Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner

Abstract

Early life adversity (ELA) is a major health burden in the United States, with 62% of adults reporting at least one adverse childhood experience. These experiences during critical stages of brain development can perturb the development of neural circuits that mediate sensory cue processing and behavioral regulation. Recent studies have reported that ELA impaired the maturation of dendritic spines on neurons in the dorsolateral striatum (DLS) but not in the dorsomedial striatum (DMS). The DMS and DLS are part of two distinct corticostriatal circuits that have been extensively implicated in behavioral flexibility by regulating and integrating action selection with the reward value of those actions. To date, no studies have investigated the multifaceted effects of ELA on aspects of behavioral flexibility that require alternating between different action selection strategies or higher-order cognitive processes, and the underlying synaptic transmission in corticostriatal circuitries. To address this, we employed whole-cell patch-clamp electrophysiology to assess the effects of ELA on synaptic transmission in the DMS and DLS. We also investigated the effects of ELA on the ability to update action control in response to outcome devaluation in an instrumental learning paradigm and reversal of action-outcome contingency in a water T-maze paradigm. At the circuit level, ELA decreased corticostriatal glutamate transmission in male but not in female mice. Interestingly, in DMS, glutamate transmission is decreased in male ELA mice, but increased in female ELA mice. ELA impaired the ability to update action control in response to reward devaluation in a context that promotes goal-directedness in male mice and induced deficits in reversal learning. Overall, our findings demonstrate the sex- and region-dependent effects of ELA on behavioral flexibility and underlying corticostriatal glutamate transmission. By establishing a link between ELA and circuit mechanisms underlying behavioral flexibility, our findings will begin to identify novel molecular mechanisms that can represent strategies for treating behavioral inflexibility in individuals who experienced early life traumatic incidents.

Keywords: action-outcome contingency; behavioral flexibility; corticostriatal circuits; early life adversity; outcome devaluation; reversal learning; synaptic transmission.

Figure 1

Male LBN mice exhibited decreased cortical glutamate release probability in the DLS and DMS. (A) Recording schematic for whole-cell patch-clamp experiments in the DMS. (B) Representative image of a recorded MSN in DMS; NeuroBiotin-filled cells were processed with an Alexa Fluor 568 conjugated streptavidin for morphological identification of MSN. (C) Recording schematic for whole-cell patch-clamp experiments in the DLS. (D) Representative image of a recorded MSN in DLS; NeuroBiotin-filled cells were processed with an Alexa Fluor 568 conjugated streptavidin for morphological identification of MSN. (E) Summary graph of input/output curve showing no changes of amplitudes in response to increasing stimulation intensities in the DMS-MSN of male LBN mice. (F,G) LBN altered relative contribution of AMPA and NMDA receptors to overall EPSCs in the DMS-MSN. (F) Representative traces of AMPA currents (−70 mV) and NMDA currents (+40 mV); shaded area denotes the region used to measure the NMDA component of EPSCs. (G) Summary graph of AMPA and NMDA ratio showing a decrease in ratio for male LBN mice. (H,I) Male LBN mice exhibited decreased probability of glutamate release in the DMS-MSN. (H) Representative traces of paired-pulse recordings; inter-stimulus interval was fixed at 25 ms (40 Hz) and traces were normalized to the first EPSC. (I) Summary graph of PPR showing a increase in ratio for male LBN mice. (J) Summary graph of input/output curve showing a significant decrease of amplitudes in response to increasing stimulation intensities in the DLS-MSN of male LBN mice. (K,L) LBN changed relative contribution of AMPA and NMDA receptors to overall EPSCs in the DLS-MSN. (K) Representative traces of AMPA currents (−70 mV) and NMDA currents (+40 mV); shaded area denotes the region used to measure the NMDA component of EPSCs. (L) Summary graph of AMPA and NMDA ratio showing no changes in ratio for male LBN mice. (M,N) Male LBN mice exhibited decreased probability of glutamate release in DLS-MSN. (M) Representative traces of paired-pulse recordings; inter-stimulus interval was fixed at 25 ms (40 Hz) and traces were normalized to the first EPSC. (N) Summary graph of PPR showing an increase in ratio for male LBN mice. Data is represented as means ± SEM. Number of neurons/mice are listed inside the bar graphs. Each open circle in the summary graphs represents the average of each recorded cell. Statistical assessments were performed by unpaired two-tailed Student’s t-test (G,I,L,N) and RM two-way ANOVA (E,J) by comparing male LBN to CTL mice with *p < 0.05, **p < 0.01, ****p < 0.0001.

