mPFC Subregions Research Articles

Age-Related Declines in Prefrontal Cortical Expression of Metabotropic Glutamate Receptors that Support Working Memory.

Glutamate signaling is essential for the persistent neural activity in prefrontal cortex (PFC) that enables working memory. Metabotropic glutamate receptors (mGluRs) are a diverse class of proteins that modulate excitatory neurotransmission via both presynaptic regulation of extracellular glutamate levels and postsynaptic modulation of ion channels on dendritic spines. This receptor class is of significant therapeutic interest for treatment of cognitive disorders associated with glutamate dysregulation. Working memory impairment and cortical hypoexcitability are both associated with advanced aging. Whether aging modifies PFC mGluR expression, and the extent to which any such alterations are regionally or subtype specific, however, is unknown. Moreover, it is unclear whether specific mGluRs in PFC are critical for working memory, and thus, whether altered mGluR expression in aging or disease is sufficient to play a causative role in working memory decline. Experiments in the current study first evaluated the effects of age on medial PFC (mPFC) mGluR expression using biochemical and molecular approaches in rats. Of the eight mGluRs examined, only mGluR5, mGluR3, and mGluR4 were significantly reduced in the aged PFC. The reductions in mGluR3 and mGluR5 (but not mGluR4) were observed in both mRNA and protein and were selectively localized to the prelimbic (PrL), but not infralimbic (IL), subregion of mPFC. Finally, pharmacological blockade of mGluR5 or mGluR2/3 using selective antagonists directed to PrL significantly impaired working memory without influencing non-mnemonic aspects of task performance. Together, these data implicate attenuated expression of PFC mGluR5 and mGluR3 in the impaired working memory associated with advanced ages.

Chronic Stress Alters Behavior in the Forced Swim Test and Underlying Neural Activity in Animals Exposed to Alcohol Prenatally: Sex- and Time-Dependent Effects.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress response has been suggested to play a role in vulnerability to stress-related disorders, such as depression. Prenatal alcohol exposure (PAE) may result in HPA dysregulation, which in turn may predispose individuals to the effects of stress exposure throughout life, and increase their risk of developing depression compared to unexposed individuals. We examined the immediate and delayed effects of chronic unpredictable stress (CUS) in adulthood on behavior of PAE animals in the forced swim test (FST) and the neurocircuitry underlying behavioral, emotional, and stress regulation. Adult male and female offspring from PAE and control conditions were tested for 2 days in the FST, with testing initiated either 1 day (CUS-1; immediate) or 14 days (CUS-14; delayed) post-CUS. Following testing, c-fos mRNA expression of the medial prefrontal cortex (mPFC), amygdala, hippocampal formation, and the paraventricular nucleus of the hypothalamus was assessed. Our results indicate that PAE and CUS interact to differentially alter FST behaviors and neural activation of several brain areas in males and females, and effects may depend on whether testing is immediate or delayed post-CUS. PAE males showed decreased time immobile (Day 1 of FST) following immediate testing, while PAE females showed increased time immobile (Day 2 of FST) following delayed testing compared to their respective control counterparts. Moreover, in males, PAE decreased c-fos mRNA expression in the lateral and central nuclei of the amygdala in the non-CUS condition, and increased c-fos mRNA expression in the CA1 in the CUS-14 condition. By contrast in females, c-fos mRNA expression in the Cg1 was decreased in PAE animals (independent of CUS) and decreased in all mPFC subregions in CUS-14 animals (independent of prenatal treatment). Constrained principal component analysis, used to identify neural and behavioral networks, revealed that PAE altered the activation of these networks and modulated the effects of CUS on these networks in a sex- and time-dependent manner. This dysregulation of the neurocircuitry underlying behavioral, emotional and stress regulation, may ultimately contribute to an increased vulnerability to psychopathologies, such as depression, that are often observed following PAE.

