Brain Res Research Articles

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Central FGF21 production regulates memory but not peripheral metabolism.

SUMMARYFibroblast growth factor 21 (FGF21) is a liver-derived endocrine hormone that functions to regulate energy homeostasis and macronutrient intake. Recently, FGF21 was reported to be produced and secreted from hypothalamic tanycytes, to regulate peripheral lipid metabolism; however, rigorous investigation of FGF21 expression in the brain has yet to be accomplished. Using a mouse model that drives CRE recombinase in FGF21-expressing cells, we demonstrate that FGF21 is not expressed in the hypothalamus, but instead is produced from the retrosplenial cortex (RSC), an essential brain region for spatial learning and memory. Furthermore, we find that central FGF21 produced in the RSC enhances spatial memory but does not regulate energy homeostasis or sugar intake. Finally, our data demonstrate that administration of FGF21 prolongs the duration of long-term potentiation in the hippocampus and enhances activation of hippocampal neurons. Thus, endogenous and pharmacological FGF21 appear to function in the hippocampus to enhance spatial memory.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Visual recognition in rhesus monkeys requires area TE but not TEO.

The primate visual system is often described as a hierarchical feature-conjunction pathway, whereby each level represents an increasingly complex combination of image elements, culminating in the representation of whole coherent images in anterior inferior temporal cortex. Although many models of the ventral visual stream emphasize serial feedforward processing ((Poggio T, Mutch J, Leibo J, Rosasco L, Tacchetti A. The computationalmagic of the ventral stream: sketch of a theory (and why some deep architectures work). TechRep MIT-CSAIL-TR-2012-035. MIT CSAIL, Cambridge, MA. 2012); (Yamins DLK, DiCarlo JJ. Eight open questions in the computational modeling of higher sensory cortex. Curr Opin Neurobiol. 2016:37:114-120.)), anatomical studies show connections that bypass intermediate areas and that feedback to preceding areas ((Distler C, Boussaoud D, Desimone R, Ungerleider LG. Cortical connections of inferior temporal area TEO in macaque monkeys. J Comp Neurol. 1993:334(1):125-150.); (Kravitz DJ, Saleem KS, Baker CI, Mishkin M. A new neural framework for visuospatial processing. Nat Rev Neurosci. 2011:12(4):217-230.)). Prior studies on visual discrimination and object transforms also provide evidence against a strictly feed-forward serial transfer of information between adjacent areas ((Kikuchi R, Iwai E. The locus of the posterior subdivision of the inferotemporal visual learning area in the monkey. Brain Res. 1980:198(2):347-360.); (Weiskrantz L, Saunders RC. Impairments of visual object transforms in monkeys. Brain. 1984:107(4):1033-1072.); (Kar K, DiCarlo JJ. Fast recurrent processing via ventrolateral prefrontal cortex is needed by the primate ventral stream for robust Core visual object recognition. Neuron. 2021:109(1):164-176.e5.)). Thus, we sought to investigate whether behaviorally relevant propagation of visual information is as strictly sequential as sometimes supposed. We compared the accuracy of visual recognition after selective removal of specific subregions of inferior temporal cortex-area TEO, area TE, or both areas combined. Removal of TEO alone had no detectable effect on recognition memory, whereas removal of TE alone produced a large and significant impairment. Combined removal of both areas created no additional deficit relative to removal of TE alone. Thus, area TE is critical for rapid visual object recognition, and detailed image-level visual information can reach area TE via a route other than through TEO.

Glutamate released by Cajal-Retzius cells impacts specific hippocampal circuits and behaviors.

SUMMARYThe impact of Cajal-Retzius cells on the regulation of hippocampal circuits and related behaviors is unresolved. Here, we directly address this issue by impairing the glutamatergic output of Cajal-Retzius cells with the conditional ablation of vGluT2, which is their main vesicular glutamate transporter. Although two distinct conditional knockout lines do not reveal major alterations in hippocampal-layer organization and dendritic length of principal neurons or GABAergic cells, we find parallel deficits in specific hippocampal-dependent behaviors and in their putative underlying microcircuits. First, conditional knockout animals show increased innate anxiety and decreased feedforward GABAergic inhibition on dentate gyrus granule cells. Second, we observe impaired spatial memory processing, which is associated with decreased spine density and reduced AMPA/NMDA ratio of postsynaptic responses at the perforant- and entorhino-hippocampal pathways. We conclude that glutamate synaptically released by Cajal-Retzius cells is critical for the regulation of hippocampal microcircuits and specific types of behaviors.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

SUMMARYAlthough midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

Choice-selective sequences dominate in cortical relative to thalamic inputs to NAc to support reinforcement learning.

