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Background: The creative arts have long been known for their therapeutic potential. These modalities, which include dance, painting, and music, among others, appear to be effective in enhancing emotional expression and alleviating adverse physiological and psychological effects. Engagement in creative arts can be pursued as a personal hobby, in a classroom setting, or through a formal therapeutic intervention with a qualified therapist. Engagement can be active (i.e., creating) or passive (i.e., viewing, listening). Regardless of the modality and manner of engagement, the mechanisms explaining the therapeutic efficacy of creative arts remain poorly understood. Objective: This study aims to systematically review research investigating the neurological mechanisms activated during active or passive engagement in creative arts, with a specific emphasis on the roles of the medial prefrontal cortex (mPFC) and the amygdala in emotional regulation (ER) and creative behaviors. The review seeks to provide preliminary evidence for the possible existence of common neural mechanisms underlying both phenomena, which could inform the development of targeted therapeutic interventions leveraging creative arts for ER. Methods: A systematic review was conducted following the Cochrane Collaboration guideline and PRISMA standards to identify studies examining the neurological mechanisms underlying creative activities. Results: A total of six out of 85 records meet the inclusion criteria, with all being basic research studies. Preliminary findings suggest that active and passive engagement with creative arts consistently activate neural circuits implicated in adaptive emotional regulation, including the mPFC and amygdala. These activations mirror the neural pathways engaged in effective ER strategies, suggesting the possible existence of shared mechanisms between creative expression and emotional processing. Conclusion: The evidence underscores the potential of creative arts as a complementary therapeutic strategy alongside conventional care and other evidence-based mind-body modalities. By elucidating the shared neural mechanisms between creative arts engagement and ER, this review contributes to the theoretical and practical understanding of the role of creative arts in mental health. Future research is recommended to further explore these neural correlations and their implications for therapeutic practice. [ABSTRACT FROM AUTHOR]

Fibromyalgia and osteoarthritis are among the most prevalent rheumatic conditions worldwide. Nonpharmacological interventions have gained scientific endorsements as the preferred initial treatments before resorting to pharmacological modalities. Repetitive transcranial magnetic stimulation (rTMS) is among the most widely researched neuromodulation techniques, though it has not yet been officially recommended for fibromyalgia. This review aims to summarize the current evidence supporting rTMS for treating various fibromyalgia symptoms. Recent findings: High-frequency rTMS directed at the primary motor cortex (M1) has the strongest support in the literature for reducing pain intensity, with new research examining its long-term effectiveness. Nonetheless, some individuals may not respond to M1-targeted rTMS, and symptoms beyond pain can be prominent. Ongoing research aims to improve the efficacy of rTMS by exploring new brain targets, using innovative stimulation parameters, incorporating neuronavigation, and better identifying patients likely to benefit from this treatment. Summary: Noninvasive brain stimulation with rTMS over M1 is a well-tolerated treatment that can improve chronic pain and overall quality of life in fibromyalgia patients. However, the data are highly heterogeneous, with a limited level of evidence, posing a significant challenge to the inclusion of rTMS in official treatment guidelines. Research is ongoing to enhance its effectiveness, with future perspectives exploring its impact by targeting additional areas of the brain such as the medial prefrontal cortex, anterior cingulate cortex, and inferior parietal lobe, as well as selecting the right patients who could benefit from this treatment. [ABSTRACT FROM AUTHOR]

Neurons project long axons that contact other distant neurons. Neurons in the medial prefrontal cortex project into the limbic system to regulate responses to reward or threat. Diminished neural activity in prefrontal cortex is associated with loss of executive function leading to drug use, yet the specific circuitry that mediate these effects is unknown. Different regions within the medial prefrontal cortex may project to differing limbic system nuclei. Here, we exploited the cell biology of intracellular membrane trafficking, fast axonal transport, to map projections from two adjacent medial prefrontal cortical regions. We used Mn(II), a calcium analog, to trace medial prefrontal cortical projections in the living animal by magnetic resonance imaging (MRI). Mn(II), a contrast agent for MRI, enters neurons through voltage-activated calcium channels and relies on kinesin-1 and amyloid-precursor protein to transport out axons to distal destinations. Aqueous MnCl2 together with fluorescent dextran (3--5 nL) was stereotactically injected precisely into two adjacent regions of the medial prefrontal cortex: anterior cingulate area (ACA) or infralimbic/prelimbic (IL/PL) region. Projections were traced, first live by manganese-enhanced MRI (MEMRI) at four time points in 3D, and then after fixation by microscopy. Data-driven unbiased voxel-wise statistical maps of aligned normalized MR images after either ACA or IL/PL injections revealed statistically significant progression of Mn(II) over time into deeper brain regions: dorsal striatum, globus pallidus, amygdala, hypothalamus, substantia nigra, dorsal raphe and locus coeruleus. Quantitative comparisons of these distal accumulations at 24 h revealed dramatic differences between ACA and IL/PL injection groups throughout the limbic system, and most particularly in subdomains of the hypothalamus. ACA projections targeted dorsomedial nucleus of the hypothalamus, posterior part of the periventricular region and mammillary body nuclei as well as periaqueductal gray, while IL/PL projections accumulated in anterior hypothalamic areas and lateral hypothalamic nuclei as well as amygdala. As hypothalamic subsegments relay CNS activity to the body, our results suggest new concepts about mind-body relationships and specific roles of distinct yet adjacent medial prefrontal cortical segments. Our MR imaging strategy, when applied to follow other cell biological processes in the living organism, will undoubtedly lead to an expanded perspective on how minute details of cellular processes influence whole body health and wellbeing. [ABSTRACT FROM AUTHOR]

Neurons project long axons that contact other distant neurons. Neurons in the medial prefrontal cortex project into the limbic system to regulate responses to reward or threat. Diminished neural activity in prefrontal cortex is associated with loss of executive function leading to drug use, yet the specific circuitry that mediate these effects is unknown. Different regions within the medial prefrontal cortex may project to differing limbic system nuclei. Here, we exploited the cell biology of intracellular membrane trafficking, fast axonal transport, to map projections from two adjacent medial prefrontal cortical regions. We used Mn(II), a calcium analog, to trace medial prefrontal cortical projections in the living animal by magnetic resonance imaging (MRI). Mn(II), a contrast agent for MRI, enters neurons through voltage-activated calcium channels and relies on kinesin-1 and amyloid-precursor protein to transport out axons to distal destinations. Aqueous MnCl2 together with fluorescent dextran (3–-5 nL) was stereotactically injected precisely into two adjacent regions of the medial prefrontal cortex: anterior cingulate area (ACA) or infralimbic/prelimbic (IL/PL) region. Projections were traced, first live by manganese-enhanced MRI (MEMRI) at four time points in 3D, and then after fixation by microscopy. Data-driven unbiased voxel-wise statistical maps of aligned normalized MR images after either ACA or IL/PL injections revealed statistically significant progression of Mn(II) over time into deeper brain regions: dorsal striatum, globus pallidus, amygdala, hypothalamus, substantia nigra, dorsal raphe and locus coeruleus. Quantitative comparisons of these distal accumulations at 24 h revealed dramatic differences between ACA and IL/PL injection groups throughout the limbic system, and most particularly in subdomains of the hypothalamus. ACA projections targeted dorsomedial nucleus of the hypothalamus, posterior part of the periventricular region and mammillary body nuclei as well as periaqueductal gray, while IL/PL projections accumulated in anterior hypothalamic areas and lateral hypothalamic nuclei as well as amygdala. As hypothalamic subsegments relay CNS activity to the body, our results suggest new concepts about mind-body relationships and specific roles of distinct yet adjacent medial prefrontal cortical segments. Our MR imaging strategy, when applied to follow other cell biological processes in the living organism, will undoubtedly lead to an expanded perspective on how minute details of cellular processes influence whole body health and wellbeing.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social interactions, impaired communication, and stereotyped behavior. The aim of this research is to investigate the changes in serotonin (5-HT) in the medial prefrontal cortex (PFC) of autism-like offspring induced by maternal lipopolysaccharide (LPS) exposure. Pregnant Sprague-Dawley rats were intraperitoneally injected with LPS to establish an autism-like model in their offspring. Offspring prenatally exposed to LPS showed autism-like behavior. The serotonin level in the mPFC of 2-week-old offspring was noticeably increased after maternal LPS exposure. Differentially expressed genes (DEGs) were enriched in pathways related to tryptophan metabolism and the serotonin system, as shown in RNA-seq findings. Consistently, tryptophan and serotonin metabolisms were altered in 2-week-old LPS-exposed offspring. The mRNA expression levels of 5-HT catabolic enzymes were remarkably reduced or tended to decrease. Moreover, maternal LPS exposure resulted in a higher serotonin 1B receptor (5-HT1BR) expression level in the mPFC but no difference in tryptophan hydroxylase 2 (TPH2) or serotonin reuptake transporter (SERT). The concentrations of 5-HT in serum and colon were increased in LPS-exposed offspring. Meanwhile, the expression level of tryptophan hydroxylase 1 (TPH1) in the colon was increased after maternal LPS treatment, whereas SERT was reduced. Furthermore, Golgi-Cox staining showed that neuronal dendritic length and spine density were significantly reduced in the mPFC of LPS-exposed offspring. The current study reveals that maternal LPS treatment resulted in an exaltation of the 5-HT of mPFC in ASD-like young rats, which may partly be caused by the abnormal elevation of 5-HT metabolism in its colon. [ABSTRACT FROM AUTHOR]

