Neural Pathways Research Articles

Two different mirror neuron pathways for social and non-social actions? A meta-analysis of fMRI studies.

Mirror neurons (MNs) represent a class of neurons that are activated when performing or observing the same action. Given their role in social cognition and previous research in patients with psychiatric disorders, we proposed that the human MN system (MNS) might display different pathways for social and non-social actions. To examine this hypothesis, we conducted a comprehensive meta-analysis of 174 published human functional magnetic resonance imaging studies. Our findings confirmed the proposed hypothesis. Our results demonstrated that the non-social MN pathway exhibited a more classical pattern of frontoparietal activation, whereas the social MN pathway was activated less in the parietal lobe but more in the frontal lobe, limbic lobe, and sublobar regions. Additionally, our findings revealed a modulatory role of the effector (i.e. face and hands) within this framework: some areas exhibited effector-independent activation, while others did not. This novel subdivision provides valuable theoretical support for further investigations into the neural mechanisms underlying the MNS and its related disorders.

Enhanced kinase translocation reporters for simultaneous real-time measurement of PKA, ERK, and Ca2.

Kinase translocation reporters (KTRs) are powerful tools for single-cell measurement of time-integrated kinase activity but suffer from restricted dynamic range and limited sensitivity, particularly in neurons. To address these limitations, we developed enhanced KTRs (eKTRs) for protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) that display high sensitivity, rapid response kinetics, broad dynamic range, cell type-specific tuning, and an ability to detect PKA and ERK activity in primary sensory neurons. Moreover, co-expression of optically separable eKTRs for PKA and ERK revealed the kinetics of expected and unexpected crosstalk between PKA, ERK, protein kinase C, and calcium signaling pathways, demonstrating the utility of eKTRs for live cell monitoring of diverse and interacting signaling pathways. These results open the door to improved live-cell and in vivo measurements of key signaling pathways in neurons, while at the same time demonstrating the importance of KTR size and NLS strength to KTR dynamics.

Role of the Kölliker-Fuse/parabrachial complex in the generation of postinspiratory vagal and sympathetic nerve activities and their recruitment by hypoxemic stimuli in the rat.

In the rat, the activity of laryngeal adductor muscles, the crural diaphragm, and sympathetic vasomotor neurons is entrained to the postinspiratory (post-I) phase of the respiratory cycle, a mechanism thought to enhance cardiorespiratory efficiency. The identity of the central neurons responsible for transmitting respiratory activity to these outputs remains unresolved. Here we explore the contribution of the Kölliker-Fuse/parabrachial nuclei (KF-PBN) in the generation of post-I activity in vagal and sympathetic outputs under steady-state conditions and during acute hypoxemia, a condition that potently recruits post-I activity. In artificially ventilated, vagotomized, and urethane-anesthetized rats, bilateral KF-PBN inhibition by microinjection of the GABAA receptor agonist isoguvacine evoked stereotypical responses on respiratory pattern, characterized by a reduction in phrenic nerve burst amplitude, a modest lengthening of inspiratory time, and an increase in breath-to-breath variability, while post-I vagal nerve activity was abolished and post-I sympathetic nerve activity diminished. During acute hypoxemia, KF-PBN inhibition attenuated tachypneic responses and completely abolished post-I vagal activity while preserving respiratory-sympathetic coupling. Furthermore, KF-PBN inhibition disrupted the decline in respiratory frequency that normally follows resumption of oxygenation. These findings suggest that the KF-PBN is a critical hub for the distribution of post-I activities to vagal and sympathetic outputs and is an important contributor to the dynamic adjustments to respiratory patterns that occur in response to acute hypoxia. Although KF-PBN appears essential for post-I vagal activity, it only partially contributes to post-I sympathetic nerve activity, suggesting the contribution of multiple neural pathways to respiratory-sympathetic coupling.NEW & NOTEWORTHY Inhibition of neurons in the pontine Kölliker-Fuse/parabrachial complex (KF-PBN) differentially inhibited postinspiratory (post-I) activity in vagal and sympathetic outputs. The strong recruitment of post-I vagal activity that occurs in response to hypoxemia is selectively abolished by KF-PBN inhibition. This suggests that 1) post-I activity in vagal and sympathetic outputs may be generated by partially independent mechanisms and 2) neurons in the KF-PBN are a preeminent source of drive for the generation of eupneic post-I activity.

How the arts heal: a review of the neural mechanisms behind the therapeutic effects of creative arts on mental and physical health.