SUMMARYHow are actions linked with subsequent outcomes to guide choices? The nucleus accumbens, which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex and midline regions of the thalamus. However, little is known about whether and how representations differ across these input pathways. By comparing these inputs during a reinforcement learning task in mice, we discovered that prelimbic cortical inputs preferentially represent actions and choices, whereas midline thalamic inputs preferentially represent cues. Choice-selective activity in the prelimbic cortical inputs is organized in sequences that persist beyond the outcome. Through computational modeling, we demonstrate that these sequences can support the neural implementation of reinforcement-learning algorithms, in both a circuit model based on synaptic plasticity and one based on neural dynamics. Finally, we test and confirm a prediction of our circuit models by direct manipulation of nucleus accumbens input neurons.

Edinger-Westphal peptidergic neurons enable maternal preparatory nesting.

SummaryOptimizing reproductive fitness in mammalians requires behavioral adaptations during pregnancy. Maternal preparatory nesting is an essential behavior for the survival of the upcoming litter. Brain-wide immediate early gene mapping in mice evoked by nesting sequences revealed that phases of nest construction strongly activate peptidergic neurons of the Edinger-Westphal nucleus in pregnant mice. Genetic ablation, bidirectional neuromodulation, and in vitro and in vivo activity recordings demonstrated that these neurons are essential to modulate arousal before sleep to promote nesting specifically. We show that these neurons enable the behavioral effects of progesterone on preparatory nesting by modulating a broad network of downstream targets. Our study deciphers the role of midbrain CART+ neurons in behavioral adaptations during pregnancy vital for reproductive fitness.

Regional synapse gain and loss accompany memory formation in larval zebrafish

Defining the structural and functional changes in the nervous system underlying learning and memory represents a major challenge for modern neuroscience. Although changes in neuronal activity following memory formation have been studied [B. F. Grewe etal., Nature 543, 670-675 (2017); M. T. Rogan, U. V. Stäubli, J. E. LeDoux, Nature 390, 604-607 (1997)], the underlying structural changes at the synapse level remain poorly understood. Here, we capture synaptic changes in the midlarval zebrafish brain that occur during associative memory formation by imaging excitatory synapses labeled with recombinant probes using selective plane illumination microscopy. Imaging the same subjects before and after classical conditioning at single-synapse resolution provides an unbiased mapping of synaptic changes accompanying memory formation. In control animals and animals that failed to learn the task, there were no significant changes in the spatial patterns of synapses in the pallium, which contains the equivalent of the mammalian amygdala and is essential for associative learning in teleost fish [M. Portavella, J. P. Vargas, B. Torres, C. Salas, Brain Res. Bull 57, 397-399 (2002)]. In zebrafish that formed memories, we saw a dramatic increase in the number of synapses in the ventrolateral pallium, which contains neurons active during memory formation and retrieval. Concurrently, synapse loss predominated in the dorsomedial pallium. Surprisingly, we did not observe significant changes in the intensity of synaptic labeling, a proxy for synaptic strength, with memory formation in any region of the pallium. Our results suggest that memory formation due to classical conditioning is associated with reciprocal changes in synapse numbers in the pallium.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

The residence of synaptically released dopamine on D2 autoreceptors.

SUMMARYNeuromodulation mediated by synaptically released endogenous transmitters acting in G-protein-coupled receptors (GPCRs) is slow primarily because of multistep downstream signaling. What is less well understood is the spatial and temporal kinetics of transmitter and receptor interaction. The present work uses the combination of the dopamine sensor, dLight, to detect the spatial release and diffusion of dopamine and a caged form of a D2-dopamine receptor antagonist, CyHQ-sulpiride, to rapidly block the D2 autoreceptors. Photoactivation of the CyHQ-sulpiride blocks receptors in milliseconds such that the time course of dopamine/receptor interaction is mapped onto the downstream signaling. The results show that highly localized release, but not dopamine diffusion, defines the time course of the functional interaction between dopamine and D2 autoreceptors, which determines downstream inhibition.

