Prefrontal Cortex Pathway Research Articles

Effects of chronic REM sleep restriction on D1 receptor and related signal pathways in rat prefrontal cortex.

The prefrontal cortex (PFC) mediates cognitive function that is sensitive to disruption by sleep loss, and molecular mechanisms regulating neural dysfunction induced by chronic sleep restriction (CSR), particularly in the PFC, have yet to be completely understood. The aim of the present study was to investigate the effect of chronic REM sleep restriction (REM-CSR) on the D1 receptor (D1R) and key molecules in D1R' signal pathways in PFC. We employed the modified multiple platform method to create the REM-CSR rat model. The ultrastructure of PFC was observed by electron microscopy. HPLC was performed to measure the DA level in PFC. The expressions of genes and proteins of related molecules were assayed by real-time PCR and Western blot, respectively. The general state and morphology of PFC in rats were changed by CSR, and DA level and the expression of D1R in PFC were markedly decreased (P < 0.01, P < 0.05); the expression of phosphor-PKAcα was significantly lowered in CSR rats (P < 0.05). The present results suggested that the alteration of neuropathology and D1R expression in PFC may be associated with CSR induced cognitive dysfunction, and the PKA pathway of D1R may play an important role in the impairment of advanced neural function.

Encoding of fear learning and memory in distributed neuronal circuits.

How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.

Effects of Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats

To observe the effects of Mongolian pharmaceutical Betel shisanwei ingredients pill on AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depressive rats. Sixty male Wistar rats were randomly divided into six groups according to the sugar consumption test (10 rats in each group), normal control group,model group,fluoxetine group (3.3 mg x kg(-1)) and low dose, medium dose and high dose group (0.25, 0.5, 1 g x kg(-1)) of Betel shisanwei ingredients pill. Except the normal control,the other groups were treated with the chronic unpredictable mild stress stimulation combined with lonely raising for 28 days. 10 mL x kg(-1) of drugs were given to each rat once daily,continuously for 28 days. The AC activity of the hippocampus and prefrontal cortex were determined by radiation immunity analysis (RIA), while cAMP and PKA quantity were determinated by Enzyme-linked immunosorbent (ELISA). The AC activity, cAMP and PKA quantity of hippocampus and prefrontal of mouse model of Chronic stress depression decreased significantly than those of control group (P < 0.05 or P < 0.01). However, the AC activity, cAMP and PKA quantity of rat hippocampus and prefrontal cortex in the fluoxetine group and the Mongolian pharmaceutical Betel shisanwei ingredients pill group indecreased significantly than those of model group (P < 0.01 or P < 0.05). Especially for the high dose group of Mongolian pharmaceutical Betel shisanwei ingredients pill. The AC-cAMP-PKA signal transduction pathways in hippocampus and prefrontal cortex of depression model of rats is down-regulated, whereas Mongolian pharmaceutical Betel shisanwei ingredients pill could up-regulated it to resist depression.

Low‐Dose Dexamethasone Treatment Promotes the Pro‐Survival Signalling Pathway in the Adult Rat Prefrontal Cortex

Synthetic glucocorticoid dexamethasone (DEX), a highly potent anti-inflammatory and immunosuppressive agent, is widely used in the treatment of brain cancer, as well as for inflammatory and autoimmune diseases. The present study aimed to determine whether low-dose subchronic DEX treatment (100μg/kg for eight consecutive days) exerts long-term effects on apoptosis in the adult rat prefrontal cortex (PFC) by examining the expression of cell death-promoting molecules [poly(ADP-ribose) polymerase (PARP), p53, procaspase 3, cleaved caspase 3, Bax] and cell-survival molecules (AKT, Bcl-2). The results obtained revealed that body, thymus and adrenal gland weights, as well corticosterone levels, in the serum and PFC were reduced 1day after the last DEX injection. In the PFC, DEX caused activation of AKT, augmentation of pro-survival Bcl-2 protein and an enhanced Bcl-2/Bax protein ratio, as well Bcl-2 translocation to the mitochondria. An unaltered profile with respect to the protein expression of apoptotic molecules PARP, procaspase 3 and Bax was detected, whereas p53 protein was decreased. Reverse transcriptase -polymerase chain reaction analysis showed a decrease of p53 mRNA levels and no significant difference in Bcl-2 and Bax mRNA expression in DEX-treated rats. Finally, a DNA fragmentation assay and Fluoro-Jade staining demonstrated no considerable changes in apoptosis in the rat PFC. Our findings support the concept that low-dose DEX creates a hypocorticoid state in the brain and also indicate that subchronic DEX treatment activates the pro-survival signalling pathway but does not change apoptotic markers in the rat PFC. This mechanism might be relevant for the DEX-induced apoptosis resistance observed during and after chemotherapy of patients with brain tumours.

