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Nature 617권, 548~554페이지(2023)이 기사 인용

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내측 전전두엽 피질 내 활동 패턴의 변화를 통해 설치류, 인간이 아닌 영장류 및 인간은 인지 작업 중 환경 변화에 적응하기 위해 행동을 업데이트할 수 있습니다1,2,3,4,5. 내측 전두엽 피질의 파발부민 발현 억제 뉴런은 규칙 전환 작업 동안 새로운 전략을 학습하는 데 중요하지만 전두엽 네트워크 역학을 작업 관련 활동 패턴 유지에서 업데이트로 전환하는 회로 상호 작용은 아직 알려지지 않았습니다. 여기에서는 파발부민 발현 뉴런, 새로운 뇌량 억제 연결 및 작업 표현의 변화를 연결하는 메커니즘을 설명합니다. 모든 뇌량 투영을 비특이적으로 억제하면 쥐가 규칙 변화를 학습하는 것을 막거나 활동 패턴의 진화가 방해받지 않는 반면, 파발부민 발현 뉴런의 뇌량 투영만 선택적으로 억제하면 규칙 전환 학습이 손상되고 학습에 필요한 감마 주파수 활동이 비동기화됩니다. 일반적으로 규칙 변화 학습에 수반되는 전두엽 활동 패턴의 재구성을 억제합니다. 이러한 해리는 뇌량 파발부민 발현 투영이 감마 동시성을 전송하고 이전에 확립된 신경 표상을 유지하기 위해 다른 뇌량 입력의 능력을 제어함으로써 전두엽 회로의 작동 모드를 유지 관리에서 업데이트로 전환하는 방법을 보여줍니다. 따라서 파발부민 발현 뉴런에서 유래한 뇌량 예측은 정신분열증 및 관련 질환9,10에 연루된 행동 유연성 및 감마 동시성의 결함을 이해하고 교정하기 위한 핵심 회로 궤적을 나타냅니다.

유기체는 환경 변화에 적응하기 위해 행동 전략을 지속적으로 업데이트해야 합니다. 시대에 뒤떨어진 전략을 부적절하게 고집하는 것은 정신분열증, 양극성 장애와 같은 질환의 특징이며 위스콘신 카드 분류 작업(WCST)에서 고전적으로 나타납니다. 전전두엽 피질은 규칙 또는 목표 표현의 적극적인 유지 관리12,13,14, 이러한 표현의 적응형 게이팅15 및 다른 표현과의 광범위한 상호 연결을 통한 감각 처리의 하향식 편향을 제공함으로써 이러한 유연한 인지 제어를 담당한다는 것이 잘 문서화되어 있습니다. 뇌 영역16,17. 연구에 따르면 내측 전전두엽 피질(mPFC) 내에서 정상적인 파브알부민 발현(PV) 개재뉴런 기능이 쥐가 '규칙 전환' 작업을 수행하는 데 필요하며, 이는 WCST와 유사하게 단서가 없는 규칙 변경을 식별하고 새로운 학습을 포함하는 것으로 나타났습니다. 이전에는 시험 결과와 관련이 없었던 단서를 사용하는 규칙입니다6,7. 더욱이, PV 개재뉴런은 감마 주파수(약 40Hz) 범위18,19에서 동기화된 리듬 활동을 생성하는 데 중요한 역할을 합니다. 실제로 규칙 전환 작업 중에 왼쪽과 오른쪽 mPFC의 PV 개재뉴런 사이의 감마 주파수 활동의 동기화는 오류 시도(즉, 쥐가 이전에 학습한 규칙이 시대에 뒤떨어졌다는 피드백을 받을 때) 후에 증가하고 광유전학적으로 이 동기화를 방해합니다. 인내를 유발한다8. 그럼에도 불구하고 회로(시냅스 연결), 네트워크 역학(반구 간 감마 동기화) 및 신경 표현(작업에 따른 활동 패턴의 변화) 간의 기본 관계는 아직 알려지지 않았습니다.

