Prefrontal Cortex Pathway Research Articles

8-weeks aerobic exercise ameliorates cognitive deficit and mitigates ferroptosis triggered by iron overload in the prefrontal cortex of APP Swe/PSEN 1dE9 mice through Xc-/GPx4 pathway.

Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of APP Swe/PSEN 1dE9 (APP/PS1) mice. Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, iron-metabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice. In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc-/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice. 8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc- pathway in PFC to reduce ferroptosis induced by AD.

Long Mu Qing Xin mixture improves behavioral performance in spontaneously hypertensive rats (SHR/NCrl) by upregulating catecholamine neurotransmitters in prefrontal cortex and striatum via DRD1/cAMP/PKA-CREB signaling pathway.

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder in children, can be effectively alleviated by the herbal preparation Long Mu Qing Xin Mixture (LMQXM), but its mechanism has not been fully elucidated. To scrutinize the potential pharmacological mechanisms by which LMQXM improves behavior in spontaneously hypertensive rats (SHR/NCrl). The SHR/NCrl rats were randomly stratified into the model (SHR) group, the methylphenidate hydrochloride (MPH) group, and groups subjected to varying dosages of LMQXM into the medium dose (MD) group with a clinically effective dose, the low dose (LD) group with 0.5 times the clinically effective dose, and high dose (HD) group with 2 times the clinically effective dose. Furthermore, the WKY/NCrl rats constituted the control group. The evaluation of behavior involved the open field test and the Morris water maze test. HPLC, LC-MS, ELISA, immunohistochemistry, Western blot, and RT-qPCR were utilized to scrutinize the catecholamine neurotransmitter content and the expression of proteins and genes associated with the dopamine receptor D1 (DRD1)/cAMP/protein kinase A (PKA)-cAMP response element-binding (CREB) pathway in prefrontal cortex (PFC) and striatum. MPH and LMQXM ameliorated hyperactivity and learning and memory deficits of SHR/NCrl rats. Among them, LMQXM-MD and MPH also upregulated dopamine (DA), norepinephrine (NE), adenylate cyclase (AC) and cAMP levels, and the expression of proteins and genes associated with the DRD1/cAMP/PKA-CREB pathway in PFC and striatum of SHR/NCrl rats. PFC and striatum DA levels were also upregulated in the LMQXM-LD group as well as the striatum DA levels in the LMQXM-HD group, but there were no statistically significant differences in their NE levels compared to the SHR group. LMQXM-LD and LMQXM-HD also upregulated some DRD1/cAMP/PKA-CREB pathway-related proteins and gene expression, but the effects were discernibly disparate in PFC and striatum. Upon comprehensive analysis, LMQXM-MD appeared to be the most effective dose. Our study tentatively suggests that LMQXM may rectify hyperactivity and learning and memory deficits of SHR/NCrl rats by elevating catecholamine neurotransmitters in the PFC and striatum. This effect may be attributed to the potential activation of the DRD1/cAMP/PKA-CREB signaling pathway, which appears to achieve an optimal response at moderate doses.

Temporal dynamics of BDNF signaling recruitment in the rat prefrontal cortex and hippocampus following a single infusion of a translational dose of ketamine

Despite several decades of investigations, the mechanisms underlying the rapid action of ketamine as antidepressant are still far from being completely understood. Several studies indicated Brain-Derived Neurotrophic Factor (BDNF) as critical for the fast antidepressant action of ketamine, due to its contribution in early and rapid synaptic adaptations. However, previous reports have been essentially based on ketamine dosing modes that differ from the clinical route of administration (slow intravenous infusion). In this report, we investigated the effects of a ketamine dosing mode in male Sprague-Dawley rats showed to be translational to the clinically effective mode in patients. We focused on the first 24 h after infusion to finely dissect potential differences in the contribution of BDNF signaling pathway in prefrontal cortex and hippocampus, two brain regions involved in the antidepressant effects of ketamine.Our data show that the slow ketamine infusion activates the BDNF-mTOR-S6 pathway in prefrontal cortex as early as 2 h and remains on until at least 6 h after the infusion. At the 12 h timepoint, this pathway is turned off in prefrontal cortex while it becomes activated in hippocampus. Interestingly, this pathway appears to be activated in both brain regions at 24 h through a BDNF-independent mechanism adding complexity to the early action of ketamine.We have captured previously unknown dynamics of the early effects of ketamine showing rapid activation/deactivation of BDNF and its downstream signaling in prefrontal cortex and hippocampus, following a precise temporal profile.

