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1.  Contribution of estrogen receptor subtypes, ERα, ERβ, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice 
Hippocampus  2015;25(12):1556-1566.
Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. The current study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3-5 month old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERβKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10-16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synaptic contacts before and following application of 17β-estradiol-3-benzoate (EB, 100 pM), the G-protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERβ selective agonist diarylpropionitrile (DPN, 1 μM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERβ selective agonists (PPT, DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal-regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes.
doi:10.1002/hipo.22475
PMCID: PMC4644731  PMID: 25980457
Estrogen; estrogen receptor alpha and beta; GPR30; GPER1; estradiol; G1; G15; hippocampus; synaptic plasticity; ERK
2.  Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence 
A decrease in N-methyl-D-aspartate receptor (NMDAR) function is associated with age-related cognitive impairments. However, NMDAR antagonists are prescribed for cognitive decline associated with age-related neurodegenerative disease, raising questions as to the role of NMDAR activity in cognitive function during aging. The current studies examined effects of NMDAR blockade on cognitive task that are sensitive to aging. Young and middle-age rats were trained on the five-choice serial reaction time task (5-CSRTT) and challenged with MK-801 (0.025, 0.05, and 0.1 mg/kg or vehicle). Attention deficits were apparent in middle-age and performance of young and middle-age rats was enhanced for low doses of MK-801 (0.025 and 0.05). The beneficial effects on attention were reversed by the highest dose of MK-801. Older animals exhibited a delay-dependent impairment of episodic spatial memory examined on a delayed-matching to place water maze task. Similarly, a low dose of MK-801 (0.05 mg/kg) impaired performance with increasing delay and aged animals were more susceptible to disruption by NMDAR blockade. Despite MK-801 impairment of episodic spatial memory, MK-801 had minimal effects on spatial reference memory. Our results confirm that NMDARs contribute to rapidly acquired and flexible spatial memory and support the idea that a decline in NMDAR function contributes to the age-related impairments in cognition.
doi:10.1016/j.nlm.2015.07.015
PMCID: PMC4648716  PMID: 26234588
aging; hippocampus; prefrontal cortex; NMDA receptor; episodic memory; attention; MK-801
3.  Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats 
Brain, behavior, and immunity  2015;49:216-232.
We trained and tested young (6–8 mo; n = 13), middle-aged (12–14 mo; n = 41), and aged (22–24 mo; n = 24) male Fischer 344 rats in a rapid acquisition water maze task and then quantified 27 stress hormones, cytokines and chemokines in their serum, hippocampi and frontal cortices using bead assay kits and xMAP technology. Middle-aged and aged rats learned the location of the hidden platform over training trials more slowly than their young counterparts. After training, young rats outperformed middle-aged and aged rats on both immediate and 24h retention probe trials and about half of the middle-aged and aged (aging) rats exhibited impaired performances when tested on the retention probe trial 24h later. The concentrations of many serum, hippocampal and cortical analytes changed with age often in networks that may represent age-sensitive signaling pathways and the concentrations of some of these analytes correlated with water maze learning and/or memory scores. Serum GRO/KC and RANTES levels, hippocampal GM-CSF levels and cortical IL-9 and RANTES levels were significantly higher in rats categorized as memory-impaired versus elite agers based upon their 24h probe trial performances. Our data add to the emerging picture of how age-related changes in immune and neuroimmune system signaling impacts cognition.
doi:10.1016/j.bbi.2015.06.005
PMCID: PMC4567443  PMID: 26093306
aging; inflammation; neuroinflammation; memory; hippocampus; water maze; xMAP technology; cytokines; chemokines
4.  Successful Aging: Advancing the Science of Physical Independence in Older Adults 
Ageing research reviews  2015;24(0 0):304-327.
