- Recent Selected Abstracts of Our Research from Publications in Scientific Journals and Presentations at Scientific Conferences.
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To
be presented at the Meeting of the Society for Neuroscience 2008 *R. F. Mervis1,2, M. Knobloch3, N. Jani4, S. Moradian4, J. Yesudas4, B. A. Thomas4, L. Nattkemper5, U. Konietzko6 and R. M. Nitsch6 1Ctr.
for Aging & Brain Repair, Univ. South Florida Coll Med., Tampa,
FL Abstract: |
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the following Link to View the Article
Activation of Estrogen Receptor Beta Regulates Hippocampal
Synaptic Plasticity and Improves Memory
1Wyeth
Research, Discovery Neuroscience, Princeton, NJ Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the relative roles of the estrogen receptors alpha (ERa) and beta (ERß) remain unclear. Utilizing pharmacological, biochemical and behavioral techniques, we demonstrate for the first time that the effects of estrogen on hippocampal synaptic plasticity and memory in rodents are mediated through ERß. Selective ERb agonists increased levels of key synaptic proteins in vivo including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERb knockout mice. In hippocampal slices ERb activation enhanced long-term potentiation (LTP), an effect that was absent in slices from ERb knockout mice. ERb activation induced morphological changes in hippocampal neurons in vivo including increased dendritic branching and density of mushroom-type spines. An ERb agonist, but not an ERa agonist, also improved performance in a variety of hippocampal-dependent memory tasks. Taken together, our data suggest that activation of ERb can regulate hippocampal synaptic plasticity and improve hippocampal-dependent cognition. |
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Ronald F. Mervis1,2, Nikki Vyas3 , Scott Moradian3, Jeremy Yesudas3, Bryan Thomas3, Leigh Nattkemper4, Silvana Gaetani5, Maria Tattoli5, Addolorata Coluccia2, and Vincenzo Cuomo1
1Ctr
of Excellence for Aging & Brain Repair, Univ. South Florida College
of Medicine, Tampa, FL, USA Even though marijuana is the most widely used illegal drug among women of reproductive age, reports dealing with the effects of prenatal exposure to this substance of abuse are still controversial. More complex and less understood is the scenario concerning the possible long-term consequences of in utero exposure to cannabis derivatives on cognitive functions. In this study the synthetic CB1 agonist WIN 55,212-2 (WIN) was administered daily to pregnant rats from gestational day 5 to 20 (0.5mg/kg). This dose is equivalent to a moderate or low exposure to marijuana in humans and has no overt toxic effects. The treatment with WIN did not affect gestational and reproduction parameters and WIN-exposed pups did not show any sign of malformations or malnutrition. However, a deeper investigation revealed that prenatal treatment with WIN altered pup performance in homing behavior and produced a decrease in the rate of separation-induced ultrasonic vocalizations. Behavioral deficits that resulted were long-lasting, since prenatal WIN exposure caused a disruption of memory retention in young and adult offspring subjected either to a passive or an active avoidance task. Moreover, an altered dendritic morphology of hippocampal CA1 pyramids was detected in young (40 day-old) rats. In particular, in the prenatally WIN-exposed rats, there was a significant 12% increase in estimated total dendritic length and a highly significant increase in branching complexity in the middle-third of the dendritic tree. These findings suggest that moderate exposure to cannabinoids during crucial periods of brain development can cause dysmorphic maturation of the hippocampus. Such subtle morphological alterations and commensurate changes in brain circuitry would be, in turn, a factor underlying the behavioral deficits observed both in early and late postnatal life. |
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1Centers
for Disease Control and Prevention, Morgantown, WV 26505 The
neural changes associated with chronic stress are of great interest
to those interested in brain health as they may be linked to the cognitive
impairments and neurodegeneration observed in many brain diseases. To
examine how chronic stress impacts brain structural elements adult C57BL/6J
male mice (N=10) were exposed to 21 consecutive days of the following
stressors in random order: (1) 8 hrs restraint; (2) 3 mins forced swim
in ice water; (3) 8 hrs of light-cycle disruption; (4) 8 hrs at 15o;
(5) social reorganization or remained in their home-cage. Immediately
following the last stressor mice were anesthetized, perfused with paraformaldehyde,
the brains removed and maintained in fixative until sections were prepared
and examined for alterations in neuronal plasticity. This chronic stress
regimen, designed to minimize habituation by presenting the stressors
in an unpredictable random order, produced a measurable but non-significant
change in body weight. It also caused a 27% decrease in thymus weight
indicating a sustained activation of the HPA axis throughout the stress
period although this decrease is minimal compared to the 93% reduction
observed in animals exposed to supra-physiological levels of corticosterone
through pellet (200 mg) implant for the 21 days. Dendritic spines were
quantified for spine density along terminal tip and internal branch
segments of the apical tree of the CA3 pyramidal neurons of the hippocampus.
