Biomedical subjects

Kristen L Brunson

Publications and source records attributed to Kristen L Brunson.

11 recordsLinked to original sources

PubMed2006

Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects.

Whereas genetic factors contribute crucially to brain function, early-life events, including stress, exert long-lasting influence on neuronal function. Here, we focus on the hippocampus as the target of these early-life events because of its crucial role in learning and memory. Using a novel immature-rodent model, we describe the deleterious consequences of chronic early-life 'psychological' stress on hippocampus-dependent cognitive tasks. We review the cellular mechanisms involved and discuss the roles of stress-mediating molecules, including corticotropin releasing hormone, in the process by which stress impacts the structure and function of hippocampal neurons.

Adaptation, Physiological↗

PubMed2005

Mechanisms of late-onset cognitive decline after early-life stress.

Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of "acquired" contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life "psychological" stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period. At the cellular level, disturbances to hippocampal long-term potentiation paralleled the behavioral changes and were accompanied by dendritic atrophy and mossy fiber expansion. These findings constitute the first evidence that a short period of stress early in life can lead to delayed, progressive impairments of synaptic and behavioral measures of hippocampal function, with potential implications to the basis of age-related cognitive disorders in humans.

Age Factors↗

PubMed2005

Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor.

Early-life experience, including maternal care, influences hippocampus-dependent learning and memory throughout life. Handling of pups during postnatal d 2-9 (P2-9) stimulates maternal care and leads to improved memory function and stress-coping. The underlying molecular mechanisms may involve early (by P9) and enduring reduction of hypothalamic corticotropin-releasing factor (CRF) expression and subsequent (by P45) increase in hippocampal glucocorticoid receptor (GR) expression. However, whether hypothalamic CRF levels influence changes in hippocampal GR expression (and memory function), via reduced CRF receptor activation and consequent lower plasma glucocorticoid levels, is unclear. In this study we administered selective antagonist for the type 1 CRF receptor, NBI 30775, to nonhandled rats post hoc from P10-17 and examined hippocampus-dependent learning and memory later (on P50-70), using two independent paradigms, compared with naive and vehicle-treated nonhandled, and naive and antagonist-treated handled rats. Hippocampal GR and hypothalamic CRF mRNA levels and stress-induced plasma corticosterone levels were also examined. Transient, partial selective blockade of CRF1 in nonhandled rats improved memory functions on both the Morris watermaze and object recognition tests to levels significantly better than in naive and vehicle-treated controls and were indistinguishable from those in handled (naive, vehicle-treated, and antagonist-treated) rats. GR mRNA expression was increased in hippocampal CA1 and the dentate gyrus of CRF1-antagonist treated nonhandled rats to levels commensurate with those in handled cohorts. Thus, the extent of CRF1 activation, probably involving changes in hypothalamic CRF levels and release, contributes to the changes in hippocampal GR expression and learning and memory functions.

Age Factors↗

PubMed2005

Hippocampal neurogenesis is not enhanced by lifelong reduction of glucocorticoid levels.

Neurogenesis of dentate gyrus granule cells is generally considered to be negatively regulated by glucocorticoids. We tested the hypothesis that exposure to low plasma corticosteroid levels starting in the early postnatal period enhances granule cell proliferation rate during adulthood. Rat pups were adrenalectomized (ADX) on postnatal day 10 and were then "clamped" throughout life at low corticosterone levels via oral supplementation. Neurogenesis was determined using BrdU immunochemistry at 3 and 12 months in clamped rats as compared with age-matched, sham-operated controls. Rate of neurogenesis did not differ between the groups at either 3 or 12 months. It was significantly lower in 12-month-old compared with 3-month-old rats, despite the presence of an age-dependent increase of plasma corticosterone only in the sham-ADX rats. Granule cell layer volume, granule cell density, and granule cell degeneration (determined using apoptotic markers) were indistinguishable in the two groups, further supporting the comparable rate of neurogenesis under differing chronic glucocorticoid levels. In addition, whereas acute deprivation of plasma glucocorticoids (adrenalectomy) in adult rats evoked a burst of granule cell neurogenesis, complete elimination of these hormones (by stopping hormone supplementation) in adult, early-life ADX/clamped rats did not. These data do not support a simple inverse relationship between chronic plasma glucocorticoid levels and granule cell neurogenesis. Specifically, chronic modulation of glucocorticoid levels commencing early in life evokes additional, adaptive, and compensatory mechanisms that contribute to the regulation of granule cell proliferation.

Adrenalectomy↗

PubMed2005

Endogenous neuropeptide Y prevents recurrence of experimental febrile seizures by increasing seizure threshold.