감마 동시성은 일반적으로 피질에서 장거리 통신의 주된 형태인 흥분성 시냅스에 의해 여러 영역으로 전달되는 것으로 가정됩니다. 그러나 우리는 mPFC21의 PV 뉴런에서 발생하는 장거리 γ-아미노부티르산 방출(GABAergic) 연결에 대한 최근 설명에서 제안된 대체 가설을 탐색했습니다. 구체적으로, 우리는 mPFC의 PV 발현 뉴런이 반대편 mPFC에서 뇌량 GABA 성 시냅스를 생성한다는 것을 처음으로 입증했습니다 (그림 1). 우리는 AAV-EF1α-DIO-ChR2-eYFP를 PV-cre 마우스의 하나의 mPFC에 주입하여 이 해부학적 연결을 확인하고 반대쪽 PFC, 특히 깊은 층 5와 6에서 바이러스로 표지된 PV 터미널을 관찰했습니다(그림 1a). 이 뇌량 PV 투영과 그 수용 뉴런을 특성화하기 위해 반대쪽 mPFC에서 녹음을 수행했습니다 (그림 1b). 우리는 캘로살 PV 투영이 피라미드 뉴런(형태 및 비빠른 스파이킹 생리학에 기초하여 식별됨, 75개 중 31개가 연결됨)에 신경을 분포시키지만 빠르게 스파이킹하는 뉴런(18개 중 0개 연결)에는 신경을 분포시키지 않음을 발견했습니다(그림 1d). PV 말단 광유전학적 자극의 리듬 열차는 ChR2 음성 피라미드 뉴런에서 시간 고정 억제 시냅스 후 전위(IPSP)를 유도했으며(그림 1e), 이는 글루타메이트 수용체 길항제인 6-시아노-7-니트로퀴녹살린-2,3에 의해 차단되지 않았습니다. -디온 이나트륨 염(CNQX)(10μM) 및 d-2-아미노-5-포스포노펜탄산(APV)(50μM)은 유형 A γ-아미노부티르산(GABAA) 수용체 길항제를 목욕 적용하여 완전히 제거되었습니다. 가바진 (10 μM; 그림 1e, f). 캘로살 mPFC PV 시냅스의 특정 표적을 추가로 특성화하기 위해 우리는 형광 염료 결합 콜레라 독소 소단위 B(CTb)를 mPFC의 4개 하류 표적에 주입한 다음 반대측 mPFC(즉, 반대측)에 투사되는 역행 표지된 mPFC 뉴런에서 기록했습니다. 녹음이 수행된 위치와 AAV-DIO-ChR2 주입과 동측), 등쪽 선조체, 중등쪽(MD) 시상 또는 측격핵(NAc)(확장 데이터 그림 1b-k). 글루타메이트 길항제(20μM 6,7-디니트로퀴녹살린-2,3-디온(DNQX) 및 50μM APV)가 있는 상태에서 캘로살 PV+ 말단을 광유전적으로 활성화하기 위한 단일 5ms 광 펄스 후, 우리는 시간 고정 IPSP를 관찰했습니다. MD 돌출 피라미드 뉴런 22개 중 22개, 뇌량 방향 돌출 피라미드 뉴런 18개 중 0개, 측좌 돌출 피라미드 뉴런 21개 중 0개, 등쪽 선조체 돌출 피라미드 뉴런 24개 중 7개와 비교됩니다.

