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

Abstract

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.

Multisensory Stimulation Reverses Memory Impairment in Adrβ3KO Male Mice

“…We know that MS increases hippocampal neuroplasticity [ 26 , 27 ] and neurogenesis [ 28 , 29 ], but we did not address this process in the present study. It is also known that MS decreases neuroinflammation [ 30 , 31 ], and our data support this important role of MS. We showed that there was a decrease in the expression of GFAP, a marker for astrocyte activation, in the HC of Adrβ 3 KO and WT mice after the 8-week MS protocol. Iba-1, a marker for microglia activation, was also reduced in Adrβ 3 KO mice exposed to the MS protocol.…”

Multisensory Stimulation Reverses Memory Impairment in Adrβ3KO Mice

“…We know that MS increases hippocampal neuroplasticity [34,35] and neurogenesis [36,37], but we did not address this process in the present study. It is also known that MS decreases neuroinflammation [38,39], and our data gives support to this important role of MS. We showed that there is a decrease in the expression of GFAP, a marker for astrocyte activation, in the HC of Adrβ3KO and WT mice after the 8-week MS protocol. Iba-1, a marker for microglia activation, was also reduced in Adrβ3KO exposed to the MS protocol Mounting evidences indicates a close relationship between glial cells in both cognitive impairments [40,41], and in the pathogenesis of neurodegenerative disorder, such as Alzheimer's disease [42,43].…”

Molecular insights into enriched environments and behavioral improvements in autism: a systematic review and meta-analysis

“…In various animal models, EE has been shown to alter a range of inflammatory mechanisms, exerting anti-inflammatory or inhibitory effects on microglial “activation” ( 75 ). Some studies have indicated that EE can reduce inflammation and oxidative stress in the brain ( 76 ).…”