Introduction: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder in women that is associated with an increased risk of infertility. This study aims to evaluate the neurobehavioral and neurochemical changes along with the associated changes in the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) of the dehydroepiandrosterone (DHEA)-induced PCOS model rats. Methods: A total of 12 female juvenile Wistar rats (30 to 50 g) about 22 to 44 days old were divided into 2 groups. The control group received sesame oil while the PCOS group received sesame oil plus DHEA. All treatment was done via daily subcutaneous injection for 21 days. Results: Subcutaneous DHEA-induced PCOS significantly depleted the line crossing and rearing frequency in the open field, along with the percentage of the time in the white box, line crossing, rearing, and peeping frequency in the black and white box, and the percentage of alternation in the Y-maze. PCOS significantly increased the immobility time, freezing period, and the percentage of time in the dark area in the forced swim test, open field test, and black and white box, respectively. The level of luteinizing hormone, follicle-stimulating hormone, malondialdehyde (MDA), reactive oxygen species (ROS), and interleukin-6 (IL-6) increased significantly, while norepinephrine depleted significantly with an obvious decrease in the brain-derived neurotrophic factor level in the PCOS model rats. PCOS rats exhibited cystic follicles in the ovaries and necrotic or degenerative like features in the hippocampal pyramidal cells. Conclusion: DHEA-induced PCOS results in anxiety and depressive behavior with structural alteration in rats, possibly through the elevation of MDA, ROS, and IL-6 levels, which also attributes to impaired emotional and executive functions in the mPFC and ACC.

TET1 (Ten-eleven translocation methylcytosine dioxygenase 1) is the enzyme methylcytosine dioxygenase of DNA demethylation in the nervous system. TET1 controls and mediates gene transcription, memory formation, and extinction. However, little is known about TET1 in Prefrontal Cortex (PFC) functions especially in the medial Prefrontal Cortex (mPFC), which controls cortex flexibility and emotional reactivity in the Central Nervous System (CNS). This study conducted behavioral tests including an open field test, sociability and social novelty preference tests, social dominance, and Prepulse Inhibition (PPI) test to examine brain functions, especially PFC functions after the deletion of TET1. The mPFC from TET1 KO mice and WT adult mice was analyzed using Quantitative Reverse-Transcription Polymerase Chain Reaction (qRT-PCR) to assess neuron growth-related genes, including GSK3ß, PI3K, CRX4, FGFR1, FGFR2, EGFR, DBN1, AKT2, VEGF, VEGFR, and AKT3. Subsequently, primary PFC neuronal cells were administered shTET1 to Knockdown (KD) the TET1 gene and function. We found that the deletion of TET1 in the mouse brains impaired social interaction, novelty, and Prepulse Inhibition (PPI) in the mice. Knockdown of the TET1 gene influenced the growth and complexity of neurons. The increase in NGF and BDNF by Western blotting was found in TET1 deficient mice. The results support and complement the view that TET1 deficiency may be related to schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: Depression is a mental disorder characterized by aberrant exploratory behavior. Environmental factors, such as chronic stress, are commonly used to induce depression-like behavior in rodent models. The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) are crucial sites in subjects with chronic stress-induced depression. The transmission of amplitude information from the mPFC to the BLA was abated during exploratory behavior in depressive rats; however, the nature of the phase interaction between these two sites remains unknown. Methods: We used chronic unpredictablemild stress (CUMS) tomodel depression in rats and acquired local field potentials (LFPs) viamultiple electrodes implanted in themPFC and the BLA while rats (both the control and CUMS groups, respectively) were allowed to explore freely in an open field. The weighted phase lag index (WPLI) within the mPFC and the BLA and phase transfer entropy (PTE) from the mPFC to BLA were computed for two groups of rats (control and CUMS rats) to quantify the phase information transmission. Results: Rats subjected to CUMS showed a decrease in exploratory behavior. The WPLI within the mPFC and the BLA showed strikingly higher phase synchrony at theta frequencies (4-12 Hz) than other frequency bands during exploratory behavior in both the control and CUMS groups. The results of theta PTE from the mPFC to BLA showed that PTE was significantly decreased in the CUMS group compared with the control group. Discussions: These findings demonstrated that attenuated phase information transfer might restrain exploratory behavior in CUMS rats. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA), a well-known environmental endocrine disruptor, has been implicated in anxiety-like behavior. But the neural mechanism remains elusive. Herein, we found that mice exposed to 0.5 mg/kg/day BPA chronically from postnatal days (PND) 21 to PND 80 exhibited depression- and anxiety-like behavior. Further study showed that medial prefrontal cortex (mPFC), was associated with BPA-induced depression- and anxiety-like behavior, as evidenced by decreased c-fos expression in mPFC of BPA-exposed mice. Both the morphology and function of glutamatergic neurons (also called pyramidal neurons) in mPFC of mice were impaired following BPA exposure, characterized by reduced primary branches, weakened calcium signal, and decreased mEPSC frequency. Importantly, optogenetic activation of the pyramidal neurons in mPFC greatly reversed BPA-induced depression- and anxiety-like behavior in mice. Furthermore, we reported that microglial activation in mPFC of mice may also have a role in BPA-induced depression- and anxiety-like behavior. Taken together, the results indicated that mPFC is the brain region that is greatly damaged by BPA exposure and is associated with BPA-induced depression- and anxiety-like behavior. The study thus provides new insights into BPA-induced neurotoxicity and behavioral changes.

