Department of Psychology

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Open Access
Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction
(Pergamon Press, 2010) Adams, Michelle M.; Donohue, H. S.; Linville, M. C.; Iversen, E. A.; Newton, I. G.; Bechtold, J. K. B.
Caloric restriction (CR) is a reduction of total caloric intake without a decrease in micronutrients or a disproportionate reduction of any one dietary component. While CR attenuates age-related cognitive deficits in tasks of hippocampal-dependent memory, the cellular mechanisms by which CR improves this cognitive decline are poorly understood. Previously, we have reported age-related decreases in key synaptic proteins in the CA3 region of the hippocampus that are stabilized by lifelong CR. In the present study, we examined possible age-related changes in the functional microcircuitry of the synapses in the stratum lacunosum-moleculare (SL-M) of the CA3 region of the hippocampus, and whether lifelong CR might prevent these age-related alterations. We used serial electron microscopy to reconstruct and classify SL-M synapses and their postsynaptic spines. We analyzed synapse number and size as well as spine surface area and volume in young (10 months) and old (29 months) ad libitum fed rats and in old rats that were calorically restricted from 4 months of age. We limited our analysis to SL-M because previous work demonstrated age-related decreases in synaptophysin confined to this specific layer and region of the hippocampus. The results revealed an age-related decrease in macular axo-spinous synapses that was not reversed by CR that occurred in the absence of changes in the size of synapses or spines. Thus, the benefits of CR for CA3 function and synaptic plasticity may involve other biological effects including the stabilization of synaptic proteins levels in the face of age-related synapse loss. © 2010 IBRO.
Open Access
Aging alters the molecular dynamics of synapses in a sexually dimorphic pattern in zebrafish (Danio rerio)
(Elsevier, 2017-06) Karoglu, Elif Tugce; Halim, Dilara Ozge; Erkaya, Bahriye; Altaytas, Ferda; Arslan-Ergul, Ayca; Konu, Ozlen; Adams, Michelle M.
The zebrafish has become a popular model for studying normal brain aging due to its large fecundity, conserved genome, and available genetic tools; but little data exists about neurobiological age-related alterations. The current study tested the hypothesis of an association between brain aging and synaptic protein loss across males and females. Western blot analysis of synaptophysin (SYP), a presynaptic vesicle protein, and postsynaptic density-95 (PSD-95) and gephyrin (GEP), excitatory and inhibitory postsynaptic receptor-clustering proteins, respectively, was performed in young, middle-aged, and old male and female zebrafish (Danio rerio) brains. Univariate and multivariate analyses demonstrated that PSD-95 significantly increased in aged females and SYP significantly decreased in males, but GEP was stable. Thus, these key synaptic proteins vary across age in a sexually dimorphic manner, which has been observed in other species, and these consequences may represent selective vulnerabilities for aged males and females. These data expand our knowledge of normal aging in zebrafish, as well as further establish this model as an appropriate one for examining human brain aging.
Open Access
Caloric restriction reinforces the stem cell pool in the aged brain without affecting overall proliferation status
(Elsevier BV, 2022-11-01) Erbaba, Begün; Macaroğlu, Duygu; Avcı, N. İlgim Ardıç; Ergül , Ayça Arslan; Adams, Michelle M.
Overfeeding (OF) and obesity increase the risk for brain aging and neurodegenerative diseases due to increased oxidative stress and neuroinflammation, which likely contribute to cellular dysfunction. In contrast, caloric restriction (CR) is an intervention known for its effects on extending both life- and health-span. In the current study, the effects on the aging brain of two short-term feeding regimens, OF and CR, were investigated. We applied these diets for 12 weeks to both young and aged zebrafish. We performed protein and mRNA level analysis to examine diet-mediated effects on any potential age-related alterations in the brain. Markers implicated in the regulation of brain aging, cell cycle, proliferation, inflammation, and cytoskeleton were analyzed. The most prominent result observed was a downregulation in the expression levels of the stem cell marker, Sox2, in CR-fed animals as compared to OF-fed fish. Furthermore, our data highlighted significant age-related downregulations in Tp53, Myca, and L-plastin levels. The multivariate analyses of all datasets suggested that as opposed to OF, the adaptive mechanisms increasing lifespan via CR are likely exerting their effects by reinforcing the stem cell pool and downregulating inflammation. The data reveal important therapeutic targets with respect to the state of nutrient uptake for the slowing down of the detrimental effects of aging, resulting in a healthy and extended lifespan, as well as lowering the risk for neurodegenerative disease.
