Prelimbic Area Research Articles

Partial ablation of frontal cortical subplate leads to developmental abnormalities in KCC2 in the prefrontal cortex

During early brain development, the subplate relays thalamocortical afferents to the overlying cortex. Disconnection of thalamic inputs to the prefrontal cortex by lesions of the subplate of the developing prefrontal cortex at early neonatal periods result in adult-onset behavioral abnormalities reminiscent of positive, negative, and cognitive symptoms of schizophrenia. Delayed maturation of γ-amino butyric acid (GABA) function may contribute to certain abnormalities of the prefrontal cortex and clinical manifestations of schizophrenia. Lesions to the subplate have also been implicated in developmental abnormalities of GABA neurotransmission in somatosensory and visual cortices. Therefore, we sought to examine the effects of subplate lesions in the developing prefrontal cortex of rats on the expression of GABA markers [parvalbumin and glutamic acid decarboxylase (GAD67)] and proteins responsible for GABAergic synaptic maturation [potassium-chloride cotransporter (KCC2) and sodium‑potassium-chloride cotransporter (NKCC1)]. Lesioned and control rats were sacrificed between postnatal days (P) 5 and 90 and immunolabeled for parvalbumin, GAD67, KCC2, and NKCC1 in the prelimbic area of the prefrontal cortex. We found decreased immunoreactivity of KCC2 on neuronal cell membranes at P11 compared to control rats. However, the overall immunoreactivity of KCC2 and NKCC1 did not differ between lesion and control animals at all time points studied. Lesioned rats also showed decreased expression of parvalbumin, but not GAD67. Our results indicate that mechanisms underlying trafficking and membrane binding of KCC2 may contribute to altered GABA receptor function during development in schizophrenia.

Unfolding of spatial representation at systems level in infant rats.

Spatial representations enable navigation from early life on. However, the brain regions essential to form spatial representations, like the hippocampus, are considered functionally immature before weaning. Here, we examined the formation of representations of space in rat pups on postnatal day (PD) 16, using a simple habituation paradigm where the pups were exposed to an arena on three occasions, separated by ~140 min. Whereas on the first two occasions the arena was the same, on the third "test" occasion either proximal cues (Prox group), or distal cues (Dist group), or proximal and distal cues (Prox-Dist group), or no cues (No-change group) were rearranged. Locomotion (distance traveled) was used as behavioral measure of habituation, and c-Fos expression to measure regional brain activity at test. Locomotion generally decreased across the first two occasions. At test, it reached a minimum in the No-change group, indicating familiarity with the spatial conditions. By contrast, the Prox-Dist group displayed a significant increase in locomotion which was less robust in the Prox group and absent in the Dist group, a pattern suggesting that the pups relied more on proximal than distal cues during spatial exploration. c-Fos activity in the No-change group was significantly suppressed in the hippocampus (CA1, CA3, dentate gyrus) but simultaneously enhanced in the prelimbic area (PL) of the medial prefrontal cortex, compared with untreated Home-cage controls, pointing to a possible involvement of the PL in regulating locomotion in familiar spaces. By contrast, in both Prox-Dist and Prox groups c-Fos activity was enhanced in hippocampal CA1 and CA3 regions, suggesting these regions might be particularly involved in regulating exploration of spatial novelty. Our findings show that functional representations of space at a systems level are formed already in pre-weanling rats.

Repeated ethanol exposure following avoidance conditioning impairs avoidance extinction and modifies conditioning-associated prefrontal dendritic changes in a mouse model of post-traumatic stress disorder.