Social Observation Increases Functional Segregation between MPFC Subregions Predicting Prosocial Consumer Decisions

Although it is now well documented that observation by others can be a powerful elicitor of prosocial behaviour, the underlying neural mechanism is yet to be explored. In the present fMRI study, we replicated the previously reported observer effect in ethical consumption, in that participants were more likely to purchase social products that are sold to support people in need than non-social products when being observed by others. fMRI data revealed that the anterior cingulate cortex (ACC) and the dorsomedial prefrontal cortex (dmPFC) encoded subject-specific value parameters of purchase decisions for social and non-social products, respectively, under social observation. The ACC showed strong functional coupling with the amygdala and the anterior insula when participants in the observation condition were making purchases of social versus non-social products. Finally, ventromedial prefrontal cortex (vmPFC) activity predicted faster reaction time and increased prosocial behavior during decisions to purchase social versus non-social products, regardless of social observation. The present findings suggest that subregions of the mPFC, namely the dmPFC, ACC, and vmPFC, are hierarchically organized to encode different levels of decision values from the value of context-sensitive reputation to that of internalized prosociality.

Differential Effects of Inactivation of Discrete Regions of Medial Prefrontal Cortex on Memory Consolidation of Moderate and Intense Inhibitory Avoidance Training.

It has been found that the medial prefrontal cortex (mPFC) is involved in memory encoding of aversive events, such as inhibitory avoidance (IA) training. Dissociable roles have been described for different mPFC subregions regarding various memory processes, wherein the anterior cingulate cortex (ACC), prelimbic cortex (PL), and infralimbic cortex (IL) are involved in acquisition, retrieval, and extinction of aversive events, respectively. On the other hand, it has been demonstrated that intense training impedes the effects on memory of treatments that typically interfere with memory consolidation. The aim of this work was to determine if there are differential effects on memory induced by reversible inactivation of neural activity of ACC, PL, or IL produced by tetrodotoxin (TTX) in rats trained in IA using moderate (1.0 mA) and intense (3.0 mA) foot-shocks. We found that inactivation of ACC has no effects on memory consolidation, regardless of intensity of training. PL inactivation impairs memory consolidation in the 1.0 mA group, while no effect on consolidation was produced in the 3.0 mA group. In the case of IL, a remarkable amnestic effect in LTM was observed in both training conditions. However, state-dependency can explain the amnestic effect of TTX found in the 3.0 mA IL group. In order to circumvent this effect, TTX was injected into IL immediately after training (thus avoiding state-dependency). The behavioral results are equivalent to those found after PL inactivation. Therefore, these findings provide evidence that PL and IL, but not ACC, mediate LTM of IA only in moderate training.

Exposure to the Abused Inhalant Toluene Alters Medial Prefrontal Cortex Physiology.

Inhalants, including toluene, target the addiction neurocircuitry and are often one of the first drugs of abuse tried by adolescents. The medial prefrontal cortex (mPFC) is involved in regulating goal-directed/reward-motivated behaviors and different mPFC sub-regions have been proposed to promote (prelimbic, PRL) or inhibit (infralimbic, IL) these behaviors. While this dichotomy has been studied in the context of other drugs of abuse, it is not known whether toluene exposure differentially affects neurons within PRL and IL regions. To address this question, we used whole-cell electrophysiology and determined the intrinsic excitability of PRL and IL pyramidal neurons in adolescent rats 24 h following a brief exposure to air or toluene vapor (10 500 p.p.m.). Prior to exposure, fluorescent retrobeads were injected into the NAc core (NAcc) or shell (NAcs) sub-regions to identify projection-specific mPFC neurons. In toluene treated adolescent rats, layer 5/6 NAcc projecting PRL (PRL5/6) neurons fired fewer action potentials and this was associated with increased rheobase, increased spike duration, and reductions in membrane resistance and amplitude of the Ih current. No changes in excitability were observed in layer 2/3 NAcc projecting PRL (PRL2/3) neurons. In contrast to PRL neurons, layer 5 IL (IL5) and layer 2/3 (IL2/3) NAcc projecting neurons showed enhanced firing in toluene-exposed animals and in IL5 neurons, this was associated with a reduction in rheobase and AHP. For NAcs projecting neurons, toluene exposure significantly decreased firing of IL5 neurons and this was accompanied by an increased rheobase, increased spike duration, and reduced Ih amplitude. The intrinsic excitability of PRL5, PRL2/3, and IL2/3 neurons projecting to the NAcs was not affected by exposure to toluene. The changes in excitability observed 24 h after toluene exposure were not observed when recordings were performed 7 days after the exposure. Finally, there were no changes in intrinsic excitability of any region in rats exposed to toluene as adults. These findings demonstrate that specific projections of the reward circuitry are uniquely susceptible to the effects of toluene during adolescence supporting the idea that adolescence is a critical period of the development that is vulnerable to drugs of abuse.

