Sustained Hippocampal Synaptic Pathophysiology Following Single and Repeated Closed-Head Concussive Impacts

Traumatic brain injury (TBI), and related diseases such as chronic traumatic encephalopathy (CTE) and Alzheimer’s (AD), are of increasing concern in part due to enhanced awareness of their long-term neurological effects on memory and behavior. Repeated concussions, vs. single concussions, have been shown to result in worsened and sustained symptoms including impaired cognition and histopathology. To assess and compare the persistent effects of single or repeated concussive impacts on mediators of memory encoding such as synaptic transmission, plasticity, and cellular Ca2+ signaling, a closed-head controlled cortical impact (CCI) approach was used which closely replicates the mode of injury in clinical cases. Adult male rats received a sham procedure, a single impact, or three successive impacts at 48-hour intervals. After 30 days, hippocampal slices were prepared for electrophysiological recordings and 2-photon Ca2+ imaging, or fixed and immunostained for pathogenic phospho-tau species. In both concussion groups, hippocampal circuits showed hyper-excitable synaptic responsivity upon Schaffer collateral stimulation compared to sham animals, indicating sustained defects in hippocampal circuitry. This was not accompanied by sustained LTP deficits, but resting Ca2+ levels and voltage-gated Ca2+ signals were elevated in both concussion groups, while ryanodine receptor-evoked Ca2+ responses decreased with repeat concussions. Furthermore, pathogenic phospho-tau staining was progressively elevated in both concussion groups, with spreading beyond the hemisphere of injury, consistent with CTE. Thus, single and repeated concussions lead to a persistent upregulation of excitatory hippocampal synapses, possibly through changes in postsynaptic Ca2+ signaling/regulation, which may contribute to histopathology and detrimental long-term cognitive symptoms.

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Chronic Traumatic Encephalopathy: A Review

Rehabilitation Research and Practice ◽

10.1155/2012/816069 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 17

Author(s):

Michael Saulle ◽

Brian D. Greenwald

Keyword(s):

Military Service ◽

Clinical Presentation ◽

Chronic Traumatic Encephalopathy ◽

Head Injuries ◽

Emotional Disturbances ◽

American Football ◽

Closed Head Injuries ◽

Apoe4 Allele ◽

Closed Head

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that is a long-term consequence of single or repetitive closed head injuries for which there is no treatment and no definitive pre-mortem diagnosis. It has been closely tied to athletes who participate in contact sports like boxing, American football, soccer, professional wrestling and hockey. Risk factors include head trauma, presence of ApoE3 or ApoE4 allele, military service, and old age. It is histologically identified by the presence of tau-immunoreactive NFTs and NTs with some cases having a TDP-43 proteinopathy or beta-amyloid plaques. It has an insidious clinical presentation that begins with cognitive and emotional disturbances and can progress to Parkinsonian symptoms. The exact mechanism for CTE has not been precisely defined however, research suggest it is due to an ongoing metabolic and immunologic cascade called immunoexcitiotoxicity. Prevention and education are currently the most compelling way to combat CTE and will be an emphasis of both physicians and athletes. Further research is needed to aid in pre-mortem diagnosis, therapies, and support for individuals and their families living with CTE.

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Neurological effects of long-term exposure to low doses of pesticides mixtures in male rats: Biochemical, histological, and neurobehavioral evaluations

Chemosphere ◽

10.1016/j.chemosphere.2020.128464 ◽

2021 ◽

Vol 264 ◽

pp. 128464

Author(s):

Morteza Ghasemnejad-Berenji ◽

Mohadeseh Nemati ◽

Bagher Pourheydar ◽

Saber Gholizadeh ◽

Mojtaba Karimipour ◽

...

Keyword(s):

Male Rats ◽

Low Doses ◽

Neurological Effects

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Repeated Mild Closed Head Injuries Induce Long-Term White Matter Pathology and Neuronal Loss That Are Correlated With Behavioral Deficits

ASN NEURO ◽

10.1177/1759091418781921 ◽

2018 ◽

Vol 10 ◽

pp. 175909141878192 ◽

Cited By ~ 20

Author(s):

Eric M. Gold ◽

Vitaly Vasilevko ◽

Jonathan Hasselmann ◽

Casey Tiefenthaler ◽

Danny Hoa ◽

...

Keyword(s):