Treatment of post-traumatic stress disorder is complicated by the presence of alcohol use disorder comorbidity. Little is known about the underlying brain mechanisms. We have recently shown, in mice, that the post-traumatic stress disorder-like phenotype is characterised by the increase and decrease in total dendritic number and length in the prelimbic and infralimbic areas of the medial prefrontal cortex, respectively. Here, we examined whether repeated ethanol exposure would exacerbate these changes and whether this would be associated with difficulty to extinguish passive avoidance behaviour, as an indicator of treatment resistance. We also analysed whether other known trauma-associated changes, like increased or decreased corticosterone and decreased brain-derived neurotrophic factor levels, would also be exacerbated. Male mice underwent trauma exposure (1.5-mA footshock), followed, 8 days later, by a conditioned place preference training with ethanol. Tests for fear sensitization, passive avoidance, anxiety-like behaviour, extinction acquisition and relapse susceptibility were used to assess behaviour changes. Plasma corticosterone and brain-derived neurotrophic factor levels and prefrontal dendritic changes were subsequently measured. Trauma-susceptible mice exposed to ethanol acquired a strong place preference and behaved differently from those not exposed to ethanol, with delayed avoidance extinction and higher avoidance relapse vulnerability. Ethanol potentiated trauma-associated dendritic changes in the prelimbic area and suppressed trauma-associated dendritic changes in the infralimbic area. However, ethanol had no effect on trauma-induced increased corticosterone and decreased brain-derived neurotrophic factor levels. These data suggest that the modification of prefrontal trauma-related changes, due to alcohol use, can characterise, and probably support, treatment-resistant post-traumatic stress disorder.

Serotonin 2C Antagonism in the Lateral Orbitofrontal Cortex Ameliorates Cue-Enhanced Risk Preference and Restores Sensitivity to Reinforcer Devaluation in Male Rats.

Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long–Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT2C antagonism may optimize choice by facilitating exploration.

Connexin43 hemichannels contribute to working memory and excitatory synaptic transmission of pyramidal neurons in the prefrontal cortex of rats

The gap junction is essential for the communication between astrocytes and neurons by various connexins. Connexin43 hemichannels (Cx43 HCs), one of important subunits of gap junction protein, is highly expressed in astrocytes. It has been demonstrated that Cx43 HCs is involved in synaptic plasticity and learning and memory. However, whether the role of Cx43 HCs in the prefrontal cortex (PFC), a key brain region mediating cognitive and executive functions including working memory, still remains unclear. Here, we investigate that the role of Cx43 HCs in working memory through pharmacological inhibition of Cx43 HCs in the PFC. Gap26, a specific hemichannels blocker for Cx43 HCs, was bilaterally infused into the prelimbic (PrL) area of the PFC and then spatial working memory was examined in delayed alternation task in T-maze. Furthermore, the effect of Gap26 on synaptic transmission of prefrontal pyramidal neurons was examined using whole-cell patch recording in slice containing PFC. The demonstrate that inhibition of prefrontal cortex Cx43 HCs impairs the working memory and excitatory synaptic transmission of PFC neurons, suggesting that Cx43 HCs in the PFC contributes to working memory and excitatory synaptic transmission of neurons in rats.

Prenatally stress-exposed male rats present lower theta prefrontal activity during attention behaviors to receptive females

Prenatal stress affects brain functionality and sexual behavior. The medial prefrontal cortex (mPFC) participates in the integration and processing of sexual stimuli. Electroencephalographic (EEG) theta activity has been associated with attention as well as rewarding and sexually motivated states. Considering that the induction of sexual motivation requires attention to, and the adequate processing of, sexual stimuli, this study aimed to evaluate the effects of exposure to stress during the prenatal period on EEG activity in the mPFC during nose pokes in adulthood, actions which are indicators of attention to a receptive female. Eighteen sexually experienced male rats were used, nine stressed prenatally by immobilization during days 14–21 of gestation (stress-exposed group). The other nine formed the control group. All rats were implanted bilaterally in the mPFC (specifically in prelimbic areas) and were allowed one intromission with a receptive female to induce a sexually motivated state before the experimental session. During this session, both nose pokes and non-contact erections in the male rats were evaluated in the presence of an inaccessible receptive female. EEGs were recorded only during nose pokes. The stress-exposed group presented lower nose poke duration, fewer non-contact erections, and lower relative power of the theta band (4–7 Hz) in both prefrontal areas. Considering that the prevalence of this band is associated with attention and motivational processes, these data confirm the deleterious effect of prenatal stress on attention and sexual activation to sexually relevant stimuli in male rats during adulthood.

