Biomedical subjects

Pramod K Dash

Publications and source records attributed to Pramod K Dash.

34 records · Page 2Linked to original sources

PubMed2004

Intra-medial prefrontal administration of SCH-23390 attenuates ERK phosphorylation and long-term memory for trace fear conditioning in rats.

The prefrontal cortex is known to be involved in the acquisition of trace conditioning, a higher-cognitive form of Pavlovian conditioning in which a conditioned stimulus and an unconditioned stimulus are separated by a time gap. We have recently reported that medial prefrontal (mPFC) extracellular-signal regulated kinase (Erk) phosphorylation is involved in the long-term memory storage of trace fear conditioning. Because of the important role dopamine D1 receptors play in prefrontal function, such as working memory, and due to evidence that dopamine D1 receptor activity can modulate plasticity, we investigated their role in prefrontal Erk phosphorylation following trace fear conditioning. We found that inhibition of dopamine D1 receptors through intra-mPFC infusion of SCH-23390 (1 microg/0.5 microL) 15 min prior to trace fear conditioning resulted in a decrease in training-related Erk phosphorylation. Additionally, pre-training intra-mPFC infusion of SCH-23390 also resulted in the impairment of long-term retention of CS-US association. These findings implicate mPFC dopamine D1 receptor activity in the storage of long-term memory for higher-cognitive associative tasks.

Analysis of Variance↗

PubMed2004

Nonredundant roles for hippocampal and entorhinal cortical plasticity in spatial memory storage.

Recently, it has been demonstrated that targeted blockade of the extracellular signal-regulated kinase (ERK) cascade in either the entorhinal cortex (EC) or hippocampus (HIP) results in spatial memory deficits. However, it is unclear if ERK-mediated plasticity in these structures has redundant functions or unique roles. In this report, we contrast the role of long-term plasticity in these two structures with side-by-side comparisons of the effects of PD098059 infusion following water maze training. Analysis of performance during the long-term retention test indicates a role for plasticity in the EC in storing broad location information. In contrast, blocking plasticity in the HIP resulted in deficits in indices of precise location information and goal-directed navigational error. To distinguish between a navigational and location deficit, a "two-room" experimental design was employed. Training in the first room allowed animals to consolidate information regarding navigational strategies prior to training and drug infusion in the second room. Hippocampal-PD098059-infused animals demonstrated behavior suggestive of an expanded representation of the platform location and, thus, a loss of precise location information, suggesting that plasticity in these structures is involved in nonredundant, but complementary, processes necessary for spatial memory.

Animals↗

PubMed2004

A molecular description of brain trauma pathophysiology using microarray technology: an overview.

It has been estimated that 50% of human transcriptome, the collection of mRNA in a cell, is expressed in the brain, making it one of the most complex organs to understand in terms of genomic responses to injury. The availability of genome sequences for several organisms coupled with the increasing affordability of microarray technologies makes it feasible to monitor the mRNA levels of thousands of genes simultaneously. In this paper, we provide an overview of findings using both cDNA- and oligonucleotide-based microarray analyses after experimental traumatic brain injury (TBI). Specifically, the utility of this methodology as a means of cataloging the biochemical sequelae of brain trauma and elucidating novel genes or pathways for further study is discussed. Furthermore, we offer future directions for the continued evaluation of microarray results and discuss the usefulness of microarray techniques as a testing format for determining the efficacy of mechanism-based therapies.

Animals↗

PubMed2004

Post-trauma administration of caffeine plus ethanol reduces contusion volume and improves working memory in rats.

It has been demonstrated that ethanol exerts dose-dependent effects, both beneficial and detrimental, on the outcome of traumatic brain injury (TBI). Recently, it has been reported that co-administration of caffeine (10 mg/kg) and a low amount of alcohol (0.65 g/kg; caffeinol) reduces cortical infarct volume up to 80%, and improves motor coordination, following a rodent model of reversible common carotid/middle cerebral artery occlusion. However, the protective effects of caffeinol following other CNS insults, nor its influence on cognitive function, have been examined. Using a controlled cortical impact model of brain injury, the effect of caffeinol administration on TBI-associated motor and cognitive deficits was assessed. When given 15 min following injury, caffeinol reduced cortical tissue loss and improved working memory. However, no influence on motor skills, Morris water maze performance or associative learning and memory was observed. Delayed administration (6 h post-injury) of caffeinol containing a dose of ethanol (1 g/kg) previously demonstrated to improve motor performance eliminated the working memory benefit and cortical protection. These results indicate that early administration of caffeinol may be beneficial in lessening some of the deficits and cortical tissue loss associated with brain trauma.

