Nucleus accumbens neurochemistry in human anxiety: A 7 T ¹H-MRS study

Abstract

Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20–30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), negative mood (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy (¹H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. No correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, negative mood, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.

Introduction

Anxiety is an emotion characterized by apprehension or dread and enhanced vigilance, frequently accompanied by behavioral, cognitive and physiological stress responses. Although anxiety can help the individual preparing to detect and deal with threats (Bateson et al., 2011), when excessive, it can be maladaptive or pathological and manifest in a variety of disorders (Price, 2003).

Individuals differ greatly in their behavioral and physiological responses to actual or potential threats, following a continuum from mild to strong. While ‘state’ anxiety refers to transitory emotional and motivational state displayed in response to immediate uncertainty (Cattell, 1966, Eysenck et al., 2007, Spielberger, 1972), ‘trait’ anxiety is the stable predisposition of an individual to judge environmental events as potentially threatening (Domschke and Reif, 2012, Mann et al., 2012, Sih et al., 2004, Toye and Cox, 2001). High trait anxious individuals are at risk to develop stress-induced neuropsychiatric disorders, particularly anxiety disorders and depression (Rogers et al., 2013, Sandi and Richter-Levin, 2009, Weger and Sandi, 2018). ‘Social’ anxiety refers to persistent fear in social interactions and performance (Heimberg et al., 1999) that, at high levels, becomes social anxiety disorder (formerly known as social phobia) (Heimberg et al., 1999).

Identifying neurobiological factors related to individual differences in temperamental and situational anxiety will advance our understanding of mechanisms underlying stress vulnerability and might lead to the development of new treatments for anxiety disorders. However, the neurobiology of anxiety is scarcely understood (Craske et al., 2017, Weger and Sandi, 2018). Previous work has highlighted imbalances in neural excitation and inhibition (E/I) in several brain areas in anxiety and mood disorders and following stress exposure (Cordero et al., 2016, Hasler et al., 2010, Houtepen et al., 2017, Moghaddam, 2002, Popoli et al., 2012, Sandi, 2011). In addition, taurine, an abundant free β-amino acid, has been shown to act as endogenous inhibitor of cellular excitability and network activity (Davison and Kaczmarek, 1971, El Idrissi and Trenkner, 2004, Jia et al., 2008). Notably, taurine treatment has been shown to be effective in reducing anxiety-like behaviors (Mezzomo et al., 2016, Zhang and Kim, 2007). However, to date, there is no information about taurine levels in the human brain in the context of anxiety.

Recently, a role for the nucleus accumbens (NAc), the main anatomical constituent of the ventral striatum (VS), is emerging in the context of anxiety (Gunaydin and Kreitzer, 2016, Levita et al., 2012) interconnected with the NAc function in behavioral adaptation (Haber and Behrens, 2014). In rodents, anxiety-like behaviors can be regulated by pharmacological (Heshmati et al., 2016, Lopes et al., 2012) or genetic (Crofton et al., 2017, Feng et al., 2017, Shen et al., 2016, Zhao and Gammie, 2018) manipulation of NAc neurochemistry. Importantly, anxiety-like behaviors have also been related to variations in NAc mitochondrial function (Hollis et al., 2015, Van Der Kooij et al., 2018) and brain energy metabolism (Larrieu et al., 2017). A few studies have also highlighted NAc structural (Kühn et al., 2011) and functional (Goff et al., 2013, Levita et al., 2012) alterations in association with anxiety and depression in humans. However, there is virtually no information on the NAc/VS neurochemical profile, nor on its relationship with anxiety.

Therefore, the aim of this study was to perform proton magnetic resonance spectroscopy (¹H-MRS) at 7 Tesla (7 T) in the NAc of individuals phenotyped for anxiety (state, trait and social) and self-perceived situational stress, with a focus on glutamate, glutamine, GABA and taurine.