Spines were also categorized into “L-“ (lollipop), “N-“
( nubby) , and “D-type” (dimple) configurations. Five to
six randomly selected Golgi-impregnated CA3 neurons were evaluated from
each subject and spines quantified along 30 um Golgi-impregnated sections.
Findings revealed a ~ 15.5% decrease in L-and N- but not D-type spines
on the apical dendrites. A lesser but still significant decrease in
all spine types was also observed on the internal segments of the apical
dendrites. A less dramatic loss of spines was observed in mice exposed
continuously to supra-physiological levels of corticosterone. Reduced
spine density may be indicative of reduced neuronal plasticity. Thus,
our data provides evidence that the CRS regimen alters plasticity in
the hippocampal area of the mouse as it does in the rat and provides
a chronic stress model that can be used in future studies utilizing
this rodent species to examine the signaling pathways suspected to mediate
the effects of stress on plasticity. |
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1Honors
College, Univ. South Florida, Tampa, FL Chlorpyrifos
(CPF) is a common organophosphate (OP) insecticide. It has extensive
use in agriculture as a pesticide. The primary mechanism of action is
inhibition of acetylcholinesterase (AchE). Exposure to OPs may have
deleterious neurobehavioral consequences. This has been well documented
in neonatal and developing animals; however, the impact on the adult
brain is more poorly understood. Analysis of Golgi stained neurons was
chosen for morphological assay which allows for complete visualization
of entire dendritic branching arbor and dendritic spines and quantification
of the morphometric changes. Adult CPF-treated rats were given 18mg/kg
for 14 days. There were six CPF and six control subjects in each group.
Five randomly-seclected neurons were evaluated from each region of each
subject: the cingulate gyrus of the frontal cortex, CA1s in the hippocampus,
and granule cells of the dentate gyrus. Dendritic branching was assessed
by preparation of camera lucida drawings and subsequent Sholl analysis
which profiles the amount and distribution of the arbor. Dendritic spines
were counted along 30um long dendritic segments. |
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1The
Honors College, University of South Florida, Tampa, FL In
future deep space missions, astronauts will be exposed to heavy particle
radiation over lengthy periods. Potentially, this exposure could result
in neuronal damage, impair brain circuitry, and compromise the astronaut’s
cognitive and behavioral capabilities which would threaten mission success.
At this time, relatively little is known of the extent of this exposure
on neuronal circuitry. The purpose of this study was to evaluate the
effects of high-energy (56)Fe particles on dendritic branching and spine
parameters in layer II-III cortical neurons in the adult rat. These
parameters are critical to the integrity of brain circuitry: dendritic
branching comprises about 95% of total neuronal volume and the vast
majority of synapses occur on the dendritic spines. |
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1College
of Arts & Sciences, USF Lithium
may serve as a treatment for bipolar disorders and other psychiatric
conditions by counteracting both mania and depression. Lithium can affect
neurotransmitter activity by increasing serotonin levels and decreasing
noradrenaline discharge. Lithium may also influence neuroplasticity
and the dendritic parameters that are the underlying neurostructural
basis for the cognitive and behavioral manifestations. |
| Presented
at the Nutrisciences and Health Conference, Charlottetown, PEI, Canada,
July, 2007 1The
Honors College, University of South Florida, Tampa, FL Aged-related
oxidative stress results in the formation of reactive oxygen species
(ROS) which can damage neurons and may an important component associated
with disruption of brain circuits and concomitant age-related cognitive
impairment. This study attempts to characterize the potential beneficial
effects of the nutritional antioxidants (e.g., polyphenols) found in
blueberries (BB), on morphological indices of brain circuitry in old
rats. Nineteen month old male Fischer 344 rats were given either a standard
NIH-31 rat chow (controls) or an NIH chow enriched with 2% BB extract
for 2.5 months. Following behavioral testing, the 21.5 mon-old rats
were killed and their brains stained using the Golgi method (N = 3 subjects/group)..
