Contact
Biomedical Research Center251 Bayview Boulevard
Baltimore, MD 21224
Education
Ph.D. - Neuroscience, University of Lethbridge
Research Interests
Dr. Keeley received her Ph.D. in Neuroscience in 2014 from the University of Lethbridge, in Lethbridge, Alberta, Canada, working with Dr. Robert McDonald. Dr. Keeley began her postdoctoral training in February 2015, under the supervision of Dr. Yihong Yang, working in the preclinical branch of the NRB.
Projects: Currently, Dr. Keeley is working to understand the effects of adolescent nicotine exposure on adult functional connectivity in brain areas related to addiction. She is approaching this problem using both behavioural and neuroimaging techniques.
Dr. Keeley is interested in understanding the neurological causes and correlates of adolescent drug use. She is specifically interested in understanding how adolescent drug use changes our brain in the long-term, increasing the likelihood of engaging in other risky behaviors as adults, including continued drug use. Dr. Keeley has a strong background in behavioral neuroscience but has recently embraced the potential of neuroimaging techniques.
Publications
Selected Publications
2016
Deibel, S H; Weishaupt, N; Regis, A M; Hong, N S; Keeley, R J; Balog, R J; Bye, C M; Himmler, S M; Whitehead, S N; McDonald, R J
Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and beta-amyloid. Journal Article
In: Brain Res, vol. 1646, pp. 12–24, 2016, ISSN: 1872-6240 (Electronic); 0006-8993 (Linking).
@article{Deibel2016,
title = {Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and beta-amyloid.},
author = {S H Deibel and N Weishaupt and A M Regis and N S Hong and R J Keeley and R J Balog and C M Bye and S M Himmler and S N Whitehead and R J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27208489},
doi = {10.1016/j.brainres.2016.05.033},
issn = {1872-6240 (Electronic); 0006-8993 (Linking)},
year = {2016},
date = {2016-05-18},
journal = {Brain Res},
volume = {1646},
pages = {12--24},
address = {Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Alberta, Canada. Electronic address: deibel@uleth.ca.},
abstract = {Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Abeta) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Abeta25-35 injections, or both cholinergic depletion and Abeta25-35 injections (Abeta+ACh group). The Abeta+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Abeta+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Abeta. These data suggest that cholinergic depletions and Abeta injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Abeta) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Abeta25-35 injections, or both cholinergic depletion and Abeta25-35 injections (Abeta+ACh group). The Abeta+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Abeta+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Abeta. These data suggest that cholinergic depletions and Abeta injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology.
2015
Deibel, Scott H; Zelinski, Erin L; Keeley, Robin J; Kovalchuk, Olga; McDonald, Robert J
Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline. Journal Article
In: Oncotarget, vol. 6, no. 27, pp. 23181–23203, 2015, ISSN: 1949-2553 (Electronic); 1949-2553 (Linking).
@article{Deibel2015,
title = {Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline.},
author = {Scott H Deibel and Erin L Zelinski and Robin J Keeley and Olga Kovalchuk and Robert J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26252151},
doi = {10.18632/oncotarget.4036},
issn = {1949-2553 (Electronic); 1949-2553 (Linking)},
year = {2015},
date = {2015-09-15},
journal = {Oncotarget},
volume = {6},
number = {27},
pages = {23181--23203},
address = {Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada.},
abstract = {Circadian rhythm dysfunction and cognitive decline, specifically memory loss, frequently accompany natural aging. Circadian rhythms and memory are intertwined, as circadian rhythms influence memory formation and recall in young and old rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which occurs during aging, contributes to age-associated cognitive decline, specifically memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Circadian rhythm dysfunction and cognitive decline, specifically memory loss, frequently accompany natural aging. Circadian rhythms and memory are intertwined, as circadian rhythms influence memory formation and recall in young and old rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which occurs during aging, contributes to age-associated cognitive decline, specifically memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline.