Neurobehavioral assessment of Danio rerio intoxicated by sodium arsenate and the use of Arsenicum Album to reverse the condition of anxiety

Background: Various studies have indicated that the zebrafish serves as a useful and easily executable experimental model. Environmental pollution caused by heavy metal waste is very relevant due to the widespread use of heavy metals in industrial and agricultural practices, and the fact that many effluents are released into the environment without any treatment. Sodium arsenate changes behavioral parameters and brain ectonucleotidase activities in zebrafish1. 
 Aims: The objective of this paper is to assess behavioral changes in zebrafish (Danio rerio) induced by sodium arsenate, through an analysis of locomotor activity and anxiety-related parameters, and determine whether ultra-diluted substances are able to mitigate neurobehavioral effects. 
 Materials and methods: Zebrafish were held in aquariums with controlled temperature and pH, until the time of the toxicological experiment. The animals were exposed for 96 hours to the heavy metal sodium arsenate and divided into four groups with eight fish in each: Arsenicum Album 6 cH, Arsenicum Album 30 cH and inert aqueous solution (positive control) groups received drugs made in distilled water, according to the Brazilian Homeopathic Pharmacopoeia; the experiment was blinded. The fourth white control group (negative control) did not receive the sodium arsenate or drugs. All the homeopathic drugs that treated the heavy metal toxicity were initiated 5 days before the end of the experiment (therefore, the animals were already taking the medication one day before exposure). Afterwards, the animals underwent behavioral tests (locomotion and anxiety) to assess neurotoxicity. All the animals went through various steps: assessment of neurotoxicity signs where the following was observed: time and frequency on the surface and erratic movements; general activity test in an Open Field, where it was observed: time in seconds of locomotion and immobility; and light/dark test (anxiety-like behavior), where it was observed: the number of times the animals crossed from the light to the dark compartment, how long they spent on each side, number of attempts to enter each compartment and immobility time on the light side. The data obtained was analyzed statistically by ANOVA, followed by Bartlett's Test and the Tukey Test, with p?0.052. CEUA Protocol No. 07/2016.
 Results and Discussion: The heavy metal sodium arsenate produced an anxiogenic effect in the animals that were subjected to it without medication (aqueous solution, positive control group). This effect was observed in the light/dark test through increased time (sec) of the animals on the dark side (245.361.82) in relation to the control group (101.162.3) and a consequent decrease in time of the animals on the light side (54.336.3) compared to the control group (198.962.3). There was also a decrease in locomotion (quadrants) on the light side (96.263.7) in relation to the control group (201.889.2). In the Open Field, there was a decrease in the total of quadrants crossed (346.241.33) compared to the control group (520.5131.6), as well as an increase in the erratic movements (3.50.7) in relation to the control group (1.70.9), proving the toxic effect of heavy metals in the animals. The group that was medicated with Arsenicum Album 30 cH showed a decrease in the erratic movements (0.661.0) in relation to the intoxicated animals, resulting values close to the control group. The group that took Arsenicum Album 6 cH reversed all the positive control parameters (aqueous solution) in a statistically significant way, maintaining the values of the dark side time, the light side time and the clear side locomotion (161.663.7; 138.496.3; 121.049.8, respectively) close to the values of the control animals. Arsenicum 6 cH also increased the total number of quadrants in the Open Field (525.0142.3) and reduced the erratic movements (2.51.1), demonstrating anxiolytic ability. Clear side time for the animals treated with Arsenicum Album 6 cH, in relation to the control group, was more similar, and the same occurred in regard to the dark side time. When fish are treated with anxiolytics, they tend to remain more time on the light side, which indicates decreased anxiety (Serra et al. 1999). In relation to locomotion on the light side, there was a greater similarity between the control group and the fish treated with Arsenicum Album 6 cH, as well as in the displacement behavior in the Open Field with respect to the total number of quadrants of the fish displacement, which coincides with data from the literature that reports increased locomotor activity, as anxiety decreases. Locomotion or swimming activity is also used as an anxiety index and suppression of this activity is indicative of anxiety3. In relation to erratic movements, it was observed that this behavior decreased in animals treated with a concentration of 6 cH as well as with those treated with a concentration of 30 cH, compared to the positive control. 
 Conclusion: The animals intoxicated by the heavy metal sodium arsenate showed increased anxiety, which was reversed by Arsenicum Album that in a concentration of 6cH proved to be more effective as a possible anxiolytic. Other studies are already being conducted by our group. 
 Keywords: Homeopathy, High Dilution, Zebrafish, Intoxication.
 References
 1. Baldissarelli, L.A.; Capiotti, K.M.; Bogo, M.R.; Ghisleni, G; Bonan, C.D. Arsenic alters behavioral parameters and brain ectonucleotidases activities in zebrafish (Danio rerio). Comparative Biochemistry and Physiology, Part C 155: 566-572, 2012.
 2. Zar, J. H. Biostatistical analysis. 5 ed. Upper Saddle River: Prentice Hall, 2010. 944 p.
 3. Blaser R.E., Chadwick L., Mcginnis G.C. Behavioral measures of anxiety in zebrafish (Danio rerio). Behav Brain Res. 2009.