The concept of ‘Successful Aging’ has long intrigued the scientific community. Despite this long-standing interest, a consensus definition has proven to be a difficult task, due to the inherent challenge involved in defining such a complex, multi-dimensional phenomenon. The lack of a clear set of defining characteristics for the construct of successful aging has made comparison of findings across studies difficult and has limited advances in aging research. The domain in which consensus on markers of successful aging is furthest developed is the domain of physical functioning. For example, walking speed appears to be an excellent surrogate marker of overall health and predicts the maintenance of physical independence, a cornerstone of successful aging. The purpose of the present article is to provide an overview and discussion of specific health conditions, behavioral factors, and biological mechanisms that mark declining mobility and physical function and promising interventions to counter these effects. With life expectancy continuing to increase in the United States and developed countries throughout the world, there is an increasing public health focus on the maintenance of physical independence among all older adults.
doi:10.1016/j.arr.2015.09.005
PMCID: PMC4661112  PMID: 26462882
age; mobility; obesity; sarcopenia; healthspan; longevity
5.  Re-Opening the Critical Window for Estrogen Therapy 
The Journal of Neuroscience  2015;35(49):16077-16093.
A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor α (ERα) or estrogen receptor β (ERβ) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ERα, ERβ, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17β-estradiol-3-benzoate (EB, 10 μg) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP + EB) and ERβ (ERβ + EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ERβ failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ERα that received EB treatment (ERα + EB), such that memory was improved relative to ERα + oil and GFP + EB. Similarly, ERα + EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ERα + oil and GFP + EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ERα.
SIGNIFICANCE STATEMENT Estradiol is neuroprotective, promotes synaptic plasticity in the hippocampus, and protects against cognitive decline associated with aging and neurodegenerative diseases. However, animal models and clinical studies indicate a critical window for the therapeutic treatment such that the beneficial effects are lost with advanced age and/or with extended hormone deprivation. We used gene therapy to upregulate expression of the estrogen receptors ERα and ERβ and demonstrate that the window for estradiol's beneficial effects on memory and hippocampal synaptic function can be reinstated by enhancing the expression of ERα. Our findings suggest that the activity of ERα controls the therapeutic window by regulating synaptic plasticity mechanisms involved in memory.
doi:10.1523/JNEUROSCI.1890-15.2015
PMCID: PMC4682778  PMID: 26658861
aging; ERα and ERβ; estrogen; hippocampus; learning and memory; NMDA receptor
6.  ROLE OF ESTROGEN RECEPTOR-α ON FOOD DEMAND ELASTICITY 
Estrogens have been shown to have an inhibitory effect on food intake under free-feeding conditions, yet the effects of estrogens on food-maintained operant responding have been studied to a much lesser extent and, thus, are not well understood. Therefore, the purpose of the present experiment was to use a behavioral economics paradigm to assess differences in demand elasticity between mice with knockout of the estrogen receptor subtype α, knockout of subtype β, and their wild type controls. The mice responded in a closed economy, and the price of food was increased by increasing the fixed-ratio response requirement every four sessions. Overall, we found that mice with the knockout of receptor subtype α had the most elastic demand functions. Therefore, under these conditions, estrogens increased food seeking via activation of the receptor subtype α. The results were inconsistent with those reported by previous studies that employed free-feeding conditions.
doi:10.1002/jeab.149
PMCID: PMC4939438  PMID: 25869426
demand; fixed-ratio schedules; mice; nose poke; sex hormones
7.  Transcription Profile of Aging and Cognition-Related Genes in the Medial Prefrontal Cortex 
Cognitive function depends on transcription; however, there is little information linking altered gene expression to impaired prefrontal cortex function during aging. Young and aged F344 rats were characterized on attentional set shift and spatial memory tasks. Transcriptional differences associated with age and cognition were examined using RNA sequencing to construct transcriptomic profiles for the medial prefrontal cortex (mPFC), white matter, and region CA1 of the hippocampus. The results indicate regional differences in vulnerability to aging. Age-related gene expression in the mPFC was similar to, though less robust than, changes in the dorsolateral PFC of aging humans suggesting that aging processes may be similar. Importantly, the pattern of transcription associated with aging did not predict cognitive decline. Rather, increased mPFC expression of genes involved in regulation of transcription, including transcription factors that regulate the strength of excitatory and inhibitory inputs, and neural activity-related immediate-early genes was observed in aged animals that exhibit delayed set shift behavior. The specificity of impairment on a mPFC-dependent task, associated with a particular mPFC transcriptional profile indicates that impaired executive function involves altered transcriptional regulation and neural activity/plasticity processes that are distinct from that described for impaired hippocampal function.
doi:10.3389/fnagi.2016.00113
PMCID: PMC4868850  PMID: 27242522
aging; cognitive flexibility; prefrontal cortex; set shifting task; transcription
8.  Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors 
The Journal of Neuroscience  2015;35(9):3966-3977.