Hyperkateifia and stress-induced alcohol cravings drive relapse in individuals with alcohol use disorder (AUD). The brain stress signal norepinephrine (also known as noradrenaline) tightly controls cognitive and affective behavior and was thought to be broadly dysregulated with AUD. The locus coeruleus (LC) is a major source of forebrain norepinephrine, and it was recently discovered that the LC sends distinct projections to addiction-associated regions suggesting that alcohol-induced noradrenergic changes may be more brain region-specific than originally thought. Here we investigated whether ethanol dependence alters adrenergic receptor gene expression in the medial prefrontal cortex (mPFC) and central amgydala (CeA), as these regions mediate the cognitive impairment and negative affective state of ethanol withdrawal. We exposed male C57BL/6J mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and assessed reference memory, anxiety-like behavior and adrenergic receptor transcript levels during 3–6 days of withdrawal. Dependence bidirectionally altered mouse brain α1 and β receptor mRNA levels, potentially leading to reduced mPFC adrenergic signaling and enhanced noradrenergic influence over the CeA. These brain region-specific gene expression changes were accompanied by long-term retention deficits and a shift in search strategy in a modified Barnes maze task, as well as greater spontaneous digging behavior and hyponeophagia. Current clinical studies are evaluating adrenergic compounds as a treatment for AUD-associated hyperkatefia, and our findings can contribute to the refinement of these therapies by increasing understanding of the specific neural systems and symptoms that may be targeted.

Nicotine has been shown to enhance object recognition memory in the novel object recognition (NOR) test by activating excitatory neurons in the medial prefrontal cortex (mPFC). However, the exact neuronal mechanisms underlying the nicotine-induced activation of mPFC neurons and the resultant memory enhancement remain poorly understood. To address this issue, we performed brain-slice electrophysiology and the NOR test in male C57BL/6J mice. Whole-cell patch-clamp recordings from layer V pyramidal neurons in the mPFC revealed that nicotine augments the summation of evoked excitatory postsynaptic potentials (eEPSPs) and that this effect was suppressed by N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2,4-dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806), a voltage-dependent potassium (Kv) 4.3 channel activator. In line with these findings, intra-mPFC infusion of NS5806 suppressed systemically administered nicotine-induced memory enhancement in the NOR test. Additionally, miRNA-mediated knockdown of Kv4.3 channels in mPFC pyramidal neurons enhanced object recognition memory. Furthermore, inhibition of A-type Kv channels by intra-mPFC infusion of 4-aminopyridine was found to enhance object recognition memory, while this effect was abrogated by prior intra-mPFC NS5806 infusion. These results suggest that nicotine augments the summation of eEPSPs via the inhibition of Kv4.3 channels in mPFC layer V pyramidal neurons, resulting in the enhancement of object recognition memory. • Nicotine augments the summation of EPSPs in mPFC layer V pyramidal neurons. • Systemic nicotine injection enhances object recognition memory. • Intra-mPFC 4-AP infusion also enhances object recognition memory. • The effects of nicotine and 4-AP are blocked by mPFC Kv4.3 channel activation. • Knockdown of mPFC Kv4.3 channels enhances object recognition memory. [ABSTRACT FROM AUTHOR]

Associative aversive learning enables animals to predict and avoid threats and thus is critical for survival and adaptive behavior. Anxiety disorders are characterized with deficits in normal aversive learning mechanisms and hence understanding the neural circuits underlying aversive learning and memory has high clinical relevance. Recent studies have revealed the dopamine system as one of the key modulators of aversive learning. In this review, we highlight recent advances that provide insights into how distinct dopaminergic circuits contribute to aversive learning and memory. [ABSTRACT FROM AUTHOR]

Introduction: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder in women that is associated with an increased risk of infertility. This study aims to evaluate the neurobehavioral and neurochemical changes along with the associated changes in the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) of the dehydroepiandrosterone (DHEA)-induced PCOS model rats. Methods: A total of 12 female juvenile Wistar rats (30 to 50 g) about 22 to 44 days old were divided into 2 groups. The control group received sesame oil while the PCOS group received sesame oil plus DHEA. All treatment was done via daily subcutaneous injection for 21 days. Results: Subcutaneous DHEA-induced PCOS significantly depleted the line crossing and rearing frequency in the open field, along with the percentage of the time in the white box, line crossing, rearing, and peeping frequency in the black and white box, and the percentage of alternation in the Y-maze. PCOS significantly increased the immobility time, freezing period, and the percentage of time in the dark area in the forced swim test, open field test, and black and white box, respectively. The level of luteinizing hormone, follicle-stimulating hormone, malondialdehyde (MDA), reactive oxygen species (ROS), and interleukin-6 (IL-6) increased significantly, while norepinephrine depleted significantly with an obvious decrease in the brain-derived neurotrophic factor level in the PCOS model rats. PCOS rats exhibited cystic follicles in the ovaries and necrotic or degenerative like features in the hippocampal pyramidal cells. Conclusion: DHEA-induced PCOS results in anxiety and depressive behavior with structural alteration in rats, possibly through the elevation of MDA, ROS, and IL-6 levels, which also attributes to impaired emotional and executive functions in the mPFC and ACC. [ABSTRACT FROM AUTHOR]

Objective·To dissect the fine anatomical structure of medial prefrontal cortex (mPFC) -basolateral amygdala (BLA) projection neurons based on regional and laminar specificity in the cortex in mice. Methods·The retrograde tracer of adenoassociated viral (AAV) vectors were injected into BLA of C57BL/6 mice. Twenty-one days after the injection, the mice were sacrificed and the brains were harvested. The coronal sections containing mPFC were prepared by using a cryostat microtome. The images were taken by fluorescence microscopy. Then the representative brain slices containing mPFC were selected and the distribution of virus-labeled cell bodies in different subregions of mPFC was analyzed. By using transgenic mouse lines (Tbr2-CreER::LSL-Flp mice and Rbp4-Cre mice) with Flp- or Cre-dependent AAV, layer 2 (L2) and layer 5 (L5) projection neurons in mPFC and their axons in BLA were marked, respectively. Twenty-eight days after the injection, the mice were sacrificed and the brains were also harvested. Coronal sections of the BLA were collected. The brain slices were imaged by fluorescence microscopy after immunofluorescence staining. By measuring the fluorescence intensity of projecting axons in different regions within BLA, the spatial distributions of the axons in BLA of mPFC L2 and L5 projection neurons were compared. Results·Through fluorescence microscopy and quantitative analysis, it was found that the cell bodies of BLA projection neurons were mainly located at L2 and L5 in the dorsal mPFC (dmPFC) which contains anterior cingulate cortex and prelimbic cortex. However, the distribution of BLA projection neurons in the ventral mPFC (vmPFC) including medial orbital cortex and infralimbic cortex did not exhibit the similar distribution. When studying the axonal distribution of dmPFC projection neurons in two layers, it was found that the axons of L2 projection neurons dispersed in the BLA, while the axons of L5 projection neurons were mainly located in the dorsal region of BLA. Conclusion·The cell body distribution of mPFC-BLA projection neurons shows regional specificity and laminar specificity. The axon projections initiated from different layers of dmPFC also exhibit regional specificity in BLA. [ABSTRACT FROM AUTHOR]

It remains unknown whether the Chinese tree shrew, regarded as the closest sister of primate, has evolved a dorsolateral prefrontal cortex (dlPFC) comparable with primates that is characterized by a fourth layer (L4) enriched with granular cells and reciprocal connections with the mediodorsal nucleus (MD). Here, we reported that following AAV-hSyn-EGFP expression in the MD neurons, the fluorescence micro-optical sectioning tomography revealed their projection trajectories and targeted brain areas, such as the hippocampus, the corpus striatum, and the dlPFC. Cre-dependent transsynaptic viral tracing identified the MD projection terminals that targeted the L4 of the dlPFC, in which the presence of granular cells was confirmed via cytoarchitectural studies by using the Nissl, Golgi, and vGlut2 stainings. Additionally, the L5/6 of the dlPFC projected back to the MD. These results suggest that the tree shrew has evolved a primate-like dlPFC which can serve as an alternative for studying cognition-related functions of the dlPFC., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Nie et al.)