Neonatal alcohol exposure reduces number of parvalbumin-positive interneurons in the medial prefrontal cortex and impairs passive avoidance acquisition in mice deficits not rescued from exercise

Developmental alcohol exposure causes a host of cognitive and neuroanatomical abnormalities, one of which is impaired executive functioning resulting from medial prefrontal cortex (mPFC) damage. This study determined whether third-trimester equivalent alcohol exposure reduced the number of mPFC GABAergic parvalbumin-positive (PV+) interneurons, hypothesized to play an important role in local inhibition of the mPFC. The impact on passive avoidance learning and the therapeutic role of aerobic exercise in adulthood was also explored. Male C57BL/6J mice received either saline or 5g/kg ethanol (two doses, two hours apart) on PD 5, 7, and 9. On PD 35, animals received a running wheel or remained sedentary for 48days before behavioral testing and perfusion on PD 83. The number of PV+ interneurons was stereologically measured in three separate mPFC subregions: infralimbic, prelimbic and anterior cingulate cortices (ACC). Neonatal alcohol exposure decreased number of PV+ interneurons and volume of the ACC, but the other regions of the mPFC were spared. Alcohol impaired acquisition, but not retrieval of passive avoidance, and had no effect on motor performance on the rotarod. Exercise had no impact on PV+ cell number, mPFC volume, or acquisition of passive avoidance, but enhanced retrieval in both control and alcohol-exposed groups, and enhanced rotarod performance in the control mice. Results support the hypothesis that part of the behavioral deficits associated with developmental alcohol exposure are due to reduced PV+ interneurons in the ACC, but unfortunately exercise does not appear to be able to reverse any of these deficits.

Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat.

Cortical slow oscillations (0.1-1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC. In rodents the medial prefrontal cortex (mPFC) consists of several subregions: anterior cingulate cortex (ACC), prelimbic (PrL), infralimbic (IL), and dorsal peduncular cortices (DP). Although each region has a distinct anatomy and function, it is not known whether slow or fast network oscillations differ between subregions in vivo. We have simultaneously recorded slow and fast network oscillations in all four subregions of the rodent mPFC under urethane anesthesia. Slow oscillations were synchronous between the mPFC subregions, and across the hemispheres, with no consistent amplitude difference between subregions. Delta (2-4 Hz) activity showed only small differences between subregions. However, oscillations in the spindle (6-15 Hz)-, beta (20-30 Hz), gamma (30-80 Hz)-, and high-gamma (80-150 Hz)-frequency bands were consistently larger in the dorsal regions (ACC and PrL) compared with ventral regions (IL and DP). In dorsal regions the peak power of spindle, beta, and gamma activity occurred early after onset of the Up-state. In the ventral regions, especially the DP, the oscillatory power in the spindle-, beta-, and gamma-frequency ranges peaked later in the Up-state. These results suggest variations in fast network oscillations within the mPFC that may reflect the different functions and connectivity of these subregions.NEW & NOTEWORTHY We demonstrate, in the urethane-anesthetized rat, that within the medial prefrontal cortex (mPFC) there are clear subregional differences in the fast network oscillations associated with the slow oscillation Up-state. These differences, particularly between the dorsal and ventral subregions of the mPFC, may reflect the different functions and connectivity of these subregions.

Encoding of Contextual Fear Memory Requires De Novo Proteins in the Prelimbic Cortex

BackgroundDespite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories, its role in the encoding of long-term memories remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory. MethodsBecause a change in the association of messenger RNAs (mRNAs) to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in the mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in the mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intraprelimbic cortex manipulation (n = 56) of Homer3, a candidate identified from polyribosome profiling. ResultsWe identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL) cortex but not in the anterior cingulate cortex region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL cortex 6 hours after CFC did not impair encoding. Furthermore, expression of Homer3, an mRNA enriched in polyribosomes following CFC, in the PL cortex constrained encoding of contextual fear memory. ConclusionsOur studies identify several molecular substrates of new protein synthesis in the mPFC and establish that encoding of contextual fear memories require new protein synthesis in PL subregion of mPFC.

The Lateral Habenula as a Relay of Cortical Information to Process Working Memory.