Genotoxic Effects of Radiofrequency-Electromagnetic Fields

Genotoxic Effects of Radiofrequency-Electromagnetic Fields.
 IntroductionRadiation is energy emission in the form of electromagnetic waves emitted from the solar system and natural resources on earth. The currents produced by the elementary particles formed by the electric current create the magnetic field. Earth's surface is under the influence of the geomagnetic field emanating from the sun. However, the outer liquid also has a magnetic field created as a result of heat transfer in the core. Therefore, all living organisms on earth live under the influence of electromagnetic fields (EMF). Today, besides these natural energy resources, rapidly developing technological developments provide most of the convenience in our lives and expose people to artificial electromagnetic fields. However, man's magnetic field is also under the influence of other natural and artificial magnetic fields around him. In particular, by ionizing radiation, which carries enough energy to break down the genetic material, die cells as a result of DNA damaging, and other diseases, especially cancer, can develop as a result of tissue damage.
 Electromagnetic Fields in Our LivesToday, apart from natural geomagnetic fields, radiation is emitted from many technological devices. The spectrum of these fields includes many different types of radiation, from subatomic radiation such as gamma and X-rays to radio waves, depending on their wavelengths. Though, as a result of the rapid increase of technological growth, the duration and amount of exposure to EMF is also steadily increasing. On the other hand, wireless gadgets such as computers, smartphones and medical radiological devices have become a necessity for humans. Almost everyone is exposed to radiofrequency electromagnetic fields (RF-EMF) from cell phone and base station antennas or other sources. Thus, the damage caused by the radiation to the environment affects living organisms even many kilometres away unlimitedly. All organisms in the world live under the influence of these negative environmental changes and a large part of the world population is exposed to radiofrequency (RF) radiation for a long time in their daily lives. So, though we are not aware of it, our organs and tissues are constantly exposed to radiation. Therefore, radiation adversely affects human, animal and plant health and disrupts the environment and ecological balance. An example of negative effects, radiation can cause genetic changes in the body (Figure 1).
 Radiation is divided into ionizing and non-ionizing. Ionizing radiations cause electron loss or gain in an atom or group of atoms in the medium they pass through. Thus, positively or negatively charged ions are formed. High energy X, gamma, ultraviolet and some visible rays in the ionized region of the electromagnetic spectrum can be counted. Since gamma rays, X rays and ultraviolet rays can ionize the molecules in living things more, they can easily disrupt the chemical structure of tissues, cells and DNA molecules in living organisms. Therefore, they can be very dangerous and deadly to living things. The energy of the waves in the non-ionizing region of the electromagnetic spectrum is low and the energy levels are insufficient for the ionization of molecules. Electricity, radio and TV waves, microwaves, and infrared rays are not ionizing because they have low energy. Waves emitted from electronic devices (cell phones, computers, microwave ovens, etc.) are absorbed by the human and animal body. The amount of energy absorbed by the unit biological tissue mass per unit time is called the specific absorption rate (SAR), and its unit is W/kg.
 Risks of Electromagnetic Fields on Living ThingsDepending on the structure of the tissues and organs, the radiation must reach a certain threshold dose for the effect to occur. Radiation levels below the threshold dose are not effective. Depending on the structure of the tissues and organs, the radiation must reach a certain threshold dose. The effects of small doses of waves are negligible. However, the clinical effects of waves above a certain threshold may increase. High dose waves can cause cell death in tissues. Damages in the cell may increase the risk of cancer and hereditary damage after a while, and somatic effects in people exposed to radiation may cause cancer to appear years later. There is much research on the effects of RF fields. In vitro and in vivo studies on rats, plants and different tissues of humans; suggests that the RF fields are not genotoxic and the fact that harmful effect is due to the heat effect. The contradictory results on this issue have brought about discussions. Therefore, there are still concerns about the potential adverse effects of RFR on human health. A good understanding of the biological effects of RF radiation will protect against potential damages. Due to these uncertainties, with the electromagnetic field project of the World Health Organization, experimental and modelling studies on the biological effects of RF radiation have been accelerated. In 2011, the International Agency for Research on Cancer decided that RF-EMR waves could be potentially carcinogenic to humans (2). Considering that almost everyone, including young children, uses mobile phones in addition to other technological devices, the danger of electromagnetic waves has increased social interest.
 Genotoxic Effects of EMFIn addition to stimulating apoptosis and changes in ion channels, RF-EMF waves also have a potential effect on genetic material. The radiation absorbed by organisms causes the ionization of target molecules. In particular, biological damage may occur as a result of stimulation/ionization of atoms and disruption of molecular structures while ionizing radiation passes through tissue. As a result of ionization in the cell, electron increases and free electrons cause damage, especially in macromolecules and DNA. Free electrons move directly or indirectly. Free electrons directly affect the phosphodiester or H-bonds of DNA. As a result, the phosphodiester bonds of DNA in the cell are broken, single or double-stranded breakages and chemical toxins increase.  DNA double-strand breaks are the most relevant biologic damage induced by ionizing radiation (3,4).
 There are no cells that are resistant to radiation. The nucleus of the cell and especially the chromosomes in dividing cells are very sensitive to radiation. One of the most important effects of radiation on the cell is to suppress cell growth. In particular, growth is impaired in cells exposed to radiation during cell division (mitosis). Consequently, cells with a high division rate are more sensitive to radiation. DNA damage in somatic cells can lead to cancer development or cell death. Cell death can occur as a result of breaking down DNA because ionizing radiation has enough energy to break down the cell's genetic material. Thus, tissues are damaged and cancer development may be triggered. DNA damage caused by radiation in cells is repaired by metabolic repair processes. If the breaks in DNA as a result of DNA damage caused by radiation in cells are not too large, they can be repaired by metabolic repair processes. Still, errors may occur during this repair. Chromosomes containing different genetic codes and information may also occur. In the cell, the released electrons interact with water molecules, indirectly causing the water to be reactively divided into two parts. Free radicals carry an electron that is not electrically shared in their orbits. Free radicals can cause genetic damage in DNA such as nucleotide changes, double and single-strand breaks. Radiation can cause chromosomes to break, stick together and rearrange. All these changes can lead to mutations or even further, the death of the cell. However, in addition to ionizing radiation, extracellular genotoxic chemicals and intracellular oxidative metabolic residues can also create stress in cells during DNA replication and cell division. Damage may occur during DNA replication under such environmental stress conditions.
 To date, conflicting results have been reported regarding the genotoxic effects of RF-EMF waves on genetic material. It has been reported that the energy of low EM fields is not sufficient to break the chemical bonds of DNA, but the increase in exposure time is effective on the formation of oxygen radicals and the disruptions in the DNA repair process. The absorption of microwaves can cause significant local warming in cells. For example, an increase in temperature has been observed in cells in culture media exposed to waves of high SAR levels. However, there is evidence that reactive oxygen species are formed in cells indirectly and experimentally exposed to RF-EMF waves. Free oxygen radicals can create nucleotide entries in DNA as well as bind cellular components to DNA bases (5). The frequency of polymorphisms observed in DNA repair mechanism genes in children with acute leukaemia living close to high energy lines reveals the effect of this energy on the repair process.  Significant evidence has been reported that genotoxic effects occur in various cell types when exposed to RF-EMF waves (6-10). Here, it has been reported that cells exposed to RF-EMF waves (1.800 MHz, SAR 2 W/kg) cause oxidative damage in mitochondrial DNA, DNA breaks in neurons and DNA breaks in amniotic cells (6,10). Similarly, the damage has been reported in lymphocytes exposed to various RF-EMF waves (8). However, exposure to RF-EMF waves is known to cause chromosome imbalance, changes in gene expression, and gene mutations. Such deleterious genetic effects have also been reported in neurons, blood lymphocytes, sperm, red blood cells, epithelial cells, hematopoietic tissue, lung cells, and bone marrow (1,11,12). It has been found that exposure to RF-EMF radiation also increases chromosome numerical aberrations (6,13). It has also been reported that increased chromosome separation in mouse oocytes exposed to EM and increased DNA fragmentation and apoptosis in fly egg cells (14,15). However, increased DNA breaks have been reported in the blastomeres of embryos of pregnant mice exposed to a frequency of 50 Hz, and a decrease in the number of blastocysts has been reported (16). Genetic damages to sex cells can lead to persistent genetic diseases in subsequent generations.
