HDAC3-Regulated PGE2 Production by Microglia Induces Phobic Anxiety Susceptibility After Stroke and Pointedly Exploiting a Signal-Targeted Gamma Visual Stimulation New Therapy

Abstract

BackgroundPhobic anxiety present after stroke (called poststroke anxiety, PSA) can hamper the rehabilitation of patients and disrupt their usual activities. Besides, the symptoms and mechanisms of PSA are different from those in nonstroke populations that have generalized anxiety disorder. What’s more, the treatment approaches for phobic anxiety are confined to unitary or general methods with poor efficiency.MethodsBehavioural test screen combined bioinformatics analysis explored molecular changes between generalized anxiety disorder in nonstroke mice (restraint stress, RS) and photothrombotic stroke mice exposed to environmental stress (PTS + RS, mimicking PSA). Multiple molecular biological and neurobiological methods were employed to explain mechanisms in vitro and in vivo. And exploiting gamma flicker stimulation device for therapy.ResultsMicroglial (MG) overactivation is a prominent characteristic of PTS + RS. HDAC3 was mainly upregulated in activated-microglia from damaged cortex and that local prostaglandin E2 (PGE2) production increased in MG via HDAC3-mediated activation of NF-κB signalling by p65 deacetylation. A high content of PGE2 in damaged ischaemic cortex could diffuse freely to amygdala, eliciting anxiety susceptibility of PSA via EP2. Importantly, gamma flicker stimulation relieved anxious behaviour of PTS + RS by modulating the HDAC3/Cox1/EP2 network at some extent.ConclusionsHDAC3-regulated PGE2 production by microglia constitutes phobic anxiety susceptibility after stroke and a protective approach of gamma visual stimulation can be a candidate new therapy.

TAT-PEP alleviated cognitive impairment by alleviating neuronal mitochondria damage and apoptosis after cerebral ischemic reperfusion injury

“…It has been reported Caspase-3 is known that the proapoptotic protein Bax and the anti-apoptotic protein Bcl-2 can migrate from the cytoplasm to mitochondria, which are distributed in a manner that is consistent with the mitochondrial release of cytochrome C and caspase [20,27]. The mitochondrial apoptotic pathway plays an essential role in neuronal injury [28,29], and TAT-PEP inhibited neuronal apoptosis after ischemic stroke by upregulating Bcl-2 expression and reducing Bax expression. The apoptotic proteins on the mitochondrial membrane, such as Bad and Bax, lead to the opening of the mitochondrial permeability transition pore and the release of cytochrome C or apoptosis factors.…”

Noteworthy perspectives on microglia in neuropsychiatric disorders

“…In the model of post-stroke anxiety, HDAC3 was upregulated in the microglia of damaged cortex, which induced p65 deacetylation and the subsequent activation of NF-κB signaling involved in prostaglandin synthesis. Prostaglandin E 2 released by cortical microglia could act on EP2 in the amygdala, potentially leading to the susceptibility to anxiety [ 207 ]. Discs large homolog 1 (Dlg1) is an adaptor protein regulating the activation of microglia, and Dlg1 knockout inhibited NF-κB and MAPK pathways in the microglia, leading to the alleviation of LPS-induced depression [ 208 ].…”

“…Gamma entrainment has been investigated in treatment of various CNS diseases [ 316 , 317 ]. In AD models, gamma entrainment enhanced microglial phagocytotic activity [ 318 , 319 ]; in post-stroke models, gamma entrainment inhibited the pro-inflammatory activation of microglia and ameliorated anxiety susceptibility [ 207 ]. However, there is emerging controversy about the neuroprotective effect of gamma entrainment, and the gamma-band visual stimulation may be aversive for mice [ 320 ].…”

Rodents’ visual gamma as a biomarker of pathological neural conditions

“…Lastly, Zhu et al. (2022) found that visual gamma entrainment can ameliorate neurological conditions other than AD. In mice exposed to post‐stroke stress, the authors reported that visual gamma stimuli were able to trigger the downregulation of histone deacetylase 3 (HDAC3), cyclooxygenase‐1 (COX1) and EP2 in the amygdala, which can alleviate susceptibility to anxiety and depression.…”