Working memory is a cognitive ability allowing the temporary storage of information to solve problems or adjust behavior. While working memory is known to mainly depend on the medial prefrontal cortex (mPFC), very few is known about how cortical information are relayed subcortically. By its connectivity, the lateral habenula (lHb) might act as a subcortical relay for cortical information. Indeed, the lHb receives inputs from several mPFC subregions, and recent findings suggest a role for the lHb in online processing of spatial information, a fundamental aspect of working memory. In rats, in a delayed non-matching to position paradigm, using focal microinjections of the GABAA agonist muscimol we showed that inactivation of the lHb (16 ng in 0.2 µL per side), as well as disconnection between the prelimbic region of the mPFC (mPFC/PrL, 32 ng in 0.4 µL in one hemisphere) and the lHb (16 ng in 0.2 µL in the lHb in the contralateral hemisphere) impaired working memory. The deficits were unlikely to result from motivational or motor deficits as muscimol did not affect reward collection or cue responding latencies, and did not increase the number of omissions. These results show for the first time the implication of the lHb in mPFC-dependent memory processes, likely as a relay of mPFC/PrL information. They also open new perspectives in the understanding of the top-down processing of high-level cognitive functions.

Sustained Attentional States Require Distinct Temporal Involvement of the Dorsal and Ventral Medial Prefrontal Cortex.

Attending the sensory environment for cue detection is a cognitive operation that occurs on a time scale of seconds. The dorsal and ventral medial prefrontal cortex (mPFC) contribute to separate aspects of attentional processing. Pyramidal neurons in different parts of the mPFC are active during cognitive behavior, yet whether this activity is causally underlying attentional processing is not known. We aimed to determine the precise temporal requirements for activation of the mPFC subregions during the seconds prior to cue detection. To test this, we used optogenetic silencing of dorsal or ventral mPFC pyramidal neurons at defined time windows during a sustained attentional state. We find that the requirement of ventral mPFC pyramidal neuron activity is strictly time-locked to stimulus detection. Inhibiting the ventral mPFC 2 s before or during cue presentation reduces response accuracy and hampers behavioral inhibition. The requirement for dorsal mPFC activity on the other hand is temporally more loosely related to a preparatory attentional state, and short lapses in pyramidal neuron activity in dorsal mPFC do not affect performance. This only occurs when the dorsal mPFC is inhibited during the entire preparatory period. Together, our results reveal that a dissociable temporal recruitment of ventral and dorsal mPFC is required during attentional processing.

Orexin neurons in the lateral hypothalamus project to the medial prefrontal cortex with a rostro-caudal gradient

Orexin neurons in the lateral hypothalamus (LH) play an important role in arousal, guaranteeing the execution of medial prefrontal cortex (mPFC)-related higher cognitive functions. The mPFC is anatomically and functionally a rostro-caudal hierarchy. Little is known about the innervation pattern, especially in the rostro-caudal model, from the arousal-promoting orexin system in the LH to the mPFC subregions, including the anterior cingulate cortex (AC), prelimbic cortex (PL) and infralimbic cortex (IL). Here, we used an anterograde tracing method and immunohistochemistry and found that the density of the LH, as well as orexinergic, fibers increased from the rostral part to the caudal part of the mPFC, regardless of AC, PL or IL. Similarly, the distribution of type 1 orexin receptors in the mPFC follows a rostro-caudal increasing gradient hierarchy. These data suggest a rostro-caudal hierarchy of LH orexinergic innervation to the mPFC. We hope to provide anatomical and morphological evidence for the regulation pattern of the arousal-promoting orexin system on the cognition-related mPFC system.

Basomedial amygdala mediates top-down control of anxiety and fear.

Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC–BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.

Differentiation of forebrain and hippocampal dopamine 1-class receptors, D1R and D5R, in spatial learning and memory.

Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1R- and D5R-specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory.

Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety.

The medial prefrontal cortex (mPFC) is implicated in processing sensory-discriminative and affective pain. Nonetheless, the underlying mechanisms are poorly understood. Here we demonstrate a role for excitatory neurons in the prelimbic cortex (PL), a sub-region of mPFC, in the regulation of pain sensation and anxiety-like behaviours. Using a chronic inflammatory pain model, we show that lesion of the PL contralateral but not ipsilateral to the inflamed paw attenuates hyperalgesia and anxiety-like behaviours in rats. Optogenetic activation of contralateral PL excitatory neurons exerts analgesic and anxiolytic effects in mice subjected to chronic pain, whereas inhibition is anxiogenic in naive mice. The intrinsic excitability of contralateral PL excitatory neurons is decreased in chronic pain rats; knocking down cyclin-dependent kinase 5 reverses this deactivation and alleviates behavioural impairments. Together, our findings provide novel insights into the role of PL excitatory neurons in the regulation of sensory and affective pain.