Young (3–6 months) and middle-age (10–14 months) rats were trained on the five-choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline.
doi:10.1523/JNEUROSCI.3523-14.2015
PMCID: PMC4348191  PMID: 25740525
aging; attention; executive function; NMDA receptor; prefrontal cortex; redox state
9.  Type 3 Adenylyl Cyclase and Somatostatin Receptor 3 Expression Persists in Aged Rat Neocortical and Hippocampal Neuronal Cilia 
The primary cilia of forebrain neurons assemble around birth and become enriched with neuromodulatory receptors. Our understanding of the permanence of these structures and their associated signaling pathways in the aging brain is poor, but they are worthy of investigation because disruptions in neuronal cilia signaling have been implicated in changes in learning and memory, depression-like symptoms, and sleep anomalies. Here, we asked whether neurons in aged forebrain retain primary cilia and whether the staining characteristics of aged cilia for type 3 adenylyl cyclase (ACIII), somatostatin receptor 3 (SSTR3), and pericentrin resemble those of cilia in younger forebrain. To test this, we analyzed immunostained sections of forebrain tissues taken from young and aged male Fischer 344 (F344) and F344 × Brown Norway (F344 × BN) rats. Analyses of ACIII and SSTR3 in young and aged cortices of both strains of rats revealed that the staining patterns in the neocortex and hippocampus were comparable. Virtually every NeuN positive cell examined possessed an ACIII positive cilium. The lengths of ACIII positive cilia in neocortex were similar between young and aged for both strains, whereas in F344 × BN hippocampus, the cilia lengths increased with age in CA1 and CA3, but not in dentate gyrus (DG). Additionally, the percentages of ACIII positive cilia that were also SSTR3 positive did not differ between young and aged tissues in either strain. We also found that pericentrin, a protein that localizes to the basal bodies of neuronal cilia and functions in primary cilia assembly, persisted in aged cortical neurons of both rat strains. Collectively, our data show that neurons in aged rat forebrain possess primary cilia and that these cilia, like those present in younger brain, continue to localize ACIII, SSTR3, and pericentrin. Further studies will be required to determine if the function and signaling pathways regulated by cilia are similar in aged compared to young brain.
doi:10.3389/fnagi.2016.00127
PMCID: PMC4885836  PMID: 27303293
aging; cerebral cortex; cilium; G protein-coupled receptor
10.  Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline 
Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline.
doi:10.3389/fnagi.2016.00158
PMCID: PMC4942756  PMID: 27468264
fMRI; DTI; magnetic resonance spectroscopy; hippocampus; memory; preclinical MRI; aging neuroscience
11.  Increased N-Ethylmaleimide-Sensitive Factor Expression in Amygdala and Perirhinal Cortex during Habituation of Taste Neophobia 
Neural Plasticity  2015;2016:2726745.
Interactions between GluR2 and N-ethylmaleimide-sensitive factor (NSF) mediate AMPA receptors trafficking. This might be linked with molecular mechanisms related with memory formation. Previous research has shown basolateral amygdala (BLA) dependent activity changes in the perirhinal cortex (PRh) during the formation of taste memory. In the present experiments we investigate both the behavioral performance and the expression profile of NSF and GluR2 genes in several brain areas, including PRh, BLA, and hippocampus. Twenty-one naïve male Wistar rats were exposed to a saccharin solution (0.4%) during the first (novel), the second (Familiar I), and the sixth presentation (Familiar II). Total RNA was extracted and gene expression was measured by quantitative PCR (qPCR) using TaqMan gene expression assays. In addition the expression of the synaptic plasticity related immediate early genes, Homer 1 and Narp, was also assessed. We have found increased expression of NSF gene in BLA and PRh in Group Familiar I in comparison with Familiar II. No changes in the expression of GluR2, Homer 1, and Narp genes were found. The results suggest the relevance of a potential network in the temporal lobe for taste recognition memory and open new possibilities for understanding the molecular mechanisms mediating the impact of sensory experience on brain circuit function.
doi:10.1155/2016/2726745
PMCID: PMC4709763  PMID: 26839712
12.  Estrogen Receptors, the Hippocampus, and Memory 
Estradiol effects on memory depend on hormone levels and the interaction of different estrogen receptors within neural circuits. Estradiol induces gene transcription and rapid membrane signaling mediated by estrogen receptor-alpha (ERα), estrogen receptor-beta (ERβ), and a recently characterized G-protein coupled estrogen receptor, each with distinct distributions and ability to influence estradiol-dependent signaling. Investigations using receptor specific agonists suggest that all three receptors rapidly activate kinase-signaling and have complex dose-dependent influences on memory. Research employing receptor knockout mice demonstrate that ERα maintains transcription and memory as estradiol levels decline. This work indicates a regulatory role of ERβ in transcription and cognition, which depends on estradiol levels and the function of ERα. The regulatory role of ERβ is due in part to ERβ acting as a negative regulator of ERα-mediated transcription. Vector-mediated expression of estrogen receptors in the hippocampus provides an innovative research approach and suggests that memory depends on the relative expression of ERα and ERβ interacting with estradiol levels. Notably, the ability of estradiol to improve cognition declines with advanced age along with decreased expression of estrogen receptors. Thus, it will be important for future research to determine the mechanisms that regulate estrogen receptor expression during aging.
doi:10.1177/1073858413519865
PMCID: PMC4317255  PMID: 24510074
estrogen; aging; memory; hippocampus; estrogen receptor-alpha (ERα)
13.  Role of antioxidant enzymes in redox regulation of NMDAR function and memory in middle-age rats 
Neurobiology of aging  2013;35(6):1459-1468.
Overexpression of superoxide dismutase 1 (SOD1) in the hippocampus results in age-dependent impaired cognition and altered synaptic plasticity suggesting a possible model for examining the role of oxidative stress in senescent neurophysiology. However, it is unclear if SOD1 overexpression involves an altered redox environment and a decrease in N-methyl-D-aspartate receptor (NMDAR) synaptic function reported for aging animals. Viral vectors were used to express SOD1 and green fluorescent protein (SOD1+GFP), SOD1 and catalase (SOD1+CAT), or GFP alone in the hippocampus of middle-age (17 mo) male Fischer 344 rats. We confirm that SOD1+GFP and SOD1+CAT reduced lipid peroxidation indicating superoxide metabolites were primarily responsible for lipid peroxidation. SOD1+GFP impaired learning, decreased glutathione peroxidase (GPx) activity, decreased glutathione (GSH) levels, decreased NMDAR-mediated synaptic responses, and impaired long-term potentiation (LTP). Co-expression of SOD1+CAT rescued the effects of SOD1 expression on learning, redox measures, and synaptic function suggesting the effects were mediated by excess hydrogen peroxide. Application of the reducing agent dithiolthreitol (DTT) to hippocampal slices increased the NMDAR-mediated component of the synaptic response in SOD1+GFP animals relative to animals that overexpress SOD1+CAT indicating that the effect of antioxidant enzyme expression on NMDAR function was due to a shift in the redox environment. The results suggest that overexpression of neuronal SOD1 and CAT in middle-age may provide a model for examining the role of oxidative stress in senescent physiology and the progression of age-related neurodegenerative diseases.
doi:10.1016/j.neurobiolaging.2013.12.002
PMCID: PMC3961498  PMID: 24388786
Aging; superoxide dismutase; catalase; glutathione peroxidase; learning and memory; NMDAR; synaptic plasticity
14.  Interaction of DHPG-LTD and synaptic-LTD at senescent CA3-CA1 hippocampal synapses 
Hippocampus  2014;24(4):466-475.