Golgi staining permits microscopic visualization and quantitative analysis
of the dendritic parameters of the impregnated neurons. From coded slides,
randomly selected layer II-III cortical neurons of frontal cortex in
the 21.5 month old rats (7 neurons/subject) were evaluated for the extent
of their dendritic branching. Two and half months of the BB-enriched
diet resulted in a significant increase in dendritic branching, primarily
in the proximal half of the basilar dendritic arbor of the layer II-III
neurons (a 14% increase). This suggests that even in old subjects, BB
dietary supplementation appears to have a neuroplastic impact on neuronal
morphology: it can mitigate normal age-related dendritic atrophy. This
would suggest that the BB-extract can exert anti-aging neuroprotection
in maintaining or enhancing the integrity of brain circuitry in the
old rats. |
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Click
the following Link to View the Article Lein PJ1, Yang D1, Bachstetter AD2,3, Tilson HA4, Harry GJ5, Mervis RF2,3, Kodavanti PR4 1Center
for Research on Occupational and Environmental Toxicology, Oregon Health
& OBJECTIVE:
Perinatal exposure to polychlorinated biphenyls (PCBs) is associated
with decreased IQ scores, impaired learning and memory, psychomotor
difficulties, and attentional deficits in children. It is postulated
that these neuropsychological deficits reflect altered patterns of neuronal
connectivity. To test this hypothesis, we examined the effects of developmental
PCB exposure on dendritic growth. METHODS: Rat
dams were gavaged from gestational day 6 through postnatal day (PND)
21 with vehicle (corn oil) or the commercial PCB mixture Aroclor 1254
(6 mg/kg/day). Dendritic growth and molecular markers were examined
in pups during development. RESULTS: Golgi
analyses of CA1 hippocampal pyramidal neurons and cerebellar Purkinje
cells indicated that developmental exposure to PCBs caused a pronounced
age-related increase in dendritic growth. Thus, even though dendritic
lengths were significantly attenuated in PCB-treated animals at PND22,
the rate of growth was accelerated at later ages such that by PND60,
dendritic growth was comparable to or even exceeded that observed in
vehicle controls. Quantitative reverse transcriptase polymerase chain
reaction analyses demonstrated that from PND4 through PND21, PCBs generally
increased expression of both spinophilin and RC3/neurogranin mRNA in
the hippocampus, cerebellum, and cortex with the most significant increases
observed in the cortex. CONCLUSIONS: This study
demonstrates that developmental PCB exposure alters the ontogenetic
profile of dendritogenesis in critical brain regions, supporting the
hypothesis that disruption of neuronal connectivity contributes to neuropsychological |
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1Ctr
of Excellence for Aging & Brain Repair, Univ South Florida College
of Medicine, Tampa, FL Disruption
of dendritic branching and/or spine components likely play a role in
the neuropathology underlying the onset of cognitive impairment seen
in Alzheimer disease (AD). Whether disruption in these components of
brain circuitry is altered in elderly people with a clinical diagnosis
of mild cognitive impairment (MCI) without frank AD remain unknown.