Animals↗

PubMed2003

Enhancement of tyrosine hydroxylase phosphorylation and activity by glial cell line-derived neurotrophic factor.

Although glial cell-line derived neurotrophic factor (GDNF) acts as a potent survival factor for dopaminergic neurons, it is not known whether GDNF can directly alter dopamine synthesis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for dopamine biosynthesis, and its activity is regulated by phosphorylation on three seryl residues: Ser-19, Ser-31, and Ser-40. Using a TH-expressing human neuroblastoma cell line and rat primary mesencephalic neuron cultures, the present study examined whether GDNF alters the phosphorylation of TH and whether these changes are accompanied by increased enzymatic activity. Exposure to GDNF did not alter the TH protein level in either neuroblastoma cells or in primary neurons. However, significant increases in the phosphorylation of Ser-31 and Ser-40 were detected within minutes of GDNF application in both cell types. Enhanced Ser-31 and Ser-40 phosphorylation was associated with increased TH activity but not dopamine synthesis in neuroblastoma cells, possibly because of the absence of l-aromatic amino acid decarboxylase activity in these cells. In contrast, increased phosphorylation of Ser-31 and Ser-40 was found to enhance dopamine synthesis in primary neurons. Pharmacological experiments show that Erk and protein kinase A phosphorylate Ser-31 and Ser-40, respectively, and that their inhibition blocked both TH phosphorylation and activity. Our results indicate that, in addition to its role as a survival factor for dopaminergic neurons, GDNF can directly increase dopamine synthesis.

Cells, Cultured↗

PubMed2003

Inhibition of conditioned stimulus pathway phosphoprotein 24 expression blocks the development of intermediate-term memory in Hermissenda.

Studies of memory consolidation have identified multiple phases or stages in the formation of memories. The multiple components of memory can be broadly divided into the three phases; short-term, intermediate-term, and long-term. Although molecular changes underlying short- and long-term memory have been examined extensively, the molecular mechanisms supporting the formation of intermediate-term memory are poorly understood. In several examples of cellular and synaptic plasticity, intermediate memory depends on translation but not transcription. One-trial conditioning in Hermissenda results in the development of intermediate memory that is associated with enhanced cellular excitability and the phosphorylation of a 24 kDa protein referred to as conditioned stimulus pathway phosphoprotein (Csp24). Using amino acid sequences derived from Csp24 peptide fragments, a full-length cDNA was cloned and shown to contain multiple beta-thymosin-like domains. The expression of Csp24 and the development of enhanced excitability, a characteristic of intermediate memory, were blocked by antisense oligonucleotide-mediated downregulation of Csp24 without affecting the induction of immediate enhanced excitability, a characteristic of short-term memory. These results demonstrate that the synthesis of Csp24 is required for the development and maintenance of intermediate memory.

Action Potentials↗

PubMed2003

Intrahippocampal infusion of a cyclooxygenase-2 inhibitor attenuates memory acquisition in rats.

Cyclooxygenase-2 (COX-2) inhibitors have been shown to block memory retention in rodents following Morris water maze training and in chicks following a passive avoidance task. However, the role of COX-2 in acquisition has not been analyzed. We show that pre-training intrahippocampal infusion of a COX-2 specific inhibitor (celecoxib) attenuated water maze acquisition. These findings, along with previously published reports, implicate COX-2 activity in both memory acquisition and retention.

Animals↗

PubMed2003

Differential effects of traumatic brain injury on the cytochrome p450 system: a perspective into hepatic and renal drug metabolism.

Traumatic brain injury is known to cause several secondary effects, one of which is altered drug clearance. Given the fact that patients who sustain TBI are subsequently treated with a variety of pharmacological agents for the purpose of either neuroprotection or physiological support, it is imperative to clarify changes in expression and/or activities of enzymes involved in clearing drugs. The mixed function oxidase system, which consists of cytochrome P450 and cytochrome P450 reductase, plays a vital role in phase I drug metabolism. This paper addresses the issue as to what extent TBI affects the levels and activity of various rat CYP450 subfamilies. Our results show that TBI induces tissue-specific and time-dependent alterations. Total hepatic CYP450 content showed a biphasic response with a decrease seen at 24 h followed by an increase at 2 weeks. CYP450 reductase, in contrast, showed an opposite temporal profile. Immunoblot analyses and marker substrate metabolism demonstrated a clear decrease in hepatic CYP1A levels while a significant increase in kidney was seen at both 24 h and 2 weeks. A dramatic induction of CYP3A was evident at 2 weeks in liver, while no changes were noticed in CYP2B or CYP2D subfamilies. CYP4F subfamily showed induction in kidney only. Collectively, the data reveal the differential effects of TBI on hepatic and renal drug metabolism.