The susceptibility, but not the magnitude, of long-term depression (LTD) induced by hippocampal CA3-CA1 synaptic activity (synaptic-LTD) increases with advanced age. In contrast, the magnitude of LTD induced by pharmacological activation of CA3-CA1 group I metabotropic glutamate receptors (mGluRs) increases during aging. The present study examined the signaling pathways involved in induction of LTD and the interaction between paired-pulse low frequency stimulation (PP-LFS)-induced synaptic-LTD and group I mGluR selective agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG, 100 µM)-induced DHPG-LTD in hippocampal slices obtained from aged (22–24 mo) male Fischer 344 rats. Prior induction of synaptic-LTD did not affect induction of DHPG-LTD; however, prior induction of the DHPG-LTD occluded synaptic-LTD suggesting that expression of DHPG-LTD may incorporate synaptic-LTD mechanisms. Application of individual antagonist for the group I mGluR (AIDA), the N-methyl-D-aspartate receptor (NMDAR) (AP-5), or L-type voltage-dependent Ca2+ channel (VDCC) (nifedipine) failed to block synaptic-LTD and any two antagonists severely impaired synaptic-LTD induction, indicating that activation of any two mechanisms is sufficient to induce synaptic-LTD in aged animals. For DHPG-LTD, AIDA blocked DHPG-LTD and individually applied NMDAR or VDCC attenuated but did not block DHPG-LTD, indicating that the magnitude of DHPG-LTD depends on all three mechanisms.
doi:10.1002/hipo.22240
PMCID: PMC3959216  PMID: 24390964
Aging; calcium; mGluR; NMDA receptors; VDCC; DHPG; synaptic plasticity; long-term depression
15.  Linking Redox Regulation of NMDAR Synaptic Function to Cognitive Decline during Aging 
The Journal of Neuroscience  2013;33(40):15710-15715.
NMDA receptors (NMDARs) play a critical role in learning and memory; however, there is a lack of evidence for a direct relationship between a well characterized decline in NMDAR function and impaired cognition during aging. The present study was designed to test the idea that a redox-mediated decrease in the NMDAR component of synaptic transmission during aging is related to a specific cognitive phenotype: impaired memory for rapidly acquired novel spatial information. Young and middle-aged male F344 rats were provided 1 d of training on the spatial version of the water maze, and retention was examined 24 h later. The performance of young rats was used as a criterion for classifying middle-aged rats as impaired and unimpaired on the task. Subsequent construction of CA3–CA1 synaptic input–output curves in hippocampal slices confirmed an age-related decrease in synaptic responses, including the NMDAR component of synaptic transmission. Examination of synaptic transmission according to behavioral classification revealed that animals classified as impaired exhibited a decrease in the total and the NMDAR component of the synaptic response relative to unimpaired animals. Furthermore, bath application of the reducing agent dithiothreitol increased the NMDAR component of the synaptic response to a greater extent in impaired animals relative to unimpaired and young rats. These results provide evidence for a link between the redox-mediated decline in NMDAR function and emergence of an age-related cognitive phenotype, impairment in the rapid acquisition and retention of novel spatial information.
doi:10.1523/JNEUROSCI.2176-13.2013
PMCID: PMC3787496  PMID: 24089479
16.  Altered behavior in experimental cortical dysplasia 
Epilepsia  2011;52(12):2293-2303.
Summary
Purpose
Developmental delay and cognitive impairment are common comorbidities in people with epilepsy associated with malformations of cortical development (MCDs). We studied cognition and behavior in an animal model of diffuse cortical dysplasia (CD), in utero irradiation, using a battery of behavioral tests for neuromuscular and cognitive function.
Methods
Fetal rats were exposed to 2.25 Gy external radiation on embryonic day 17 (E17). At 1 month of age they were tested using an open field task, a grip strength task, a grid walk task, inhibitory avoidance, an object recognition task, and the Morris water maze task.
Key Findings
Rats with CD showed reduced nonlocomotor activity in the open field task and impaired motor coordination for grid walking but normal grip strength. They showed a reduced tendency to recognize novel objects and reduced retention in an inhibitory avoidance task. Water maze testing showed that learning and memory were impaired in irradiated rats for both cue discrimination and spatially oriented tasks. These results demonstrate significant deficits in cortex-and hippocampus-dependent cognitive functions associated with the diffuse abnormalities of cortical and hippocampal development that have been documented in this model.
