PSA-NCAM expression in the rat medial prefrontal cortex

Modulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) is altered in brain from cirrhotic patients. The aim of this work was to assess whether an animal model of cirrhosis, bile duct ligation, alone or combined with diet-induced hyperammonemia for 7-10 days reproduces the alterations in NO modulation of sGC found in brains from cirrhotic patients. sGC activity was measured under basal conditions and in the presence of NO in cerebellum and cerebral cortex of the following groups of rats: controls, bile duct ligation without or with hyperammonemia and hyperammonemia without bile duct ligation. In cerebellum activation of sGC by NO was significantly lower in bile duct ligated rats with (12 +/- five-fold) or without (14 +/- six-fold) hyperammonemia than in control rats (23 +/- seven-fold). In cerebral cortex activation of sGC by NO was higher in rats with bile duct ligation with hyperammonemia (124 +/- 30-fold) but not without hyperammonemia (59 +/- 15-fold) than in control rats (66 +/- 11-fold). The combination of bile duct ligation and hyperammonemia reproduces the alterations in the modulation of soluble guanylate cyclase by NO found in cerebral cortex and cerebellum of cirrhotic patients while bile duct ligation or hyperammonemia alone reproduces the effects in cerebellum but not in cerebral cortex.     

Reversible inactivations of rat medial prefrontal cortex impair the ability to wait for a stimulus

In simple reaction time tasks, lesions of rat dorsomedial prefrontal cortex impair the ability to wait for trigger stimuli and result in increased premature responding. This effect could be due to impairments in attending to trigger stimuli, estimating the timing of trigger stimuli, or inhibitory control of the motor response. Here, we examined these issues by reversibly inactivating dorsomedial prefrontal cortex during simple reaction time tasks with variable or fixed foreperiods. There were three consistent effects of dorsomedial prefrontal cortex inactivation: 1) increased premature responding, 2) increased variability in the timing of premature responses, and 3) speeded response latencies, especially on trials with short foreperiods in tasks with variable foreperiods. We observed these effects independent of differences in foreperiod duration, foreperiod variability, and stimulus probabilities. Therefore, dorsomedial prefrontal cortex appears not to be involved in attending to the trigger stimulus or in time estimation. Instead, we suggest that dorsomedial prefrontal cortex is critical for inhibiting responses before the maximum foreperiod duration, i.e. the "deadline" [Ollman RT, Billington MJ (1972) The deadline model for simple reaction times. Cognit Psychol 3:311-336], after which the rat should respond even if the trigger stimulus has not occurred.     

Involvement of the rat medial prefrontal cortex in novelty detection

The prefrontal cortex in humans has been implicated in processes that underlie novelty detection and attention. This study examined the contribution of the rat medial prefrontal cortex to novelty detection using the targeting, or orienting, response (OR) as a behavioral index. Lesions to the medial prefrontal cortex (specifically the prelimbic and infralimbic cortices) influenced neither the OR to a novel visual stimulus from a localized light source (V1), nor the change in this OR over the course of a series of exposures to V1. However, after exposure to V1, the OR to a 2nd visual stimulus from the same source, V2, was more pronounced in control rats than in lesioned rats. These results suggest that the medial prefrontal cortex in the rat contributes to the process of novelty detection.     

Response durations encode nociceptive stimulus intensity in the rat medial prefrontal cortex

We examined whether the medial prefrontal cortex (mPFC) encodes nociceptive stimulus intensity by applying mechanical pressure stimulation, for 2 s at 50, 100, or 300 g constant force (gf) to the tails of urethane-anesthetized rats. In a total of 1208 neurons sampled, 242 (20.0%) were responsive to mechanical stimuli. One hundred thirteen of the 242 (46.7%) were mechanical high threshold neurons (nociceptive specific neurons, NS; threshold >or=100 gf), and 35 (14.5%) exhibited a graded increase in excitator responses to a stepwise increase in stimulus intensity (wide dynamic range-like neurons, WDR-L). These 148 response discharges persisted during stimulation followed by post-stimulus discharges. The nociceptive response duration of NS neurons, but not discharge frequency, was reduced dose-dependently by intraventricular injection of morphine (0.3, and 30 microg/3 microl). Different doses of morphine may set the stimulus intensity at relatively different brain activity levels. Thus, the NS neurons used the response duration as a sensory transduction code. In WDR-L neurons, the response duration, but not always the firing frequency, was linearly related to stimulus intensity. The WDR-L neurons in the mPFC encoded stimulus intensity with response duration, although the coding method is not likely to be the same as that of sensory discriminating WDR cells in the primary somatosensory cortex. Both types of mPFC neurons encode nociceptive (absolute or relative) stimulus intensity and transform the information into the temporal duration of the next stage of pain-related modulation in animal behavior.     

Catalepsy after microinjection of haloperidol into the rat medial prefrontal cortex

Summary To investigate the behavioural role of mesocortical dopamine innervation we performed bilateral microinjections of haloperidol into various parts of the rat frontal cortex and into adjacent subcortical forebrain structures. Haloperidol (2.5 g/ 0.5 l) locally injected into the medial prefrontal cortex or into the rostral part of the neostriatum resulted in the development of catalepsy as measured in the bar test. In contrast, injections of haloperidol into the nucleus accumbens, more caudal parts of the neostriatum, anterior cingulate cortex, rostral and lateral parts of the prefrontal cortex and into the lateral ventricles failed to induce catalepsy. It is concluded that blockade of dopamine receptors located in the rostral neostriatum and in the medial prefrontal cortex contributes to the development of haloperidol induced catalepsy.     

Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat

The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. Using retrograde tracing techniques, we examined, compared, and contrasted afferent projections to the four divisions of the mPFC in the rat: the medial (frontal) agranular (AGm), anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices. Each division of the mPFC receives a unique set of afferent projections. There is a shift dorsoventrally along the mPFC from predominantly sensorimotor input to the dorsal mPFC (AGm and dorsal AC) to primarily ‘limbic’ input to the ventral mPFC (PL and IL). The AGm and dorsal AC receive afferent projections from widespread areas of the cortex (and associated thalamic nuclei) representing all sensory modalities. This information is presumably integrated at, and utilized by, the dorsal mPFC in goal directed actions. In contrast with the dorsal mPFC, the ventral mPFC receives significantly less cortical input overall and afferents from limbic as opposed to sensorimotor regions of cortex. The main sources of afferent projections to PL/IL are from the orbitomedial prefrontal, agranular insular, perirhinal and entorhinal cortices, the hippocampus, the claustrum, the medial basal forebrain, the basal nuclei of amygdala, the midline thalamus and monoaminergic nuclei of the brainstem. With a few exceptions, there are few projections from the hypothalamus to the dorsal or ventral mPFC. Accordingly, subcortical limbic information mainly reaches the mPFC via the midline thalamus and basal nuclei of amygdala. As discussed herein, based on patterns of afferent (as well as efferent) projections, PL is positioned to serve a direct role in cognitive functions homologous to dorsolateral PFC of primates, whereas IL appears to represent a visceromotor center homologous to the orbitomedial PFC of primates.     

Characterization of the role of medial prefrontal cortex dopamine receptors in cocaine-induced locomotor activity

Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D2-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D4 receptor agonist PD 168,077 or the selective D1 receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D1 and D2 receptors. These results suggest that D2 receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine.     

Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.     

Long-term potentiation in visual cortical projections to the medial prefrontal cortex of the rat

In order to investigate neural mechanisms by which the prefrontal cortex adaptively modifies its activities based on past experience, we examined whether or not sensory cortical projections to the medial prefrontal cortex support long-term potentiation (LTP) in rats. Monosynaptic projections from the secondary visual cortex, mediomedial area (V2MM) to the infralimbic cortex were confirmed by orthodromic as well as antidromic activation of single units. High-frequency stimulation (50 Hz, 2 s) induced LTP (approximately 45% increase over the baseline) in the V2MM projection to the infralimbic cortex. LTP induction in this pathway was completely blocked by an injection (i.p.) of CPP, an N-methyl-D-aspartate receptor antagonist. LTP was also induced in the ventral hippocampal projection to the infralimbic cortex by the same high-frequency stimulation. The present results suggest that modification of synaptic weights of afferent sensory cortical projections is one mechanism underlying learning-induced changes in prefrontal cortical neural activities.     

The basolateral limbic circuit and self-stimulation of the medial prefrontal cortex in the rat

The effects of lesions of the basolateral nucleus of the amygdala (ABL) and the mediodorsal nucleus of the thalamus (MD) on self-stimulation (SS) of the medial prefrontal cortex (MPC) were investigated. Spontaneous motor activity (SMA) was measured as a control for possible non-specific effects of the lesions. Bilateral electrolytic lesions of ABL or MD produced a parallel transient decrease of SS and SMA. However, combined lesion of ABL and MD produced clearly different effects on both parameters. SMA decreased during the 1st day post-lesion and recovered to control levels by the 3rd day post-lesion. SS, on the contrary, was significantly decreased during the first five days post-lesion and after that time SS rate recovered to control levels. These results suggest the involvement of the basolateral limbic circuit in the neural substate underlying SS behavior of the MPC.     

