Biology subjects

Aldridge, G.

Publications and source records attributed to Aldridge, G..

7 recordsLinked to original sources

bioRxiv2026

PARP inhibition with 3-aminobenzimide attenuates behavioral, cardiovascular, and neuroinflammatory effects of chronic stress

BackgroundMajor depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling. MethodsWe conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1{beta}, TNF-, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. ResultsSaline-treated stressed rats demonstrated significantly elevated anhedonia compared to the 3-AB/Stress rats and social avoidance compared to the 3-AB/Stress and Control/ No-Stress groups. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented changes in systolic and mean blood pressure. Neurobiological analyses of PARP-1 expression in PFC did not reveal significant group differences. Microglial morphological analysis revealed a shift toward more prolate (activated) soma morphology in the saline-treated stressed rats compared to the non-stressed controls. Additionally, 3-AB-treated rats showed significantly more oblate (quiescent) microglia than saline-treated rats. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically attenuating TNF- and IL-1{beta} levels. Conclusion3-AB treatment provided multi-system protection against chronic stress effects, preventing behavioral deficits and cardiovascular dysfunction, and attenuating select markers of neuroinflammation. These findings suggest that 3-AB, and potentially PARP-1 inhibition, warrants further investigation as a therapeutic approach for stress-related disorders. Significant OutcomesO_LI3-aminobenzamide (3-AB) treatment was associated with reduced stress-induced behavioral anhedonia and social avoidance relative to saline-treated stressed rats in a validated rodent model combining social defeat and chronic unpredictable stress. C_LIO_LI3-AB treatment prevented stress-induced increases in arterial blood pressure. C_LIO_LI3-AB treatment prevented the stress-induced shift toward a more prolate microglial morphology and significantly attenuated the stress-induced increase in hippocampal TNF- and IL-1{beta}. C_LIO_LIThe multi-domain protective effects of 3-AB, spanning behavioral, cardiovascular, and neuroinflammatory measures, support further investigation of PARP inhibition as a potential therapeutic strategy for stress-related disorders. C_LI LimitationsO_LIThis study examined only male rats, limiting generalizability to female subjects despite the higher prevalence of MDD in women. C_LIO_LIBehavioral assessments were limited to anhedonia and social interaction; additional tests of other depression-relevant behaviors would provide a more comprehensive phenotypic profile. C_LIO_LILong-term effects of 3-AB treatment beyond the 10-day stress paradigm remain unexplored. C_LI

neuroscience↗

bioRxiv2026

Male mice are particularly vulnerable to cognitive impairment following mTBI

Traumatic brain injuries (TBIs) result from impact to or rapid displacement of the brain and can lead to various neurological deficits involving working memory, decision-making, and anxiety. While large-scale effects of brain damage are well-described for more severe TBIs, less is known about the extent and duration of cognitive deficits at the mild level. Interval timing can provide a helpful window into cognition in mice and humans. Interval-timing behavior is impaired in a wide range of neuropsychiatric disease states, such as Parkinsons disease. Furthermore, novel object recognition (NOR) and the Barnes maze (BM) tests are valuable assays for evaluating spatial learning, working memory, and anxiety-like behavior in mice. Here, we employed a weight-drop model of mild TBI (mTBI) to investigate changes in internal cognitive states resulting from mTBI treatment. mTBI mice were not significantly impaired in either interval timing or NOR, but they demonstrated impaired spatial memory in the Barnes Maze. Interestingly, within-sex comparisons revealed impairments in male mTBI mice in the interval-timing task and the NOR, suggesting that male and female mice may be differently affected by mTBIs.

neuroscience↗

bioRxiv2025

Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Terazosin (TZ) is an 1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsons disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimers disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (A{beta}) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimers Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.

neuroscience↗

bioRxiv2024

Renovating the Barnes maze for mouse models of Dementia with STARR FIELD: A 4-day protocol that probes learning rate, retention and cognitive flexibility.

Land-based spatial mazes are a low-stress method to evaluate learning in rodent models of dementia. By using innate exploratory and hiding behavior, the Barnes maze requires fewer trials, allowing examination of early learning rate and retention, as well as executive and motivational features that can be characteristic of non-amnestic dementias. However, unwanted odor cues may disrupt interpretation of acquisition rate during typical learning trials. We designed and tested our Barnes FIELD protocol (Find the Invisible Exit to Locate the Domicile) to improve reproducibility, allow evaluation of learning trials, and limit experimenter influence. The protocol uses 3D-printed escape shuttles and docking tunnels, allowing mice to exit the maze to the home cage. We show evidence that our shuttles mitigate the possibility of undesired cues. We demonstrate the feasibility of our protocol across several models of cognitive impairment and aging, and develop an additional stage, the STARR (Spatial Training And Rapid Reversal) maze, to better challenge behavioral flexibility. By examining commonly used outcome measures we identify important considerations for interpretation. These insights are used to evaluate several models of cognitive change, including deficits in an Alzheimers disease mouse model, and behavioral flexibility in a model of brainstem dysfunction. This work provides comprehensive instructions to build, perform, and analyze a robust spatial maze that expands the range of behavioral and motivational outcomes that can be identified and screened. Our findings will aid interpretation of traditional protocols, enhance rigor and reproducibility, and provide an updated method to screen for cognitive changes in mice.

neuroscience↗

bioRxiv2023

Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex

Lewy Body Dementias (LBD), including Parkinsons disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

neuroscience↗

bioRxiv2023

Mice expressing A53T / A30P mutant alpha-synuclein in dopamine neurons do not display behavioral deficits

Alpha-synuclein has been implicated in neurodegenerative diseases such as Parkinsons disease and Dementia with Lewy bodies, with A53T and A30P mutations shown to be disease-causing. It has been reported that transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T / A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing dopaminergic neuronal cell death and related behavioral deficits. Here, we report a lack of replication of this finding. Despite detecting robust overexpression of A53T / A30P mutant alpha-synuclein in dopamine neurons, we observed neither cell death or related behavioral deficits in these mice. Our results demonstrate that preclinical models of synucleinopathy need careful validation in the field.

animal behavior and cognition↗

bioRxiv2021

Cortical alpha-synuclein preformed fibrils do not affect interval timing in mice

One hallmark feature of Parkinsons disease (PD) is Lewy body pathology associated with misfolded alpha-synuclein. Previous studies have shown that striatal injection of alpha-synuclein preformed fibrils (PFF) can induce misfolding and aggregation of native alpha-synuclein in a prion-like manner, leading to cell death and motor dysfunction in mouse models. Here, we tested whether alpha-synuclein PFFs injected into the medial prefrontal cortex results in cognitive deficits in mouse models as measured by interval timing, which is reliably disrupted in PD patients and in rodent models. We injected human alpha-synuclein PFF or monomers in the medial prefrontal cortex pre-injected with adeno-associated virus (AAV) overexpressing human alpha-synuclein. Despite notable medial prefrontal cortical synucleinopathy, we did not observe consistent deficits in fixed-interval timing. These results suggest that cortical alpha-synuclein does not reliably disrupt interval timing in rodent models. HighlightsCortical injection of alpha-synuclein preformed fibrils (PFF) induces diffuse synucleinopathy Cortical injection of PFFs does not affect interval timing in mice Medial prefrontal cortical synucleinopathy does not reliably disrupt interval timing

neuroscience↗