50 Hz, fast after hyperpolarization (fAHP) amplitude > 14 mV, and spike-frequency accommodation (SFA) index < 2./p>1,000 times stronger than the measured scattered light power. Both 532 nm and 638 nm at this final light power ipsilateral to the viral injection site was used./p>

0.05 and were considered not significant. No statistical methods were used to pre-determine sample sizes but our sample size choice was based on previous studies6,8 and are consistent with those generally employed in the field. Data distribution was assumed to be normal, but this was not formally tested./p> 0.99). d,e,k,l, Two-way ANOVA (task day × virus) comparing rule-shift (RS) performance across groups (interaction: P < 0.0001), showed no group difference on day 1 but significant impairment on days 2 and 3 for DIO-eNpHR compared to DIO-mCherry and Syn-tdTomato. e, Optogenetic inhibition of mPFC callosal PV terminals impairs rule shifts in DIO-eNpHR mice compared to DIO-mCherry controls (day 1 to 2: P = 0.014; day 1 to 3: P = 0.012; day 2 to 3: P = 0.075). For Fig. 3f,g, full statistics are: 30–50 Hz synchronization is higher after RS errors than after RS correct decisions across task days in controls (n = 4 mice; two-way ANOVA; main effect of trial type: P = 0.0056; day 1: P = 0.004; day 2: P = 0.005; day 3: P = 0.022). g, Gamma synchrony is higher after RS errors than after RS correct decisions for DIO-eNpHR mice on day 1 (no light), but not days 2 and 3 (n = 5 mice; two-way ANOVA (trial type × task day); interaction: P = 0.0039; day 1: P = 0.0056; day 2: P = 0.16; day 3: P = 0.23). Differences in gamma synchrony between RS errors and correct trials are also significantly lower in DIO-eNpHR mice compared to controls on days 2 (two-way ANOVA (trial type × virus); interaction: P = 0.018) and 3 (two-way ANOVA (trial type × virus); interaction: P = 0.034). We then performed two-way ANOVA (task day × virus, type of error) comparing gamma synchrony across groups with appropriate post hoc tests corrected for multiple comparisons; gamma synchrony is lower for DIO-eNpHR mice compared to matched controls on error (interaction: P = 0.049), but not correct trials (interaction: P = 0.93) on both days 2 (P = 0.0089) and 3 (P = 0.016). For Fig. 3k–n, full statistics are: inhibiting callosal terminals does not affect rule shifts in Syn-eNpHR mice (n = 5) compared to controls (n = 4) across days (two-way ANOVA (task day × virus); P = 0.37). k, Performance of controls did not change across days (day 1 to 2: P = 0.48; day 1 to 3: P > 0.99; day 2 to 3: P > 0.99). l, Performance of Syn-eNpHR mice did not change across days (day 1 to 2: P > 0.99; day 1 to 3: P = 0.96; day 2 to 3: P = 0.85). m, Interhemispheric 30–50 Hz synchronization is higher after RS errors than RS correct decisions across days in controls (n = 4 mice; two-way ANOVA; main effect of trial type: P = 0.020; day 1: P = 0.015; day 2: P = 0.049; day 3: P = 0.025). n, Gamma synchrony is higher after RS errors than RS correct decisions for Syn-eNpHR mice on day 1 (no light). This was abolished with light on day 2, then restored in the absence of light on day 3 (n = 5 mice; two-way ANOVA; (trial type × task day); interaction: P = 0.011; day 1: P = 0.037; day 2: P = 0.46; day 3: P = 0.021). Gamma synchrony is lower for Syn-eNpHR mice compared to matched controls on error (two-way ANOVA; interaction: P = 0.045) but not correct trials (interaction: P = 0.74) on day 2 (P = 0.043), but