scholarly journals Elimination of Vesicular Zinc Alters the Behavioural and Neuroanatomical Effects of Social Defeat Stress in Mice

2018 ◽  
Author(s):  
Brendan B. McAllister ◽  
David K. Wright ◽  
Ryan C. Wortman ◽  
Sandy R. Shultz ◽  
Richard H. Dyck
Keyword(s):  
Corpus Callosum ◽  
Chronic Stress ◽  
Social Defeat ◽  
Volumetric Analysis ◽  
Hippocampal Neurogenesis ◽  
Wild Type ◽  
Enhanced Sensitivity ◽  
Y Maze ◽  
Genetic Deletion ◽  
Stress Susceptibility

ABSTRACTChronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc – zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice.

scholarly journals Effects of social defeat stress and fluoxetine treatment on neurogenesis and behaviour in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

2019 ◽  
Author(s):  
Brendan B. McAllister ◽  
Angela Pochakom ◽  
Selena Fu ◽  
Richard H. Dyck
Keyword(s):  
Knockout Mice ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Social Defeat ◽  
Zinc Transporter ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Social Avoidance ◽  
Wild Type ◽  
Social Defeat Stress ◽  
Fluoxetine Treatment

ABSTRACTDepression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behaviour and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress-induced behavioural symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression-like effects, including social avoidance and anxiety-like behaviour. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety-like behaviour. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioural benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

2021 ◽  
Vol 80 (5) ◽  
pp. 467-475
Author(s):  
Yu-Qing Li ◽  
C Shun Wong
Keyword(s):  
Cell Fate ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Neuronal Development ◽  
Adenosine Monophosphate ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Wild Type ◽  
Newborn Neuron ◽  
Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

scholarly journals TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nassir U. Al-Khishman ◽  
Qi Qi ◽  
Austyn D. Roseborough ◽  
Alexander Levit ◽  
Brian L. Allman ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Tracer Uptake ◽  
Translocator Protein ◽  
Imaging Biomarkers ◽  
Wild Type ◽  
Activated Microglia ◽  
Fischer 344 ◽  
Histocompatibility Complex ◽  
Prodromal Alzheimer’S Disease ◽  
Tspo Expression

Abstract Background Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer’s disease and acute subcortical stroke. Methods Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. Results [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). Conclusion TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

scholarly journals Chronic non-discriminatory social defeat stress reduces effort-related motivated behaviors in male and female mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrew Dieterich ◽  
Tonia Liu ◽  
Benjamin Adam Samuels
Keyword(s):  
Mood Disorders ◽  
Chronic Stress ◽  
Choice Behavior ◽  
Progressive Ratio ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Male And Female ◽  
Female Mice ◽  
High Reward ◽  
Motivated Behaviors

AbstractReward and motivation deficits are prominent symptoms in many mood disorders, including depression. Similar reward and effort-related choice behavioral tasks can be used to study aspects of motivation in both rodents and humans. Chronic stress can precipitate mood disorders in humans and maladaptive reward and motivation behaviors in male rodents. However, while depression is more prevalent in women, there is relatively little known about whether chronic stress elicits maladaptive behaviors in female rodents in effort-related motivated tasks and whether there are any behavioral sex differences. Chronic nondiscriminatory social defeat stress (CNSDS) is a variation of chronic social defeat stress that is effective in both male and female mice. We hypothesized that CNSDS would reduce effort-related motivated and reward behaviors, including reducing sensitivity to a devalued outcome, reducing breakpoint in progressive ratio, and shifting effort-related choice behavior. Separate cohorts of adult male and female C57BL/6 J mice were divided into Control or CNSDS groups, exposed to the 10-day CNSDS paradigm, and then trained and tested in instrumental reward or effort-related behaviors. CNSDS reduced motivation to lever press in progressive ratio and shifted effort-related choice behavior from a high reward to a more easily attainable low reward in both sexes. CNSDS caused more nuanced impairments in outcome devaluation. Taken together, CNSDS induces maladaptive shifts in effort-related choice and reduces motivated lever pressing in both sexes.

scholarly journals ΔMST and the Regulation of Cardiac CSE and OTR Expression in Trauma and Hemorrhage

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 233
Author(s):  
Britta Trautwein ◽  
Tamara Merz ◽  
Nicole Denoix ◽  
Csaba Szabo ◽  
Enrico Calzia ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Life Stress ◽  
Early Life Stress ◽  
Significant Loss ◽  
Mouse Heart ◽  
Wild Type ◽  
Complex Iv ◽  
Mercaptopyruvate Sulfurtransferase ◽  
Cellular Bioenergetics ◽  
Genetic Deletion