Vitamin A deficiency from maternal gestation may contribute to autistic-like behaviors and gastrointestinal dysfunction in rats through the disrupted purine and tryptophan metabolism

Vitamin A deficiency (VAD) has been linked to autism spectrum disorder (ASD) in multiple studies, and autistic children with gastrointestinal (GI) symptoms have been found to have lower VA levels than those without GI symptoms. However, the exact mechanism by which VAD causes both core symptoms and GI symptoms in ASD is ill defined. We constructed VAD and vitamin A normal (VAN) rat models from maternal gestation onwards. Autism-related behaviors were tested using the open-field test and the three-chamber test, and GI function was assessed with the GI transit time, the colonic transit time and fecal water content. Untargeted metabolomic analysis on the prefrontal cortex (PFC) and fecal samples was performed. VAD rats displayed autistic-like behaviors and impaired GI function compared to VAN rats. Metabolic profiles of both PFC and feces from VAD and VAN rats were significantly different. The differential metabolites in both PFC and feces between the VAN and VAD rats were mostly enriched in the purine metabolic pathway. Moreover, the most significantly affected metabolic pathway in PFC of VAD rats was the phenylalanine, tyrosine and tryptophan biosynthesis pathway, and the most remarkably altered metabolic pathway in the feces of VAD rats was the tryptophan metabolism pathway. These results indicate that VAD starting from maternal gestation might be linked to core symptoms of ASD and its GI co-occurring disorders through the purine and tryptophan-related metabolism disorders.

Hydrogen Sulfide Interacting with Cannabinoid 2 Receptors during Sciatic Nerve Injury-Induced Neuropathic Pain.

Hydrogen sulfide (H2S) donors make opioids more effective in inhibiting nociception during inflammatory and neuropathic pain. We examined whether the analgesic, anxiolytic and/or antidepressant actions of the cannabinoid 2 receptor (CB2R) agonist, JWH-133, might be improved by pretreatment with H2S donors, DADS and GYY4137 in mice with sciatic nerve injury-provoked neuropathy (CCI). The reversion of the antinociceptive effects of these treatments with the CB2R antagonist, AM630, and the regulatory actions of H2S in the phosphorylation of NF-κB inhibitor alpha (IKBα) and in the brain-derived neurotrophic factor (BDNF), CB2R, Nrf2 and heme oxygenase 1 (HO-1) levels in prefrontal cortex (PFC), ventral hippocampus (vHIP) and periaqueductal gray matter (PAG), were examined. Data showed that the analgesic effects of JWH-133, systemically and locally administered, were improved by the DADS or GYY4137 pretreatment. The co-treatment of GYY4137 with JWH-133 also stopped anxiodepressive-like activities that concur with neuropathy. Our data likewise showed that both H2S donors normalized the inflammatory (p-IKBα), neurotrophic (BDNF) variations caused by CCI, increased the expression of CB2R and activated the Nrf2/HO-1 antioxidant pathway in PFC, v-HIP and/or PAG of animals with neuropathic pain. In addition, the blockade of the analgesia produced by high doses of DADS and GYY4137 with AM630 indicated the contribution of the endocannabinoid system in the effects of H2S during neuropathic pain, thus supporting the positive interaction between H2S and CB2R. Therefore, this study demonstrates the potential use of CB2R agonists combined with H2S donors as a possible treatment for peripheral nerve injury-caused neuropathic pain and the associated emotional disturbances.

