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Repeated cocaine exposure affects the trajectory of ensemble recruitment in an immediate early gene–dependent fashion. (A) Schematic showing experimental groups tagged by Arc (TdTomato) and c-FOS. (B) (i) Representative images of tdTomato expression in the NAc core of Arc-CreERT2 3 Ai14 mice. Mice were injected with 4-OHT, opening a window during which Arc transcription resulted in tdTomato expression in the same cells. Transcriptionally active neurons were labeled following: (left) a saline injection, (middle) cocaine injection (10 mg/kg intraperitoneally), or (right) cocaine injection (10 mg/kg intraperitoneally) following 10 days of repeated cocaine injections. (ii) Representative images of c-FOS–immunoreactive nuclei in the NAc core in the same ensembles: (left) saline injection, (middle) cocaine injection, or (right) cocaine injection (10 mg/kg intraperitoneally) following 10 days of repeated cocaine injections. (C) Number of tdTomato-positive nuclei in NAc core— indicating neurons that expressed Arc during the tagging window—in the saline, acute cocaine, and repeated cocaine ensembles normalized to the number of neurons identified in the saline ensemble (1-sample t test: saline t9 = 0.00036, p = .99; acute cocaine t9 = 0.36, p = .73; repeated cocaine t6 = 8.27, p = .0002). (D) c-FOS1 nuclei normalized to the number of nuclei detected in the saline ensemble (1-sample t test: saline t3 = 8.54 3 1025, p . .99; acute cocaine t3 = 1.074, p = .36; repeated cocaine t3 = 5.90, p = .0097). (E) The change in the number of cells labeled with c-FOS or Arc for each treatment group normalized to the saline ensemble for each respective immediate early gene (2-way analysis of variance, interaction: F2,33 = 4.09, p = .026; 2-way analysis of variance, main effect immediate early gene: F1,33 = 11.75, p = .0016; Sidak’s test for c-FOS vs. Arc repeated cocaine: t33 = 3.93, p = .0012). Values indicate mean 6 SEM unless otherwise indicated. Data points in panels (C) and (D) represent individual animals. **p # .01, ***p # .001. AC, anterior commissure; NAc, nucleus accumbens. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/585084c4-df5e-4185-8f0d-2a69d39be41f/Copy+of+Fig2+%282%29.jpg Recent Publications - Make it stand out Figure 2. The number of neurons activated by cocaine in vivo is reduced over repeated cocaine exposure. (A) Schematic of the timeline of calcium imaging. Miniscope recordings were performed on the first day and the tenth day of cocaine (10 mg/kg intraperitoneally) injections in the same animal. Calcium activity was recorded during a 5-minute baseline period (0–5 minutes), for 5 minutes after a saline injection (5–10 minutes), and for 10 minutes after a cocaine injection (10–20 minutes). An additional recording was collected 1 hour after the cocaine injection (60–65 minutes). (B) Representative maximum projection image for the field of view through the miniscope (yellow = excited, blue = inhibited, red = no change). (C) Representative traces showing different cellular responses to cocaine that we identified. One group of neurons was excited in response to cocaine injections (yellow); 1 group was inhibited in response to cocaine (blue); a third group showed no change (gray). (D) Heatmaps for cell activity (events/min) on day 1 and day 10. Cells were sorted according to activity following cocaine injection. (E) Venn diagram depicting cells that showed increased firing activity on day 1 in response to either cocaine or saline, where a significant minority of neurons showed increased activity to both injections. The numbers in the Venn diagram represent the number of cells. (F) Proportions of each activity phenotype observed after cocaine for each mouse (n = 5) on days 1 and 10. With repeated cocaine injections, more neurons were inhibited on day 10, and fewer neurons were excited on day 10 (inhibited c2 4 = 350.00, p , .0001; no change c2 4 = 32.86, p , .0001; excited c2 4 = 37.81, p , .0001). (G) Proportions of cells excited (yellow), inhibited (blue), or showed no change (gray) in activity after cocaine injection were significantly different on day 1 and day 10 (c2 2 = 28.97, p , .0001). Data points in panel (F) indicate individual animals. Values indicate mean 6 SEM unless otherwise indicated. ****p , .0001. GRIN, gradient-index; NAc, nucleus accumbens. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/d8e4084c-ab36-4a2d-b55c-5137ee02d595/Figure+1.jpg Recent Publications - Make it stand out Figure 1. D1 and D2 MSNs do not track stimulus valence (A) Cre-dependent GCaMP6f (AAV5.hsyn.flex.CGaMP6f) was expressed in D1 MSNs (D1-cre mice) or D2 (A2A-cre mice) MSNs. (Right) Example of GCaMP6f expression in NAc core. (B) D1 MSNs showed a positive response to sucrose retrieval in a positive reinforcement operant task (two-tailed independent sample t test, t45 = 2.897, p = 0.0058, n = 5 mice). Dark gray dots are individual trials across all animals, light gray dots are averaged responses for each animal. (C) D2 MSNs showed a decrease to sucrose retrieval in the same task (two-tailed independent sample t test, t60 = 6.29, p < 0.0001, n = 5 mice). (D) D1 MSNs showed an intensity-dependent positive response to unsignaled shock (nested ANOVA, F(1,39) = 6.53, p = 0.016, n = 5 mice). (E) D2 MSNs showed an intensity-dependent positive response to unsignaled shock (nested ANOVA, F(1,47) = 5.04, p = 0.031, n = 6 mice). (F) Intracranial self-stimulation (ICSS) task design. An excitatory opsin (ChR2; AAV5.Ef1a.DIO.hChR2) or a control vector (eYFP; AAV5.hSyn1.eYFP) was expressed in D1 MSNs or D2 MSNs in the NAc core. Nose pokes resulted in laser illumination (14 Hz, 2 s, 8 mW, 470 nM). Viral expression of ChR2 in the NAc core. (G) Mice were trained to nose poke for optical stimulation of either D1 MSNs or D2 MSNs over 4 days. (H) D1-Cre (D1 MSN) and A2A-Cre (D2 MSN) mice showed a preference for the active nose poke as compared with eYFP controls (repeated measures ANOVA, trial × group interaction F(6,42) = 3.17, p = 0.0118). (I) D1-cre (n = 5 mice) and A2A-Cre (D2 MSNs, n = 7 mice) showed a greater percentage of total responses on the active operanda as compared with the eYFP controls (n = 5 mice, one-way ANOVA, F(2,14) = 8.96, p = 0.0031; Dunnett’s post-hoc eYFP versus D1, p = 0.036; eYFP versus D2, p = 0.0016). (J) Training-dependent increase in responses in D1-Cre and A2A-Cre mice as compared with eYFP (one-way ANOVA, F(2,14) = 4.60, p = 0.0291; Dunnett’s post-hoc eYFP versus D1, p = 0.025; eYFP versus A2A, p = 0.049). Data represented as mean ± SEM; ∗p < 0.05; ∗∗p < 0.01, ∗∗∗∗p < 0.0001. Scale bars = 50 μm. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1b0fb6a5-2fa4-40e3-a39a-a1d7ac802a9b/Figure+6+%281%29.jpg Recent Publications - Make it stand out Figure 6. D2 MSNs, but not D1 MSNs, change dynamically over learning in both the pattern and timing of responses to learned cues (A) Neural trajectories summarizing the activity of D1-MSNs in fear-conditioning session 1 (FC1, [i], n = 157 neurons), D1-MSNs in fear-conditioning session 4 (FC4, [ii], n = 180 neurons), D2-MSNs in FC1 ([iii], n = 107 neurons), and D2-MSNs in FC4 ([iv], n = 111 neurons.) Each time point is depicted as an arrow pointing in the direction of the next time point. The size of each arrow is proportional to the delay until the next time point (i.e., how fast the activity is moving along the trajectory with large arrows depicting more rapid changes). The pre-cue baseline period is colored light gray, the cue period is color coded (D2-MSN/FC1, red; D2-MSN/FC4, orange; D1-MSN/FC1, dark blue; D1-MSN/FC4, light blue), and the shock period is colored dark gray. As mice learn the cue-footshock contingency, D2 MSN cue responses, but not D1 MSN responses, become more variable. (B) D2 MSNs were categorized based on observed activity patterns in the NAc during the initial fear-conditioning session (FC1) in the following categories: (i) response only to the cue, (ii) response only to the shock, and (iii) response both to the cue and shock. (C) In D1 MSNs, most of the cells only responded to the shock during the initial fear-conditioning session (FC1). (D) The D1 MSN cell recruitment to the cue and the shock was similar in the last fear-conditioning session (FC4), with a majority of cells responding only to the shock. (E) In D2 MSNs, initially (on FC1) only a small percentage of cells responded to both the cue and shock. (F) In FC4, a majority of D2 MSNs responded to both the cue and shock. (G) D2 MSNs were recorded on the first session (FC1) and cells detected during this session were longitudinally co-registered with cells in the last session (FC4) based on activity during each session. (H) Most of the cells that only responded to the cue in FC1 were not detected as active during the final fear-conditioning session (FC4, only 13% co-registered). The majority of D2 MSNs that responded to the shock (either shock alone, or both cue and shock) were re-recruited in FC4. (I) Heatmaps showing cue responses for fear-conditioning session 1 and 4 ordered by the tune of response following cue presentation. (J) Histogram of event numbers for each second of the cue period, superimposed on the Z scored averaged calcium responses. Event analysis showed that the number of D2 MSN events within the cue period increased with learning (chi square = 34.32, p < 0.0001) and the amplitude of those events became larger as well ([i] the whole cue period, unpaired t test, t718 = 4.26, p < 0.0001, n = 239–481 events). When clustered based on the timing of the response the peak event amplitude was larger in FC4 during the early segment ([ii] from the cue onset to 3 s; unpaired t test, t301 = 3.76, p = 0.0002, n = 78–225 events) but not during the middle ([iii] 3.5 