Significance
This study documents multimodal cognitive deficits associated with CD and can serve as the foundation for future investigations into the mechanisms of and possible therapeutic interventions for this problem.
doi:10.1111/j.1528-1167.2011.03267.x
PMCID: PMC4364520  PMID: 21933180
Comorbidity; Memory; Cognition
17.  Assessing the emergence and reliability of cognitive decline over the life span in Fisher 344 rats using the spatial water maze 
The spatial water maze is routinely used to investigate hippocampal-dependent spatial memory and the biological mechanisms that underlie variability in cognitive decline during aging. The utility of the task for repeated testing in order to examine the trajectory of cognitive decline and to prescreen animals prior to therapeutic interventions maybe limited due to carryover effects of repeated training. The current study examines the role of carryover effects, as well as the reliability of individual differences, in determining age-related impairment on episodic and reference memory versions of the water maze task. Results indicate that impaired acquisition of episodic spatial information emerges in middle-age and the propensity for impairment increases with advancing age. While learning was variable across animals, acquisition deficits for episodic information were reliable across training sessions in middle-age and aged rats. A significant impairment in the 24~h retention of episodic spatial information was observed in aged animals. When animals were trained to the same location (i.e., reference memory), an impairment was limited to the rate of acquisition in aged animals. However, with continued training, all aged animals were able to acquire a reference memory and no age differences were observed in the 24~h retention of a spatial reference memory. Together, the results point to a progressive impairment in episodic spatial memory with advancing age and suggest that tests of episodic spatial memory are reliable and more sensitive than reference memory for detecting cognitive decline.
doi:10.3389/fnagi.2014.00002
PMCID: PMC3896816  PMID: 24478698
aging; F344 rats; hippocampus; episodic memory; reference memory; learning and memory; spatial water maze
18.  Role of Estrogen Receptor α and β in Preserving Hippocampal Function during Aging 
The expression of the ERα and ERβ estrogen receptors in the hippocampus may be important in the etiology of age-related cognitive decline. To examine the role of ERα and ERβ in regulating transcription and learning, ovariectomized wild-type (WT) and ERα and ERβ knockout (KO) mice were used. Hippocampal gene transcription in young ERαKO mice was similar to WT mice 6 h after a single estradiol treatment. In middle-age ERαKO mice, hormone deprivation was associated with a decrease in the expression of select genes associated with the blood–brain barrier; cyclic estradiol treatment increased transcription of these select genes and improved learning in these mice. In contrast to ERαKO mice, ERβKO mice exhibited a basal hippocampal gene profile similar to WT mice treated with estradiol and, in the absence of estradiol treatment, young and middle-age ERβKO mice exhibited preserved learning on the water maze. The preserved memory performance of middle-age ERβKO mice could be reversed by lentiviral delivery of ERβ to the hippocampus. These results suggest that one function of ERβ is to regulate ERα-mediated transcription in the hippocampus. This model is supported by our observations that knockout of ERβ under conditions of low estradiol allowed ERα-mediated transcription. As estradiol levels increased in the absence of ERα, we observed that other mechanisms, likely including ERβ, regulated transcription and maintained hippocampal-dependent memory. Thus, our results indicate that ERα and ERβ interact with hormone levels to regulate transcription involved in maintaining hippocampal function during aging.
doi:10.1523/JNEUROSCI.4937-12.2013
PMCID: PMC3692013  PMID: 23392694
19.  Role of Estrogen Receptor α and β in Preserving Hippocampal Function during Aging 
The Journal of Neuroscience  2013;33(6):2671-2683.
The expression of the ERα and ERβ estrogen receptors in the hippocampus may be important in the etiology of age-related cognitive decline. To examine the role of ERα and ERβ in regulating transcription and learning, ovariectomized wild-type (WT) and ERα and ERβ knockout (KO) mice were used. Hippocampal gene transcription in young ERαKO mice was similar to WT mice 6 h after a single estradiol treatment. In middle-age ERαKO mice, hormone deprivation was associated with a decrease in the expression of select genes associated with the blood–brain barrier; cyclic estradiol treatment increased transcription of these select genes and improved learning in these mice. In contrast to ERαKO mice, ERβKO mice exhibited a basal hippocampal gene profile similar to WT mice treated with estradiol and, in the absence of estradiol treatment, young and middle-age ERβKO mice exhibited preserved learning on the water maze. The preserved memory performance of middle-age ERβKO mice could be reversed by lentiviral delivery of ERβ to the hippocampus. These results suggest that one function of ERβ is to regulate ERα-mediated transcription in the hippocampus. This model is supported by our observations that knockout of ERβ under conditions of low estradiol allowed ERα-mediated transcription. As estradiol levels increased in the absence of ERα, we observed that other mechanisms, likely including ERβ, regulated transcription and maintained hippocampal-dependent memory. Thus, our results indicate that ERα and ERβ interact with hormone levels to regulate transcription involved in maintaining hippocampal function during aging.
