Biology subjects

Jensen, F. E.

Publications and source records attributed to Jensen, F. E..

5 recordsLinked to original sources

bioRxiv2025

Temporal and cell-specific changes to cellular iron sequestration and lipid peroxidation in a murine model of neonatal hypoxic-ischemic brain injury.

BackgroundIron accumulation and lipid peroxidation are pathophysiologic mechanisms that drive neonatal hypoxic-ischemic (HI) brain injury. Characterization of spatiotemporal changes in these processes will help elucidate their role in ischemic neuronal injury as an initial step towards developing targeted interventions. MethodsHI was induced in post-natal day 9 mice using the modified-Vannucci model. Hippocampal tissue from ipsilateral HI exposed, contralateral hypoxia exposed and sham animals was collected at 6h, 24h, 72h and 7d post-HI. Tissue was subsequently evaluated for markers of cell death (TUNEL), intracellular iron changes (FerroOrange, fluorescent in situ and immunofluorescence), and lipid peroxidation (real time PCR, Gpx4 immunofluorescence and mass spectrometry). Mass spectrometry measured isoprostanes (15-F2t-IsoP) and neuroprostanes (4-F4t-NP) as lipid peroxidation markers of arachidonic (ARA) and docosahexaenoic acid (DHA), respectively. ResultsCompared to sham, the HI hippocampus showed increased intracellular labile iron levels that was maximal at 6h post-HI with subsequent elevation in only neuroprostanes at 24h post-HI. TUNEL labeling peaked at 24h post-HI. At 72h, labile iron levels and lipid peroxidation declined corresponding with peak infiltration of ferritin positive microglia/macrophages and the start of TUNEL staining decline. In addition, surviving neurons had increased expression of Gpx4 peaking at 72h post-HI that normalized by 7d post-HI. ConclusionsThese findings suggest that following HI, an acute increase in labile iron and DHA peroxidation are correlated with markers of cell death that peak at 24h post-HI. Microglial/macrophage iron sequestration and neuronal antioxidant responses may ameliorate further injury and represent targets for neuroprotective therapies.

neuroscience↗

bioRxiv2025

Amplifying and ameliorating light avoidance in mice with photoreceptor targeting and CGRP sensitization

ObjectiveTo determine the photoreceptor basis of light avoidance in mice and assess the effect of CGRP sensitization on this behavior. BackgroundPrior studies have suggested that photophobia is mediated by a subset of retinal ganglion cells (RGCs) that contain melanopsin, making them intrinsically photosensitive (ipRGCs). These cells also receive extrinsic input from cones, which can also mediate light sensitivity. Here, we examined whether spectral variation targeting melanopsin or specific cone types in mice could effectively model light sensitivity. Also, we assessed whether sensitizing mice with calcitonin gene-related peptide (CGRP) could amplify ipRGC-mediated light avoidance. MethodsLight avoidance behavior was observed in a two-zone chamber illuminated by narrow-band LEDs targeting photopic opsins: 365 nm (UV; rodent S-cone), 460 nm (blue; melanopsin), and 630 nm (red; human L-cone). In a non-targeted assay, we assessed the degree of light avoidance in wildtype C57BL/6J mice to varying intensities (5 to 100%) of the blue and red LEDs. In a targeted assay, mice were given a choice to spend time between zones with differing relative contrast levels (0.50, 0.75, or 1.00) for the targeted photoreceptor(s). This was assessed in two transgenic mice with: 1) human red cone knock-in (RCKI), or 2) adult-onset ablation of M1 ipRGCs (Opn4aDTA). Mice were studied without intervention or following priming with either peripheral CGRP or vehicle administration every other day for 9 days. A primary measure (mean +/- SEM) was the asymptote value (AV). ResultsWildtype mice showed greater light avoidance with increasing light intensity, demonstrating a parametric response. RCKI mice showed avoidance of the high melanopsin (1.00: 0.52 {+/-} 0.08; n = 18) and L-cone (1.00: 0.30 {+/-} 0.11; n = 15) contrast zones but showed a preference for the higher S-cone (1.00: -0.35 {+/-} 0.06; n = 16) contrast zone. These effects decreased with less relative contrast and, thus, contrast dependent. Adding S-cone contrast opposed avoidance to melanopsin (0.10 {+/-} 0.12; n = 14) or L-cone (-0.19 {+/-} 0.10; n = 15) contrast. Ablation of ipRGCs in Opn4aDTA mice attenuated avoidance of melanopsin and preference for S-cone stimulation compared to control littermates. On day 9, CGRP priming led to significantly increased avoidance of melanopsin stimulation (0.58 {+/-} 0.08, n = 21) as compared to vehicle priming (0.26 {+/-} 0.09, n = 22) (F (1,41) = 5.70, p = 0.02). ConclusionsOur findings further support that ipRGCs play a key role in mediating photophobia. This aversive response to light stems from ipRGCs combining excitatory input from intrinsic melanopsin stimulation and extrinsic L-cone input, which can be opposed by extrinsic inhibitory S-cone input. Chronic exposure to CGRP is likely one of many mechanisms in migraine that can amplify ipRGC signals, leading to photophobia. Plain Language SummaryTo better understand light sensitivity, we studied which cells in the eye cause mice to avoid light. We found that mice avoided blue and red light but preferred UV light, and this is the result of a special cell (ipRGCs) in the eye that combines these light signals. Repeated exposure to CGRP, a key nervous system messenger in migraine, increased avoidance of blue light, which may model what happens in people with chronic migraine who experience light sensitivity.