IntroductionSpatial working memory is a kind of short-term memory that allows temporarily storing and manipulating spatial information. Evidence suggests that spatial working memory is processed through three distinctive phases: Encoding, maintenance, and retrieval. Though the medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval, how the functional interactions and information transfer between mPFC and MD remains largely unclear.MethodsWe recorded local field potentials (LFPs) from mPFC and MD while mice performed a spatial working memory task in T-maze. The temporal dynamics of functional interactions and bidirectional information flow between mPFC and MD was quantitatively assessed by using directed transfer function.ResultsOur results showed a significantly elevated information flow from mPFC to MD, varied in time and frequency (theta in particular), accompanying successful memory retrieval.DiscussionElevated theta information flow, a feature that was absent on error trials, indicates an important role of the directional information transfer from mPFC to MD for memory retrieval.

Associative aversive learning enables animals to predict and avoid threats and thus is critical for survival and adaptive behavior. Anxiety disorders are characterized with deficits in normal aversive learning mechanisms and hence understanding the neural circuits underlying aversive learning and memory has high clinical relevance. Recent studies have revealed the dopamine system as one of the key modulators of aversive learning. In this review, we highlight recent advances that provide insights into how distinct dopaminergic circuits contribute to aversive learning and memory.

Background: Chronic pain refers to pain that persists for over three months. Chronic pain may restrict activities of daily living, including work, learning, social life, and can lead to anxiety, depression, and sleep disturbance. Imaging data have demonstrated that central sensitization often occurs in the brain of patients with chronic pain, which arises from imbalanced neurotransmission in the central nervous system. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel to serve as an inflammatory detector in the brain. We aim to determine the properties of acupoint catgut embedding (ACE) on cold stress-induced mice fibromyalgia (FM) and surveyed the character of TRPV1 and linked molecules in chronic FM pain. Methods: Intermittent cold stress (ICS) was used to induce mice FM model. Mice were subgrouped into normal mice, ICS-induced FM group, FM mice with ACE, and FM in Trpv1-⁣/- group. ACE is a novel acupuncture technique that provides convenience and continuous nerve stimulation that has been reported effective on pain management. Results: Our behavioral experiments showed similar levels of pain response among all groups before treatment. After ICS, prolonged mechanical and thermal pain was initiated (mechanical threshold: 1.96 ± 0.12 g; thermal latency: 4.86 ± 0.21 s) and were alleviated by ACE treatment and TRPV1 gene deletion. Inflammatory mediators were increased in the plasma of FM mice, while TRPV1 and related kinases were amplified in the hypothalamus and cerebellum. These changes were ameliorated in the ACE-treated and Trpv1-⁣/- groups. Conclusions: These novel findings suggest that chronic FM pain can be modulated by ACE or TRPV1 gene deletion. The analgesic effect of ACE through the TRPV1 pathway may reflect its potential as a therapeutic target for FM treatment.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social interactions, impaired communication, and stereotyped behavior. The aim of this research is to investigate the changes in serotonin (5-HT) in the medial prefrontal cortex (PFC) of autism-like offspring induced by maternal lipopolysaccharide (LPS) exposure. Pregnant Sprague-Dawley rats were intraperitoneally injected with LPS to establish an autism-like model in their offspring. Offspring prenatally exposed to LPS showed autism-like behavior. The serotonin level in the mPFC of 2-week-old offspring was noticeably increased after maternal LPS exposure. Differentially expressed genes (DEGs) were enriched in pathways related to tryptophan metabolism and the serotonin system, as shown in RNA-seq findings. Consistently, tryptophan and serotonin metabolisms were altered in 2-week-old LPS-exposed offspring. The mRNA expression levels of 5-HT catabolic enzymes were remarkably reduced or tended to decrease. Moreover, maternal LPS exposure resulted in a higher serotonin 1B receptor (5-HT1BR) expression level in the mPFC but no difference in tryptophan hydroxylase 2 (TPH2) or serotonin reuptake transporter (SERT). The concentrations of 5-HT in serum and colon were increased in LPS-exposed offspring. Meanwhile, the expression level of tryptophan hydroxylase 1 (TPH1) in the colon was increased after maternal LPS treatment, whereas SERT was reduced. Furthermore, Golgi-Cox staining showed that neuronal dendritic length and spine density were significantly reduced in the mPFC of LPS-exposed offspring. The current study reveals that maternal LPS treatment resulted in an exaltation of the 5-HT of mPFC in ASD-like young rats, which may partly be caused by the abnormal elevation of 5-HT metabolism in its colon.

Exposure to severe, uncontrollable and long-lasting stress is a strong risk factor for the development of numerous mental and somatic disorders. Animal studies document that chronic stress can alter neuronal morphology and functioning in limbic brain structures such as the prefrontal cortex. Mitochondria are intracellular powerhouses generating chemical energy for biochemical reactions of the cell. Recent findings document that chronic stress can lead to changes in mitochondrial function and metabolism. Here, we studied putative mitochondrial damage in response to chronic stress in neurons of the medial prefrontal cortex. We performed a systematic quantitative ultrastructural analysis to examine the consequences of 9-weeks of chronic mild stress on mitochondria number and morphology in the infralimbic cortex of adult male rats. In this preliminary study, we analyzed 4,250 electron microscopic images and 67000 mitochondria were counted and examined in the brains of 4 control and 4 stressed rats. We found significantly reduced number of mitochondria in the infralimbic cortex of the stressed animals, but we could not detect any significant alteration in mitochondrial morphology. These data support the concept that prolonged stress can lead to mitochondrial loss. This in turn may result in impaired energy production. Reduced cellular energy may sensitize the neurons to additional injuries and may eventually trigger the development of psychopathologies. [ABSTRACT FROM AUTHOR]

The medial prefrontal cortex (mPFC) is thought to be closely associated with emotional processes, decision making, and memory. Previous studies have identified the prefrontal cortex as one of the most vulnerable brain regions in Alzheimer's disease (AD). Running exercise has widely been recognized as a simple and effective method of physical activity that enhances brain function and slows the progression of AD. However, the effect of exercise on the mPFC of AD is unclear. To address these issues, we investigated the effects of 4 months of exercise on the numbers of spinophilin‐immunoreactive puncta and neurons in the mPFC of 12‐month‐old APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice using stereological methods. The spatial learning and memory abilities of mice were tested using the Morris water maze. Four months of running exercise delayed declines in spatial learning and memory abilities. The stereological results showed significantly lower numbers of spinophilin‐immunoreactive puncta and neurons in the mPFC of APP/PS1 mice than in the wild‐type control group. The numbers of spinophilin‐immunoreactive puncta and neurons in the mPFC of running APP/PS1 mice were significantly greater than those in the APP/PS1 control mice. In addition, running‐induced improvements in spatial learning and memory were significantly associated with running‐induced increases in spinophilin‐immunoreactive puncta and neurons numbers in the mPFC. Running exercise could delay the loss of spinophilin‐immunoreactive puncta and neurons in the mPFC of APP/PS1 mice. This finding might provide an important structural basis for exercise‐induced improvements in the spatial learning and memory abilities of individuals with AD. [ABSTRACT FROM AUTHOR]