doi:10.1523/JNEUROSCI.4937-12.2013
PMCID: PMC3692013  PMID: 23392694
20.  PHLPP1 splice variants differentially regulate AKT and PKCα signaling in hippocampal neurons: characterization of PHLPP proteins in the adult hippocampus 
Journal of neurochemistry  2010;115(4):941-955.
Pleckstrin homology and leucine rich repeat protein phosphatases (PHLPPs) are a novel class of potent protein kinase B (AKT) inhibitors that have been intensely investigated in relation to AKT activity in cancer. Currently, our understanding of the role of PHLPP1α in the central nervous system is limited. In this study, we characterized PHLPP protein expression and target kinases in the adult hippocampus. We directly verify PHLPP1α inhibits AKT in hippocampal neurons and demonstrate a novel role for PHLPP1β/SCOP, to promote AKT activation. PHLPP1α expression changes dramatically in the hippocampus during development, constituting the most abundant PHLPP protein in adult neurons. Further, while all PHLPP proteins could be observed in the cytosolic fraction, only PHLPP1α could be localized to the nucleus. The results provide unique evidence for a divergence in the function of PHLPP1α and PHLPP1β/SCOP, and suggest that PHLPP1α plays a major role in regulating AKT signaling in neurons.
doi:10.1111/j.1471-4159.2010.06984.x
PMCID: PMC3730267  PMID: 20819118
AKT; FOXO3a; hippocampus; PHLPP1; PHLPP2; PKC
21.  Role of Estrogen Receptor Alpha and Beta Expression and Signaling on Cognitive Function During Aging 
Hippocampus  2011;22(4):656-669.
This review presents evidence for the idea that the expression of estrogen receptor alpha and beta (ERα and ERβ) interacts with the level of estradiol (E2) to influence the etiology of age-related cognitive decline and responsiveness to E2 treatments. There is a nonmonotonic dose response curve for E2 influences on behavior and transcription. Evidence is mounting to indicate that the dose response curve is shifted according to the relative expression of ERα and ERβ. Recent work characterizing age-related changes in the expression of ERα and ERβ in the hippocampus, as well as studies using mutant mice, and viral mediated delivery of estrogen receptors indicate that an age-related shift in ERα/ERβ expression, combined with declining gonadal E2 can impact transcription, cell signaling, neuroprotection, and neuronal growth. Finally, the role of ERα/ERβ on rapid E2 signaling and synaptogenesis as it relates to hippocampal aging is discussed.
doi:10.1002/hipo.20935
PMCID: PMC3704216  PMID: 21538657
estradiol; hippocampus; memory; transcription; synaptogenesis
22.  Influence of Viral Vector–Mediated Delivery of Superoxide Dismutase and Catalase to the Hippocampus on Spatial Learning and Memory During Aging 
Antioxidants & Redox Signaling  2012;16(4):339-350.