Ketamine Strengthens CRF-Activated Amygdala Inputs to Basal Dendrites in mPFC Layer V Pyramidal Cells in the Prelimbic but not Infralimbic Subregion, A Key Suppressor of Stress Responses.

A single sub-anesthetic dose of ketamine, a short-acting NMDA receptor blocker, induces a rapid and prolonged antidepressant effect in treatment-resistant major depression. In animal models, ketamine (24 h) reverses depression-like behaviors and associated deficits in excitatory postsynaptic currents (EPSCs) generated in apical dendritic spines of layer V pyramidal cells of medial prefrontal cortex (mPFC). However, little is known about the effects of ketamine on basal dendrites. The basal dendrites of layer V cells receive an excitatory input from pyramidal cells of the basolateral amygdala (BLA), neurons that are activated by the stress hormone CRF. Here we found that CRF induces EPSCs in PFC layer V cells and that ketamine enhanced this effect through the mammalian target of rapamycin complex 1 synaptogenic pathway; the CRF-induced EPSCs required an intact BLA input and were generated primarily in basal dendrites. In contrast to its detrimental effects on apical dendritic structure and function, chronic stress did not induce a loss of CRF-induced EPSCs in basal dendrites, thereby creating a relative imbalance in favor of amygdala inputs. The effects of ketamine were complex: ketamine enhanced apical EPSC responses in all mPFC subregions, anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) but enhanced CRF-induced EPSCs only in AC and PL-responses were unchanged in IL, a critical area for suppression of stress responses. We propose that by restoring the strength of apical inputs relative to basal amygdala inputs, especially in IL, ketamine would ameliorate the hypothesized disproportional negative influence of the amygdala in chronic stress and major depression.

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is associated with hypofunctional medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). Methylphenidate (MPH) remediates ADHD, in part, by inhibiting the norepinephrine transporter (NET). MPH also reduces ADHD-like symptoms in spontaneously hypertensive rats (SHRs), a model of ADHD. However, effects of chronic MPH treatment on NET function in mPFC and OFC in SHR have not been reported. In the current study, long-term effects of repeated treatment with a therapeutically relevant oral dose of MPH during adolescence on NET function in subregions of mPFC (cingulate gyrus, prelimbic cortex and infralimbic cortex) and in the OFC of adult SHR, Wistar-Kyoto (WKY, inbred control) and Wistar (WIS, outbred control) rats were determined using in vivo voltammetry. Following local ejection of norepinephrine (NE), uptake rate was determined as peak amplitude (Amax)×first-order rate constant (k−1). In mPFC subregions, no strain or treatment effects were found in NE uptake rate. In OFC, NE uptake rate in vehicle-treated adult SHR was greater than in adult WKY and WIS administered vehicle. MPH treatment during adolescence normalized NE uptake rate in OFC in SHR. Thus, the current study implicates increased NET function in OFC as an underlying mechanism for reduced noradrenergic transmission in OFC, and consequently, the behavioral deficits associated with ADHD. MPH treatment during adolescence normalized NET function in OFC in adulthood, suggesting that the therapeutic action of MPH persists long after treatment cessation and may contribute to lasting reductions in deficits associated with ADHD.

Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections.

