Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat

How is your doctor and psychologist  helping you through losing most if not all of your friends post-stroke?
http://www.jneurosci.org/content/36/9/2590.abstract

1. Daniel B. McKim¹,²,*,
2. Anzela Niraula¹,²,*,
3. Andrew J. Tarr¹,²,
4. Eric S. Wohleb¹,²,
5. John F. Sheridan¹,³,⁴, and
6. Jonathan P. Godbout²,³,⁴

+Show Affiliations

+ Author Notes

• E. S. Wohleb's present address: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519.

1. Author contributions: D.B.M., A.N., E.S.W., J.F.S., and J.P.G. designed research; D.B.M., A.N., A.J.T., and E.S.W. performed research; J.F.S. and J.P.G. contributed unpublished reagents/analytic tools; D.B.M., A.N., A.J.T., and E.S.W. analyzed data; D.B.M., A.N., and J.P.G. wrote the paper.
2. ↵*D.B.M. and A.N. contributed equally to this work.

1. The Journal of Neuroscience, 2 March 2016, 36(9): 2590-2604; doi: 10.1523/JNEUROSCI.2394-15.2016

• Abstract
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Abstract

Repeated social defeat (RSD) is a murine stressor that recapitulates key physiological, immunological, and behavioral alterations observed in humans exposed to chronic psychosocial stress. Psychosocial stress promotes prolonged behavioral adaptations that are associated with neuroinflammatory signaling and impaired neuroplasticity. Here, we show that RSD promoted hippocampal neuroinflammatory activation that was characterized by proinflammatory gene expression and by microglia activation and monocyte trafficking that was particularly pronounced within the caudal extent of the hippocampus. Because the hippocampus is a key area involved in neuroplasticity, behavior, and cognition, we hypothesize that stress-induced neuroinflammation impairs hippocampal neurogenesis and promotes cognitive and affective behavioral deficits. We show here that RSD caused transient impairments in spatial memory recall that resolved within 28 d. In assessment of neurogenesis, the number of proliferating neural progenitor cells (NPCs) and the number of young, developing neurons were not affected initially after RSD. Nonetheless, the neuronal differentiation of NPCs that proliferated during RSD was significantly impaired when examined 10 and 28 d later. In addition, social avoidance, a measure of depressive-like behavior associated with caudal hippocampal circuitry, persisted 28 d after RSD. Treatment with minocycline during RSD prevented both microglia activation and monocyte recruitment. Inhibition of this neuroinflammatory activation in turn prevented impairments in spatial memory after RSD but did not prevent deficits in neurogenesis nor did it prevent the persistence of social avoidance behavior. These findings show that neuroinflammatory activation after psychosocial stress impairs spatial memory performance independent of deficits in neurogenesis and social avoidance.

SIGNIFICANCE STATEMENT Repeated exposure to stress alters the homeostatic environment of the brain, giving rise to various cognitive and mood disorders that impair everyday functioning and overall quality of life. The brain, previously thought of as an immune-privileged organ, is now known to communicate extensively with the peripheral immune system. This brain–body communication plays a significant role in various stress-induced inflammatory conditions, also characterized by psychological impairments. Findings from this study implicate neuroimmune activation rather than impaired neurogenesis in stress-induced cognitive deficits. This idea opens up possibilities for novel immune interventions in the treatment of cognitive and mood disturbances, while also adding to the complexity surrounding the functional implications of adult neurogenesis.

Neural precursor cells in the ischemic brain – integration, cellular crosstalk, and consequences for stroke recovery

We need to know how to use this in our recovery. Ask about the stroke protocol that will be coming in 50 years.
http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00291/full?utm_source=newsletter&utm_medium=email&utm_campaign=Neuroscience-w41-2014
Dirk M. Hermann^1*, Luca Peruzzotti-Jametti², Jana Schlechter¹, Joshua D. Bernstock², Thorsten R. Doeppner¹ and Stefano Pluchino^2*

• ¹Chair of Vascular Neurology, Dementia and Cognitive Health of the Elderly, Department of Neurology, University Hospital Essen, Essen, Germany
• ²John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, NIHR Biomedical Research Centre, and Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK

After an ischemic stroke, neural precursor cells (NPCs) proliferate within major germinal niches of the brain. Endogenous NPCs subsequently migrate toward the ischemic lesion where they promote tissue remodeling and neural repair. Unfortunately, this restorative process is generally insufficient and thus unable to support a full recovery of lost neurological functions. Supported by solid experimental and preclinical data, the transplantation of exogenous NPCs has emerged as a potential tool for stroke treatment. Transplanted NPCs are thought to act mainly via trophic and immune modulatory effects, thereby complementing the restorative responses initially executed by the endogenous NPC population. Recent studies have attempted to elucidate how the therapeutic properties of transplanted NPCs vary depending on the route of transplantation. Systemic NPC delivery leads to potent immune modulatory actions, which prevent secondary neuronal degeneration, reduces glial scar formation, diminishes oxidative stress and stabilizes blood–brain barrier integrity. On the contrary, local stem cell delivery allows for the accumulation of large numbers of transplanted NPCs in the brain, thus achieving high levels of locally available tissue trophic factors, which may better induce a strong endogenous NPC proliferative response. Herein we describe the diverse capabilities of exogenous (systemically vs. locally transplanted) NPCs in enhancing the endogenous neurogenic response after stroke, and how the route of transplantation may affect migration, survival, bystander effects and integration of the cellular graft. It is the authors’ claim that understanding these aspects will be of pivotal importance in discerning how transplanted NPCs exert their therapeutic effects in stroke.