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. 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. A systematic review was conducted following the Cochrane Collaboration guideline and PRISMA standards to identify studies examining the neurological mechanisms underlying creative activities. 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. 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.

Cerliponase alfa decreases Aβ load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAβ1–42

Extracellular aggregation of amyloid-beta (Aβ) in the brain plays a central role in the onset and progression of Alzheimer's disease (AD). Moreover, intraneuronal accumulation of Aβ via oligomer internalization might play an important role in the progression of AD. Deficient autophagy, which is a lysosomal degradation process, occurs during the early stages of AD. Tripeptidyl peptidase-1 (TPP1) functions as a lysosomal enzyme, and TPP1 gene mutations are associated with type 2 late infantile neuronal ceroid lipofuscinosis (LINCL). Nevertheless, there is little information about the role of TPP1 in the pathogenesis of AD; therefore, the present study aimed to measure the decrease in intraneuronal Aβ accumulation by a recombinant analog of the TPP1 enzyme, cerliponase alfa (CER) (Brineura®), and to determine whether autophagy pathways play a role in this decrease. In this study, endogenous Aβ accumulation was induced by fAβ1–42 (a toxic fragment of full-length Aβ) exposure, and mouse hippocampal neuronal cells (HT-22) were treated with CER (human recombinant rhTPP1 1 mg mL−1). Soluble Aβ, TPP1, and the proteins involved in autophagy, including mammalian target of rapamycin (p-mTOR/mTOR), p62/sequestosome-1 (p62/SQSTM1), and microtubule-associated protein 1 A/1B-light chain 3 (LC3), were evaluated using western blotting. The sirtuin-1, beclin-1, and Atg5 genes were also studied using RT-PCR. Aβ and TPP1 localizations were observed via immunocytochemistry. CER reduced the Aβ load in HT-22 cells by inducing TPP1 expression and converting pro-TPP1 into the mature form. Furthermore, exposure to CER and fAβ1–42 induced the autophagy-regulatory/related pathways in HT-22 cells and exposure to CER alone increased sirtuin-1 activity. Based on the present findings, we suggest that augmentation of TPP1 with enzyme replacement therapy may be a potential therapeutic option for the treatment of AD.

The analgesic effect and mechanism of the active components screening from Corydalis yanhusuo by P2X3 receptors

Ethnopharmacological relevanceCavidine (CAV) is the main bioactive ingredient of Corydalis ternata f. yanhusuo (Y.H.Chou & Chun C.Hsu) Y.C.Zhu, which is a traditional Chinese herbal containing a variety of uses such as analgesic, anticancer, and anti-inflammatory properties. Aim of the studyThe goal is to screen Corydalis yanhusuo for anti-central sensitization active components and investigate and clarify the pharmacological mechanism and therapeutic efficacy of the active ingredient CAV in the treatment of chronic pain. Material and MethodsFirst, cell membrane immobilized chromatography was used to screen the bioactive ingredients in Corydalis yanhusuo. Spare nerve injury (SNI) model and complete Freund's adjuvant (CFA) mice model were constructed to identify the analgesic effect of CAV. RNA-seq and bioinformatics analyses were used to explore the potential targets of CAV in CFA mice and SNI mice. HE staining was used to observe the infiltration of inflammatory cells in the dorsal root ganglion (DRG) and spinal cord(SC) of CFA mice and SNI mice. WB and qPCR were used to detect the level of inflammatory factors TNF-α, IL-1β, and IL-6 in DRG and SC of mice. SNI and CFA mice were used to study the effect and mechanism of CAV on microglial activation. Results9 potential active ingredients were screened out from Corydalis yanhusuo that can regulate P2X3 receptors. CAV showed good analgesic effects, increased the mechanical pain and thermal pain thresholds of CFA mice and SNI mice, inhibited the expression of DRG and SC inflammatory factors, downregulated IBA-1, and inhibited microglial activation. Further in vivo and in vitro experiments showed that CAV significantly inhibited the expression of P2X3 receptors and the activation of its downstream MAPK pathway in DRG neurons and SC. ConclusionThis study is the first to indicate that CAV exerts an analgesic effect by inhibiting microglia activation via the P2X3 signaling pathway axis, providing the clinical utility of CAV in chronic pain therapy.

Transcriptomic Plasticity of the Circadian Clock in Response to Photoperiod: A Study in Male Melatonin-Competent Mice.

Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel candidate genes for molecular mechanisms of photoperiod plasticity, we performed RNA sequencing on whole SCN dissected from mice raised in long (light:dark [LD] 16:8) and short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in mice subjected to long photoperiod, and in general, the timing of gene expression rhythms was advanced 4-6 h. However, a few genes showed significant delays, including Gem. There were significant changes in the expression of the clock-associated gene Timeless and in SCN genes related to light responses, neuropeptides, gamma aminobutyric acid (GABA), ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genes Prokr2 and Cck, as well as convergent regulation of the expression of 3 SCN light response genes, Dusp4, Rasd1, and Gem. Transcriptional modulation of Dusp4 and Rasd1 and phase regulation of Gem are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation of Prokr2 and Cck may critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity. Data are also available at http://circadianphotoperiodseq.com/, where users can view the expression and rhythmic properties of genes across these photoperiod conditions.

Ethyl pyruvate alleviates NLRP3/Caspase-1/GSDMD-mediated neuronal pyroptosis in neonatal rats with hypoxic-ischemic brain damage.

Pyroptosis is an inflammation-associated programmed cell death, and neuroinflammation is strongly associated with severe neurological deficits in neonatal hypoxic-ischemic encephalopathy (HIE). Ethyl pyruvate (EP), a known anti-inflammatory agent, has shown promise in the treatment of hypoxic-ischemic brain damage (HIBD) rats; nevertheless, the therapeutic mechanism of EP and its capacity to suppress neuronal pyroptosis in HIBD rats remain unclear. In both the neonatal Rice-Vannucci rat model and the OGD/R model, this study examined alterations in the NLRP3/Caspase-1/GSDMD classical pyroptosis pathway in hippocampal neurons during HIE and the potential inhibitory impact of ethyl pyruvate on this pathway. We used HE staining, immunofluorescence double staining, transmission electron microscopy, and western blot to demonstrate that EP effectively inhibited hippocampal neuronal pyroptosis and attenuated the activation of the NLRP3/Caspase-1/GSDMD signaling pathway in HIBD rats, which resulted in a reduction of neuroinflammation and facilitated neural recovery. The results suggest that EP may be a promising neuroprotective agent for treating HIE.

Harmony in the brain: A narrative review on the shared neural substrates of emotion regulation and creativity

The contribution of creativity in overall well-being through regulating emotions has sparkled research interest in employing artistic interventions recently for the improvement of mental health. Although the behavioural links between emotion regulation and creativity have been established, the neural networks reflecting these relations are yet to be investigated. In this mini review, we describe the neural underpinnings of all forms of creativity and of the emotion regulation strategies. Given the complexity of both of these constructs, we separate creativity in its various forms and report the regions and the neural networks involved. Similarly, we distinguish between the differential emotion regulation strategies and describe the relevant brain areas and networks. We then proceed to a critical exploration of common regions of interest and of neural pathways among these important functions. The studies included in this review point towards certain brain regions that are shared among creativity and affective control, such as the prefrontal cortex, the anterior cingulate cortex, the dorsolateral prefrontal cortex, the medial temporal lobe and the inferior parietal lobule. The common neural networks of emotion regulation and creativity mainly focus on the default mode, the executive control and the salience networks. We then suggest a shared neural mechanism that may underlie emotion regulation and creativity, involving both control and affective processing. Drawing on the limitations of the studies reviewed, directions for future research are suggested that could significantly inform the field.

Potentiation of cortico-spinal output via targeted electrical stimulation of the motor thalamus

Cerebral white matter lesions prevent cortico-spinal descending inputs from effectively activating spinal motoneurons, leading to loss of motor control. However, in most cases, the damage to cortico-spinal axons is incomplete offering a potential target for therapies aimed at improving volitional muscle activation. Here we hypothesize that, by engaging direct excitatory connections to cortico-spinal motoneurons, stimulation of the motor thalamus could facilitate activation of surviving cortico-spinal fibers thereby immediately potentiating motor output. To test this hypothesis, we identify optimal thalamic targets and stimulation parameters that enhance upper-limb motor-evoked potentials and grip forces in anesthetized monkeys. This potentiation persists after white matter lesions. We replicate these results in humans during intra-operative testing. We then design a stimulation protocol that immediately improves strength and force control in a patient with a chronic white matter lesion. Our results show that electrical stimulation targeting surviving neural pathways can improve motor control after white matter lesions.

Early Brain Development and Public Health.