Promising approaches in the search for biomarkers of bipolar disorder.

Promising approaches in the search for biomarkers of bipolar disorder.

Central medial thalamic nucleus dynamically participates in acute itch sensation and chronic itch-induced anxiety-like behavior in male mice

Itch is an annoying sensation consisting of both sensory and emotional components. It is known to involve the parabrachial nucleus (PBN), but the following transmission nodes remain elusive. The present study identified that the PBN-central medial thalamic nucleus (CM)-medial prefrontal cortex (mPFC) pathway is essential for itch signal transmission at the supraspinal level in male mice. Chemogenetic inhibition of the CM-mPFC pathway attenuates scratching behavior or chronic itch-related affective responses. CM input to mPFC pyramidal neurons is enhanced in acute and chronic itch models. Specifically chronic itch stimuli also alter mPFC interneuron involvement, resulting in enhanced feedforward inhibition and a distorted excitatory/inhibitory balance in mPFC pyramidal neurons. The present work underscores CM as a transmit node of the itch signal in the thalamus, which is dynamically engaged in both the sensory and affective dimensions of itch with different stimulus salience.

Assessment of suberoylanilide hydroxamic acid on a Alzheimer's disease model induced by β-amyloid(1-42) in aged female mice: Neuromodulatory and epigenetic effect

Alzheimer's disease (AD) is a neurodegenerative disease that affects several elderly people per years. AD is a pathology of multifactorial etiology, resulting from multiple environmental and genetic determinants. However, there is no effective pharmacological alternative for the treatment of this illness. In this sense, the purpose of current study was to characterize the mechanisms by which Aβ1-42 injection via intracerebroventricular induces neurobehavioral changes in a time-course curve. In addition, suberoylanilide hydroxamic acid (SAHA) inhibitor of histone deacetylase (HDAC) was used to investigate the involvement of epigenetic modifications Aβ1-42-caused in aged female mice. In general manner, Aβ1-42 injection induced a major neurochemical disturbance in hippocampus and prefrontal cortex of animals and a serious impairment of memory. Overall, SAHA treatment attenuated neurobehavioral changes caused by Aβ1-42 injection in aged female mice. The subchronic effects presented of SAHA were through modulation of HDAC activity, regulation of brain-derived neurotrophic factor (BDNF) levels and expression of BDNF mRNA, accompanied by unlocking cAMP/PKA/pCREB pathway in hippocampus and prefrontal cortex of animals.

Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury.

Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.

The amygdala-insula-medial prefrontal cortex-lateral prefrontal cortex pathway and its disorders.

Smith and Lane have suggested a model of emotion processing with at least three stations: areas like the amygdala, which process discrete body features areas like the anterior insula, which process whole-body patterns and areas like the medial prefrontal cortex, which process emotion concepts. Ben Shalom and Bonneh have suggested a model of the prefrontal cortex, in which medial BA 9 integrates emotional states, and lateral BA 9 performs selection/inhibition on these states. Taken together, the current paper suggests a pathway for emotion processing with at least four stations: areas like the amygdala, which process discrete body features areas like the anterior insula, which process whole-body patterns, medial BA 9 which integrates emotion concepts, and lateral BA 9, which performs selection/inhibition on these concepts. Following the existing literature, it then suggest that there is a significant involvement of the amygdala in psychopathy (Blair), of the anterior insula in alexithymia (Bird), of the medial BA 9 in deficits in somatosensory discrimination (Ben Shalom), and of lateral BA 9 in emotional impulsivity (Ronel).

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure.