To evaluate these dendritic alterations, formalin fixed frontal (area
9) cortical tissue blocks were Golgi stained from individuals who died
with a clinical diagnosis of either No Cognitive Impairment (NCI), MCI,
or AD obtained from the University of Kentucky. Layer II-III pyramidal
neurons (6/subject) were randomly selected from coded slides. This data
represents the initial phase of a larger on-going Golgi investigation
of neo- and limbic brain circuitry in the progression of AD. Sholl analysis
revealed significant dendritic atrophy in the MCI compared to AD and
controls. However, there was a significant increase in pyramidal neuron
spine density in MCI as compared to controls and AD (which did not differ
from each other). The underlying molecular mechanisms are unknown: mutations
in amyloid beta (Aß) (and/or tau) genes may enhance dendritic
pruning (microtubule depolymerization in the shafts of dendrites) by
promoting enhanced calcium influx from the endoplasmic reticulum, or
Aß could promote spine formation via actin polymerization. Similar
dichotomous findings were seen in the 3xtg triple AD transgenic mouse
model of AD, further implicating genetic mutation in APP and tau genes
in this process. These findings may represent compensatory neuroplastic
responses, which may assist in maintaining cortical circuitry and delay
severe cognitive dysfunction in MCI. |
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Dichotomous
Dendritic Changes in the Aging Triple Transgenic Mouse Model of Alzheimer’s
Disease: Dendritic Spines Increase and Branching Decreases in Layer
V Pyramidal Cells. 1The
Honors College, Univ South Florida, Tampa, FL The
triple transgenic mouse model of Alzheimer’s disease (3xTgAD)
was generated by expressing three different mutant genes (APP, PS1 and
tau) linked to inherited forms of dementia. 3xTgAD mice exhibit age-related
amyloid and tau pathology that is associated with synaptic dysfunction
and memory impairment. From randomly selected Golgi stained neurons,
we evaluated neocortical layer V dendritic spine density (basilar tree
and main apical branch) and basilar dendritic branching in aging (15
mon-old) 3xTgAD male and female mice and age-matched controls. Branching
analysis of the basilar dendritic arbor of both 3xTg males and females
showed significant mild-to-moderate branching atrophy in the distal
2/3rds of the tree (~15%). Conversely, for both aging males and females,
there was an overall significant average increase in spines (~ 50%)
for these layer V cortical neurons. A possible mechanism for the contradictory
dendritic findings is that Abeta, the PS1 mutation (and tau mutations
as well) promote enhanced calcium influx and release from the ER; therefore,
this would tend to cause dendritic pruning (microtubule depolymerization
in the shafts of dendrites), but could also promote spine formation
(actin polymerization). We have also seen a similar dichotomous dendritic
response in cortical neurons from autopsied humans diagnosed with mild
cognitive impairment (a prodromal stage of AD); this lends additional
strength to the 3xtg mouse as a valid model of Alzheimer’s. These
dendritic findings would suggest that alterations in cortical circuitry
are contributing to the cognitive dysfunction associated with the progression
of the disease. |
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Human Umbilical Cord Blood Cell Treatment Mitigates Loss of Dendritic Branching and Spines in the Aged Rat Brain.
1College
of Liberal Arts & Sciences, Univ South Florida, Tampa, FL Human
Umbilical Cord Blood (HUCB) cells are enriched for stem cells that have
the potential to initiate and maintain tissue repair. The potential
neuroprotective role of HUCB on the circuitry of the aging brain is
unknown. However, HUCB may release certain neurotrophic factors that
protect the dendritic and synaptic circuitry from age-related deterioration.
This study was designed to provide new insight into the neuroprotective
role of HUCB in aging rats. The brains from 22 month-old aging rats
and 4 month-old young controls were evaluated for dendritic branching
and spine morphology from several cell populations. The old rats were
administered a single treatment of HUCB either i.v. or directly into
the hippocampus. Cortical and hippocampal neurons were assessed using
Golgi impregnated preparations which can reveal the amount of dendritic
material and the numbers of dendritic spines of randomly stained neurons.