not on day 3 (P = 0.58). Two-way ANOVA followed by Bonferroni post hoc comparisons was used./p> 0.99). f, Performance of Syn-eNpHR mice did not change (day 1 to 2: P = 0.58; day 1 to 3: P = 0.82; day 2 to 3: P > 0.99). For Fig. 4h,j, full statistics are: optogenetic inhibition changes the similarity of activity vectors specifically in DIO-eNpHR mice (two-way ANOVA, main effect of task day: P = 0.017; task day × group interaction: P = 0.32). h, For controls (n = 6 mice), there is no change across days in the similarity between activity vectors after RS errors and those after correct decisions (day 1 to 2: P = 0.57; day 1 to 3: P = 0.32; day 2 to 3: P = 0.90). i, In DIO-eNpHR mice (n = 6 mice), there is an increase in the similarity between activity vectors after RS errors and those after correct decisions from day 1 (before optogenetic inhibition) to days 2 and 3 (during and after inhibition, respectively) (day 1 to 2: P = 0.044; day 1 to 3: P = 0.0067; day 2 to 3: P = 0.71). j, For Syn-eNpHR mice (n = 6 mice), there is no change across days in the similarity between activity vectors after RS errors and those after correct decisions (day 1 to 2: P = 0.99; day 1 to 3: P = 0.93; day 2 to 3: P = 0.98). Two-way ANOVA to compare the change in activity vector similarity from day 1 to 2 in the DIO-eNpHR group to a group consisting of the eNpHR-negative and synapsin-eNpHR mice, using mouse, day, and day × group interaction as factors revealed a significant day × group interaction (P = 0.040). k–m, The similarity between activity vectors after decisions on error trials during the initial association (IA) and those during the RS. There is increased similarity across days in DIO-eNpHR mice (n = 6; two-way ANOVA (task day × virus); interaction: P = 0.025). k, There is no change in the similarity of population activity vectors after IA errors and RS errors across days in controls (n = 6; day 1 to 2: P = 0.99; day 1 to 3: P = 0.52; day 2 to 3: P = 0.50). l, During and following optogenetic inhibition on days 2 and 3 in DIO-eNpHR mice, there is an increase in the similarity of population activity vectors following IA versus RS error trials (day 1 to 2: P = 0.0038; day 1 to 3: P = 0.0045; day 2 to 3: P = 0.95). m, In Syn-eNpHR mice, there is no change in the similarity of population activity vectors following IA versus RS errors trials across days (n = 6; day 1 to 2: P = 0.41; day 1 to 3: P = 0.90; day 2 to 3: P = 0.24). n, Controls have increases in average activity (fraction of frames in which a neuron is active, averaged across all neurons) during the 10 s following RS errors compared to the 10 s following RS correct decisions on all days (n = 6; two-way ANOVA, main effect of trial type: P = 0.010; day 1: Bonferroni P = 0.022; day 2: Bonferroni P = 0.015; day 3: Bonferroni P = 0.016). o, DIO-eNpHR mice have an increase in average activity after errors that depends on the day (n = 6; two-way ANOVA (task day × trial type); interaction: P = 0.0003). This difference occurs on day 1 (Bonferroni P < 0.0001), but is abolished with light delivery on day 2 (Bonferroni P > 0.99), and continues to be absent even without further light delivery on day 3 (Bonferroni P > 0.99). p, In Syn-eNpHR mice, there is an overall increase in average activity following error trials (n = 6; two-way ANOVA, main effect of trial type: P = 0.0088). This occurs on days 1 (Bonferroni P = 0.038) and 3 (Bonferroni P = 0.016), but not with light delivery on day 2 (Bonferroni P > 0.99). Two-way ANOVA followed by Tukey post hoc comparisons was used unless otherwise noted./p>

