Ketamine, a non-competitive N-methyl-D-aspartate acid (NMDA) receptor antagonist, produces rapid and sustained antidepressant actions, but the underlying molecular mechanism remains unclear. The CX3CL1/CX3CR1 signaling is closely related to mood disorders, and this study aims to investigate its role in ketamine's antidepressant actions. We pharmacologically (AZD8797, a selective CX3CR1 antagonist) and genetically (intra-mPFC microinjection with AAV-CX3CR1-siRNA) manipulated the CX3CL1/CX3CR1 signaling and investigated their effects on ketamine's antidepressant-like effects in mice treated with corticosterone (Cort), and observed changes in synaptic plasticity in response to these manipulations. We found that 24 h after drug injection, ketamine (10 mg/kg, i.p.) significantly reversed the Cort-induced depression-like behaviors, and inhibited the overexpression of pro-inflammatory cytokines and microglial activation. Ketamine significantly improved the Cort-induced impairment in the dendritic complexity and spine densities. In addition, our ELISA results showed that ketamine significantly inhibited the activation of CX3CL1/CX3CR1 signaling, and ketamine attenuated the upregulation of CX3CR1 and CX3CL1 expression in Cort-treated HT22 and BV2 cells in vitro. Furthermore, pretreatment with AZD8797 (0.8 mg/kg, i.p., twice a week) completely blocked ketamine's antidepressant-like behavioral effects and eliminated ketamine-induced enhancement in the synaptic plasticity; intra-mPFC microinjection with AAV-CX3CR1-siRNA also prevented ketamine's behavioral effects and beneficial effects on the synaptic plasticity. These findings demonstrated that CX3CL1/CX3CR1 signaling-mediated synaptic plasticity played essential roles in ketamine's antidepressant-like effects, which opened a new door to targeting chemokines to improve depression symptoms.
Clarifying the patterns of neural activation during fear extinction in anxiety disorders (ADs) is essential for advancing our understanding of inhibitory learning. However, the underlying mechanisms remain poorly characterized in large, heterogeneous cohorts of patients. Utilizing a delayed fear extinction fMRI paradigm, this study examined neural responses in 280 patients with ADs — comprising panic disorder, agoraphobia, panic disorder with agoraphobia, social anxiety disorder, and multiple specific phobias — compared to 103 healthy controls (HC). The attenuation of neural activation to conditioned fear (CS+) and safety (CS−) stimuli from early versus late extinction was compared between groups. Subjective ratings of US-expectancy, arousal, and valence were also collected. In a whole-brain voxelwise analysis, patients showed significantly reduced attenuation of neural activation across both CS+ and CS− relative to HC from early compared to late phases of extinction learning. This pattern was observed in a broad network, encompassing the insular cortex (IC) and bilateral supplementary motor area (SMA), among other regions. No interaction between group and stimulus type was observed. Region-of-interest analysis of the left anterior insular cortex confirmed that reduced attenuation in this region represents a robust neural signature of altered extinction learning in ADs. Furthermore, patients reported persistently higher fear expectancy and arousal than HC, consistent with sustained alterations in threat-related processing following extinction training. Together, these findings highlight altered extinction-related neural attenuation as a transdiagnostic feature of ADs, offering novel insights into the neural mechanisms underlying fear extinction.