Interference of commissural connections through the genu of the corpus callosum specifically impairs sensorimotor gating

White matter abnormalities in schizophrenic patients are characterized as regional tract-specific. Myelin loss at the genu of the corpus callosum (GCC) is one of the most consistent findings in schizophrenic patients across the different populations. We characterized the axons that pass through the GCC by stereotactically injecting an anterograde axonal tracing viral vector into the forceps minor of the corpus callosum in one hemisphere, and identified the homotopic brain structures that have commissural connections in the two hemispheres of the prefrontal cortex, including the anterior cingulate area, the prelimbic area, the secondary motor area, and the dorsal part of the agranular insular area, along with commissural connections with the primary motor area, caudoputamen, and claustrum. To investigate whether dysmyelination in these commissural connections is critical for the development of schizophrenia symptoms, we generated a mouse model with focal demyelination at the GCC by stereotactically injecting demyelinating agent lysolecithin into this site, and tested these mice in a battery of behavioral tasks that are used to model the schizophrenia-like symptom domains. We found that demyelination at the GCC influenced neither the social interest or mood state, nor the locomotive activity or motor coordination. Nevertheless, it specifically reduced the prepulse inhibition of acoustic startle that is a well-known measure of sensorimotor gating. This study advances our understanding of the pathophysiological contributions of the GCC-specific white matter lesion to the related disease, and demonstrates an indispensable role of interhemispheric communication between the frontal cortices for the top-down regulation of the sensorimotor gating.

Sex differences in dopamine innervation and microglia are altered by synthetic progestin in neonatal medial prefrontal cortex.

The synthetic progestin 17-α-hydroxyprogesterone caproate (17-OHPC) is commonly prescribed to pregnant women with a history of preterm delivery, despite little evidence of efficacy. The timing of 17-OHPC administration coincides with fetal mesocortical dopamine pathway development, yet the potential effects on cortical development and cognition are almost unknown. In rodent models, exposure to 17-OHPC significantly increased dopaminergic innervation of the medial prefrontal cortex (mPFC), an aberrant pattern of connectivity that may underlie deficits in cognitive flexibility observed in adulthood. In the present study, tyrosine hydroxylase (TH) immunoreactivity was used to determine whether 17-OHPC altered dopaminergic innervation of the mPFC during a neonatal period of synaptogenesis in males and females. Although there were no differences in the amount of TH-immunoreactive (-IR) fibres, there was a sex difference in TH-IR fibre distribution in deep layers of the prelimbic area (PL) mPFC; males had a narrower pattern of dopaminergic innervation than females. 17-OHPC exposure abolished these sex-specific patterns, such that 17-OHPC females had a narrower pattern in the PL than control females. In the infralimbic mPFC (IL), 17-OHPC males had a broader pattern of distribution of TH-immunoreactivity than control males with no differences in the amount of TH-IR fibres. 17-OHPC also created a sex difference in which males had a lower TH-IR fibre density than females. We also examined microglia, brain macrophages that play a key role in sculpting dopaminergic axon outgrowth in development, using phenotype as an indirect measure of microglial activity. Females had a greater number of reactive stout microglia compared to males in the PL, and males had more active round microglia than females in the IL. 17-OHPC treatment abolished the sex differences in both regions. These findings demonstrate that developmental exposure to 17-OHPC can exert differential effects in males and females and may diminish sex differences in cortical maturation.

Reward signaling by the rodent medial frontal cortex.