Glucocorticoid exerts its non‐genomic effect on IPSC by activation of a phospholipase C‐dependent pathway in prefrontal cortex of rats

In response to stressor, the brain activates a comprehensive stress system. Among others, this stress system causes release of glucocorticoids that also feed back to the brain. Glucocorticoids affect brain function by activation of both delayed, genomic and rapid, non-genomic mechanisms in rodents. Here we report that application of the potent glucocorticoid receptor agonist dexamethasone (DEX) caused a rapid increase of spontaneous and miniature inhibitory postsynaptic currents (IPSCs) and elicited intermittent burst activities through a non-genomic pathway, involving membrane-located receptors. The onset of the rapid effect in prefrontal cortex (PFC, <15 min) was much slower than in hippocampus (<5 min). The intermittent burst activities were abolished in the presence of TTX. Furthermore, the nitric oxide (NO) pathway was present and endogenously activated in PFC. Part of the rapid DEX effect in PFC remained after blocking NO-sensitive guanylyl cyclase that was due to activation of a phospholipase C-diacylglycerol-dependent signalling pathway. Thus, our data demonstrated that glucocorticoids could rapidly enhance IPSCs and evoke burst activities by activation of at least two different signalling pathways in hippocampus and PFC of rats.

Synaptic Modulation via Basolateral Amygdala on the Rat Hippocampus– Medial Prefrontal Cortex Pathway in Fear Extinction

The present study elucidated the functional role of modulatory effects of basolateral amygdala (BLA) on synaptic transmission in the rat hippocampus–medial prefrontal cortex (mPFC) pathway, compared with the hippocampal dentate gyrus (DG). Exposure to conditioned fear stress (CFS) or prior BLA activation enhanced tetanus-induced long-term potentiation (LTP) in DG. A similar synaptic response was found by low frequency stimulation (LFS) prior to tetanus. In mPFC, they did not affect LTP, but prior BLA activation, as well as pretreatment with the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 (0.1 mg/kg, i.p.), suppressed LFS-primed LTP. This BLA-mediated synaptic pattern was mimicked by synaptic changes observed in the fear extinction process; prior BLA activation suppressed the synaptic potentiation responsible for extinction retrieval and attenuated decreases in fear-related freezing behavior. These data suggest that LFS-primed LTP in mPFC is related to the neural basis of extinction. Extinction-related synaptic potentiation did not occur in a juvenile stress model that exhibited extinction deficit. In addition, LFS-primed LTP was suppressed in this model, which was reversed by the NMDA-receptor agonist d-cycloserine (15 mg/kg, i.p.). These findings suggest that modulatory effects of BLA on synaptic function in the hippocampus–mPFC pathway play a significant role in fear extinction in rats.

The Change of Heterosexual Preference in Adolescents: Implications of Stress and Cognitive Regulation on Sexual Orientation

Sexual orientation is a complex area. It is unclear to date how people precisely establish their preferred sexual objects. This paper presents two cases, whose heterosexual preference were changed in late adolescent age after a severe psychological event, to draw attention to the study of the possible underlying mechanism. Case 1, one identical male twin, was seriously punished at age 12 years, as he loved a girl in his classroom. Afterwards, he feared to contact with girls, and became attracted to young men at age 17 years, and kept same-sex sexual behaviors since then. However, his twin brother is always heterosexual. Case 2, a girl at age 16 years, was unexpectedly betrayed by her boyfriend, she bore great pain and distress in the beginning. Since then, she had a definite opinion that men were unbelievable, and gradually turned her heterosexual preference and had same-sex sexual behaviors with a girl classmate more than 3 years. Our case presentation indicates that severe frustration of primary heterosexual desires or behaviors and the successive cognitive regulation might lead susceptible adolescents into reorienting their sexual preference. The role of prefrontal cortex and related neuromodulatory pathways were discussed.

Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression?