Behavior-dependent short-term assembly dynamics in the medial prefrontal cortex

Although short-term plasticity is believed to play a fundamental role in cortical computation, empirical evidence bearing on its role during behavior is scarce. Here we looked for the signature of short-term plasticity in the fine-timescale spiking relationships of a simultaneously recorded population of physiologically identified pyramidal cells and interneurons, in the medial prefrontal cortex of the rat, in a working memory task. On broader timescales, sequentially organized and transiently active neurons reliably differentiated between different trajectories of the rat in the maze. On finer timescales, putative monosynaptic interactions reflected short-term plasticity in their dynamic and predictable modulation across various aspects of the task, beyond a statistical accounting for the effect of the neurons' co-varying firing rates. Seeking potential mechanisms for such effects, we found evidence for both firing pattern-dependent facilitation and depression, as well as for a supralinear effect of presynaptic coincidence on the firing of postsynaptic targets.     

In vivo electrochemical studies of monoamine release in the medial prefrontal cortex of the rat

The magnitude and duration of release of monoamines evoked by local applications of potassium were measured in vivo in the medial prefrontal cortex using high-speed chronoamperometry. Typical electrochemical signals reflecting released of electroactive species ranging from 0.5 to 3.0 microM and lasting 90-120 s were detected at a variety of dorsal-ventral and anterior-posterior electrode placements in the medial prefrontal cortex. The magnitude of the reduction current measured following the oxidation reaction suggests a contribution of both serotonin and dopamine to the electrochemical signal, dopamine serving as the predominant monoamine in the medial prefrontal cortex proper and serotonin appearing to predominant in the more posterior regions of the frontal cortex. This conclusion was reinforced by the fact that unilateral 6-hydroxydopamine lesions of ascending dopamine fibers almost completely abolished electrochemical signals in the ipsilateral but not in the contralateral medial prefrontal cortex. The present study provides an in vivo characterization of monoamine release in the mesocortical dopamine terminal field, where it has been suggested that psychomotor stimulants may produce some of their positive reinforcing effects.     

Multiple forms of short-term plasticity at excitatory synapses in rat medial prefrontal cortex

Short-term synaptic plasticity, in particular short-term depression and facilitation, strongly influences neuronal activity in cerebral cortical circuits. We investigated short-term plasticity at excitatory synapses onto layer V pyramidal cells in the rat medial prefrontal cortex, a region whose synaptic dynamic properties have not been systematically examined. Using intracellular and extracellular recordings of synaptic responses evoked by stimulation in layers II/III in vitro, we found that short-term depression and short-term facilitation are similar to those described previously in other regions of the cortex. In addition, synapses in the prefrontal cortex prominently express augmentation, a longer lasting form of short-term synaptic enhancement. This consists of a 40-60% enhancement of synaptic transmission which lasts seconds to minutes and which can be induced by stimulus trains of moderate duration and frequency. Synapses onto layer III neurons in the primary visual cortex express substantially less augmentation, indicating that this is a synapse-specific property. Intracellular recordings from connected pairs of layer V pyramidal cells in the prefrontal cortex suggest that augmentation is a property of individual synapses that does not require activation of multiple synaptic inputs or neuromodulatory fibers. We propose that synaptic augmentation could function to enhance the ability of a neuronal circuit to sustain persistent activity after a transient stimulus. This idea is explored using a computer simulation of a simplified recurrent cortical network.     

创伤后应激障碍大鼠前额叶内侧皮质糖皮质激素受体表达增高

目的 观察创伤后应激障碍（PTSD）大鼠前额叶内侧皮质（mPFC）神经元糖皮质激素受体（GR）表达的变化。 方法 采用单一连续应激(SPS)方法建立PTSD大鼠模型,取成年健康雄性Wistar大鼠90只,随机分为PTSD模型1d、7d、14d、28d和正常对照组。采用免疫组织化学、免疫印迹和RT-PCR方法分别进行各组mPFC神经元GR表达变化的观察及检测,进行图像分析和统计学处理。结果PTSD大鼠mPFC神经元GR的表达高于对照组,SPS后14d最高,SPS后28d恢复性下调,但仍然高于对照组(P<0.05)。结论PTSD模型大鼠经SPS处理后,mPFC区域出现GR表达的增高。     

Diminished medial prefrontal cortex activity in blood-injection-injury phobia

We examined the effects of symptom induction on neural activation in blood-injection-injury (BII) phobia. Nine phobic and 10 non-phobic subjects participated in an fMRI study in which they were presented with disorder-relevant, generally disgust-inducing, generally fear-evoking and neutral pictures. We observed diminished medial prefrontal cortex (MPFC) activity in patients compared to controls for phobia-relevant and disgust-inducing pictures. The MPFC has been shown to be critically involved in the automatic and effortful cognitive regulation of emotions. Therefore, the results might reflect reduced cognitive control of emotions in BII phobics during the experience of phobic symptoms as well as during states of disgust. The latter response component might be a result of the elevated disgust sensitivity of BII phobics.     

