Brain rhythms control microglial response and cytokine expression via NF-κB signaling.

Microglia transform in response to changes in sensory or neural activity, such as sensory deprivation. However, little is known about how specific frequencies of neural activity, or brain rhythms, affect microglia and cytokine signaling. Using visual noninvasive flickering sensory stimulation (flicker) to induce electrical neural activity at 40 hertz, within the gamma band, and 20 hertz, within the beta band, we found that these brain rhythms differentially affect microglial morphology and cytokine expression in healthy animals. Flicker induced expression of certain cytokines independently of microglia, including interleukin-10 and macrophage colony-stimulating factor. We hypothesized that nuclear factor κB (NF-κB) plays a causal role in frequency-specific cytokine and microglial responses because this pathway is activated by synaptic activity and regulates cytokines. After flicker, phospho-NF-κB colabeled with neurons more than microglia. Inhibition of NF-κB signaling down-regulated flicker-induced cytokine expression and attenuated flicker-induced changes in microglial morphology. These results reveal a mechanism through which brain rhythms affect brain function by altering microglial morphology and cytokines via NF-κB.

The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex.

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.

Depression and sterile inflammation: Essential role of danger associated molecular patterns.

Stress is a major risk factor for psychiatric disorder including major depressive disorder (MDD) and can induce inflammation, which is known to be dysregulated in depression. Several clinical and pre-clinical studies have demonstrated a strong association between depressive symptoms and the expression of factors that increase inflammation. Conversely, administration of anti-inflammatory agents has been shown to ameliorate depressive symptoms, demonstrating the importance of inflammation as a mediator of depression. Although it is clear that inflammation plays a role in the pathophysiology of depression, the mechanism by which inflammation is activated in mood disorders remains unclear. To address this issue, studies have investigated the role of pattern recognition receptor (PRR) activation in stress-induced inflammation and mood disorders. However, the identification of the endogenous factors, referred to as danger-associated molecular patterns (DAMP) that activate these receptors remains understudied. Here we review the role of DAMPs in depression and highlight the clinical evidence for elevation of DAMP signaling in MDD patients and in pre-clinical animal stress models of depression.

Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

BACKGROUND: Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. METHODS: Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. RESULTS: The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. CONCLUSIONS: Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure.