mPFC Area Research Articles

Anatomy and connectivity of the Göttingen minipig subgenual cortex (Brodmann area 25 homologue)

BackgroundThe subgenual gyrus is a promising target for deep brain stimulation (DBS) against depression. However, to optimize this treatment modality, we need translational animal models.AimTo describe the anatomy and connectivity of the Göttingen minipig subgenual area (sgC).Materials and methodsThe frontal pole of 5 minipigs was cryosectioned into 40 μm coronal and horizontal sections and stained with Nissl and NeuN-immunohistochemistry to visualize cytoarchitecture and cortical lamination. Eight animals were unilaterally stereotaxically injected in the sgC with anterograde (BDA) and retrograde (FluoroGold) tracers to reveal the sgC connectivity.ResultsIn homology with human nomenclature (Brodmann 1909), the minipig sgC can be subdivided into three distinct areas named area 25 (BA25), area 33 (BA33), and indusium griseum (IG). BA25 is a thin agranular cortex, approximately 1 mm thick. Characteristically, perpendicular to the pial surface, cell-poor cortical columns separate the otherwise cell-rich cortex of layer II, III and V. In layer V the cells are of similar size as seen in layer III, while layer VI contains more widely dispersed neurons. BA33 is less differentiated than BA25. Accordingly, the cortex is thinner and displays a complete lack of laminar differentiation due to diffusely arranged small, lightly stained neurons. It abuts the IG, which is a neuron-dense band of heavily stained small neurons separating BA33 directly from the corpus callosum and the posteriorly located septal nuclear area.Due to the limited area size and nearby location to the lateral ventricle and longitudinal cerebral fissure, only 3/8 animals received sgC injections with an antero- and retrograde tracer mixture. Retrograde tracing was seen primarily to the neighbouring ipsilateral ventral- and mPFC areas with some contralateral labelling as well. Prominent projections were furthermore observed from the ipsilateral insula, the medial aspect of the amygdala and the hippocampal formation, diencephalon and the brainstem ventral tegmental area. Anterograde tracing revealed prominent projections to the neighbouring medial prefrontal, mPFC and cingulate cortex, while moderate staining was noted in the hippocampus and adjoining piriform cortex.ConclusionThe minipig sgC displays a cytoarchitectonic pattern and connectivity like the human and may be well suited for further translational studies on BA25-DBS against depression.

FNDC5/irisin mediates the protective effects of Innovative theta-shaking exercise on mouse memory

As a passive motion and non-invasive treatment, theta-shaking exercise is considered an alternative to traditional active exercise for slowing down brain ageing. Here, we studied the influence of theta-shaking exercise on fibronectin type III domain containing 5/irisin (FNDC5/irisin) in the anterior nucleus of the thalamus, hippocampus, and medial prefrontal cortex (ATN–HPC–MPFC). Further, we assessed memory in senescence-accelerated prone mice (SAMP-10 mice) using a behavioural test to confirm the protective effect of theta-shaking exercise against age-related memory decline. SAMP-10 mice were subjected to theta-shaking exercise for 9–30 weeks. Mice then performed the T-maze test and passive avoidance task. Immunohistochemical analysis and ELISA were used to assess FNDC5/irisin, nerve growth factor (NGF), and neurotrophin 4/5 (NT4/5) expression in the ATN–HPC–MPFC. In the shaking group, FNDC5 was locally upregulated within the hippocampus and MPFC area rather than exhibiting even distribution throughout brain tissue. Irisin levels were generally higher in the control group. Meanwhile, hippocampal NGF levels were significantly higher in the shaking group, with no differences noted in neurotrophin levels. Theta-shaking preserved normal neurons in certain sub-regions. However, no beneficial changes in neuronal density were noted in the ATN. Theta-shaking exercise positively affects memory function in SAMP-10 mice. FNDC5 upregulation and higher levels of NGF, along with the potential involvement of irisin, may have contributed to the preservation of normal neuronal density in the hippocampus and MPFC subregions.

