Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Neurobiol Aging ; 30(5): 782-92, 2009 May.
Article in English | MEDLINE | ID: mdl-17919783

ABSTRACT

Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.


Subject(s)
Aging/metabolism , Atrophy/enzymology , Cognition Disorders/enzymology , Prefrontal Cortex/enzymology , Protein Kinase C/metabolism , Aging/pathology , Aging/psychology , Animals , Atrophy/pathology , Atrophy/physiopathology , Benzophenanthridines/pharmacology , Cognition Disorders/pathology , Cognition Disorders/physiopathology , Dendrites/enzymology , Dendrites/pathology , Dendritic Spines/enzymology , Dendritic Spines/pathology , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Female , Macaca mulatta , Male , Nerve Degeneration/enzymology , Nerve Degeneration/pathology , Neurons/enzymology , Neurons/pathology , Neuropsychological Tests , Prefrontal Cortex/pathology , Prefrontal Cortex/physiopathology , Protein Kinase C/antagonists & inhibitors , Rats , Rats, Sprague-Dawley
2.
Epilepsia ; 50(1): 44-55, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18637833

ABSTRACT

PURPOSE: Central nervous system plasticity is essential for normal function, but can also reinforce abnormal network behavior, leading to epilepsy and other disorders. The role of altered ion channel expression in abnormal plasticity has not been thoroughly investigated. Nav1.6 is the most abundantly expressed sodium channel in the nervous system. Because of its distribution in the cell body and axon initial segment, Nav1.6 is crucial for action potential generation. The goal of the present study was to investigate the possible role of changes in Nav1.6 expression in abnormal, activity-dependent plasticity of hippocampal circuits. METHODS: We studied kindling, a form of abnormal activity-dependent facilitation. We investigated: (1) sodium channel protein expression by immunocytochemistry and sodium channel messenger RNA (mRNA) by in situ hybridization, (2) sodium current by patch clamp recordings, and (3) rate of kindling by analysis of seizure behavior. The initiation, development, and expression of kindling in wild-type mice were compared to Nav1.6 +/-med(tg) mice, which have reduced expression of Nav1.6. RESULTS: We found that kindling was associated with increased expression of Nav1.6 protein and mRNA, which occurred selectively in hippocampal CA3 neurons. Hippocampal CA3 neurons also showed increased persistent sodium current in kindled animals compared to sham-kindled controls. Conversely, Nav1.6 +/-med(tg) mice resisted the initiation and development of kindling. DISCUSSION: These findings suggest an important mechanism for enhanced excitability, in which Nav1.6 may participate in a self-reinforcing cycle of activity-dependent facilitation in the hippocampus. This mechanism could contribute to both normal hippocampal function and to epilepsy and other common nervous system disorders.


Subject(s)
Epilepsy/genetics , Epilepsy/physiopathology , Hippocampus/metabolism , Kindling, Neurologic/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Sodium Channels/genetics , Sodium Channels/metabolism , Animals , Disease Progression , Immunohistochemistry , In Situ Hybridization , NAV1.6 Voltage-Gated Sodium Channel , Patch-Clamp Techniques , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley
3.
Ann N Y Acad Sci ; 1129: 236-45, 2008.
Article in English | MEDLINE | ID: mdl-18591484

ABSTRACT

Neuropsychological and imaging studies indicate that attention deficit hyperactivity disorder (ADHD) is associated with alterations in prefrontal cortex (PFC) and its connections to striatum and cerebellum. Research in animals, in combination with observations of patients with cortical lesions, has shown that the PFC is critical for the regulation of behavior, attention, and affect using representational knowledge. The PFC is important for sustaining attention over a delay, inhibiting distraction, and dividing attention, while more posterior cortical areas are essential for perception and the allocation of attentional resources. The PFC in the right hemisphere is especially important for behavioral inhibition. Lesions to the PFC produce a profile of distractibility, forgetfulness, impulsivity, poor planning, and locomotor hyperactivity. The PFC is very sensitive to its neurochemical environment, and either too little (drowsiness) or too much (stress) catecholamine release in PFC weakens cognitive control of behavior and attention. Recent electrophysiological studies in animals suggest that norepinephrine enhances "signals" through postsynaptic alpha2A adrenoceptors in PFC, while dopamine decreases "noise" through modest levels of D1 receptor stimulation. alpha2A-Adrenoceptor stimulation strengthens the functional connectivity of PFC networks, while blockade of alpha2 receptors in the monkey PFC recreates the symptoms of ADHD, resulting in impaired working memory, increased impulsivity, and locomotor hyperactivity. Genetic alterations in catecholamine pathways may contribute to dysregulation of PFC circuits in this disorder. Medications may have many of their therapeutic effects by optimizing stimulation of alpha2A adrenoceptors and D1 receptors in the PFC, thus strengthening PFC regulation of behavior and attention.


Subject(s)
Arousal/physiology , Attention Deficit Disorder with Hyperactivity/physiopathology , Neurons/physiology , Prefrontal Cortex/physiopathology , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/genetics , Catecholamines/metabolism , Environment , Humans
4.
Learn Mem ; 15(3): 93-6, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18285467

ABSTRACT

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.


