Prelimbic mPFC Research Articles

Context memory formed in medial prefrontal cortex during infancy enhances learning in adulthood

Adult behavior is commonly thought to be shaped by early-life experience, although episodes experienced during infancy appear to be forgotten. Exposing male rats during infancy to discrete spatial experience we show that these rats in adulthood are significantly better at forming a spatial memory than control rats without such infantile experience. We moreover show that the adult rats’ improved spatial memory capability is mainly based on memory for context information during the infantile experiences. Infantile spatial experience increased c-Fos activity at memory testing during adulthood in the prelimbic medial prefrontal cortex (mPFC), but not in the hippocampus. Inhibiting prelimbic mPFC at testing during adulthood abolished the enhancing effect of infantile spatial experience on learning. Adult spatial memory capability only benefitted from spatial experience occurring during the sensitive period of infancy, but not when occurring later during childhood, and when sleep followed the infantile experience. In conclusion, the infantile brain, by a sleep-dependent mechanism, favors consolidation of memory for the context in which episodes are experienced. These representations comprise mPFC regions and context-dependently facilitate learning in adulthood.

Noradrenergic regulation of cue-guided decision making and impulsivity is doubly dissociable across frontal brain regions

RationaleWin-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding.ObjectiveThe key neural loci mediating these effects were unknown. The lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC), which are highly implicated in risk assessment, action selection, and impulse control, receive dense noradrenergic innervation. We therefore infused atomoxetine and guanfacine directly into either the lOFC or prelimbic (PrL) mPFC prior to task performance.ResultsWhen infused into the lOFC, atomoxetine improved decision making score and adaptive lose-shift behaviour in males, but not in females, without altering motor impulsivity. Conversely, intra-PrL atomoxetine improved impulse control in risk preferring animals of both sexes, but did not alter decision making. Guanfacine administered into the PrL, but not lOFC, also altered motor impulsivity in all subjects, though in the opposite direction to atomoxetine.ConclusionsThese data highlight a double dissociation between the behavioural effects of noradrenergic signaling across frontal regions with respect to risky choice and impulsive action. Given that the influence of noradrenergic manipulations on motor impulsivity could depend on baseline risk preference, these data also suggest that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win-associated cues.

Prefrontal cortex glutamatergic adaptations in a mouse model of alcohol use disorder

Alcohol use disorder (AUD) produces cognitive deficits, indicating a shift in prefrontal cortex (PFC) function. PFC glutamate neurotransmission is mostly mediated by α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic receptors (AMPARs); however preclinical studies have mostly focused on other receptor subtypes. Here we examined the impact of early withdrawal from chronic ethanol on AMPAR function in the mouse medial PFC (mPFC). Dependent male C57BL/6J mice were generated using the chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) paradigm. Non-dependent mice had access to water and ethanol bottles but did not receive ethanol vapor. Naïve mice had no ethanol exposure. We used patch-clamp electrophysiology to measure glutamate neurotransmission in layer 2/3 prelimbic mPFC pyramidal neurons. Since AMPAR function can be impacted by subunit composition or plasticity-related proteins, we probed their mPFC expression levels. Dependent mice had higher spontaneous excitatory postsynaptic current (sEPSC) amplitude and kinetics compared to the Naïve/Non-dependent mice. These effects were seen during intoxication and after 3–8 days withdrawal, and were action potential-independent, suggesting direct enhancement of AMPAR function. Surprisingly, 3 days withdrawal decreased expression of genes encoding AMPAR subunits (Gria1/2) and synaptic plasticity proteins (Dlg4 and Grip1) in Dependent mice. Further analysis within the Dependent group revealed a negative correlation between Gria1 mRNA levels and ethanol intake. Collectively, these data establish a role for mPFC AMPAR adaptations in the glutamatergic dysfunction associated with ethanol dependence. Future studies on the underlying AMPAR plasticity mechanisms that promote alcohol reinforcement, seeking, drinking and relapse behavior may help identify new targets for AUD treatment.