Inducible Nitric Oxide Synthase Inhibition in the Medial Prefrontal Cortex Attenuates the Anxiogenic-Like Effect of Acute Restraint Stress via CB1 Receptors.

Stress exposure can result in several proinflammatory alterations in the brain, including overexpression of the inducible isoform of nitric oxide synthase (iNOS) in the medial prefrontal cortex (mPFC). These changes may be involved in the development of many psychiatric conditions. However, it is unknown if iNOS in mPFC plays a significant role in stress-induced behavioral changes. The endocannabinoid (ECB) system is also influenced by stress. Its activation seems to be a counter regulatory mechanism to prevent or decrease the stress-mediated neuroinflammatory consequences. However, it is unclear if the ECB system and iNOS interact to influence stress consequences. This study aimed to test the hypothesis that the anti-stress effect of iNOS inhibition in mPFC involves the local ECB system, particularly the CB1 cannabinoid receptors. Male Wistar rats with guide cannula aimed at the mPFC were submitted to acute restraint stress (RS) for 2 h. In the following morning, rats received bilateral microinjections of vehicle, AM251 (CB1 antagonist; 100 pmol), and/or 1400W (iNOS selective inhibitor; 10−4, 10−3, or 10−2 nmol) into the prelimbic area of mPFC (PL-mPFC) before being tested in the elevated plus-maze (EPM). iNOS inhibition by 1400W prevented the anxiogenic-like effect observed in animals submitted to RS. The drug did not promote behavior changes in naive animals, demonstrating a stress-dependent effect. The 1400W-anti-stress effect was prevented by local pretreatment with AM251. Our data suggest that iNOS inhibition may facilitate the local endocannabinoid signaling, attenuating stress effects.

An evolutionary gap in primate default mode network organization

SUMMARYThe human default mode network (DMN) is engaged at rest and in cognitive states such as self-directed thoughts. Interconnected homologous cortical areas in primates constitute a network considered as the equivalent. Here, based on a cross-species comparison of the DMN between humans and non-hominoid primates (macaques, marmosets, and mouse lemurs), we report major dissimilarities in connectivity profiles. Most importantly, the medial prefrontal cortex (mPFC) of non-hominoid primates is poorly engaged with the posterior cingulate cortex (PCC), though strong correlated activity between the human PCC and the mPFC is a key feature of the human DMN. Instead, a fronto-temporal resting-state network involving the mPFC was detected consistently across non-hominoid primate species. These common functional features shared between non-hominoid primates but not with humans suggest a substantial gap in the organization of the primate’s DMN and its associated cognitive functions.

Pathways for Memory, Cognition and Emotional Context: Hippocampal, Subgenual Area 25, and Amygdalar Axons Show Unique Interactions in the Primate Thalamic Reuniens Nucleus.

The reuniens nucleus (RE) is situated at the most ventral position of the midline thalamus. In rats and mice RE is distinguished by bidirectional connections with the hippocampus and medial prefrontal cortex (mPFC) and a role in memory and cognition. In primates, many foundational questions pertaining to RE remain unresolved. We addressed these issues by investigating the composition of the rhesus monkey RE in both sexes by labeling for GABA, a marker of inhibitory neurons, and for the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR), which label thalamic excitatory neurons that project to cortex. As in rats and mice, the macaque RE was mostly populated by CB and CR neurons, characteristic of matrix-dominant nuclei, and had bidirectional connections with hippocampus and mPFC area 25 (A25). Unlike rodents, we found GABAergic neurons in the monkey RE and a sparser but consistent population of core-associated thalamocortical PV neurons. RE had stronger connections with the basal amygdalar complex than in rats or mice. Amygdalar terminations were enriched with mitochondria and frequently formed successive synapses with the same postsynaptic structures, suggesting an active and robust pathway to RE. Significantly, hippocampal pathways formed multisynaptic complexes that uniquely involved excitatory projection neurons and dendrites of local inhibitory neurons in RE, extending this synaptic principle beyond sensory to high-order thalamic nuclei. Convergent pathways from hippocampus, A25, and amygdala in RE position it to flexibly coordinate activity for memory, cognition, and emotional context, which are disrupted in several psychiatric and neurologic diseases in humans.SIGNIFICANCE STATEMENT The primate RE is a central node for memory and cognition through connections with the hippocampus and mPFC. As in rats or mice, the primate RE is a matrix-dominant thalamic nucleus, suggesting signal traffic to the upper cortical layers. Unlike rats or mice, the primate RE contains inhibitory neurons, synaptic specializations with the hippocampal pathway, and robust connections with the amygdala, suggesting unique adaptations. Convergence of hippocampal, mPFC, and amygdalar pathways in RE may help unravel a circuit basis for binding diverse signals for conscious flexible behaviors and the synthesis of memory with affective significance in primates, whereas disruption of distinct circuit nodes may occur in psychiatric disorders in humans.

Potential Alterations of Functional Connectivity Analysis in the Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the most common diseases in urology, but its pathogenesis remains unclear. As a kind of chronic pain which the patients suffered for more than 3 months, we investigated the influence on patients' brain functional connectivity in resting state. Methods We recruited a cohort of 18 right-handed male patients with CP/CPPS and 21 healthy male right-handed age-matched controls. Their resting-state fMRI data and structural MRI data were preprocessed and processed by RESTPlus V1.22. To assess the integrity of the default mode network (DMN), we utilized the voxel-wised analysis that we set medial prefrontal cortex (mPFC) and posterior cingulate gyrus (PCC) as seed points to compare the global functional connectivity (FC) strength. Results Compared with healthy control, the FC strength between left mPFC and posterior DMN decreased in the group of CP/CPPS (P < 0.05, GFR correction, voxel P < 0.01, cluster P < 0.05), and the FC strength between the left anterior cerebellar lobe and posterior DMN increased (P < 0.05, GFR correction, voxel P < 0.01, cluster P < 0.05). In the patient group, there was a positive correlation between the increased FC strength and the score of the Hospital Anxiety and Depression Scale (HADS) anxiety subscale (r = 0.5509, P = 0.0178) in the left anterior cerebellar lobe, a negative correlation between the decreased FC strength and the score of the National Institutes of Health Chronic Prostatitis Symptom Index (r = −0.6281, P = 0.0053) in the area of left mPFC, and a negative correlation between the decreased FC strength and the score of HADS anxiety subscale (r = −0.5252, P = 0.0252). Conclusion Patients with CP/CPPS had alterations in brain function, which consisted of the default mode network's compromised integrity. These alterations might play a crucial role in the pathogenesis and development of CP/CPPS.

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

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

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

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

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.

AGE-RELATED DIFFERENCES IN THE MODULATION OF RESTING-STATE FUNCTIONAL CONNECTIVITY FOLLOWING REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION

Resting-state intrinsic functional connectivity (rs-iFC) reveals that the brain is organized in several networks (Smith et al., PNAS.2009. Aug4;106(31):13040–5) that relate to cognition and behavior. Brain networks, particularly the Default-Mode Network (DMN) dynamics, can be disrupted by advancing age (Vidal-Piñeiro et al., FrontAgingNeurosci.2014. Sep25;6:256), which may relate to age-related cognitive decline. Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS), can modulate DMN expression and influence cognitive abilities (Eldaief et al., PNAS.2011. Dec27;108(52):21229–34). In the present study we examined whether the effects of rTMS on DMN connectivity differ between young and elders. Twenty-four young (mean age: 23.42±1.64) and twenty-seven healthy elders (mean age: 68.15±4.61) were randomly assigned to receive real (Nyoung=11, Nelders=15) or sham (Nyoung=13, Nelders=12) intermittent theta burst stimulation (iTBS) over the left inferior parietal lobe (lIPL). Changes in rs-iFC induced by iTBS were investigated using seed-based approaches within DMN nodes (Fig.1). Neuroimaging data was analysed using FSL (http://fsl.fmrib.ox.ac.uk/fsl/). Statistical significance was set at p≤0.05 FWE-corrected, except when stated specifically. An interaction between age and rTMS in mPFC was revealed through seed-to-brain analyses (Fig.2A). A main effect of stimulation was evidenced within PMC and mPFC (Fig.2B). Changes in mPFC were mainly driven by a connectivity increase following rTMS in young participants (Fig.3A). Conversely, connectivity increases were restricted within PMC amongst elders (p<0.005 uncorrected; Fig.3B). Seed-to-seed analyses revealed increased mPFC connectivity in young (p<0.001), whereas in elders, regions showing increased connectivity were proximal to the stimulation site (lIPL: p=0.023; PMC: p<0.001 and rIPL: p<0.001). Amongst elders, greater functional responses to rTMS in mPFC regions were positively related to better baseline memory performance (r=0.686; p=0.014). Our results reveal that resting-state connectivity responses to iTBS within DMN are modulated by age. Advancing age appears to attenuate functional connectivity involving long-range connections, while it increases local connectivity. This pattern of effects is coherent with observational neuroimaging studies (Sala-Llonch et al., NeurobiolAging.2014. Oct;35(10):2193–202). Furthermore, ‘young-like’ responses to rTMS appear to be characteristic of elders with better preserved cognitive function. Further studies might investigate if particular connectivity responses to TMS are distinctive of elders at risk or in preclinical stages of dementia. Seed-based approaches used to explore the iTBS-induced intrinsic functional connectivity (iFC) modulation within the DMN. Through these analyses it was studied the iFC modulation between the stimulation site (represented as a flash) and left inferior parietal lobe (IIPL), right inferior parietal lobe (rIPL), posteromedial cortex (PMC), left hippocampus (IHC), right hippocampus (rHC) and medial prefrontal cortex (mPFC) nodes. Figure 1A. Seed-to-brain approach: Representation of the stimulation site (flash) and the main regions included in the network analyses. Figure 1B. Seed-to-seed approach: Representation of the stimulation site (flash) and the six main DMN nodes selected to explore the iFC modulation in an isolated way. Interaction between stimulation and age. A significant interaction between stimulation and age in mPFC (FWE-corrected, p<0.05) is shown in green. Figure 2B. Main stimulation effect: A main effect of stimulation within PMC and mPFC areas of the DMN (FWE-corrected, p<0.05) is shown in red-yellow. iTBS effects in young group: In young group a significant iFC increase in mPFC after iTBS intervention compared with sham condition (FWE-corrected, p<0.05) is shown in red-yellow. Figure 3B. iTBS effects in elder group: In elder group a significant iFC increase in PMC compared to sham condition is shown at a lower threshold (p<0.005 uncorrected).

Regional differences in dendritic spine density confer resilience to chronic social defeat stress.

Although alterations in the dendritic spine density in the brain regions may play a role in the stress-induced depression-like phenotype, the precise mechanisms are unknown. The aim was to investigate the role of spine density in the brain regions after chronic social defeat stress (CSDS). We examined dendritic spine density in the medial prefrontal cortex (mPFC), CA1, CA3, dentate gyrus (DG) of hippocampus, nucleus accumbens (NAc), and ventral tegmental area (VTA) of susceptible and resilient mice after CSDS. Spine density in the prelimbic area of mPFC, CA3, and DG in the susceptible group, but not resilient group, was significantly lower than control group. In contrast, spine density in the NAc and VTA in the susceptible group, but not resilient group, was significantly higher than control group. The results suggest that regional differences in spine density may contribute to resilience versus susceptibility in mice subjected to CSDS.

