Increased and sex-differentiated medial prefrontal cortex activation during the MATRICS Consensus Cognitive Battery in schizophrenia: A fNIRS study.

Executive impairment in schizophrenia is common, but the mechanism remains unclear. This is the first study to use simultaneously functional near-infrared spectroscopy (fNIRS) to monitor the hemodynamic response in schizophrenia during the MATRICS Consensus Cognitive Battery (MCCB). Here, we monitored relative changes in oxyhemoglobin concentration in the medial prefrontal cortex (mPFC) during Trail Making Test, Symbol Coding Test and Mazes Test of the MCCB in 63 patients (29 females) with schizophrenia and 32 healthy controls (15 females). Results showed that patients with schizophrenia scored lower than healthy controls on all three tests (P < 0.001), but mPFC activation was significantly higher during the test (P < 0.03). Higher activation of the mPFC may reflect abnormal information processing in schizophrenia. In addition, the results also showed sex differences in hemodynamic activation during the task in patients with schizophrenia, and fNIRS has the potential to be a clinical adjunct to screening for cognitive function in schizophrenia.

[Research Progress in the Role of the Ventral Tegmental Area-Medial Prefrontal Cortex Neural Circuit in the Regulation of Arousal].

There are mutual neural projections between the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC),which form a circuit.Recent studies have shown that this circuit is vital in regulating arousal from sleep and general anesthesia.This paper introduces the anatomical structures of VTA and mPFC and the roles of various neurons and projection pathways in the regulation of arousal,aiming to provide new ideas for further research on the mechanism of arousal from sleep and general anesthesia.

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Clemastine improves emotional and social deficits in adolescent social isolation mice by reversing demyelination.

Adolescence is a critical period for social experience-dependent oligodendrocyte maturation and myelination. Adolescent stress predisposes to cause irreversible changes in brain structure and function with lasting effects on adulthood or beyond. However, the molecular mechanisms linking adolescent social isolation stress with emotional and social competence remain largely unknown. In our study, we found that social isolation during adolescence leads to anxiety-like behaviors, depression-like behaviors, impaired social memory and altered patterns of social ultrasonic vocalizations in mice. In addition, adolescent social isolation stress induces demyelination in the prefrontal cortex and hippocampus of mice, with decreased myelin-related gene expression and disrupted myelin structure. More importantly, clemastine was sufficient to rescue the impairment of emotional and social memory by promoting remyelination. These findings reveal the demyelination mechanism of emotional and social deficits caused by social isolation stress in adolescence, and provides potential therapeutic targets for treating stress-related mental disorders.

Repetitive Transcranial Magnetic Stimulation in Fibromyalgia: Exploring the Necessity of Neuronavigation for Targeting New Brain Regions.

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.

Role of medial prefrontal cortex voltage-dependent potassium 4.3 channels in nicotine-induced enhancement of object recognition memory in male mice.

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.

The neurophysiological mechanisms of medial prefrontal-perirhinal cortex circuit mediating temporal order memory decline in early stage of AD rats.

The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.

Behavioral dishonesty in multiscenes: Associations with trait honesty and neural patterns during (dis)honesty video-watching.

Cross-situational inconsistency is common in the expression of honesty traits; yet, there is insufficient emphasis on behavioral dishonesty across multiple contexts. The current study aimed to investigate behavioral dishonesty in various contexts and reveal the associations between trait honesty, behavioral dishonesty, and neural patterns of observing others behave honestly or dishonestly in videos (abbr.: (dis)honesty video-watching). First, the results revealed limitations in using trait honesty to reflect variations in dishonest behaviors and predict behavioral dishonesty. The finding highlights the importance of considering neural patterns in understanding and predicting dishonest behaviors. Second, by comparing the predictive performance of seven types of data across three neural networks, the results showed that functional connectivity in the hypothesis-driven network during (dis)honesty video-watching provided the highest predictive power in predicting multitask behavioral dishonesty. Last, by applying the feature elimination method, the midline self-referential regions (medial prefrontal cortex, posterior cingulate cortex, and anterior cingulate cortex), anterior insula, and striatum were identified as the most informative brain regions in predicting behavioral dishonesty. In summary, the study offered insights into individual differences in deception and the intricate connections among trait honesty, behavioral dishonesty, and neural patterns during (dis)honesty video-watching.