The medial prefrontal cortex (mPFC) exerts top-down control of primary visual cortex (V1) activity. As there is no direct neuronal projection from mPFC to V1, this functional connection may use an indirect route, i.e., via basalo-cortical cholinergic projections. The cholinergic projections to V1 originate from neurons in the horizontal limb of the diagonal band of Broca (HDB), which receive neuronal projections from the ventral part of the mPFC, composed of prelimbic (PrL) and infralimbic cortices (IL). Therefore, the objective of this study was to determine whether electrical stimulation of mice mPFC subregions activate (1) V1 neurons; and (2) HDB cholinergic neurons, suggesting that the HDB serves as a relay point in the mPFC-V1 interaction. Neuronal activation was quantified using c-Fos immunocytochemistry or thallium autometallography for each V1 layer using automated particle analysis tools and optical density measurement. Stimulation of IL and PrL induced significantly higher c-Fos expression or thallium labeling in layers II/III and V of V1 in the stimulated hemisphere only. A HDB cholinergic neuron-specific lesion by saporin administration reduced IL-induced c-Fos expression in layers II/III of V1 but not in layer V. However, there was no c-Fos expression or thallium labeling in the HDB neurons, suggesting that this area was not activated by IL stimulation. Stimulation of another mPFC subarea, the anterior cingulate cortex (AC), which is involved in attention and receives input from V1, activated neither V1 nor HDB. The present results indicate that IL and PrL, but not AC, stimulation activates V1 with the minor involvement of the HDB cholinergic projections. These results suggest a functional link between the ventral mPFC and V1, but this function is only marginally supported by HDB cholinergic neurons and may involve other brain regions.

Differential roles of medial prefrontal subregions in the regulation of drug seeking

The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction. This dichotomy of mPFC function may be a general attribute, as similar dorsal–ventral distinctions exist for expression vs. extinction of fear conditioning. However, other results indicate that the role of mPFC neurons in reward processing is more complex than a simple PL-seek vs. IL-extinguish dichotomy. Both PL and IL have been shown to drive and inhibit drug seeking (and other types of behaviors) depending on a range of factors including the behavioral context, the drug-history of the animal, and the type of drug investigated. This heterogeneity of findings may reflect multiple subcircuits within each of these PFC areas supporting unique functions. It may also reflect the fact that the mPFC plays a multifaceted role in shaping cognition and behavior, including those overlapping with cocaine seeking and extinction. Here we discuss research leading to the hypothesis that dorsal and ventral mPFC differentially control drug seeking and extinction. We also present recent results calling the absolute nature of a PL vs. IL dichotomy into question. Finally, we consider alternate functions for mPFC that correspond less to response execution and inhibition and instead incorporate the complex cognitive behavior for which the mPFC is broadly appreciated.This article is part of a Special Issue entitled Addiction circuits.

Taking action in the face of threat: neural synchronization predicts adaptive coping.

The ability to take action in the face of threat is highly diverse across individuals. What are the neural processes that determine individual differences in the ability to cope with danger? We hypothesized that the extent of synchronization between amygdala, striatum, and medial prefrontal cortex (mPFC) would predict successful active coping performance. To test this, we developed a novel computer task based on the principals of Sidman avoidance. Healthy human participants learned through trial and error to move a marker between virtual game board compartments once every 3 s to avoid mild shocks. Behaviorally, participants exhibited large individual differences. Strikingly, both amygdala-mPFC and caudate-mPFC coupling during active coping trials covaried with final active coping performance across participants. These findings indicate that synchronization between mPFC subregions, and both amygdala and caudate predicts whether individuals will achieve successful active coping performance by the end of training. Thus, successful performance of adaptive actions in the face of threat requires functional synchronization of a neural circuit consisting of mPFC, striatum, and amygdala. Malfunction in the crosstalk between these components might underlie anxiety symptoms and impair individuals' ability to actively cope under stress. This opens an array of possibilities for therapeutic targets for fear and anxiety disorders.

Reflections of Oneself: Neurocognitive Evidence for Dissociable Forms of Self-Referential Recollection.

Research links the medial prefrontal cortex (mPFC) with a number of social cognitive processes that involve reflecting on oneself and other people. Here, we investigated how mPFC might support the ability to recollect information about oneself and others relating to previous experiences. Participants judged whether they had previously related stimuli conceptually to themselves or someone else, or whether they or another agent had performed actions. We uncovered a functional distinction between dorsal and ventral mPFC subregions based on information retrieved from episodic long-term memory. The dorsal mPFC was generally activated when participants attempted to retrieve social information about themselves and others, regardless of whether this information concerned the conceptual or agentic self or other. In contrast, a role was discerned for ventral mPFC during conceptual but not agentic self-referential recollection, indicating specific involvement in retrieving memories related to self-concept rather than bodily self. A subsequent recognition test for new items that had been presented during the recollection task found that conceptual and agentic recollection attempts resulted in differential incidental encoding of new information. Thus, we reveal converging fMRI and behavioral evidence for distinct neurocognitive forms of self-referential recollection, highlighting that conceptual and bodily aspects of self-reflection can be dissociated.