine parameters from Fig.6. (a–d) Dendritic spine density for all spines (F1,10 = 5.12, p = 0.047), and by mushroom- (F1,10 = 5.71, p = 0.038), thin- (F1,10 = 1.14, p = 0.311), and stubby-type spines (F1,10 < 1). (e–h) Percent change (trained mouse vs. yoked [∅] cage mate) in dendritic spine density for all spines (F1,10 = 1.43, p = 0.259), and by mushroom- (F1,10 < 1), thin- (F1,10 = 8.79, p = 0.014), and stubby-type spines (F1,10 = 1.10, p = 0.319). (i-j) Mushroom-to-thin spine-type ratio (F1,10 = 4.88, p = 0.052). Percent change (F1,10 = 4.03, p = 0.073). (k, l) Head volume of mushroom-type spines (F1,10 < 1). Percent change (F1,10 = 8.82, p = 0.014). Data presented as individual points. 95% confidence interval (grey shading). *p < 0.05. †p = 0.052. #p = 0.073. Panels g and l reproduced in Fig.6. Centre lines indicate regression.
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Li, D.C., Dighe, N.M., Barbee, B.R. et al. A molecularly integrated amygdalo-fronto-striatal network coordinates flexible learning and memory. Nat Neurosci 25, 1213–1224 (2022). https://doi.org/10.1038/s41593-022-01148-9
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