Early brain development research is important to public health professionals for understanding early development and strengthening systemic supports for young children's healthy brain growth. This overview describes basic processes of early brain development, including prenatal development and the "fetal programming" of brain and behavior, neural proliferation and the essential influence of experience in the creation of neural networks, the maturational timing of different brain systems and their behavioral consequences, the myelination of neural pathways and its influence on children's action and thinking, and the capacity of the brain to create new neural connections throughout life, which contributes to its continuing adaptability to new experiences. The implications of this research for public health and for strengthening support for early brain development are considered throughout this discussion.

The neural substrates of bruxism: current knowledge and clinical implications.

Bruxism is a complex orofacial behavior that can occur during sleep or wakefulness, characterized by the involuntary grinding or clenching of teeth, involving repetitive activity of the jaw muscles. Its etiology is multifactorial, influenced by genetic, psychological, physiological, and lifestyle factors. While the mild bruxism may not necessitate treatment, severe bruxism can lead to significant consequences, including tooth damage, jaw pain, fatigue, and headaches. The bruxism has been associated with medical conditions, such as stress, anxiety, sleep disorders, and various neurological disorders; however, the exact pathophysiology remains elusive. Although the central nervous system is strongly implicated in the development of bruxism, specific neural substrates have not yet been conclusively established. Furthermore, there is evidence to suggest that individuals with bruxism may exhibit neural plasticity, resulting in the establishment of distinct neural circuitry that control the jaw movements. The application of various neurophysiological techniques in both clinical and pre-clinical studies provides valuable insights into the neural mechanisms underlying bruxism. This review aims to comprehensively examine the current literature on the neural pathways involved in bruxism, with the goal of improving the clinical approach and therapeutics for this condition. A deeper understanding of the neural circuitry controlling bruxism holds the potential to advance future treatment approaches and improve the management of patients with bruxism.

Activated sympathetic nerve post stroke downregulates Toll-like receptor 5 and disrupts the gut mucosal barrier

The gut permeability significantly increases after ischemic stroke, partly due to disrupted mucosal barrier, but the mechanism remains elusive. Here, we found that the mucus disruption starts at 2h post stroke, whereas goblet cell functions remain intact. Meanwhile, the flagellated bacteria Helicobacter thrives and penetrates in the mucus layer. Elimination of the mucosal microbiota or transplantation of Helicobacter in germ-free mice reveals an important role of the mucosal microbiota in mucus disruption. The bacterial invasion is due to downregulated Toll-like receptor 5 (TLR5) and its downstream products flagellin-specific IgA and antimicrobial peptides. Knockdown of intestinal TLR5 increases the abundance of flagellated bacteria and exacerbates mucus injury. Intestinal TLR5 is downregulated by the activation of sympathetic nerve. Serum noradrenaline level is positively associated with flagellin level in patients with stroke and patients' prognosis. These findings reveal a neural pathway in which the sympathetic nerve disrupts the mucosal barrier, providing potential therapeutic targets for stroke injury.

Therapeutic efficacy of Genistein in activation of neuronal AC/cAMP/CREB/PKA and mitochondrial ETC-Complex pathways in experimental model of autism: Evidence from CSF, blood plasma and brain analysis

Autism is a complex neurodevelopmental condition characterized by repetitive behaviors, impaired social communication, and various associated conditions such as depression and anxiety. Its multifactorial etiology includes genetic, environmental, dietary, and gastrointestinal contributions. Pathologically, Autism is linked to mitochondrial dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances involving GABA, glutamate, dopamine, and oxytocin. Propionic acid (PRPA) is a short-chain fatty acid produced by gut bacteria, influencing central nervous system functions. Elevated PRPA levels can exacerbate Autism-related symptoms by disrupting metabolic processes and crossing the blood–brain barrier. Our research investigates the neuroprotective potential of Genistein (GNT), an isoflavone compound with known benefits in neuropsychiatric and neurodegenerative disorders, through modulation of the AC/cAMP/CREB/PKA signaling pathway and mitochondrial ETC complex (I-IV) function. In silico analyses revealed GNT’s high affinity for these targets. Subsequent in vitro and in vivo experiments using a PRPA-induced rat model of autism demonstrated that GNT (40 and 80 mg/kg., orally) significantly improves locomotion, neuromuscular coordination, and cognitive functions in PRPA-treated rodents. Behavioral assessments showed reduced immobility in the forced swim test, enhanced Morris water maze performance, and restored regular locomotor activity. On a molecular level, GNT restored levels of key signaling molecules (AC, cAMP, CREB, PKA) and mitochondrial complexes (I-V), disrupted by PRPA exposure. Additionally, GNT reduced neuroinflammation and apoptosis, normalized neurotransmitter levels, and improved the complete blood count profile. Histopathological analyses confirmed that GNT ameliorated PRPA-induced brain injuries, restored normal brain morphology, reduced demyelination, and promoted neurogenesis. The study supports GNT’s potential in autism treatment by modulating neural pathways, reducing inflammation, and restoring neurotransmitter balance.