 Today, X-ray devices used for medical diagnosis have become one of the largest sources of radiation. These radiological procedures used for diagnosis constitute an important part of ionizing radiation. During these processes, the human body is visibly or invisibly affected by X-rays. As a matter of fact, X-rays have effects of disrupting the structure and biochemical activities of DNA, RNA, proteins and enzymes that are vital in the organism (17).  Many studies on this subject have revealed that radiation has suppressive and mutational effects on DNA synthesis. These effects can cause serious damage to the cell as well as DNA and chromosome damage. In a recent study, chromosome damage was investigated in patients with X-ray angiography and personnel working in radiological procedures (18). Our findings showed that the beams used in interventional radiological procedures caused chromosomal damage and the rate of chromosomal abnormalities (CAs) increased significantly in patients after the procedure and this damage increased with the amount of radiation dose. Therefore, the radiation dose to be given to the patient should be chosen carefully. Besides, our findings showed that the frequency of CA is significantly higher in personnel working in radiological procedures. This reveals that interventional cardiologists are exposed to high radiation exposure. For this reason, we can say that the personnel working in radiological procedures (physician, health technician and nurse) are very likely to get diseases after years because they are exposed to low doses but long-term X-rays. Therefore, both the potential risks and safety of exposure to medical radiological devices must be continuously monitored. Furthermore, the fact that chromatid and chromosome breaks are very common among structural CAs in our findings suggests that they may be the cause of malignancy. Because, there are many cancer genes, tumour suppressor genes, enzyme genes involved in DNA repair and important genes or candidate genes responsible forapoptosis on these chromosomes. All this information shows that patients are more susceptible to DNA damage and inappropriate radiological examinations should be avoided. Therefore, X-ray and other diagnostic imaging techniques should not be applied unless necessary, and physicians and patients should be more careful in this regard.
 It has been reported that RF-EMR waves emitted from wireless communication device mobile phones have a genotoxic effect on human and mammalian cells (6,19). In a recent study; The effects of 900 and 1800 MHz cell phone frequencies on human chromosomes were investigated in amniotic cell cultures (6). Here, it has been reported that chromosome packing delays, damage and breaks occur in amniotic cells exposed to 900 and 1800 MHz every day at 3, 6 and 12 hours for twelve days. However, it was found that the frequency of 1800 MHz caused more CAs than 900 MHz, and the amount of damage increased with increasing usage time. These results confirm that GSM-like RF-EMR causes direct genotoxic effects in human in vitro cultures and has adverse effects on human chromosomes, and these effects increase in parallel with exposure time. This shows us that the mobile phone carries a risk for human health and these genetic damages can cause cancer. Therefore, necessary precautions should be taken for these harmful effects of mobile phones. Among these measures, the periods of mobile phone use should be kept short, especially the exposure of developing children and infants to mobile phones should be prevented, and avoiding excessive use of mobile phones may be one of the precautions against cancer. However, in order to evaluate it in more detail, the effects of mobile phones with environmental mutagens and/or carcinogens should be considered in subsequent researches.
 ConclusionToday, in parallel with the increasing technological developments, the demand of the society for electronic devices and phones and the frequency ranges of electronic devices are constantly increasing. Waves emitted from electronic devices are absorbed by human and animal bodies. Especially, the use of phones by contact with our body and the increase in usage time affects not only adults but also young children. Therefore, there is increasing concern in society about the negative biological effects of EM waves emitted from phones and other electronic devices. Results from all studies show that RF-EMF waves may be carcinogenic due to their genotoxic effect. Because cancer is a disease that occurs as a result of genetic damage. Considering these negative and harmful effects, regulations following international standards regarding the use of electronic devices should be made and society should be made aware of the risks.References
 
