Investigating the role of Prefrontal Neurons in cognitive tasks through Fiber Photometry and Adapted Barnes Maze Protocols

The medial prefrontal cortex (mPFC) is essential in the execution of cognitive tasks, however very little is known on how these neurons are modulated during specific tasks and which subtype of neurons are responsible for so. Therego, with the intention of addressing this issue, we recorded mPFC gabaergic and glutamatergic activation patterns through fiber photometry (FIP) in mice, while simultaneously performing the Barnes Maze (BM) cognitive task (4 day behavioral trial). In addition, an altered structural and procedural protocol for BM was validated in this study due to necessary modifications allowing FIP and BM to happen simultaneously. A successful protocol validation was followed by our preliminary results, which showed that both glutamatergic and gabaergic neurons presented significant change in activation intensity and number of events in specific contexts throughout the task days. In addition, when stratified and crossed with BM performance parameters, such as latency to complete tasks and adopted strategy, glutamatergic and gabaergic neurons presented a significant decline in both activation patterns and number of activation events throughout the days. This data suggest not only an important role of glutamatergic and gabaergic mPFC neurons in learning, memory and decision making, but also that activation patterns of each of these groups may serve as markers for cognitive progression and/or dysfunction. KEY-WORDS: Memory, Learning, Decision Making, Medial Prefrontal Cortex (mPFC), Fiber Photometry (FIP), Barnes Maze (BM), Glutamatergic, Gabaergic, Neuronal Activity, Neuronal Activation Patterns, Neuronal Dynamics.

O córtex pré-frontal medial (mPFC) é essencial na execução de tarefas cognitivas, no entanto, pouco se sabe sobre como esses neurônios são modulados durante tarefas específicas e qual subtipo de neurônios é responsável por isso. Portanto, com a intenção de abordar essa questão, registramos os padrões de ativação de neurônios gabaérgicos e glutamatérgicos do mPFC por meio de fotometria de fibra (FIP) em camundongos, enquanto realizávamos simultaneamente a tarefa cognitiva do Labirinto de Barnes (BM) (ensaio comportamental de 4 dias). Além disso, um protocolo estrutural e procedimental alterado para o BM foi validado neste estudo devido a modificações necessárias que permitiram a realização simultânea de FIP e BM. Uma validação bem-sucedida do protocolo foi seguida pelos nossos resultados preliminares, que mostraram que tanto os neurônios glutamatérgicos quanto os gabaérgicos apresentaram mudanças significativas na intensidade de ativação e no número de eventos em contextos específicos ao longo dos dias da tarefa. Além disso, quando estratificados e cruzados com parâmetros de desempenho do BM, como latência para completar as tarefas e estratégia adotada, os neurônios glutamatérgicos e gabaérgicos apresentaram uma diminuição significativa nos padrões de ativação e no número de eventos de ativação ao longo dos dias. Esses dados sugerem não apenas um papel importante dos neurônios glutamatérgicos e gabaérgicos do mPFC na aprendizagem, memória e tomada de decisões, mas também que os padrões de ativação de cada um desses grupos podem servir como marcadores de progressão e/ou disfunção cognitiva. PALAVRAS-CHAVE: Memória, Aprendizagem, Tomada de Decisões, Córtex Pré-Frontal Medial (mPFC), Fotometria de Fibra (FIP), Labirinto de Barnes (BM), Glutamatérgico, Gabaérgico, Atividade Neuronal, Padrões de Ativação Neuronal, Dinâmica Neuronal.

Electroacupuncture suppresses glucose metabolism and GLUT-3 expression in medial prefrontal cortical in rats with neuropathic pain

