Biology subjects

Savage, L. M.

Publications and source records attributed to Savage, L. M..

5 recordsLinked to original sources

bioRxiv2025

Adolescent intermittent ethanol exacerbates Aβ with age in the dorsal hippocampus of female TgF344-AD rats.

BackgroundAlcohol misuse increases Alzheimers disease (AD) risk, however the mechanisms linking these conditions are unknown. In rodents, chronic and acute ethanol increases amyloid-{beta} (A{beta}), however those studies have been limited to a single sex or brain region. ObjectiveThis study explored how adolescent intermittent ethanol (AIE), alters A{beta} in multiple regions of the brain in female and male TgF344-AD rats as they age. MethodsFrom P28-P58, female and male TgF344-AD rats were administered either water (CON) or 5.0 g/kg ethanol (AIE; 20% ethanol w/v) via intragastric gavage on a 2-day on/off cycle. In Experiment 1, A{beta} was measured in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), piriform cortex (PC), entorhinal cortex (EC), ventral hippocampus (vHPC), and dorsal hippocampus (dHPC) in 6- and 10-month-old rats. In Experiment 2, in vivo microdialysis was used in 3-month-old female rats to measure how ethanol directly modulates A{beta} levels in the dHPC. ResultsIn the OFC, PC, EC, vHPC, and dHPC, A{beta}40 and A{beta}42 was higher in 6-month-old female TgF344-AD rats compared to males. However, at 10 months A{beta}40 and A{beta}42 levels were only elevated in the dHPC of AIE-treated females, compared to all other groups. An acute ethanol challenge at 3 months selectively evoked a sustained increase in ISF A{beta}40 levels in AIE-treated females. ConclusionsIn aged females, the dHPC is a region sensitive to ethanol-associated A{beta} pathology. This may be due to disruptions in A{beta} clearance in early life, which may have an additive effect on A{beta} aggregation over the lifespan.

neuroscience↗

bioRxiv2024

Adolescent alcohol exposure alters age-related progression of behavioral and neurotrophic dysfunction in the TgF344-AD model in a sex-specific manner

Alzheimers Disease (AD) and heavy alcohol use are widely prevalent and lead to brain pathology. Both alcohol-related brain damage (ABRD) and AD result in cholinergic dysfunction, reductions in hippocampal neurogenesis, and the emergence of hippocampal-dependent cognitive impairments. It is still unknown how ARBD caused during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study utilized a longitudinal design to characterize behavioral and pathological changes in a transgenic rat model of AD (TgF344-AD) following adolescent intermittent ethanol (AIE) exposure. We found that AIE accelerates cognitive decline associated with AD transgenes in female rats at 6 months of age, and male AD-rats are impaired on spatial navigation by 3-months with no additional deficits due to AIE exposure. Protein levels of various AD-pathological markers were analyzed in the dorsal and ventral hippocampus of male and female rats. The data suggests that AIE-induced alterations of the tropomyosin-related kinase A receptor (TrkA) / p75 neurotrophin receptor (p75NTR) ratio creates a brain that is vulnerable to age- and AD-related pathologies, which leads to an acceleration of cognitive decline, particularly in female rats.

neuroscience↗

bioRxiv2024

Modulation of the p75NTR during adolescent alcohol exposure prevents cholinergic neuronal atrophy and associated acetylcholine activity and behavioral dysfunction

Binge alcohol consumption during adolescence produces lasting deficits in learning and memory, while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the Nucleus Basalis Magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from PND 25-57. A subset of these groups also received a protective dose of LM11A-31 (50mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) while recording activity with a fluorescent acetylcholine indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, mPFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration.

neuroscience↗

bioRxiv2021

Adolescent ethanol exposure decreases cholinergic markers, blunts behaviorally-evoked acetylcholine and increases in apical dendritic branching within the orbital frontal cortex.

During adolescence, heavy binge-like ethanol consumption can lead to frontocortical structural and functional impairments. These impairments are likely driven by adolescence being a critical time point for maturation of brain regions associated with higher-order cognitive functioning. Rodent models of heavy binge-like ethanol exposure show consistent disruptions to the typical development of the prefrontal cortex (PFC). All deep cortical layers receive cholinergic projections that originate from the Nucleus basalis of Meynert (NbM) complex. These cholinergic projections are highly involved in learning, memory, and attention. Adolescent intermittent ethanol exposure (AIE) induces cholinergic dysfunction as a result of an epigenetic suppression of the genes that drive the cholinergic phenotype. The current study used a model of AIE to assess structural and functional changes to the frontal cortex and NbM following binge-like ethanol exposure in adolescence. Western blot analysis revealed long-term disruptions of the cholinergic circuit following AIE: choline acetyltransferase (ChAT) was suppressed in the NbM and vesicular acetylcholine transporter (VAChT) was suppressed in the orbitofrontal cortex (OFC). In vivo microdialysis for acetylcholine efflux during a spatial memory task determined changes in cholinergic modulation within the PFC following AIE. However, AIE spared performance on the spatial memory task and on an operant reversal task. In a second study, Golgi-Cox staining determined that AIE increased apical dendritic complexity in the OFC, with sex influencing whether the increase in branching occurred near or away from the soma. Spine density or maturity was not affected, likely compensating for a disruption in neurotransmitter function following AIE. Significance StatementAdolescent ethanol exposure decreases cholinergic markers in the basal forebrain to orbital frontal cortical circuit, which lead to a massive suppression of behaviorally-activated tonic release acetylcholine and sex-dependent increases in dendritic branching. We concluded that cholinergic dysfunction is a contributor to cognitive impairments associated with heavy alcohol exposure during adolescence. Data SharingThe data that support the findings of this study are available from the corresponding author upon reasonable request.

neuroscience↗

bioRxiv2018

Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Adult neurogenesis is impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in a progressing decline in hippocampal acetylcholine and the slow emergence of profound working memory deficits. These deficits were accompanied by compensatory rewiring of cholinergic dentate gyrus inputs such that ventrally projecting neurons were recruited by the dorsal projection. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

neuroscience↗