The PrLGlu→avBNSTGABA circuit rapidly modulates depression-like behaviors in male mice

Depression is a global disease with a high prevalence. Here, we examine the role of the circuit from prelimbic mPFC (PrL) to the anterior ventral bed nucleus of the stria terminalis (avBNST) in depression-like mice through behavioral tests, immunofluorescence, chemogenetics, optogenetics, pharmacology, and fiber photometry. Mice exposed to chronic restraint stress with individual housing displayed depression-like behaviors. Optogenetic or chemogenetic activation of the avBNST-projecting glutamatergic neurons in the PrL had an antidepressant effect. Moreover, we found that α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptors (AMPARs) play a dominant role in this circuit. Systemic administration of ketamine profoundly alleviated depression-like behaviors in the mice and rapidly rescued the decreased activity in the PrLGlu→avBNSTGABA circuit. Furthermore, the fast-acting effect of ketamine on depressive behaviors was diminished when the circuit was inhibited. To summarize, activating the PrLGlu→avBNSTGABA circuit quickly ameliorated depression-like behaviors. Thus, we propose the PrLGlu→avBNSTGABA circuit as a target for fast regulation of depression.

Rearing is critical for forming spatial representations in pre-weanling rats

Rearing, i.e., standing on the hind limbs in an upright posture, is part of a rat’s innate exploratory motor program. Here, we examined in developing rats whether rearing is critical for the pup’s capability to form spatial representations based on distal environmental cues. Pups (male) were tested at PD18, i.e., the first day they typically exhibit stable rearing, on a spatial habituation paradigm comprising a Familiarization session (with the pup exposed to an arena with a specific configuration of distal cues) followed, 3 h later, by a Test session where the pups were either re-exposed to the identical distal cue configuration (NoChange) or a changed configuration (DistalChange). In Experiment 1, rearing activity (rearing events, duration) decreased from Familiarization to Test in the NoChange pups but, remained elevated in the DistalChange group indicating that these pups recognized the distal novelty. Recognition of distal novelty was associated with increased c-Fos expression in hippocampal and medial prefrontal cortex (mPFC) areas, compared with NoChange pups. Analysis of GAD67+ cells suggested a parallel increase in excitation and inhibition specifically in prelimbic mPFC networks in response to distal cue changes. In Experiment 2, the pups were mechanically prevented from rearing while still seeing the distal cues during Familiarization. Rearing activity in the Test session of these pups did not differ between groups that were or were not exposed to a changed distal cue configuration at Test. The findings evidence a critical role of rearing for the emergence of allocentric representations integrating distal space during early development.

Differences in the neural basis and transcriptomic patterns in acute and persistent pain-related anxiety-like behaviors.

Both acute and persistent pain is associated with anxiety in clinical observations, but whether the underlying neural mechanisms differ is poorly understood. We used formalin or complete Freund's adjuvant (CFA) to induce acute or persistent pain. Behavioral performance was assessed by the paw withdrawal threshold (PWT), open field (OF), and elevated plus maze (EPM) tests. C-Fos staining was used to identify the activated brain regions. Chemogenetic inhibition was further performed to examine the necessity of brain regions in behaviors. RNA sequencing (RNA-seq) was used to identify the transcriptomic changes. Both acute and persistent pain could lead to anxiety-like behavior in mice. The c-Fos expression indicates that the bed nucleus of the stria terminalis (BNST) is activated only in acute pain, whereas the medial prefrontal cortex (mPFC) is activated only in persistent pain. Chemogenetic manipulation reveals that the activation of the BNST excitatory neurons is required for acute pain-induced anxiety-like behaviors. In contrast, the activation of the prelimbic mPFC excitatory neurons is essential for persistent pain-induced anxiety-like behaviors. RNA-seq reveals that acute and persistent pain induces differential gene expression changes and protein-protein interaction networks in the BNST and prelimbic mPFC. The genes relevant to neuronal functions might underline the differential activation of the BNST and prelimbic mPFC in different pain models, and be involved in acute and persistent pain-related anxiety-like behaviors. Distinct brain regions and gene expression patterns are involved in acute and persistent pain-related anxiety-like behaviors.