Cortical Neurons ◽

Chronic Traumatic Encephalopathy ◽

Head Injuries ◽

Closed Head Injury ◽

Neuronal Loss ◽

Significant Loss ◽

Behavioral Deficits ◽

Closed Head ◽

Behavioral Impairments

An estimated 5.3 million Americans are living with a disability from a traumatic brain injury (TBI). There is emerging evidence of the detrimental effects from repeated mild TBIs (rmTBIs). rmTBI manifests its own unique set of behavioral and neuropathological changes. A subset of individuals exposed to rmTBI develop permanent behavioral and pathological consequences, defined postmortem as chronic traumatic encephalopathy. We have combined components of two classic rodent models of TBI, the controlled cortical impact model and the weight drop model, to develop a repeated mild closed head injury (rmCHI) that produces long-term deficits in several behaviors that correlate with neuropathological changes. Mice receiving rmCHI performed differently from 1-hit or sham controls on the elevated plus maze; these deficits persist up to 6 months postinjury (MPI). rmCHI mice performed worse than 1-hit and control sham mice at 2 MPI and 6 MPI on the Morris water maze. Mice receiving rmCHI exhibited significant atrophy of the corpus callosum at both 2 MPI and 6 MPI, as assessed by stereological volume analysis. Stereological analysis also revealed significant loss of cortical neurons in comparison with 1-hit and controls. Moreover, both of these pathological changes correlated with behavioral impairments. In human tau transgenic mice, rmCHI induced increases in hyperphosphorylated paired helical filament 1 tau in the hippocampus. This suggests that strategies to restore myelination or reduce neuronal loss may ameliorate the behavioral deficits observed following rmCHI and that rmCHI may model chronic traumatic encephalopathy in human tau mice.

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Long-term effects of testosterone phenylacetate on sexual morphology and behavior in castrated male rats

Hormones and Behavior ◽

10.1016/0018-506x(70)90016-4 ◽

1970 ◽

Vol 1 (3) ◽

pp. 223-234 ◽

Cited By ~ 6

Author(s):

Frank A Beach ◽

Larry P Nucci

Keyword(s):

Male Rats ◽

Long Term Effects ◽

And Behavior

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17β-Estradiol Enhances NMDA Receptor-Mediated EPSPs and Long-Term Potentiation

Journal of Neurophysiology ◽

10.1152/jn.1999.81.2.925 ◽

1999 ◽

Vol 81 (2) ◽

pp. 925-929 ◽

Cited By ~ 335

Author(s):

M. R. Foy ◽

J. Xu ◽

X. Xie ◽

R. D. Brinton ◽

R. F. Thompson ◽

...

Keyword(s):

Nmda Receptor ◽

Hippocampal Slices ◽

Pyramidal Cells ◽

Long Term Potentiation ◽

Male Rats ◽

High Frequency Stimulation ◽

Term Potentiation ◽

17Β Estradiol ◽

Fepsp Slope

17β-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. Gonadal steroid hormones influence CNS functioning through a variety of different mechanisms. To test the hypothesis that estrogen modulates synaptic plasticity in the hippocampus, in vitro hippocampal slices from 2-mo-old Sprague-Dawley male rats were used to determine the effect of 17β-estradiol on both N-methyl-d-aspartate (NMDA) receptor-mediated excitatory postsynaptic potentials (EPSPs) through intracellular recordings and long-term potentiation (LTP) through extracellular recordings. Intracellular EPSPs and extracellular field EPSPs (fEPSPs) were recorded from CA1 pyramidal cells by stimulating Schaffer collateral fibers. In intracellular experiments, slices were perfused with medium containing bicuculline (5 μM) and low Mg2+(0.1 mM) to enhance the NMDA receptor-mediated currents and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (10 μM) to block the α-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate (AMPA) receptor-mediated component. The effects of 17β-estradiol on NMDA receptor-mediated activity were excitatory; concentrations >10 nM induced seizure activity, and lower concentrations (1 nM) markedly increased the amplitude of NMDA-mediated EPSPs (both the first and second responses increased during paired pulse stimulation by 180 and 197%, respectively). In extracellular experiments, slices perfused with 17β-estradiol (100 pM) exhibited a pronounced, persisting, and significant enhancement of LTP of both the fEPSP slope (192%) and fEPSP amplitude (177%) compared with control slices (fEPSP slope = 155%; fEPSP amplitude = 156%) 30 min after high-frequency stimulation. These data demonstrate that estrogen enhances NMDA receptor-mediated currents and promotes an enhancement of LTP magnitude.

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New Research in Animals Reveals Possible Long-Term Effects of Stimulants on Brain and Behavior

PsycEXTRA Dataset ◽

10.1037/e493102006-001 ◽

2003 ◽

Author(s):

Keyword(s):

Long Term Effects ◽

Brain And Behavior ◽

New Research ◽

And Behavior

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Faculty Opinions recommendation of Long term facilitation of respiratory motor output decreases with age in male rats.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718021187.793478915 ◽

2013 ◽

Author(s):

Frank L Powell

Keyword(s):

Motor Output ◽

Male Rats ◽

Long Term Facilitation

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Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

Biological Research ◽

10.1186/s40659-021-00328-4 ◽

2021 ◽

Vol 54 (1) ◽

Author(s):

Mayarling Francisca Troncoso ◽

Mario Pavez ◽

Carlos Wilson ◽

Daniel Lagos ◽

Javier Duran ◽

...

Keyword(s):

Glucose Metabolism ◽

Cardiac Hypertrophy ◽

Glucose Uptake ◽

Male Rats ◽

Cardiomyocyte Hypertrophy ◽

Mrna Levels ◽

Elevated Glucose ◽

Amp Activated Protein Kinase ◽

Cultured Cardiomyocytes

Abstract Background Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake—via AMP-activated protein kinase (AMPK)—after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). Methods Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). Results Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated β-mhc, Hk2 and Pfk2 mRNA levels. Conclusion These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

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