Animals↗

PubMed2003

Expression of the prodynorphin gene after experimental brain injury and its role in behavioral dysfunction.

Traumatic brain injury (TBI) causes excess release of neurotransmitters, such as glutamate, and increases intracellular calcium levels. Elevated levels of calcium, and perhaps other intracellular second messengers, as a result of TBI can alter the expression of many genes. The protein products of some of these genes may be signals for TBI-associated memory dysfunction. Therefore, identification of genes whose expression is altered after TBI in the hippocampus, a structure in the medial temporal lobe that plays a critical role in memory formation and storage, and elucidation of the role(s) of their protein products may shed light on the molecular mechanisms underlying TBI-elicited memory dysfunction. The prodynorphin gene is expressed in hippocampal granule cells, and its expression has been reported to be enhanced as a result of elevated intracellular calcium. The prodynorphin protein is proteolytically cleaved to generate multiple dynorphin peptides, which can modulate neurotransmitter release through the activation of presynaptic kappa opioid receptors. In this study, we report that 1) TBI transiently increases prodynorphin mRNA in the hippocampus, 2) dynorphin peptide immunoreactivity is enhanced for up to 24 hr after TBI and 3) intracerebroventricular infusion of the kappa receptor antagonist nor-binaltorphimine (nor-BNI) impairs subsequent performance in a spatial memory task. These results suggest that dynorphin action may serve a beneficial role after TBI.

Animals↗

PubMed2002

High-density microarray analysis of hippocampal gene expression following experimental brain injury.

Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. Traumatic brain injury (TBI) often causes spatial memory deficits, which are thought to arise from the death as well as the dysfunction of hippocampal neurons. Cell death and dysfunction are commonly associated with and often caused by altered expression of specific genes. The identification of the genes involved in these processes, as well as those participating in postinjury cellular repair and plasticity, is important for the development of mechanism-based therapies. To monitor the expression levels of a large number of genes and to identify genes not previously implicated in TBI pathophysiology, a high-density oligonucleotide array containing 8,800 genes was interrogated. RNA samples were prepared from ipsilateral hippocampi 3 hr and 24 hr following lateral cortical impact injury and compared to samples from sham-operated controls. Cluster analysis was employed using statistical algorithms to arrange the genes according to similarity in patterns of expression. The study indicates that the genomic response to TBI is complex, affecting approximately 6% (at the time points examined) of the total number of genes examined. The identity of the genes revealed that TBI affects many aspects of cell physiology, including oxidative stress, metabolism, inflammation, structural changes, and cellular signaling. The analysis revealed genes whose expression levels have been reported to be altered in response to injury as well as several genes not previously implicated in TBI pathophysiology.

Animals↗

PubMed2002

Acute ethanol intake attenuates inflammatory cytokines after brain injury in rats: a possible role for corticosterone.

It has been reported that acute ethanol intoxication exerts dose-dependent effects, both beneficial and detrimental, on the outcome of traumatic brain injury (TBI), although the mechanism(s) has not been determined. Given that pro-inflammatory cytokines are either neuroprotective or neurotoxic, depending on their tissue levels, ethanol-induced alterations in brain cytokine production may be involved in determining the recovery after TBI. The present study was undertaken to examine the effect of acute ethanol pretreatments (producing blood alcohol concentrations of 100+/-16 mg/dL, and 220+/-10 mg/dL, considered low and intoxicating doses, respectively) on interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels in discrete brain regions. In addition, serum corticosterone levels were also examined because the hormone is a modulator of cytokine production, its secretion is stimulated by ethanol, and it has been associated with the severity of post-injury neurologic dysfunction. The data presented in this report demonstrate that moderate cortical impact brain injury elicits a marked increase in IL-1beta and TNF-alpha in the injured cortex as well as in the hippocampus ipsilateral to the injury. Ethanol pretreatment lowered cytokine levels in the cortex, hippocampus and hypothalamus in a dose-dependent manner after TBI compared to the untreated injured rats. Serum corticosterone levels were markedly increased in the injured rats, and were further augmented in the ethanol-pretreated injured animals in a dose-dependent manner. Our findings suggest that ethanol-induced decrease in pro-inflammatory cytokine production may be linked to increased circulating corticosterone, both of which may contribute to the outcome of brain injury.

Animals↗

PubMedDate not supplied

Extracellular signal-regulated kinase activity in the entorhinal cortex is necessary for long-term spatial memory.