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Decision-making as transdiagnostic construct for mental health research

Transdiagnostic research and linking behavioral, neural, and symptom measures are important endeavors in clinical neuroscience and biological psychiatry. In this issue of Neuron, Moutoussis etal. (2021) describe a new cognitive construct-decision acuity-that is related to mental health symptoms and distinct resting-state networks.

Neurologic Complications of Poverty: the Associations Between Poverty as a Social Determinant of Health and Adverse Neurologic Outcomes.

Increasing attention has been paid in recent decades to social determinants of health as a risk factor for disease development and disease severity. While traditionally heart disease, family history, lipid profile, and tobacco use have all been associated with increased risk of neurological disease, numerous studies now show that the influence of poverty may be just as strong a risk factor. This study summarizes the recent literature on poverty as it contributes to neurological disease. Children growing up in poverty have increased risk for cognitive deficits and behavioral disorders as reported by Noble et al. (Dev Sci. 9(6):642-54, 2006) and Farah et al. (Brain Res. 1110(1):166-74, 2006) as well as worse outcomes when it comes to epilepsy management and disease course as discussed by Camfield et al. (Epilepsia. 57(11):1826-33, 2016). In adulthood, as the number of social determinants of health increases, the incidence of stroke and severe stroke increases significantly as reported by Reshetnyak et al. (Stroke. 51:2445-53, 2020) as does exposure to neurologically significant infectious diseases and incidence of dementia as reported by Sumilo et al. (Rev Med Virol. 18(2):81-95, 2008) and Zuelsdorff et al. (Alzheimer's Dement. 6(1):e12039, 2020). Social determinants of health including poverty should be considered a risk factor for disease. More attention is needed from clinicians as well as from a public health perspective to address this disparity.

Apical intercalated cell cluster: A distinct sensory regulator in the amygdala.

GABAergic neurons regulate different aspects of information processing in the amygdala. Among these are clusters of intercalated cells (ITCs), which have been implicated in fear-related behaviors. Although a few of the ITC clusters have been studied, the functional role of apical ITCs (apITCs) is unknown. Here, we combine monosynaptic rabies tracing with optogenetics and demonstrate that apITCs receive synaptic input from medial geniculate nucleus (MGm), posterior intralaminar nucleus (PIN), and medial dorsal nucleus of the thalamus and from a diverse range of cortical areas including temporal association, entorhinal, insular, piriform, and somatosensory cortex. Upon fear learning, PIN/MGm inputs are strengthened, indicative of their involvement in fear behaviors. 3-D reconstruction of apITCs reveals local arborization and innervation of the dorsal striatum and lateral amygdala. We further show that apITCs provide sensory feedforward inhibition to LA principal cells, a putative mechanism for controlling plasticity during fear learning.

Bimanual coordination associated with left- and right-hand dominance: testing the limb assignment and limb dominance hypothesis

In an experiment conducted by Kennedy et al. (Exp Brain Res 233:181–195, 2016), dominant right-handed individuals were required to produce a rhythm of isometric forces in a 2:1 or 1:2 bimanual coordination pattern. In the 2:1 pattern, the left limb performed the faster rhythm, while in the 1:2 pattern, the right limb produced the faster pattern. In the 1:2 pattern, interference occurred in the limb which had to produce the slower rhythm of forces. However, in the 2:1 condition, interference occurred in both limbs. The conclusion was that interference was not only influenced by movement frequency, but also influenced by limb dominance. The present experiment was designed to replicate these findings in dynamic bimanual 1:2 and 2:1 tasks where performers had to move one wrist faster than the other, and to determine the influence of limb dominance. Dominant left-handed (N = 10; LQ = − 89.81) and dominant right-handed (N = 14; LQ = 91.25) participants were required to perform a 2:1 and a 1:2 coordination pattern using Lissajous feedback. The harmonicity value was calculated to quantify the interference in the trial-time series. The analysis demonstrated that regardless of limb dominance, harmonicity was always lower in the slower moving limb than in the faster moving limb. The present results indicated that for dominant left- and dominant right-handers the faster moving limb influenced the slower moving limb. This is in accordance with the assumption that movement frequency has a higher impact on limb control in bimanual 2:1 and 1:2 coordination tasks than handedness.

