Differential effects of peripheral and brain tumor necrosis factor on inflammation, sickness, emotional behavior and memory in mice

Abstract

Tumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions. Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned stimulus. These effects co-occurred with increased plasma interleukin-6 and increased IPderived TNF in brain peri-ventricular regions. An adenovirus-associated viral TNF vector (AAV-TNF) was constructed, brain injection of which resulted in dose-dependent, sustained and region-specific TNF expression, and was without effect on blood cytokine levels. Lateral ventricle AAV-TNF yielded increased TNF in the same brain regions as IP-TNF. In contrast to IP-TNF it was without effect on body weight, saccharin consumption and fear memory, although it did increase anxiety. Hippocampal AAV-TNF led to decreased body weight. It increased conditioning to but not subsequent memory of an aversive context, suggesting impaired consolidation; it also increased anxiety. Amygdala AAV-TNF was without effect on body weight and aversive stimulus learning-memory, but reduced saccharin consumption and increased anxiety. This study adds significantly to the evidence that both peripheral and brain region-specific increases in TNF lead to both sickness and depression-and anxiety disorder-relevant behavior and do so via different pathways. It thereby highlights the complexity in terms of indirect and direct pathways via which increased TNF can act and which need to be taken into account when considering it as a therapeutic target. AbstractTumor necrosis factor alpha (TNF) is increased in depression and clinical-trial evidence indicates that blocking peripheral TNF has some antidepressant efficacy. In rodents, peripheral or intracerebroventricular TNF results in sickness e.g. reduced body weight, altered emotional behavior and impaired memory. However, the underlying pathways and responsible brain regions are poorly understood. The aim of this mouse study was to increase understanding by comparing the effects of sustained increases in TNF in the circulation, in brain regions impacted by increased circulating TNF, or specific brain regions.Increased peripheral TNF achieved by repeated daily injection (IP-TNF) or osmotic pump resulted in decreased body weight, decreased saccharin (reward) consumption, and increased memory of an aversive conditioned. These effects co-occurred with increased plasma interleukin-6 and increased I...

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice

“…In experiment 5, some of the same mice studied in behavioral tests ( n = 6 per group, selected at random) were transcardially perfused on day 27 for immunoperoxidase staining of IBA1. The methodology was similar to that described for CA II, with rabbit anti‐mouse IBA1 primary antibody (1:1000; Wako, Neuss, Germany) and staining visualized with DAB‐Nickel . One section at bregma −1.22 mm was used for BLA sensu stricto and EC, and one section at bregma 0.74 mm for corpus callosum.…”

“…The methodology was similar to that described for CA II, with rabbit anti-mouse IBA1 primary antibody (1:1000; Wako, Neuss, Germany) and staining visualized with DAB-Nickel. 61 One section at bregma −1.22 mm was used for BLA sensu stricto and EC, and one section at bregma 0.74 mm for corpus callosum. In addition, one section per mouse was stained for CA II in amygdala gray matter (BLA and CeA) to assess for compensatory effects of Cnp heterozygosity.…”

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

“…Self-complementary (sc) adenovirus-associated virus (AAV) vector TNF (AAV-TNF) scAAV-2/8-hCMV-chI-floxedmTNFalpha-SV40p(A) and its corresponding control AAV vector (AAV-control) scAAV-2/8-hCMV-chI-loxP-SV40p(A) were kindly provided by the laboratory of Christopher Pryce (University of Zurich, Switzerland). The AAV vectors were characterized in their recent publication [21]. AAV-control and AAV-TNF were injected as described above at a final titer of 1.1 × 10 11 vg/ml (280 μl, n = 10, 5 mice per group).…”

Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking Is Associated with Distinct Neuroadaptations in the Dentate Gyrus<strong> </strong>

“…These findings suggest that changes in the density of axons of mature GCNs are perhaps influenced to a greater extent in females than males, and in males are compensatory to the effects on mature progenitors. It is also evident that newly born progenitors contribute to neuroimmune responses in the DG (Klaus et al, 2016;Marshall et al, 2016;Peng et al, 2017;Goodfellow et al, 2018). Furthermore, high doses of methamphetamine experience is associated with microglial activation in the DG (Buchanan et al, 2010).…”