Anterior cingulate cortex activity regulates effort-based decision making

Prior evidence suggests that the anterior cingulate cortex (ACC) is required for choosing high effort options over less effortful alternatives. Here, rats earned a high-value sucrose reward by lever pressing on a progressive ratio schedule in either the presence (choice) or absence (no-choice) of freely available, low-value lab chow. Disruption of ACC, either via chemogenetic inhibition or excitation, reduced lever pressing for high-value reward in the choice, but not in the no-choice, condition. In vivo calcium imaging revealed cell populations in ACC that selectively responded prior to lever pressing and during sucrose retrieval. These responses were significantly weaker during choice than no-choice sessions, which may have rendered them more susceptible to chemogenetic disruption. Our results suggest that neural responses in ACC encode the relative value of competing outcomes, and that the amount of effort an animal is willing to exert is proportional to the magnitude of this relative value signal.


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Real-world decisions rarely involve choosing between unambiguously favorable vs. 53 unfavorable options. Often, options must be evaluated along multiple dimensions that incorporate 54 an evaluation of the rewards themselves as well as the actions or efforts to procure them 55 (Skvortsova et al., 2014). For example, we typically make decisions between options in 56 comparison, where one outcome may be more costly (i.e. more effortful) yet more preferred than 57 the other. 58 Outside of the striatum, which has been the major region of study in such effort-based    Lever press training. Rats were trained over a series of days to press a lever for food on a 147 progressive ratio (PR) schedule (where the required number of presses to earn each pellet increased 148 throughout the session according to a prescribed formula; see Methods whereas during PR sessions, the only reward option was to lever press for sucrose pellets. In 157 general, lever pressing rates were higher during PR sessions than PRC sessions (Figures 3 and 4), 158 indicating the free chow draws behavior away from lever pressing (Salamone et Figure 1A). Hence, food preference was intact and not affected by CNO injection. and compared against baseline using a binomial probability test (bin width = 133.33 ms, derived 268 from the 7.5 Hz frame rate). Any cell exhibiting at least 3 bins with spike rate exceeding baseline 269 at the p<.01 level was classified as "responsive" within the 6 s period surrounding the trigger event.

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To analyze how responses to HP and LE events varied with session type (PR, PRC, CON), 271 we identified a subset of 449 neurons (39% of all recorded cells) that were: 1) active during at least 272 one session of each type, and 2) significantly responsive to either LP or HE events (or both) during 273 at least one of the three session types ( Figure 6E). The natural sequence of task behavior caused 274 LP events to often be followed within 3 s by HE events, and likewise, for HE events to often be 275 preceded within 3 s by LP events (Supplementary Figure 3). This was because immediately after 276 completing the required number of LPs for a trial, the lever was retracted and the rat went to the 277 magazine where it generated an HE event that closely followed the last LPs of that trial.

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Consequently, cells that responded after LP events or before HE events could not be 279 unambiguously classified as responsive to one kind of event or the other (LPs versus HEs, because 280 the response was proximal to both kinds of events). By contrast, LP events were rarely preceded 281 within 3 s by HE events, and HE events were rarely followed within 3 s by LP events 282 (Supplementary Figure 3). We thus restricted further analysis to cells that consistently responded 283 before but not after LP events ("pre-LP" cells, n=131), or after but not before HE events ("post-284 HE" cells, n=135), or both ("LP-HE" cells, n=89); cells that responded after LP events or before 285 HE events (n=94) were omitted from further analysis ( Figure 6F).

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Population responses preceding LP events. For every cell that responded prior to LP events 287 (that is, cells belonging to either the pre-LP or LP-HE cell populations), three LP-triggered PETHs  We found that either chemogenetic silencing or stimulation of ACC excitatory neurons resulted in 325 decreased PR lever pressing for a qualitatively preferred option, but this effect was only observed 326 when a concurrently available, lower effort alternative was available, and not when lever pressing

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ACC calcium imaging. We used in vivo calcium imaging to investigate how ACC neurons 368 responded during lever pressing and reward retrieval (i.e., reward port head entry) during PR, PRC, 369 and CON sessions (Figure 7). A total of 449 neurons from 4 rats were successfully recorded during 370 at least one session of each type and had a significant response to surrounding lever press or head 371 entry. About half of these neurons (220/449) fired significantly above baseline during the 3s time 372 window preceding lever presses in at least one of the three session types (Figure 7A-C). These 373 pre-lever responses were significantly lower during CON than PR sessions, and since rats were 374 sated on chow before lever pressing during CON but not PR sessions, it appears that satiety from 375 chow consumption may have attenuated neural responses during the pre-lever period. Consistent 376 with this interpretation, calcium activity during the pre-lever period was also lower during PRC 377 than PR sessions. However, pre-lever activity was even lower during PRC than CON sessions 378 (despite the fact that rats were similarly sated on chow at the start of both PRC and CON sessions), 379 suggesting that satiety on chow plus free chow availability attenuated pre-lever calcium activity 380 even more than satiety alone.

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About half of the recorded ACC neurons (224/449) fired significantly above baseline 382 during the 3s time window following head entry into the reward magazine, which was the period 383 during which the rat retrieved and consumed the high value sucrose reward (Figure 7D-F) sessions. However, since pre-lever calcium activity was also lower during CON sessions than PR 404 sessions, satiety may have also attenuated calcium activity prior to lever pressing.

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In summary, neural activity associated with sucrose pellet collection in ACC may be 406 strongest when sucrose is the only available option, and weakened by the presence of the 407 counterfactual choice. This is consistent with prior evidence that rat ACC encodes "the utility of body weight, and were never permitted to drop below their 85% free feeding baseline weight.

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Training and testing were conducted during the early portion of the dark cycle (~0800 to 1200 H).

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Experiments were conducted 5-7 d per week, and rats were fed once daily on weekends (12 g) 480 when testing was not conducted. All procedures were reviewed and approved by the Chancellor's 481 Animal Research Committee (ARC) at the University of California, Los Angeles.

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Food restriction. One day before behavioral testing began, rats were singly-housed, the 483 amount of chow given to each rat was reduced to 12 g/d, and rats were given ~10 sucrose pellets Bregma. Since no differences emerged from this differential targeting, we combined the Cg1 505 groups. In the imaging experiment, coordinates were: AP= +2.0 mm, ML= ±0.7 mm, DV= −1.4 506 mm (0.5 μL) from Bregma, and a second 0.5 μL bolus of virus was injected at DV= -0.9 mm.

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Injectors extended 1 mm beyond the tip of the cannula. Following the 5-minute diffusion time, the 508 cannulae and injectors were removed, incisions were stapled closed, and the rats were placed on a 509 heating pad and kept in recovery until ambulatory before being returned to the vivarium.  where % is equal to the number of presses required on the i th ratio, rounded to the nearest whole 548 number (Richardson and Roberts, 1996)  press. This control condition allowed rats to reach a comparable motivational (more sated) state 665 relative to the PR-only condition, and thus controlled for satiety differences between PR and PRC 666 sessions.