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1.  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.
PMCID: PMC4317255  PMID: 24510074
estrogen; aging; memory; hippocampus; estrogen receptor-alpha (ERα)
2.  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.
PMCID: PMC3961498  PMID: 24388786
Aging; superoxide dismutase; catalase; glutathione peroxidase; learning and memory; NMDAR; synaptic plasticity
3.  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.
PMCID: PMC3787496  PMID: 24089479
4.  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.
PMCID: PMC3959216  PMID: 24390964
Aging; calcium; mGluR; NMDA receptors; VDCC; DHPG; synaptic plasticity; long-term depression
5.  Altered behavior in experimental cortical dysplasia 
Epilepsia  2011;52(12):2293-2303.
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.
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.
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.
PMCID: PMC4364520  PMID: 21933180
Comorbidity; Memory; Cognition
6.  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.
PMCID: PMC3896816  PMID: 24478698
aging; F344 rats; hippocampus; episodic memory; reference memory; learning and memory; spatial water maze
7.  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.
PMCID: PMC3692013  PMID: 23392694
8.  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.
PMCID: PMC3692013  PMID: 23392694
9.  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.
PMCID: PMC3730267  PMID: 20819118
AKT; FOXO3a; hippocampus; PHLPP1; PHLPP2; PKC
10.  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.
PMCID: PMC3704216  PMID: 21538657
estradiol; hippocampus; memory; transcription; synaptogenesis
11.  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.
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.
PMCID: PMC3246419  PMID: 21942371
12.  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.
PMCID: PMC3439636  PMID: 22988436
spatial; contextual; memory; aging; hippocampus
13.  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.
PMCID: PMC3545095  PMID: 23078985
adult neurogenesis; hippocampus; running; cytokine; chemokine; biomarker; learning; memory; water maze; Fisher 344; Bio-Plex
14.  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.
PMCID: PMC3581260  PMID: 23210611
15.  Environmental enrichment restores neurogenesis and rapid acquisition in aged rats 
Neurobiology of aging  2012;34(1):263-274.
Strategies combatting cognitive decline among the growing aging population are vital. We tested whether environmental enrichment could reverse age-impaired rapid spatial search strategy acquisition concomitantly with hippocampal neurogenesis in rats. Young (5–8 mo) and aged (20–22 mo) male Fischer 344 rats were pair-housed and exposed to environmental enrichment (n=7 young, 9 aged) or housed individually (n=7 young, 7 aged) for ten weeks. After five weeks, hidden platform trials (5 blocks of 3 trials; 15m IBI), a probe trial, and then visible platform trials (5 blocks of 3 trials; 15m IBI) commenced in the water maze. One week after testing, rats were given 5 daily bromodeoxyuridine (BrdU, 50mg/kg; i.p.) injections and perfused 4 weeks later to quantify neurogenesis. Although young rats outperformed aged rats, aged enriched rats outperformed aged individually-housed rats on all behavioral measures. Neurogenesis decreased with age but enrichment enhanced new cell survival, regardless of age. The novel correlation between new neuron number and behavioral measures obtained in a rapid water maze task among aged rats, suggests that environmental enrichment increases their ability to rapidly acquire and flexibly use spatial information along with neurogenesis.
PMCID: PMC3480541  PMID: 22795793
adult neurogenesis; learning; memory; enrichment; water maze; age-related; Fisher 344; neural progenitor cell; hippocampus
16.  Intracellular Redox State Alters N-Methyl D-Aspartate Receptor Response during Aging through Ca2+/Calmodulin-Dependent Protein Kinase II 
The contribution of the N-methyl D-aspartate receptors (NMDARs) to synaptic plasticity declines during aging and the decline is thought to contribute to memory deficits. Here, we demonstrate that an age-related shift in intracellular redox state contributes to the decline in NMDAR responses through Ca2+/calmodulin-dependent protein kinase II (CaMKII). The oxidizing agent xanthine/xanthine oxidase (X/XO) decreased the NMDAR mediated synaptic responses at hippocampal CA3-CA1 synapses in slices from young (3–8 mo), but not aged (20–25 mo) rats. Conversely, the reducing agent dithiothreitol (DTT) selectively enhanced NMDAR response to a greater extent in aged hippocampal slices. The enhancement of NMDAR responses facilitated induction of long-term potentiation (LTP) in aged but not young animals. The DTT-mediated growth in the NMDAR response was not observed for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) mediated synaptic responses. A similar increase was observed by intracellular application of the membrane impermeable reducing agent, L-glutathione (L-GSH), through the intracellular recording pipette, indicating the increased NMDAR response was dependent on intracellular redox state. DTT enhancement of the NMDAR response was dependent on CaMKII activity and was blocked by the CaMKII inhibitor – myristoylated autocamtide-2 related inhibitory peptide (myr-AIP), but not by inhibition of the activity of protein phosphatases - PP1 and calcineurin (CaN/PP2B) or protein kinase C. CaMKII activity assays established that DTT increased CaMKII activity in CA1 cytosolic extracts in aged but not in young animals. These findings indicate a link between oxidation of CaMKII during aging, a decline in NMDAR responses, and altered synaptic plasticity.