The influence of proinflammatory challenges, such as maternal immune activation (MIA) or postnatal exposure to drugs of abuse, on brain molecular pathways has been reported. On the other hand, the simultaneous effects of MIA and drugs of abuse have been less studied and sometimes offered inconsistent results. The effects of morphine exposure on a pig model of viral-elicited MIA were characterized in the prefrontal cortex of males and females using RNA-sequencing and gene network analysis. Interacting and main effects of morphine, MIA, and sex were detected in approximately 2000 genes (false discovery rate-adjusted p-value < 0.05). Among the enriched molecular categories (false discovery rate-adjusted p-value < 0.05 and −1.5 > normalized enrichment score > 1.5) were the cell adhesion molecule pathways associated with inflammation and neuronal development and the long-term depression pathway associated with synaptic strength. Gene networks that integrate gene connectivity and expression profiles displayed the impact of morphine-by-MIA interaction effects on the pathways. The cell adhesion molecules and long-term depression networks presented an antagonistic effect between morphine and MIA. The differential expression between the double-challenged group and the baseline saline-treated Controls was less extreme than the individual challenges. The previous findings advance the knowledge about the effects of prenatal MIA and postnatal morphine exposure on the prefrontal cortex pathways.

The Road Not Taken: Disconnection of a Human-Unique Cortical Pathway Underlying Naturalistic Social Perception in Schizophrenia

BackgroundEfficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity anomalies affect the neural substrates of social perception remains unknown. Here we measured these relationships using functionally based localization of social perception areas, resting-state functional connectivity, and movie-watching data. MethodsIn 42 participants with schizophrenia (SzPs) and 41 healthy control subjects, we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind (ToM), and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal ToM areas in both populations to assess the impact of these changes in functional connectivity on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the ToM network (posterior temporoparietal junction [TPJp]). ResultsSzPs had pronounced decreases in connectivity in TPJ/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t81 = 4.4, p = .00002). In healthy control subjects, the shortest path connecting visual and medial prefrontal ToM areas passed through TPJ-pSTS, whereas in SzPs, the shortest path passed through the prefrontal cortex. While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r = 0.43, p = .002), it additionally correlated with connectivity along the prefrontal cortex pathway only in SzPs (rSzP = 0.56, p = .003). ConclusionsThese results suggest that connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal connectivity anomalies can have widespread impacts across the cortex.

Changes in gut viral and bacterial species correlate with altered 1,2-diacylglyceride levels and structure in the prefrontal cortex in a depression-like non-human primate model

Major depressive disorder (MDD) is a debilitating mental disease, but its underlying molecular mechanisms remain obscure. Our previously established model of naturally occurring depression-like (DL) behaviors in Macaca fascicularis, which is characterized by microbiota-gut–brain (MGB) axis disturbances, can be used to interrogate how a disturbed gut ecosystem may impact the molecular pathology of MDD. Here, gut metagenomics were used to characterize how gut virus and bacterial species, and associated metabolites, change in depression-like monkey model. We identified a panel of 33 gut virus and 14 bacterial species that could discriminate the depression-like from control macaques. In addition, using lipidomic analyses of central and peripheral samples obtained from these animals, we found that the DL macaque were characterized by alterations in the relative abundance, carbon-chain length, and unsaturation degree of 1,2-diacylglyceride (DG) in the prefrontal cortex (PFC), in a brain region-specific manner. In addition, lipid-reaction analysis identified more active and inactive lipid pathways in PFC than in amygdala or hippocampus, with DG being a key nodal player in these lipid pathways. Significantly, co-occurrence network analysis showed that the DG levels may be relevant to the onset of negative emotions behaviors in PFC. Together our findings suggest that altered DG levels and structure in the PFC are hallmarks of the DL macaque, thus providing a new framework for understanding the gut microbiome’s role in depression.

Effects of electroacupuncture on BNDF/mTORC1 signaling pathway and synaptic plasticity in prefrontal cortex of rats exposed to chronic unpredictable mild stress

