Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency

Abstract

Background: Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition--in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs)-has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult.

Methods: A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the basis of the assumption that dietary trends toward decreased consumption of these fats began 4-5 decades ago when the parents of current adolescents were born. Behavioral performance in a wide range of tasks as well as markers of dopamine-related neurotransmission was compared in adolescents and adults fed n-3 PUFA adequate and deficient diets.

Results: In adolescents, dietary n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum.

Conclusions: These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. Furthermore, they suggest that n-3 PUFA deficiency disrupts adolescent behaviors through enhanced dorsal striatal dopamine availability.

Keywords: Addiction; anxiety; cognition; fatty acids; nutrition; schizophrenia.

Figure 1

Effects of generational n-3 fatty acid deficiency in the open field test. (A) G1 DEF rats displayed a trend toward less time spent in the center (p=0.07), while G2 DEF rats spent significantly less time in open area (*** p<0.001) compared to ADQ-fed animals. (B) There were no dietary effects on locomotion in G1 rats, whereas G2 DEF rats displayed hyperlocomotion seen as increased mean number of total square crossings during the 5 min test (*** p < 0.001). Data shown as mean ± SEM, n = 16–28/group.

Figure 2

Novel object recognition memory in consecutive generations of n-3 PUFA deficient animals. No differences were observed between groups in cumulative time spent exploring the identical objects during the 5 min acquisition phase (A), but G2 DEF rats displayed significantly higher square crossings than ADQ rats (*** p < 0.001) (B). During the 5 min retention test phase, both G1 groups and G2 ADQ group spent significantly more time exploring the novel object (discrimination index > 0.5), but G2 DEF rats did not differentiate between the novel and familiar objects compared to G2 ADQ rats (* p < 0.05) (C). There were no differences in locomotion assessed as mean square grid crossings (D). Data presented as mean ± SEM, n = 15–26/group. Significance set at p < 0.05.

Figure 3

Effects of generational n-3 fatty acid deficiency on instrumental learning performance and extinction during adolescence. G2 DEF adolescent rats displayed consistently slower learning measured by total trials compared with their ADQ counterparts (A), while G1 DEF adolescent rats performed poorer only on some sessions. G2 DEF adolescent rats also displayed a trend for higher task-irrelevant pokes (p=0.06) (B) and significantly higher latencies for pellet retrieval (C). Data expressed as mean ± SEM, n = 10–12/group. Significance set at p < 0.05.

Figure 4

n-3 polyunsaturated fatty acid generational deficiency induced cognitive set-shifting performance impairments in G2 adolescent rats. (A) Adolescent G2 DEF rats learned the initial discrimination during Set 1 at a rate comparable to ADQ rats, but required significantly more trials to reach criterion during the extradimensional set shift (Set 2). (B) No differences in average time per trial were detected between ADQ and DEF rats on either test day. (C) G2 DEF adolescent rats displayed comparable performance accuracy from PA arm starts; however they showed significantly reduced performance accuracy from RA arm starts. Data expressed as mean ± SEM, n = 6–9/group. Significance set at p < 0.05.

Figure 5

G2 DEF adult rats displayed a similar pattern of impaired instrumental learning compared with ADQ rats, such as adolescents (A), with no differences in other measures recorded (B–C). Data expressed as mean ± SEM, n = 9/group. Significance set at p < 0.05.

Figure 6

N-3 dietary generational deficiency induced cognitive learning impairments in G2 adult rats. (A) Adult G2 DEF rats exhibited learning impairments during the initial discrimination in the T-maze set-shifting test, but performed the extradimensional set-shift comparably to ADQ rats. (B) No differences in average time per trial were detected between ADQ and DEF rats on either test day. (C) G2 DEF adults displayed significantly reduced performance accuracy from PA arm starts on Set 2 but there were no performance accuracy differences from RA arms. Data expressed as mean ± SEM, n = 8–9/group. Significance set at p < 0.05.

Figure 7

N-3 PUFA generational deficiency changed markers of dopamine neurotransmission in dorsal striatum (dStr) of G2 DEF adolescent and adult rats compared to the ADQ-fed group. Protein levels of VMAT2 and TH in G2 DEF rats, adolescents or adults, were not different than those in ADQ rats in prefrontal cortex (PFC) (Panel A, top and bottom) and nucleus accumbens (NAc) (Panel B, top and bottom). In the dStr (Panel C), TH protein expression was elevated significantly in G2 DEF adolescent rats relative to the control protein, tubulin. Conversely, in the dStr of G2 DEF adult rats, protein levels of VMAT2 were elevated significantly, while TH protein expression was reduced significantly compared to ADQ-fed counterparts. Representative images are shown correspondingly below each bar graph for both the protein of interest and tubulin. Upper histology panels represent coronal rat brain atlas diagrams (66) indicating regions of interest dissected for analyses. Data are shown as mean optical density of protein of interest relative to tubulin ± SEM, n = 6–8/group, * p < 0.05 compared to age-matched respective G2 ADQ group.