Enriched Environment Attenuates Enhanced Trait Anxiety in Association with Normalization of Aberrant Neuro-Inflammatory Events.

Neuroinflammation is discussed to play a role in specific subgroups of different psychiatric disorders, including anxiety disorders. We have previously shown that a mouse model of trait anxiety (HAB) displays enhanced microglial density and phagocytic activity in key regions of anxiety circuits compared to normal-anxiety controls (NAB). Using minocycline, we provided causal evidence that reducing microglial activation within the dentate gyrus (DG) attenuated enhanced anxiety in HABs. Besides pharmacological intervention, "positive environmental stimuli", which have the advantage of exerting no side-effects, have been shown to modulate inflammation-related markers in human beings. Therefore, we now investigated whether environmental enrichment (EE) would be sufficient to modulate upregulated neuroinflammation in high-anxiety HABs. We show for the first time that EE can indeed attenuate enhanced trait anxiety, even when presented as late as adulthood. We further found that EE-induced anxiolysis was associated with the attenuation of enhanced microglial density (using Iba-1 as the marker) in the DG and medial prefrontal cortex. Additionally, EE reduced Iba1 + CD68+ microglia density within the anterior DG. Hence, the successful attenuation of trait anxiety by EE was associated in part with the normalization of neuro-inflammatory imbalances. These results suggest that pharmacological and/or positive behavioral therapies triggering microglia-targeted anti-inflammatory effects could be promising as novel alternatives or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals predisposed to trait anxiety.

Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline.

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia 'inhibitor' in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxiety-related behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.

Looking and thinking: how individuals with Williams syndrome make judgements about mental states.

Individuals with the neuro-developmental disorder Williams syndrome (WS) are characterised by a combination of features which makes this group vulnerable socially, including mild-moderate cognitive difficulties, pro-social drive, and indiscriminate trust. The purpose of this study was to explore a key socio-communicative skill in individuals with WS, namely, mental state recognition abilities. We explored this skill in a detailed way by looking at how well individuals with WS recognise complex everyday mental states, and how they allocate their attention while making these judgements. Participants with WS were matched to two typically developing groups for comparison purposes, a verbal ability matched group and a chronological age matched group. While eye movements were recorded, participants were shown displays of eight different mental states in static and dynamic form, and they performed a forced-choice judgement on the mental state. Mental states were easier to recognise in dynamic form rather than static form. Mental state recognition ability for individuals with WS was poorer than expected by their chronological age, and at the level expected by their verbal ability. However, the pattern of mental state recognition for participants with WS varied according to mental state, and we found some interesting links between ease/difficulty recognising some mental states (worried/do not trust) and the classic behavioural profile associated with WS (high anxiety/indiscriminate trust). Furthermore, eye tracking data revealed that participants with WS allocated their attention atypically, with less time spent attending the information from the face regions. This challenges the widely held understanding of WS being associated with prolonged face and eye gaze, and indicates that there is more heterogeneity within this disorder in terms of socio-perception than previous reports would suggest.