0.9999), Day 2 (post hoc t(28) = 0.6978, P > 0.9999), nor Day 3 (post hoc t(28) = 0.4652, P > 0.9999). o, Inhibition disrupts rule shift performance in DIO-eNpHR-expressing mice compared to controls when light is delivered continuously throughout the RS on Day 4 (post hoc t(28) = 9.886, P < 0.0001). Two-way ANOVA followed by Bonferroni post hoc comparisons was used. ****P < 0.0001./p>

0.9999; same and incorrect post hoc t(26) = 0.1486, P > 0.9999; different location two-way ANOVA (trial type × virus); interaction: F(1,13) = 13.87, P = 0.0026; different and correct post hoc t(26) = 3.724, P = 0.0019; different and incorrect post hoc t(26) = 3.724, P = 0.0019). i, Same as h but for the next 5 RS trials (n = 7 DIO-mCherry control mice; same location two-way ANOVA (trial type × virus); interaction: F(1,13) = 3.214, P = 0.0963; same and correct post hoc t(26) = 1.793, P = 0.1693; same and incorrect post hoc t(26) = 1.793, P = 0.1693; different location two-way ANOVA (trial type × virus); interaction: F(1,13) = 8.948, P = 0.0104; different and correct post hoc t(26) = 2.991, P = 0.0120; different and incorrect post hoc t(26) = 2.991, P = 0.0120). j–k, The overall speed (meters per second) of mice during the first 5 IA and RS trials across days in the cohort of mice used for microendoscopic Ca2+ imaging (n = 6 eNpHR-negative controls; n = 6 DIO-eNpHR mice; two-way ANOVA (IA vs. RS × task day) for control mice: interaction: F(1,10) = 0.00271, P = 0.9595; two way-ANOVA (IA vs. RS × task day) for DIO-eNpHR mice: interaction: F(1,10) = 1.378, P = 0.2677). l–m, There is no difference in the amount of time (seconds) mice spent exploring bowls before making a decision during the first 5 IA and RS trials across days in the microendoscope experimental dataset (n = 6 eNpHR-negative controls; n = 6 DIO-eNpHR mice; two-way ANOVA (IA vs. RS × task day) for control mice: interaction: F(1,10) = 0.5053, P = 0.4934; two way-ANOVA (IA vs. RS × task day) for DIO-eNpHR mice: interaction: F(1,10) = 0.1147, P = 0.7419). n–o, The first move of the mouse toward the correct bowl (percent) during the first 5 IA and RS trials across days in the Ca2+ imaging experimental dataset (n = 6 eNpHR-negative controls; n = 6 DIO-eNpHR mice; two-way ANOVA (IA vs. RS × task day) for control mice: interaction: F(1,10) = 3.347, P = 0.0973; two way-ANOVA (IA vs. RS × task day) for DIO-eNpHR mice: interaction: F(1,10) = 0.1316, P = 0.7244). p–z, Effects of inhibiting callosal PV+ projections during a version of the RS task using a shorter (30 second) intertrial interval (ITI). p, Experimental design: Day 1, no light delivery; Day 2, continuous light during the RS for optogenetic inhibition of callosal PV terminals ; Day 3, no light was delivered. q, Representative image showing DIO-eYFP expression in one mPFC and a fiber-optic cannula implanted in the contralateral mPFC in a PV-Cre mouse. r, Representative image showing DIO-eNpHR-mCherry (DIO-eNpHR) expression in one mPFC and a fiber-optic cannula implanted in the contralateral mPFC in a PV-Cre mouse. s,w, IA performance with a 30 s ITI in eNpHR-negative mice (n = 6) and eNpHR-expressing mice (n = 8; two-way ANOVA (task day × virus); interaction: F(2,24) = 0.1585, P = 0.8543). t,x, Optogenetic inhibition of mPFC callosal PV terminals with a 30 s ITI impairs rule shift performance