Genetic deletion of 3-mercaptopyruvate sulfurtransferase (MST) is known to result in hypertension and cardiac hypertrophy in older mice, and is associated with increased anxiety-like behaviors. Endogenous hydrogen sulfide (H2S) produced by MST in the mitochondria is also known to be involved in physiological and cellular bioenergetics, and its dysfunction associated with depressive behavior and increased cardiovascular morbidity. Interestingly, early life stress has been shown to lead to a significant loss of cystathionine-γ-lyase (CSE) and oxytocin receptor (OTR) expression in the heart. Thus, we were interested in testing the hypothesis of whether genetic MST mutation (ΔMST) would affect cardiac CSE and OTR expression and affect the mitochondrial respiration in a clinically relevant, resuscitated, mouse model of trauma and hemorrhagic shock. In ΔMST mice, we found a reduction of CSE and OTR in both the naive as well as injured state, in contrast to the wild type (wt) controls. Interestingly, the ΔMST showed a different complex IV response to injury than the wt controls, although our claims are based on the non-demonstrated assumption that naive wt and naive ΔMST mice have comparable complex IV activity. Finally, hemorrhagic shock led to a reduction of CSE and OTR, confirming previous results in the injured mouse heart. To date, the exact mechanisms of the cardiac interaction between H2S and OT are not clear, but they point the way to potential cardioprotective therapies.

scholarly journals Phenotypic and Genetic Analysis of “Chameleon,” a Paramecium Mutant With an Enhanced Sensitivity to Magnesium

Genetics ◽  
1997 ◽  
Vol 146 (3) ◽  
pp. 871-880
Author(s):  
Robin R Preston ◽  
Jocelyn A Hammond
Keyword(s):  
Genetic Analysis ◽  
Single Locus ◽  
Behavioral Analysis ◽  
Paramecium Tetraurelia ◽  
Wild Type ◽  
Ion Conductance ◽  
Membrane Excitation ◽  
Enhanced Sensitivity ◽  
Electrophysiological Analysis ◽  
Mutant Strains

Three mutant strains of Paramecium tetraurelia with an enhanced sensitivity to magnesium have been isolated. These new “Chameleon” mutants result from partial- or codominant mutations at a single locus, Cha. Whereas the wild type responded to 5 mm Mg2+ by swimming backward for 10–15 sec, Cha mutants responded with ∼30 sec backward swimming. Electrophysiological analysis suggested that this behavior may be caused by slowing in the rate at which a Mg2+-specific ion conductance deactivates following membrane excitation. This would be consistent with an observed increase in the sensitivity of Cha mutants to nickel poisoning, since Ni2+ is also able to enter the cell via this pathway. More extensive behavioral analysis showed that Cha cells also overresponded to Na+, but there was no evidence for a defect in intracellular Ca2+ homeostasis that might account for a simultaneous enhancement of both the Mg2+ and Na+ conductances. The possibility that the Cha locus may encode a specific regulator of the Mg2+- and Na+-permeabilities is considered.

Sexual activity counteracts the suppressive effects of chronic stress on adult hippocampal neurogenesis and recognition memory

2013 ◽  
Vol 1538 ◽  
pp. 26-40 ◽  
Author(s):  
Jong-In Kim ◽  
Jae Won Lee ◽  
Young Ah Lee ◽  
Dong-Hun Lee ◽  
Nam Soo Han ◽  
...  
Keyword(s):  
Recognition Memory ◽  
Sexual Activity ◽  
Chronic Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis

scholarly journals Sex-dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats

Hippocampus ◽  
2013 ◽  
Vol 23 (6) ◽  
pp. 476-487 ◽  
Author(s):  
Katharina M. Hillerer ◽  
Inga D. Neumann ◽  
Sebastien Couillard-Despres ◽  
Ludwig Aigner ◽  
David A. Slattery
Keyword(s):  
Chronic Stress ◽  
Hippocampal Neurogenesis ◽  
Stress Conditions

scholarly journals Roles of multiple lipid mediators in stress and depression

2019 ◽  
Vol 31 (9) ◽  
pp. 579-587 ◽  
Author(s):  
Tomoyuki Furuyashiki ◽  
Satoshi Akiyama ◽  
Shiho Kitaoka
Keyword(s):  
Chronic Stress ◽  
Social Defeat ◽  
Lipid Mediators ◽  
Mental Illnesses ◽  
Lipid Mediator ◽  
Receptor Subtype ◽  
Social Defeat Stress ◽  
Beneficial Effects ◽  
Prostaglandin Synthase ◽  
Depressive Patients

AbstractProlonged or excessive stress may induce emotional and cognitive disturbances, and is a risk factor for mental illnesses. Using rodent chronic stress models of depression, roles of multiple lipid mediators related to inflammation have been revealed in chronic stress-induced emotional alterations. Prostaglandin (PG) E2, an arachidonic acid (AA)-derived lipid mediator, and its receptor subtype EP1 mediate depression-like behavior induced by repeated social defeat stress through attenuating prefrontal dopaminergic activity. Repeated social defeat stress activates microglia through innate immune receptors, and induces PGE2 synthesis through cyclooxygenase-1, a prostaglandin synthase enriched in microglia. PGD2, another AA-derived lipid mediator, has been implicated in depression induced by chronic stress, although either pro-depressive or anti-depressive actions have been reported. Chronic stress up-regulates hippocampal expression of 5-lipoxygenase, hence synthesis of cysteinyl leukotrienes, thereby inducing depression through their receptors. Consistent with beneficial effects of n-3 fatty acids in the diet of depressive patients, resolvins—a novel class of pro-resolving lipid mediators—in the brain attenuate neuroinflammation-associated depression. These findings in animal models of depression offer lipid mediators and related molecules as novel therapeutic targets for treating depression. To translate these findings into clinics, translational biomarkers to visualize lipid mediator profiles in depressive patients need to be established.

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