Open Access
Dietary and pharmacological interventions that inhibit mammalian target of rapamycin activity alter the brain expression levels of neurogenic and glial markers in an age-and treatment-dependent manner
(Mary Ann Liebert, 2020) Çelebi-Birand, Dilan; Ardıç, Narin İlgim; Karoğlu-Eravşar, Elif Tuğçe; Şengül, Göksemin Fatma; Kafalıgönül, Hulusi; Adams, Michelle M.
Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6–10 months) and old (26–31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were age-specific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.
Open Access
Effects of caloric restriction on the antagonistic and integrative hallmarks of aging
(Elsevier, 2021) Erbaba, Begün; Arslan-Ergül, Ayça; Adams, Michelle M.
Aging is a significant risk factor for cognitive decline associated with neurodegenerative diseases, which makes understanding what promotes ‘healthy brain aging’ very important. Studies suggest that caloric restriction (CR) is a non-genetic intervention that reliably extends life- and healthspan. Here, we review the CR literature related to both the subject of aging and alterations in cell cycle machinery, especially surrounding the regulation of the E2F/DP1 complex, to elucidate the cellular protection mechanisms in the brain induced via dietary applications. The alterations extending lifespan via CR appear to exert their effects by promoting survival of individual cells, downregulating cell proliferation, and inducing stem cell quiescence, which results in keeping the stem cell reserve for extreme needs. This survival instinct of cells is believed to cause some molecular adaptations for their maintenance of the system. Avoiding energy waste of proliferation machinery promotes the long term survival of the individual cells and this is due to adaptations to the limited nutrient supply in the environment. Such a protective mechanism induced by diet could be promoted via the downregulation of crucial cell cycle-related transcription activators. This review article aims to bring attention to the importance of molecular adaptations induced by diet that promote healthy brain aging. It will provide insights into alternative targets for new treatments or neuroprotective approaches against neurodegenerative pathophysiologies.
Open Access
Gene expression changes in aging zebrafish (Danio rerio) brains are sexually dimorphic
(BioMed Central, 2014) Arslan-Ergül, Ayça; Adams, Michelle M.
Background: Brain aging is a multi-factorial process due to both genetic and environmental factors. The zebrafish has recently become a popular model organism for examining aging and age-related diseases because as in humans they age gradually and exhibit cognitive decline. Few studies have examined the biological changes in the aging brain that may contribute to these declines and none have examined them within individuals with respect to gender. Our aim was to identify the main genetic pathways associated with zebrafish brain aging across gender. We chose males and females from specific age groups (young, 7.5-8.5 months and old, 31-36 months) based on the progression of cognitive decline in zebrafish. RNA was isolated from individual brains and subjected to microarray and qPCR analysis. Statistical analyses were performed using a two-way ANOVA and the relevant post-hoc tests. Results: Our results demonstrated that in the brains of young and old male and female zebrafish there were over 500 differentially expressed genes associated with multiple pathways but most notably were those related to neurogenesis and cell differentiation, as well as brain and nervous system development. Conclusions: The gene expression of multiple pathways is altered with age and differentially expressed in males and females. Future studies will be aimed at determining the causal relationships of age-related changes in gene expression in individual male and female brains, as well as possible interventions that counteract these alterations.