Intranasal oxytocin is a promising therapeutic approach for social and stress-regulatory difficulties in autism spectrum disorder. However, there is limited understanding regarding whether chronic administration regimes can induce neuroplastic changes at the brain’s anatomical level and how such microstructural changes might underlie clinical-behavioral effects. This placebo-controlled pilot assessed the effects of a four-week oxytocin regimen (24 IU daily) on white matter microstructure in 27 young adult men with autism. Diffusion tensor imaging was performed at baseline, post-treatment, and after four-week and one-year retention periods. Tractography focused on fractional anisotropy (FA) in amygdala-centered tracts associated with socio-emotional processing: the bilateral Inferior Longitudinal Fasciculus (ILF), Inferior Fronto-Occipital Fasciculus (IFOF), and Uncinate Fasciculus (UF). Following four weeks of oxytocin administration, a spatially selective impact of intranasal oxytocin administration was demonstrated, indicating bilateral improvements in UF integrity and a hemispherically lateralized pattern of changes for the ILF and IFOF tracts, with FA increases predominantly emerging in the right hemisphere, while reductions were evident in left-sided segments. Especially for bilateral UF and right IFOF, the observed changes were clinically relevant, correlating with enhanced social responsiveness and reduced feelings of avoidant attachment. In conclusion, exploratory findings from this pilot neuroimaging trial suggest that a four-week oxytocin regimen may induce long-lasting neuroplastic changes in white-matter tracts relevant to behavioral improvements in adult men with autism. These hypothesis-generating findings may inform future confirmatory trials. Further investigation of the neuroplastic changes associated with oxytocin’s clinical and behavioral effects may help refine oxytocin-based interventions, not only for autism but also for other neuropsychiatric conditions in which oxytocin is being explored as a potential therapeutic option.
Despite rising global rates for cocaine addiction, treatments options are limited. Psychological treatments remain the standard option but have only modest effectiveness. One major barrier to treatment success is that patients often make disadvantageous decisions that go against recovery, highlighting the need for strategies to support decision-making. Converging evidence indicates that decision-making deficits in cocaine addiction are driven by impaired processing of outcomes and risks. We investigated how patients with cocaine addiction use explicit outcomes and risk information to guide decision-making. One-hundred-and-five patients with moderate-to-severe cocaine use disorder (CUD) and 80 healthy control volunteers completed a decision-making task in which reward, loss, and probability information were provided explicitly. A subset of participants underwent diffusion-weighted magnetic resonance imaging to investigate the orbitofronto-striatal white matter tracts that underpin decision-making. We used generalized linear mixed-effects models to determine how rewards, losses, and probability influence decisions, and combined probabilistic tractography with principal component analysis to characterize the white matter tracts. We found that patients incorporated explicit probability information into their decisions to the same degree as control participants but showed reduced integration of outcomes. Notably, patients were less likely to integrate losses into their decisions than rewards. Although orbitofronto-striatal white matter tracts did not differ between groups, individual variability predicted the extent to which reward and loss information guided decisions, irrespective of diagnosis. Overall, these findings reveal fundamental challenges in using outcomes, particularly negative ones, to guide decision-making in patients with CUD, emphasizing the need for additional support to promote adaptive choices during recovery.
The brain-liver axis is important in maintaining whole-body glucose homeostasis. Antipsychotics are used to treat schizophrenia, but one of their side-effects is disruption of metabolism. We previously reported that the antipsychotics olanzapine and haloperidol block the ability of central glucose to stimulate whole-body glucose metabolism and suppress glucose production by the liver (EGP, endogenous glucose production). Both effects by central glucose require the conversion of glucose to lactate centrally. In the current study, we therefore examined whether antipsychotics affect the ability of central lactate to stimulate whole-body glucose metabolism and suppress EGP. Using our previous model of central (third ventricle to target the hypothalamus) infusion, acute subcutaneous administration of antipsychotics, and the pancreatic euglycemic clamp in rats, we found that olanzapine completely inhibited the ability of central lactate to stimulate whole-body glucose metabolism and partially blocked central lactate-induced suppression of EGP. Since activation of the hypothalamus-liver axis of glycemic control requires central glucose and lactate to be metabolized, relevant pathways were also investigated. The adverse effects of olanzapine on central lactate sensing were not associated with decreased levels of citrate, a tricarboxylic acid cycle intermediate, in the hypothalamus or robust alterations in hypothalamic mitochondrial complex I activity assessed with the positron emission tomography tracer [18F]BCPP-EF. In summary, olanzapine impairs the ability of central lactate to control whole-body glucose metabolism and partially inhibits suppression of EGP by central lactate.