Lycopene mitigates atrazine-induced hypothalamic neural stem cell senescence by modulating the integrated stress response pathway

BackgroundAtrazine, a widely used herbicide, has become a major pollutant in agricultural water bodies. Pesticide contamination, including atrazine, is linked to a high incidence of age-related neurodegenerative diseases, suggesting its neurotoxic potential. Lycopene, a potent antioxidant, is renowned for its diverse pharmacological effects, especially its neuroprotective properties. However, the underlying pharmacological mechanisms of lycopene and its impact on potential pathways against atrazine-induced hypothalamic damage have not been elucidated. PurposeOur study aimed to elucidate how lycopene ameliorates hypothalamic injury triggered by atrazine exposure, with a special focus on the pluripotency of neural stem cells (NSCs) and pathways involved in cell senescence. MethodsMice were administered lycopene and/or atrazine via gavage for 21 days. The C17.2 NSC cell line and specific molecular inhibitors were utilized to examine the potential protective effects of lycopene in vitro. Morphological changes and ultrastructural damage in the hypothalamus were observed by hematoxylin-eosin staining and transmission electron microscopy, respectively. The mechanisms of action of lycopene were explored through various methods, including senescence β-galactosidase staining, multiplex immunofluorescence, Western blotting and qRT‒PCR. ResultsOur results indicated that lycopene notably ameliorated atrazine-induced histological and ultrastructural damage, as well as the loss of intact and mature neurons in mouse hypothalami. Additionally, hypothalamic NSCs (HtNSCs) and microglia were recruited to areas of neuronal injury after atrazine exposure; intriguingly, lycopene treatment reduced this recruitment. Through in vivo and in vitro assays, we elucidated the outcomes of atrazine-induced HtNSC recruitment and neuronal loss, along with the neuroprotective mechanisms of lycopene. Mechanistically, lycopene prevents atrazine-induced senescence in HtNSCs and enhances their proliferation and differentiation by inhibiting the integrated stress response (ISR) signaling pathway, thus promoting the renewal of damaged neurons in the hypothalamus. ConclusionsCollectively, the results of the present study reveal, for the first time, that lycopene mitigates atrazine-induced HtNSC senescence by modulating the ISR signaling pathway. These findings offer novel insights into the role of lycopene in preventing and alleviating NSC senescence and suggest its potential development as a new therapy for neurodegenerative diseases.

Unlocking choline's potential in Alzheimer's disease: A narrative review exploring the neuroprotective and neurotrophic role of phosphatidylcholine and assessing its impact on memory and learning

Background and aimsGrowing evidence suggests nutritional intervention may influence the development and progression of Alzheimer‘s Disease (AD). Choline, an essential dietary nutrient plays a critical role in neurological development and brain function, however, its effects on AD in humans is unclear. The research aims to investigate mechanistic links between dietary choline intake and cognitive functioning, focusing on the role of phosphatidylcholine (PC) in neuroplasticity and its interaction with amyloid beta (Aβ) peptides in neuron membranes. Additionally, human evidence on potential benefits of PC interventions on AD, cognition and proposed mechanisms are evaluated. MethodsA reproducible systematic literature search was performed using a three-tranche strategy, consisting of a review, mechanism and intervention search. Using PubMed as the main database, 1254 titles and abstracts were screened, 149 papers were read in full and 65 peer-reviewed papers were accepted, critically appraised and analysed in a narrative review. ResultsPredominantly preclinical evidence demonstrated that PC enhances neuroplasticity, a key biological substrate for cognition, by activating intracellular neuronal signalling pathways or through neuron membrane function.Molecular dynamic simulation methods provided mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of Aβ peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aβ aggregation and neuronal damage, protecting the neuron from Aβ toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease.Altered PC metabolism in AD was evidenced in observational studies; however, whether this relationship represents a cause or consequence of AD remains to be determined. Human intervention studies did not produce conclusive evidence supporting its effectiveness in enhancing cognitive function. This lack of consistency primarily stems from methodological constraints within the conducted studies. Human observational research provided the most compelling evidence linking a higher dietary PC intake to reduced risk of dementia and significant improvements in cognitive testing. ConclusionDespite the lack of randomised control trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role.This review establishes an evidence-based framework through chains of mechanistic evidence, that may provide potential strategies for enhanced neuroprotection and reduced neurodegeneration caused by AD. Considering the escalating global burden of AD and the current shortcomings in effective treatments, this review together with the limitations and gaps identified in the existing research present valuable insights that emphasise the urgency of more comprehensive research into the relationship between PC and AD.