neuroscience↗

bioRxiv2024

Hyperactive neuronal networks facilitate tau spread in an Alzheimer's disease mouse model

Pathological tau spreads via neuronal connections in Alzheimers disease (AD). Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized that neuronal hyperactivity and seizures exacerbate tau spread. To examine the impacts of brain-wide network and population hyperactivity on tau spread, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) and the 5 times familial AD mice (5X-TRAP) that allows for the permanent labelling of seizure-activated neurons. To explore the effects of seizures on tau spread, we injected these mice with human AD brain-derived tau to induce pathological tau spread, and induced seizures with pentylenetetrazol (PTZ) kindling. Brain mapping revealed that seizures increased tau spread in 5X-TRAP mice, which correlated extensively with memory deficits in PTZ kindled 5X-TRAP mice. Using computational models, we found data supportive of increased anterograde tau spread in 5X-TRAP mice and that regional neuronal activity levels were predictive of tau pathology. On a cellular level, we found that hyperactive neurons drive elevated tau propagation in 5X-TRAP mice. We also found corroborating evidence of increased tau spread in AD patients with a seizure history compared to those without. Our study identifies neuronal hyperactivity and seizures as key, targetable factors underlying AD progression.

neuroscience↗

bioRxiv2024

Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.

Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43{Delta}NLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43{Delta}NLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies. Significance StatementCytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.

neuroscience↗

bioRxiv2023

Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease with attenuation after rapamycin treatment in 5XFAD mice.

Approximately 22% of Alzheimers disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbate AD pathology and related cognitive deficits. Hence seizures may be a targetable component of AD progression. As epileptogenesis is associated with changes in neuronal excitatory: inhibitory (E:I) balance, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients and exacerbated further when seizures were a comorbidity. We similarly hypothesized that an E:I imbalance would be present in five times familial AD (5XFAD) mice and augmented following pentylenetetrazol (PTZ) seizure kindling. AD temporal cortical tissue from patients with or without seizure history and brain tissue from 5XFAD mice were examined for changes in several markers of E:I balance, including the inhibitory GABAA receptor, the chloride cotransporters, sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2), and the excitatory NMDA and AMPA type glutamate receptors. We found that AD patients had decreased GABAA receptor subunits and those with comorbid seizures had worsened cognitive and functional scores, and increased in NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. The E:I imbalance appears to occur early in the disease course, as patch clamp recordings from CA1 neurons in hippocampal slices from prodromal 5XFAD mice showed decreased GABAergic inhibitory transmission and increased intrinsic excitability. In addition, seizure induction in prodromal 5XFAD mice further dysregulated NKCC1/KCC2, and altered the excitatory AMPA glutamate receptor protein expression, with a reduction in GluA2 subunit, indicative of calcium permeable-receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced -amyloid pathology and cognitive deficits, could reverse aspects of E:I imbalance in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that FDA-approved mTOR inhibitors hold therapeutic promise for AD patients with a seizure history.

neuroscience↗