Depression is a common neuropsychiatric illness observed worldwide, and reduced interest in exploration is one of its symptoms. The control of dysregulated medial prefrontal cortex (mPFC) over the basolateral amygdala (BLA) is related to depression. However, the oscillation interaction in the mPFC-BLA circuit has remained elusive. Therefore, this study used phase–amplitude coupling (PAC), which provides complicated forms of information transmission by the phase of low-frequency rhythm, modulating the amplitude of high-frequency rhythm, and has a potential application for the treatment of neurological disease. The chronic unpredictable mild stress (CUMS) was used to prepare the rat models of depression. Moreover, multichannel in vivo recording was applied to obtain the local field potentials (LFPs) of the mPFC, the BLA in rats in control, and CUMS groups, while they explored the open field. The results showed prominent coupling between the phase of theta oscillation (4–12 Hz) in the mPFC and the amplitude of high-gamma oscillation (70–120 Hz) in the BLA. Compared to the control group, this theta–gamma PAC was significantly decreased in the CUMS group, which was accompanied by the diminished exploratory behaviour. The results indicate that the coupling between the phase of theta in the mPFC and the amplitude of gamma in the BLA is involved in exploratory behaviour, and this decreased coupling may inhibit exploratory behaviour of rats exposed to CUMS. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mood disorders involve disturbances in reward and cognitive functions. • TAAR1 mutations correlate with such disturbances in humans and rodents. • TAAR1 agonists alleviate reward and cognitive symptoms in animals and schizophrenics. • TAAR1 agonists seem to enhance limbic ion-homeostasis, neuroplasticity, and metabolism. • TAAR1 agonists may be therapeutic in mood disorders by improving cognitive control. There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1's functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system. [ABSTRACT FROM AUTHOR]

Abstract Background Over-stimulation of dopamine signaling is thought to underlie the pathophysiology of a list of mental disorders, such as psychosis, mania and attention-deficit/hyperactivity disorder. These disorders are frequently associated with cognitive deficits in attention or learning and memory, suggesting that persistent activation of dopamine signaling may change neural plasticity to induce cognitive or emotional malfunction. Methods Dopamine transporter knockdown (DAT-KD) mice were used to mimic a hyper-dopamine state. Novel object recognition (NOR) task was performed to assess the recognition memory. To test the role of dopamine D3 receptor (D3R) on NOR, DAT-KD mice were treated with either a D3R antagonist, FAUC365 or by deletion of D3R. Total or phospho-GSK3 and –ERK1/2 signals in various brain regions were measured by Western blot analyses. To examine the impact of GSK3 signal on NOR, wild-type mice were systemically treated with GSK3 inhibitor SB216763 or, micro-injected with lentiviral shRNA of GSK3β or GSK3α in the medial prefrontal cortex (mPFC). Results We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D3R or exposure to FAUC365. In WT mice, p-GSK3α and p-GSK3β were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3α/β levels. DAT-KD mice treated with FAUC365 or with D3R deletion exhibited restored novelty-induced GSK3 dephosphorylation in the mPFC. Moreover, inhibition of GSK3 in WT mice diminished NOR performance and impaired recognition memory. Lentiviral shRNA knockdown of GSK3β, but not GSK3α, in the mPFC of WT mice also impaired NOR. Conclusion These findings suggest that D3R acts via GSK3β signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D3R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients.

Depression is a common neuropsychiatric illness observed worldwide, and reduced interest in exploration is one of its symptoms. The control of dysregulated medial prefrontal cortex (mPFC) over the basolateral amygdala (BLA) is related to depression. However, the oscillation interaction in the mPFC-BLA circuit has remained elusive. Therefore, this study used phase–amplitude coupling (PAC), which provides complicated forms of information transmission by the phase of low-frequency rhythm, modulating the amplitude of high-frequency rhythm, and has a potential application for the treatment of neurological disease. The chronic unpredictable mild stress (CUMS) was used to prepare the rat models of depression. Moreover, multichannel in vivo recording was applied to obtain the local field potentials (LFPs) of the mPFC, the BLA in rats in control, and CUMS groups, while they explored the open field. The results showed prominent coupling between the phase of theta oscillation (4–12 Hz) in the mPFC and the amplitude of high-gamma oscillation (70–120 Hz) in the BLA. Compared to the control group, this theta–gamma PAC was significantly decreased in the CUMS group, which was accompanied by the diminished exploratory behaviour. The results indicate that the coupling between the phase of theta in the mPFC and the amplitude of gamma in the BLA is involved in exploratory behaviour, and this decreased coupling may inhibit exploratory behaviour of rats exposed to CUMS.

Abstract Adolescent binge drinking represents a major public health challenge and can lead to persistent neurological and mental conditions, but the underlying pathogenic mechanisms remain poorly understood. Using a mouse model of adolescent binge ethanol treatment (ABET), we found that this treatment induced behavioral changes associated with demyelination in different brain regions. After ABET, adolescent mice exhibited anxiogenic behaviors with no change in locomotion on the elevated plus maze, and impaired spatial memory indicated by a significant reduction in spontaneous alternation in the Y maze test. Both effects persisted into adulthood. Anatomical studies further showed that ABET induced a significant reduction of parvalbumin-positive (PV+) GABAergic interneurons and myelin density in the hippocampus and medial prefrontal cortex (mPFC). While these deficits in PV+ interneurons and myelin persisted into early adulthood in the hippocampus, the myelin density recovered in the mPFC. Moreover, whereas ABET mainly damaged myelin of PV+ axons in the hippocampus, it primarily damaged myelin of PV-negative axons in the mPFC. Thus, our findings reveal that an adolescent binge alcohol treatment regimen disrupts spatial working memory, increases anxiety-like behaviors, and exerts unique temporal and spatial patterns of gray matter demyelination in the hippocampus and mPFC.

The prelimbic (PL) region of the medial prefrontal cortex (mPFC) has been implicated in both driving and suppressing motivated behaviors, including cocaine-seeking in rats. These seemingly opposing functions may be mediated by different efferent targets of PL projections, such as the nucleus accumbens (NAc) core and rostromedial tegmental nucleus (RMTg), which have contrasting roles in reward-seeking behaviors. We sought to characterize the anatomical connectivity differences between PL neurons projecting to NAc core and RMTg. We used conventional retrograde tracers to reveal distinct subpopulations of PL neurons projecting to NAc core vs. RMTg in rats, with very little overlap. To examine potential differences in input specificity for these two PL subpopulations, we then used Cre-dependent rabies virus (EnvA-RV-EGFP) as a monosynaptic retrograde tracer and targeted specific PL neurons via injections of retrograde CAV2-Cre in either NAc core or RMTg. We observed a similar catalog of cortical, thalamic, and limbic afferents for both NAc- and RMTg-projecting populations, with the primary source of afferent information arising from neighboring prefrontal neurons in ipsilateral PL and infralimbic cortex (IL). However, when the two subpopulations were directly compared, we found that RMTg-projecting PL neurons received a greater proportion of input from ipsilateral PL and IL, whereas NAc-projecting PL neurons received a greater proportion of input from most other cortical areas, mediodorsal thalamic nucleus, and several other subcortical areas. NAc-projecting PL neurons also received a greater proportion of contralateral cortical input. Our findings reveal that PL subpopulations differ not only in their efferent target but also in the input specificity from afferent structures. These differences in connectivity are likely to be critical to functional differences of PL subpopulations.