s to 6.5 s, unpaired t test, t169 = 1.13, p = 0.26, n = 57–114 events) or the late ([iv] 7 s to the cue offset, unpaired t test, t191 = 1.33, p = 0.18, n = 73–120 events) segments of the cue period. (K) The event onset was earlier in FC4 compared with FC1 (unpaired t test, t718 = 3.61, p = 0.0003, n = 239–481 events). Data represented as mean ± SEM, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001, ns, not significant. (fear-conditioning session 1 [FC1]; fear-conditioning session 4 [FC4]). https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/b05bba99-cf3a-4b0c-9e24-109c8a25667a/NatureNeuro_Fig1_HTML.jpg Recent Publications - Make it stand out Neutral stimuli elicit dopamine responses that decrease over repeated presentations. a, Mice (n = 5; 4 males, 1 female) received unilateral injections of the fluorescent dopamine sensor dLight1.1 in the NAc. A fiber optic cannula was placed directly above the injection site in the NAc core. Representative histology showing viral expression (green) restricted to the NAc core and schematic showing fiber optic placements (red) in experimental animals. b, Stimulus exposure paradigm. A white noise stimulus was pseudo-randomly presented at 85 dB for 6–7 presentations for two sessions. c, Heatmap showing the trial-by-trial dopamine response (z-scores) to the neutral stimulus from each mouse (n = 5 for each trial; 6 trials in total). d, Session 1 dopamine signal to repeated white noise presentations (6–7 presentations per animal). The first presentation of the neutral stimulus evoked a significant positive dopamine response (peak height for the first presentation; two-tailed independent sample t-test, t4 = 4.02, P = 0.01, n = 5 mice). e, Averaged dopamine responses to white noise presentations on session 1 versus session 2, showing that dopamine is reduced to neutral stimuli both within and across sessions. f, Peak dopamine response evoked by the white noise decreased from session 1 to session 2 (nested ANOVA F(1,57) = 7.26, P = 0.009, Session 1 n = 30 and Session 2 n = 33 stimulus presentations, n = 5 mice). g, The time for the dopamine signal to return to baseline in seconds did not significantly differ across sessions, suggesting that changes are driven by release, rather than clearance, mechanisms (nested ANOVA F(1,57) = 0.40, P = 0.5316). h, Tau is another measure of dopamine clearance and is defined by the time in seconds for the signal to return to two-thirds of peak height. This measure did not differ across sessions (nested ANOVA F(1,57) = 2.65, P = 0.1093). Data are represented as mean ± s.e.m.; *P < 0.05; **P < 0.01; NS, not significant. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/6b9d1cba-1b61-4255-8d56-139e30973378/NatureNeuro_Fig2_HTML.jpg Recent Publications - Make it stand out Cue pre-exposure leads to decreased dopamine responses and learning rate during subsequent fear learnings. Latent inhibition is a learning phenomenon where pre-exposure to a neutral stimulus reduces learning rates for that stimulus. a, Mice (n = 7; 5 males, 2 females) were pre-exposed to a stimulus (Pre-exposed CS+) for four sessions. b, The pre-exposed CS+ as well as a novel stimulus (CS+) were paired with a footshock for two sessions. A novel stimulus (CS−) was presented between each CS+ presentation and signaled the absence of the footshock. c, Freezing to the pre-exposed CS+, CS+ and CS− was measured (session 1; for session 2 see Extended Data Fig. 4). There was a main effect of pre-exposure (RM ANOVA F(2,12) = 11.50, P = 0.001) and freezing was higher to the CS+ than the pre-exposed CS+ (Tukey post-hoc P = 0.035). Freezing was increased to the CS+ as compared with the CS− (Tukey post-hoc P = 0.001). d, Percentage of time freezing across session 1. Freezing to the CS+ was greater than the pre-exposed CS+ (RM ANOVA main effect of pre-exposure F(1,8) = 9.76, P = 0.014, n = 5 mice). e, Trial-by-trial dopamine response (z-scores) to the pre-exposed CS+ and f, CS+ (c) (n = 5 mice for each trial; 6 trials in total). g, Averaged dopamine response over trials. ITI, averaged dopamine response during the time between CS+ presentations in the same session. h, Peak dopamine response to the CS+ was higher than the ITI responses (nested ANOVA F(2,113) = 2.51, P = 0.0006, Bonferroni post-hoc: CS+ versus pre-exposed CS+ P = 0.08; CS+ versus ITI P = 0.0002; n = 30 trials, n = 5 mice); pre-exposed CS+ did not differ from the ITI responses (Bonferroni post-hoc P = 0.32). i, Time for dopamine to return to baseline was slower for the CS+ compared with the pre-exposed CS+ (nested ANOVA F(2,113) = 19.70, P = 0.0001, Bonferroni post-hoc P < 0.0001; n = 30 trials, n = 5 mice) and the ITI dopamine response (Bonferroni post-hoc P < 0.0001). j, Tau (time for signal to return to two-thirds of peak) did not change between CS+ and pre-exposed CS+ (nested ANOVA F(2,113) = 2.13, P = 0.123, Bonferroni post-hoc: P > 0.05). Data are represented as mean ± s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. RM, repeated measures ANOVA. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1632888574537-SKVVLMCFF2VMT00OPHO2/gr1.jpeg Recent Publications - Make it stand out Dopamine in the nucleus accumbens core does not track reward prediction error in negative reinforcement tasks. (A) Positive reinforcement task. (B) Dopamine was recorded via fiber photometry using dLight1.1. (C) Mice made more active than inactive responses during the post-training session (t6 = 3.18, p = 0.024; n = 6). (D and E) Heatmaps showing dopamine responses aligned around Sd,sucrose (left) and head entry (right) during (D) pre-training and (E) post-training. Each row represents a single Sd,sucrose presentation or head entry. (F and G) Averaged traces showing Sd,sucrose (F) and (G) head entry responses during pre- and post-training. (H) Dopamine increased to the Sd,sucrose (F1,153 = 10.79, p = 0.0013) and decreased to head entries over training (F1,75 = 11.17, p = 0.0013). (I) Negative reinforcement task. (J) Fiber photometry recording design. (K) Behavioral performance during negative reinforcement post-training session (t4 = 9.35, p < 0.001; n = 5). (L and M) Heatmaps of dopamine responses aligned around Sd,shock (left), footshock (center), and safety cue (right) during pre-training (L) and (M) post-training. (N–P) Dopamine traces to Sd,shock (N), (O) safety cue, and (P) footshock pre- and post-training. (Q) Dopamine response to Sd,shock (F1,96 = 1.52, p = 0.220), footshock (F1,127 = 4.00, p = 0.047), and safety cues (F1,95 = 15.46, p = 0.0002). Error bars represent ± S.E.M. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1632888894644-2G2CG6EH1LQ2M2X1SDKW/gr7.jpeg Recent Publications - Make it stand out Dopamine release signals perceived saliency (A) The Kutlu-Calipari-Schmajuk (KCS) model. The model has 4 core components. (1) Associative component: based on a Rescorla-Wagner prediction error term. (2) Attentional component: mismatch between predicted/unpredicted stimuli increases novelty, and in turn, attention to all stimuli in the environment. (3) Perceived saliency: novelty, attention, and the physical intensity of a stimulus determine perceived saliency. (4) Behavioral response component: perceived saliency is combined with associative strength to produce an outcome. (B–F) Experiments from Figure 4 were replotted to map onto model simulations. (B) Switching from positive reinforcement to punishment (denoted by dotted line) decreased simulated and actual nose pokes (r = 0.79, p < 0.0001; n = 5). (C) Perceived saliency of (gray) and dopamine responses to (blue) the cue similarly increased. (D–F) Dopamine response to the cue increased after a shock was introduced (t4 = 2.76, p = 0.025). KCS model simulations show that perceived saliency (E, R = 0.67, p < 0.0001) matches dopamine response patterns but prediction error does not (F, r = 0.092, p = 0.23).(G) Dopamine release was stimulated from terminals in the NAc core via optogenetics.(H) Dopamine release was evoked during fear conditioning to the cue on 25% of cue-shock pairings. (I) Increasing NAc core dopamine decreased freezing compared to EYFP controls (F1,20 = 17.84, p = 0.0004; ChR2-Tone + Stim versus EYFP-Tone + Stim, p ≤ 0.0001; ChR2-Tone + Stim versus ChR2-Tone only, p ≤ 0.0001; n = 5–6) and non-stimulated trials in the same animals (ChR2-Tone + Stim versus ChR2-Tone only, p = 0.0002). (J) KCS model simulations show that this behavior is predicted by increased perceived saliency. (K) NAc core dopamine release was evoked at the time of the omitted shock during extinction. (L) Dopamine stimulation prevented fear extinction in the ChR2 group compared to EYFP controls (F1,9 = 5.90, p = 0.038; last 4 trial block, t9 = 3.32, p = 0.0089; n = 5–6). (M) KCS simulations show that enhancing perceived saliency of the omitted shocks prevents extinction https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1629313503658-XYHOUPKDOZ2GV3OZWIG6/Screen+Shot+2021-08-18+at+2.00.14+PM.png Recent Publications - Make it stand out Sexual dimorphisms in the proteomic landscape of the nucleus accumbens. Mass spectrometry was run on tissue from the nucleus accumbens (NAc) of male and female mice to determine the proteomic landscape. Differential expression between females as compared to males was assessed in control mice. (a) Volcano plot showing sexually dimorphic proteins in the nucleus accumbens from female versus male mice. Male and female accumbens proteomes diverge at key proteins—some associated with reward and drug response are noted. (b) Heat map of baseline sexually dimorphic proteins in the accumbens. Insets showing the top 15 proteins that were decreased (left) and increased (right) in females as compared to males. (c) In order to conduct Gene Ontology (GO) analysis protein names had to be converted to associated gene names. These conversions are available in Supplementary Data 1. Top GO terms in proteins downregulated in females (compared to males) and (d) proteins upregulated in females (compared to males). (e) Proteins making up the representative GO terms (top) downregulated in females (cytoplasmic part) and (bottom) upregulated in females (protein binding). (f) STRING analysis of predicted protein interaction network of proteins differentially expressed in males and females (g) within the protein binding cluster, and (h) neuron projection. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1629313236731-PRPE09KV3YGBMJK6WMNR/Screen+Shot+2021-08-18+at+1.58.22+PM.png Recent Publications - Make it stand out Cocaine self-administration regulates different proteins in males and females even when cocaine intake and self-administration behavior are not different. (a) A series of behavioral experiments were run to assess sex differences in motivation for cocaine self-administration in males and females. Schematic/timeline of self-administration. (b) Average responses for cocaine under escalating fixed ratio schedules in male and female mice. Male and female mice acquire and consume cocaine at comparable rates under FR1, 3, and 5 schedules of reinforcement. (c) A concentration–response curve was run across days with doses counterbalanced between animals (0.1, 0.3, 1, and 3 mg/kg). Data were plotted as a demand curve where consumption was plotted on the y-axis and price (in responses required to obtain 1 mg cocaine) was plotted on the x-axis. Curves were fit to determine consumption at a minimally constraining price (Q0) and the maximal price paid (Pmax) in males and females. Standardized Pmax (Q0 × Pmax) was calculated to allow for comparisons that are not influenced by the relative level of consumption and are comparable across groups. (d) Q0—plotted as mg/kg to control for body weight differences—was not significantly different between males and females. (e) Standardized Pmax was also not significantly different between males and females. (f) In a separate group of animals, mice were trained to self-administer cocaine (or saline for control) for 10 days, after which NAc tissue was collected and processed for mass spectrometry. Schematic of self-administration, tissue collection, and processing for mass spectrometry. (g) Male and female mice consumed cocaine at the same rate and (h) there were no differences in total cocaine consumption. (i) Proteins significantly altered by cocaine self-administration in the NAc of female mice. Dotted lines on the volcano plot denote the significance cut off. (j) Proteins significantly altered by cocaine self-administration in the NAc of male mice. (k) Volcano plot showing only the proteins that are significantly regulated in females and those same proteins in males. Most of the proteins significantly regulated in females are not regulated in males. (l) Volcano plot showing only the proteins that are significantly regulated in males and those same proteins from the female group. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1592419309548-EBMNI6AI78RUJGFULVW2/Variable+Reinforcement+SUD_Figure+4.jpg Recent Publications New procedure for drug self-administration in mice that requires no food pre-training, shows robust self-administration, and increases drug intake. (A, left) Schematic for mouse intravenous cocaine self-administration. (A, right) Training and Self-administration schedule. (B) Active and inactive responses for cocaine (1mg/kg/inj) self-administration in mice on VR3 and VR5 schedules of reinforcement. Animals show a preference for active nose-poke compared to inactive that is schedule dependent. (C) Total cocaine infusions per session. (D) Active and inactive responses for saline in mice on VR3 and VR5 schedules of reinforcement. Mice do not show a preference for either the active or inactive nose-poke. (E) Total saline infusions per session. (F) Cumulative record of active and inactive responses across cocaine self-administration. (G) Cumulative record of cocaine infusions across cocaine self-administration. (H) Cumulative record of active and inactive responses across saline self-administration. (I) Cumulative record of saline infusions across saline self-administration. (J) Response rates on the active poke throughout training and self-administration. Cocaine animals demonstrate increased response rates on the active nose-poke throughout cocaine self-administration compared to saline controls. (K) Total active responses for saline and cocaine animals during VR3 and VR5. Cocaine animals respond more on active poke and increase responding under VR5 compared to saline controls. (L) Total inactive responses for saline and cocaine animals during VR3 and VR5. Cocaine animals respond less on the inactive poke compared to saline controls. (M) Cocaine animals demonstrate increased bias for active nose-poke during VR self-administration compared to saline controls. (N) Cocaine animals show increased bias during VR self-administration compared to saline controls. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1592419067468-2MD2Y3VCR5VZZQ92UAC1/41386_2020_692_MOESM2_ESM.jpg Recent Publications Females are biased towards avoiding aversive outcomes. Males and females demonstrate divergent rates of learning for positive and reinforcement; however, while females learn negative reinforcement at a slower rate they are biased towards avoiding aversive outcomes when they are presented concurrently with options to obtain rewards. Further, females demonstrate a bias for punishment avoidance and males demonstrate a bias for reward-seeking in the face of an aversive stimulus. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1592418734050-EUQ9V69J3L2761RYA6DU/Figure+6+%282%29.jpg Recent Publications Chemogenetic inhibition of D1 MSNs in the NAc disrupts positive reinforcement and enhances negative reinforcement learning. a Representative image of viral expression of DREADDs (hM4Di—inhibitory) in the NAc core of D1-Cre mice. b Schematic of experimental design. c Chemogenetic inhibition of NAc D1 MSNs during positive reinforcement learning reduced active responses. d,e After the learning criterion was met, inhibition of D1 MSNs did not affect task performance. f D1 MSN inhibition enhanced acquisition of negative reinforcement. g D1 MSN inhibition did not affect post-training performance. e D1 MSN inhibition did not alter discrimination between sucrose and avoidance responses. h D1 MSN inhibition did not change response bias during conflict trials. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1550072392698-SJ15NTNWKQA6QDJHUYMQ/41386_2019_320_Fig5_HTML+%281%29.png Recent Publications Figure 5. Cues are critical in the expression of sex differences in motivation. b Self-administration responses based on cycle stage on test day. There were no differences in responses across the dose-response curve. c No effect of cycle stage on the day of testing for motivation as measured by Pmax (left) or Q0 (right). d There was no change in responding over the dose-response curve or in Pmax (inset) in the presence of the diestrus paired cue when animals were in diestrus. e Similarly, there was no change in responding or in Pmax (inset) when cue was paired during diestrus and animal was tested in estrus. f No change in responding or in Pmax (inset) in the presence or absence of the cue in males. Cues that were paired in estrus increase motivation regardless of the cycle stage that the animal is in during testing. g Animals increased responding and Pmax (inset) in the presence of the estrus-paired cue during diestrus. h Similarly, estrus-paired cues increased responding and Pmax (inset) when animals were tested in estrus. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1550072520278-EJ28BGLQZJS3L05EW1G8/41386_2019_320_Fig4_HTML.png Recent Publications Figure 4. Mesolimbic and mesocortical activation patterns that underlie enhanced cue effects on motivation. c Number of c-fos+ and TH+ double-labeled cells in the VTA across groups. d c-fos+ and NeuN+ double-labeled cells in the infralimbic and prelimbic regions of the prefrontal cortex, *p < 0.05 compared to diestrus group (e) dorsolateral striatum, *p < 0.05 compared to male group (f) dorsomedial striatum, (g) NAc core, *p < 0.05 compared to male group and (i) NAc shell, *p < 0.05 compared to diestrus-paired group. h Correlation between number of lever presses and number of double-labeled c-fos+ and NeuN+ cells in the NAc core or (j) NAc shell. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1525098415066-GRRPC457AU31AIVL016A/gr1_lrg.jpg Recent Publications https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1517333890376-ROT64OO5KNVCFN4751G5/CombinedMainFigures_FINAL_Page_1.jpg Recent Publications Fig. 1 Serum multiplex analysis after self- and experimenter-administered cocaine in mice. a Timeline of experimenter-administered chronic cocaine injections. b Cocaine resulted in robust locomotor sensitization. c Timeline of cocaine self-administration in mice. d Average daily intake of cocaine across self-administration sessions. e Multiplex serum analysis of 32 chemokines, cytokines, and growth factors after experimenter- or self-administered cocaine. For each analyte, the heatmap depicts fold-change values compared to the respective saline group. Correlation heatmap of individual analyte levels with either locomotor sensitization (Day 10/Day 1) or daily intake of cocaine https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1517333263100-E517LL78HCXL8RZVG4P5/CombinedMainFigures_FINAL_Page_2.jpg Recent Publications Fig. 5 G-CSF levels are increased by the selective activation of mPFC to NAc projections. a Experimental design of projection-specific DREADD stimulation. Mice were injected with a retrograde traveling CAV2-Cre virus in the NAc and a Cre-dependent hM3Dq-DREADD virus in either the mPFC or the VTA to allow for the specific stimulation of either mPFC to NAc or VTA to NAc. b Csf3 (G-CSF) mRNA levels in the NAc were increased after mPFC to NAc stimulation. c Csf3r (G-CSFR) mRNA levels in the NAc were increased only after mPFC to NAc stimulation. d Peripheral G-CSF serum levels were not affected by stimulation. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495554779781-Z23MM36OEEAU46QH8SF0/SchematicDIagram-01.jpg Recent Publications Proposed schematic highlighting a potential mechanism for the activity-dependent changes in reward processing that occur during oestrus. (1) The VTA to NAc pathway comprises dopaminergic neurons (purple) and other neuronal subpopulations (grey). (2) Dopamine neuron firing is enhanced during oestrus. (3) The increased activity of this pathway leads to downstream ERK activation and concomitant phosphorylation of Thr53 (blue) on DAT. (4) These changes in DAT lead to alterations in cocaine affinity, whereby cocaine is more able to bind to DAT and increase extracellular dopamine levels. This increased cocaine binding leads to increased dopamine levels in the NAc. (5) In vivo this drives increased associations between cocaine and contextual cues, which leads to enhanced cocaine CPP due to differences in the perceived rewarding value of cocaine. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495555478374-H9C6J8TB2II9W3VJZ3RY/Figure+5_CNO.jpg Recent Publications Figure 5. Download manuscript PDF below. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495555604220-N2HQWIU1C8XI6S1L35PW/Cover+Art_FINAL.jpg Recent Publications This work outlined the temporally signature of D1 and D2 medium spiny neuron encoding of reward information and how it is dysregulated by cocaine exposure to drive addictive behaviors. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495556075884-4F19LT351RTWLXSV8DVW/Figure+2.jpg Recent Publications Figure 2. Download manuscript PDF below. http://caliparilab.com/work-with-dreadds daily 0.75 2017-06-08 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495579904402-B704LD3DHNSNIB7LQ52S/Figure+5_CNO.jpg Work with DREADDs Figure 5. Calipari et al., Nature Communications, 2017 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495580242213-UCBQ7X7H01VDWG9NWXLN/pnas.1521238113fig04.jpg Work with DREADDs Figure 4. Calipari et al., PNAS, 2016 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495580246513-MI3954ESSQIAPHJ0LQ1F/pnas.1521238113sfig06.jpg Work with DREADDs Supplementary Figure 6. Calipari et al., PNAS, 2016 http://caliparilab.com/work-with-tracing daily 0.75 2017-06-08 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1496845215889-SRMMG30Z2TV2Y7TNT7NE/Recombination.jpg Work with Rabies Tracing Using Cre-recombinase to express transgenes in a cell-type specific fashion in vivo. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1496858796411-81E00M9D7YY73LITLU3N/Tracing-05.jpg Work with Rabies Tracing Defining projections to Cre-expressing neuronal populations http://caliparilab.com/work-with-operant-conditioning daily 0.75 2017-05-24 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495576935155-ULI21M5X69W8BP29E9PN/Figure3.jpg Work with Operant Conditioning Figure 3. Calipari et al, Nature Communications, 2013 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495578117232-4I42YA9YO5J6W31JG9JQ/npp2014238f4.jpg Work with Operant Conditioning Figure 4. Calipari et al., Neuropsychopharmacology, 2015 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495576957210-VBTDRDIFUMTFJAMAVZKA/jpet.114.212993f1.jpg Work with Operant Conditioning Figure 1. Calipari et al., Neuropsychopharmacology, 2015 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495579087464-MHL52OQDT0KINM99VB0X/npp2013136f1.jpg Work with Operant Conditioning Figure 1. Calipari et al., Neuropsychopharmacology, 2013 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495579210203-P5PZ0ESSPEDH385CLAN0/npp2013136f3.jpg Work with Operant Conditioning Figure 3. Calipari et al, Neuropsychopharmacology, 2013 http://caliparilab.com/work-with-fp daily 0.75 2017-06-08 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495576098179-UGWAXMLNOEX0XIB16WK9/pnas.1521238113fig01.jpg Work with FP Figure 1. Calipari et al., PNAS, 2016 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495574690345-AQO1SBU6ITT2CRJP9SDX/Figure+2.jpg Work with FP Figure 2. Calipari et al., PNAS, 2016 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495574801197-WNJKO7SXHV4UTCUT2GHL/ncomms13877-f3.jpg Work with FP Figure 3. Calipari et al, Nature Communications, 2017 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495574805484-NOHVFROJL7R853KCLM4B/ncomms13877-f4.jpg Work with FP Figure 4. Calipari et al., Nature Communications, 2017 