Anatomical segmentation of the human medial prefrontal cortex

The medial prefrontal areas 32, 24, 14, and 25 (mPFC) form part of the limbic memory system, but little is known about their functional specialization in humans. To add anatomical precision to structural and functional magnetic resonance imaging (MRI) data, we aimed to identify these mPFC subareas in histological preparations of human brain tissue, determine sulci most consistently related with mPFC areal boundaries, and use these sulci to delineate mPFC areas in MRIs. To achieve this, we obtained three-dimensional MRI data from 11 ex vivo hemispheres and processed them for cyto- and myelo-architectonic analysis. The architectonic boundaries of mPFC areas were identified in histology and cortical surface length and volumes were measured. Unfolded maps of histologically determined boundaries were generated to identify the association of mPFC areal boundaries with sulci across cases. This analysis showed that cingulate and superior rostral were the sulci most consistently related to mPFC areal boundaries. Based on presence/absence and anastomosis between such sulci, 6 sulci patterns in the 11 hemispheres were found. A further analysis of 102 hemispheres of in vivo MRI scans (N = 51 males, mean ± SD 24.1 ± 3.1 years of age) showed similar sulci patterns, which allowed us to delineate the mFPC areas in them. The volumes of mPFC areas across histological, ex vivo and in vivo MRI delineations were comparable and probabilistic maps generated from the MRIs of the102 hemispheres. Probabilistic maps of mPFC areas were registered to MNI space and are available for regional analysis of functional magnetic resonance imaging data.

P113 Modulation of food and body weight implicit attitudes with non-invasive brain stimulation techniques

Introduction Non-invasive brain stimulation (NiBS) techniques have been increasingly used in experimental and clinical studies on food-related behaviours and psychopathologies. However, results are still controversial on what concerns the neural mechanisms underlying eating disorders and the possibility to modulate eating behaviours with NiBS techniques in healthy and clinical populations. This study investigates these issues assessing the effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) on attitudes towards food in healthy volunteers and patients with eating disorders. Methods & results In experiment 1, we applied TMS on the medial prefrontal cortex (mPFC) of healthy participants and showed that this area was causally involved in monitoring implicit attitudes towards food measured with the implicit association test (IAT). In experiment 2, we are assessing in healthy volunteers and patients with anorexia or bulimia nervosa the effect of applying anodal tDCS over mPFC and extrastriate body area (EBA) on attitudes towards food and underweight or overweight body shapes, as measured by IATs. Preliminary results on a healthy sample show no significant modulation of IATs by mPFC- or EBA-tDCS, in particular, differently from mPFC-TMS, mPFC-tDCS does not affect IAT on food preference. However, we expect different behavioural performances and tDCS-related modulations in the clinical population. Conclusion Taken together, our results could shed light on the effects of different NiBS protocols on implicit attitudes in eating disorders. In particular, using the same behavioural paradigm with different populations and NiBS techniques we aim at clarifying the role of different target areas which could be selected for clinical trials in future research.

Effect of Treadmill Running on Morphine Dependence Before and After Medial Prefrontal Cortex Lesion in Rats

BackgroundPrevious studies on the medial prefrontal cortex (mPFC) has shown that this area plays an important role in addiction behavior. Other studies also indicated that exercise decreases use of morphine.ObjectivesThe aim of this study was to evaluate the effects of short-term exercise on trends for use of morphine with an intact mPFC and lesion of that area.Methods50 rats randomly were selected and divided into 5 groups. 1-exercise. 2- Morphine + Lesion. 3- Morphine + Exercise + Lesion. 4- Morphine. 5- Morphine and Exercise. All groups received morphine for 9 days except exercise group. On the 10th day, the symptoms of addiction were evaluated. To determine the effects of exercise, a treadmill apparatus was used for exercising.ResultsOur results indicated that exercise with intact mPFC area significantly decreased the tendency of using morphine which is verified by changes in symptoms (P < 0.05), but after a lesion of this area exercise did not significantly affect these withdrawal symptomsConclusionsIt seems that a lesion of mPFC area significantly reduced the effect of short-term exercise on the usage pattern of morphine.