BackgroundPsychological stress, particularly in chronic form, can lead to mood and cognitive dysfunction and is a major risk factor in the development of depressive states. How stress affects the brain to cause psychopathologies is incompletely understood. We sought to characterise potential depression related mechanisms by analysing gene expression and molecular pathways in the infralimbic medial prefrontal cortex (ILmPFC), following a repeated psychological stress paradigm. The ILmPFC is thought to be involved in the processing of emotionally contextual information and in orchestrating the related autonomic responses, and it is one of the brain regions implicated in both stress responses and depression.ResultsGenome-wide microarray analysis of gene expression showed sub-chronic restraint stress resulted predominantly in a reduction in transcripts 24 hours after the last stress episode, with 239 genes significantly decreased, while just 24 genes had increased transcript abundance. Molecular pathway analysis using DAVID identified 8 pathways that were significantly enriched in the differentially expressed gene list, with genes belonging to the brain-derived neurotrophic factor – neurotrophin receptor tyrosine kinase 2 (BDNF-Ntrk2) pathway most enriched. Of the three intracellular signalling pathways that are downstream of Ntrk2, real-time quantitative PCR confirmed that only the PI3K-AKT-GSK3B and MAPK/ERK pathways were affected by sub-chronic stress, with the PLCγ pathway unaffected. Interestingly, chronic antidepressant treatment with the selective serotonin reuptake inhibitor, fluoxetine, prevented the stress-induced Ntrk2 and PI3K pathway changes, but it had no effect on the MAPK/ERK pathway.ConclusionsThese findings indicate that abnormal BDNF-Ntrk2 signalling may manifest at a relatively early time point, and is consistent with a molecular signature of depression developing well before depression-like behaviours occur. Targeting this pathway prophylactically, particularly in depression-susceptible individuals, may be of therapeutic benefit.

A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex

The dopamine D5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study, we identified a novel physiological function for the D(5)R as a regulator of brain-derived neurotrophic factor (BDNF) and Akt signalling in PFC. Specifically, acute activation of the D(5)R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, tropomyosin receptor kinase B (TrkB), in rats and in mice gene-deleted for the D1 receptor but not the D(5)R. These changes were concomitant with increased expression of GAD67, a protein whose down-regulation has been implicated in the aetiology of schizophrenia. Furthermore, D(5)R activation increased phosphorylation of Akt at the Ser(473) site, consequently decreasing the activity of its substrate GSK-3β. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression.

Indução prévia de LTP na via CA1-córtex pré-frontal medial de ratos bloqueia os prejuízos de plasticidade pré-sináptica induzidos por modelo de psicose pós-ictal in vivo

O objetivo do presente trabalho foi testar se a indução de potenciação de longa duração (LTP) no córtex frontal seria capaz de bloquear os efeitos depressores sobre a plasticidade pré-sináptica da via hipocampo (CA1)-córtex pré-frontal medial (mPFC) induzidos por pós-descarga no hipocampo (AD; atividade epiléptica) ou pela injeção sistêmica de cetamina (KET; modelo farmacológico de psicose). Ratos anestesiados com uretana receberam implantes de eletrodos de estimulação e registro, em CA1 e mPFC, respectivamente. Estímulos elétricos monofásicos pareados foram aplicados em CA1 a cada 20s para eliciar potenciais pós-sinápticos de campo (P1 e P2) no mPFC. Avaliamos a plasticidade de curta duração através da facilitação por pulso pareado (PPF), definida pela razão entre as amplitudes de P2 e P1. Após 90min de registros de linha de base, grupos independentes de animais receberam aplicação de AD, injeção de KET-S(+) (12,5 mg/kg i.p.) ou injeção de veículo (NaCl 0,15M), e foram registrados por mais 120min. Em outro experimento registramos 30min de linha de base e aplicamos estímulos de alta frequência (HFS) para indução de LTP aos 30 e 60min. Trinta minutos depois, os animais receberam KET, AD ou veículo e tiveram seus potenciais corticais registrados por mais 120 min. Nossos resultados mostram que AD gera significativa redução (-50%) da eficiência de transmissão basal na via CA1-mPFC, enquanto KET promove leve aumento (+10%). Ambos os tratamentos também promovem prejuízo significativo da PPF na mesma via (-15%). Além disso, observamos que a indução prévia de LTP atenua as alterações da eficiência basal e bloqueia os prejuízos da PPF na via CA1-mPFC induzidos por KET e AD. Nossos achados reforçam evidências recentes de que moduladores alostéricos positivos de NMDA e AMPA atenuam os prejuízos cognitivos em modelos animais de psicose. Acreditamos, portanto, que a aplicação prévia de HFS na região CA1 do hipocampo pode ser uma ferramenta útil para melhor entendermos como prevenir os prejuízos de plasticidade sináptica no mPFC em modelos de psicose e psicose pós-ictal.