The anatomical relevance and functional significance of medial parts of the rodent frontal cortex have been intensely debated over the modern history of neuroscience. Early studies emphasized common functions among medial frontal regions in rodents and the dorsolateral prefrontal cortex of primates. Behavioral tasks emphasized memory-guided performance and persistent neural activity as a marker of working memory. Over time, it became clear that long-standing concerns about cross-species homology were justified and the view emerged that rodents are useful for understanding medial parts of the frontal cortex in primates, and not the dorsolateral prefrontal cortex. Here, we summarize a series of studies on the rodent medial frontal cortex that began with an interest in studying working memory in the perigenual prelimbic area and ended up studying reward processing in the medial orbital region. Our experiments revealed a role for a 4-8Hz "theta" rhythm in tracking engagement in the consumption of rewarding fluids and denoting the value of a given reward. Evidence for a functional differentiation between the rostral and caudal medial frontal cortex and its relationship to other frontal cortical areas is also discussed with the hope of motivating future work on this part of the cerebral cortex.

Concurrent LI-rTMS induces changes in c-Fos expression but not behavior during a progressive ratio task with adult ephrin-A2A5-/- mice

Changes within the dopaminergic system induced by repetitive transcranial magnetic stimulation (rTMS) may contribute to its therapeutic effects; however, dopamine-related behavioral effects of rTMS have not been widely investigated. We recently showed that ephrin-A2A5-/- mice completed significantly fewer trials in a visual task than wildtype mice, and that concurrent low-intensity (LI-) rTMS during the task could partially rescue the abnormal behavior [Poh et al. 2018, eNeuro, vol. 5]. Here, we investigated whether the behavioral differences in ephrin-A2A5-/- mice are due to abnormal motivation, primarily a dopamine-modulated behavior, and whether LI-rTMS would increase motivation.Ephrin-A2A5-/- and wildtype mice underwent 14 daily sessions of progressive ratio (PR) tasks and received either sham or LI-rTMS during the first 10 min. Ephrin-A2A5-/- mice responded more than wildtype comparisons, and LI-rTMS did not influence task performance for either strain. Therefore concurrent stimulation does not influence motivation in a PR task. However, ephrin-A2A5−/− mice did have abnormal performance in the PR tasks after a change in the PR schedule which suggests perseverative behavior.We stained for c-Fos in the prelimbic area (PrL), ventral tegmental area and nucleus accumbens (NAc) core and shell to examine neuronal activity from the final PR session. Sham ephrin-A2A5-/- mice had lower c-Fos expression in the PrL and NAc vs. wildtype mice. Ephrin-A2A5-/- mice that received LI-rTMS showed c-Fos expression closer to wildtype levels in the NAc. Combined with high PR performance, ephrin-A2A5−/− mice show an abnormal shift to habitual responding and LI-rTMS may attenuate this shift.

Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression.

A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these mechanisms, especially since previous findings show that astrocytes are affected and exhibit reactive-like features in depression. Moreover, it has been shown that reactive astrocytes increase the synthesis and release of GABA, contributing significantly to tonic GABA inhibition. In this study we found decreased plasticity and increased tonic GABA inhibition in the prelimbic area in acute slices from the medial prefrontal cortex in the Flinders Sensitive Line (FSL) rat model of depression. The tonic inhibition can be reduced by either blocking astrocytic intracellular Ca2+ signaling or by reducing astrocytic GABA through inhibition of the synthesizing enzyme MAO-B with Selegiline. Blocking GABA synthesis also restores the impaired synaptic plasticity in the FSL prefrontal cortex, providing a new antidepressant mechanism of Selegiline.

Ketamine contributes to the alteration of Ca2+ transient evoked by behavioral tests in the prelimbic area of mPFC: A study on chronic CORT-induced depressive mice

Recent studies have showed that ketamine is a rapid and efficient antidepressant, but the mechanism of its antidepressant effect is not fully clear. It is still lack of the research investigating the relation between depressive-like behaviors and neuronal activities in specific brain area after administration of ketamine in vivo. Medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. As a result of effective assessments after behavioral test, most studies lack of direct evidence of the relation between efficacy and the activity of specific brain area. Therefore, we used fiber photometry to explore the alteration of Ca2+ transient in the prelimbic (PrL) area of mPFC during behavioral tests in freely moving mice. Our results showed that the chronic corticosterone (CORT) protocol induced depressive-like behaviors. Administration of ketamine reversed these effects. The activation of Ca2+ transients was associated with some behaviors during behavioral tests. Struggling, rearing and exploring evoked strong Ca2+ transients, but moving and grooming did not. The Ca2+ transients amplitude reductions of struggling, rearing and exploring induced by CORT were reversed by ketamine. The results indicated that ketamine ameliorated depressive-like behaviors via mediating neural activation in PrL.