Keeley, R J; Trow, J; McDonald, R J
Strain and sex differences in puberty onset and the effects of THC administration on weight gain and brain volumes. Journal Article
In: Neuroscience, vol. 305, pp. 328–342, 2015, ISSN: 1873-7544 (Electronic); 0306-4522 (Linking).
@article{Keeley2015,
title = {Strain and sex differences in puberty onset and the effects of THC administration on weight gain and brain volumes.},
author = {R J Keeley and J Trow and R J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26186896},
doi = {10.1016/j.neuroscience.2015.07.024},
issn = {1873-7544 (Electronic); 0306-4522 (Linking)},
year = {2015},
date = {2015-07-14},
journal = {Neuroscience},
volume = {305},
pages = {328--342},
address = {University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada. Electronic address: rj.keeley@uleth.ca.},
abstract = {The use of recreational marijuana is widespread and frequently begins and persists through adolescence. Some research has shown negative consequences of adolescent marijuana use, but this is not seen across studies, and certain factors, like genetic background and sex, may influence the results. It is critical to identify which characteristics predispose an individual to be susceptible to the negative consequences of chronic exposure to marijuana in adolescence on brain health and behavior. To this end, using males and females of two strains of rats, Long-Evans hooded (LER) and Wistar (WR) rats, we explored whether these anatomically and behaviorally dimorphic strains demonstrated differences in puberty onset and strain-specific effects of adolescent exposure to Delta9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. Daily 5 mg/kg treatment began on the day of puberty onset and continued for 14 days. Of particular interest were metrics of growth and volumetric estimates of brain areas involved in cognition that contain high densities of cannabinoid receptors, including the hippocampus and its subregions, the amygdala, and the frontal cortex. Brain volumetrics were analyzed immediately following the treatment period. LER and WR females started puberty at different ages, but no strain differences were observed in brain volumes. THC decreased weight gain throughout the treatment period for all groups. Only the hippocampus and some of its subregions were affected by THC, and increased volumes with THC administration was observed exclusively in females, regardless of strain. Long-term treatment of THC did not affect all individuals equally, and females displayed evidence of increased sensitivity to the effects of THC, and by extension, marijuana. Identifying differences in adolescent physiology of WR and LER rats could help determine the cause for strain and sex differences in brain and behavior of adults and help to refine the use of animal models in marijuana research.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The use of recreational marijuana is widespread and frequently begins and persists through adolescence. Some research has shown negative consequences of adolescent marijuana use, but this is not seen across studies, and certain factors, like genetic background and sex, may influence the results. It is critical to identify which characteristics predispose an individual to be susceptible to the negative consequences of chronic exposure to marijuana in adolescence on brain health and behavior. To this end, using males and females of two strains of rats, Long-Evans hooded (LER) and Wistar (WR) rats, we explored whether these anatomically and behaviorally dimorphic strains demonstrated differences in puberty onset and strain-specific effects of adolescent exposure to Delta9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. Daily 5 mg/kg treatment began on the day of puberty onset and continued for 14 days. Of particular interest were metrics of growth and volumetric estimates of brain areas involved in cognition that contain high densities of cannabinoid receptors, including the hippocampus and its subregions, the amygdala, and the frontal cortex. Brain volumetrics were analyzed immediately following the treatment period. LER and WR females started puberty at different ages, but no strain differences were observed in brain volumes. THC decreased weight gain throughout the treatment period for all groups. Only the hippocampus and some of its subregions were affected by THC, and increased volumes with THC administration was observed exclusively in females, regardless of strain. Long-term treatment of THC did not affect all individuals equally, and females displayed evidence of increased sensitivity to the effects of THC, and by extension, marijuana. Identifying differences in adolescent physiology of WR and LER rats could help determine the cause for strain and sex differences in brain and behavior of adults and help to refine the use of animal models in marijuana research.
Keeley, R J; McDonald, R J
Part III: Principal component analysis: bridging the gap between strain, sex and drug effects. Journal Article
In: Behav Brain Res, vol. 288, pp. 153–161, 2015, ISSN: 1872-7549 (Electronic); 0166-4328 (Linking).
