Browsing by Subject "hippocampus"

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Open Access
GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen.
(Frontiers in molecular neuroscience, 2022-01) Demchenko, Ivan T; Suliman, Hagir B; Zhilyaey, Sergey Y; Alekseeva, Olga S; Platonova, Tatyana F; Makowski, Matthew S; Piantadosi, Claude A; Gasier, Heath G
Oxygen breathing at elevated partial pressures (PO₂'s) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO₂ remains elevated during hyperbaric oxygen (HBO₂) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO₂ at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO₂ seizure latencies. In mice pretreated with tiagabine and exposed to HBO₂ at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO₂, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis.
Open Access
Hippocampal Avoidance in Multitarget Radiosurgery.
(Cureus, 2021-06-02) Gude, Zachary; Adamson, Justus; Kirkpatrick, John P; Giles, William
Brain metastases are a common complication for patients diagnosed with cancer. As stereotactic radiosurgery (SRS) becomes a more prevalent treatment option for patients with many brain metastases, further research is required to better characterize the ability of SRS to treat large numbers of metastases (≥4) and the impact on normal brain tissue and, ultimately, neurocognition and quality of life (QOL). This study serves first as an evaluation of the feasibility of hippocampal avoidance for SRS patients, specifically receiving single-isocenter multitarget treatments (SIMT) planned with volumetric modulated arc therapy (VMAT). Second, this study analyzes the effects of standard-definition (SD) multileaf collimators (MLCs) (5 mm width) on plan quality and hippocampal avoidance. The 40 patients enrolled in this Institutional Review Board (IRB)-approved study had between four and 10 brain metastases and were treated with SIMT using VMAT. From the initial 40 patients, eight hippocampi across seven patients had hippocampal doses exceeding the maximum biologically effective dose (BED) constraint given by RTOG 0933. With the addition of upper constraints in the optimization objectives and one arc angle adjustment in one patient plan, four out of seven patient plans were able to meet the maximum hippocampal BED constraint, avoiding five out of eight total hippocampi at risk. High-definition (HD) MLCs allowed for an average decrease of 29% ± 23% (p = 0.007) in the maximum BED delivered to all eight hippocampi at risk. The ability to meet dose constraints depended on the distance between the hippocampus and the nearest planning target volume (PTV). Meeting the maximum hippocampal BED constraint in re-optimized plans was equally likely with the use of SD-MLCs (five out of eight hippocampi at risk were avoided) but resulted in increased dose to normal tissue volumes (23.67% ± 16.3% increase in V50%[cc] of normal brain tissue, i.e., brain volume subtracted by the total PTV) when compared to the HD-MLC re-optimized plans. Comparing the effects of SD-MLCs on plans not optimized for hippocampal avoidance resulted in increases of 48.2% ± 32.2% (p = 0.0056), 31.5% ± 16.3% (p = 0.024), and 16.7% ± 8.5% (p = 0.022) in V20%[cc], V50%[cc], and V75%[cc], respectively, compared to the use of HD-MLCs. The conformity index changed significantly neither when plans were optimized for hippocampal avoidance nor when SD-MLC leaves were used for treatment. In plans not optimized for hippocampal avoidance, mean hippocampal dose increased with the use of SD-MLCs by 38.0% ± 37.5% (p = 0.01). However, the use of SD-MLCs did not result in an increased number of hippocampi at risk.
Open Access
Revealing context-specific conditioned fear memories with full immersion virtual reality.
(Front Behav Neurosci, 2011) Huff, Nicole C; Hernandez, Jose Alba; Fecteau, Matthew E; Zielinski, David J; Brady, Rachael; Labar, Kevin S
The extinction of conditioned fear is known to be context-specific and is often considered more contextually bound than the fear memory itself (Bouton, 2004). Yet, recent findings in rodents have challenged the notion that contextual fear retention is initially generalized. The context-specificity of a cued fear memory to the learning context has not been addressed in the human literature largely due to limitations in methodology. Here we adapt a novel technology to test the context-specificity of cued fear conditioning using full immersion 3-D virtual reality (VR). During acquisition training, healthy participants navigated through virtual environments containing dynamic snake and spider conditioned stimuli (CSs), one of which was paired with electrical wrist stimulation. During a 24-h delayed retention test, one group returned to the same context as acquisition training whereas another group experienced the CSs in a novel context. Unconditioned stimulus expectancy ratings were assayed on-line during fear acquisition as an index of contingency awareness. Skin conductance responses time-locked to CS onset were the dependent measure of cued fear, and skin conductance levels during the interstimulus interval were an index of context fear. Findings indicate that early in acquisition training, participants express contingency awareness as well as differential contextual fear, whereas differential cued fear emerged later in acquisition. During the retention test, differential cued fear retention was enhanced in the group who returned to the same context as acquisition training relative to the context shift group. The results extend recent rodent work to illustrate differences in cued and context fear acquisition and the contextual specificity of recent fear memories. Findings support the use of full immersion VR as a novel tool in cognitive neuroscience to bridge rodent models of contextual phenomena underlying human clinical disorders.