Muscimol injected into the medial prefrontal cortex of the rat alters ethanol self-administration.

The role of the rodent prefrontal cortex in the regulation of ethanol self-administration has not been widely explored. Understanding the role of GABAergic transmission in this area in relation to ethanol self-administration is important, as the GABA system may be one of several targets for alcohol's actions in the brain. Rats were initiated to drink 10% ethanol from a dipper using a sucrose-substitution procedure. When baseline behavior was stable, bilateral microinjections of muscimol (a GABA(A) agonist) into the prefrontal cortex were tested at doses of 17.5, 30, 100 and 300 ng/microl. Ethanol self-administration was decreased by approximately 40% at the 30-ng dose and 30% at the 100-ng dose. No effects were observed at either the 17.5- or 300-ng dose. The effect on the pattern of self-administration was to shorten the size of the first run of drinking without affecting the rate of drinking. The hypothesis is put forward that the injections increased glutamatergic output to the nucleus accumbens (nAcc) that in turn increased accumbens output. This increased output is proposed as similar to the effects of dopaminergic (DA) manipulations within this system.     

Efferent connections of the medial prefrontal cortex in the rabbit

The different cytoarchitectonic regions of the medial prefrontal cortex (mPFC) have recently been shown to play divergent roles in associative learning in rabbits. To determine if these subareas of the mPFC, including areas 24 (anterior cingulate cortex), 25 (infralimbic cortex), and 32 (prelimbic cortex) have differential efferent connections with other cortical and subcortical areas in the rabbit, anterograde and retrograde tracing experiments were performed using thePhaseolus vulgaris leukoagglutinin (PHA-L), and horseradish peroxidase (HRP) techniques. All three areas showed local dorsal-ventral projections into each of the other areas, and a contralateral projection to the homologous area on the other side of the brain. All three also revealed a trajectory through the striatum, resulting in heavy innervation of the caudate nucleus, the claustrum, and a lighter projection to the agranular insular cortex. The thalamic projections of areas 24 and 32 were similar, but not identical, with projections to the mediodorsal nucleus (MD) and all of the midline nuclei. However, the primary thalamic projections from area 25 were to the intralaminar and midline nuclei. All three areas also projected to the ventromedial and to a lesser extent to the ventral posterior thalamic nuclei. Projections were also observed in the lateral hypothalamus, in an area just lateral to the descending limb of the fornix. Amygdala projections from areas 32 and 24 were primarily to the lateral, basolateral and basomedial nuclei, but area 25 also projected to the central nucleus. All three areas also showed projections to the midbrain periaqueductal central gray, median raphe nucleus, ventral tegmental area, substantia nigra, locus coeruleus and pontine nuclei. However, only areas 24 and the more dorsal portions of area 32 projected to the superior colliculus. Area 25 and the ventral portions of area 32 also showed a bilateral projection to the parabrachial nuclei and dorsal and ventral medulla. The dorsal portions of area 32, and all of area 24 were, however, devoid of these projections. It is suggested that these differential projections are responsible for the diverse roles that the cytoarchitectonic subfields of the mPFC have been demonstrated to play in associative learning.     

