A mixed polyunsaturated fatty acid diet normalizes hippocampal neurogenesis and reduces anxiety in serotonin transporter knockout rats

Abstract

The aim of this study was to investigate the effects of a mixed dietary intervention on behavioral symptoms in serotonin transporter knockout (5-HTT⁻/⁻) rats modeling the human 5-HTT length polymorphic region short-allele. Twenty female 5-HTT⁻/⁻ and 19 wild-type (5-HTT⁺/⁺) rats were fed for 3 months on a mixed polyunsaturated fatty acid (PUFA) diet comprising n-3 PUFAs, B vitamins and phospholipids, or an isocaloric control diet, and a subgroup was subsequently tested in an array of anxiety-related behavioral tests. All brains were harvested and immunostained for doublecortin, a neurogenesis marker. In addition, hippocampal volume was measured. 5-HTT⁻/⁻ rats on the control diet displayed increased anxiety-related behavioral responses, and impaired fear extinction. These effects were completely offset by the mixed PUFA diet, whereas this diet had no behavioral effect in 5-HTT⁺/⁺ rats. In parallel, dentate gyrus doublecortin immunoreactivity was increased in 5-HTT⁻/⁻ rats fed on the control diet, which was reversed by the mixed PUFA diet. Hippocampal volume was unaffected by the mixed PUFA diet in 5-HTT⁻/⁻ subjects, whereas it increased in 5-HTT⁺/⁺ rats. We conclude that a mixed n-3 PUFA diet ameliorates anxiety-related symptoms in a genotype-dependent manner, potentially by normalizing neurogenesis. We suggest that such a mixed diet may serve as an attractive adjuvant to treat anxiety in 5-HTT length polymorphic region short-allele carriers.

Bioactive lipids as modulators of immunity, inflammation and emotions

“…These findings are in line with human and animal studies demonstrating that increased dietary intake of v-3 PUFAs ameliorates stress/anxiety and depression symptoms [51][52][53][54]. Indeed, DHA deficiency is associated with dysfunctions of neuronal membrane stability and transmission of serotonin, norepinephrine and dopamine (possibly connecting to the aetiology of mood and cognitive dysfunction of depression), whereas the role of EPA in balancing the immune function and physical health by reducing synthesis of classical eicosanoids might be linked to the somatic manifestations and physical comorbidity in depression [55 ].…”

Behavioural therapy based on distraction alleviates impaired fear extinction in male serotonin transporter knockout rats

“…In line with 5-HTTLPR findings in humans, serotonin transporter knockout (5-HTT -/-) rats and mice have shown a failure to extinguish fear 7,8 as well as improved adaptive responses to positive stimuli. 9,10 In the present study, we used 5-HTT -/-rats, which are well accepted as a model for the 5-HTTLPR s-allele, 3,11 to test our prediction, and we designed a "distraction" therapy in which the fear-eliciting stimulus was copresented with a sucrose pellet-predicting stimulus during fear extinction.…”

The role of serotonin in adult hippocampal neurogenesis

“…Although survival and differentiation of newborn neurons were not affected, increased numbers of proliferating cells have been observed in the CA3 region of mouse hippocampus (Karabeg et al, 2013), whereas adult rat deficient in SERT showed increased numbers of immature neurons expressing DCX in the DG (Schipper et al, 2011). SERT knockdown by siRNA in adulthood also contributes to antidepressant action (Ferres-Coy et al, 2013).…”