Browsing by Subject "Cholinergic system"

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Open Access
Genetic and environmental interventions altering the course of brain aging: evidence from the zebrafish (Danio Rerio) model
(2021-04) Eravşar, Elif Tuğce Karoğlu
Age-related cognitive decline occurs during normal aging, although there is no prominent neural loss in the brain. Subtle molecular alterations in synaptic and cellular dynamics are likely underlying these cognitive alterations. One challenge is the widely heterogeneous profile regarding age-related behavioral changes and neurobiological underpinnings. Therefore, it is crucial to characterize how individual factors can contribute to successful or unsuccessful aging and whether these factors can induce shared patterns of alterations in the cellular and synaptic dynamics. Three different intervention approaches were utilized in the current study. The first intervention was a genetic manipulation in the cholinergic system component acetylcholinesterase (AChE), which results in reduced levels of this enzyme in the achesb55/+ mutants. Previous studies have characterized this model as a delayed aging model because of its preserved cognitive abilities at an older age. The current study was the first study analyzing the neurobiological changes in this mutant model within the context of aging. It was shown that reduced brain AChE activity levels persist in different age groups, including old age in the mutant animals. This reduction was accompanied by subtle decreases in the other elements of the cholinergic system, including acetylcholine and nicotinic acetylcholine receptor subunit alpha-7. Genotype significantly altered key glutamatergic receptor subunits such as N-methyl D-aspartate-type receptor subunit 2B (NR2B) and glutamate receptor subunits 2 and 3 (GluR2/3), with these markers significantly reduced in the achesb55/+ mutants and likely maintaining homeostatic synaptic scaling. At old age, a significant age-related elevation was observed in the synaptophysin levels (SYP) of the old achesb55/+ mutants, and this mutation prevented an age-related decline in the gephyrin (GEP) levels which was evident in the wild-type controls. This mutation also altered the cellular dynamics; an immature neuronal marker, embryonic lethal abnormal-vision (ELAV Drosophila) like-3 (HuC) was significantly upregulated in the achesb55/+ mutants at all ages. In contrast, the levels of inflammation-related markers, glial fibrillary acidic protein (GFAP) and reactive oxygen species (ROS), were downregulated subtly in the mutants. It can be concluded that reduced levels of brain AChE can be associated with altered excitatory homeostasis and preserved levels of GEP and SYP through aging. At the same time, the neuronal marker was upregulated, and inflammation-related markers were downregulated. The second intervention was applying short-term environmental enrichment using the sensory cues to young and old zebrafish to induce successful aging. It was shown that environmental enrichment increases the brain weight in old zebrafish, prevents age-related decrements in the levels of synaptic proteins, including SYP and NR2B, and doublecortin-like kinase (DCAMKL1). Additionally, environmentally enriched old zebrafish had elevated levels of GEP while applying this environmental intervention did not modulate the age-related increases in oxidative stress indicators. The third intervention was also a non-genetic approach. Two short-term opposing dietary treatments, such as caloric restriction (CR) and over-feeding (OF), were applied to young and old zebrafish and an ad-libitum diet. It was demonstrated that a short-term CR regimen upregulated the glutamatergic components of neurotransmission such as GluR2/3 and post-synaptic density 95 (PSD95). Significant age-related decline in GEP levels was observed in old zebrafish in the OF dietary condition. Expression levels of synaptic and regulatory genes were relatively stable, while inflammation-related gene tnfa was altered in an age-dependent manner. Additionally, in the young zebrafish, a significant elevation of trunk cortisol was demonstrated in the OF group compared to CR-fed young zebrafish. Taken together, evaluating different components such as the cholinergic system, diet, and environment can provide us insights into the neurobiological underpinning of successful aging and possible determinants of unhealthy aging.
Open Access
Long-term acetylcholinesterase depletion alters the levels of key synaptic proteins while maintaining neuronal markers in the aging zebrafish (Danio rerio) Brain
(S. Karger AG, 2023-10-04) Karoğlu-Eravsar, Elif Tuğçe; Tüz-Şaşik, Melek Umay; Karaduman, Ayşenur; Keşküş, Ayse Gökçe; Arslan-Ergul, Ayça; Konu, Özlen; Kafalıgönül, Hulusi; Adams, Michelle M.
Introduction: Interventions targeting cholinergic neurotransmission like acetylcholinesterase (AChE) inhibition distinguish potential mechanisms to delay age-related impairments and attenuate deficits related to neurodegenerative diseases. However, the chronic effects of these interventions are not well described. Methods: In the current study, global levels of cholinergic, cellular, synaptic, and inflammation-mediating proteins were assessed within the context of aging and chronic reduction of AChE activity. Long-term depletion of AChE activity was induced by using a mutant zebrafish line, and they were compared with the wildtype group at young and old ages. Results: Results demonstrated that AChE activity was lower in both young and old mutants, and this decrease coincided with a reduction in ACh content. Additionally, an overall age-related reduction in AChE activity and the AChE/ACh ratio was observed, and this decline was more prominent in wildtype groups. The levels of an immature neuronal marker were upregulated in mutants, while a glial marker showed an overall reduction. Mutants had preserved levels of inhibitory and presynaptic elements with aging, whereas glutamate receptor subunit levels declined. Conclusion: Long-term AChE activity depletion induces synaptic and cellular alterations. These data provide further insights into molecular targets and adaptive responses following the long-term reduction of AChE activity that was also targeted pharmacologically to treat neurodegenerative diseases in human subjects.
Open Access
Passive exposure to visual motion leads to short-term changes in the optomotor response of aging zebrafish
(Cambridge University Press, 2024-03) Karaduman, Ayşenur; Karaoğlu-Eravşar, Elif Tuğçe; Adams, Michelle M.; Kafalıgönül, Hulusi
Numerous studies have shown that prior visual experiences play an important role in sensory processing and adapting behavior in a dynamic environment. A repeated and passive presentation of visual stimulus is one of the simplest procedures to manipulate acquired experiences. Using this approach, we aimed to investigate exposure- based visual learning of aging zebrafish and how cholinergic intervention is involved in exposure-induced changes. Our measurements included younger and older wild-type zebrafish and achesb55/+mutants with decreased acetylcholinesterase activity. We examined both within-session and across-day changes in the zebrafish optomotor responses to repeated and passive exposure to visual motion. Our findings revealed short- term (within-session) changes in the magnitude of optomotor response (i.e., the amount of position shift by fish as a response to visual motion) rather than long-term and persistent effects across days. Moreover, the observed short-term changes were age- and genotype-dependent. Compared to the initial presentations of motion within a session, the magnitude of optomotor response to terminal presentations decreased in the older zebrafish. There was a similar robust decrease specific to achesb55/+mutants. Taken together, these results point to short- term (within-session) alterations in the motion detection of adult zebrafish and suggest differential effects of neural aging and cholinergic system on the observed changes. These findings further provide important insights into adult zebrafish optomotor response to visual motion and contribute to understanding this reflexive behavior in the short- and long-term stimulation profiles.