Subject(s)
Inositol 1,4,5-Trisphosphate Receptors/metabolism , Maze Learning/physiology , Memory/physiology , Prefrontal Cortex/metabolism , Signal Transduction/physiology , Small-Conductance Calcium-Activated Potassium Channels/metabolism , Animals , Apamin/administration & dosage , Apamin/pharmacology , Boron Compounds/administration & dosage , Boron Compounds/pharmacology , Injections , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/pharmacology , Male , Memory/drug effects , Oxazoles/administration & dosage , Oxazoles/pharmacology , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects
5.
Cell ; 129(2): 397-410, 2007 Apr 20.
Article in English | MEDLINE | ID: mdl-17448997

ABSTRACT

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.


Subject(s)
Ion Channels/physiology , Memory, Short-Term/physiology , Neurons/physiology , Prefrontal Cortex/physiology , Receptors, Adrenergic, alpha-2/physiology , Adrenergic alpha-Agonists/pharmacology , Animals , Cyclic AMP/metabolism , Cyclic Nucleotide-Gated Cation Channels , Dendritic Spines/chemistry , Dendritic Spines/ultrastructure , Electrophysiology , Guanfacine/pharmacology , Ion Channels/analysis , Macaca mulatta , Male , Neurons/chemistry , Prefrontal Cortex/cytology , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-2/analysis
6.
Behav Brain Funct ; 2: 8, 2006 Mar 07.
Article in English | MEDLINE | ID: mdl-16522198

ABSTRACT

BACKGROUND: Restraint stress has been shown to elicit numerous effects on hippocampal function and neuronal morphology, as well as to induce dendritic remodeling in the prefrontal cortex (PFC). However, the effects of acute restraint stress on PFC cognitive function have not been investigated, despite substantial evidence that the PFC malfunctions in many stress-related disorders. METHODS: The present study examined the effects of restraint stress on PFC function in both male rats and cycling female rats in either the proestrus (high estrogen) or estrus (low estrogen) phase of the estrus cycle. Animals were restrained for 60 or 120 minutes and then tested on spatial delayed alternation, a PFC-mediated task. Performance after stress was compared to performance on a different day under no-stress conditions, and analyzed using analysis of variance (ANOVA). RESULTS: Sixty minutes of restraint impaired only females in proestrus, while 120 minutes of restraint produced significant impairments in all animals. Increases in task completion times did not affect performance. CONCLUSION: These results demonstrate an interaction between hormonal status and cognitive response to stress in female rats, with high estrogen levels being associated with amplified sensitivity to stress. This effect has been previously observed after administration of a pharmacological stressor (the benzodiazepine inverse agonist FG7142), and results from both studies may be relevant to the increased prevalence of stress-related disorders, such as major depressive disorder, in cycling women. Overall, the results show that restraint stress has important effects on the cognitive functions of the PFC, and that hormonal influences in the PFC are an important area for future research.

7.
Biol Psychiatry ; 55(5): 512-7, 2004 Mar 01.
Article in English | MEDLINE | ID: mdl-15023579

ABSTRACT

BACKGROUND: Neuroanatomic sexual dimorphisms have been correlated with behavioral differences between healthy men and women. We have reported higher orbitofrontal cortex to amygdala ratio (OAR) in women than men. Although gender differences in schizophrenia are evident clinically and correlate with neuroanatomic measures, their relationship to OAR has not been examined. METHODS: Magnetic resonance imaging was performed in 31 neuroleptic-naïve schizophrenic patients (16 men) and 80 healthy volunteers (34 men), aged less than 50 years. An automated tissue segmentation procedure was combined with expert-guided parcellation of orbitofrontal and amygdala volumes. RESULTS: Men with schizophrenia had increased OAR relative to healthy men, whereas women had decreased OAR. Increased OAR in men with schizophrenia reflected abnormally low amygdala volumes, whereas decreased OAR in women reflected abnormally low orbitofrontal volumes. Less severe negative symptoms were associated with increased OAR in men but with decreased OAR in women. In men, increased amygdala volume was associated with greater symptom severity, whereas in women higher volumes of both amygdala and orbitofrontal regions were associated with lesser severity of negative symptoms. CONCLUSIONS: These opposite OAR abnormalities, whereby men show feminization and women masculinization, suggest gender-mediated effects of the underlying neuropathologic processes. The correlations with symptom severity suggest that neuroanatomic abnormalities in OAR reflect compensatory brain changes.


Subject(s)
Affective Symptoms/etiology , Amygdala/pathology , Frontal Lobe/pathology , Schizophrenia/complications , Schizophrenia/pathology , Sex Characteristics , Adult , Affective Symptoms/diagnosis , Amygdala/physiopathology , Anthropometry , Female , Frontal Lobe/physiopathology , Humans , Magnetic Resonance Imaging/statistics & numerical data , Male , Psychiatric Status Rating Scales/statistics & numerical data , Schizophrenia/diagnosis , Severity of Illness Index
8.
Front Biosci ; 7: c83-96, 2002 Aug 01.
Article in English | MEDLINE | ID: mdl-12133810

ABSTRACT

As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Chemistry, Pharmaceutical/trends , Drug Design , Orphan Drug Production , Animals , Chemistry, Pharmaceutical/economics , Cooperative Behavior , Drug Industry/economics , Drug Industry/trends , Foundations/trends , Humans , Orphan Drug Production/economics , Research Support as Topic/economics , Research Support as Topic/trends
SELECTION OF CITATIONS
SEARCH DETAIL
...