@article{Keeley2015b,
title = {Part III: Principal component analysis: bridging the gap between strain, sex and drug effects.},
author = {R J Keeley and R J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25813745},
doi = {10.1016/j.bbr.2015.03.027},
issn = {1872-7549 (Electronic); 0166-4328 (Linking)},
year = {2015},
date = {2015-03-23},
journal = {Behav Brain Res},
volume = {288},
pages = {153--161},
address = {University of Lethbridge, 4001 University Drive, Lethbridge, AB T1K 3M4, Canada. Electronic address: rj.keeley@uleth.ca.},
abstract = {Previous work has identified the adolescent period as particularly sensitive to the short- and long-term effects of marijuana and its main psychoactive component Delta9-tetrahydrocannabinol (THC). However, other studies have identified certain backgrounds as more sensitive than others, including the sex of the individual or the strain of the rat used. Further, the effects of THC may be specific to certain behavioural tasks (e.g. measures of anxiety), and the consequences of THC are not seen equally across all behavioural measures. Here, data obtained from adolescent male and female Long-Evans and Wistar rats exposed to THC and tested as adults, which, using standard ANOVA testing, showed strain- and sex-specific effects of THC, was analyzed using principal component analysis (PCA). PCA allowed for the examination of the relative contribution of our variables of interest to the variance in the data obtained from multiple behavioural tasks, including the skilled reaching task, the Morris water task, the discriminative fear-conditioning to context task, the elevated plus maze task and the conditioned place preference task to a low dose of amphetamine, as well as volumetric estimates of brain volumes and cfos activation. We observed that early life experience accounted for a large proportion of variance across data sets, although its relative contribution varied across tasks. Additionally, THC accounted for a very small proportion of the variance across all behavioural tasks. We demonstrate here that by using PCA, we were able to describe the main variables of interest and demonstrate that THC exposure had a negligible effect on the variance in the data set.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Previous work has identified the adolescent period as particularly sensitive to the short- and long-term effects of marijuana and its main psychoactive component Delta9-tetrahydrocannabinol (THC). However, other studies have identified certain backgrounds as more sensitive than others, including the sex of the individual or the strain of the rat used. Further, the effects of THC may be specific to certain behavioural tasks (e.g. measures of anxiety), and the consequences of THC are not seen equally across all behavioural measures. Here, data obtained from adolescent male and female Long-Evans and Wistar rats exposed to THC and tested as adults, which, using standard ANOVA testing, showed strain- and sex-specific effects of THC, was analyzed using principal component analysis (PCA). PCA allowed for the examination of the relative contribution of our variables of interest to the variance in the data obtained from multiple behavioural tasks, including the skilled reaching task, the Morris water task, the discriminative fear-conditioning to context task, the elevated plus maze task and the conditioned place preference task to a low dose of amphetamine, as well as volumetric estimates of brain volumes and cfos activation. We observed that early life experience accounted for a large proportion of variance across data sets, although its relative contribution varied across tasks. Additionally, THC accounted for a very small proportion of the variance across all behavioural tasks. We demonstrate here that by using PCA, we were able to describe the main variables of interest and demonstrate that THC exposure had a negligible effect on the variance in the data set.
Keeley, R J; Burger, D K; Saucier, D M; Iwaniuk, A N
The size of non-hippocampal brain regions varies by season and sex in Richardson's ground squirrel. Journal Article
In: Neuroscience, vol. 289, pp. 194–206, 2015, ISSN: 1873-7544 (Electronic); 0306-4522 (Linking).