in DIO-eNpHR mice (n = 8) compared to controls (n = 6; two-way ANOVA (task day × virus); interaction: F(2,24) = 50.79, P < 0.0001). t, Performance of DIO-eYFP controls did not change from Day 1 to Day 2 (Tukey’s post hoc q(5) = 1.606, P = 0.5356), Day 1 to Day 3 (Tukey’s post hoc q(5) = 1.035, P = 0.7567), nor Day 2 to Day 3 (Tukey’s post hoc q(5) = 0.4344, P = 0.9498). x, Inhibition disrupts rule shift performance in DIO-eNpHR mice from Day 1 to Day 2 (Tukey’s post hoc q(7) = 15.34, P < 0.0001), Day 1 to Day 3 (Tukey’s post hoc q(7) = 21.75, P < 0.0001), but not Day 2 to Day 3 (Tukey’s post hoc q(7) = 2.679, P = 0.2101). u, y, Optogenetic inhibition of callosal PV terminals increases perseverative errors in DIO-eNpHR mice (n = 8 mice) compared to DIO-eYFP controls (n = 6 mice; two-way ANOVA (task day × virus) interaction: F(2,24) = 19.79, P < 0.0001). v, z, Optogenetic inhibition of callosal PV terminals has no effect on random errors in DIO-eNpHR mice (n = 8) compared to DIO-eYFP controls (n = 6; two-way ANOVA (task day × virus); interaction: F(2,24) = 1.079, P = 0.3559). u, v, Light delivery does not affect the number of perseverative (post hoc t(5) = 0.000 – 1.000, P > 0.9999) or random (post hoc t(5) = 0.4152 – 0.7906, P > 0.9999) errors in DIO-eYFP controls across days. y, z, Optogenetic inhibition of callosal PV terminals on Day 2 increased the number of perseverative (post hoc t(7) = 6.008, P = 0.0016 from Day 1 to Day 2; post hoc t(7) = 5.844, P = 0.0019 from Day 1 to Day 3; but not from Day 2 to Day 3: post hoc t(7) = 1.111, P = 0.9093) but not random (post hoc t(7) = 0.000 – 2.198, P = 0.1918 – > 0.9999) errors compared to no stimulation. Two-way ANOVA followed by Bonferroni post hoc comparisons was used unless otherwise noted. Data were expressed as mean ± s.e.m. **P < 0.01, ****P < 0.0001; scale bar, 100 μm./p>

0.9999) errors in DIO-eYFP controls. g, h, Optogenetic inhibition of callosal PV terminals on Day 2 increased the number of perseverative (post hoc t(13) = 10.75, P < 0.0001) and random (post hoc t(13) = 3.145, P = 0.0155) errors compared to no stimulation on Day 1. k, l, o, p, Optogenetic inhibition of all callosal projections has no effect on perseverative errors in Syn-eNpHR mice (n = 6) compared to controls (n = 4; two-way ANOVA (task day × virus); interaction: F(1,8) = 0.0, P > 0.9999) nor on random errors (two-way ANOVA (task day × virus); interaction: F(1,8) = 0.07805, P = 0.787). Two-way ANOVA followed by Bonferroni post hoc comparisons was used. *P < 0.05, ****P < 0.0001; scale bars, 250 μm and 100 μm, respectively./p>

0.9999). By contrast, rule shift performance in mice expressing both NpHR and ChR2 (h; n = 8) is significantly different across days than that of mice which express NpHR-only (two-way ANOVA (task day × virus); interaction: F(3,27) = 6.747, P = 0.0015). Optogenetic inhibition of mPFC callosal PV terminals causes NpHR+ChR2-expressing mice (n = 8) to take a large number of trials to learn rule shifts on Day 1 and this does not change on Day 2 (no light) (post hoc t(7) = 1.446, P > 0.9999). However, RS learning is rescued by 40 Hz optogenetic stimulation on Day 3 (post hoc t(7) = 10.91, P < 0.0001) and this improvement does not change on ‘Day 4’ of testing which occurs one week later (post hoc t(7) = 0.6394, P > 0.9999). f, i: Optogenetic inhibition followed by stimulation of callosal PV terminals changes the number of perseverative errors in mice expressing both