Open Access
Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats
(Age Company, 2013) Molina, D. P.; Ariwodola, O. J.; Weiner, J. L.; Bechtold, J. K. B.; Adams, Michelle M.
In rats, as in humans, normal aging is characterized by a decline in hippocampal-dependent learning and memory, as well as in glutamatergic function. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels have been reported to decrease with age, and treatment with either GH or IGF-I can ameliorate age-related cognitive decline. Interestingly, acute GH and IGF-I treatments enhance glutamatergic synaptic transmission in the rat hippocampus of juvenile animals. However, whether this enhancement also occurs in old rats, when cognitive impairment is ameliorated by GH and IGF-I (des-IGF-I), remains to be determined. To address this issue, we used an in vitro CA1 hippocampal slice preparation and extracellular recording techniques to study the effects of acute application of GH and IGF-I on compound field excitatory postsynaptic potentials (fEPSPs), as well as AMPA- and NMDA-dependent fEPSPs, in young adult (10 months) and old (28 months) rats. The results indicated that both GH and IGF-I increased compound-, AMPA-and NMDA-dependent fEPSPs to a similar extent in slices from both age groups and that this augmentation was likely mediated via a postsynaptic mechanism. Initial characterization of the signaling cascades underlying these effects revealed that the GH-induced enhancement was not mediated by the JAK2 signaling element in either young adult or old rats but that the IGF-Iinduced enhancement involved a PI3K-mediated mechanism in old, but not young adults. The present findings are consistent with a role for a GH-or IGF-I-induced enhancement of glutamatergic transmission in mitigating age-related cognitive impairment in old rats. © 2012 American Aging Association.
Open Access
Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats
(Elsevier, 2012) Molina, D. P.; Ariwodola, O. J.; Linville, C.; Sonntag, W. E.; Weiner, J. L.; Brunso-Bechtold, J. K.; Adams, Michelle M.
Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R) and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6-8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R-dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline. © 2012 Elsevier Inc.
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
Mammalian target of rapamycin (mTOR), aging, neuroscience, and their association with aging-related diseases
(Elsevier Inc., 2016) Celebi-Birand, Ergül Dilan; Karoğlu, Elif Tuğçe; Doldur-Ballı, Füsun; Adams, Michelle M.; Maiese, K.
Normal aging is accompanied by cognitive impairment with subtle cellular and molecular changes in the brain, whereas, pathological brain aging manifests as severe behavioral impairments with cellular pathology. Understanding the factors that contribute to both states is undoubtedly important for determining appropriate interventions that alter their progression. Mammalian target of rapamycin (mTOR) signaling has been implicated in affecting lifespan and age-related diseases such as cancer. The relationship of mTOR signaling with pathological brain aging has been more extensively studied, whereas the association with normal brain aging is not well understood. In this chapter we present information about normal and pathological brain aging, the relationship with mTOR signaling and use information from other age-related diseases to suggest that mTOR may have a role in promoting the cellular and molecular changes that underlie age-related cognitive changes. Future work should be directed towards understanding the precise role of mTOR signaling in brain aging. © 2016 Elsevier Inc. All rights reserved.
Open Access
Novel object recognition is not affected by age despite age-related brain changes
(Scientific Research Publishing, 2013) Aktoprak, İlay; Dinç, Pelin; Günay, Gizem; Adams, Michelle M.
Age-related memory impairments show a progressive decline across lifespan. Studies have demonstrated equivocal results in biological and behavioral outcomes of aging. Thus, in the present study we examined the novel object recognition task at a delay period that has been shown to be impaired in aged rats of two different strains. Moreover, we used a strain of rats, Fisher 344XBrown Norway, which have published age-related biological changes in the brain. Young (10 month old) and aged (28 month old) rats were tested on a standard novel object recognition task with a 50-minute delay period. The data showed that young and aged rats in the strain we used performed equally well on the novel object recognition task and that both young and old rats demonstrated a righthanded side preference for the novel object. Our data suggested that novel object recognition is not impaired in aged rats although both young and old rats have a demonstrated side preference. Thus, it may be that genetic differences across strains contribute to the equivocal results in behavior, and genetic variance likely influences the course of cognitive aging.