In the neocortex and hippocampus, layer II-III pyramids and granule
cells, respectively, showed age-related spine loss which was largely
attenuated by the single HUCB cell treatment. Also, age-related granule
cell dendritic branch atrophy was reversed by HUCB. These results will
have significant impact on future applications of umbilical cord therapies |
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Presented at the 2006 Annual Meeting of the Society for Neuroscience. Atlanta, GA Disruption of Normal Cortical Dendritic Growth in the Akt3 KnockOut Mouse. Elizabeth
Brachowicz1,
Rachael M. Easton2,
Morris J. Birnbaum2,3,
1The
Honors College, University of South Florida, Tampa, FL
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Effects of Hyper- and Hypoglycemia on Dendritic Branching and Spines in the Young Adult Diabetic Rat. Jaimie Waite1, Corinne Althauser2, Ronald F. Mervis3,4,5, Suzanne Hanna6, Samuel Saporta3,4,7, John I. Malone6 1Honors
College, Univ South Florida, Tampa, FL Childhood
diabetes and related medical issues are a growing health problem. Children
with diabetes onset before 5 years old may have reduced neurocognitive
function. Typically, this problem has been attributed to hypoglycemia,
a complication of insulin therapy. However, hyperglycemia is much more
common than intermittent hypoglycemia during early childhood diabetes.
Relatively little is known about the effects of hyperglycemia on development
of neural circuitry. The purpose of this study was to evaluate the effects
of chronic hyperglycemia and intermittent hypoglycemia on dendritic
branching and spines in the young rat neocortex. Starting at four weeks
of age, experimental rats were exposed to 4 weeks of either chronic
hyperglycemia or intermittent (3 hours, 3x/week) hypoglycemia. Tissue
was stained using Golgi impregnation methods to assess dendritic parameters.
Compared to age-matched controls, evaluation of the basilar tree of
layer II-III pyramids in the parietal cortex showed that although the
intermittent hypoglycemia did not affect dendritic branching, the hyperglycemic
paradigm resulted in significantly smaller (-16%, p < 0.05) and less
complex dendritic arbors relative to the controls. There was also a
9% loss of dendritic spines on the internal branch segments of the basilar
tree (p < 0.004). These findings indicate that chronic hyperglycemia
in the developing brain – which is associated with early childhood
diabetes – may result in damage to cortical neurons, compromise
brain circuitry and could be the neuroanatomical basis for the neurocognitive
impairment found in this disorder. Other studies on hippocampal neurons
and using additional dosages are currently in progress. (Supported
by a grant from the Juvenile Diabetes Research Foundation) |
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R.F Mervis1,4, D. S. Barber2, M. Ehrich3, J. Hinckley3, J. Kotick1,5, M. Shah1,5, T. Amato5, B.S. Jortner3 1Neurostructural
Research Laboratories, Tampa, FL Studies
of rats with intramuscular implantation of depleted uranium (DU) reveal
that in addition to the well-described accumulation of this metal in
kidney and bone, it is also increased in brain (Pellmar et al, 1999).
In addition, Gulf War I veterans with long-term residual DU shrapnel
had lowered performance efficiency in selected neurocognitive tests
(McDairmond et al, 2000). This study was undertaken to additionally
assess the neurotoxicologic effects of implanted DU in rats, and to
see if stress altered this response, focusing on changes to the hippocampal
pyramidal cells. Adult male Sprague-Dawley rats each had 20 DU or tantalum
(control) pellets (1mm x 2mm) implanted in the gastrocnemius muscles,
for a six month period. Stress was applied 5 days/week for the entire
exposure period in a random pattern of handling, restraint, and swimming
to minimize habituation. At terminal sacrifice, cerebral regions from
animals exposed to the stress, DU, the combination of stress and DU
and the tantalum controls were removed and stained by the Golgi impregnation
procedure. The basilar dendritic arbor of hippocampal CA1 pyramidal
cells was assessed using Sholl analysis. Preliminary data shows that
relative to the negative controls, there was an increase in dendritic
material in the inner 1/3 of the arbor in rats administered DU alone.