NpHR and ChR2 (n = 8 mice) compared to controls expressing only NpHR (n = 3 mice; two-way ANOVA; main effect of task day: F(2.015,18.13) = 7.167, P = 0.0050; main effect of virus: F(1,9) = 14.31, P = 0.0043; interaction: F(3,27) = 5.324, P = 0.0052). By contrast, there is no difference in numbers of random errors (two-way ANOVA; main effect of task day: F(1.491,13.42) = 1.706, P = 0.2189; main effect of virus: F(1,9) = 1.523, P = 0.2483; interaction: F(3,27) = 0.2901, P = 0.8322). f, Once mice expressing NpHR only receive optogenetic inhibition on Day 1, the number of perseverative errors is stable across days (n = 3 mice; Day 1 to Day 2: post hoc t(2) = 1.222, P > 0.9999; Day 1 to Day 3: post hoc t(2) = 1.299, P > 0.9999; Day 1 to Day 4: post hoc t(2) = 0.3111, P > 0.9999; Day 2 to Day 3: post hoc t(2) = 0.3780, P > 0.9999; Day 2 to Day 4: post hoc t(2) = 1.606, P > 0.9999; Day 3 to Day 4: post hoc t(2) = 2.000, P > 0.9999). g, In mice that express NpHR only (n = 3 mice), numbers of random errors are also stable across days (Day 1 to Day 2: post hoc t(2) = 1.387, P > 0.9999; Day 1 to Day 3: post hoc t(2) = 1.732, P > 0.9999; Day 1 to Day 4: post hoc t(2) = 1.000, P > 0.9999; Day 2 to Day 3: post hoc t(2) = 1.000, P > 0.9999; Day 2 to Day 4: post hoc t(2) = 1.000, P > 0.9999; Day 3 to Day 4: post hoc t(2) = 0.3780, P > 0.9999). i, 40 Hz stimulation of callosal PV terminals on Day 3 reduces the number of perseverative errors in mice expressing both NpHR and ChR2 (n = 8; Day 1 to Day 2: post hoc t(7) = 0.6494, P > 0.9999; Day 1 to Day 3: post hoc t(7) = 5.218, P = 0.0074; Day 1 to Day 4: post hoc t(7) = 6.416, P = 0.0022; Day 2 to Day 3: post hoc t(7) = 4.822, P = 0.0115; Day 2 to Day 4: post hoc t(7) = 12.33, P < 0.0001; Day 3 to Day 4: post hoc t(7) = 0.4971, P > 0.9999). j, 40 Hz stimulation on Day 3 does not affect the number of random errors in mice expressing both NpHR and ChR2 (n = 8 mice; Day 1 to Day 2: post hoc t(7) = 0.7061, P > 0.9999; Day 1 to Day 3: post hoc t(7) = 0.6417, P > 0.9999; Day 1 to Day 4: post hoc t(7) = 1.210, P > 0.9999; Day 2 to Day 3: post hoc t(7) = 0.3140, P > 0.9999; Day 2 to Day 4: post hoc t(7) = 0.4237, P > 0.9999; Day 3 to Day 4: post hoc t(7) = 0.7977, P > 0.9999). Two-way ANOVA followed by Bonferroni post hoc comparisons was used. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; scale bars, 100 μm and 50 μm, respectively./p>

0.9999) or random (Day 1 to Day 2: post hoc t(14) = 0.284, P > 0.9999; Day 1 to Day 3: post hoc t(14) = 0.284, P > 0.9999; Day 2 to Day 3: post hoc t(14) = 0.0, P > 0.9999) errors in controls across days. g, h, Optogenetic inhibition of callosal PV terminals induces perseveration on Day 2 and Day 3 compared to no stimulation on Day 1 (Day 1 to Day 2: post hoc t(14) = 4.092, P = 0.0033; Day 1 to Day 3: post hoc t(14) = 6.405, P < 0.0001; Day 2 to Day 3: post hoc t(14) = 2.313, P = 0.1094), but has no effect on random errors (Day 1 to Day 2: post hoc t(14) = 1.524, P = 0.4493; Day 1 to Day 3: post hoc t(14) = 0.254, P > 0.9999; Day 2 to Day 3: post hoc t(14) = 1.27, P = 0.6744). i, PV-Cre Ai14 mice had bilateral AAV-DIO-Ace2N-4AA-mNeon (Ace-mNeon) injections, an ipsilateral AAV-Synapsin-eNpHR-BFP (Syn-eNpHR) or AAV-Synapsin-mCherry (Syn-mCherry) injection and multimode fiber-optic implants in both prefrontal cortices. j, Representative images from mice injected with a control virus (Syn-mCherry), showing mCherry, Ace-mNeon, and tdTomato expression in the mPFC ipsi to the virus injection, and Ace-mNeon and tdTomato in the contra hemisphere. k, n, Experimental design: Day 1, no light delivery; Day 2, continuous light for inhibition during the R; Day 3, no light delivery. l, m, o, p, Optogenetic inhibition of callosal terminals does not change the number of perseverative errors in Syn-eNpHR mice (n = 5 mice, l-m) compared to Syn-mCherry controls (n = 4 mice, l-m; two-way ANOVA (task day × virus); interaction: F(2,14) = 1.933, P = 0.1814), and has no effect on random errors (two-way ANOVA (task day × virus); interaction: F(2,14) = 0.3789, P = 0.6914). l, m, Light delivery does not affect the number of perseverative (Day 1 to Day 2: post hoc t(3) = 1.464, P = 0.7183; Day 1 to Day 3: post hoc t(3) = 0.8783, P > 0.9999; Day 2 to Day 3: post hoc t(3) = 0.4804, P > 0.9999) or random (Day 1 to Day 2: post hoc t(3) = 1.732, P = 0.5451; Day 2 to Day 3: post hoc t(3) = 1.732, P = 0.5451) errors in controls across days. o, p, Nonspecific optogenetic inhibition of all callosal projections does not affect the number of perseverative (n = 5 mice; Day 1 to Day 2: post hoc t(4) = 0.6882, P > 0.9999; Day 1 to Day 3: post hoc t(4) = 2.108, P = 0.3081; Day 2 to Day 3: post hoc t(4) = 1.121, P = 0.9752) or random (Day 1 to Day 2: post hoc t(4) = 0.4082, P > 0.9999; Day 1 to Day 3: post hoc t(4) = 1.000, P > 0.9999; Day 2 to Day 3: post hoc t(4) = 0.000, P > 0.9999) errors in Syn-eNpHR mice across days. Two-way ANOVA followed by Bonferroni post hoc comparisons was used. **P < 0.01, ****P < 0.0001; scale bars, 50 μm./p>

0.9999; Day 3: post hoc t(24) = 1.763, P = 0.2717). g–i, We also re-analyzed the TEMPO data collected from PV-Cre Ai14 mice injected in one mPFC with DIO-eNpHR to identify specific times when optogenetic inhibition of callosal PV+ projections disrupts gamma synchrony. We measured the change in gamma synchrony (calculated in 1 s windows for various time points relative to behavioral events) between Day 1 (control) and Day 2 (optogenetic inhibition) for both errors (filled circles) and correct choices (open circles) during the first 5 RS trials in PV-Cre mice expressing DIO-eNpHR. g, This change in gamma synchrony (change = Day 2 – Day 1) is not significantly different for error vs. correct trials around the time of trial start (n = 5 mice; two-way ANOVA (time point × error vs. correct); interaction: F(15,64) = 1.642, P = 0.0874). h, This change in gamma synchrony is more negative for error vs. correct trials around the start of digging (n = 5 mice; two-way ANOVA (time point × error vs. correct); interaction: F(15,64) = 1.931, P = 0.0360). i, This change in gamma synchrony is more negative for error vs. correct trials around the end of digging (n = 5 mice; two-way ANOVA (time point × error vs. correct); interaction: F(10,44) = 2.096, P = 0.0454). j, Example traces of left (L) and right (R) Ace2n-4AA-mNeon (Ace-mNeon) traces (green and red, respectively), from 0–10 s after dig start on RS correct and error trials in a DIO-eNpHR-expressing mouse and k, zoomed in on the period 6–7 s after dig start. l, The time course of gamma synchrony (correlation values calculated from filtered and cleaned Ace-mNeon signals) from 0–10 s after dig start for these two example trials. Two-way ANOVA followed by Bonferroni post hoc comparisons was used. Data were expressed as mean ± s.e.m. *P < 0.05, **P < 0.01./p>

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