Febrile seizures (FSs) typically occur at the onset of fever and do not recur within the same febrile episode despite enduring or increased hyperthermia. Recurrent seizures during the same febrile episode are considered "complex," with potentially altered prognosis. A characterized immature rat model of FS was used to test the hypotheses that (1) a first FS influences the threshold temperature for subsequent ones, and (2) the underlying mechanisms involve the release and actions of the endogenous inhibitory hippocampal neuropeptide Y (NPY). Experimental FSs were induced two or three times, at 3- to 4-h intervals, and threshold temperatures measured. To determine the potential effects of seizure-induced endogenous NPY on thresholds for subsequent seizures, an antagonist of the major hippocampal NPY receptor (type 2) was infused prior to induction of the second seizure. As an indicator of NPY release, NPY expression was determined 4 and 24 h later. Threshold core and brain temperatures for hyperthermic seizures were consistent with those observed during human fever. Threshold temperatures for a second and third seizure were significantly and progressively higher than those required for the first. This "protective" effect involved induction of endogenous NPY because it was abolished by the NPY antagonist. In addition, NPY mRNA expression was increased in dentate gyrus, CA3 and CA1, after an experimental FS, consistent with peptide release. Collectively these data indicate that the absence of repetitive seizures during a febrile episode involves the inhibitory actions of endogenous NPY, suggesting that the signaling cascade triggered by this peptide might provide targets for therapeutic intervention.

Age Factors↗

PubMed2004

Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus.

The interplay of environmental and genetic factors in the developmental organization of the hippocampus has not been fully elucidated. The neuropeptide corticotropin-releasing factor (CRF) is released from hippocampal interneurons by environmental signals, including stress, to increase synaptic efficacy. In the early postnatal hippocampus, we have previously characterized a transient population of CRF-expressing Cajal-Retzius-like cells. Here we queried whether this stress-activated neuromodulator influences connectivity in the developing hippocampal network. Using mice deficient in the principal hippocampal CRF receptor [CRF(1)(-/-)] and organotypic cultures grown in the presence of synthetic CRF, or CRF receptor antagonists, we found robust effects of CRF on dendritic differentiation in hippocampal neurons. In CRF(1)(-/-) mice, the dendritic trees of hippocampal principal cells were exuberant, an effect that was induced in normal hippocampi in vitro by the presence of CRF(1) antagonists. In both cases, total dendritic length and dendritic branching were significantly increased. In contrast, exogenous synthetic CRF blunted the dendritic growth in hippocampal organotypic cultures. Taken together, these findings suggest that endogenous CRF, if released excessively by previous early postnatal stress, might influence neuronal connectivity and thus function of the immature hippocampus.

Animals↗

PubMed2004

Region-specific onset of handling-induced changes in corticotropin-releasing factor and glucocorticoid receptor expression.

Early-life experience including maternal care profoundly influences hormonal stress responses during adulthood. Daily handling on postnatal day (P) 2-9, eliciting augmented maternal care upon returning pups to their cage, permanently modifies the expression of the stress neuromodulators corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR). We have previously demonstrated reduced hypothalamic CRF expression already at the end of the handling period, followed by enhanced hippocampal GR mRNA levels (by P45). However, the initial site(s) and time of onset of these enduring changes have remained unclear. Therefore, we used semiquantitative in situ hybridization to delineate the spatiotemporal evolution of CRF and GR expression throughout stress-regulatory brain regions in handled (compared with undisturbed) pups. Enhanced CRF mRNA expression was apparent in the amygdaloid central nucleus (ACe) of handled pups already by P6. By P9, the augmented CRF mRNA levels persisted in ACe, accompanied by increased peptide expression in the bed nucleus of the stria terminalis and reduced expression in the paraventricular nucleus. The earliest change in GR consisted of reduced expression in the ACe of handled pups on P9, a time point when hippocampal GR expression was not yet affected. Thus, altered gene expression in ACe, bed nucleus of the stria terminalis as well as paraventricular nucleus may contribute to the molecular cascade by which handling (and increased maternal care) influences the stress response long term.

Aging↗

PubMed2003

Stress and the developing hippocampus: a double-edged sword?

The mechanisms that regulate neuronal function are a sum of genetically determined programs and experience. The effect of experience on neuronal function is particularly important during development, because early-life positive and adverse experience (stress) may influence the still "plastic" nervous system long-term. Specifically, for hippocampal-mediated learning and memory processes, acute stress may enhance synaptic efficacy and overall learning ability, and conversely, chronic or severe stress has been shown to be detrimental. The mechanisms that enable stress to act as this "double-edged sword" are unclear. Here, we discuss the molecular mediators of the stress response in the hippocampus with an emphasis on novel findings regarding the role of the neuropeptide known as corticotropin-releasing hormone (CRH). We highlight the physiological and pathological roles of this peptide in the developing hippocampus, and their relevance to the long-term effects of early-life experience on cognitive function during adulthood.