To investigate the effects of electroacupuncture (EA) on the expression of related proteins in the brain-derived neurotrophic factor (BDNF)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and synapse-associated proteins and the density of dendrite spines in the prefrontal cortex (PFC) of depression model rats, and to reveal the underlying mechanism by which EA regulates the synaptic plasticity to improve depressive symptoms. Thirty-six healthy male Sprague-Dawley (SD) rats were randomly divided into normal group, model group, EA group, and scopolamine (SCOP) group, with 9 in each group. The depression model was established by exposing rats to chronic unpredictable mild stress (CUMS) combined with isolated feeding. Rats in the EA group were treated with EA (2 Hz/100 Hz, 1-1.2 mA) at "Baihui" (GV20), "Yintang" (EX-HN3), "Hegu" (LI4), and "Taichong" (LR3), 20 min each time, once per day, for 14 d, while those in the SCOP group treated with intraperitoneal injection of 25 μg/kg SCOP, once every 16 h, for 14 d. The sucrose preference and feeding latency of rats in each group were observed in the sucrose preference test (SPT) and novelty-suppressed feeding test. The expression levels of proteins in the BDNF/mTORC1 signaling pathway and synapse-associated proteins PSD95, Synapsin Ⅰ, and GluR1 were assayed by Western blot. Golgi-Cox staining was conducted for exploring the total density of dendritic spines on the apical dendrites of layer Ⅴ pyramidal neurons in PFC as well as the densities of mature, immature, and filopodial-like dendritic spines. Compared with the normal group, the model group exhibited significantly decreased sucrose preference (P<0.001), prolonged feeding latency (P<0.001), down-regulated BDNF, mTORC1, phosphorylated mTORC1 (p-mTORC1), PSD95, Synapsin Ⅰ, and GluR1 expression (P<0.001，P<0.01), and diminished total, mature, and immature spine dendritic densities (P<0.001). Compared with the model group, both EA and SCOP remarkably increased the sucrose preference (P<0.001), shortened the feeding latency (P<0.001), up-regulated the BDNF, mTORC1, p-mTORC1, PSD95, Synapsin Ⅰ, and GluR1 expression in PFC(P<0.05，P<0.01，P<0.001), and elevated the total and immature spine dendritic densities (P<0.001,P<0.01). The density of filopodial-like dendritic spine in the EA group was obviously enhanced (P<0.01), whereas the mature dendritic spine density in the SCOP group rose sharply (P<0.001). However, there were no significant differences between the EA group and SCOP group (P>0.05). EA alleviates the depressive symptoms of CUMS model rats possibly by up-regulating the expression of proteins in the BDNF/mTORC1 signaling pathway and synapse-asso-ciated proteins PSD95, Synapsin Ⅰ, and GluR1, increasing the dendritic spine density, and enhancing the synaptic plasticity in PFC.

Two opposing hippocampus to prefrontal cortex pathways for the control of approach and avoidance behaviour

The decision to either approach or avoid a potentially threatening environment is thought to rely upon the coordinated activity of heterogeneous neural populations in the hippocampus and prefrontal cortex (PFC). However, how this circuitry is organized to flexibly promote both approach or avoidance at different times has remained elusive. Here, we show that the hippocampal projection to PFC is composed of two parallel circuits located in the superficial or deep pyramidal layers of the CA1/subiculum border. These circuits have unique upstream and downstream connectivity, and are differentially active during approach and avoidance behaviour. The superficial population is preferentially connected to widespread PFC inhibitory interneurons, and its activation promotes exploration; while the deep circuit is connected to PFC pyramidal neurons and fast spiking interneurons, and its activation promotes avoidance. Together this provides a mechanism for regulation of behaviour during approach avoidance conflict: through two specialized, parallel circuits that allow bidirectional hippocampal control of PFC.

The role of the medial prefrontal cortex-perirhinal cortex pathway in the nicotine-induced enhancement of object recognition memory in mice

The role of the medial prefrontal cortex-perirhinal cortex pathway in the nicotine-induced enhancement of object recognition memory in mice

The anxiety-specific hippocampus-prefrontal cortex pathways links to procrastination through self-control.

