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The Journal of comparative neurology  2008;507(1):1141-1150.
Anatomical alterations in the medial prefrontal cortex (mPFC) are associated with hypothalamo-pituitary adrenal (HPA) axis dysregulation, altered stress hormone levels, and psychiatric symptoms of stress-related mental illnesses. Functional imaging studies reveal impairment and shrinkage of the mPFC in such conditions, and these findings are paralleled by experimental studies showing dendritic retraction and spine loss following repeated stress in rodents. Here we extend this characterization to how repeated stress affects dendritic spine morphology in mPFC through the utilization of an automated approach which rapidly digitizes, reconstructs 3-dimensionally, and calculates geometric features of neurons. Rats were perfused after being subjected to 3 weeks of daily restraint stress (6 hours/day), and intracellular injections of Lucifer Yellow were made in layers II/III pyramidal neurons in the dorsal mPFC. To reveal spines in all angles of orientation, deconvolved high-resolution confocal laser scanning microscopy image stacks of dendritic segments were reconstructed and analyzed for spine volume, surface area, and length using a Rayburst-based automated approach (8,091 and 8,987 spines for control and stress, respectively). We found that repeated stress results in an overall decrease in mean dendritic spine volume and surface area, which was most pronounced in the distal portion of apical dendritic fields. Moreover, we observed an overall shift in the population of spines, manifested by a reduction in large spines and increase in small spines. These results suggest a failure of spines to mature and stabilize following repeated stress, and are likely to have major repercussions on function, receptor expression, and synaptic efficacy.
PMCID: PMC2796421  PMID: 18157834
dendritic spine; morphometry; plasticity; prefrontal cortex; stress
2.  Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease 
Neurobiology of aging  2007;29(9):1296-1307.
The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer’s disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5% and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
PMCID: PMC2569870  PMID: 17420070
Alzheimer’s disease; cognition; synapses; tangles
3.  Interactive Effects of Age and Estrogen on Cortical Neurons: Implications for Cognitive Aging 
Neuroscience  2011;191:148-158.
In the past few decades it has become clear that estrogen signaling plays a much larger role in modulating the cognitive centers of the brain than previously thought possible. We have developed a nonhuman primate (NHP) model to investigate the relationships between estradiol (E) and cognitive aging. Our studies of cyclical E treatment in ovariectomized (OVX) young and aged rhesus monkeys have revealed compelling cognitive and synaptic effects of E in the context of aging. Delayed response (DR), a task that is particularly dependent on integrity of dorsolateral prefrontal cortex (dlPFC) area 46 revealed the following: 1) that young OVX rhesus monkeys perform equally well whether treated with E or vehicle (V), and 2) that aged OVX animals given E perform as well as young adults with or without E, whereas OVX V-treated aged animals display significant DR impairment. We have analyzed the structure of layer III pyramidal cells in area 46 in these same monkeys. We found both age and treatment effects on these neurons that are consistent with behavioral data. Briefly, reconstructions of pyramidal neurons in area 46 from these monkeys showed that cyclical E increased the density of small, thin spines in both young and aged monkeys. However, this effect of E was against a background of age-related loss of small, thin spines, leaving aged V-treated monkeys with a particularly low density of these highly plastic spines and vulnerable to cognitive decline. Our current interpretation is that E not only plays a critically important role in maintaining spine number, but also enables synaptic plasticity through a cyclical increase in small highly plastic spines that may be stabilized in the context of learning. Interestingly, recent studies demonstrate that chronic E is less effective at inducing spinogenesis than cyclical E. We have begun to link certain molecular attributes of excitatory synapses in area 46 to E effects and cognitive performance in these monkeys. Given the importance of synaptic estrogen receptor α (ER-α) in rat hippocampus, we focused our initial studies on synaptic ER-α in area 46. Three key findings have emerged from these studies: 1) synaptic ER-α is present in axospinous synapses in area 46; 2) it is stable across treatment and age groups (which is not the case in rat hippocampus); and 3) the abundance and distribution of synaptic ER-α is a key correlate of individual variation in cognitive performance in certain age and treatment groups. These findings have important implications for the design of hormone treatment strategies for both surgically and naturally menopausal women.
PMCID: PMC3166405  PMID: 21664255
Prefrontal cortex; estrogen; aging; primate; cognition; hormone replacement therapy
4.  Estrogen Promotes Stress Sensitivity in a Prefrontal Cortex–Amygdala Pathway 
Cerebral Cortex (New York, NY)  2010;20(11):2560-2567.
We have recently reported in male rats that medial prefrontal cortex (mPFC) neurons that project to the basolateral nucleus of the amygdala (BLA) are resilient to stress-induced dendritic remodeling. The present study investigated whether this also occurs in female rats. This pathway was identified using the retrograde tracer Fast Blue injected into the BLA of ovariectomized female rats with estrogen replacement (OVX + E) and without (OVX + veh). Animals were exposed for 10 days either to 2-h immobilization stress or to home cage rest, after which layer III mPFC neurons that were either retrogradely labeled by Fast Blue or unlabeled were filled with Lucifer Yellow and analyzed for apical dendritic length and spine density. No dendritic remodeling occurred in unlabeled neurons from OVX + veh or OVX + E animals. In BLA-projecting neurons, however, stress had no effect on length in OVX + veh animals, but stressed OVX + E females showed greater dendritic length than controls at intermediate branches. Stress also caused an increase in spine density in all neurons in OVX + veh animals and a spine density increase in BLA-projecting neurons in OVX + E females. Estrogen also increased spine density on BLA-projecting neurons in unstressed animals. These data demonstrate both independent effects of estrogen on pyramidal cell morphology and effects that are interactive with stress, with the BLA-projecting neurons being sensitive to both kinds of effects.