Different Multidimensional Representations across the Amygdalo-Prefrontal Network during an Approach-Avoidance Task

The prelimbic (PL) area and basolateral amygdala (lateral [LA] and basolateral [BL] nuclei) have closely related functions and similar extrinsic connectivity. Reasoning that the computational advantage of such redundancy should be reflected in differences in how these structures represent information, we compared the coding properties of PL and amygdala neurons during a task that requires rats to produce different conditioned defensive or appetitive behaviors. Rather than unambiguous regional differences in the identities of the variables encoded, we found gradients in how the same variables are represented. Whereas PL and BL neurons represented many different parameters through minor variations in firing rates, LA cells coded fewer task features with stronger changes in activity. At the population level, whereas valence could be easily distinguished from amygdala activity, PL neurons could distinguish both valence and trial identity as well as or better than amygdala neurons. Thus, PL has greater representational capacity.

Concomitant D1 and D2 dopamine receptor agonist infusion in prelimbic cortex is required to foster extinction of amphetamine-induced conditioned place preference

Dopamine (DA) in medial prefrontal cortex is crucial in extinction of aversive or appetitive experiences. Although attention has been mostly focused on the infralimbic area of prefrontal cortex, a role of the prelimbic (PL) area has been envisaged pointing to DA transmission in the extinction of drug conditioned behavior. Evidence shows that DA exerts its action also via both D1 and D2 receptor subtypes.Here we investigated the effects of D1 and D2 receptor agonist microinfusion in the PL cortex of C57BL/6J mice on expression and extinction of amphetamine-induced conditioned place preference (CPP), in order to ascertain the effects of selective vs concomitant receptor subtypes stimulation.SKF38393 and Quinpirole were used at doses not impairing expression of amphetamine-induced CPP on the day of infusion. Acute infusion of each agonist alone did not affect extinction in subsequent days in comparison with Vehicle-treated mice, while concomitant infusion of both agonists produced a clear-cut advance of extinction of preference for the compartment previously paired with amphetamine.These results show that concomitant stimulation of D1 and D2 receptors in PL is required to foster extinction suggesting a synergic action between receptors or a heteromeric receptor involvement.

Prelimbic input to basolateral amygdala facilitates the acquisition of trace cued fear memory under weak training conditions

The ability to predict the occurrence of an aversive outcome based on available cues requires associative learning and plastic changes in the amygdala. When the predictive cue and aversive shock outcome are separated in time as in trace fear conditioning, additional circuitry is needed, including the prelimbic (PL) area of the prefrontal cortex. We have previously shown that neuronal firing in the PL during the trace interval separating the cue and shock is required for trace cued fear memory formation, but whether this mnemonic signal is conveyed to the amygdala is unknown. Here we show in males that silencing PL activity during the trace interval reduces Arc protein in the basolateral amygdala (BLA) of trace-conditioned rats. Then, using pathway-specific optogenetic and chemogenetic silencing, we show a role for direct PL-BLA communication in trace cued fear learning under weak training conditions, but not standard training. These results suggest that PL input to the BLA may serve to promote cued learning when the cue-shock relationship is most ambiguous and that other trace fear circuitry can compensate for the loss of this connection with additional training. This also highlights the challenge to studying how emotional memories are formed and stored within a distributed network and suggests that the function of individual connections within such a network may best be determined using weak training conditions.

Altered Cognitive Flexibility and Synaptic Plasticity in the Rat Prefrontal Cortex after Exposure to Low (≤15 cGy) Doses of 28Si Radiation.

