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Neural basis of anticipation and premature impulsive action in the frontal cortex

Nature Neuroscience volume 25, pages 1683–1692 (2022)Cite this article

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Abstract

Planning motor actions can improve behavioral performance; however, it can also lead to premature actions. Although the anterior lateral motor cortex (ALM) is known to be important for correct motor planning, it is currently unknown how it contributes to premature impulsive motor output. This was addressed using whole-cell voltage recordings from layer 2/3 pyramidal neurons within the ALM while mice performed a cued sensory association task. Here, a robust voltage response was evoked during the auditory cue, which was greater during incorrect premature behavior than during correct performance in the task. Optogenetically suppressing ALM during the cued sensory association task led to enhanced behavior, with fewer, and more delayed, premature responses and faster correct responses. Taken together, our findings extend the current known roles of the ALM, illustrating that ALM plays an important role in impulsive behavior by encoding and influencing premature motor output.

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Fig. 1: Instructive cues shift the behavioral licking response in a cued sensory association task.
Fig. 2: ALM neurons have a robust voltage response during the auditory cue in expert mice.
Fig. 3: ALM neurons have an enhanced voltage response to the auditory cue during correct performance.
Fig. 4: M1 neurons have a small voltage response to the instructive auditory cue during the cued sensory association task.
Fig. 5: ALM neurons have a large voltage response during impulsive premature behavior.
Fig. 6: The cue-evoked voltage response during premature behavior is larger than during correct behavior.
Fig. 7: Suppression of ALM activity during the auditory cue reduces impulsive premature behavior.

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Data availability

Data supporting the findings of this study are available within the paper and its Supplementary Information files. Source data are provided with this paper.

Code availability

Source code for acquisition and analysis of voltage recordings is available by request.

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Acknowledgements

We thank D. Scott for providing the AAV1/2-muGFP and V. Bahr, J. Kremkow and R. Sachdev for custom software for measuring online pupil diameter. This work was supported by the NHMRC (grant nos. APP1086082 and APP1063533, L.M.P.), the Sylvia and Charles Viertel Charitable Foundation (L.M.P.), the Australian Research Council (grant no. DP160103047, L.M.P.), IBRO (Return Home Fellowship and Early Career Award, R.G.) and an MJJ (Marius Jakulis Jason) fellowship (R.G.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia

    Robertas Guzulaitis, Luca Godenzini & Lucy Maree Palmer

  2. The Life Sciences Center, Vilnius University, Vilnius, Lithuania

    Robertas Guzulaitis

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  1. Robertas Guzulaitis
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Contributions

R.G. and L.M.P. conceptualized and designed the study. R.G. performed and analyzed all experiments. L.G. performed control opto-inactivation experiments. R.G. and L.M.P. interpreted the results and wrote the paper.

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Correspondence to Robertas Guzulaitis or Lucy Maree Palmer.

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Extended data

Extended Data Fig. 1 Performance in tactile association task.

(a) The tactile-association task design. Mice were trained to lick a water port within 1 s of a tactile stimulation delivered to the forepaw (200 Hz, 100 ms). Correct responses (HIT) were rewarded with sucrose water (5–10 µl, 10% sucrose). Go-trials (tactile stimulus) were randomly interleaved with Catch-trials (no tactile stimulus). (b) Rate of HIT (green) and false alarm (FA; fawn) trials throughout learning of the tactile-asociation task (n = 32 mice). Data presented from individual mice (lines) and as mean (circles). (c) Discriminability index (d’) throughout learning (n = 32 mice). Data presented as individual mice (lines) and mean (circles).

Source data

Extended Data Fig. 2 Improvement in performance during the cued sensory association task following the introduction of an auditory cue.

(a) HIT (correct), (b) False-alarm (FA), (c) Discriminability index (d’), and (d) Early-lick (EL) rate in the first and last day after introducing the auditory cue during the cued-sensory association task (HIT, P < 0.0001; FA, P < 0.0001; d’, P < 0.0001; EL, P = 0.82; two tailed Wilcoxon tests, n = 32 mice). ns, P > 0.05; ****, P < 0.0001.

Source data

Extended Data Fig. 3 Performance in the cued-sensory association task during cue omission.

(a) The cued sensory association task design. Mice were trained to lick a water port within 1 s of a tactile stimulation (200 Hz, 100 ms). Tactile stimulus was presented either in isolation (non-cued trials; TAC) or preceded by an auditory cue (cued trials; CueTAC; 1 s, 7 kHz, 60 dB). Trials were randomly interleaved. (b) Rate of HIT during CueTAC and TAC trials (P = 0.69, two tailed Wilcoxon test, n = 6 mice). Data presented as individual mice (lines) and mean of all mice (bars). (c) The average onset of the licking response during CueTAC and TAC trials (P = 0.03, two tailed Wilcoxon test, n = 6 mice). Data presented as individual mice (lines) and mean of all mice (bars). ns, P > 0.05; *, p < 0.05.

Source data

Extended Data Fig. 4 Performance in the cued sensory association task during variable cue duration.