This diminished in the outer 2/3 of the arbor, a region where the combination
of stress and DU elicited increase in dendritic material. There also
was decrease in dendritic material in animals only exposed to stress
in this outer region. Thus, 24 weeks exposure to a high dose of implanted
DU pellets alters the dendritic tree of CA1 pyramidal neurons which
may influence cognitive behavior. (Supported by DAMD17-01-1-0775, US
Army Medical Research and Materiel Command) |
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The Increase in CA1 Spines Produced by Spatial Learning is Blocked by Pre-Training, but Not Pre-Retrieval, Predator Stress. Diamond, D.M.1,2,3, Campbell, A.M.1,2, Woodson, J.C.4, Park, C.R.1,2, Bachstetter, A.D.5, Mervis, R.F.5 1Medical
Research, VA Hospital, Tampa, FL, USA
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Hyperglycemia Induced Alteration of Cortex and Hippocampus in the Rat Samuel Saporta1,2,4, Suzan Hanna3, Ronald F. Mervis2,4,5, Christopher P. Phelps1 and John I. Malone3 Departments
of 1Anatomy,
3Pediatrics
and 2Neurosurgery,
University of South Florida College of Medicine, Tampa, FL 33612 Children with diabetes onset before 5 years of age have reduced neurocognitive function. This problem has been attributed to hypoglycemia, a complication of insulin therapy. The eye, kidney and nerve complications of diabetes have been reduced by intensified Insulin therapy which is associated with a 3 fold increase in severe hypoglycemia and therefore was not recommended for children less than13 years of age. Since hyperglycemia is much more common than intermittent hypoglycemia during early childhood diabetes, it is important to determine if hyperglycemia affects brain growth and development. Rats were exposed to 4 weeks of either chronic hyperglycemia or intermittent (3 hours, 3 times/week) hypoglycemia from 4 to 8 weeks of age. The brains of these animals were compared to those of similarly aged normal control animals. Overall cell density, and the density of Map-2-positive neurons and S-100b-positive astrocytes in the entorhinal cortex and hippocampus of these animals were compared between groups. The number of cells was increased and the cell size reduced in the cortex of diabetic animals as assessed by DNA/ wet weight of brain and protein/DNA content. Reduced amounts of protein, fatty acids, and cholesterol/ µgram DNA also indicate smaller cells with reduced myelin content in the cortex of the diabetic animals. Histologic evaluation of these brains confirmed that there was an increase in the number of small neurons in these areas with a slight decrease in the number of astrocytes. These observations require further confirmation and evaluation, but indicate that chronic hyperglycemia may be more damaging than intermittent hypoglycemia to the developing brain. Supported by a grant 1-2004-751 from the Juvenile Diabetes Research Foundation |
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Neurofunctional Consequences of Developmental Exposure to Moderate Doses of Cannabinoids in a Rat Model. Silvana Gaetani1, Maria Tattoli2, Addolorata Coluccia2, Ronald F Mervis3,4, Adam Bachstetter4, Nisida Berberi5, and Vincenzo Cuomo1 1Dept
of Human Physiology and Pharmacology, Univ. of Rome “La Sapienza”,
Italy Even
though marijuana is the most widely used illegal drug among women of
reproductive age, reports dealing with the effects of prenatal exposure
to this substance of abuse are still controversial. More complex and
less understood is the scenario concerning the possible long-term consequences
of in utero exposure to cannabis derivatives on cognitive functions.
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This Is Your (Child's) Brain on Drugs: in utero Exposure to a Cannabinoid Agonist Affects Dendritic Morphology of Hippocampal CA1 Neurons in the Young Rat.