PMCID: PMC2853968  PMID: 20130200
NMDA receptor; aging; hippocampus; ROS; oxidative stress; CaMKII; long-term potentiation
17.  Regional Health and Function in the hippocampus: Evolutionary compromises for a critical brain region 
Bioscience hypotheses  2009;2(4):245-251.
The hippocampus is especially vulnerable to damage caused by metabolic dysregulation. However distinct sub-regions within the hippocampus differ by their relative susceptibility to such damage. Region CA1 pyramidal neurons are most sensitive to metabolic perturbations while region CA3 pyramidal neurons show more resistance, and these unique profiles of susceptibility are but one example that differentiates CA1/CA3 neurons. We present here a hypothesis that inextricably links the unique biochemistries of learning and memory in region CA1, to that of cell survival signaling, and in so doing, suggest an explanation for region CA1 susceptibility to metabolic dysfunction. Further, we propose a signaling mechanism to explain how both pathways can be simultaneously regulated. Critical to this process is the protein phosphatase PHLPP1. Finally we discuss the implications of this hypothesis and the inherent challenges it poses for treatment of neurological disorders resulting in reduced hippocampal function by increased neuron death.
PMCID: PMC2713439  PMID: 20161206
18.  Comparison of lifelong and late life exercise on oxidative stress in the cerebellum 
Neurobiology of aging  2007;30(6):903-909.
Aging was associated with increased oxidation of DNA, RNA, and lipids in the cerebellum of male rats. DNA and lipid oxidation was reduced by lifelong (94 weeks) voluntary exercise on a running wheel. A reduction in cerebellar lipid oxidation, but not RNA or DNA oxidation, was observed following 3 months of moderate exercise or dietary supplementation of vitamin E, initiated at 18 months of age. The level of lipid oxidation correlated with measures of forelimb grip strength. The results indicate that lifelong exercise attenuates multiple molecular markers of age-related oxidative damage in the cerebellum. In addition, modest exercise initiated late in life can have a beneficial effect on lipid oxidation and motor function.
PMCID: PMC2695411  PMID: 17976863
aging; cerebellum; voluntary exercise; nucleic acid oxidation; lipid peroxidation; rat
19.  Estrogen effects on cognition and hippocampal transcription in middle-aged mice 
Neurobiology of aging  2007;30(6):932-945.
Young and middle-aged female mice were ovariectomized and given cyclic injections of either estradiol or vehicle treatments. During the fifth week after surgery the Morris water maze was used to assess cognitive function. Age and treatment effects emerged over the course of spatial training such that middle-aged vehicle treated mice exhibited deficits in acquiring a spatial search strategy compared to younger vehicle treated mice and middle-age estradiol treated mice. Following behavioral characterization, mice were maintained on their injection schedule until week seven and hippocampi were collected 24 hr after the last injection. Hippocampal RNA was extracted and genes responsive to age and estrogen were identified using cDNA microarrays. Estradiol treatment in middle-aged mice altered the expression of genes related to transcriptional regulation, biosynthesis, growth, neuroprotection, and elements of cell signaling pathways. Expression profiles for representative genes were confirmed in a separate set of animals using oligonucleotide arrays and RT-PCR. Our results indicate that estrogen treatment in middle-aged animals may promote hippocampal health during the aging process.
PMCID: PMC2730158  PMID: 17950954
Estrogen; estradiol; hippocampus; ageing; microarray
20.  Regional hippocampal differences in AKT survival signaling across the lifespan: Implications for CA1 vulnerability with aging 
Cell death and differentiation  2008;16(3):439-448.
Distinct neuronal populations differ by the degree of damage caused from cellular stress. Hippocampal neurons of area CA1 are especially vulnerable to several stressors that increase with advanced age. We show here that survival signaling, as measured by activated AKT, was significantly reduced in the nuclear CA1 region across the lifespan compared to CA3. In agreement with these findings the pro-apoptotic protein, and AKT nuclear substrate, FOXO3a was significantly higher in CA1. Further, regional differences in PHLPP1, a recently discovered inhibitor of AKT, inversely correlated with nuclear phosphorylated AKT at Ser473. Together our data suggest that regional differences in nuclear levels of activated AKT may contribute to regional differences in hippocampal vulnerability, and implicate PHLPP1 as a potential target for therapeutic intervention to improve hippocampal health.