BACKGROUND: Accumulating evidence has demonstrated that the electroacupuncture (EA) stimulation could effectively alleviate neuropathic pain. The medial prefrontal cortex (mPFC) is a vital part of the cortical representation of pain in the brain, and its glucose metabolism is mostly affected in the progression of pain. However, the central mechanism of EA analgesia remains unclear. METHODS: Fifty-four male SD rats were equally randomized into sham surgery (Sham) group, chronic constriction injury (CCI) group and EA stimulation (EA) group. The CCI model, involving ligature of the right sciatic nerve, was established in all animals except the Sham group. EA stimulation was applied on the right side acupoints of Huantiao (GB30) and Yanglingquan (GB34) in the EA group. Paw withdrawal threshold (PWT) and paw thermal withdrawal latency (PWL) were measured. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to evaluate glucose metabolism changes in the mPFC. The expression of glucose transporter 3 (GLUT-3) in the mPFC was determined by immune histochemistry and ELISA. RESULTS: Comparing with CCI groups, EA treatment was obviously reversed CCI-induced mechanical allodynia (P < 0.01), thermal hyperalgesia (P < 0.01) and the increase of glucose metabolism in the left mPFC (P < 0.05). Furthermore, EA treatment significantly decreased the protein expression of GLUT-3 in the left mPFC (P < 0.01). CONCLUSIONS: Our results indicate that EA analgesia effect may be related to suppressing the glucose metabolism and GLUT-3 expression in the mPFC. This study could provide a potential insight into the central mechanisms involved in the analgesic effect of EA.

Projections from Infralimbic Cortex to Paraventricular Thalamus Mediate Fear Extinction Retrieval / 神经科学通报·英文版

The paraventricular nucleus of the thalamus (PVT), which serves as a hub, receives dense projections from the medial prefrontal cortex (mPFC) and projects to the lateral division of central amygdala (CeL). The infralimbic (IL) cortex plays a crucial role in encoding and recalling fear extinction memory. Here, we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval. Silencing PVT neurons inhibited extinction retrieval at recent time point (24 h after extinction), while activating them promoted extinction retrieval at remote time point (7 d after extinction), suggesting a critical role of the PVT in extinction retrieval. In the mPFC-PVT circuit, projections from IL rather than prelimbic cortex to the PVT were dominant, and disrupting the IL-PVT projection suppressed extinction retrieval. Moreover, the axons of PVT neurons preferentially projected to the CeL. Silencing the PVT-CeL circuit also suppressed extinction retrieval. Together, our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.

Connectivity pattern of action potentials causal network in prefrontal cortex during anxiety / 生物医学工程学杂志

Anxiety disorder is a common emotional handicap, which seriously affects the normal life of patients and endangers their physical and mental health. The prefrontal cortex is a key brain region which is responsible for anxiety. Action potential and behavioral data of rats in the elevated plus maze (EPM) during anxiety (an innate anxiety paradigm) can be obtained simultaneously by using the and in conscious animal multi-channel microelectrode array recording technique. Based on maximum likelihood estimation (MLE), the action potential causal network was established, network connectivity strength and global efficiency were calculated, and action potential causal network connectivity pattern of the medial prefrontal cortex was quantitatively characterized. We found that the entries (44.13±6.99) and residence period (439.76±50.43) s of rats in the closed arm of the elevated plus maze were obviously higher than those in the open arm [16.50±3.25, <0.001; (160.23±48.22) s, <0.001], respectively. The action potential causal network connectivity strength (0.017 3±0.003 6) and the global efficiency (0.044 2±0.012 8) in the closed arm were both higher than those in the open arm (0.010 4±0.003 2, <0.01; 0.034 8±0.011 4, <0.001), respectively. The results suggest that the changes of action potential causal network in the medial prefrontal cortex are related to anxiety state. These data could provide support for the study of the brain network mechanism in prefrontal cortex during anxiety.

Reversal of Social Recognition Deficit in Adult Mice with MECP2 Duplication via Normalization of MeCP2 in the Medial Prefrontal Cortex / 神经科学通报·英文版

Methyl-CpG binding protein 2 (MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing. Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, heightened anxiety, epilepsy, autistic phenotypes, and early death. Reversal of the abnormal phenotypes in adult mice with MECP2 duplication (MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated. However, whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown. Here, we found that MECP2-TG mice showed a significant social recognition deficit, and were prone to display aversive-like behaviors, including heightened anxiety-like behaviors and a fear generalization phenotype. In addition, reduced locomotor activity was observed in MECP2-TG mice. However, appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice. Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors. We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex (mPFC) and bed nuclei of the stria terminalis (BST) of adult MECP2-TG mice, and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit. These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice, and provide new insight into potential therapies for MECP2 duplication syndrome.