@article{Keeley2015e,
title = {The size of non-hippocampal brain regions varies by season and sex in Richardson's ground squirrel.},
author = {R J Keeley and D K Burger and D M Saucier and A N Iwaniuk},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25595988},
doi = {10.1016/j.neuroscience.2014.12.077},
issn = {1873-7544 (Electronic); 0306-4522 (Linking)},
year = {2015},
date = {2015-01-13},
journal = {Neuroscience},
volume = {289},
pages = {194--206},
address = {Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada. Electronic address: rj.keeley@uleth.ca.},
abstract = {Sex- and season-specific modulation of hippocampal size and function is observed across multiple species, including rodents. Other non-hippocampal-dependent behaviors exhibit season and sex differences, and whether the associated brain regions exhibit similar variation with sex and season remains to be fully characterized. As such, we examined the brains of wild-caught Richardson's ground squirrels (RGS; Urocitellus richardsonii) for seasonal (breeding, non-breeding) and sex differences in the volumes of specific brain areas, including: total brain volume, corpus callosum (CC), anterior commissure (AC), medial prefrontal cortex (mPFC), total neocortex (NC), entorhinal cortex (EC), and superior colliculus (SC). Analyses of variance and covariance revealed significant interactions between season and sex for almost all areas studied, primarily resulting from females captured during the breeding season exhibiting larger volumes than females captured during the non-breeding season. This was observed for volumes of the AC, mPFC, NC, EC, and SC. Where simple main effects of season were observed for males (the NC and the SC), the volume advantage favoured males captured during the NBr season. Only two simple main effects of sex were observed: males captured in the non-breeding season had significantly larger total brain volume than females captured in the non-breeding season, and females captured during the breeding season had larger volumes of the mPFC and EC than males captured in the breeding season. These results indicate that females have more pronounced seasonal differences in brain and brain region sizes. The extent to which seasonal differences in brain region volumes vary with behaviour is unclear, but our data do suggest that seasonal plasticity is not limited to the hippocampus and that RGS is a useful mammalian species for understanding seasonal plasticity in an ecologically relevant context.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sex- and season-specific modulation of hippocampal size and function is observed across multiple species, including rodents. Other non-hippocampal-dependent behaviors exhibit season and sex differences, and whether the associated brain regions exhibit similar variation with sex and season remains to be fully characterized. As such, we examined the brains of wild-caught Richardson's ground squirrels (RGS; Urocitellus richardsonii) for seasonal (breeding, non-breeding) and sex differences in the volumes of specific brain areas, including: total brain volume, corpus callosum (CC), anterior commissure (AC), medial prefrontal cortex (mPFC), total neocortex (NC), entorhinal cortex (EC), and superior colliculus (SC). Analyses of variance and covariance revealed significant interactions between season and sex for almost all areas studied, primarily resulting from females captured during the breeding season exhibiting larger volumes than females captured during the non-breeding season. This was observed for volumes of the AC, mPFC, NC, EC, and SC. Where simple main effects of season were observed for males (the NC and the SC), the volume advantage favoured males captured during the NBr season. Only two simple main effects of sex were observed: males captured in the non-breeding season had significantly larger total brain volume than females captured in the non-breeding season, and females captured during the breeding season had larger volumes of the mPFC and EC than males captured in the breeding season. These results indicate that females have more pronounced seasonal differences in brain and brain region sizes. The extent to which seasonal differences in brain region volumes vary with behaviour is unclear, but our data do suggest that seasonal plasticity is not limited to the hippocampus and that RGS is a useful mammalian species for understanding seasonal plasticity in an ecologically relevant context.
Keeley, R J; Trow, J; Bye, C; McDonald, R J
In: Behav Brain Res, vol. 288, pp. 132–152, 2015, ISSN: 1872-7549 (Electronic); 0166-4328 (Linking).