Beyond the Gender Binarism: Neural Correlates of Trans Men in a Functional Connectivity–Resting-State fMRI Pilot Study

Introduction: Several studies have investigated the specific neural correlates of trans people, highlighting mixed results. This study aimed to compare the presence of specific functional connectivity and differences in cognitive profile and hormone levels in trans men diagnosed with gender dysphoria (GD), and a homogeneous group of cisgender men and cisgender women. Methods: A total of 42 participants (19 trans men, 11 cisgender men, and 12 cisgender women) underwent a resting state fMRI and were measured for blood levels of testosterone, estradiol, and progesterone. A neuropsychological battery evaluated executive functions, attention, visual-perceptual ability, verbal fluency, manual preference, and general intelligence. Results: Trans men showed weaker functional connectivity in the precentral gyrus, subcallosal cortex, paracingulate gyrus, temporal pole, and cingulate gyrus than cisgender men (p < 0.01). Trans men performed worse than cisgender men in verbal and visuospatial working memory but similarly to cisgender women (p < 0.05). In trans men, functional connectivity of the precentral gyrus correlated positively with testosterone (r = 0.459, p = 0.064) and negatively with estradiol (r = −0.654, p = 0.004) and progesterone blood levels (r = −0.475, p = 0.054). The cluster involving the subcallosal cortex showed a positive correlation with testosterone (r = 0.718, p = 0.001), and a negative correlation with estradiol (r = −0.602, p = 0.011). The functional connectivity from a cluster involving the paracingulate gyrus showed a positive correlation with testosterone (r = 0.592, p = 0.012). Conclusions: This study highlights the importance of overpassing the binary model by underlining the presence of neural pathways that could represent the peculiarity of the neural profile of people with GD.

The Gut: The Body’s Second Brain

The term “gut health” has become popular in medical literature and the food industry. Gut health includes a variety of aspects of the gastrointestinal (GI) tract, which include proper digestion and absorption of nutrients, absence of GI illness, normal intestinal microbiota, and adequate immune status (Bischoff 2011). The gut microbiome has become a potential therapeutic target for mental illness because gut bacteria has been shown to play a crucial role in gut-brain communication through the influence on neural, immune, and endocrine pathways (Butler et al. 2019). Studies have shown that various environmental factors related to diet, drugs, and anthropometric measures are more significant determinants of gut microbiota than heritable components. This comic provides an overview of the gut microbiome and gut-brain communication. We summarize the current evidence-based solutions that can improve gut-microbiome diversity and provide practical advice for patients seeking probiotic elements for mental health benefits.

Postnatal Development of the Circadian Rhythmicity of Human Pineal Melatonin Synthesis and Secretion (Systematic Review).

Introduction: According to current knowledge, at birth, the pineal gland and melatonin receptors are already present and the suprachiasmatic nucleus is largely functional, and noradrenaline, the key pineal transmitter, can be detected in the early foetal period. It is still unclear why the pineal gland is not able to start its own pulsatile synthesis and secretion of melatonin in the first months of life, and as a result, infants during this time are dependent on an external supply of melatonin. Method: The causes and consequences of this physiological melatonin deficiency in human infancy are examined in a systematic review of the literature, in which 40 of 115 initially selected publications were evaluated in detail. The references of these studies were checked for relevant studies on this topic. References from previous reviews by the author were taken into account. Results: The development and differentiation of the pineal gland, the pinealocytes, as the site of melatonin synthesis, and the development and synaptic coupling of the associated predominantly noradrenergic neural pathways and vessels and the associated Lhx4 homebox only occurs during the first year of life. Discussion: The resulting physiological melatonin deficiency is associated with sleep disorders, infant colic, and increased crying in babies. Intervention studies indicate that this deficiency should be compensated for through breastfeeding, the administration of nonpooled donor milk, or through industrially produced chrononutrition made from nonpooled cow's milk with melatonin-poor day milk and melatonin-rich night milk.

Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke.

Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY-cAMP-PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY-PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.