Transcranial magnetic stimulation of the medial prefrontal cortex for psychiatric disorders: a systematic review

Objective: The medial prefrontal cortex (mPFC) is a highly connected cortical region that acts as a hub in major large-scale brain networks. Its dysfunction is associated with a number of psychiatric disorders, such as schizophrenia, autism, depression, substance use disorder (SUD), obsessive-compulsive disorder (OCD), and anxiety disorders. Repetitive transcranial magnetic stimulation (rTMS) studies targeting the mPFC indicate that it may be a useful therapeutic resource in psychiatry due to its selective modulation of this area and connected regions. Methods: This review examines six mPFC rTMS trials selected from 697 initial search results. We discuss the main results, technical and methodological details, safety, tolerability, and localization strategies. Results: Six different protocols were identified, including inhibitory (1 Hz) and excitatory (5, 10, and 20 Hz) frequencies applied therapeutically to patient populations diagnosed with major depressive disorder, OCD, autistic spectrum disorder, SUD, specific phobia, and post-traumatic stress disorder (PTSD). In the OCD and acrophobia trials, rTMS significantly reduced symptoms compared to placebo. Conclusion: These protocols were considered safe and add interesting new evidence to the growing body of mPFC rTMS literature. However, the small number and low methodological quality of the studies indicate the need for further research.

Dysfunctional Social Reinforcement Processing in Disruptive Behavior Disorders: An Functional Magnetic Resonance Imaging Study

OBJECTIVE: Prior functional magnetic resonance imaging (fMRI) work has revealed that children/adolescents with disruptive behavior disorders (DBDs) show dysfunctional reward/non-reward processing of non-social reinforcements in the context of instrumental learning tasks. Neural responsiveness to social reinforcements during instrumental learning, despite the importance of this for socialization, has not yet been previously investigated. METHODS: Twenty-nine healthy children/adolescents and 19 children/adolescents with DBDs performed the fMRI social/non-social reinforcement learning task. Participants responded to random fractal image stimuli and received social and non-social rewards/non-rewards according to their accuracy. RESULTS: Children/adolescents with DBDs showed significantly reduced responses within the caudate and posterior cingulate cortex (PCC) to non-social (financial) rewards and social non-rewards (the distress of others). Connectivity analyses revealed that children/adolescents with DBDs have decreased positive functional connectivity between the ventral striatum (VST) and the ventromedial prefrontal cortex (vmPFC) seeds and the lateral frontal cortex in response to reward relative to non-reward, irrespective of its sociality. In addition, they showed decreased positive connectivity between the vmPFC seed and the amygdala in response to non-reward relative to reward. CONCLUSION: These data indicate compromised reinforcement processing of both non-social rewards and social non-rewards in children/adolescents with DBDs within core regions for instrumental learning and reinforcement-based decision-making (caudate and PCC). In addition, children/adolescents with DBDs show dysfunctional interactions between the VST, vmPFC, and lateral frontal cortex in response to rewarded instrumental actions potentially reflecting disruptions in attention to rewarded stimuli.

Effect of reward alteration following acupuncture for morphine withdrawal rats on neuronal discharges in the ventral medial prefrontal cortex / 针灸推拿医学（英文版）

Objective:To observe the effect of reward alteration following acupuncture for morphine withdrawal rats on the behavior and neuronal discharges in the medial prefrontal cortex (mPFC). Methods:The Sprague-Dawley (SD) rats were randomly allocated into a model group, a confinement group, an electroacupuncture (EA) group, and a control group. Rats with morphine addiction were made by intraperitoneal injection of naloxone (same dose injection of saline for rats in the control group), followed by a 2-week morphine withdrawal. Acupuncture and confinement were completed during the morphine withdrawal period. Upon withdrawal, the rats received conditioned place preference (CPP) training and open field test. The multi-channel neural signal processor was used in the electrophysiological experiment to measure the neuronal discharges in different subareas of prefrontal cortex in CPP box and aversion box. Results:Rats in the model group and the confinement group spent longer period of time in CPP box than those in the EA group and the control group (allP<0.01); there was no statistically significant difference between the EA group and the control group. The total distances of movement by rats in the model group and the confinement group were longer than those in the EA group and the control group (allP<0.01). The mPFC neuronal discharge frequencies were compared between morphine preference box and aversion box. The mPFC neuronal discharge frequencies in the model group and the confinement group were higher than those in the EA group and the control group (allP<0.05); there was no statistically significant difference between the EA group and the control group. Conclusion:Acupuncture can effectively interfere with the reward alteration following morphine withdrawal, possibly because of its involvement with the mPFC neuronal discharges.