Animals↗

PubMed2002

Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation.

It is well established that adrenal stress hormone-induced activation of the basolateral complex of the amygdala (BLA) influences memory consolidation. The present experiments investigated the involvement of corticotropin-releasing hormone (CRH) in the BLA in modulating memory consolidation. Bilateral infusions of the CRH receptor antagonist [9-41]-alpha-helical CRH (0.3, 1.0, or 3.0 microg in 0.2 microl) administered into the BLA of male Sprague-Dawley rats immediately after aversively motivated inhibitory avoidance training produced dose-dependent impairment of 48-h retention performance. Because the CRH receptor antagonist infusions did not impair retention when administered into the BLA 3 h after training, the retention impairment selectively was due to time-dependent influences on memory consolidation. Furthermore, because immediate posttraining infusions of [9-41]-alpha-helical CRH into the adjacent central nucleus of the amygdala (CEA) were ineffective, the effect selectively involved the BLA. Immunocytochemistry showed that the aversive training stimulus of a single, brief footshock increased CRH levels in the CEA. These findings indicate that activation of CRH receptors in the BLA, likely by training-induced release of endogenous peptide originating from the CEA, participates in mediating stress effects on memory consolidation.

Amygdala↗

PubMed2002

Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain.

In addition to regulating the neuroendocrine stress response, corticotropin-releasing hormone (CRH) has been implicated in both normal and pathological behavioral and cognitive responses to stress. CRH-expressing cells and their target neurons possessing CRH receptors (CRF1 and CRF2) are distributed throughout the limbic system, but little is known about the regulation of limbic CRH receptor function and expression, including regulation by the peptide itself. Because CRH is released from limbic neuronal terminals during stress, this regulation might play a crucial role in the mechanisms by which stress contributes to human neuropsychiatric conditions such as depression or posttraumatic stress disorder. Therefore, these studies tested the hypothesis that CRH binding to CRF1 influenced the levels and mRNA expression of this receptor in stress-associated limbic regions of immature rat. Binding capacities and mRNA levels of both CRF1 and CRF2 were determined at several time points after central CRH administration. CRH downregulated CRF1 binding in frontal cortex significantly by 4 h. This transient reduction (no longer evident at 8 h) was associated with rapid increase of CRF1 mRNA expression, persisting for >8 h. Enhanced CRF1 expression-with a different time course-occurred also in hippocampal CA3, but not in CA1 or amygdala, CRF2 binding and mRNA levels were not altered by CRH administration. To address the mechanisms by which CRH regulated CRF1, the specific contributions of ligand-receptor interactions and of the CRH-induced neuronal stimulation were examined. Neuronal excitation without occupation of CRF1 induced by kainic acid, resulted in no change of CRF1 binding capacity, and in modest induction of CRF1 mRNA expression. Furthermore, blocking the neuroexcitant effects of CRH (using pentobarbital) abolished the alterations in CRF1 binding and expression. These results indicate that CRF1 regulation involves both occupancy of this receptor by its ligand, as well as "downstream" cellular activation and suggest that stress-induced perturbation of CRH-CRF1 signaling may contribute to abnormal neuronal communication after some stressful situations.

Amygdala↗

PubMed2002

Stressed-out, or in (utero)?

The molecular and cellular mechanisms by which plasticity is induced in the mature CNS (and, specifically, in the hippocampus) by environmental input are progressively being elucidated. However, the mechanisms - and even the existence - of functional and structural effects of environmental input (and, particularly, stress) early in life are incompletely understood. Here, we discuss recent evidence that stressful stimuli have a significant impact on neonatal (rat) and prenatal (human) hippocampal function and integrity. Stressful signals provoke expression and release of neuromodulators, including the peptide corticotropin-releasing hormone (CRH), leading to activation of CRH receptors on principal hippocampal neurons. Although physiological activation of these receptors promotes synaptic efficacy, pathological levels of CRH at hippocampal synapses contribute to neuronal death. Thus, early-life stress could constitute a 'double-edged sword': mild stress might promote hippocampal-dependent cognitive function, whereas severe stress might impair neuronal function and survival, both immediately and in the long-term. Importantly, these CRH-mediated processes could be targets of preventive and interventional strategies.

Aging↗