Oxytocin modulation in the medial prefrontal cortex of pair-exposed rats during fear conditioning

IntroductionSocial buffering is the phenomenon, in which stress and fear reactions caused by exposure to stressful stimuli when animals are exposed to homogeneous relationships are attenuated. Social buffering reduces fear memory behavior such as escape, avoidance, and freezing behavior in rodents due to social existence. Here, we aimed to determine alterations of fear behavior and neural activity in the medial prefrontal cortex (mPFC) in response to the presence of another rat in fear-exposed conditions and to confirm the role of oxytocin in mPFC in regulating social buffering. MethodsWe performed a passive avoidance test and determined positive c-Fos expression in single- and pair-exposed rats. Anisomycin (a protein synthesis inhibitor) and oxytocin receptor regulators (carbetocin; agonist and atosiban; antagonist) were microinjected into the mPFC to clarify the role of oxytocin in the mPFC. ResultsWhile single-exposed rats showed a significant increase in both freezing and passive avoidance behaviors compared to control rats, pair-exposed rats showed significantly less fear behavior compared to single-exposed rats. The c-Fos expression in the prelimbic (PL) mPFC was significantly increased in pair-exposed rats compared to that in control and single-exposed rats. The pair-exposed effect was blocked by anisomycin injections into the PL mPFC of pair-exposed rats. Furthermore, when a carbetocin was injected into the PL mPFC in single-exposed rats, fear behavior was decreased, and these changes were blocked by atosiban. DiscussionOur findings suggest that reduction of fear-related behavior induced by acute pair-exposure is mediated by oxytocin receptors in the PL mPFC. Pair exposure with conspecifics during fear-inducing situations helps coping with fear by significantly increasing the role of oxytocin in the PL mPFC.

Medial prefrontal cortex-basolateral amygdala circuit dysfunction in chronic alcohol-exposed male rats

Alcohol is a commonly used drug that can produce alcohol use disorders (AUDs). Few individuals with AUDs receive treatment and treatment options are complicated by issues with effectiveness and compliance. Alcohol has been shown to differentially affect specific brain regions and an improved understanding of circuit-specific dysregulation caused by alcohol is warranted. Previous work has implicated both the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in alcohol-associated plasticity, however studies directly examining the impact of alcohol exposure on this circuit are lacking. The current study employed an optogenetic strategy to investigate the prelimbic mPFC to BLA circuit and changes in circuit activity following chronic intragastric ethanol exposure in male Sprague Dawley rats. We observed monosynaptic connections with light-evoked stimulation of mPFC terminals in the BLA with efficacy and short latency. We also found that mPFC-BLA projections are primarily glutamatergic under basal inhibitory control, with a lesser population of GABAergic projections. We examined optically-evoked glutamate currents in the BLA using repeated trains of stimulation that displayed accommodation, or a reduction in evoked current amplitude over repeated stimulations. We found that following chronic ethanol exposure mPFC-BLA glutamatergic connections were dysregulated such that there were decreases in overall function, notably in synaptic strength and accommodation, with no change in probability of evoked glutamate release. The lesser GABAergic component of the mPFC-BLA circuit was not altered by chronic ethanol exposure. Collectively these data indicate that mPFC-BLA circuitry is a significant target of alcohol-associated plasticity, which may contribute to pathological behavior associated with AUDs.This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Chemogenetic inhibition of corticostriatal circuits reduces cued reinstatement of methamphetamine seeking.