Altered Functional Connectivity of the Default Mode Network in Low-Empathy Subjects

Empathy is the ability to identify with or make a vicariously experience of another person's feelings or thoughts based on memory and/or self-referential mental simulation. The default mode network in particular is related to self-referential empathy. In order to elucidate the possible neural mechanisms underlying empathy, we investigated the functional connectivity of the default mode network in subjects from a general population. Resting state functional magnetic resonance imaging data were acquired from 19 low-empathy subjects and 18 medium-empathy subjects. An independent component analysis was used to identify the default mode network, and differences in functional connectivity strength were compared between the two groups. The low-empathy group showed lower functional connectivity of the medial prefrontal cortex and anterior cingulate cortex (Brodmann areas 9 and 32) within the default mode network, compared to the medium-empathy group. The results of the present study suggest that empathy is related to functional connectivity of the medial prefrontal cortex/anterior cingulate cortex within the default mode network. Functional decreases in connectivity among low-empathy subjects may reflect an impairment of self-referential mental simulation.

The influence of restraint water-immersion stress on firing activities of pyramidal neurons in the medial prefrontal cortex in rats / 中华行为医学与脑科学杂志

Objective To explore the effects of restraint water-immersion stress (RWIS) on the firing activities of pyramidal neurons in the medial prefrontal cortex (MPFC) of rats.Methods Multi-channel in vivo recording techniques were used to record firing activities of pyramidal neurons before and during 4-h RWIS in rats.Firing rates,inter-spike intervals and burst firing rates were taken as indices to study the influence of RWIS on neuronal firing activities.Results Twenty-five pyramidal neurons of 12 rats were recorded.The opposite patterns of firing activities were observed in two different classes of neurons,type A and type B neurons which account for 72％ and 28％,respectively.In type A neurons,inhibited firing activities were in direct proportion to the stress-exposure.Mean firing rates and mean burst firing rates were significantly reduced to (0.81 ± 0.11) Hz and (1.012 ± 0.50) counts/min after 4h constant RWIS compared with those before RWIS,(3.57 ± 0.63) Hz and (10.29 ± 3.04) counts/min.However,in type B neurons,firing activities were enhanced.After 2h constant RWIS,mean firing rates and mean burst firing rates were increased from (1.77±0.45) Hz and (2.01±0.73) counts/min to (2.67±0.74)Hz and (9.04±2.42) counts/min,respectively.Moreover,the percentage of spikes in bursts was significantly increased and mean inter-spike intervals were remarkably shortened.Interestingly,the effect of RWIS on type B neurons lasted for shorter time compared with its effect on type A neurons.Conclusion RWIS differentially affects the firing activity of pyramidal neuron in the MPFC,i.e.,inhibiting the firing activity of type A neurons,but enhancing the firing activity of type B neurons.

Effect of mPFC neuron synaptic plasticity changes in the formation of morphine related reward memory / 中华行为医学与脑科学杂志

Objective To observe the effect of mPFC neuron synaptic plasticity changes in the formation of morphine related reward memory.Methods 40 SD rats were administered morphine (10 mg/kg,ip) or saline (2 ml/kg,ip)and sacrificed 0,2,4 and 8 h after the treatment.The temporal profile of activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) expression in medial prefrontal cortex (mPFC) was analyzed.Another 40 rats receiving a single injection of morphine at different doses (0,5,10 or 20 mg/kg),and rats were sacrificed by decapitation 2 h later.In mPFC,changes of Arc/Arg 3.1 protein was analyzed by Western Blot,Arc/Arg 3.1 positive cells was detected by immunohistochemistry (IHC),and number of spines were analyzed by Golgi-cox method.In the second experiment,CPP model was established by 5 mg/kg morphine for 8 days.Arc/Arg 3.1 antisense oligodeoxynucleotide (AS) or the control (CS) was microinjected into mPFC 15 minutes before each morphine injection,then CPP score was evaluated.Results Compared with saline groups,Arc/Arg 3.1 protein,Arc/Arg 3.1 positive cells,number of spines ((1.01±0.04) vs (1.58±0.18),P＜0.01 ; (42.80±7.63) vs (74.47±8.02),P＜0.01 ;(17.27±5.64) vs (39.47±7.56),P＜0.01) were significantly increased 2 hours after morphine administration.All three doses of morphine (5,10 and 20 mg/kg) increased Arc/Arg 3.1 protein expression in the mPFC,and there were no dose-dependent effects.In CPP experiments,compared with microinjection of Arc/Arg 3.1 CS (0.74±0.02),Arc/Arg 3.1 AS microinjection significantly decreased the CPP score (0.51±0.01) in morphine group (P＜0.01).Conclusion It is enough to increase Arc/Arg 3.1 protein content and synaptic plasticity in mPFC by 10 mg/kg,and the changes implied in formation of morphine relative reward memory.

