Long-Term Implicit Epigenetic Stress Information in the Enteric Nervous System and its Contribution to Developing and Perpetuating IBS.

Psychiatric and mood disorders may play an important role in the development and persistence of irritable bowel syndrome (IBS). Previously, we hypothesized that stress-induced implicit memories may persist throughout life via epigenetic processes in the enteric nervous system (ENS), independent of the central nervous system (CNS). These epigenetic memories in the ENS may contribute to developing and perpetuating IBS. Here, we further elaborate on our earlier hypothesis. That is, during pregnancy, maternal prenatal stresses perturb the HPA axis and increase circulating cortisol levels, which can affect the maternal gut microbiota. Maternal cortisol can cross the placental barrier and increase cortisol-circulating levels in the fetus. This leads to dysregulation of the HPA axis, affecting the gut microbiota, microbial metabolites, and intestinal permeability in the fetus. Microbial metabolites, such as short-chain fatty acids (which also regulate the development of fetal ENS), can modulate a range of diseases by inducing epigenetic changes. These mentioned processes suggest that stress-related, implicit, long-term epigenetic memories may be programmed into the fetal ENS during pregnancy. Subsequently, this implicit epigenetic stress information from the fetal ENS could be conveyed to the CNS through the bidirectional microbiota-gut-brain axis (MGBA), leading to perturbed functional connectivity among various brain networks and the dysregulation of affective and pain processes.

Monitoring Alzheimer's disease via ultraweak photon emission.

In an innovative experiment, we detected ultraweak photon emission (UPE) from the hippocampus of male rat brains and found significant correlations between Alzheimer's disease (AD), memory decline, oxidative stress, and UPE intensity. These findings may open up novel methods for screening, detecting, diagnosing, and classifying neurodegenerative diseases, particularly AD. The study suggests that UPE from the brain's neural tissue can serve as a valuable indicator. It also proposes the development of a minimally invasive brain-computer interface (BCI) photonic chip for monitoring and diagnosing AD, offering high spatiotemporal resolution of brain activity. The study used a rodent model of sporadic AD, demonstrating that STZ-induced sAD resulted in increased hippocampal UPE, which was associated with oxidative stress. Treatment with donepezil reduced UPE and improved oxidative stress. These findings support the potential utility of UPE as a screening and diagnostic tool for AD and other neurodegenerative diseases.

Effect of methamphetamine on ultraweak photon emission and level of reactive oxygen species in male rat brain.

All living cells, including neurons, generate ultra-weak photon emission (UPE) during biological activity, and in particular, in the brain, it has been shown that UPE is correlated with neuronal activity and associated metabolic processes. Various intracellular factors, as well as external factors, can reduce or increase the intensity of UPE. In this study, we have used Methamphetamine (METH) as one potentially effective external factor, which is a substance that has the property of stimulating the central nervous system. METH can impair mitochondrial function by causing toxicity via various pathways, including an increase in the number of mitochondria, hyperthermia, the increased metabolic activity of the brain, and the production of glutamate and excess calcium. In addition to mitochondrial dysfunction, METH alters cellular homeostasis, leading to cell damage and the production of excess ROS. The aim of this study is to measure and compare the UPE intensity and reactive oxygen species (ROS) levels of the prefrontal, motor, and visual cortex before and after METH administration. Twenty male rats were randomly assigned to two groups, the control, and METH groups. In the control group, 2 h after injection of normal saline and without any intervention, and in the experimental group 2 h after IP injection of 20 mg/kg METH, sections were prepared from three areas: prefrontal, motor, and V1-V2 cortex, which were used to evaluate the emission of UPE using a photomultiplier tube (PMT) device and to evaluate the amount of ROS. The results showed that the amount of ROS and UPE in the experimental group in all three areas significantly increased compared to the control group. So, METH increases UPE and ROS in the prefrontal, motor, and visual regions, and there is a direct relationship between UPE intensity and ROS production. Therefore, UPE may be used as a dynamic reading tool to monitor oxidative metabolism in physiological processes related to ROS and METH research. Also, the results of this experiment may create a new avenue to test the hypothesis that the excess in UPE generation may lead to the phenomenon of phosphene and visual hallucinations.

A Multidisciplinary Hypothesis about Serotonergic Psychedelics. Is it Possible that a Portion of Brain Serotonin Comes From the Gut?

Here we present a complex hypothesis about the psychosomatic mechanism of serotonergic psychedelics. Serotonergic psychedelics affect gut microbes that produce a temporary increase of 5-HT by their host enterochromaffin cells (ECs). This increased 5-HT production-which is taken up and distributed by platelets-may work as a hormone-like regulatory signal that could influence membrane permeability in the host organs and tissues and in the brain. Increased plasma 5-HT levels could enhance permeability of the blood-brain barrier (BBB). Transiently increased permeability of the BBB allows for plasma 5-HT to enter the central nervous system (CNS) and be distributed by the volume transmission. Next, this gut-derived 5-HT could modulate excitatory and inhibitory neurotransmission and produce special network disintegration in the CNS. This transient perturbation of the normal neural hierarchy allows patients access to suppressed fear information and perform an emotional reset, in which the amygdale may have a key role.

COVID-19: The Significance of Platelets, Mitochondria, Vitamin D, Serotonin and the Gut Microbiota.

We provide a brief review of the significance of platelets, mitochondria, vitamin D, serotonin, and the gut microbiome in COVID-19. We hypothesize that hyperactive platelets and mitochondrial dysfunction, as well as low vitamin D level, gut dysbiosis, and increased serum serotonin produced by enterochromaffin cells, may all represent important aspects in the pathophysiology of COVID-19.

Gut dysbiosis and serotonin: intestinal 5-HT as a ubiquitous membrane permeability regulator in host tissues, organs, and the brain.

The microbiota and microbiome and disruption of the gut-brain axis were linked to various metabolic, immunological, physiological, neurodevelopmental, and neuropsychiatric diseases. After a brief review of the relevant literature, we present our hypothesis that intestinal serotonin, produced by intestinal enterochromaffin cells, picked up and stored by circulating platelets, participates and has an important role in the regulation of membrane permeability in the intestine, brain, and other organs. In addition, intestinal serotonin may act as a hormone-like continuous regulatory signal for the whole body, including the brain. This regulatory signal function is mediated by platelets and is primarily dependent on and reflects the intestine's actual health condition. This hypothesis may partially explain why gut dysbiosis could be linked to various human pathological conditions as well as neurodevelopmental and neuropsychiatric disorders.

An Experimental Investigation of Ultraweak Photon Emission from Adult Murine Neural Stem Cells.

Neurons like other living cells may have ultraweak photon emission (UPE) during neuronal activity. This study is aimed to evaluate UPE from neural stem cells (NSC) during their serial passaging and differentiation. We also investigate whether the addition of silver nanoparticles (AgNPs) or enhancement of UPE (by AgNPs or mirror) affect the differentiation of NSC. In our method, neural stem and progenitor cells of subventricular zone (SVZ) are isolated and expanded using the neurosphere assay. The obtained dissociated cells allocated and cultivated into three groups: groups: I: cell (control), II: cell + mirror, and III: cell + AgNPs. After seven days, the primary neurospheres were counted and their mean number was obtained. Serial passages continuous up to sixth passages in the control group. Differentiation capacity of the resulting neurospheres were evaluated in vitro by immunocytochemistry techniques. Measurement of UPE was carried out by photomultiplier tube (PMT) in the following steps: at the end of primary culture, six serial cell passages of the control group, before and after of the differentiation for 5 minutes. The results show that neither mirror nor AgNPs affect on the neurosphere number. The UPE of the NSC in the sixth subculturing passage was significantly higher than in the primary passage (P < 0.05). AgNPs significantly increased the UPE of the NSC compared to the control group before and after the differentiation (P < 0.05). Also, the treatment with AgNPs increased 44% neuronal differentiation of the harvested NSCs. UPE of NSC after the differentiation was significantly lower than that before the differentiation in each groups, which is in appropriate to the cell numbers (P < 0.0001). The mirror did not significantly increase UPE, neither before nor after the differentiation of NSC. As a conclusion, NSC have UPE-properties and the intensity is increased by serial passaging that are significant in the sixth passage. The AgNPs increases the UPE intensity of NSC that pushes more differentiation of NSC to the neurons. The mirror was not effective in enhancement of UPE. As a result, UPE measurement may be suitable for assessing and studying the effects of nanoparticles in living cells and neurons.

Classic psychedelics: the special role of the visual system.

Here, we briefly overview the various aspects of classic serotonergic hallucinogens reported by a number of studies. One of the key hypotheses of our paper is that the visual effects of psychedelics might play a key role in resetting fears. Namely, we especially focus on visual processes because they are among the most prominent features of hallucinogen-induced hallucinations. We hypothesize that our brain has an ancient visual-based (preverbal) intrinsic cognitive process that, during the transient inhibition of top-down convergent and abstract thinking (mediated by the prefrontal cortex) by psychedelics, can neutralize emotional fears of unconscious and conscious life experiences from the past. In these processes, the decreased functional integrity of the self-referencing processes of the default mode network, the modified multisensory integration (linked to bodily self-consciousness and self-awareness), and the modified amygdala activity may also play key roles. Moreover, the emotional reset (elimination of stress-related emotions) by psychedelics may induce psychological changes and overwrite the stress-related neuroepigenetic information of past unconscious and conscious emotional fears.

A possible key role of vision in the development of schizophrenia.

Based on a brief overview of the various aspects of schizophrenia reported by numerous studies, here we hypothesize that schizophrenia may originate (and in part be performed) from visual areas. In other words, it seems that a normal visual system or at least an evanescent visual perception may be an essential prerequisite for the development of schizophrenia as well as of various types of hallucinations. Our study focuses on auditory and visual hallucinations, as they are the most prominent features of schizophrenic hallucinations (and also the most studied types of hallucinations). Here, we evaluate the possible key role of the visual system in the development of schizophrenia.

Mother-newborn separation at birth in hospitals: A possible risk for neurodevelopmental disorders?

In the 20th century, mother-infant separation shortly after birth in hospitals became routine and unique to humans. However, this hospital birth practice is different from the practice in our evolutionary history, where newborn survival depended on close and essentially continuous maternal contact. This time shortly after birth represents a psychophysiologically sensitive or critical period for programming future physiology and behaviour. We hypothesize that early maternal separation as conducted in conventional hospital practice may induce similar epigenetic changes similar to those found in various mental diseases that may also be implicated in neurodevelopmental disorders.

Phosphenes, retinal discrete dark noise, negative afterimages and retinogeniculate projections: A new explanatory framework based on endogenous ocular luminescence.

Cellular luminescence is the emission of photons by living cells due to various biophysical and biochemical processes, mostly associated with cellular metabolism. In this review paper we summarize today's understanding of four luminescence-dependent phenomena in the eye, i.e., phosphenes, retinal discrete dark noise, negative afterimages and the development of retinogeniculate projections in the brain. We review the phenomena above in the context of knowledge gained from experimental and theoretical works. Finally, we discuss this knowledge in terms of its physiological significance.

Possible role of biochemiluminescent photons for lysergic acid diethylamide (LSD)-induced phosphenes and visual hallucinations.

Today, there is an increased interest in research on lysergic acid diethylamide (LSD) because it may offer new opportunities in psychotherapy under controlled settings. The more we know about how a drug works in the brain, the more opportunities there will be to exploit it in medicine. Here, based on our previously published papers and investigations, we suggest that LSD-induced visual hallucinations/phosphenes may be due to the transient enhancement of bioluminescent photons in the early retinotopic visual system in blind as well as healthy people.

The Physical Mechanism for Retinal Discrete Dark Noise: Thermal Activation or Cellular Ultraweak Photon Emission?

For several decades the physical mechanism underlying discrete dark noise of photoreceptors in the eye has remained highly controversial and poorly understood. It is known that the Arrhenius equation, which is based on the Boltzmann distribution for thermal activation, can model only a part (e.g. half of the activation energy) of the retinal dark noise experimentally observed for vertebrate rod and cone pigments. Using the Hinshelwood distribution instead of the Boltzmann distribution in the Arrhenius equation has been proposed as a solution to the problem. Here, we show that the using the Hinshelwood distribution does not solve the problem completely. As the discrete components of noise are indistinguishable in shape and duration from those produced by real photon induced photo-isomerization, the retinal discrete dark noise is most likely due to 'internal photons' inside cells and not due to thermal activation of visual pigments. Indeed, all living cells exhibit spontaneous ultraweak photon emission (UPE), mainly in the optical wavelength range, i.e., 350-700 nm. We show here that the retinal discrete dark noise has a similar rate as UPE and therefore dark noise is most likely due to spontaneous cellular UPE and not due to thermal activation.

REM sleep and its Loss-Associated Epigenetic Regulation with Reference to Noradrenaline in Particular.

Sleep, an essential physiological process, has been divided into rapid eye movement sleep (REMS) and non-REMS (NREMS) in higher animals. REMS is a unique phenomenon that unlike other sleep-waking states is not under voluntary control. Directly or indirectly it influences or gets influenced by most of the physiological processes controlled by the brain. It has been proposed that REMS serves house-keeping function of the brain. Extensive research has shown that during REMS at least noradrenaline (NA)-ergic neurons must cease activity and upon REMS loss, there is increased level of NA in the brain, which then induces many of the REMS loss associated acute and chronic effects. The NA level is controlled by many bio-molecules, which are regulated at the molecular and transcriptional levels. Similarly, NA may also directly or indirectly modulate synthesis and levels of many molecules, which in turn may affect physiological processes. The burgeoning field of behavioral neuro-epigenetics has gained importance in recent years and explains the regulatory mechanisms underlying several behavioral phenomena. As REMS and its loss associated changes in NA modulates several pathophysiological processes, in this review we have attempted to explain on one hand how the epigenetic mechanisms regulating the gene expression of factors like tyrosine hydroxylase (TH), monoamine oxidase (MAO), noradrenaline transporter (NAT) control NA levels and on the other hand, how NA per se may affect other molecules in neural circuitry at epigenetic level resulting in behavioral changes in health and diseases. An understanding of these events will expose the molecular basis of REMS and its loss-associated pathophysiological changes; which are presented as testable hypothesis for confirmation.

Phosphene perception is due to the ultra-weak photon emission produced in various parts of the visual system: glutamate in the focus.

Phosphenes are experienced sensations of light, when there is no light causing them. The physiological processes underlying this phenomenon are still not well understood. Previously, we proposed a novel biopsychophysical approach concerning the cause of phosphenes based on the assumption that cellular endogenous ultra-weak photon emission (UPE) is the biophysical cause leading to the sensation of phosphenes. Briefly summarized, the visual sensation of light (phosphenes) is likely to be due to the inherent perception of UPE of cells in the visual system. If the intensity of spontaneous or induced photon emission of cells in the visual system exceeds a distinct threshold, it is hypothesized that it can become a conscious light sensation. Discussing several new and previous experiments, we point out that the UPE theory of phosphenes should be really considered as a scientifically appropriate and provable mechanism to explain the physiological basis of phosphenes. In the present paper, we also present our idea that some experiments may support that the cortical phosphene lights are due to the glutamate-related excess UPE in the occipital cortex.

Endogenous spontaneous ultraweak photon emission in the formation of eye-specific retinogeniculate projections before birth.

In 1963, it was suggested [Sperry, R.W. (1963). Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc. Natl. Acad. Sci. USA 50, 703-710.] that molecular cues can direct the development of orderly connections between the eye and the brain (the "chemoaffinity hypothesis"). In the same year, the amazing degree of functional accuracy of the visual pathway in the absence of any external light/photon perception prior to birth [Wiesel, T.N and Hubel, D.H. (1963). Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003-1017.] was discovered. These recognitions revealed that the wiring of the visual system relies on innate cues. However, how the eye-specific retinogeniculate pathway can be developed before birth without any visual experience is still an unresolved issue. In the present paper, we suggest that Müller cells (functioning as optical fibers), Müller cell cone (i.e. the inner half of the foveola that is created of an inverted cone-shaped zone of Müller cells), discrete retinal noise of rods, and intrinsically photosensitive retinal ganglion cells might have key functions by means of retinal spontaneous ultraweak photon emission in the development of eye-specific retinogeniculate pathways prior to birth.

fMRI of retina-originated phosphenes experienced by patients with Leber congenital amaurosis.

A phenomenon characterized by the experience of seeing light without any light actually entering the eye is called phosphenes or photopsias. Phosphenes can occur spontaneously or via induction by external stimuli. Previous reports regarding phosphenes have primarily focused on externally induced phosphenes such as by applying alternating or direct current to the cortex. A few of these reports used functional magnetic resonance (fMRI) to study activations induced by cortical phosphenes. However, there are no fMRI reports on spontaneous phosphenes originating from the retina and the resulting pattern of cortical activations. We performed fMRI during a reversing checkerboard paradigm in three LCA patients who underwent unilateral gene therapy and reported experiencing frequent phosphene on a daily basis. We observed bilateral cortical activation covering the entire visual cortices when patients reported experiencing phosphenes. In contrast, in the absence of phosphenes, activation was regulated by patient's visual ability and demonstrated improved cortical activation due to gene therapy. These fMRI results illustrate the potential impact of phosphene perception on visual function and they may explain some of the variability that clinicians find in visual function testing in retinal degeneration. Although we did not perform correlations between visual function and phosphenes, we hope data presented here raises awareness of this phenomenon and its potential effect on visual function and the implications for clinical testing. We recommend a thorough history for phosphene experiences be taken in patients with retinal disease who are candidates for gene or molecular therapy. Lastly, these data illustrate the potential power of fMRI as an outcome measure of gene therapy and the negative impact phosphenes may have on vision testing. fMRI has proven to be a sensitive, non-invasive, and reproducible test paradigm for these purposes and can complement standard visual function testing.