This study has established the impact that 1-15 cGy 600 MeV/n 28Si radiation had on cognitive flexibility performance, glutamatergic synaptic transmission and plasticity in the prelimbic area (PrL) of the medial prefrontal cortex (mPFC) of ∼10-month-old (at the time of irradiation) male Wistar rats. Exposure to 1 cGy 600 MeV/n 28Si ions resulted in significantly impaired performance in the simple (SD) and compound discrimination (CD) stages of the attentional set shifting (ATSET) task. However, there was a pronounced non-linear dose response for cognitive impairment. Should similar effects occur in astronauts, the impairment of SD performance would result in a decreased ability to identify and learn the "rules" required to respond to new tasks/situations, while the impaired CD performance would result in a decreased ability to identify and maintain focus on relevant aspects of the task being conducted. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem solving. Exposure to 1, 5 and 10 cGy resulted in a significant reduction in UCFlex performance, in an apparent all-or-none responsive manner. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. After completion of the cognitive flexibility testing, in vitro electrophysiological assessments of glutamatergic synaptic transmission and plasticity were performed in slices of the PrL cortex of 10 cGy irradiated rats. Extracellular recordings of field excitatory postsynaptic potentials revealed that radiation significantly decreased long-term depression in layer L5. Patch-clamp whole cell recordings in pyramidal neurons of the L2-3 revealed reduced frequency of spontaneous excitatory postsynaptic currents indicating alterations in presynaptic glutamate release and impaired neuronal spiking (e.g., decreased action potential amplitudes) in irradiated neurons. However, there was no obvious correlation between magnitudes of these electrophysiological decrements and the cognitive performance status of the irradiated rats. These data suggest that while radiation-induced changes in synaptic plasticity in the PrL cortex may be associated with cognitive impairment, they are most likely not the sole determinant of the incidence and severity of such impairments.

(R)-Ketamine Rapidly Ameliorates the Decreased Spine Density in the Medial Prefrontal Cortex and Hippocampus of Susceptible Mice After Chronic Social Defeat Stress.

BackgroundA recent study demonstrated that spine formation rates by ketamine in the prefrontal cortex (PFC) were not altered at 3–6 h following a single injection, but were markedly altered at 12–24 h. Here, we investigated the acute (3 h post-treatment) effects of (R)-ketamine in the decreased spine density in the medial PFC (mPFC) and hippocampus in susceptible mice after chronic social defeat stress (CSDS).Methods(R)-ketamine (10 mg/kg) or saline was administered intraperitoneally to CSDS-susceptible mice. Dendritic spine density in the mPFC and hippocampus was measured 3 h after a single injection.Results(R)-ketamine significantly ameliorated the decreased spine density in the prelimbic area of mPFC, Cornu Ammonis3, and dentate gyrus of the hippocampus of CSDS-susceptible miceConclusionsThis study suggests that (R)-ketamine rapidly ameliorates the decreased spine density in the mPFC and hippocampus of CSDS-susceptible mice, resulting in its rapid-acting antidepressant effects.

The rat medial frontal cortex controls pace, but not breakpoint, in a progressive ratio licking task.

The medial frontal cortex (MFC) is crucial for selecting actions and evaluating their outcomes. Outcome monitoring may be triggered by rostral parts of the MFC, which contain neurons that are modulated by reward consumption and are necessary for the expression of relative reward value. Here, we examined if the MFC further has a role in the control of instrumental licking. We used a progressive ratio licking task in which rats had to make increasing numbers of licks to receive liquid sucrose rewards. We determined what measures of progressive ratio performance are sensitive to value by testing rats with rewards containing 0%-16% sucrose. We found some measures (breakpoint, number of licking bouts) were sensitive to sucrose concentration and others (response rate, duration of licking bouts) were not. Then, we examined the effects of reversibly inactivating rostral (medial orbital) and caudal (prelimbic) parts of the MFC. We were surprised to find that inactivation had no effects on measures associated with value (e.g., breakpoint). Instead, inactivation altered behavioral measures associated with the pace of task performance (response rate and time to break). These effects depended on where inactivations were made. Response rates increased and time to break decreased when the caudal prelimbic area was inactivated. By contrast, response rates decreased and the time to break increased when the rostral medial orbital cortex was inactivated. Our findings suggest that the medial frontal cortex has a role in maintaining task engagement, but not in the motivational control of action, in the progressive ratio licking task. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