Influence of intraventricular inj ection of 5,7-drhydroxytryptamine in 5-HT1A receptor sensitivity of pyramidal neurons in medial prefrontal cortex / 吉林大学学报(医学版)

Objective To explore the influence of intraventricular injection of 5, 7-drhydroxytryptamine (5, 7-DHT)in 5-HT1A receptor sensitivity of medial prefrontal cortex pyramidal neurons in the rats,and to clarity the effect of 5-HT1A receptor on the eletronic response of pyramidal neurons.Methods 36 male SD rats were randomly divided into sham operation group (n=21)and 5,7-DHT lesion group (n=15).5,7-DHT was injected intraventricularly in the rats in 5,7-DHT lesion group,and the same dose saline was injected in the rats in sham operation group.The rats in two groups were intravenously injected with different doses(0.5-128.0μg·kg-1 )of 8-CH-DPAT.The firing rate of mPFC pyramidal neurons was recorded with extracellular electrophysioological examination.The rats in two groups were intravenously injected with WAY100635,the sensitivites of the rats to 8-OH-DPAT and WAY100635 in 5, 7-DHT lesion group were observed, and compared with sham operation group.Results The different doses (0.5-128.0μg·L-1 )of 8-OH-DDAT had an excitatory-inhibitory effect on the firing rate of mPFC pyamidal neurons in sham operation group;the neurons were excited when the doses of 8-OH-DPAT were 0.5-38.0μg·kg-1 ,and the firing rates were increased(P<0.05);the neurons were inhibited when the dose of 8-OH-DPAT was 128.0μg·kg-1 ,and the firing rate was decreased.The different doses(0.5-218.0μg·L-1 )of 8-OH-DPAT inhibited the elecctronic response of pyramidal neurons of the rats in 5,7-DHT lesion group in a dose-dependent manner (df=5,F=3.44,P=0.003),and the firing rates were reduced. WAY-100635 (50μg·kg-1 )reversed completely the inhibition of 8-OH-DPAT.Conclusion The sensitivity of 5-HT1A receptor of rat mPFC pyramidal neurons can be decreased by intraventricular injection of 5,7-DHT.

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 / Prevention of the CA1-mPFC pre-synaptic plasticity impairments in a post-ictal psychosis model '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.

The present work aimed to test whether the induction of cortical long-term potentiation (LTP) was able to prevent the presynaptic plasticity impairment in the hippocampus (CA1)-medial prefrontal cortex (mPFC) pathway induced by hippocampal after-discharge (AD; epileptic activity) or systemic injection of ketamine (KET; pharmacological model of psychosis). Electrodes were stereotaxically positioned into CA1 and mPFC in urethane-anesthetized rats. Monophasic paired-pulses of electrical stimuli were applied to CA1 in order to evoke field post-synaptic potentials (P1 and P2) in the mPFC every 20s. Short-term plasticity was evaluated by measuring paired-pulse facilitation (PPF), defined as the amplitude ratio P2/P1. After 90min of baseline recordings, three independent groups of animals received hippocampal-AD, KET-S(+) (12.5mg/kg, i.p.) or vehicle (NaCl 0.15M) followed by 120min of evoked response monitoring. In an additional experiment, two applications of high-frequency stimuli (HFS) were given at 30 and 60min after baseline. Thirty minutes after the second HFS, the rats received KET, AD or vehicle and their cortical evoked potentials were monitored for further 120min. Our results showed that AD significantly decreased (-50%) whereas KET enhanced (+10%) CA1-mPFC basal synaptic transmission. In addition, AD and KET similarly impaired short-term plasticity in the mPFC (-15%). Interestingly, pre-induction of LTP in the mPFC prevented the PPF disruption induced by KET and AD. Altogether, our findings support recent evidences that positive allosteric modulators of NMDA and AMPA receptors attenuate cognitive impairments in animal models of psychosis. We believe that controlled HFS in CA1 can be a useful tool to better understand how to prevent synaptic plasticity disruptions observed in experimental models of psychosis and pos-ictal psychosis.