Sensory responses in the medial prefrontal cortex of anesthetized rats. Implications for sensory processing

The medial prefrontal cortex (mPFC) plays a key role in higher functions such as memory and attention. In order to demonstrate sensory responses in the mPFC, we used electrophysiological recordings of urethane-anesthetized rats to record somatosensory-evoked potentials (SEPs) or auditory-evoked potentials (AEPs) elicited by whisker deflections and click stimulation, respectively. Contralateral whisker stimulation or auditory stimuli were also applied to study sensory interference in the mPFC. Interference with other sensory stimuli or recent stimulation history reduced whisker responses in the infralimbic and prelimbic cortices of the ventral mPFC. This effect could be mediated by activation of parvalbumin (PV) interneurons since the effect was blocked by the P/Q calcium channel antagonist ω-agatoxin. In contrast, sensory interference or the recent stimulation history was not detected by the dorsal mPFC or the primary somatosensory cortex. Results obtained from retrograde tracer injections in the dorsal and ventral regions of the mPFC indicated that somatosensory and auditory sensory inputs may arrive at the dorsal mPFC through secondary sensory cortical areas, and through the insular and temporal cortical areas. The ventral mPFC may receive sensory information through the strong anatomical connections between the dorsal and ventral mPFC areas. In conclusion, results suggest mPFC plays an important role in sensory processing, which may have important implications in attentional and memory processes.

Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories.

In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in "neuronal ensembles." Thus, we hypothesize that different neuronal ensembles encode reward- and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area. A current popular hypothesis is that neuronal ensembles in different prefrontal cortex areas control reward-associated versus extinction-associated memories: the dorsal medial prefrontal cortex (mPFC) promotes reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area.

Altered neuronal spontaneous activity correlates with glutamate concentration in medial prefrontal cortex of major depressed females: An fMRI-MRS study

BackgroundMajor depressive disorder (MDD) is twice more prevalent in females than in males. Yet, there have only been a few studies on the functional brain activity in female MDD patients and the detailed mechanisms underlying their neurobiology merit further investigations. In the present work, we used combined fMRI-MRS methods to investigate the altered intrinsic neuronal activity and its association with neurotransmitter concentration in female MDD patients. MethodsThe whole brain amplitude of low frequency fluctuation (ALFF) analysis using resting state functional magnetic resonance imaging (fMRI) was performed to explore the alteration of intrinsic neuronal signals in MDD females (n=11) compared with female healthy controls (n=11). With a specific interest in the medial prefrontal cortex (mPFC) area, we quantified the concentration of amino acid neurotransmitters including GABA ((r-aminobutyric acid)), Glu (Glutamate), and Glx (Glutamate + Glutamine) using 1H-MRS technology. Moreover, we conducted Pearson correlation analysis between the ALFF value and neurotransmitter concentration to find out the functional-biochemical relation in mPFC area. The relationship between the metabolites concentration and MDD symptomatology was also examined through Spearman correlation analysis. ResultsWe found that the female MDD patients showed increased neuronal spontaneous activity in left medial prefrontal cortex (mPFC) and left middle frontal cortex, with decreased ALFF level in right putamen and right middle temporal cortex (p<0.01, Alphasim corrected). The ALFF in mPFC was shown positively correlated with Glu concentration in female MDD patients (r=0.67, p=0.023). The Glu concentration in mPFC was positively correlated with patients HAMA scores (r=0.641, p=0.033). LimitationsThe relatively small sample size, metabolite information acquired only in mPFC and not all patients were unmedicated are the major limitations of our study. ConclusionsUsing combined fMRI-MRS methods, we found increased spontaneous neuronal activity was correlated with Glu concentration in mPFC of female MDD patients. Other regions including left middle frontal gyrus, right putamen and middle temporal gyrus also showed altered spontaneous neuronal activities. The abnormal intrinsic neuronal activities in fronto-cortical regions shed light on the pathogenesis underlying MDD females. The multimodal resting-state neuroimaging technique served as a useful tool for functional-biochemical investigation of MDD pathophysiology.

Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: a single and double retrograde tracing study in rats.

