Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

Abstract

Inhibitor of kB kinase (IkK) has historically been studied in the context of immune response and inflammation, but recent evidence demonstrates that IkK activity is necessary and sufficient for regulation of neuronal function. Chronic social defeat stress of mice increases IkK activity in the nucleus accumbens (NAc) and this increase is strongly correlated to depression-like behaviors. Inhibition of IkK signaling results in a reversal of chronic social defeat stress-induced social avoidance behavior. Here, we more completely define the role of IkK in anxiety and depressive-like behaviors. Mice underwent stereotaxic microinjection of a herpes simplex virus expressing either green fluorescent protein, a constitutively active form of IkK (IkKca), or a dominant negative form of IkK into the NAc. Of all three experimental groups, only mice expressing IkKca show a behavioral phenotype. Expression of IkKca results in a decrease in the time spent in the nonperiphery zones of an open field arena and increased time spent immobile during a forced swim test. No baseline differences in sucrose preference were observed, but following the acute swim stress we noted a marked reduction in sucrose preference. To determine whether IkK activity alters responses to other acute stressors, we examined behavior and spine morphology in mice undergoing an acute social defeat stress. We found that IkKca enhanced social avoidance behavior and promoted thin spine formation. These data show that IkK in NAc is a critical regulator of both depressive-and anxiety-like states and may do so by promoting the formation of immature excitatory synapses.

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress

“…This evidence builds upon a previously study that demonstrated an antidepressant-like response to acute stress in constitutive IL-6 knockouts and suggests that leukocyte-derived sources of IL-6 may be critical in mediating these behavioral effects (34). Our results are interesting in light of recent studies showing that social defeat stress induces downstream inflammatory signaling pathways, such as NFkB (26,(35)(36)(37), and increases monocyte trafficking (29) throughout a number of CNS structures known to control depression and anxiety behavior. It will be important for future studies to define the brain regions and molecular pathways induced by stress-responsive IL-6 from leukocytes that mediate adverse behavioral responses to chronic stress.…”

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

“…Furthermore, as DFosB is a transcription factor, further studies will be necessary to identify the exact target genes that are regulated by DFosB following antipsychotic drug treatment and delineating which genes are responsible for the various negative behavioral outcomes seen. One established gene target for DFosB in medial PFC is that which encodes the cholecystokinin B receptor (Vialou et al, 2012), which is highly implicated in anxiogenic responses consistent with observations of our studies (Ang et al, 2001;Bowers et al, 2012;Christoffel et al, 2012;McClung and Nestler, 2003). It will now be interesting to use more open-ended approaches to identify many more relevant DFosB target genes.…”

Spine synapse remodeling in the pathophysiology and treatment of depression

“…These changes were correlated with social avoidance behavior [13]. These authors also showed that the social avoidance phenotype and the formation of new stubby spines depended on the inhibitor of kappaB kinase (IkK)-nuclear factor kappaB (NFkB) pathway and that constitutively active IkK was sufficient to promote immature spine synapse formation in mice vulnerable to SDS [14]. …”