Inactivation of the Medial Prefrontal Cortex Interferes with the Expression But Not the Acquisition of Differential Fear Conditioning in Rats

The medial prefrontal cortex (mPFC) has been implicated in the processing of emotionally significant stimuli, particularly the inhibition of inappropriate responses. We examined the role of the mPFC in regulation of fear responses using a differential fear conditioning procedure in which the excitatory conditioned stimulus (CS+) was paired with an aversive footshock and intermixed with the inhibitory conditioned stimulus (CS-). In the first experiment, using rats as subjects, muscimol, a gamma-amino-butyric acid type A (GABAA) receptor agonist, or artificial cerebrospinal fluid (aCSF) was infused intracranially into the mPFC across three conditioning sessions. Twenty-four hours after the last conditioning session, freezing response of the rats was tested in a drug-free state. Neither the muscimol nor the aCSF infusion had any effect on differential responding. In the second experiment, the same experimental procedure was used except that the infusion was made before the testing session rather than the conditioning sessions. The results showed that muscimol infusion impaired differential responding: the level of freezing to CS- was indiscriminable from that to CS+. Taken together, these results suggest that the mPFC is responsible for the regulation of fear response by inhibiting inappropriate fear expressions.

Lesions of the medial prefrontal cortex of guinea pig inhibit acoustic startle reflex / 中华行为医学与脑科学杂志

Objective To observe and analyze the role of different subfields of medial prefrontal cortex (mPFC) in the expression course of startle reflex.Methods 24 healthy male British kind of albino guinea pigs were randomly divided into 4 groups:anterior cingulated cortex lesion ( n =6) and sham-lesion ( n =6) ( Experiment 1 ) ; prelimbic cortex lesion/joint lesion of prelimbic cortex and anterior cingulated cortex(n=6) and sham-lesion ( n =6) ( Experiment 2 ).The animals were injected lidocaine ( lesion ) or physiological saline ( sham-lesion ).Each group received paired training of conditioned stimulus( CS,a tone) and unconditioned stimulus (US,a air puff),to observe the acoustic startle reflex(ASR) change of these groups.Results As the results of experiment 1 suggested,SR rate did not change significantly after anterior cingulated cortex lesion ( time effect:F =15.421,P =0.098 ; group effect:F =14.753,P =0.084).As the results of experiment 2 suggested,SR rate did not change significantly after prelimbic cortex lesion ( time effect:F =14.975,P =0.178 ; group effect:F =18.643,P =0.089).When prelimbic cortex and anterior cingulated cortex were lesioned at the same time,SR rate declined significantly and didn ' t recover with the following training ( group effect:F =67.743,P =0.009 ).ConclusionLesions of the prelimbic cortex and anterior cingulated cortex in mPFC cause the significantly decline of acoustic startle reflex( ASR),which don' t recover with the following training.This study indicates that mPFC involves in the regulation of ASR,but the regulation mechanism needs to be discussed.

Changes of phosphorylated ERK 1/2 and c-fos in the medial prefrontal cortex of post-traumatic stress disorder rats / 解剖学报

ObjectiveTo observe the changes of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and c-fos in the medial prefrontal cortex (mPFC) of post-traumatic stress disorder (PTSD) rats. Methods Male Wistar rats were randomly divided into control group and PTSD model group. The model group rats were exposed to the single-prolonged stress (SPS) to set up the rat PTSD model. The expression of pERK1/2 was detected using immunohistochemistry and Western blotting, and the expression of c-fos mRNA was detected using reverse transcription-polymerase chain reaction (RT-PCR). Results The result of immunohistochemistry analysis showed that the number of pERK1/2-positive cells of control group and model group were 10.4±2.07 and 48.8±10.08 respectively (P<0.01), and integral optical density were 24.955±3.691 and 110.810±10.643 respectively (P<0.01). And Western blotting showed that relative expression quantities of pERK/β-actin were 0.510±0.052 and 1.109±0.106 respectively (P<0.01). The quantities of c-fos mRNA relative expression of control group and model group were 0.267±0.067 and 1.049±0.131 (P<0.01). Conlusion The levels of pERK1/2 and c-fos increase significantly in mPFC of PTSD model rats. The ERK signal transduction pathway in mPFC might play an important role in the pathogenesis of PTSD.