The amygdala and medial prefrontal cortex (mPFC) are highly interconnected telencephalic areas critical for cognitive processes, including associative learning and decision making. Both structures strongly innervate the lateral hypothalamus (LHA), an important component of the networks underlying the control of feeding and other motivated behaviors. The amygdala-prefrontal-lateral hypothalamic system is therefore well positioned to exert cognitive control over behavior. However, the organization of this system is not well defined, particularly the topography of specific circuitries between distinct cell groups within these complex, heterogeneous regions. This study used two retrograde tracers to map the connections from the amygdala (central and basolateral area nuclei) and mPFC to the LHA in detail, and to determine whether amygdalar pathways to the mPFC and to LHA originate from the same or different neurons. One tracer was placed into a distinct mPFC area (dorsal anterior cingulate, prelimbic, infralimbic, or rostromedial orbital), and the other into dorsal or ventral LHA. We report that the central nucleus and basolateral area of the amygdala send projections to distinct LHA regions, dorsal and ventral, respectively. The basolateral area, but not central nucleus, also sends substantial projections to the mPFC, topographically organized rostrocaudal to dorsoventral. The entire mPFC, in turn, projects to the LHA, providing a separate route for potential amygdalar influence following mPFC processing. Nearly all amygdalar projections to the mPFC and to the LHA originated from different neurons suggesting amygdala and amygdala-mPFC processing influence the LHA independently, and the balance of these parallel pathways ultimately controls motivated behaviors.

Early-life exposure to noise reduces mPFC astrocyte numbers and T-maze alternation/discrimination task performance in adult male rats.

In this experiment, we evaluated the long-term effects of noise by assessing both astrocyte changes in medial prefrontal cortex (mPFC) and mPFC-related alternation/discrimination tasks. Twenty-one-day-old male rats were exposed during a period of 15 days to a standardized rats’ audiogram-fitted adaptation of a human noisy environment. We measured serum corticosterone (CORT) levels at the end of the exposure and periodically registered body weight gain. In order to evaluate the long-term effects of this exposure, we assessed the rats’ performance on the T-maze apparatus 3 months later. Astrocyte numbers and proliferative changes in mPFC were also evaluated at this stage. We found that environmental noise (EN) exposure significantly increased serum CORT levels and negatively affected the body weight gain curve. Accordingly, enduring effects of noise were demonstrated on mPFC. The ability to solve alternation/discrimination tasks was reduced, as well as the number of astroglial cells. We also found reduced cytogenesis among the mPFC areas evaluated. Our results support the idea that early exposure to environmental stressors may have long-lasting consequences affecting complex cognitive processes. These results also suggest that glial changes may become an important element behind the cognitive and morphological alterations accompanying the PFC changes seen in some stress-related pathologies.

Topographic mapping between basal forebrain cholinergic neurons and the medial prefrontal cortex in mice.

The basal forebrain cholinergic innervation of the medial prefrontal cortex (mPFC) is crucial for cognitive performance. However, little is known about the organization of connectivity between the basal forebrain and the mPFC in the mouse. Using focal virus injections inducing Cre-dependent enhanced yellow fluorescent protein expression in ChAT-IRES-Cre mice, we tested the hypothesis that there is a topographic mapping between the basal forebrain cholinergic neurons and their axonal projections to the mPFC. We found that ascending cholinergic fibers to the mPFC follow four pathways and that cholinergic neurons take these routes depending on their location in the basal forebrain. In addition, a general mapping pattern was observed in which the position of cholinergic neurons measured along a rostral to caudal extent in the basal forebrain correlated with a ventral to dorsal and a rostral to caudal shift of cholinergic fiber distribution in mPFC. Finally, we found that neurons in the rostral and caudal parts of the basal forebrain differentially innervate the superficial and deep layers of the ventral regions of the mPFC. Thus, a frontocaudal organization of the cholinergic system exists in which distinct mPFC areas and cortical layers are targeted depending on the location of the cholinergic neuron in the basal forebrain.