Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology

Abstract

A major challenge for neuroscience, public health, and evolutionary biology is to understand the effects of scarcity and uncertainty on the developing brain. Currently, a significant fraction of children and adolescents worldwide experience insecure access to food. The goal of our work was to test in mice whether the transient experience of insecure versus secure access to food during the juvenile-adolescent period produced lasting differences in learning, decision-making, and the dopamine system in adulthood. We manipulated feeding schedules in mice from postnatal day (P)21 to P40 as food insecure or ad libitum and found that when tested in adulthood (after P60), males with different developmental feeding history showed significant differences in multiple metrics of cognitive flexibility in learning and decision-making. Adult females with different developmental feeding history showed no differences in cognitive flexibility but did show significant differences in adult weight. We next applied reinforcement learning models to these behavioral data. The best fit models suggested that in males, developmental feeding history altered how mice updated their behavior after negative outcomes. This effect was sensitive to task context and reward contingencies. Consistent with these results, in males, we found that the two feeding history groups showed significant differences in the AMPAR/NMDAR ratio of excitatory synapses on nucleus-accumbens-projecting midbrain dopamine neurons and evoked dopamine release in dorsal striatal targets. Together, these data show in a rodent model that transient differences in feeding history in the juvenile-adolescent period can have significant impacts on adult weight, learning, decision-making, and dopamine neurobiology.

Keywords: adaptive; cognitive flexibility; dopamine, sex differences, adolescent, reversal, adversity, mouse; feeding; food insecurity.

Figure 1.. Food insecurity feeding paradigm, experimental timeline, and mouse weight gain.

A, Mice were assigned to 2 different groups, Ad lib (AL) and Food Insecurity (FI) at P21. After P41, both AL and FI mice were fed ad libitum until testing. Behavioral or neurobiological testing were performed after P60. B, Schematic illustrates the P21-P40 treatment differences. AL mice had free access to food daily while FI mice received food in alternating ‘feast and famine’ days. C, Food was delivered to the FI mice with variable ratio (with a 5.0g total baseline delivered every 48 hours). D, FI mice showed transient disruption of weight gain during the P21-40 (n(AL)=30, n(FI)=25). E, Male mice weight (n(AL)=16, n(FI)=12) showed no group differences in weight gain in adulthood. Note, all mice underwent food restriction for 4COF task in the P60s. F, Female mice (n(AL)=14, n(FI)=13) showed significant differences in weight gain in adulthood. **p<0.01, ***p<0.001, ****p<0.0001. D-F, Data are represented as mean ± SEM. See also Figure S1.

Figure 2.. In male mice, developmental feeding history affected adult cognitive flexibility in reversal learning. RL modeling suggests this effect was driven by differences in the learning rate in response to negative outcomes.

A, Schematic of the 4COF task. O1 was rewarded in the discrimination phase and unrewarded in the reversal phase. Previously unrewarded O2 became rewarded in the reversal phase. B,C, Discrimination performance was similar between the adult male AL (n=10) and FI (n=12) mice. D,E, The FI mice took significantly more trials than the AL mice to reach criterion in the reversal phase, driven by a greater number of errors. F, The FI mice made significantly more reversal errors (O1 Error), especially Perseverative O1 errors. G,I, Inverse temperatures in both phases, ${\beta }_{dis}$ and ${\beta }_{rev}$, were similar between the AL and FI mice. H, Learning rate, ${\alpha }_{dis}$, in the discrimination phase were comparable. J,K, In reversal phase, learning rates ${\alpha }_{revpos}(\alpha +)$, were not significantly different between groups, but learning rates in response to negative outcomes, ${\alpha }_{revneg}(\alpha -)$, were significantly smaller in the FI group. **p<0.01, ***p<0.001, ****p<0.0001. Data are represented as mean ± SEM. See also Figure S2,S3 and Table S1.

Figure 3.. In female mice, developmental feeding history did not affect adult cognitive flexibility in reversal learning.

A, Schematic of the 4COF task. B,C, Discrimination phase, B, Trials to criterion (t(21)=0.72, p=0.48) C, Total numbers of errors (t(21)=0.72, p=0.48). D-F, Reversal phase. D, Trials to criterion (t(21)=0.40, p=0.70), E, Total numbers of errors (t(21)=0.46, p=0.65), F, O1 errors (t(21)=0.61, p=0.55), Perseverative O1 error (U=56.5, p=0.61), Regressive O1 error (t(21)=0.0035, p=0.99), Irrelevant error (t(21)=0.41, p=0.69), Novel error (U=62.5, p=0.89) and Omission (t(21)=0.79, p=0.44). n(AL)=10, n(FI)=13. Unpaired two-tailed t-test or Mann-Whitney two-tailed test. Data are represented as mean ± SEM. See also Figure S2,S3 and Table S1.

Figure 4.. In male mice, developmental feeding history affected adult cognitive flexibility and the learning rate in response to negative outcomes in the probabilistic 2-armed bandit task.

A, Schematic of the 2ABT. B-D, Comparing to adult male AL mice (n=8), FI mice (n=8) took significantly fewer trials to switch in Phase 1 and 3 (when the context was more probabilistic, 75% and 65% respectively). Groups did not differ in Phase 2 (90%). E-G, After a reward block switch, performance drops and then recovers. The FI mice reached 0.5 fraction of correct choice faster after a switch trial in Phase 1 and 3. This difference was present but less prominent in Phase 2. H, Within both groups, mice reached 0.5 fraction of L-choice faster in Phase 3. I-L, RL model with 4 parameters, $\beta ,{\alpha }_{pos}(a+)$, and ${\alpha }_{neg}(a-)$, and $st$ in Phase 1. The FI group had significantly greater ${\alpha }_{neg}(a-)$ and smaller st values than the AL group. *p<0.05, ****p<0.0001. Dotted line at trial 0 indicates the reward block switching. Note the trial before the switch was always rewarded. Data are represented as mean ± SEM. See also Figure S4,S5 and Table S1.

Figure 5.. Developmental feeding history had no impact on performance in the 2-armed bandit task in adult female mice.

A-C, Adult female AL (n=8) and FI mice (n=8) did not differ in the number of trials to switch in all phases. D-F, The female AL and FI groups did not differ in fraction of correct choice in all phases. Data are represented as mean ± SEM. See Figure S4,S5 and Table S1.

Figure 6.. In male mice, developmental feeding history affected AMPAR/NMDAR ratio in mesolimbic dopamine neurons in adulthood.

A, Retrobeads were injected into the NAc core and recordings were made from the VTA in naïve male AL and FI mice at P61-70. B, Example of evoked EPSC traces before and after application of D-AP5. The dual components of AMPAR-mediated and NMDAR-mediated EPSCs were recorded. D-AP5 was applied to isolate AMPAR-mediated currents. C, The AMPAR/NMDAR ratio was significantly reduced in the FI group (n=10) compared to the AL group (n=11). D,E, AMPAR-mediated EPSC(I)-Voltage(V) relationship curve. There was a trend level difference in current at +40mV in the slices from the FI group (treatment: F(1,90)=1.367, p=0.25, voltage: F(4,90)=56.56, p<0.0001, interaction: F(4,90)=1.105, p=0.36, post-hoc Tukey at +40mV: p=0.096). There was no significant difference in rectification index between the AL(n=9) and FI (n=9) groups. F,G, Paired-pulse ratios were not significantly different between groups at 50, 100, and 200 ms intervals. *p<0.05. Data are represented as mean ± SEM.

Figure 7.. In male mice, developmental feeding history affected evoked dopamine release in the dorsal striatum in adulthood.

A, Evoked dopamine release [DA]_o in striatal subregions showing single pulse (1p) data. Inset, cyclic voltammogram shows characteristic dopamine waveforms. B, Quantification of peak [DA]_o by 1p stimulation. N= 17-32 transients per site from 5 mice per group. The evoked peak [DA]_o in the DLS was significantly lower in the FI group compared to the AL group. C, Peak [DA]_o by a 4p train 100 Hz stimulation. N= 9-16 transients per site from 5 mice per group. The evoked peak [DA]_o in the DLS was significantly lower in the FI group. D, Ratio of 4p/1p peak [DA]_o. The 4p/1p ratio in the DMS was significantly lower in the FI group compared to the AL group. See also Figure S6. Paired two-tailed t-test. Slices were paired such that one FI and one AL brain were recorded using the same electrode on the same day. *p<0.05, **p<0.01, ***p<0.001. DMS, dorsomedial striatum. DCS, dorsocentral striatum; DLS, dorsolateral striatum. CS, central striatum. VLS, ventrolateral striatum. NAc, nucleus accumbens. VMS, ventromedial striatum. Data are represented as mean ± SEM.