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

Developmental exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate, disrupts the mesocortical serotonin pathway and alters impulsive decision-making in rats.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to women at risk for preterm birth during a critical period of fetal development for mesocortical pathways. Yet, little information is available regarding the potential effects of 17-OHPC on the developing fetal brain. In rat models, the mesocortical serotonin pathway is sensitive to progestins. Progesterone receptor (PR) is expressed in layer 3 pyramidal neurons of medial prefrontal cortex (mPFC) and in serotonergic neurons of the dorsal raphe. The present study tested the hypothesis that exposure to 17-OHPC during development disrupts serotonergic innervation of the mPFC in adolescence and impairs behavior mediated by this pathway in adulthood. Administration of 17-OHPC from postnatal days 1-14 decreased the density of SERT-ir fibers within superficial and deep layers and decreased the density of synaptophysin-ir boutons in all layers of prelimbic mPFC at postnatal day 28. In addition, rats exposed to 17-OHPC during development were less likely to make impulsive choices in the Delay Discounting task, choosing the larger, delayed reward more often than controls at moderate delay times. Interestingly, 17-OHPC exposed rats were more likely to fail to make any choice (i.e., increased omissions) compared to controls at longer delays, suggesting disruptions in decision-making. These results suggest that further investigation is warranted in the clinical use of 17-OHPC to better inform a risk/benefit analysis of progestin use in pregnancy.

Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression

Chronic treatment with fluoxetine (FLX) is required for its antidepressant effects, but the role of serotonin (5-HT) axonal plasticity in FLX action is unknown. To address this, we examined mice with a stroke in the left medial prefrontal cortex (mPFC) resulting in persistent anxiety-like and depression-like behaviors and memory deficits as a model of post-stroke depression. Chronic treatment with FLX (but not exercise) completely reversed the behavioral phenotype and partially reversed changes in FosB-labeled cells in the mPFC, nucleus accumbens, septum, hippocampus, basolateral amygdala (BLA), and dorsal raphe. In these regions, 5-HT or norepinephrine (NE) innervation was quantified by staining for 5-HT or NE transporters, respectively. 5-HT synapses and synaptic triads were identified as synaptophysin-stained sites on 5-HT axons located proximal to gephyrin-stained or PSD95-stained spines. A week after stroke, 5-HT innervation was greatly reduced at the stroke site (left cingulate gyrus (CG) of the mPFC) and the left BLA. Chronically, 5-HT and NE innervation was reduced at the left CG, nucleus accumbens, and BLA, with no changes in other regions. In these areas, pre-synaptic and post-synaptic 5-HT synapses and triads to inhibitory (gephyrin+) sites were reduced, while 5-HT contacts at excitatory (PSD95+) sites were reduced in the CG and prelimbic mPFC. Chronic FLX, but not exercise, reversed these reductions in 5-HT innervation but incompletely restored NE projections. Changes in 5-HT innervation were verified using YFP staining in mice expressing YFP-tagged channelrhodopsin in 5-HT neurons. Thus, FLX-induced 5-HT axonal neuroplasticity of forebrain projections may help mediate recovery from brain injury.

Cocaine memory reactivation induces functional adaptations within parvalbumin interneurons in the rat medial prefrontal cortex.

Substance use disorder is a complex disease created in part by maladaptive learning and memory mechanisms following repeated drug use. Exposure to drug-associated stimuli engages prefrontal cortex circuits, and dysfunction of the medial prefrontal cortex (mPFC) is thought to underlie drug-seeking behaviors. Growing evidence supports a role for parvalbumin containing fast-spiking interneurons (FSI) in modulating prefrontal cortical microcircuit activity by influencing the balance of excitation and inhibition, which can influence learning and memory processes. Most parvalbumin FSIs within layer V of the prelimbic mPFC are surrounded by specialized extracellular matrix structures called perineuronal nets (PNN). Previous work by our group found that cocaine exposure altered PNN-surrounded FSI function, and pharmacological removal of PNNs reduced cocaine-seeking behavior. However, the role of FSIs and associated constituents (parvalbumin and PNNs) in cocaine-related memories was not previously explored and is still unknown. Here, we found that reactivation of a cocaine conditioned place preference memory produced changes in cortical PNN-surrounded parvalbumin FSIs, including decreased parvalbumin intensity, increased parvalbumin cell axis diameter, decreased intrinsic excitability, and increased excitatory synaptic input. Further investigation of intrinsic properties revealed changes in the interspike interval, membrane capacitance, and afterhyperpolarization recovery time. Changes in these specific properties suggest an increase in potassium-mediated currents, which was validated with additional electrophysiological analysis. Collectively, our results indicate that cocaine memory reactivation induces functional adaptations in PNN-surrounded parvalbumin neurons, which likely alters cortical output to promote cocaine-seeking behavior.