Open Access
A novel, low-cost Anesthesia and injection system for Zebrafish Researchers
(Mary Ann Liebert, Inc. Publishers, 2018) Oskay, Yiğit; Çetin Barbaros; Şerifoğlu, Naz; Arslan-Ergül, Ayça; Adams, Michelle M.
In this study, we designed and developed a novel low-cost system for anesthetizing and injecting adult zebrafish. The system utilizes a gradual cooling method for the anesthesia and maintains the fish in a stable anesthetic plane, as well as stabilizes the animal so that intraperitoneal injections can be consistently performed. It is a system that any laboratory with access to a workshop can build for their group. Moreover, it is a safe system for researchers, as well as a reliable one for repeated experiments since multiple fish can be injected quickly and there is little physical contact necessary between the investigator and the animal. This will likely reduce any unnecessary stress in the fish, as compared with manual methods of injection. Finally, the system is adaptable so that as the investigators' procedural needs change due to different research questions, that is, gradual rewarming or something of that nature, it could be modified.
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.
Open Access
Short-term dietary restriction in old zebrafish changes cell senescence mechanisms
(Elsevier, 2016-10) Arslan-Ergul, Ayca; Erbaba, Begun; Karoglu, Elif Tugce; Halim, Dilara Ozge; Adams, Michelle M.
Brain aging is marked by a decline in cognitive abilities and associated with neurodegenerative disorders. Recent studies have shown, neurogenesis continues into adulthood but is known to be decreasing during advancing age and these changes may contribute to cognitive alterations. Advances, which aim to promote better aging are of paramount importance. Dietary restriction (DR) is the only non-genetic intervention that reliably extends life- and health-span. Mechanisms of how and why DR and age affect neurogenesis are not well-understood, and have not been utilized much in the zebrafish, which has become a popular model to study brain aging and neurodegenerative disease due to widely available genetic tools. In this study we used young (8–8.5 months) and old (26–32.5 months) zebrafish as the model to investigate the effects of a short-term DR on actively proliferating cells. We successfully applied a 10-week DR to young and old fish, which resulted in a significant loss of body weight in both groups with no effect on normal age-related changes in body growth. We found that age decreased cell proliferation and increased senescence associated β-galactosidase, as well as shortened telomere lengths. In contrast, DR shortened telomere lengths only in young animals. Neither age nor DR changed the differentiation patterns of glial cells. Our results suggest that the potential effects of DR could be mediated by telomere regulation and whether these are beneficial or negative remains to be determined.
Open Access
Zebrafish brain RNA sequencing reveals that cell adhesion molecules are critical in brain aging
(Elsevier, 2020) Erbaba, Begün; Burhan, Özge Pelin; Şerifoğlu, Naz; Muratoğlu, B.; Kahveci, Fatma; Adams, Michelle M.; Arslan-Ergül, A.
Brain aging is a complex process, which involves multiple pathways including various components from cellular to molecular. This study aimed to investigate the gene expression changes in zebrafish brains through young-adult to adult, and adult to old age. RNA sequencing was performed on isolated neuronal cells from zebrafish brains. The cells were enriched in progenitor cell markers, which are known to diminish throughout the aging process. We found 176 statistically significant, differentially expressed genes among the groups, and identified a group of genes based on gene ontology descriptions, which were classified as cell adhesion molecules. The relevance of these genes was further tested in another set of zebrafish brains, human healthy, and Alzheimer’s disease brain samples, as well as in Allen Brain Atlas data. We observed that the expression change of 2 genes, GJC2 and ALCAM, during the aging process was consistent in all experimental sets. Our findings provide a new set of markers for healthy brain aging and suggest new targets for therapeutic approaches to neurodegenerative diseases.

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