Figure 2

Female LBN mice exhibited increased cortical glutamate release probability in the DMS. (A) Recording schematic for whole-cell patch-clamp experiments in the DMS. (B) Representative image of a recorded MSN in DMS; NeuroBiotin-filled cells were processed with an Alexa Fluor 568 conjugated streptavidin for morphological identification of MSN. (C) Recording schematic for whole-cell patch-clamp experiments in the DLS. (D) Representative image of a recorded MSN in DLS; NeuroBiotin-filled cells were processed with an Alexa Fluor 568 conjugated streptavidin for morphological identification of MSN. (E) Summary graph of input/output curve showing no changes of amplitudes in response to increasing stimulation intensities in the DMS-MSN of female LBN mice. (F,G) LBN has no effect on the relative contribution of AMPA and NMDA receptors to overall EPSC in the DMS-MSN. (F) Representative traces of AMPA currents (−70 mV) and NMDA currents (+40 mV); shaded area denotes the region used to measure the NMDA component of EPSCs. (G) Summary graph of AMPA and NMDA ratio showing no changes in ratio for female LBN mice. (H,I) Female LBN mice exhibited increased probability of glutamate release in the DMS-MSN. (H) Representative traces of paired-pulse recordings; inter-stimulus interval was fixed at 25 ms (40 Hz) and traces were normalized to first EPSC. (I) Summary graph of PPR showing a decrease in ratio for female LBN mice. (J) Summary graph of input/output curve showing no changes of amplitudes in response to increasing stimulation intensities in the DLS-MSN of female LBN mice. (K,L) LBN had no effect on the relative contribution of AMPA and NMDA receptors to overall EPSC in the DLS-MSN. (K) Representative traces of AMPA currents (−70 mV) and NMDA currents (+40 mV); shaded area denotes the region used to measure the NMDA component of EPSCs. (L) Summary graph of AMPA and NMDA ratio showing no changes in ratio for female LBN mice. (M,N) Female LBN mice had no changes in the probability of glutamate release in the DLS-MSN. (M) Representative traces of paired-pulse recordings; inter-stimulus interval was fixed at 25 ms (40 Hz) and traces were normalized to first EPSC. (N) Summary graph of PPR showing no changes in ratio for female LBN mice. Data is represented as means ± SEM. Number of neurons/mice are listed inside the bar graphs. Each open circle in the summary graphs represents the average of each recorded cell. Statistical assessments were performed by RM two-way ANOVA (E,J) and unpaired two-tailed Student’s t-test (G,I,L,N) by comparing female LBN to CTL mice with *p < 0.05.

Figure 3

Male LBN mice failed to differentially distribute their lever presses in response to outcome devaluation in a context that promotes goal-directedness. (A) Experimental timeline of operant conditioning paradigm in mice. (B,C) Male LBN mice failed to differentially distribute their lever presses between valued (V) and devalued (DV) days in the RR context. (B) Summary graph of response rate (lever presses/min) on V and DV days. (C) Summary graph of normalized lever presses showing distribution of lever presses between V and DV days. (D,E) Male LBN mice exhibited normal habitual responding behavior in response to outcome devaluation in the RI context. (D) Summary graph of response rate (lever presses/min) on valued (V) and devalued (DV) days. (E) Summary graph of normalized lever presses showing distribution of lever presses between V and DV days. Data is represented as means ± SEM. Number of mice is listed inside the bar graphs. Each open circle in the summary graphs represents each mouse. Statistical assessments were performed by RM two-way ANOVA (B,D) by comparing male LBN to CTL mice with *p < 0.05 or one-sample t-test (C,E) by comparing normalized lever presses within each group of mice against a “no devaluation” point of 0.5 with *p < 0.05.

Figure 4

Female LBN mice did not exhibit impairments in action selection strategy in response to outcome devaluation. (A,B) Female LBN mice exhibited goal-directed behavior in response to outcome devaluation in the RR context. (A) Summary graph of response rate (lever presses/min) on V and DV days. (B) Summary graph of normalized lever presses showing distribution of lever presses between V and DV days. (C,D) Female LBN mice exhibited normal habitual responding behavior in response to outcome devaluation in the RI context. (C) Summary graph of response rate (lever presses/min) on valued (V) and devalued (DV) days. (D) Summary graph of normalized lever presses showing distribution of lever presses between V and DV days. Data is represented as means ± SEM. Number of mice is listed inside the bar graphs. Each open circle in the summary graphs represents each mouse. Statistical assessments were performed by RM two-way ANOVA (A,C) or one-sample t-test (B,D) by comparing normalized lever presses within each group of mice against a “no devaluation” point of 0.5 with *p < 0.05.

Figure 5

LBN mice exhibited impaired behavioral flexibility in a water T-maze reversal learning paradigm. (A–C) LBN mice exhibited normal spatial navigation. (A) Summary graph of incorrect arm entries during the spatial task on days 1 and 2. (B) Summary graph of percentage of successful trials during the spatial task on days 1 and 2. (C) Summary graph of total number of days taken to learn the spatial task. (D–F) LBN mice exhibited reversal learning deficits. (D) Summary graph of incorrect arm entries during reversal learning task on days 1 and 2. (E) Summary graph of percentage of successful trials during the reversal learning task on days 1 and 2. (F) Summary graph of total number of trials taken to learn the reversal task. Data is represented as means ± SEM. Number of mice is listed inside the bar graphs. Each open circle in the summary graphs represents each mouse. Statistical assessments were performed by RM two-way ANOVA (A,B,D,E) or two-tailed Student’s t-test (C,F) by comparing CTL to LBN mice with *p < 0.05.