Border cells without theta rhythmicity in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one's current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.

Medial prefrontal cortex suppresses reward-seeking behavior with risk of punishment by reducing sensitivity to reward.

Reward-seeking behavior is frequently associated with risk of punishment. There are two types of punishment: positive punishment, which is defined as addition of an aversive stimulus, and negative punishment, involves the omission of a rewarding outcome. Although the medial prefrontal cortex (mPFC) is important in avoiding punishment, whether it is important for avoiding both positive and negative punishment and how it contributes to such avoidance are not clear. In this study, we trained male mice to perform decision-making tasks under the risks of positive (air-puff stimulus) and negative (reward omission) punishment, and modeled their behavior with reinforcement learning. Following the training, we pharmacologically inhibited the mPFC. We found that pharmacological inactivation of mPFC enhanced the reward-seeking choice under the risk of positive, but not negative, punishment. In reinforcement learning models, this behavioral change was well-explained as an increase in sensitivity to reward, rather than a decrease in the strength of aversion to punishment. Our results suggest that mPFC suppresses reward-seeking behavior by reducing sensitivity to reward under the risk of positive punishment.

Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice.

BACKGROUND: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRß in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. RESULTS: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. CONCLUSIONS: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.

Noradrenergic Regulation of the Medial Prefrontal Cortex Mediates Stress Coping in Postpartum Female Mice.

The prevalence of depression in women increases during the postpartum period. We previously reported that subchronic exposure to social stress decreased passive coping in postpartum female mice. This study aimed to investigate whether noradrenaline regulation might regulate coping styles in mice. We first determined whether a different type of stress, subchronic physical stress, decreases passive coping in postpartum females. Postpartum female, virgin female, and male mice were exposed to subchronic restraint stress (restraint stress for 4 h for 5 consecutive days). Subchronic restraint stress decreased passive coping in postpartum females but not in virgin females and males in the forced swim and tail suspension tests. We next examined the neuronal mechanism by which subchronic stress decreases passive coping in postpartum female mice. Neuronal activity and expression of noradrenergic receptors in the medial prefrontal cortex (mPFC) were analyzed using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction, respectively. The mPFC was manipulated using chemogenetics, knockdown, or an α2A adrenergic receptor (AR) antagonist. Immunohistochemistry revealed that subchronic restraint stress increased glutamatergic neuron activation in the mPFC via forced swim stress and decreased α2A AR expression in postpartum females. Chemogenetic activation of glutamatergic neurons in the mPFC, knockdown of α2AAR in the mPFC, and the α2A AR receptor antagonist atipamezole treatment decreased passive coping in postpartum females. Subchronic restraint stress decreased passive coping in postpartum females by increasing glutamatergic neuron activity in the mPFC through α2A AR attenuation. The noradrenergic regulation of the mPFC may be a new target for treating postpartum depression.

Modulation of Nicotine-Associated Behaviour in Rats By µ-Opioid Signals from the Medial Prefrontal Cortex to the Nucleus Accumbens Shell.

Nicotine addiction is a concern worldwide. Most mechanistic investigations are on nicotine substance dependence properties based on its pharmacological effects. However, no effective therapeutic treatment has been established. Nicotine addiction is reinforced by environments or habits. We demonstrate the neurobiological basis of the behavioural aspect of nicotine addiction. We utilized the conditioned place preference to establish nicotine-associated behavioural preferences (NABP) in rats. Brain-wide neuroimaging analysis revealed that the medial prefrontal cortex (mPFC) was activated and contributed to NABP. Chemogenetic manipulation of µ-opioid receptor positive (MOR+) neurons in the mPFC or the excitatory outflow to the nucleus accumbens shell (NAcShell) modulated the NABP. Electrophysiological recording confirmed that the MOR+ neurons directly regulate the mPFC-NAcShell circuit via GABAA receptors. Thus, the MOR+ neurons in the mPFC modulate the formation of behavioural aspects of nicotine addiction via direct excitatory innervation to the NAcShell, which may provide new insight for the development of effective therapeutic strategies.

Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats.

Rationale: Adolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest Δ9-tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence. Objective: We determined how 14 daily THC injections (5mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition. Methods: In adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks-strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impacts probabilistic discounting. Results: AdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats. Conclusions: These studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine projections to mPFC, or via alterations of non-VTA dopamine neurons.

To update or to create? The influence of novelty and prior knowledge on memory networks.

Schemas are foundational mental structures shaped by experience. They influence behaviour, guide the encoding of new memories and are shaped by associated information. The adaptability of memory schemas facilitates the integration of new information that aligns with existing knowledge structures. First, we discuss how novel information consistent with an existing schema can be swiftly assimilated when presented. This cognitive updating is facilitated by the interaction between the hippocampus and the prefrontal cortex. Second, when novel information is inconsistent with the schema, it likely engages the hippocampus to encode the information as part of an episodic memory trace. Third, novelty may enhance hippocampal dopamine through either the locus coeruleus or ventral tegmental area pathways, with the pathway involved potentially depending on the type of novelty encountered. We propose a gradient theory of schema and novelty to elucidate the neural processes by which schema updating or novel memory traces are formed. It is likely that experiences vary along a familiarity-novelty continuum, and the degree to which new experiences are increasingly novel will guide whether memory for a new experience either integrates into an existing schema or prompts the creation of a new cognitive framework. This article is part of the theme issue 'Long-term potentiation: 50 years on'.

Serine racemase expression profile in the prefrontal cortex and hippocampal subregions during aging in male and female rats.

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.

Neuroanatomical Substrates of Circuit-Specific Cholinergic Modulation across the Primate Anterior Cingulate Cortex.

Acetylcholine is a robust neuromodulator of the limbic system and a critical regulator of arousal and emotions. The anterior cingulate cortex (ACC) and the amygdala (AMY) are key limbic structures that are both densely innervated by cholinergic afferents and interact with each other for emotional regulation. The ACC is composed of functionally distinct dorsal (A24), rostral (A32), and ventral (A25) areas that differ in their connections with the AMY. The structural substrates of cholinergic modulation of distinct ACC microcircuits and outputs to AMY are thought to depend on the laminar and subcellular localization of cholinergic receptors. The present study examines the distribution of muscarinic acetylcholine receptors, m1 and m2, on distinct excitatory and inhibitory neurons and on AMY-targeting projection neurons within ACC areas, via immunohistochemistry and injections of neural tracers into the basolateral AMY in adult rhesus monkeys of both sexes. We found that laminar densities of m1+ and m2+ expressing excitatory and inhibitory neurons depended on area and cell type. Among the ACC areas, ventral subgenual ACC A25 exhibited greater m2+ localization on presynaptic inhibitory axon terminals and greater density of m1+ and m2+ expressing AMY-targeting (tracer+) pyramidal neurons. These patterns suggest robust cholinergic disinhibition and potentiation of amygdalar outputs from the limbic ventral ACC, which may be linked to the hyperexcitability of this subgenual ACC area in depression. These findings reveal the anatomical substrate of diverse cholinergic modulation of specific ACC microcircuits and amygdalar outputs that mediate cognitive-emotional integration and dysfunctions underlying stress and affective disorders.

Chronic restraint stress induces depression-like behaviors and alterations in the afferent projections of medial prefrontal cortex from multiple brain regions in mice.

INTRODUCTION: The medial prefrontal cortex (mPFC) forms output pathways through projection neurons, inversely receiving adjacent and long-range inputs from other brain regions. However, how afferent neurons of mPFC are affected by chronic stress needs to be clarified. In this study, the effects of chronic restraint stress (CRS) on the distribution density of mPFC dendrites/dendritic spines and the projections from the cortex and subcortical brain regions to the mPFC were investigated. METHODS: In the present study, C57BL/6 J transgenic (Thy1-YFP-H) mice were subjected to CRS to establish an animal model of depression. The infralimbic (IL) of mPFC was selected as the injection site of retrograde AAV using stereotactic technique. The effects of CRS on dendrites/dendritic spines and afferent neurons of the mPFC IL were investigaed by quantitatively assessing the distribution density of green fluorescent (YFP) positive dendrites/dendritic spines and red fluorescent (retrograde AAV recombinant protein) positive neurons, respectively. RESULTS: The results revealed that retrograde tracing virus labeled neurons were widely distributed in ipsilateral and contralateral cingulate cortex (Cg1), second cingulate cortex (Cg2), prelimbic cortex (PrL), infralimbic cortex, medial orbital cortex (MO), and dorsal peduncular cortex (DP). The effects of CRS on the distribution density of mPFC red fluorescence positive neurons exhibited regional differences, ranging from rostral to caudal or from top to bottom. Simultaneously, CRS resulted a decrease in the distribution density of basal, proximal and distal dendrites, as well as an increase in the loss of dendritic spines of the distal dendrites in the IL of mPFC. Furthermore, varying degrees of red retrograde tracing virus fluorescence signals were observed in other cortices, amygdala, hippocampus, septum/basal forebrain, hypothalamus, thalamus, mesencephalon, and brainstem in both ipsilateral and contralateral brain. CRS significantly reduced the distribution density of red fluorescence positive neurons in other cortices, hippocampus, septum/basal forebrain, hypothalamus, and thalamus. Conversely, CRS significantly increased the distribution density of red fluorescence positive neurons in amygdala. CONCLUSION: Our results suggest a possible mechanism that CRS leads to disturbances in synaptic plasticity by affecting multiple inputs to the mPFC, which is characterized by a decrease in the distribution density of dendrites/dendritic spines in the IL of mPFC and a reduction in input neurons of multiple cortices to the IL of mPFC as well as an increase in input neurons of amygdala to the IL of mPFC, ultimately causing depression-like behaviors.

Downregulation of lysine-specific histone demethylase 1A (KDM1A/LSD1) in medial prefrontal cortex facilitates chronic stress-induced pain and emotional dysfunction in female mice.

Chronic primary pain, characterized by overlapping symptoms of chronic pain, anxiety, and depression, is strongly associated with stress and is particularly prevalent among females. Recent research has convincingly linked epigenetic modifications in the medial prefrontal cortex (mPFC) to chronic pain and chronic stress. However, our understanding of the role of histone demethylation in the mPFC in chronic stress-induced pain remains limited. In this study, we investigated the function of lysine-specific histone demethylase 1A (KDM1A/LSD1) in the context of chronic overlapping pain comorbid with anxiety and depression in female mice. We employed a chronic variable stress model to induce pain hypersensitivity in the face and hindpaws, as well as anxiety-like and depression-like behaviors, in female mice. Our findings revealed that chronic stress led to a downregulation of KDM1A mRNA and protein expression in the mPFC. Notably, overexpressing KDM1A in the mPFC alleviated the pain hypersensitivity, anxiety-like behaviors, and depression-like behaviors in female mice, without affecting basal pain responses or inducing emotional distress. Conversely, conditional knockout of KDM1A in the mPFC exacerbated pain sensitivity and emotional distress specifically in females. In summary, this study highlights the crucial role of KDM1A in the mPFC in modulating chronic stress-induced overlapping pain, anxiety, and depression in females. Our findings suggest that KDM1A may serve as a potential therapeutic target for treating chronic stress-related overlap pain and associated negative emotional disorders.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia.

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.