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. 2015 Jul 15;87(2):437-50.
doi: 10.1016/j.neuron.2015.06.021. Epub 2015 Jul 2.

Cell-Type-Specific Activity in Prefrontal Cortex during Goal-Directed Behavior

Lucas Pinto  1 , Yang Dan  2
Affiliations

Cell-Type-Specific Activity in Prefrontal Cortex during Goal-Directed Behavior

Lucas Pinto et al. Neuron. .

Abstract

The prefrontal cortex (PFC) plays a key role in controlling goal-directed behavior. Although a variety of task-related signals have been observed in the PFC, whether they are differentially encoded by various cell types remains unclear. Here we performed cellular-resolution microendoscopic Ca(2+) imaging from genetically defined cell types in the dorsomedial PFC of mice performing a PFC-dependent sensory discrimination task. We found that inhibitory interneurons of the same subtype were similar to each other, but different subtypes preferentially signaled different task-related events: somatostatin-positive neurons primarily signaled motor action (licking), vasoactive intestinal peptide-positive neurons responded strongly to action outcomes, whereas parvalbumin-positive neurons were less selective, responding to sensory cues, motor action, and trial outcomes. Compared to each interneuron subtype, pyramidal neurons showed much greater functional heterogeneity, and their responses varied across cortical layers. Such cell-type and laminar differences in neuronal functional properties may be crucial for local computation within the PFC microcircuit.

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Figures

Figure 1
Figure 1. Experimental approach
(A) Schematic of the behavioral task. (B) Learning curves of an example mouse (left) and population of imaged mice (right, n = 20). The surgery for GRIN lens implantation happened between sessions 2 and 11 (5.8 ± 3.6, mean ± SD), and it did not seem to affect learning of the task. Line: mean, shaded area: ± SEM. (C) Bilateral muscimol injections in dmPFC reversibly impaired task performance. Lines correspond to individual mice. Dashed horizontal line: chance performance. *: p < 0.05; n.s.: not significant. (D) Schematic of GRIN lens implanted in dmPFC. (E) Example of GCaMP6f expression and immunostaining for cell type-specific marker for each cell type. (F) Cell-type specificity and efficiency of GCaMP6f expression. PYR (CAMKIIα): 97.4% (2,313/2,375) of GCaMP6f-expressing cells were CAMKIIα+, n = 3 mice; PV+: 96.1% (342/356), n = 2; SST+: 97.2% (522/537), n = 2; VIP+: 97.5% (348/357), n = 3; conversely, 92.8%, 74.1%, 91.3% and 94.0% of antibody-labeled cells expressed GCaMP6f for PYR, SST+, PV+, VIP+ neurons, respectively. (G – J) Fluorescence (ΔF/F) traces of example PYR (G), SST+ (H), PV+ (I) and VIP+ (J) neurons while each animal performed the task. The neurons shown in each plot were simultaneously recorded. Vertical lines of different types and colors represent different task-related events. See also Figure S1.
Figure 2
Figure 2. Performance of the GLM
(A) Fluorescence traces measured in several example trials for an example neuron of each cell type (solid gray lines), and those predicted by the GLM (dashed black lines). Data from these trials were not used to fit the model. (B) Cumulative distribution of CCs for task-modulated neurons of each type (n = 631, 388, 243 and 390 for PYR, SST+, PV+ and VIP+ neurons, respectively).
Figure 3
Figure 3. Sensory-related activity
(A) Example ΔF/F traces of a PYR (left) and a PV+ (right) neuron (4 trials each) around the time of sensory cues (prep cue and stim). (B – E) Trial-averaged ΔF/F traces at prep cue (gray vertical line) from a representative PYR (B), SST+ (C), PV+ (D) and VIP+ (E) recording. Each plot shows the trial-averaged responses of 10 example neurons recorded simultaneously in the same field of view (top, thin colored lines), along with corresponding licking rate histograms (bottom, gray lines and shaded areas, mean ± SEM). (F – I) Trial-averaged ΔF/F traces at the target (left) and non-target (right) auditory stimulus onset for the same neurons shown in B – E, with corresponding licking rate histograms. (J) Top: population average of prep cue responses averaged across all task-modulated neurons of each type (PYR: n = 631; SST+: n = 388; PV+: n = 243; VIP+: n = 390). Bottom: average licking rate triggered by prep cue (n = 104 sessions, 20 mice). Thick lines: mean; thin dashed lines: ± SEM. (K) Population average of responses to target and non-target stimuli averaged across all task-modulated neurons of each type. (L) GLM coefficients for prep cue averaged across all task-modulated neurons of each type with statistically significant fits (see Supplemental Experimental Procedures, PYR: n = 604; SST+: n = 385; PV+: n = 242; VIP+: n = 370). Thick lines: mean; thin dashed lines: ± SEM. (M) GLM coefficients for target (left) and non-target (right) stimuli averaged across each cell type. See also Figure S2.
Figure 4
Figure 4. Motor-related activity
(A) ΔF/F traces of an SST+ (top) and a VIP+ (bottom) neuron at onset (left) and offset (right) of several example licking bouts. (B – E) Trial-averaged ΔF/F traces at lick-bout onset (left) and offset (right) from a representative recording for each cell type. Each plot contains trial-averaged responses of 10 example neurons recorded simultaneously in the same field of view (top, thin colored lines), with corresponding licking rate histograms (bottom). The same neurons are shown on the left and right plots. Note that all licking bouts were included in this analysis, regardless of when they occurred in the trial. (F and G) Top: population average of responses to licking onset (F) and offset (G) averaged across all significantly modulated cells of each type. Bottom: population average of licking histograms (truncated for the bin at t = 0 since by definition there is always a lick in that bin). Thick lines: mean; thin dashed lines: ± SEM. (H and I) GLM coefficients for licking onset (H) and offset (I) averaged across each cell type. Thick lines: mean, thin dashed lines: ± SEM. See also Figure S3.
Figure 5
Figure 5. Outcome-related activity
(A) Top: schematic showing reward (RW, water drop) and punishment (PN, airpuff + time-out) as trial outcomes. Middle/Bottom: ΔF/F traces of two PYR neurons at several example RW (left) and PN (right) trials. (B – E) Trial-averaged ΔF/F traces at RW (left) and PN (right) from a representative recording for each cell type. Each plot contains trial-averaged responses of 10 example neurons recorded simultaneously in the same field of view (top, thin colored lines), with corresponding licking rate histograms (bottom; histograms were truncated for the bin at t = 0 since there is always a lick in that bin given that in our task design RW and PN were triggered by licking). The same neurons are shown on the left and right plots. (F and G) Top: population average of responses to RW (F) and PN (G) averaged across all significantly modulated cells of each type. Bottom: population average of licking histograms. Thick lines: mean; thin dashed lines: ± SEM. (H and I) GLM coefficients for RW (H) and PN (I) averaged across each cell type. Thick lines: mean, thin dashed lines: ± SEM. See also Figure S4.
Figure 6
Figure 6. Modulation of responses by trial outcome
(A) Behavioral adjustment based on previous outcome. Performance (% correct, left) was significantly higher, and false alarm (FA) rate (right) was significantly lower, in trials following punishment (post-PN) than those following reward (post-RW). Hit rates were not significantly different (middle). Lines correspond to individual mice (n = 20, from all genotypes). **: p < 0.01, n.s.: not significant. (B) Responses of an example PYR neuron to prep cue in a post-RW trial (top, blue) and a post-PN trial (bottom, red). (C) Responses to prep cue averaged across all task-modulated neurons of each cell type, in post-RW (blue) and post-PN (red) trials. PYR and VIP+ neurons showed significantly higher responses in post-PN than post-RW trials, while PV+ neurons showed the opposite difference. No significant difference was observed for SST+ neurons. Shaded areas, ± SEM. (D) Activity of an example VIP+ neuron at lick-bout offset immediately following punishment (bottom, red) and from a lick bout occurring elsewhere in the trial (top, gray). (E) Activity at licking offset averaged across all task-modulated neurons of each cell type. For all types, licking offset occurring < 2 s after PN (red) was associated with higher activity than for other licking bouts (gray). Note that the licking offset responses in this analysis are based on the same data shown in Figure 4 except that we separated the lick bouts occurring after PN delivery and all other bouts. Shaded areas, ± SEM. Note that in some trials the airpuff triggered by a single lick inhibited further licking, so that licking offset coincided with PN. These trials were excluded in this analysis to minimize the confound between the activity evoked by PN and that associated with licking offset. See also Figure S5.
Figure 7
Figure 7. Spatial organization of task-related activity of each cell type
(A) CC between ΔF/F traces of each cell pair vs. distance of the pair, averaged across all recordings for each cell type (PYR: n = 9,500 neuron pairs; PV+: n = 1,579; SST+: n = 2,959; VIP+: n = 4,379). Error bars, ± SEM. (B) Example maps showing simultaneously imaged neurons in the same field of view (left, white and color). GLM coefficients of the neurons highlighted with color and indicated by numbers are plotted on the right. Note that inhibitory neurons of the same subtype showed similar GLM coefficients regardless of spatial position, whereas PYR cells are much more diverse. Pc: Prep cue, ts: target stimulus, nts: non-target stimulus, lon: licking onset, lk: mid-burst licks, loff: licking offset, rw: reward, pn: punishment. (C) CC between GLM coefficients of each cell pair vs. distance of the pair, averaged across all recordings for each cell type (PYR: n = 8,263 neuron pairs with significant GLM fits; PV+: n = 1,562; SST+: n = 2,865; VIP+: n = 3,891). Error bars, ± SEM. See also Figure S6.
Figure 8
Figure 8. Laminar organization of PYR neuron responses
(A) CC between ΔF/F traces of each PYR neuron pair vs. distance across (perpendicular to) layers (left) or distance within (parallel to) each layer (right) (perpendicular: r = −0.77, p = 0.009, n = 8,547 pairs; parallel: r = 0.33, p = 0.34, n = 9,262 pairs). Error bars, ± SEM. (B) CC between GLM coefficients of each PYR neuron pair vs. distance across (perpendicular to) layers (left) or distance within (parallel to) each layer (right) (perpendicular: r = −0.96, p = 1.1 × 10−5, n = 7,425 pairs with significant GLM fits; parallel: −0.79, p = 0.007, n = 8,023 pairs). Error bars, ± SEM. (C) Two example maps (from different animals) showing the spatial distribution of prep cue response amplitude (color-coded, scale bar at bottom). Note that in both examples the responses were larger in more superficial cells. (D) Left: Population average of prep cue responses (n = 816) as a function of estimated distance from the pia. Right: average prep cue GLM coefficients at three cortical depths (indicated by arrows on the left). Shaded areas, ± SEM. See also Figure S7.
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