@article{Keeley2015c,
title = {Part II: Strain- and sex-specific effects of adolescent exposure to THC on adult brain and behaviour: Variants of learning, anxiety and volumetric estimates.},
author = {R J Keeley and J Trow and C Bye and R J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25591471},
doi = {10.1016/j.bbr.2015.01.001},
issn = {1872-7549 (Electronic); 0166-4328 (Linking)},
year = {2015},
date = {2015-01-12},
journal = {Behav Brain Res},
volume = {288},
pages = {132--152},
address = {University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 4N8, Canada. Electronic address: rj.keeley@uleth.ca.},
abstract = {Marijuana is one of the most highly used psychoactive substances in the world, and its use typically begins during adolescence, a period of substantial brain development. Females across species appear to be more susceptible to the long-term consequences of marijuana use. Despite the identification of inherent differences between rat strains including measures of anatomy, genetics and behaviour, no studies to our knowledge have examined the long-term consequences of adolescent exposure to marijuana or its main psychoactive component, Delta(9)-tetrahydrocannabinol (THC), in males and females of two widely used rat strains: Long-Evans hooded (LER) and Wistar (WR) rats. THC was administered for 14 consecutive days following puberty onset, and once they reached adulthood, changes in behaviour and in the volume of associated brain areas were quantified. Rats were assessed in behavioural tests of motor, spatial and contextual learning, and anxiety. Some tasks showed effects of injection, since handled and vehicle groups were included as controls. Performance on all tasks, except motor learning, and the volume of associated brain areas were altered with injection or THC administration, although these effects varied by strain and sex group. Finally, analysis revealed treatment-specific correlations between performance and brain volumes. This study is the first of its kind to directly compare males and females of two rat strains for the long-term consequences of adolescent THC exposure. It highlights the importance of considering strain and identifies certain rat strains as susceptible or resilient to the effects of THC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Marijuana is one of the most highly used psychoactive substances in the world, and its use typically begins during adolescence, a period of substantial brain development. Females across species appear to be more susceptible to the long-term consequences of marijuana use. Despite the identification of inherent differences between rat strains including measures of anatomy, genetics and behaviour, no studies to our knowledge have examined the long-term consequences of adolescent exposure to marijuana or its main psychoactive component, Delta(9)-tetrahydrocannabinol (THC), in males and females of two widely used rat strains: Long-Evans hooded (LER) and Wistar (WR) rats. THC was administered for 14 consecutive days following puberty onset, and once they reached adulthood, changes in behaviour and in the volume of associated brain areas were quantified. Rats were assessed in behavioural tests of motor, spatial and contextual learning, and anxiety. Some tasks showed effects of injection, since handled and vehicle groups were included as controls. Performance on all tasks, except motor learning, and the volume of associated brain areas were altered with injection or THC administration, although these effects varied by strain and sex group. Finally, analysis revealed treatment-specific correlations between performance and brain volumes. This study is the first of its kind to directly compare males and females of two rat strains for the long-term consequences of adolescent THC exposure. It highlights the importance of considering strain and identifies certain rat strains as susceptible or resilient to the effects of THC.
Keeley, R J; Hong, N S; Fisher, A; McDonald, R J
In: Neurobiol Learn Mem, vol. 119, pp. 42–51, 2015, ISSN: 1095-9564 (Electronic); 1074-7427 (Linking).
@article{Keeley2015d,
title = {Co-morbid beta-amyloid toxicity and stroke produce impairments in an ambiguous context task in rats without any impairment in spatial working memory.},
author = {R J Keeley and N S Hong and A Fisher and R J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25576791},
doi = {10.1016/j.nlm.2015.01.001},
issn = {1095-9564 (Electronic); 1074-7427 (Linking)},
year = {2015},
date = {2015-01-07},
journal = {Neurobiol Learn Mem},
volume = {119},
pages = {42--51},
address = {Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada. Electronic address: rj.keeley@uleth.ca.},
abstract = {Sporadic Alzheimer's disease (AD) accounts for a high proportion of AD cases. Therefore, it is of importance to investigate other factors that contribute to the etiology and progression of AD. AD is characterized by decreased cholinergic tone, tau hyperphosphorylation and beta-amyloid (Abeta) accumulation. In addition to the hallmark pathology, other factors have been identified that increase the risk of AD, including stroke. This study examined the combined effects of beta-amyloid administration and unilateral stroke in an animal model of AD. Adult rats were given a sham surgery, bilateral intraventricular infusion of 10 muL of 50n mol Abeta(25-35), a unilateral injection of endothelin-1 into the right striatum, or Abeta and endothelin-1 administration in combination. Following a recovery period, rats were tested in the 1-trial place learning variant of the Morris water task followed by an ambiguous discriminative fear-conditioning to context task. After behavioural assessment, rats were euthanized, and representative sections of the medial septum were analyzed for differences in choline-acetyltransferase (ChAT) immunohistochemistry. No