Group II Metabotropic Glutamate Receptor Agonist Ameliorates MK801-Induced Dysfunction of NMDA Receptors via the Akt/GSK-3β Pathway in Adult Rat Prefrontal Cortex

Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of an mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration. This effect was attributable to the direct regulatory action of LY379268 on NMDA receptors via activation of the Akt/GSK-3β signaling pathway. As occurs with the antipsychotic drug clozapine, acute treatment with LY379268 significantly increased the expression and phosphorylation of NMDA receptors, as well as Akt and GSK-3β. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3β inhibitor occluded this effect. In contrast to the widely proposed mechanism of modulating presynaptic glutamate release, our results strongly argue that mGluR2/3 agonists modulate the function of NMDA receptors through postsynaptic actions and reverse the MK-801-induced NMDA dysfunction via the Akt/GSK-3β pathway. This study provides novel evidence for postsynaptic mechanisms of mGluR2/3 in regulation of NMDA receptors and presents useful insights into the mechanistic actions of mGluR2/3 agonists as potential antipsychotic agents for treating schizophrenia.

Stress and Amygdala Suppression of Metaplasticity in the Medial Prefrontal Cortex

The term "metaplasticity" refers to the modulation of the ability to induce synaptic plasticity of the form of long-term potentiation (LTP) or long-term depression (LTD) following prior activation of the synapses. While often electrophysiological manipulations are used to demonstrate this phenomenon, prior behavioral manipulations such as exposure to stress were also found to affect the ability to induce LTP and LTD. Interestingly, amygdala stimulation was found to have effects on subsequent LTP induction that resemble those of stress. Here, we report that exposure to stress or basolateral amygdala (BLA) stimulation induces a form of metaplasticity, which prevents the ability of a second episode of stress or BLA activation to suppress LTP in the ventral hippocampus-medial prefrontal cortex (mPFC) pathway. This form of metaplasticity is N-methyl-D-aspartic acid (NMDA)-dependent since the injection of the NMDA partial agonist D-cycloserine prevented the inhibition of LTP induced by prior exposure of stress or BLA activation. Furthermore, blocking NMDA receptors by MK801 before the exposure to stress prevented the ability of the emotional manipulation to inhibit the subsequent modulation of plasticity, resulting in impaired LTP in the mPFC. Taken together, these findings demonstrate a new form of NMDA-dependent emotional metaplasticity in the ventral hippocampus-mPFC pathway.

Diazepam-Induced Increases of Synaptic Efficacy in the Hippocampal – Medial Prefrontal Cortex Pathway Are Associated With Its Anxiolytic-like Effect in Rats

The medial prefrontal cortex (mPFC) has recently been shown to be an important brain region for emotional function as well as cognitive ability. In previous experiments, we studied the population spike amplitude (PSA) in the mPFC induced by stimulation of the CA1/subicular region as an index of synaptic efficacy in the hippocampal-mPFC pathway. In the present study, we investigated the relationship between the anxiolytic effect of diazepam and the changes of synaptic efficacy in this pathway. In contextual fear conditioning tests, diazepam (0.1 mg/kg) was not effective for fear-related freezing behavior. At a dose of 0.5 mg/kg, diazepam decreased freezing behavior 20 min after administration, with no discernible effect 30 min after administration. In electrophysiological experiments, 0.1 mg/kg diazepam had no effect on the PSA in the mPFC. In contrast, 0.5 mg/kg diazepam increased the PSA in the mPFC within 30 min of administration; however, this PSA increase was attenuated over the 30-min period. Based on these results, we propose that the diazepam-induced PSA increase in the mPFC is associated with its anxiolytic-like effect.