(a) The cued sensory association task design. Mice were trained to lick a water port within 1 s of a tactile stimulation (200 Hz, 100 ms). Tactile stimulus was preceded with an auditory cue (7 kHz, 60 dB) with variable duration (0.75 s, 1 s and 1.25 s). (b) Rate of EL performance during trials with different cue duration (1 s versus 0.75 s, P = 0.03; 1 s versus 1.25 s, P = 0.03; two tailed Wilcoxon test, n = 6 mice). (c) The average onset of the EL licking response during trials with different cue duration (1 s versus 0.75 s, P = 0.03; 1 s versus 1.25 s, P = 0.03; two tailed Wilcoxon test, n = 6 mice). (d) Rate of HIT performance during trials with different cue duration (1 s versus 0.75 s, P = 0.25; 1 s versus 1.25 s, P = 0.63; two tailed Wilcoxon test, n = 6 mice). (e) The average onset of the HIT licking response during trials with different cue duration (1 s versus 0.75 s, P = 0.99; 1 s versus 1.25 s, P = 0.84; two tailed Wilcoxon test, n = 6 mice). Data presented from individual mice (lines) and as mean (bars). ns, P > 0.05; *, P < 0.05.

Source data

Extended Data Fig. 5 Performance in the cued sensory association task during omission of the tactile stimulus.

(a) The cued sensory association task design. Mice were initially trained to lick a water port in response to tactile stimulation (200 Hz, 100 ms) which was preceded by an auditory cue (1 s, 7 kHz, 60 dB; CueTAC). Then, in a subset of randomly interleaved trials, the tactile stimulus was omitted and only the auditory cue was presented to the mouse (Cue). Therefore, mice were presented with either the cue with (CueTAC) or without (Cue) the tactile stimulus. (b) HIT rate and (c) average onset of the licking response during CueTAC and Cue trials (HIT rate, P = 0.03; HIT Onset, P = 0.03; two tailed Wilcoxon test, n = 6 mice). Data presented as individual mice (lines) and mean of all mice (bars). *, P < 0.05.

Source data

Extended Data Fig. 6 Voltage response during correct HIT performance in the cued sensory association task and its relation to timing of the licking response.

(a) Overlay of individual voltage responses during HIT trials (grey) and average of all HIT trials (black) in an example L2/3 pyramidal neuron. (b) Overlay of the average voltage responses during HIT trials of individual (grey) and average of all (black) L2/3 pyramidal neurons (n = 11 neurons, 4 mice) during HIT performance (light green) and its average (dark green). (c) Average voltage response (top) and licking response (bottom) during all HIT trials in the example L2/3 pyramidal neuron shown in (a). (d) Onset of the voltage occured before the first lick in HIT trials (P = 0.004, two tailed Wilcoxon test, n = 9 neurons, 4 mice). **, P < 0.01.

Source data

Extended Data Fig. 7 Voltage responses in ALM neurons during the auditory cue.

(a) Overlay of the grand average (dark) and sem (light) voltage response for all recorded neurons during HIT (green) and MISS (grey) trials. Insert, zoom of voltage during the auditory cue. Auditory cue separated into 1st (0–500 ms) and 2nd (500–1000 ms) portion. (b) Amplitude of the voltage response in HIT trials during the 1st and 2nd portion of the auditory cue compared to baseline (baseline versus 1st portion of the cue, P = 0.0001; baseline versus 2nd portion of the cue, P = 0.0002; two tailed Wilcoxon test, n = 14 neurons, 4 mice). (c) Amplitude of the voltage response in MISS trials during the 1st and 2nd portion of the auditory cue compared to baseline (baseline versus 1st portion of the cue, P = 0.03; baseline versus 2nd portion of the cue, P = 0.44; two tailed Wilcoxon test, n = 6 neurons, 4 mice). ns, P > 0.05; *, P < 0.05; ***, P < 0.001.

Source data

Extended Data Fig. 8 Nuchal EMG activity during HIT and early-lick trials.

(a) Example EMG activity during HIT (top) and early-lick (bottom; EL) trials. (b) Grand average (dark) and sem (light) EMG activity during HIT (green) and early-lick (red) trials from example in (a). (c) Average EMG activity during the beginning of the cue prior to licking responses (0–0.3 s) in HIT and early-lick trials (P = 0.47, two tailed Wilcoxon test, n = 7 sessions, 3 mice). ns, P > 0.05.

Source data

Extended Data Fig. 9 Ramping baseline during early-lick trials.

(a) Example voltage responses recorded from a layer 2/3 pyramidal neuron within ALM during early-lick (EL) and correct (HIT) trials. Average baseline voltage at the start (0–1.5 s) and end (1.5–2 s) of the baseline epoch during (b) early-lick trials (P = 0.02, two tailed Wilcoxon test, n = 11 neurons, 4 mice) and (c) HIT trials (P = 0.32, two tailed Wilcoxon test, n = 11 neurons, 4 mice). ns, P > 0.05; *, P < 0.05.

Source data

Extended Data Fig. 10 Firing rates of ALM pyramidal neurons during and after photo-activation of PV interneurons.

(a) Experimental design. PV+  Cre transgenic mice were previously injected with the light sensitive opsin ChR2 (pAAV-EF1a-doublefloxed-hChR2(H134R)-EYFP-WPRE-HGHpA) into the ALM (AP 2.5, ML 1.5 from Bregma). After 2 weeks expression, whole-cell patch-clamp recordings were performed in pyramidal neurons within the ALM during photo-activation of PV interneurons by blue LED pulses (470 nm, 40 Hz, 10 ms, 2–5 mW) delivered to the cortical surface. (b) Average (black) and sem (grey) firing rate during ChR2 activation for all recorded ALM neurons (n = 21 neurons, 5 mice). (c) Firing rate of ALM pyramidal neurons before, during and after photoactivation of PV interneurons (P = 0.29, two tailed Wilcoxon test, n = 21 neurons, 5 mice). ns, P > 0.05.

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Guzulaitis, R., Godenzini, L. & Palmer, L.M. Neural basis of anticipation and premature impulsive action in the frontal cortex. Nat Neurosci 25, 1683–1692 (2022). https://doi.org/10.1038/s41593-022-01198-z

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