What do neurons do? And what controls their behavior? Learn how surrounding cells control neuronal stem cell function and what this could mean for therapy!

Two ways to understand this; I'm going for the video. Your doctor I'm sure explained all this in detail to you.
the paper here;
Neural Progenitor Cells Regulate Microglia Functions and Activity.
 or a whiteboard demonstration and video here:
http://www.yourekascience.com/Conversations_in_the_brain.html

Neural Progenitor Cell Implants Modulate Vascular Endothelial Growth Factor and Brain-Derived Neurotrophic Factor Expression in Rat Axotomized Neurons

Pretty much over my head but your doctor will understand. Have them put this into understandable terms and add it to your stroke protocol. You do have a stroke protocol?
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054519

Abstract

Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might contribute to the restorative effects of these implants.

Exercise training and the promotion of neurogenesis and neurite outgrowth in the hippocampus

Ask your doctor how to incorporate this into your stroke protocol. I'm thinking neurite outgrowth would be excellent for us. But I know nothing, nothing.
https://www.jstage.jst.go.jp/article/jpfsm/1/2/1_333/_article
There is a developing consensus that physical exercise is useful as a preventive strategy for cognitive impairment found in patients with dementia, particularly those affected by Alzheimer’s disease. Many reports state that the exercise-induced improvement of cognitive performance is an enhanced expression of a brain-derived neurotrophic factor and adult neurogenesis in the hippocampus, which is an area of the brain that is important for learning and memory. The process of adult hippocampal neurogenesis consists of the proliferation of neural progenitor cells (NPCs) and neural differentiation and maturation involving the neurite (axons and dendrites) extension of NPCs. Exercise training is well known as a promoter of cell proliferation and survival in the hippocampus; however, little is known about the effects of exercise training on neurite outgrowth in the hippocampus. This review presents the effect of exercise training on neurogenesis and neurite outgrowth in the hippocampus.

Full text here;
https://www.jstage.jst.go.jp/article/jpfsm/1/2/1_333/_pdf

Soluble Amyloid Precursor Protein Regulates Neurogenesis: Implications for Brain Repair

We need neurogenesis so get your researcher cracking on clinical trials and a stroke protocol.
https://dspace-prod-lib.cc.uic.edu/handle/10027/9149
Amyloid precursor protein (APP) has been studied extensively in the pathophysiology of Alzheimer’s disease due to the fact that mutations in APP are causative of familial forms of the disease. However, the physiological significance of the protein has yet to be fully elucidated. APP undergoes sequential metabolism through two distinct pathways involving three enzymatic cleavage events via enzymes termed α-, β, and γ-secretase. These cleavage events produce a number of intra- and extra-cellular metabolites that add complexity to the potential physiological function of APP. α-secretase cleavage produces a soluble extracellular metabolite, soluble amyloid precursor protein alpha (sAPPα), that has been previously shown to have trophic characteristics and contain a cysteine-rich growth factor like domain. In the adult brain, neural progenitor cells (NPC) represent a proliferating population of cells that have the ability to form new neurons in discrete regions. These NPC have been shown to have binding sites for sAPP. In Alzheimer’s disease and normal aging, there is a dramatic decline in the adult neurogenesis. We hypothesized that sAPPα is a growth factor for NPC of the adult brain and alterations in the metabolism of APP/sAPPα during normal aging or in Alzheimer’s disease could contribute to stem cell senescence. In this work we show that sAPPα potently stimulates the proliferation of NPC following α-secretase inhibition independently of epidermal growth factor or basic fibroblast growth factor. Further, sAPPα induces phosphorylation of extracellular signal-regulated kinase (Erk) and transcription of genes associated with cell cycle, neurogenesis and energy metabolism. The soluble metabolite derived from the alternative, pathological, cleavage pathway of APP, sAPPβ, shows only slight proliferative qualities in NPC suggesting that alterations in the normal cleavage pattern of APP could underlie neurogenic impairments in Alzheimer’s disease. Finally, we show that sAPP levels decline with age in a manner that correlates with the timing of neurogenic decline and that a single intracerebroventricular injection of sAPPα is sufficient to ameliorate aging-linked deficits in neurogenesis. Taken together, these results suggest that sAPPα is a proliferation factor for NPC of the adult brain whose decline in aging or Alzheimer’s disease could contribute to neurogenic deficits.