Dopamine D1 receptor antagonism in the prelimbic cortex blocks the reinstatement of heroin-seeking in an animal model of relapse

In brain regions that have been implicated in the reinstatement of drug-seeking, the prelimbic cortex has emerged as a critical regulator of relapse behaviours. Here, the effects of prelimbic cortex dopamine (DA) D(1) receptor antagonism on drug-seeking produced by heroin-paired cues, or by a single priming dose of heroin are examined. Rats lever-pressed daily for i.v. heroin discretely paired with a conditioned stimulus during 3-h sessions for a period of 2 wk, followed by extinction and reinstatement of drug-seeking by previously heroin-paired cues (tone+light) or heroin-priming injections (0.25 mg/kg) in the absence of heroin reinforcement. Intracranial infusion of the DA D(1) receptor antagonist, SCH 23390 (0.02-2.0 microg/side), into the prelimbic cortex potently and dose dependently attenuated heroin-seeking in response to either cue presentations or a priming dose of heroin. These results suggest that DA D1 receptors regulate prefrontal cortex pathways necessary for the reinstatement of heroin-seeking.

Differential Contributions of Prefrontal and Hippocampal Dopamine D1and D2Receptors in Human Cognitive Functions

Dopamine D(1) receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D(1) receptors induces an inverted U-shaped response, such that too little or too much D(1) receptor stimulation impairs prefrontal functions. Less is known of the role of D(2) receptors in cognition, but previous studies showed that D(2) receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D(1) and D(2) receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D(1) and D(2) receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D(1) receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D(2) binding has no relation with any neuropsychological measures. Hippocampal D(2) receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D(1) receptor binding had no association with any memory and prefrontal functions. Hippocampal D(2) receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D(1) receptors and hippocampal D(2) receptors might be necessary for human executive function including working memory.

Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: Implication of MEK signaling

We previously reported that exposure to acute and chronic stress impairs long-term potentiation (LTP) in the hippocampal–prefrontal cortex pathway and showed evidence for a fundamental role of the prefrontal cortex in maladaptive responses to stress. The goal of the current studies was to examine whether blockade of glucocorticosteroid receptors (GR), by mifepristone (a Type II glucocorticoid receptor antagonist), just after exposure to acute stress could prevent stress-induced impairment of prefrontal LTP. We further examine the effects of mifepristone on mitogen-activated protein/ERK kinase (MEK) signaling pathway in the prefrontal cortex. The data show that an acute injection of mifepristone after stress restored the stress-induced blockade of prefrontal LTP and reduction of phospho-Ser217/221-MEK. These findings have significance for the treatment of memory deficits in hypercortisolemic states, such as stress and depression.

Reduced activation of intracellular signaling pathways in rat prefrontal cortex after chronic phencyclidine administration

Evidence exists that schizophrenia is characterized by deficits in cell–cell communication and information processing. In the present study, we used the phencyclidine (PCP) animal model of schizophrenia to investigate possible defects in intracellular signaling proteins involved in neuroplasticity. Western Blot analysis has been performed to determine total and phospho-protein levels of extracellular signal-regulated kinases 1/2 (ERK1/2), type II calcium/calmodulin-dependent protein kinase (αCaMKII) and cAMP-response element binding protein (CREB) in prefrontal cortex (PFC) and hippocampus (HIP) of rat chronically treated with PCP, whereas their mRNA levels were determined by real time RT-PCR. We found reduced levels of P-ERK1/2, P-αCaMKII and P-CREB in prefrontal cortex of PCP-treated animals when compared to controls, whereas no effects were observed on total protein or mRNA levels. Conversely, no significant changes were detected on protein levels or mRNA expression in hippocampus. Given the role of ERK1/2, αCaMKII and CREB in neuroplastic mechanisms and cell communication, our data suggest that their decreased activation following chronic PCP administration can contribute to cortical defects occurring in schizophrenia, and may therefore represent potential targets for pharmacological intervention.

Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal–prefrontal cortex pathway of rats in vivo: A possible involvement of monoaminergic systems