Abstract
Aims: Studies employing transgenic mice indicate that overexpression of superoxide dismutase 1 (SOD1) improves memory during aging. It is unclear whether the improvement is due to a lifetime of overexpression, decreasing the accumulation of oxidized molecules, or if increasing antioxidant enzymes in older animals could reduce oxidative damage and improve cognitive function. We used adeno-associated virus to deliver antioxidant enzymes (SOD1, SOD2, catalase [CAT], and SOD1+CAT) to the hippocampus of young (4 months) and aged (19 months) F344/BN F1 male rats and examined memory-related behavioral performance 1 month and 4 months postinjection. Results: Overexpression of antioxidant enzymes reduced oxidative damage; however, memory function was not related to the level of oxidative damage. Increased expression of SOD1, initiated in advanced age, impaired learning. Increased expression of SOD1+CAT provided protection from impairments associated with overexpression of SOD1 alone and appears to guard against cognitive impairments in advanced age. Innovation: Viral vector gene delivery provides a novel approach to test the hypothesis that increased expression of antioxidant enzymes, specifically in hippocampal neurons, will provide protection from age-related cognitive decline. Further, expression of multiple vectors permits more detailed investigation of mechanistic pathways. Conclusion: Oxidative stress is a likely component of aging; however, it is unclear whether increased production of reactive oxygen species or the accumulation of oxidative damage is the primary cause of functional decline. The results provide support for the idea that altered redox-sensitive signaling rather than the accumulation of damage may be of greater significance in the emergence of age-related learning and memory deficits. Antioxid. Redox Signal. 16, 339–350.
doi:10.1089/ars.2011.4054
PMCID: PMC3246419  PMID: 21942371
23.  Characterizing cognitive aging of spatial and contextual memory in animal models 
Episodic memory, especially memory for contextual or spatial information, is particularly vulnerable to age-related decline in humans and animal models of aging. The continuing improvement of virtual environment technology for testing humans signifies that widely used procedures employed in the animal literature for examining spatial memory could be developed for examining age-related cognitive decline in humans. The current review examines cross species considerations for implementing these tasks and translating findings across different levels of analysis. The specificity of brain systems as well as gaps in linking human and animal laboratory models is discussed.
doi:10.3389/fnagi.2012.00012
PMCID: PMC3439636  PMID: 22988436
spatial; contextual; memory; aging; hippocampus
24.  Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats 
We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18 mo upon arrival). Twelve weeks after conditioned running or control group assignment (n = 6 per group), the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12 days after behavioral testing and killed 3 weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24 h water maze discrimination index (DI) scores and 24 h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found a novel positive correlation between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling.
doi:10.1016/j.bbi.2012.09.013
PMCID: PMC3545095  PMID: 23078985
adult neurogenesis; hippocampus; running; cytokine; chemokine; biomarker; learning; memory; water maze; Fisher 344; Bio-Plex
25.  AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis 
Human Gene Therapy  2012;24(2):189-202.
Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1). GUCY2D encodes photoreceptor-specific, retinal guanylate cyclase-1 (RetGC1). Reports of retinal degeneration in LCA1 are conflicting; some describe no obvious degeneration and others report loss of both rods and cones. Proof of concept studies in models representing the spectrum of phenotypes is warranted. We have previously demonstrated adeno-associated virus (AAV)-mediated RetGC1 is therapeutic in GC1ko mice, a model exhibiting loss of cones only. The purpose of this study was to characterize AAV-mediated gene therapy in the RetGC1/RetGC2 double knockout (GCdko) mouse, a model lacking rod and cone function and exhibiting progressive loss of both photoreceptor subclasses. Use of this model also allowed for the evaluation of the functional efficiency of transgenic RetGC1 isozyme. Subretinal delivery of AAV8(Y733F) vector containing the human rhodopsin kinase (hGRK1) promoter driving murine Gucy2e was performed in GCdko mice at various postnatal time points. Treatment resulted in restoration of rod and cone function at all treatment ages and preservation of retinal structure in GCdko mice treated as late as 7 weeks of age. Functional gains and structural preservation were stable for at least 1 year. Treatment also conferred cortical- and subcortical-based visually-guided behavior. Functional efficiency of transgenic RetGC1 was indistinguishable from that of endogenous isozyme in congenic wild-type (WT) mice. This study clearly demonstrates AAV-mediated RetGC1 expression restores function to and preserves structure of rod and cone photoreceptors in a degenerative model of retinal guanylate cyclase deficiency, further supporting development of an AAV-based vector for treatment of LCA1.
Boye and colleagues report that subretinal injection of AAV8 vector carrying the murine retinal guanylate cyclase-1 gene results in restoration of rod and cone function in a mouse model of Leber congenital amaurosis (LCA). Correction was seen at all treatment ages, with functional gains and structural preservation stable for at least 1 year.
doi:10.1089/hum.2012.193
PMCID: PMC3581260  PMID: 23210611

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