The prelimbic (PL) region of the medial prefrontal cortex (mPFC) has been implicated in both driving and suppressing motivated behaviors, including cocaine-seeking in rats. These seemingly opposing functions may be mediated by different efferent targets of PL projections, such as the nucleus accumbens (NAc) core and rostromedial tegmental nucleus (RMTg), which have contrasting roles in reward-seeking behaviors. We sought to characterize the anatomical connectivity differences between PL neurons projecting to NAc core and RMTg. We used conventional retrograde tracers to reveal distinct subpopulations of PL neurons projecting to NAc core vs. RMTg in rats, with very little overlap. To examine potential differences in input specificity for these two PL subpopulations, we then used Cre-dependent rabies virus (EnvA-RV-EGFP) as a monosynaptic retrograde tracer and targeted specific PL neurons via injections of retrograde CAV2-Cre in either NAc core or RMTg. We observed a similar catalog of cortical, thalamic, and limbic afferents for both NAc- and RMTg-projecting populations, with the primary source of afferent information arising from neighboring prefrontal neurons in ipsilateral PL and infralimbic cortex (IL). However, when the two subpopulations were directly compared, we found that RMTg-projecting PL neurons received a greater proportion of input from ipsilateral PL and IL, whereas NAc-projecting PL neurons received a greater proportion of input from most other cortical areas, mediodorsal thalamic nucleus, and several other subcortical areas. NAc-projecting PL neurons also received a greater proportion of contralateral cortical input. Our findings reveal that PL subpopulations differ not only in their efferent target but also in the input specificity from afferent structures. These differences in connectivity are likely to be critical to functional differences of PL subpopulations. [ABSTRACT FROM AUTHOR]

Aging is associated with a decrease in N-methyl-D-aspartate (NMDA) receptor function, which is critical for maintaining synaptic plasticity, learning, and memory. Activation of the NMDA receptor requires binding of the neurotransmitter glutamate and also the presence of co-agonist D-serine at the glycine site. The enzymatic conversion of L-serine to D-serine is facilitated by the enzyme serine racemase (SR). Subsequently, SR plays a pivotal role in regulating NMDA receptor activity, thereby impacting synaptic plasticity and memory processes in the central nervous system. As such, age-related changes in the expression of SR could contribute to decreased NMDA receptor function. However, age-associated changes in SR expression levels in the medial and lateral prefrontal cortex (mPFC, lPFC), and in the dorsal hippocampal subfields, CA1, CA3, and dentate gyrus (DG), have not been thoroughly elucidated. Therefore, the current studies were designed to determine the SR expression profile, including protein levels and mRNA, for these regions in aged and young male and female Fischer-344 rats. Our results demonstrate a significant reduction in SR expression levels in the mPFC and all hippocampal subfields of aged rats compared to young rats. No sex differences were observed in the expression of SR. These findings suggest that the decrease in SR levels may play a role in the age-associated reduction of NMDA receptor function in brain regions crucial for cognitive function and synaptic plasticity.

As the frequency of cannabis use by 14–16-year-olds increases, it becomes increasingly important to understand the effect of cannabis on the developing central nervous system. Using mice as a model system, we treated adolescent (28 day old) C57BL6/J mice of both sexes for 3 weeks with 3 mg/kg tetrahydrocannabinol (THC). Starting a week after the last treatment, several cognitive behaviors were analyzed. Mice treated with THC as adolescents acquired proficiency in a working memory task more slowly than vehicle-treated mice. Working memory recall in both sexes of THC-treated mice was also deficient during increasing cognitive load compared to vehicle-treated mice. Our adolescent THC treatment did not strongly affect social preference, anxiety behaviors, or decision-making behaviors on the elevated T maze task. In summary, under the conditions of this study, adolescent THC treatment of mice markedly affected the establishment, and persistence of working memory, while having little effect on decision-making, social preference or anxiety behaviors. This study provides further support that adolescent THC affects specific behavioral domains.

Sleep disturbances have been recognized as a core symptom of post-traumatic stress disorders (PTSD). However, the neural basis of PTSD-related sleep disturbances remains unclear. It has been challenging to establish the causality link between a specific brain region and traumatic stress-induced sleep abnormalities. Here, we found that single prolonged stress (SPS) could induce acute changes in sleep/wake duration as well as short- and long-term electroencephalogram (EEG) alterations in the isogenic mouse model. Moreover, the medial prefrontal cortex (mPFC) showed persistent high number of c-fos expressing neurons, of which more than 95% are excitatory neurons, during and immediately after SPS. Chemogenetic inhibition of the prelimbic region of mPFC during SPS could specifically reverse the SPS-induced acute suppression of delta power (1–4 Hz EEG) of non-rapid-eye-movement sleep (NREMS) as well as most of long-term EEG abnormalities. These findings suggest a causality link between hyper-activation of mPFC neurons and traumatic stress-induced specific sleep–wake EEG disturbances.

As the frequency of cannabis use by 14–16-year-olds increases, it becomes increasingly important to understand the effect of cannabis on the developing central nervous system. Using mice as a model system, we treated adolescent (28 day old) C57BL6/J mice of both sexes for 3 weeks with 3 mg/kg tetrahydrocannabinol (THC). Starting a week after the last treatment, several cognitive behaviors were analyzed. Mice treated with THC as adolescents acquired proficiency in a working memory task more slowly than vehicle-treated mice. Working memory recall in both sexes of THC-treated mice was also deficient during increasing cognitive load compared to vehicle-treated mice. Our adolescent THC treatment did not strongly affect social preference, anxiety behaviors, or decision-making behaviors on the elevated T maze task. In summary, under the conditions of this study, adolescent THC treatment of mice markedly affected the establishment, and persistence of working memory, while having little effect on decision-making, social preference or anxiety behaviors. This study provides further support that adolescent THC affects specific behavioral domains. [ABSTRACT FROM AUTHOR]

Sleep disturbances have been recognized as a core symptom of post-traumatic stress disorders (PTSD). However, the neural basis of PTSD-related sleep disturbances remains unclear. It has been challenging to establish the causality link between a specific brain region and traumatic stress-induced sleep abnormalities. Here, we found that single prolonged stress (SPS) could induce acute changes in sleep/wake duration as well as short- and long-term electroencephalogram (EEG) alterations in the isogenic mouse model. Moreover, the medial prefrontal cortex (mPFC) showed persistent high number of c-fos expressing neurons, of which more than 95% are excitatory neurons, during and immediately after SPS. Chemogenetic inhibition of the prelimbic region of mPFC during SPS could specifically reverse the SPS-induced acute suppression of delta power (1–4 Hz EEG) of non-rapid-eye-movement sleep (NREMS) as well as most of long-term EEG abnormalities. These findings suggest a causality link between hyper-activation of mPFC neurons and traumatic stress-induced specific sleep–wake EEG disturbances. [ABSTRACT FROM AUTHOR]

Background: Over-stimulation of dopamine signaling is thought to underlie the pathophysiology of a list of mental disorders, such as psychosis, mania and attention-deficit/hyperactivity disorder. These disorders are frequently associated with cognitive deficits in attention or learning and memory, suggesting that persistent activation of dopamine signaling may change neural plasticity to induce cognitive or emotional malfunction. Methods: Dopamine transporter knockdown (DAT-KD) mice were used to mimic a hyper-dopamine state. Novel object recognition (NOR) task was performed to assess the recognition memory. To test the role of dopamine D3 receptor (D3R) on NOR, DAT-KD mice were treated with either a D3R antagonist, FAUC365 or by deletion of D3R. Total or phospho-GSK3 and –ERK1/2 signals in various brain regions were measured by Western blot analyses. To examine the impact of GSK3 signal on NOR, wild-type mice were systemically treated with GSK3 inhibitor SB216763 or, micro-injected with lentiviral shRNA of GSK3β or GSK3α in the medial prefrontal cortex (mPFC). Results: We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D3R or exposure to FAUC365. In WT mice, p-GSK3α and p-GSK3β were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3α/β levels. DAT-KD mice treated with FAUC365 or with D3R deletion exhibited restored novelty-induced GSK3 dephosphorylation in the mPFC. Moreover, inhibition of GSK3 in WT mice diminished NOR performance and impaired recognition memory. Lentiviral shRNA knockdown of GSK3β, but not GSK3α, in the mPFC of WT mice also impaired NOR. Conclusion: These findings suggest that D3R acts via GSK3β signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D3R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients. [ABSTRACT FROM AUTHOR]