Procrastination, which is defined as delaying an intended course of action despite negative outcomes, is demonstrated to have a deal with negative emotion including trait anxiety. Although highly anxious individuals showed impoverished control ability, no studies have indicated the role of self‐control in the relationship between trait anxiety and procrastination, and its neural correlates. To this end, we used the sliding window method to calculate the temporal deviation of dynamic functional connectivity (FC) in 312 healthy participants who underwent the resting‐state functional magnetic resonance imaging (fMRI) scanning. In line with our hypothesis, higher trait anxiety is linked to more procrastination via poorer self‐control. Besides, the dynamic FC analyses showed that trait anxiety was positively correlated with dynamic FC variability in hippocampus–prefrontal cortex (HPC–PFC) pathways, including left rostral hippocampus–left superior frontal gyrus (left rHPC–left SFG), and left rHPC–right middle frontal gyrus (left rHPC–‐MFG). Furthermore, the structural equation modeling (SEM) uncovered a mediated role of self‐control in the association between the anxiety‐specific brain connectivity and procrastination. These findings suggest that the HPC–PFC pathways may reflect impoverished regulatory ability over the negative thoughts for anxious individuals, and thereby incurs more procrastination, which enhances our understanding of how trait anxiety links to procrastination.

Alterations in amperometric cholinergic signals accompanied by synaptic plasticity and γ oscillations in the hippocampus-medial prefrontal cortex pathway.

Neural projections from the ventral hippocampal CA1 (vCA1) to the medial prefrontal cortex (mPFC) and from the posterior dorsal hippocampal CA1 (pdCA1) to the mPFC are important for information processing. Previous studies have revealed that two forms of long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), and γ oscillations, which are all believed to be neural bases for learning and memory in the vCA1-mPFC and the pdCA1-mPFC pathways, exhibited distinct profiles. However, the underlying mechanism is unclear. In the present study, amperometric cholinergic signals were monitored during in-vivo electrophysiological recordings of evoked extracellular postsynaptic potentials and spontaneous local field potentials. The results demonstrated that in the vCA1-mPFC pathway, increased cholinergic currents and γ power of the amperometric cholinergic signals were accompanied by the induction of LTD and increased γ power of local field potentials, whereas, in the pdCA1-mPFC pathway, decreased cholinergic currents and increased γ power of the amperometric cholinergic signals were accompanied by the induction of LTP and increased γ power of local field potentials. These findings indicated that some correlations may exist between amperometric cholinergic signals and synaptic plasticity in the hippocampus-mPFC pathway. The pattern of alterations in cholinergic signals may help to illustrate the specific properties of synaptic plasticity and γ oscillations in the vCA1-mPFC and the pdCA1-mPFC pathways.

Modafinil rescues repeated morphine-induced synaptic and behavioural impairments via activation of D1R-ERK-CREB pathway in medial prefrontal cortex.

Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse.

Dopaminergic signaling in prefrontal cortex contributes to the antidepressant effect of electroacupuncture: An iTRAQ-based proteomics analysis in a rat model of CUMS.

Electroacupuncture (EA) is used as an adjunctive treatment for depression. This study was conducted to evaluate the efficacy and mechanisms of EA in the depressive rat model induced by chronic unpredictable mild stress (CUMS) in male adult Wistar rats. The underlying mechanisms were explored by using isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis of the proteins in the prefrontal cortex (PFC), and observing the number of the PFC neurons stained with hematoxylin and eosin (H&E) and synaptic morphological changes under transmission electron microscopy (TEM). The results showed that EA plus paroxetine (EA + Par) for 1 week significantly relieved depression-like anhedonia symptoms and improved anxiety-like behavior, accompanied by the improvements in synaptic morphology and a significant increase of PFC neurons. Moreover, EA or paroxetine alone significantly alleviated anhedonia symptoms after 2 weeks of intervention. Additionally, iTRAQ analysis showed that dopaminergic signaling was significantly altered in CUMS rats after 1 week of EA treatment. As the critical enzyme of this pathway, aromatic-l-amino-acid decarboxylase (DDC) was significantly upregulated after the treatment with EA + Par for 1 week. These findings suggested that the dopaminergic signaling pathway in PFC may be involved in the antidepressant mechanisms of EA.