N-methyl-d-aspartate Receptors in the Prelimbic Cortex are Critical for the Maintenance of Neuropathic Pain

The mechanisms underlying chronic and neuropathic pain pathology involve peripheral and central sensitisation. The medial prefrontal cortex (mPFC) seems to participate in pain chronification, and glutamatergic neurotransmission may be involved in this process. Thus, the aim of the present work was to investigate the participation of the prelimbic (PrL) area of the mPFC in neuropathic pain as well as the role of N-methyl D-aspartate (NMDA) glutamate receptors in neuropathic pain induced by a modified sciatic nerve chronic constriction injury (CCI) protocol in Wistar rats. Neural inputs to the PrL cortex were inactivated by intracortical treatment with the synapse blocker cobalt chloride (CoCl2, 1.0mM/200 nL) 7, 14, 21, or 28days after the CCI or sham procedure. The glutamatergic agonist NMDA (0.25, 1 or 4nmol) or the selective NMDA receptor antagonist LY235959 (2, 4 or 8nmol) was microinjected into the PrL cortex 21days after surgery. CoCl2 administration in the PrL cortex decreased allodynia 21 and 28days after CCI. NMDA at 1 and 4nmol increased allodynia, whereas LY235959 decreased mechanical allodynia at the highest dose (8nmol) microinjected into the PrL cortex. These findings suggest that NMDA receptors in the PrL cortex participate in enhancing the late phase of mechanical allodynia after NMDA-induced increases and LY235959-induced decreases in allodynia 21days after CCI. The glutamatergic system potentiates chronic neuropathic pain by NMDA receptor activation in the PrL cortex. Mechanism of neuropathic pain. The infusion of CoCl2, a synapse activity blocker, into the prelimbic (PrL) division of the medial prefrontal cortex (mPFC) decreased the severity of mechanical allodynia, showing the late participation of the limbic cortex. The glutamatergic system potentiates chronic neuropathic pain via NMDA receptor activation in the PrL cortex.

The effect of D2 dopaminergic system in nucleus accumbens and glutamatergic system of prelimbic area on anxiety- like behaviors in Wistar male rats.

Background: Neutrustransmitter systems of dopaminergic and glutamatergic of the prefrontal cortex (PFC) and nucleus accumbens (NAc) are involved in the regulation of anxiety-like behaviors. In addition, the activity of the NAc dopaminergic system is mediated by the glutamatergic inputs, which is mainly from the PFC. This study investigated the role of D2 dopaminergic system in nucleus accumbens and glutamatergical system of prelimbic area on anxiety- like behaviors in male rats. Methods: This study was performed on four experimental groups in 35 groups of 8 male rats. after 5 days of surgery in a stereotaxic frame, the Elevated Plus maze apparatus was employed for the recording parameters of anxiety-like behaviors due to intr-abrain injection of quinpirole (Dopamine receptor agonist), sulpiride (Dopaminergic D2 receptor antagonist), NMDA(NMDA receptor agonist) and D-AP7 (NMDA receptor antagonist. Results: Unilateral intra- left prelimbic injection of NMDA (0.9 μg/μl) reduced the anxiety-like behaviors (P<0.01), which was blocked by D-AP7 injection (P<0.01). Also, unilateral infusion of sulpiride (0.4 and 0.6 μg/μl) into the NAc shell induced anxiolytic-like behaviors (P<0.05). Furthermore, the administration of the sub threshold dose of sulpiride (0.2 μg/μl) in the NAc shell strengthened the effect of low dose NMDA (P<0.05), whereas reduced its high dose (P<0.01) in prelimbic. Conclusion: The results indicate the regulatory effect of the dopamine D2 system of NAc shell on the anxiolytic-like response caused by NMDA injection in prelimbic region.