The prefrontal cortex is continuously required for working memory processing during wakefulness, but is particularly hypoactivated during sleep and in psychiatric disorders such as schizophrenia. Ammon's horn CA1 hippocampus subfield (CA1) afferents provide a functional modulatory path that is subjected to synaptic plasticity and a prominent monoaminergic influence. However, little is known about the muscarinic cholinergic effects on prefrontal synapses. Here, we investigated the effects of the muscarinic agonist, pilocarpine (PILO), on the induction and maintenance of CA1-medial prefrontal cortex (mPFC) long-term potentiation (LTP) as well as on brain monoamine levels. Field evoked responses were recorded in urethane-anesthetized rats during baseline (50 min) and after LTP (130 min), and compared with controls. LTP was induced 20 min after PILO administration (15 mg/kg, i.p.) or vehicle (NaCl 0.15 M, i.p.). In a separate group of animals, the hippocampus and mPFC were microdissected 20 min after PILO injection and used to quantify monoamine levels. Our results show that PILO potentiates the late-phase of mPFC LTP without affecting either post-tetanic potentiation or early LTP (20 min). This effect was correlated with a significant decrease in relative delta (1–4 Hz) power and an increase in sigma (10–15 Hz) and gamma (25–40 Hz) powers in CA1. Monoamine levels were specifically altered in the mPFC. We observed a decrease in dopamine, 5-HT, 5-hydroxyindolacetic acid and noradrenaline levels, with no changes in 3,4-hydroxyphenylacetic acid levels. Our data, therefore, suggest that muscarinic activation exerts a boosting effect on mPFC synaptic plasticity and possibly on mPFC-dependent memories, associated to monoaminergic changes.

Apoptotic gene expression in neuropathic pain

AbstractPain initiated or caused by a primary lesion or dysfunction in the nervous system is defined as neuropathic pain. It results from direct injury to nerves in the peripheral or central nervous system and is associated with several clinical symptoms. Neuropathic pain treatment is extremely difficult, as it is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury.This study used several experimental pain models to demonstrate the occurrence of programmed cell death in the centers controlling pain induction and maintenance, such as spinal cord and pre-frontal cortex. We combined behavioural, molecular and morphological approaches to assess the involvement of bcl-2 gene family and caspases in neuropathic pain. Chronic constriction injury (CCI) and spared nerve injury (SNI) of rodent sciatic nerve induced the appearance of pain-like behaviours, such as hyperalgesia and allodynia. An early (2-3 days post-CCI) apoptosis appeared in the spinal cord neurons as the pro-apoptotic bax gene increased (320±19%). The incidence of apoptosis appeared to be limited to the first few days following nerve injury. Subsequently, increased expression of anti-apoptotic bcl-2 family genes may inhibit further neuron loss. SNI triggered apoptotic pathway and caspases activation in pre-frontal cortex 7, 14, and 21 days post-injury. Among the time-points analyzed, RT-PCR analysis showed increased expression of the bax/bcl-2 ratio (40±2%), bid (16±2%), caspase-1 (84±3%), caspase-8 (53±6%), caspase-9 (25±6%), caspase-12 (58±2%), TNF (32±2%) genes in the cortex by 7 days post-injury. Western blot analysis showed increased active Caspase-3 protein levels in the cortex at 3, 7, 14, and 21 post-surgery. This study shows that apoptotic genes could be an useful pharmacological target in neuropathic pain controlling.

Apoptotic gene expression in neuropathic pain

Pain initiated or caused by a primary lesion or dysfunction in the nervous system is defined as neuropathic pain. It results from direct injury to nerves in the peripheral or central nervous system and is associated with several clinical symptoms. Neuropathic pain treatment is extremely difficult, as it is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury.This study used several experimental pain models to demonstrate the occurrence of programmed cell death in the centers controlling pain induction and maintenance, such as spinal cord and pre-frontal cortex. We combined behavioural, molecular and morphological approaches to assess the involvement of bcl-2 gene family and caspases in neuropathic pain. Chronic constriction injury (CCI) and spared nerve injury (SNI) of rodent sciatic nerve induced the appearance of pain-like behaviours, such as hyperalgesia and allodynia. An early (2-3 days post-CCI) apoptosis appeared in the spinal cord neurons as the pro-apoptotic bax gene increased (320±19%). The incidence of apoptosis appeared to be limited to the first few days following nerve injury. Subsequently, increased expression of anti-apoptotic bcl-2 family genes may inhibit further neuron loss. SNI triggered apoptotic pathway and caspases activation in pre-frontal cortex 7, 14, and 21 days post-injury. Among the time-points analyzed, RT-PCR analysis showed increased expression of the bax/bcl-2 ratio (40±2%), bid (16±2%), caspase-1 (84±3%), caspase-8 (53±6%), caspase-9 (25±6%), caspase-12 (58±2%), TNF (32±2%) genes in the cortex by 7 days post-injury. Western blot analysis showed increased active Caspase-3 protein levels in the cortex at 3, 7, 14, and 21 post-surgery. This study shows that apoptotic genes could be an useful pharmacological target in neuropathic pain controlling.