PMCID: PMC2680608  PMID: 19039330
21.  Muscleblind-Like 2 Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy 
Neuron  2012;75(3):437-450.
The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs which disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated CNS features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDAR synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, mis-regulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly mis-regulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.
PMCID: PMC3418517  PMID: 22884328
22.  Viral Vector–mediated Delivery of Estrogen Receptor-α to the Hippocampus Improves Spatial Learning in Estrogen Receptor-α Knockout Mice 
Estrogen, which influences both classical genomic and rapid membrane-associated signaling cascades, has been implicated in the regulation of hippocampal function, including spatial learning. Gene mutation studies suggest that estrogen effects are mediated by estrogen receptor-α (ER-α); however, because gonadal steroids influence the organization of the hippocampus during development, it has been difficult to distinguish developmental effects from those specific to adults. In this study we show that lentiviral delivery of the gene encoding ER-α to the hippocampus of adult ER-α-knockout (ER-αKO) mice restores hippocampal responsiveness to estrogen and rescues spatial learning. We propose that constitutive estrogen receptor activity is important for maintaining hippocampus-dependent memory function in adults.
PMCID: PMC2638757  PMID: 18594506
23.  Behavioral Model for Assessing Cognitive Decline 
The water maze task can be used to assess sensory motor and cognitive function in rodents. When properly employed, this task can behaviorally assess acquisition of a spatial search strategy, as well as working and reference memory. The following section uses research on age-related, cognitive decline to illustrate the methods employed and highlight areas that can, if not properly controlled, confound a study.
PMCID: PMC3704044  PMID: 22231811
Spatial water maze; Hippocampus; Memory; Sensory motor; Stress
24.  Session III: Mechanisms of Age-Related Cognitive Change and Targets for Intervention: Inflammatory, Oxidative, and Metabolic Processes 
There is increasing evidence from basic science and human epidemiological studies that inflammation, oxidative stress, and metabolic abnormalities are associated with age-related cognitive decline and impairment. This article summarizes selected research on these topics presented at the Cognitive Aging Summit II. Speakers in this session presented evidence highlighting the roles of these processes and pathways on age-related cognitive decline, pointing to possible targets for intervention in nondemented older adults. Specific areas discussed included age differences in the production of cytokines following injury or infection, mechanisms underlying oxidative stress-induced changes in memory consolidation, insulin effects on brain signaling and memory, and the association between metabolic syndrome and cognitive decline in older adults. These presentations emphasize advances in our understanding of mechanisms and modifiers of age-related cognitive decline and provide insights into potential targets to promote cognitive health in older adults.
PMCID: PMC3536547  PMID: 22570133
Aging; Cognition; Inflammation; Oxidative stress; Metabolism
25.  Enhanced Expression of Pctk1, Tcf12 and Ccnd1 in Hippocampus of Rats: Impact on Cognitive Function, Synaptic Plasticity and Pathology 
We previously identified a set of 50 genes that were differentially transcribed in the hippocampal CA1 region of aged, learning-impaired rats compared to aged, superior learning animals during a Morris water maze paradigm. In the current study we expressed three of these genes (Pctk1, Tcf12 and Ccnd1), which had shown increased transcription in aged, learning impaired rats, in the hippocampus of young rats using viral gene transfer and tested for learning and memory deficits at age 7–14 months. Pctk1 injected animals displayed a modest deficit in acquiring latency in both the Morris Water Maze and the reverse Morris maze. In the radial arm water maze paradigm, Pctk1, Tcf12 and Ccnd1 expressing animals all showed significant deficits in spatial working memory compared to controls. Rats injected with Ccnd1 and Tcf12, but not Pctk1, also showed a significant deficit in spatial reference memory in the radial arm water maze. Electrophysiological experiments revealed no difference in LTP in Ccnd1 and Pctk1 animals. However, LTD induced by low frequency stimulation was observed in control and Ccnd1 animals, but not in Pctk1 treated animals. In addition, neither Ccnd1 nor Pctk1 expression produced any detectable neuropathology. In contrast Tcf12 expressing animals displayed significant neurodegeneration in both CA1 and dentate gyrus. Several Tcf12 animals also developed tumors that appeared to be glioblastomas, suggesting that aberrant Tcf12 expression in the hippocampus is tumorigenic. Thus, behavioral experiments suggested that overexpression of Pctk1 and Ccnd1 produce a deficit in learning and memory, but electrophysiological experiments do not point to a simple mechanism. In contrast, the learning and memory deficits in Tcf12 animals are likely due to neuropathology associated with Tcf12 gene expression.
PMCID: PMC3694440  PMID: 21982980

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