PMCID: PMC2951843  PMID: 20139149
connectivity; dendritic arborization; medial prefrontal cortex; neural plasticity; sex difference
5.  Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery 
Neuroscience  2009;164(2):798-808.
Chronic stress has been shown in animal models to result in altered dendritic morphology of pyramidal neurons of the medial prefrontal cortex (mPFC). It has been hypothesized that the stress-induced dendritic retractions and spine loss lead to disrupted connectivity that results in stress-induced functional impairment of mPFC. While these alterations were initially viewed as a neurodegenerative event, it has recently been established that stress induced dendritic alterations are reversible if animals are given time to recover from chronic stress. However, whether spine growth accompanies dendritic extension remains to be demonstrated. It is also not known if recovery-phase dendritic extension allows for re-establishment of functional capacity. The goal of this study, therefore, was to characterize the structural and functional effects of chronic stress and recovery on the infralimbic (IL) region of the rat mPFC. We compared neuronal morphology of layer V IL pyramidal neurons from animals subjected to 21 days of chronic restraint stress (CRS) to those that experienced CRS followed by a 21 day recovery period. Layer V pyramidal cell functional capacity was assessed by intra-IL long-term potentiation (LTP) both in the absence and presence of SKF38393, a dopamine receptor partial agonist and a known PFC LTP modulator. We found that stress-induced IL apical dendritic retraction and spine loss co-occur with receptor-mediated impairments to catecholaminergic facilitation of synaptic plasticity. We also found that while post-stress recovery did not reverse distal dendritic retraction, it did result in over-extension of proximal dendritic neuroarchitecture and spine growth as well as a full reversal of CRS-induced impairments to catecholaminergic-mediated synaptic plasticity. Our results support the hypothesis that disease-related PFC dysfunction is a consequence of network disruption secondary to altered structural and functional plasticity and that circuitry reestablishment may underlie elements of recovery. Accordingly, we believe that pharmacological treatments targeted at preventing dendritic retraction and spine loss or encouraging circuitry reestablishment and stabilization may be advantageous in the prevention and treatment of mood and anxiety disorders.
PMCID: PMC2762025  PMID: 19723561
infralimbic; dendritic morphology; dendritic spines; dopamine; long-term potentiation
6.  Stress-Induced Dendritic Remodeling in the Prefrontal Cortex is Circuit Specific 
Cerebral Cortex (New York, NY)  2009;19(10):2479-2484.
Chronic stress exposure has been reported to induce dendritic remodeling in several brain regions, but it is not known whether individual neural circuits show distinct patterns of remodeling. The current study tested the hypothesis that the projections from the infralimbic (IL) area of the medial prefrontal cortex (mPFC) to the basolateral nucleus of the amygdala (BLA), a pathway relevant to stress-related mental illnesses like depression and post-traumatic stress disorder, would have a unique pattern of remodeling in response to chronic stress. The retrograde tracer FastBlue was injected into male rats’ BLA or entorhinal cortex (EC) 1 week prior to 10 days of immobilization stress. After cessation of stress, FastBlue-labeled and unlabeled IL pyaramidal neurons were loaded with fluorescent dye Lucifer Yellow to visualize dendritic arborization and spine density. As has been previously reported, randomly selected (non-FastBlue-labeled) neurons showed stress-induced dendritic retraction in apical dendrites, an effect also seen in EC-projecting neurons. In contrast, BLA-projecting neurons showed no remodeling with stress, suggesting that this pathway may be particularly resilient against the effects of stress. No neurons showed stress-related changes in spine density, contrasting with reports that more dorsal areas of the mPFC show stress-induced decreases in spine density. Such region- and circuit-specificity in response to stress could contribute to the development of stress-related mental illnesses.
PMCID: PMC2742599  PMID: 19193712
amygdala; chronic stress; connectivity; infralimbic cortex; neural plasticity; spine density
7.  The distribution of NMDA and AMPA receptor subunits at thalamo-amygdala dendritic spines 
Brain research  2007;1134(1):87-94.
Synapses onto dendritic spines in the lateral amygdala formed by afferents from the auditory thalamus represent a site of plasticity in Pavlovian fear conditioning. Previous work has demonstrated that thalamic afferents synapse onto LA spines expressing glutamate receptor (GluR) subunits, but the GluR subunit distribution at the synapse and within the cytoplasm has not been characterized. Therefore, we performed a quantitative analysis for ∝-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) receptor subunits GluR2 and GluR3 and N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2B by combining anterograde labeling of thalamo-amygdala afferents with postembedding immunoelectron microscopy for the GluRs in adult rats. A high percentage of thalamo-amygdala spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%), while a smaller proportion of spines expressed NR2B (59%). To compare across the various subunits, the cytoplasmic to synaptic ratios of GluRs were measured within thalamo-amygdala spines. Analyses revealed that the cytoplasmic pool of GluR2 receptors was twice as large compared to the GluR3, NR1 and NR2B subunits. Our data also show that in adult brain, the NR2B subunit is expressed in the majority of in thalamo-amygdala spines and that within these spines, the various GluRs are differentially distributed between synaptic and non-synaptic sites. The prevalence of the NR2B subunit in thalamo-amygdala spines provides morphological evidence supporting its role in the fear conditioning circuit while the differential distribution of the GluR subtypes may reflect distinct roles for their involvement in this circuitry and synaptic plasticity.
PMCID: PMC2359729  PMID: 17207780
GluR2; GluR3; excitatory amino acids; immunogold; NR1; NR2B; postembedding; immunohistochemistry; tracing; electron microscopy

Results 1-7 (7)