Epidemiological studies revealed deficits in cognitive learning and memory in smokers who withdrawal from smoking, but the molecular mechanisms underlying it is unclear. Here, we employed the novel object recognition task (NORT) to evaluate cognitive memory and found impaired memory and motor skills after withdrawal from chronic nicotine. Myelin sheath hastens the conduction of signals along axons and thus plays a critical role in learning and memory. We found no effect of nicotine withdrawal on the myelination in both of the Ventral tegmental area (VTA) and Nucleus accumbens (NAc) regions, but unexpectedly, we observed a demyelination phenomenon in the medial prefrontal cortex (mPFC) after withdrawal from chronic nicotine. Moreover, we found a positive correlation between the impaired memory and demyelination, and pharmaceutical rescue of myelination by clemastine specifically improved the impaired recognition memory but not the decreased motor skills caused by withdrawal from chronic nicotine. We further found nicotine directly acts on oligodendrocytes with OPCs potential to decrease their myelination process. Taken together, these results demonstrate demyelination in the mPFC causes impaired recognition memory and reveal a potential of enhancing myelination as a therapeutic strategy to alleviate cognitive memory deficits caused by smoking withdrawal. • Withdrawal from chronic nicotine causes impaired cognitive memory. • Withdrawal from chronic nicotine leads to demyelination in the mPFC. • Demyelination in the mPFC after nicotine withdrawal causes impaired cognitive memory. • Pro-remyelination rescued impaired cognitive memory induced by nicotine withdrawal. [ABSTRACT FROM AUTHOR]

IQSEC2 is a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor 6 (Arf6), of which protein is exclusively localized to the postsynaptic density of the excitatory synapse. Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism. In this study, we examined the behavior and synapse function in IQSEC2 knockout (KO) mice that we generated using CRIPSR/Cas9-mediated genome editing to solve the relevance between IQSEC2 deficiency and the pathophysiology of neurodevelopmental disorders. IQSEC2 KO mice exhibited autistic behaviors, such as overgrooming and social deficits. We identified that up-regulation of c-Fos expression in the medial prefrontal cortex (mPFC) induced by social stimulation was significantly attenuated in IQSEC2 KO mice. Whole cell electrophysiological recording identified that synaptic transmissions mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and γ-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice.

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Women are more susceptible to developing cocaine dependence than men, but paradoxically, are more responsive to treatment. The potent estrogen, 17β-estradiol (E2), mediates these effects by augmenting cocaine seeking but also promoting extinction of cocaine seeking through E2's memory-enhancing functions. Although we have previously shown that E2 facilitates extinction, the neuroanatomical locus of action and underlying mechanisms are unknown. Here we demonstrate that E2 infused directly into the infralimbic-medial prefrontal cortex (IL-mPFC), a region critical for extinction consolidation, enhances extinction of cocaine seeking in ovariectomized (OVX) female rats. Using patch-clamp electrophysiology, we show that E2 may facilitate extinction by potentiating intrinsic excitability of IL-mPFC neurons. Because the mnemonic effects of E2 are known to be regulated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), we examined whether BDNF/TrkB signaling was necessary for E2-induced enhancement of excitability and extinction. We found that E2-mediated increases in excitability of IL-mPFC neurons were abolished by Trk receptor blockade. Moreover, blockade of TrkB signaling impaired E2-facilitated extinction of cocaine seeking in OVX female rats. Thus, E2 enhances IL-mPFC neuronal excitability in a TrkB-dependent manner to support extinction of cocaine seeking. Our findings suggest that pharmacological enhancement of E2 or BDNF/TrkB signaling during extinction-based therapies would improve therapeutic outcome in cocaine-addicted women. [ABSTRACT FROM AUTHOR]

• Adolescent stress induced cognitive inflexibility and deficiency of microglia and TNFα in the mPFC. • Inhibition of TNFα signaling in the mPFC impaired cognitive flexibility. • Chronic antidepressant treatment ameliorated cognitive and immune alterations of stressed mice. • Acute immune activation with LPS recovered cognitive and immune alterations of stressed mice. • mPFC microglia and TNFα involve in cognitive dysfunction induced by adolescent stress. The crucial roles played by microglia and their release of cytokines in the regulation of brain maturation are increasingly being recognized. Adolescence is a unique period characterized by continued brain maturation, especially in the area of the prefrontal cortex. Our previous studies showed that adolescent social stress induced impairment in extradimensional set-shifting (EDS), a core component of cognitive flexibility mediated by the medial prefrontal cortex (mPFC) in adult mice. The present study further determined the role of microglia and the inflammatory cytokine tumor necrosis factor alpha (TNFα) in cognitive dysfunction. Accompanied by a deficit in EDS in adulthood, previously stressed mice showed significant reductions in the expression of the microglial molecular biomarker Iba1, cell numbers, and the levels of TNFα mRNA and protein in the mPFC. Pharmacological inhibition of TNFα signaling by direct injection of a neutralizer into the mPFC also specifically impaired EDS performance. Moreover, the cognitive and immune alterations in previously stressed adult mice were ameliorated by both acute LPS and chronic antidepressant treatment. Together, our data suggest that microglia and TNFα play important roles in cognitive flexibility and can provide attractive therapeutic targets for the treatment of cognitive deficits in psychiatric disorders. [ABSTRACT FROM AUTHOR]

Highlights • Enrichment synergizes with ceftriaxone to suppress cue-induced reinstatement. • Ceftriaxone suppresses amphetamine-induced reinstatement in standard and enriched housed rats. • Amphetamine self-administration does not change GLT1 expression in the mPFC or NAc. • Amphetamine behavioral sensitization does not change GLT1 or xCT expression in the mPFC or NAc. Abstract Extrasynaptic glutamate within the nucleus accumbens (NAc) is a driver of relapse. Cocaine, ethanol, and methamphetamine reduce the expression of cystine-glutamate antiporter (xCT) and primary glial glutamate transporter 1 (GLT1) leading to increased extrasynaptic glutamate. Ceftriaxone (CTX) restores xCT and GLT1 expression and effectively suppresses cocaine and ethanol reinstatement, however, the effects of CTX on amphetamine (AMP) reinstatement are not determined. Rodents were reared in an enriched condition (EC), isolated (IC), or standard condition (SC) and trained in AMP self-administration (0.1 mg/kg/infusion). EC, IC, and SC rats received injections of SAL or CTX (200 mg/kg) after daily extinction sessions. Then rats were tested in cue- and AMP-induced reinstatement tests. We hypothesized that EC rearing would reduce reinstatement by altering GLT1 or xCT expression in the NAc and medial prefrontal cortex (mPFC). In Experiment 2, pair-housed rats received once-daily AMP (1.0 mg/kg i.p.) or SAL for eight days followed by once-daily CTX (200 mg/kg i.p.) or SAL injections for 10 days. CTX treatment reduced cue-induced drug seeking in EC rats but not IC or SC rats. In an AMP-induced reinstatement test, CTX reduced AMP-induced drug seeking in EC and SC rats, but not IC rats. Western blot analyses revealed that AMP self-administration and non-contingent repeated AMP exposure did not downregulate GLT1 or xCT in the NAc or mPFC. Therefore, the ability for EC housing to reduce amphetamine seeking may work through other mechanisms. [ABSTRACT FROM AUTHOR]