Chronic ethanol exposure alters prelimbic prefrontal cortical Fast-Spiking and Martinotti interneuron function with differential sex specificity in rat brain

Chronic ethanol exposure results in numerous neurobiological adaptations that promote deficits in medial prefrontal cortical (mPFC) function associated with blunted inhibitory control and elevated anxiety during withdrawal. Studies exploring alcohol dependence-related changes in this region have largely investigated adaptations in glutamatergic signaling, with inhibitory neurotransmission remaining relatively understudied. To address this, we used biochemical and electrophysiological methods to evaluate the effects of ethanol on the activity of deep-layer prelimbic mPFC Fast-Spiking (FS) and Martinotti interneurons after chronic ethanol exposure in male and female rats. We report that chronic alcohol exposure significantly impairs FS neuron excitability in both males and females. Interestingly, we observed a marked sex difference in the baseline activity of Martinotti cells that furthermore displayed differential sex-specific responses to alcohol exposure. In addition, alcohol effects on Martinotti neuron excitability negatively correlated with hyperpolarization-activated currents mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels, indicative of a causal relationship. Analysis of HCN1 protein expression also revealed a substantial sex difference, although no effect of ethanol on HCN1 protein expression was observed. Taken together, these findings further elucidate the complex adaptations that occur in the mPFC after chronic ethanol exposure and reveal fundamental differences in interneuron activity between sexes. Furthermore, this disparity may reflect innate differences in intracortical microcircuit function between male and female rats, and offers a tenable circuit-level explanation for sex-dependent behavioral responses to alcohol.

Age- and sex-dependent impact of repeated social stress on morphology of rat prefrontal cortex pyramidal neurons

Chronic stress can lead to psychiatric illness characterized by impairments of executive function, implicating the prefrontal cortex as a target of stress-related pathology. Previous studies have shown that various types of chronic stress paradigms reduce dendritic branching, length and spines of medial prefrontal cortex (mPFC) pyramidal neurons. However, these studies largely focused on layer II/III pyramidal neurons in adult male rats with less known about layer V, the site of projection neurons. Because the prefrontal cortex develops throughout adolescence, stress during adolescence may have a greater impact on structure and function than stress occurring during adulthood. Furthermore, females display greater risk of stress-related psychiatric disorders, indicating sex-specific responses to stress. In this study, male and female adolescent (42–48 days old, 4 rats per group) or adult (68–72 days old, 4 rats per group) Sprague-Dawley rats were exposed to 5 days of repeated social stress in the resident-intruder paradigm or control manipulation. We examined dendritic morphology of cells in the mPFC in both layer II/III and Layer V. Repeated social stress resulted in decreased dendritic branching in layer II/III apical dendrites regardless of sex or age. In apical layer V dendrites, stress increased branching in adult males but decreased it in all other groups. Stress resulted in a decrease in dendritic spines in layer V apical dendrites for male adolescents and female adults, and this was mostly due to a decrease in filopodial and mushroom spines for male adolescents, but stubby spines for female adults. In sum, these results suggest that repeated stress reduces complexity and synaptic connectivity in adolescents and female adults in both input and output layers of prelimbic mPFC, but not in male adults. These changes may represent a potential underlying mechanism as to why adolescents and females are more susceptible to the negative cognitive effects of repeated or chronic stress.

SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex

Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, is a key regulator of cellular metabolism. Recent genome-wide association studies identified genetic variants of SIRT1 linked to major depressive disorders. SIRT1 is widely expressed in the brain; however, neuronal substrates that mediate SIRT1 action on depressive behaviors remain largely unknown. Here we show that selective deletion of SIRT1 in forebrain excitatory neurons causes depression-like phenotypes in male but not female mice. AAV-Cre-mediated SIRT1 knockdown in the medial prefrontal cortex (mPFC) of adult male mice induces depressive-like behaviors. Whole-cell patch-clamp recordings demonstrate that loss of SIRT1 decreases intrinsic excitability and spontaneous excitatory synaptic transmission in layer V pyramidal neurons in the prelimbic mPFC. Consistent with neuronal hypoexcitability, SIRT1 knockout reduces mitochondrial density and expression levels of genes involved in mitochondrial biogenesis and dynamics in the prelimbic mPFC. When a SIRT1 activator (SRT2104) is injected into the mPFC or lateral ventricle of wild-type mice, it reverses chronic unpredictable stress-induced anhedonia and behavioral despair, indicating an antidepressant-like effect. These results suggest that SIRT1 in mPFC excitatory neurons is required for normal neuronal excitability and synaptic transmission and regulates depression-related behaviors in a sex-specific manner.

Adult Ube3a Gene Reinstatement Restores the Electrophysiological Deficits of Prefrontal Cortex Layer 5 Neurons in a Mouse Model of Angelman Syndrome.

E3 ubiquitin ligase (UBE3A) levels in the brain need to be tightly regulated, as loss of functional UBE3A protein is responsible for the severe neurodevelopmental disorder Angelman syndrome (AS), whereas increased activity of UBE3A is associated with nonsyndromic autism. Given the role of mPFC in neurodevelopmental disorders including autism, we aimed to identify the functional changes resulting from loss of UBE3A in infralimbic and prelimbic mPFC areas in a mouse model of AS. Whole-cell recordings from layer 5 mPFC pyramidal neurons obtained in brain slices from adult mice of both sexes revealed that loss of UBE3A results in a strong decrease of spontaneous inhibitory transmission and increase of spontaneous excitatory transmission potentially leading to a marked excitation/inhibition imbalance. Additionally, we found that loss of UBE3A led to decreased excitability and increased threshold for action potential of layer 5 fast spiking interneurons without significantly affecting the excitability of pyramidal neurons. Because we previously showed that AS mouse behavioral phenotypes are reversible upon Ube3a gene reactivation during a restricted period of early postnatal development, we investigated whether Ube3a gene reactivation in a fully mature brain could reverse any of the identified physiological deficits. In contrast to our previously reported behavioral findings, restoring UBE3A levels in adult animals fully rescued all the identified physiological deficits of mPFC neurons. Moreover, the kinetics of reversing these synaptic deficits closely followed the reinstatement of UBE3A protein level. Together, these findings show a striking dissociation between the rescue of behavioral and physiological deficits.SIGNIFICANCE STATEMENT Here we describe significant physiological deficits in the mPFC of an Angelman syndrome mouse model. We found a marked change in excitatory/inhibitory balance, as well as decreased excitability of fast spiking interneurons. A promising treatment strategy for Angelman syndrome is aimed at restoring UBE3A expression by activating the paternal UBE3A gene. Here we find that the physiological changes in the mPFC are fully reversible upon gene reactivation, even when the brain is fully mature. This indicates that there is no critical developmental window for reversing the identified physiological deficits in mPFC.

Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.

Prefrontal Cortex Dysfunction Increases Susceptibility to Schizophrenia-Like Changes Induced by Adolescent Stress Exposure.