1Ctr
for Aging & Brain Repair, Dept Neurosurgery., Univ. South Florida
College of Medicine, Tampa, FL Among women of reproductive age marijuana is the most widely used illegal drug. The impact of cannabis exposure on the developing brain is poorly understood. A specific cannab-inoid receptor (CB1) is highly expressed in many brain regions, including the hippocampus. The synthetic CB1 agonist WIN 55,212-2 was administered daily to pregnant rats from gestational day 5 to 20 (0.5mg/kg). This dose is equivalent to a moderate or low exposure of marijuana in humans and has no overt toxic effects. The behavioral consequences in 40 day-old (do) rats included hyperactive behavior and memory impairment. To assess the effects of this prenatal exposure on dendritic morphology of CA1 pyramids of the hippocampus, fixed brain tissue from WIN-exposed 40 do offspring (N= 6) and age-matched controls (N=5) was Golgi stained. The basilar dendritic arbors of CA1s were quantified. In the prenatally WIN-exposed 40 do rats, there was a significant 12% increase in estimated total dendritic length and a highly significant increase in branching in the middle-third of the dendritic tree. This finding suggests that hippocampal circuitry was affected by the cannabinoid agonist; perhaps due to failure of normal developmental pruning back of the dendritic tree. Dysmorphic maturation of the hippocampus would be a factor underlying behavioral and cognitive changes seen in the young 40 day-old rats. |
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Presented at the 7th International Conference on Alzheimer's and Parkinson's Diseases, Sorrento, Italy, March, 2005 Cortical and Hippocampal Dendritic Spine Alterations in the Triple Transgenic Mouse Model of Alzheimer's Disease. Ronald
F. Mervis1,2,
Adam Bachstetter2,
Mohamed Mughal3,
Peter Mouton3,4 1Center
for Aging and Brain Repair, Department of Neurosurgery, University of
South Florida College of Medicine, Tampa, FL The triple transgenic mouse model of Alzheimer's disease (3xTgAD) was generated by expressing three different mutant genes (APP, PS1 and tau) linked to inherited forms of dementia. 3xTgAD mice exhibit age-related amyloid and tau pathology which is associated with synaptic dysfunction and memory impairment. Memory impairment in AD correlates strongly with synaptic loss. In the present study we evaluated the density and configuration of dendritic spines in neocortex and hippocampus of male 3xTgAD mice. From coded slides, dendritic spines of Golgi stained neurons were evaluated on randomly selected layer II/III pyramids of the parietal neocortex and on the basilar tree of hippocampal CA1 pyramids. For 3xTgAD mice (12 months old, n=4) and nontransgenic controls (11.5 months old, n=5) spines were assessed for density and configuration, properties that are known to influence synaptic efficacy. In CA1 neurons, spines on the terminal tip segments of the basilar tree were quantified. Total spine density was reduced in the aged 3xTgAD mice. Most strongly affected were spines lacking well-defined spine heads. On neocortical layer II/III pyramids, spines were assessed throughout the dendritic arbor. Compared to controls, there was no significant total spine loss in the 3xTgAD mice. However, there was a significant increase in small-headed spines, a form of spine believed to be dysfunctional. These initial findings suggest that both hippocampal and cortical circuitry in the aged 3xTgAD mice are altered, but in different ways. In the hippocampus spine loss occurs, whereas in the parietal neocortex an increase in dysfunctional spines may occur. |
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Presented at the meeting
of the Society for Neuroscience, San Diego, Alterations in the Morphology of Dendrites in the Nucleus Accumbens and Frontal Cortex Following Repeated Neonatal Isolation Stress. W.J. Shoemaker1, J. Costill1, A.
Bachstetter2, A. Cupples3, J. Kotick4
1University of Connecticut Health Center.,
Farmington, CT, Newborn rat pups isolated from the dam and littermates for 1 hr. per day (PN 2-9) display behavioral sensitization when tested as juveniles and adults and also have a hyper-responsive mesolimbic dopamine system to either a drug or stress challenge. We have analyzed fixed brain tissue from adult male rats using the rapid Golgi method in order to quantify changes in dendrites and synaptic spines. In addition, some animals were given memantine, an NMDA receptor antagonist, at the time of isolation to test whether blockade of NMDA receptors will attenuate stress-induced sensitized behavior and morphological changes. Memantine (10 mg/kg) was given by oral gavage at each animal’s 1-hr isolation on each day from PN 2-9. Isolation-only (ISO), non-isolation only (NON-ISO) and memantine only (MEM) groups were included in the design. The drug was tolerated well and had no effect on body weight over time for any treatment group. Examination of Golgi-stained sections using the Sholl analysis reveals that, compared to NON-ISO controls, ISO animals had a 23% increase in the branching of dendrites in medium spiny neurons of the nucleus accumbens shell. There were no significant alterations in spine number or type, or in cell soma size. ISO-MEM and MEM animals had dendritic branching levels intermediate between the ISO and NON-ISO levels, consistent with behavioral data that indicated memantine could attenuate the effects of isolation, but had other effects of its own. In the layer II/III pyramidal cells of the frontal cortex, there were no differences between ISO and NON-ISO animals in dendritic branching, but both groups receiving memantine were significantly lower than controls. There was a trend to increase in spine number (14%) but it was not significant. However, soma |