Abstract A patient with motor conversion disorder presented with a functional paresis of the left hand. After exclusion of structural brain damage, she was repeatedly examined with whole-brain functional magnetic resonance imaging, while she performed visually paced finger-tapping tasks. The dorsal premotor cortex showed a bilateral deactivation in the acute-subacute phase. Recovery from unilateral hand paresis was associated with a gradual increase in task-based activation of the dorsal premotor cortex bilaterally. The right medial prefrontal cortex displayed the opposite pattern, showing initial task-based activation that gradually diminished with recovery. The inverse dynamics of premotor and medial prefrontal activity over time were found during unimanual finger-tapping with the affected and non-affected hand as well as during bimanual finger-tapping. These observations suggest that reduced premotor and increased medial prefrontal activity reflect an effector-independent cortical dysfunction in conversion paresis which gradually disappears in parallel with clinical remission of paresis. The results link the medial prefrontal and dorsal premotor areas to the generation of intentional actions. We hypothesise that an excessive 'veto' signal generated in medial prefrontal cortex along with decreased premotor activity might constitute the functional substrate of conversion disorder. This notion warrants further examination in a larger group of affected patients. Highlights • We mapped finger-tapping activity in a patient recovering from conversion paresis. • Activity of dorsal premotor cortex gradually emerged during repeated fMRI sessions. • Conversely, medial prefrontal activity tapered off with recovery from paresis. • The pattern was also expressed during finger-tapping with the non-affected hand. • It may represent a substrate of cortical dysfunction in conversion disorder. [ABSTRACT FROM AUTHOR]

Highlights • Synchronous recording from rat vHPC and mPFC during a spatial working memory task. • Estimation of causal connectivity and information flow using maximum likelihood estimation. • Increased bidirectional information flow in vHPC-mPFC network during spatial working memory. • Information transmission from vHPC to mPFC may be predominant for spatial working memory. Abstract Spatial working memory is a short-term system for the temporary holding and manipulation of spatial information. Evidence shows that the hippocampus (HPC) and prefrontal cortex (PFC) play important roles in spatial working memory. Though the communication between HPC and PFC is recognized as essential for successful execution of spatial working memory tasks, the directional information transmission in the HPC-PFC network is largely unclear. Therefore, in the present study, neuronal activity was recorded from rat ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) while the rats performed a spatial working memory task in Y-maze. Then the causality connectivity among the spikes from recorded neurons was estimated using the maximum likelihood estimation and the information flow in the vHPC-mPFC network was calculated to investigate the functional dynamics of the vHPC-mPFC information transmission. Our results showed the increased bidirectional information flow in the vHPC-mPFC network during the spatial working memory task. Both directions of information flow were observed only on trials in which the animal subsequently made the correct response, indicating that the increase in information flow predicted memory accuracy. Furthermore, the information flow from vHPC to mPFC was remarkably higher and preceded that from mPFC to vHPC. These findings suggest that the direct vHPC-mPFC information transmission may be predominant for spatial working memory in rat. [ABSTRACT FROM AUTHOR]

Previous studies postulated that chronic administration of varenicline, a partial and full agonist at α4β2 and α7 nicotinic acetylcholine receptors (nAChRs), respectively, enhances recognition memory. However, whether its acute administration is effective, on which brain region(s) it acts, and in what signaling it is involved, remain unknown. To address these issues, we conducted a novel object recognition test using male C57BL/6J mice, focusing on the medial prefrontal cortex (mPFC), a brain region associated with nicotine-induced enhancement of recognition memory. Systemic administration of varenicline before the training dose-dependently enhanced recognition memory. Intra-mPFC varenicline infusion also enhanced recognition memory, and this enhancement was blocked by intra-mPFC co-infusion of a selective α7, but not α4β2, nAChR antagonist. Consistent with this, intra-mPFC infusion of a selective α7 nAChR agonist augmented object recognition memory. Furthermore, intra-mPFC co-infusion of U-73122, a phospholipase C (PLC) inhibitor, or 2-aminoethoxydiphenylborane (2-APB), an inositol trisphosphate (IP 3) receptor inhibitor, suppressed the varenicline-induced memory enhancement, suggesting that α7 nAChRs may also act as Gq-coupled metabotropic receptors. Additionally, whole-cell recordings from mPFC layer V pyramidal neurons in vitro revealed that varenicline significantly increased the summation of evoked excitatory postsynaptic potentials, and this effect was suppressed by U-73122 or 2-APB. These findings suggest that varenicline might acutely enhance recognition memory via mPFC α7 nAChR stimulation, followed by mPFC neuronal excitation, which is mediated by the activation of PLC and IP 3 receptor signaling. Our study provides evidence supporting the potential repositioning of varenicline as a treatment for cognitive impairment. • Acute systemic injection of varenicline (Var) enhances object recognition memory. • Intra-mPFC infusion of Var also enhances the recognition memory. • α7 but not α4β2 nAChRs in the mPFC mediate the enhancing effect of Var. • Var enhances the summation of evoked EPSPs in mPFC layer V pyramidal neurons. • PLC and IP 3 receptor activation via α7 nAChR stimulation mediates the Var effects. [ABSTRACT FROM AUTHOR]

Many leading theories suggest that the neural processes underlying the experience of one’s own emotional reactions partially overlap with those underlying bodily perception (i.e., interoception, somatosensation, and proprioception). However, the goal-directed maintenance of one’s own emotions in working memory (EWM) has not yet been compared to WM maintenance of one’s own bodily reactions (BWM). In this study, we contrasted WM maintenance of emotional vs. bodily reactions to affective stimuli in 26 healthy individuals while they underwent functional magnetic resonance imaging. Specifically, we examined the a priori hypothesis that individual differences in trait emotional awareness (tEA) would lead to greater differences between these two WM conditions within medial prefrontal cortex (MPFC). We observed that MPFC activation during EWM (relative to BWM) was positively associated with tEA. Whole-brain analyses otherwise suggested considerable similarity in the neural activation patterns associated with EWM and BWM. In conjunction with previous literature, our findings not only support a central role of body state representation/maintenance in EWM, but also suggest greater engagement of MPFC-mediated conceptualization processes during EWM in those with higher tEA.

Motor sequence learning, planning and execution of goal-directed behaviors, and decision making rely on accurate time estimation and production of durations in the seconds-to-minutes range. The pathways involved in planning and execution of goal-directed behaviors include cortico-striato-thalamo-cortical circuitry modulated by dopaminergic inputs. A critical feature of interval timing is its scalar property, by which the precision of timing is proportional to the timed duration. We examined the role of medial prefrontal cortex (mPFC) in timing by evaluating the effect of its reversible inactivation on timing accuracy, timing precision and scalar timing. Rats were trained to time two durations in a peak-interval (PI) procedure. Reversible mPFC inactivation using GABA agonist muscimol resulted in decreased timing precision, with no effect on timing accuracy and scalar timing. These results are partly at odds with studies suggesting that ramping prefrontal activity is crucial to timing but closely match simulations with the Striatal Beat Frequency (SBF) model proposing that timing is coded by the coincidental activation of striatal neurons by cortical inputs. Computer simulations indicate that in SBF, gradual inactivation of cortical inputs results in a gradual decrease in timing precision with preservation of timing accuracy and scalar timing. Further studies are needed to differentiate between timing models based on coincidence detection and timing models based on ramping mPFC activity, and clarify whether mPFC is specifically involved in timing, or more generally involved in attention, working memory, or response selection/inhibition.

5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the β2-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 μM). Epinephrine (0.3–10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3–3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective β2-adrenergic receptor antagonist ICI-118,553 (0.01–1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, β2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears to extend this suppressant action to a Gs-coupled GPCR. Furthermore, the modulation of 5-HT2A receptor activation-induced glutamate release onto mPFC layer V pyramidal neurons apical dendrites by a range GPCRs in rat brain slices appears to results in behaviorally salient effects of relevance when screening for novel CNS therapeutic drugs.