Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice

Abstract

Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2 mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2 mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2 mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems.

Regulator of G protein signaling 2 differentially regulates nicotine‐induced anxiolytic‐ and antidepressant‐like effects in mice

“…An unpaired t ‐test ( t (22) = 2.226; p = 0.0365) indicated a significant increase in time spent in the open arms in RGS2 WT mice after administration of nicotine (0.05 mg/kg) compared to saline, suggesting a nicotine‐induced anxiolytic‐like effect. Further as reported previously (Lifschytz et al., ; Raab et al., ), RGS2 KO mice compared to RGS2 WT mice spent significantly less time in the open arms compared to RGS2 WT mice [unpaired t ‐test; ( t (22) = 3.479; p = 0.002); Figure a], suggesting anxiety‐like behavior in RGS2 KO mice. Overall, nicotine‐induced anxiolytic‐like effects were more robust in RGS2 KO mice compared to RGS2 WT mice, suggesting that anxiolytic‐like effects of nicotine were facilitated by genetic deletion of RGS2.…”

“…The interaction between nicotine and RGS2 is most likely indirect via nicotine‐induced increase in monoaminergic neurotransmission. RGS2 KO mice have disrupted serotonin and noradrenaline neurotransmission in brain regions involved in mediating anxiety (Lifschytz et al., ; Raab et al., ). Nicotine facilitates both serotonin and noradrenaline neurotransmission in the brain via excitatory nicotinic acetylcholine receptors located as heteroreceptors on serotoninergic and noradrenergic neurons (Wonnacott, ).…”

“…Additionally, activation of 5HT1A receptors facilitated nicotine‐induced anxiogenic response (Cheeta, Kenny, & File, ). Thus, a decrease in expression of 5HT1A receptors, which occurs with genetic deletion of RGS2 (Raab et al., ), would facilitate nicotine‐induced anxiolytic‐like effects. Taken together, reversal of disrupted serotonin and noradrenaline neurotransmission in RGS2 KO mice possibly mediates observed facilitation of nicotine‐induced anxiolytic‐like effects.…”

“…RGS2 is extensively found in brain regions implicated in anxiety and depression such as the hippocampus, amygdala, raphe nucleus, and cortex (Neubig, ). Serotonin and noradrenaline levels were significantly reduced in the prefrontal cortex in RGS2 knockout (KO) mice compared to RGS2 wildtype (WT) mice (Raab et al., ). Additionally, the same study showed decreased expression of both 5HT1A and α2A receptors in the amygdala.…”

Biomarker discovery in attention deficit hyperactivity disorder: RNA sequencing of whole blood in discordant twin and case-controlled cohorts

“…Likewise, RGS2 is thought to mediate the anxiolytic effects of oxytocin [ 57 ], and affects T cell activation, anxiety, and male aggressive behavior [ 58 ]. RGS2 knockout mice exhibit increased fear learning, spatial learning, and neophobia [ 59 ]. Further, RGS2 modulates the activity and internalization of the dopamine D2 receptor in neuroblastoma cells [ 60 ], and has been implicated in dopamine receptor signaling during amphetamine self-administration [ 61 ].…”