http://caliparilab.com/work-with-fip daily 0.75 2017-06-07 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495574889965-XLB77JREON519V7DKAA3/ncomms13877-f4.jpg Work with FIP Figure 4. Calipari et al., Nature Communications, 2017 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495576779427-6QC7A1GN9ABN7N01FAI1/ncomms13877-f2.jpg Work with FIP Figure 2. Calipari et al., Nature Communications, 2017; VTA cell body recordings https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495579724530-L7COR9LYTSC09WVIMQOE/ncomms13877-s1.jpg Work with FIP Supplementary Figure 6. Calipari et al., Nature Communications, 2017; VTA terminal recordings in the NAc http://caliparilab.com/work-with-fscv daily 0.75 2017-05-24 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495657667403-4HHU6BTCO8MYR8TIXS8A/Figure3.jpg Work with FSCV Figure 2. Calipari et al., Nature Communications, 2013. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495574532127-RI3VWCNXNN6SM7QV0FHG/nihms-580901-f0004.jpg Work with FSCV Figure 4. Calipari et al., Neuropharmacology, 2015 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495572909149-40R6HCTVWTS3IRFMEO4J/Figure+5_CNO.jpg Work with FSCV Figure 5. Calipari et al., Nature Communications, 2017 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1495574365181-K1ZJC5HSMD76GWZY0I9B/Figure1_Baselinediff.jpg Work with FSCV Figure 1. Calipari et al., Nature Communications, 2017 http://caliparilab.com/work-with-optogenetics daily 0.75 2017-06-06 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1496787821078-BANWW50RC28UO1QXIOEO/opto-02.jpg Work with optogenetics https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1496792307837-4ZBI4G8KL93G19B5LFK2/OptoSA-04.jpg Work with optogenetics https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1496792985951-QMVQLY4GFTMQW5OUGA4E/ICSS-07.jpg Work with optogenetics http://caliparilab.com/previous-trainees daily 0.75 2025-12-05 https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/9b2e8abf-e7b8-4bf7-ba53-ce4fc7542610/calipari%2Blab%2Bpic.webp Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1602264134960-I92X3TJHMWG5A699G8VI/File+%281%29.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1604609938575-RCRI38CAVTH6BZH00W68/Gunes+avatar+2020.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1558366398903-MPJGL429LECF0E2Q46CT/IMG_20190517_143003.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/912a0c99-34bb-448a-852c-b87f40d50471/Lopez+Alberto_Headshot.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/189c76da-026b-487e-a816-410449615094/image+%282%29.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/61189e88-e957-4533-a372-7312a22d6046/IMG_20201205_111747_040.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/7c60a462-4963-4e1f-bafa-3eac7162c741/Jennifer%2BZachry.jpeg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/97aaf7f4-322c-483e-b0fd-7fe22fbec895/IMG_8364.webp Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/50513a7a-e86d-4bbc-a5f9-d7142d539816/Image%2Bfrom%2BiOS.webp Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/bace83e5-3489-4802-88ce-2809a41e5d23/Courtney%2BKim_Pic.jpeg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/f9ba50f0-5d18-48a3-a704-63ae7c238b86/Personal%2BPic%2B1.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/861bae07-214b-4f90-a1f1-2debfbbec5a1/IMG_5643.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/c8373028-c59e-4881-8c92-ef9666276757/Image%2Bfrom%2BiOS%2B%283%29.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/981eff28-2c33-4ce3-94ed-a444974e5c83/Headshot.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/63068247-9a90-405a-8230-8325c7584995/Image+from+iOS.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/44e8a7bb-6954-41a7-b4c6-00370a635b2f/Allie+Morris+headshot.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/bdb54f5e-c531-4d85-8efc-282bd4d49316/Headshot+72019+%281%29.jpg Previous Trainees - Make it stand out Whatever it is, the way you tell your story online can make all the difference. https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1558366773273-VQA6Z30J2ZBZIWHDDCFB/CMS%2BLab%2BHeadshot.jpg Previous Trainees https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1547149174237-48UX4UFOCURUYIXIO0X0/IMG_2827.jpg Previous Trainees https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1521479462668-A7Z45IS4HKN325GRAN11/LinkedinPhoto.jpg Previous Trainees https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1521485376716-8DMATLGTMNQO20U7T3K0/IMG_4603.jpg Previous Trainees https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1521485594905-LPA2RGMVOLS1NO8G0UEH/AAIA_wDGAAAAAQAAAAAAAAp_AAAAJDgxMzM5ODgxLWE3OWQtNDU4Ni1hOWFjLTFjNTZmZDU5YWI5NQ.jpg Previous Trainees https://images.squarespace-cdn.com/content/v1/5693000869492ec8d747fd8e/1ce92eef-eee6-4349-9383-59481bcc5be2/47040481_1970222563032749_8024487153750769664_n.jpg Previous Trainees