Lesion studies have provided evidence that the entorhinal cortex (EC) participates in spatial memory. However, the molecular cascades that underlie memory-associated changes in the EC and its specific role in spatial memory, however, have not been clearly delineated. Recently, it has been shown that activation of extracellular signal-regulated kinase (Erk, a mitogen-activated protein kinase family member) in the dorsal hippocampus is necessary for spatial memory. To examine whether similar mechanisms are used for spatial memory storage in the EC, Erk activity was inhibited after training in the Morris water maze. Bilateral infusion of the mitogen-activated protein kinase kinase inhibitor PD098059 into the EC immediately after training resulted in a memory deficit observed during a retention test performed 48 h later. This deficit was abolished with pretraining in a different water maze in which animals were able to learn the general task requirements and the appropriate search strategies. The absence of a deficit indicates that Erk activity in the EC may be involved in storing the task requirements or the search strategies. The findings presented in this article are consistent with the idea that the EC is involved in spatial memory and indicate that Erk activity is necessary for memory consolidation in this structure.

Animals↗

PubMedDate not supplied

Intrahippocampal wortmannin infusion enhances long-term spatial and contextual memories.

The transition from short- to long-term memory involves several biochemical cascades, some of which act in an antagonistic manner. Post-training intrahippocampal administration of wortmannin, a pharmacological inhibitor of phosphatidylinositol 3-kinase, had no effect on memory tested 3 h later, but improved long-term memory tested 48 h following the completion of training. This effect was seen in two hippocampus-dependent tasks: the Morris water maze, using both massed and distributed training paradigms, and contextual fear conditioning. The improvement of long-term memory appears to be the result of enhanced consolidation, as wortmannin had no effect on memory recall. These results are consistent with the hypothesis that memory consolidation involves competing processes, and that blockade of an inhibitory constraint facilitates the consolidation process.

Androstadienes↗

PubMedDate not supplied

A cell-permeable phospholipase Cgamma1-binding peptide transduces neurons and impairs long-term spatial memory.

Growth factor-mediated signaling has emerged as an essential component of memory formation. In this study, we used a phospholipase C gamma 1 (PLCgamma1) binding, cell-penetrating peptide to sequester PLCgamma1 away from its target, the phosphotyrosine residues within the activated growth factor receptor. Peptides appear to transduce neurons but not astrocytes or oligodendrocytes. The presence of the peptides in the hippocampus during training in the Morris water maze significantly impaired long-term memory, but not memory acquisition. These results, along with previous studies on extracellular signal-regulated kinase (ERK) and phosphoinositide-3 kinase (PI3K), implicate all three key growth factor receptor-activated intracellular signaling pathways in memory storage.

Animals↗

PubMedDate not supplied

A role for prefrontal calcium-sensitive protein phosphatase and kinase activities in working memory.

The prefrontal cortex is involved in the integration and interpretation of information for directing thoughts and planning action. Working memory is defined as the active maintenance of information in mind and is thought to lie at the core of many prefrontal functions. Although dopamine and other neurotransmitters have been implicated, the intracellular events activated by their receptors that influence working memory are poorly understood. We demonstrate that working memory involves transient changes in prefrontal G(q/11)-signaling and in calcium-dependent intracellular protein phosphatase and kinase activity. Interestingly, inhibition of the calcium activated phosphatase calcineurin impaired, while calcium/calmodulin dependent kinase II (CaMKII) and calcium-dependent protein kinase C (PKC) enhanced, working memory. Our findings suggest that the active maintenance of information required for working memory involves transient changes in the balance of these enzymes' activities.

Animals↗

PubMedDate not supplied

Distinct prefrontal molecular mechanisms for information storage lasting seconds versus minutes.

The prefrontal cortex (PFC) is known to actively hold information "online" for a period of seconds in working memory for guiding goal-directed behavior. It has been proposed that relevant information is stored in other brain regions, which is retrieved and held in working memory for subsequent assimilation by the PFC in order to guide behavior. It is uncertain whether PFC stores information outside the temporal limits of working memory. Here, we demonstrate that although enhanced cAMP-dependent protein kinase A (PKA) activity in the PFC is detrimental to working memory, it is required for performance in tasks involving conflicting representations when memory storage is needed for minutes. This study indicates that distinct molecular mechanisms within the PFC underlie information storage for seconds (working memory) and for minutes (short-term memory). In addition, our results demonstrate that short-term memory storage within the prefrontal cortex is required for guiding behavior in tasks with conflicts and provides a plausible mechanism by which the prefrontal cortex executes cognitive control.

Animals↗