Open Access
Staying cool when things get hot: emotion regulation modulates neural mechanisms of memory encoding.
(Front Hum Neurosci, 2010) Hayes, Jasmeet Pannu; Morey, Rajendra A; Petty, Christopher M; Seth, Srishti; Smoski, Moria J; McCarthy, Gregory; Labar, Kevin S
During times of emotional stress, individuals often engage in emotion regulation to reduce the experiential and physiological impact of negative emotions. Interestingly, emotion regulation strategies also influence memory encoding of the event. Cognitive reappraisal is associated with enhanced memory while expressive suppression is associated with impaired explicit memory of the emotional event. However, the mechanism by which these emotion regulation strategies affect memory is unclear. We used event-related fMRI to investigate the neural mechanisms that give rise to memory formation during emotion regulation. Twenty-five participants viewed negative pictures while alternately engaging in cognitive reappraisal, expressive suppression, or passive viewing. As part of the subsequent memory design, participants returned to the laboratory two weeks later for a surprise memory test. Behavioral results showed a reduction in negative affect and a retention advantage for reappraised stimuli relative to the other conditions. Imaging results showed that successful encoding during reappraisal was uniquely associated with greater co-activation of the left inferior frontal gyrus, amygdala, and hippocampus, suggesting a possible role for elaborative encoding of negative memories. This study provides neurobehavioral evidence that engaging in cognitive reappraisal is advantageous to both affective and mnemonic processes.
Open Access
TrkB-Shc Signaling Protects against Hippocampal Injury Following Status Epilepticus.
(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019-06) Huang, Yang Zhong; He, Xiao-Ping; Krishnamurthy, Kamesh; McNamara, James O
Temporal lobe epilepsy (TLE) is a common and commonly devastating form of human epilepsy for which only symptomatic therapy is available. One cause of TLE is an episode of de novo prolonged seizures [status epilepticus (SE)]. Understanding the molecular signaling mechanisms by which SE transforms a brain from normal to epileptic may reveal novel targets for preventive and disease-modifying therapies. SE-induced activation of the BDNF receptor tyrosine kinase, TrkB, is one signaling pathway by which SE induces TLE. Although activation of TrkB signaling promotes development of epilepsy in this context, it also reduces SE-induced neuronal death. This led us to hypothesize that distinct signaling pathways downstream of TrkB mediate the desirable (neuroprotective) and undesirable (epileptogenesis) consequences. We subsequently demonstrated that TrkB-mediated activation of phospholipase Cγ1 is required for epileptogenesis. Here we tested the hypothesis that the TrkB-Shc-Akt signaling pathway mediates the neuroprotective consequences of TrkB activation following SE. We studied measures of molecular signaling and cell death in a model of SE in mice of both sexes, including wild-type and TrkBShc/Shc mutant mice in which a point mutation (Y515F) of TrkB prevents the binding of Shc to activated TrkB kinase. Genetic disruption of TrkB-Shc signaling had no effect on severity of SE yet partially inhibited activation of the prosurvival adaptor protein Akt. Importantly, genetic disruption of TrkB-Shc signaling exacerbated hippocampal neuronal death induced by SE. We conclude that therapies targeting TrkB signaling for preventing epilepsy should spare TrkB-Shc-Akt signaling and thereby preserve the neuroprotective benefits.SIGNIFICANCE STATEMENT Temporal lobe epilepsy (TLE) is a common and devastating form of human epilepsy that lacks preventive therapies. Understanding the molecular signaling mechanisms underlying the development of TLE may identify novel therapeutic targets. BDNF signaling thru TrkB receptor tyrosine kinase is one molecular mechanism promoting TLE. We previously discovered that TrkB-mediated activation of phospholipase Cγ1 promotes epileptogenesis. Here we reveal that TrkB-mediated activation of Akt protects against hippocampal neuronal death in vivo following status epilepticus. These findings strengthen the evidence that desirable and undesirable consequences of status epilepticus-induced TrkB activation are mediated by distinct signaling pathways downstream of this receptor. These results provide a strong rationale for a novel therapeutic strategy selectively targeting individual signaling pathways downstream of TrkB for preventing epilepsy.