differences were observed in spatial working memory, but the combined effect of Abeta and stroke resulted in deficits in the discriminative fear-conditioning to context task. A trend towards decreased ChAT-positive staining in the medial septum was observed. This study indicates that Abeta and stroke in combination produce worse functional consequences than when experienced alone, furthering the concept of AD as a disease with multiple and complex etiologies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sporadic Alzheimer's disease (AD) accounts for a high proportion of AD cases. Therefore, it is of importance to investigate other factors that contribute to the etiology and progression of AD. AD is characterized by decreased cholinergic tone, tau hyperphosphorylation and beta-amyloid (Abeta) accumulation. In addition to the hallmark pathology, other factors have been identified that increase the risk of AD, including stroke. This study examined the combined effects of beta-amyloid administration and unilateral stroke in an animal model of AD. Adult rats were given a sham surgery, bilateral intraventricular infusion of 10 muL of 50n mol Abeta(25-35), a unilateral injection of endothelin-1 into the right striatum, or Abeta and endothelin-1 administration in combination. Following a recovery period, rats were tested in the 1-trial place learning variant of the Morris water task followed by an ambiguous discriminative fear-conditioning to context task. After behavioural assessment, rats were euthanized, and representative sections of the medial septum were analyzed for differences in choline-acetyltransferase (ChAT) immunohistochemistry. No differences were observed in spatial working memory, but the combined effect of Abeta and stroke resulted in deficits in the discriminative fear-conditioning to context task. A trend towards decreased ChAT-positive staining in the medial septum was observed. This study indicates that Abeta and stroke in combination produce worse functional consequences than when experienced alone, furthering the concept of AD as a disease with multiple and complex etiologies.
2014
Keeley, R J; Bye, C; Trow, J; McDonald, R J
Strain and sex differences in brain and behaviour of adult rats: Learning and memory, anxiety and volumetric estimates. Journal Article
In: Behav Brain Res, vol. 288, pp. 118–131, 2014, ISSN: 1872-7549 (Electronic); 0166-4328 (Linking).
@article{Keeley2014,
title = {Strain and sex differences in brain and behaviour of adult rats: Learning and memory, anxiety and volumetric estimates.},
author = {R J Keeley and C Bye and J Trow and R J McDonald},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25446747},
doi = {10.1016/j.bbr.2014.10.039},
issn = {1872-7549 (Electronic); 0166-4328 (Linking)},
year = {2014},
date = {2014-11-03},
journal = {Behav Brain Res},
volume = {288},
pages = {118--131},
address = {University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 4N8, Canada. Electronic address: rj.keeley@uleth.ca.},
abstract = {Alterations in behaviour can arise through a number of factors, including strain and sex. Here, we explored strain and sex differences between Long-Evans (LER) and Wistar (WR) male and female rats that had been trained in a myriad of behavioural tasks. Tests included those assessing motor learning (skilled reaching task), spatial learning and memory (Morris water task), contextual learning (discriminative fear-conditioning to context) and anxiety behaviour (elevated plus maze). Following behavioural assessment, associated brain areas were examined for volumetric differences, including the hippocampus and its subregions, prefrontal cortex areas and the amygdala. LER and WR differed in their rates of performance in the skilled reaching task throughout the training period. Overall, LER outperformed WR in tasks related to contextual and spatial learning, although this was not accompanied by larger volumes of associated brain areas. Males outperformed females in spatial learning, and females outperformed males in the contextual fear-conditioning task and had an associated larger amygdalar volume, although these sexual dimorphisms were only observed within the LER strain. Overall, this study highlights differences between these two rat strains as well as highlights that larger volumetric estimates of brain areas do not always confer improved function of associated behaviours.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Alterations in behaviour can arise through a number of factors, including strain and sex. Here, we explored strain and sex differences between Long-Evans (LER) and Wistar (WR) male and female rats that had been trained in a myriad of behavioural tasks. Tests included those assessing motor learning (skilled reaching task), spatial learning and memory (Morris water task), contextual learning (discriminative fear-conditioning to context) and anxiety behaviour (elevated plus maze). Following behavioural assessment, associated brain areas were examined for volumetric differences, including the hippocampus and its subregions, prefrontal cortex areas and the amygdala. LER and WR differed in their rates of performance in the skilled reaching task throughout the training period. Overall, LER outperformed WR in tasks related to contextual and spatial learning, although this was not accompanied by larger volumes of associated brain areas. Males outperformed females in spatial learning, and females outperformed males in the contextual fear-conditioning task and had an associated larger amygdalar volume, although these sexual dimorphisms were only observed within the LER strain. Overall, this study highlights differences between these two rat strains as well as highlights that larger volumetric estimates of brain areas do not always confer improved function of associated behaviours.