Efferent connections of the medial prefrontal cortex in the rabbit

The different cytoarchitectonic regions of the medial prefrontal cortex (mPFC) have recently been shown to play divergent roles in associative learning in rabbits. To determine if these subareas of the mPFC, including areas 24 (anterior cingulate cortex), 25 (infralimbic cortex), and 32 (prelimbic cortex) have differential efferent connections with other cortical and subcortical areas in the rabbit, anterograde and retrograde tracing experiments were performed using the Phaseolus vulgaris leukoagglutinin (PHA-L), and horseradish peroxidase (HRP) techniques. All three areas showed local dorsal-ventral projections into each of the other areas, and a contralateral projection to the homologous area on the other side of the brain. All three also revealed a trajectory through the striatum, resulting in heavy innervation of the caudate nucleus, the claustrum, and a lighter projection to the agranular insular cortex. The thalamic projections of areas 24 and 32 were similar, but not identical, with projections to the mediodorsal nucleus (MD) and all of the midline nuclei. However, the primary thalamic projections from area 25 were to the intralaminar and midline nuclei. All three areas also projected to the ventromedial and to a lesser extent to the ventral posterior thalamic nuclei. Projections were also observed in the lateral hypothalamus, in an area just lateral to the descending limb of the fornix. Amygdala projections from areas 32 and 24 were primarily to the lateral, basolateral and basomedial nuclei, but area 25 also projected to the central nucleus. All three areas also showed projections to the midbrain periaqueductal central gray, median raphe nucleus, ventral tegmental area, substantia nigra, locus coeruleus and pontine nuclei. However, only areas 24 and the more dorsal portions of area 32 projected to the superior colliculus. Area 25 and the ventral portions of area 32 also showed a bilateral projection to the parabrachial nuclei and dorsal and ventral medulla. The dorsal portions of area 32, and all of area 24 were, however, devoid of these projections. It is suggested that these differential projections are responsible for the diverse roles that the cytoarchitectonic subfields of the mPFC have been demonstrated to play in associative learning.Abbreviations ACC anterior cingullate cortex - ACN amygdaloid central nucleus - AD anterodorsal nucleus of thalamus - AIC, Iag agranular insular cortex - AM anteromedial nucleus of thalamus - AMG amygdala - AV anteroventral nucleus of thalamus - BL basolateral nucleus of amygdala - BM basomedial nucleus of amygdala - CdN, CD caudate nucleus - CL claustrum - CN centromedian nucleus of thalamus - D MV, DVM dorsal motor nucleus of vagus - IC internal capsule - L lateral nucleus of amygdala - LC locus coeruleus - LH lateral hypothalamus - MB mammillary bodies - MDN mediodorsal nucleus of thalamus - mPFC medial prefrontal cortex - MRN, R median raphe nucleus - MV medioventral nucleus of thalamus - NA nucleus ambiguus - NTS nucleus of solitary tract - PAG periaqueductal central gray - PAV, PV para ventricular nucleus of thalamus - PC paracentral nucleus of thalamus - PF parafascicular nucleus of thalamus - PN,LP pontine nuclei - PS posterior subiculum - PS CG posterior cingulate cortex - PT paratenial nucleus of thalamus - Put putamen - ReN nucleus reuniens of thalamus - RF reticular formation - RN reticular nucleus of thalamus - RhN rhomboid nucleus of thalamus - RS CX retrosplenial cortex - S septum - SC superior colliculus - SN substantia nigra - tt tenia tecta - VL ventrolateral nucleus of thalamus - VM ventromedial nucleus of thalamus - VP ventroposterior nucleus of thalamus - VTA ventral tegmental area     

Heterogeneity in the pyramidal network of the medial prefrontal cortex

The prefrontal cortex is specially adapted to generate persistent activity that outlasts stimuli and is resistant to distractors, presumed to be the basis of working memory. The pyramidal network that supports this activity is unknown. Multineuron patch-clamp recordings in the ferret medial prefrontal cortex showed a heterogeneity of synapses interconnecting distinct subnetworks of different pyramidal cells. One subnetwork was similar to the pyramidal network commonly found in primary sensory areas, consisting of accommodating pyramidal cells interconnected with depressing synapses. The other subnetwork contained complex pyramidal cells with dual apical dendrites displaying nonaccommodating discharge patterns; these cells were hyper-reciprocally connected with facilitating synapses displaying pronounced synaptic augmentation and post-tetanic potentiation. These cellular, synaptic and network properties could amplify recurrent interactions between pyramidal neurons and support persistent activity in the prefrontal cortex.     

Glutamate receptors regulate actin-based plasticity in dendritic spines

Dendritic spines at excitatory synapses undergo rapid, actin-dependent shape changes which may contribute to plasticity in brain circuits. Here we show that actin dynamics in spines are potently inhibited by activation of either AMPA or NMDA subtype glutamate receptors. Activation of either receptor type inhibited actin-based protrusive activity from the spine head. This blockade of motility caused spines to round up so that spine morphology became both more stable and more regular. Inhibition of spine motility by AMPA receptors was dependent on postsynaptic membrane depolarization and influx of Ca 2+ through voltage-activated channels. In combination with previous studies, our results suggest a two-step process in which spines initially formed in response to NMDA receptor activation are subsequently stabilized by AMPA receptors.