Enhanced novelty-induced corticosterone spike and upregulated serotonin 5-HT1A and cannabinoid CB1 receptors in adolescent BTBR mice

Abstract

Hypothalamic pituitary adrenal (HPA) axis responses to change and social challenges during adolescence can influence mental health and behavior into adulthood. To examine how HPA tone in adolescence may contribute to psychopathology, we challenged male adolescent (5 wk) and adult (16 wk) BTBR T+tf/J (BTBR) and 129S1/SvImJ (129S) mice with novelty in sociability tests. In prior studies these strains had exaggerated or altered HPA stress responses and low sociability relative to C57BL/6J mice in adulthood. In adolescence these strains already exhibited similar or worse sociability deficits than adults or age-matched C57 mice. Yet BTBR adolescents were less hyperactive and buried fewer marbles than adults. Novelty-induced corticosterone (CORT) spikes in adolescent BTBR were double adult levels, and higher than 129S or C57 mice at either age. Due to their established role in HPA feedback, we hypothesized that hippocampal Gαi/o-coupled serotonin 5-HT1A and cannabioid CB1 receptor function might be upregulated in BTBR mice. Adolescent BTBR mice had higher hippocampal 5-HT1A density as measured by [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) binding than C57 mice, and adult BTBR 8-OH-DPAT-stimulated GTPγS binding was higher than in either C57 or 129S mice in this region. Further, BTBR hippocampal CB1 density measured by [3H]CP55,940 binding was 15-20% higher than in C57. CP55,940-stimulated GTPγS binding in adult BTBR dentate gyrus was 30% higher then 129S (p<0.05), but was not a product of greater neuronal or cell density defined by NeuN and DAPI staining. Hence hyperactive HPA responsiveness during adolescence may underlie 5-HT1A and CB1 receptor up-regulation and behavioral phenotype of BTBR mice.

Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains

“…Previously, naïve 129S fed Teklad chow exhibited impaired sociability, in agreement with Moy et al (2007), even as collinear (129S) strangers were used (Gould et al, 2014). However, distinct oxytocin-mediated responses to same vs. different mouse strains were found in other studies (Macbeth et al, 2009; Hattori et al, 2014).…”

“…We postulate this change may stem from confluence of the following factors: 1) novelty of diet, 2) +TRP in diet, 3) sociability test duration and phase (social novelty test after 30 min in arena), and 4) previously characterized contextual fear-extinction deficiencies in 129S that resemble post-traumatic stress disorder (Camp et al, 2012; Temme et al, 2014). Previously we found evidence for involvement of hippocampal 5-HT 1A receptors in the abnormal CORT responses of 129S mice, highlighting an important role for 5-HT in this process (Gould et al, 2014). In accord, the CORT response in +TRP 129S after behavior tests was relatively blunted (** in Fig.…”

“…Preference tests for social interaction and social novelty were performed in three chambered testing arenas between 9:00 and 16:00 h CST, as described in prior studies (Gould et al, 2011; 2014; Silverman et al, 2010; Yang et al, 2011). Conditioning and sociability tests were conducted under low red lighting (16 lux).…”

“…Preferences for social interaction and novelty, chamber entries, self-grooming during sociability tests and subsequent marble burying were compared among strains and overnight TRP diet treatments. After behavior tests, brain TRP, 5-HT turnover and plasma corticosterone (CORT) -- since it can be suppressed by central 5-HT transmission (Gould et al, 2014) -- were measured in tissues collected from all strain × diet treatment groups to assess their central 5-HT status.…”

The serotonin system in autism spectrum disorder: From biomarker to animal models

“…Mouse models of 15q11-q13 duplication and Smith-Lemli-Opitz syndromes show alterations in the central 5-HT system (Waage-Baudet et al, 2003, Nakatani et al, 2009, Farook et al, 2012, Korade et al, 2013). The BTBR inbred mouse strain, which shows many autism-relevant behavioral phenotypes, shows decreased baseline SERT binding throughout the brain and increased 5-HT 1A activity in the hippocampus (Gould et al, 2011, Gould et al, 2014). Further, short-term tryptophan supplementation as well as acute treatment with the serotonin reuptake inhibitor fluoxetine or the 5-HT 1A partial agonist buspirone result in increased sociability in BTBR mice (Chadman, 2011, Gould et al, 2011, Gould et al, 2014, Zhang et al, 2015).…”