Amtul, Zareen; Whitehead, Shawn N; Keeley, Robin J; Bechberger, John; Fisher, Alicia L; McDonald, Robert J; Naus, Christian C; Munoz, David G; Cechetto, David F
Comorbid rat model of ischemia and beta-amyloid toxicity: striatal and cortical degeneration. Journal Article
In: Brain Pathol, vol. 25, no. 1, pp. 24–32, 2014, ISSN: 1750-3639 (Electronic); 1015-6305 (Linking).
@article{Amtul2014,
title = {Comorbid rat model of ischemia and beta-amyloid toxicity: striatal and cortical degeneration.},
author = {Zareen Amtul and Shawn N Whitehead and Robin J Keeley and John Bechberger and Alicia L Fisher and Robert J McDonald and Christian C Naus and David G Munoz and David F Cechetto},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24725245},
doi = {10.1111/bpa.12149},
issn = {1750-3639 (Electronic); 1015-6305 (Linking)},
year = {2014},
date = {2014-05-19},
journal = {Brain Pathol},
volume = {25},
number = {1},
pages = {24--32},
address = {CIHR Group on Vascular Cognitive Impairment, Department of Anatomy and Cell Biology, Western University, London, ON, Canada.},
abstract = {Levels of cerebral amyloid, presumably beta-amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin-1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in beta-amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta-treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Levels of cerebral amyloid, presumably beta-amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin-1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in beta-amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta-treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.
Amtul, Zareen; Nikolova, Simona; Gao, Lulu; Keeley, Robin J; Bechberger, John F; Fisher, Alicia L; Bartha, Robert; Munoz, David G; McDonald, Robert J; Naus, Christian C; Wojtowicz, Martin J; Hachinski, Vladimir; Cechetto, David F
Comorbid Abeta toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit. Journal Article
In: Neurobiol Aging, vol. 35, no. 7, pp. 1605–1614, 2014, ISSN: 1558-1497 (Electronic); 0197-4580 (Linking).
@article{Amtul2014b,
title = {Comorbid Abeta toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit.},
author = {Zareen Amtul and Simona Nikolova and Lulu Gao and Robin J Keeley and John F Bechberger and Alicia L Fisher and Robert Bartha and David G Munoz and Robert J McDonald and Christian C Naus and Martin J Wojtowicz and Vladimir Hachinski and David F Cechetto},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24491422},
doi = {10.1016/j.neurobiolaging.2014.01.005},
issn = {1558-1497 (Electronic); 0197-4580 (Linking)},
year = {2014},
date = {2014-01-08},
journal = {Neurobiol Aging},
volume = {35},
number = {7},
pages = {1605--1614},
address = {Department of Anatomy and Cell Biology, Canadian Institutes of Health Research Group on Vascular Cognitive Impairment, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. Electronic address: zamtul@uwo.ca.},
abstract = {Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and beta-amyloid (Abeta) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Abeta toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Abeta. Gross morphologic changes in comorbid Abeta and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Abeta precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Abeta toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and beta-amyloid (Abeta) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Abeta toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Abeta. Gross morphologic changes in comorbid Abeta and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Abeta precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Abeta toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.
