Biology subjects

Turner, S. M.

Publications and source records attributed to Turner, S. M..

6 recordsLinked to original sources

bioRxiv2025

Tau pathology reprograms glucose metabolism to support glutamatergic activity and excitatory imbalance

Alzheimers disease (AD) is not only characterized by amyloid-beta (A{beta}) and tau pathology, but also by early and progressive disruptions in metabolism. Neuronal excitability is tightly coupled with metabolic demand, and aberrant excitatory activity - observed in AD patients and models - can drive changes in metabolism. While A{beta}-related metabolic impairments are well-described, less is known about how tau pathology independently contributes to altered metabolic states and excitatory tone. Therefore, we explored how tau pathology impacted whole body and CNS metabolism in mouse models of tauopathy, including the P301S PS19 and Tau4RTg2652 mice. In both models, hyperphosphorylated tau prevents the age-related decline in whole-body metabolism by preserving glucose tolerance and mitigating shifts in fuel utilization (respiratory exchange ratio; RER), suggesting the mice are "glucose needy". Tau pathology also preserves diurnal rhythms in hippocampal interstitial fluid (ISF) glucose and lactate, likely due to increased neuronal activity during the active (dark) phase. Stable isotope-resolved metabolomics following 13C-glucose administration revealed that glucose is preferentially shunted toward glutamate synthesis--at the expense of GABA--highlighting a shift in excitatory/inhibitory balance. Interestingly, these changes were not explained by a primary deficit in synaptic mitochondria but by alterations in glycolytic flux. Adaptations were time of day dependent, where ISF glutamate rises after a glucose injection in the dark period but not the light period. This suggests increased glutamatergic activity may drive metabolic demand during the dark period when mice are more active. Together, these studies fundamentally highlight the important coupling between metabolism and excitability, which is disrupted by hyperphosphorylated tau, tau aggregation, and neurodegeneration. Understanding how tau pathology and metabolism interrelate provides a novel lens for the development of therapeutic targets in late stage AD.

neuroscience↗

bioRxiv2022

Warmer water temperature and epizootic shell disease reduces diversity but increases cultivability of bacteria on the shells of American Lobster (Homarus americanus).

The American lobster, Homarus americanus, is an economically valuable and ecologically important crustacean along the North Atlantic coast of North America. Populations in southern locations have declined in recent decades due to increasing ocean temperatures and disease, and these circumstances are progressing northward. We monitored 57 adult female lobsters, healthy and shell-diseased, under three seasonal temperature cycles for a year, to track shell bacterial communities using culturing and 16S rRNA gene sequencing, progression of ESD using visual assessment, and antimicrobial activity of hemolymph. The richness of bacterial taxa present, evenness of abundance, and community similarity between lobsters was affected by water temperature at the time of sampling, water temperature over time based on seasonal temperature regimes, shell disease severity, and molt stage. Several bacteria were prevalent on healthy lobster shells but missing or less abundant on diseased shells, although putative pathogens were found on all shells regardless of health status. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/512360v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@7c17e1org.highwire.dtl.DTLVardef@103e122org.highwire.dtl.DTLVardef@1b1b718org.highwire.dtl.DTLVardef@6b95d5_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Unilateral Perforant Path Transection Does Not Alter Lateral Entorhinal Cortical or Hippocampal CA3 Arc Expression

It is well established that degradation of perforant path fibers is associated with age-related cognitive dysfunction and CA3 hyperactivity. Whether this fiber loss triggers a cascade of other functional changes within the hippocampus circuit has not been causatively established, however. Thus, the current study evaluated the effect of perforant path fiber loss on neuronal activity in CA3 and layer II of the lateral entorhinal cortex (LEC) in relation to mnemonic similarity task performance. Expression of the immediate early gene Arc was quantified in rats that received a unilateral right hemisphere transection of the perforant path or sham surgery that cut the cortex but left the fibers intact. Behavior-related expression of Arc mRNA was measured to test the hypothesis that fiber loss leads to elevated activation of CA3 and LEC neurons, as previously observed in aged rats that were impaired on the mnemonic similarity task. Transection of perforant path fibers, which has previously been shown to lead to a decline in mnemonic similarity task performance, did not alter Arc expression. Arc expression in CA3, however, was correlated with task performance on the more difficult discrimination trials across both surgical groups. These observations further support a link between CA3 activity and mnemonic similarity task performance but suggest the reduced input from the entorhinal cortex to the hippocampus, as observed in old age, does not causatively elevate CA3 activity.

neuroscience↗

bioRxiv2020

Rodent mnemonic similarity task performance requires the prefrontal cortex

Mnemonic similarity task performance, in which a known target stimulus must be distinguished from similar lures, is supported by the hippocampus and perirhinal cortex and is known to decline in advanced age. Interestingly, disrupting hippocampal activity leads to mnemonic discrimination impairments when lures are novel, but not when they are familiar. This observation suggests other brain structures can support discrimination abilities as stimuli are learned. The prefrontal cortex (PFC) is critical for retrieval of remote events and executive functions, such as working memory, and is also particularly vulnerable to dysfunction in aging. Importantly, the medial PFC is reciprocally connected to the perirhinal cortex and neuron firing in this region coordinates communication between lateral entorhinal and perirhinal cortices to presumably modulate hippocampal activity. This anatomical organization and function of the medial PFC suggests that it contributes to mnemonic discrimination; however, this notion has not been empirically tested. In the current study, young adult male and female F344 x Brown Norway F1 hybrid rats were trained on a rodent object-based mnemonic similarity task, and surgically implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial PFC. Prior to mnemonic discrimination tests, rats received PFC infusions of the GABAA agonist muscimol. Analyses of expression of the neuronal activity-dependent immediate-early gene Arc in medial PFC and adjacent cortical regions confirmed muscimol infusions led to neuronal inactivation in the infralimbic and prelimbic cortices. Moreover, muscimol infusions in PFC impaired mnemonic discrimination performance relative to the vehicle control across all testing blocks when lures shared 50-90% feature overlap with the target. Thus, in contrast to prior results from rats given hippocampal muscimol infusions, PFC inactivation impaired target-lure discrimination regardless of the novelty or familiarity of the lures. These findings indicate the PFC plays a critical role in mnemonic similarity task performance, but the time course of PFC involvement is dissociable from that of the hippocampus.

neuroscience↗

bioRxiv2018

Experience-dependent effects of muscimol-induced hippocampal excitation on mnemonic discrimination

Memory requires similar episodes with overlapping features to be represented distinctly, a process that is disrupted in many clinical conditions as well as normal aging. Data from humans have linked this ability to activity in hippocampal CA3 and dentate gyrus (DG). While animal models have shown the perirhinal cortex is critical for disambiguating similar stimuli, hippocampal activity has not been causally linked to discrimination abilities. The goal of the current study was to determine how disrupting CA3/DG activity would impact performance on a rodent mnemonic discrimination task. Rats were surgically implanted with bilateral guide cannulae targeting dorsal CA3/DG. In Exp.1, the effect of intra-hippocampal muscimol on target-lure discrimination was assessed within subjects in randomized blocks. Muscimol initially impaired discrimination across all levels of target-lure similarity, but performance improved on subsequent test blocks irrespective of stimulus similarity and infusion condition. To clarify these results, Exp.2 examined whether prior experience with objects influenced the effect of muscimol on target-lure discrimination. Rats that received vehicle infusions in a first test block, followed by muscimol in a second block, did not show discrimination impairments for target-lure pairs of any similarity. In contrast, rats that received muscimol infusions in the first test block were impaired across all levels of target-lure similarity. Sustained effects of muscimol in disrupting behavioral performance after repeated infusions were verified in a spatial alternation task. At the conclusion of behavioral experiments, fluorescence in situ hybridization for the immediate-early genes Arc and Homer1a was used to determine the proportion of neurons active following muscimol infusion. Contrary to expectations, muscimol increased neural activity in DG. An additional experiment was carried out to quantify neural activity in naive rats that received an intra-hippocampal infusion of vehicle or muscimol. Results confirmed that muscimol led to DG excitation, likely through its actions on interneuron populations in hilar and molecular layers of DG and consequent disinhibition of principal cells. Taken together, our results suggest disruption of coordinated neural activity across the hippocampus impairs mnemonic discrimination when lure stimuli are novel.

neuroscience↗

bioRxiv2018

Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age

The functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multi-scale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multi-task. Aged behaviorally-impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex and dorsal striatum. Moreover, the old rats had less stable rich club participation that increased with cognitive training. The altered functional connectome of aged rats was associated with a greater engagement of neurons in the dorsal striatum during cognitive multi-tasking. These findings point to aberrant large-scale functional connectivity in aged animals that is associated with altered cellular activity patterns within individual brain regions.

neuroscience↗