Stress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different stressful events during adolescence (restraint stress [RS], footshock [FS], or the combination of FS and RS) on behaviors correlated with schizophrenia in rats as adults. At adulthood, animals were tested for anxiety responses (elevated plus-maze), cognitive function (novel-object recognition test) and dopamine (DA) system responsivity (locomotor response to amphetamine and DA neuron activity in the ventral tegmental area (VTA) using in vivo electrophysiology). All adolescent stressors impaired weight gain and induced anxiety-like responses in adults. FS and FS + RS also disrupted cognitive function. Interestingly, only the combination of FS and RS induced a DA hyper-responsivity as indicated by augmented locomotor response to amphetamine and increased number of spontaneously active DA neurons which was confined to the lateral VTA. Additionally, prelimbic (pl) mPFC lesions triggered a DA hyper-responsivity in animals exposed to FS alone during adolescence. Our results are consistent with previous studies showing long-lasting changes induced by stressful events during adolescence. The impact on DA system activity, however, seems to depend on intense multiple stressors. Our data also suggest that plPFC dysfunction increases the vulnerability to stress in terms of changes in the DA system. Hence, stress during adolescence could be a precipitating factor for the transition to schizophrenia, and stress control at this vulnerable period may circumvent these changes to prevent the emergence of psychosis.

Patterns of Theta Activity in Limbic Anxiety Circuit Preceding Exploratory Behavior in Approach-Avoidance Conflict.

Theta oscillations within the hippocampus-amygdala-medial prefrontal cortex (HPC-AMY-mPFC) circuit have been consistently implicated in the regulation of anxiety behaviors, including risk-assessment. To study if theta activity during risk-assessment was correlated with exploratory behavior in an approach/avoidance paradigm we recorded simultaneous local field potentials from this circuit in rats exploring the elevated-plus maze (EPM). Opposing patterns of power variations in the ventral hippocampus (vHPC), basolateral amygdala (BLA), and prelimbic (PrL) mPFC, but not in the dorsal hippocampus (dHPC), during exploratory risk-assessment of the open arms preceded further exploration of the open arms or retreat back to the safer closed arms. The same patterns of theta power variations in the HPC-BLA-mPFC(PrL) circuit were also displayed by animals submitted to chronic unpredictable stress protocol known to induce an anxious state. Diverging patterns of vHPC-mPFC(PrL) theta coherence were also significantly correlated with forthcoming approach or avoidance behavior in the conflict situation in both controls and stressed animals; interestingly, vHPC-BLA, and BLA-mPFC(PrL) theta coherence correlated with future behavior only in stressed animals, underlying the pivotal role of the amygdala on the stress response.

Binge Drinking Decreases Corticotropin‐Releasing Factor‐Binding Protein Expression in the Medial Prefrontal Cortex of Mice

Dysregulation of the corticotropin-releasing factor (CRF) system has been observed in rodent models of binge drinking, with a large focus on CRF receptor 1 (CRF-R1). The role of CRF-binding protein (CRF-BP), a key regulator of CRF activity, in binge drinking is less well understood. In humans, single-nucleotide polymorphisms in CRHBP are associated with alcohol use disorder and stress-induced alcohol craving, suggesting a role for CRF-BP in vulnerability to alcohol addiction. The role and regulation of CRF-BP in binge drinking were examined in mice exposed to the drinking in the dark (DID) paradigm. Using insitu hybridization, the regulation of CRF-BP, CRF-R1, and CRF mRNA expression was determined in the stress and reward systems of C57BL/6J mice after repeated cycles of DID. To determine the functional role of CRF-BP in binge drinking, CRF-BP knockout (CRF-BP KO) mice were exposed to 6 cycles of DID, during which alcohol consumption was measured and compared to wild-type mice. CRF-BP mRNA expression was significantly decreased in the prelimbic (PL) and infralimbic medial prefrontal cortex (mPFC) of C57BL/6J mice after 3 cycles and in the PL mPFC after 6 cycles of DID. No significant changes in CRF or CRF-R1 mRNA levels were observed in mPFC, ventral tegmental area, bed nucleus of the stria terminalis, or amygdala after 3 cycles of DID. CRF-BP KO mice do not show significant alterations in drinking compared to wild-type mice across 6 cycles of DID. These results reveal that repeated cycles of binge drinking alter CRF-BP mRNA expression in the mPFC, a region responsible for executive function and regulation of emotion and behavior, including responses to stress. We observed a persistent decrease in CRF-BP mRNA expression in the mPFC after 3 and 6 DID cycles, which may allow for increased CRF signaling at CRF-R1 and contribute to excessive binge-like ethanol consumption.