Cortical Reorganization: Reallocated Responses without Rewiring

Is the brain able to reorganise following loss of sensory input? New work on individuals with sight loss shows that, while brain areas normally allocated to vision respond to other sensory stimuli, those responses are unlikely to mean the brain has rewired. Is the brain able to reorganise following loss of sensory input? New work on individuals with sight loss shows that, while brain areas normally allocated to vision respond to other sensory stimuli, those responses are unlikely to mean the brain has rewired. Ask someone in the street about the capacity of the adult brain to take on a new processing role in the light of disease or damage and you will get an answer that would lead you to believe that the human brain is almost infinitely flexible. Careful scientific evaluation of the brain’s plastic characteristics leads to a far more complex picture, however. A well-constrained way to address the question is to examine how the sensory areas of the brain change following the partial removal of the inputs they systematically map. Amputating a finger of an adult monkey, for example, resulted in the representation of the remaining fingers in the somatosensory cortex expanding into the neighbouring region that originally represented the removed finger1Merzenich M.M. Nelson R.J. Stryker M.P. Cynader M.S. Schoppmann A. Zook J.M. Somatosensory cortical map changes following digit amputation in adult monkeys.J. Comp. Neurol. 1984; 224: 591-605Crossref PubMed Scopus (987) Google Scholar. Research has shown analogous remapping of the visual cortex following lesioning of the retina2Kaas J.H. Krubitzer L.A. Chino Y.M. Langston A.L. Polley E.H. Blair N. Reorganization of retinotopic cortical maps in adult mammals after lesions of the retina.Science. 1990; 248: 229-231Crossref PubMed Scopus (495) Google Scholar,3Heinen S.J. Skavenski A.A. Recovery of visual responses in foveal V1 neurons following bilateral foveal lesions in adult monkey.Exp. Brain Res. 1991; 83: 670-674Crossref PubMed Scopus (168) Google Scholar; however, these findings were later questioned by some4Smirnakis S.M. Brewer A.A. Schmid M.C. Tolias A.S. Schüz A. Augath M. Inhoffen W. Wandell B.A. Logothetis N.K. Lack of long-term cortical reorganization after macaque retinal lesions.Nature. 2005; 435: 300-307Crossref PubMed Scopus (151) Google Scholar, while others have argued that even more remarkable reorganization of visual processing occurs in humans5Baker C.I. Peli E. Knouf N. Kanwisher N.G. Reorganization of visual processing in macular degeneration.J. Neurosci. 2005; 25: 614-618Crossref PubMed Scopus (197) Google Scholar. A paper by Masuda et al.6Masuda Y. Takemura H. Terao M. Miyazaki A. Ogawa S. Horiguchi H. Nakadomari S. Matsumoto K. Nakano T. Wandell B.A. Amano K. V1 projection zone signals in human macular degeneration depend on task despite absence of visual stimulus.Curr. Biol. 2021; 31: 406-412Abstract Full Text Full Text PDF Scopus (5) Google Scholar in this issue of Current Biology examines how signals in deprived parts of the visual cortex can arise and in so doing shows that the visual cortex does not undergo large scale remapping when individuals have lost their central vision. Sensory brain areas largely share a common feature — they map the peripheral sense organ systematically. In somatosensory cortex, therefore, there is a map of the body, while in visual cortex there is a map of the retina. Removing input from the cortical maps can result in shifts within them to give more territory to the sensory inputs that remain1Merzenich M.M. Nelson R.J. Stryker M.P. Cynader M.S. Schoppmann A. Zook J.M. Somatosensory cortical map changes following digit amputation in adult monkeys.J. Comp. Neurol. 1984; 224: 591-605Crossref PubMed Scopus (987) Google Scholar. In the body of work on the macaque visual cortex the shifts observed, while relatively modest, were linked to axonal sprouting7Yamahachi H. Marik S.A. McManus J.N.J. Denk W. Gilbert C.D. Rapid axonal sprouting and pruning accompany functional reorganization in primary visual cortex.Neuron. 2009; 64: 719-729Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar. It has been put forward that such reorganization of the brain could explain the phenomenon whereby individuals who lost vision as a result of retinal disease ‘fill in’ their regions of blindness3Heinen S.J. Skavenski A.A. Recovery of visual responses in foveal V1 neurons following bilateral foveal lesions in adult monkey.Exp. Brain Res. 1991; 83: 670-674Crossref PubMed Scopus (168) Google Scholar. When functional magnetic resonance imaging (fMRI) made examining the visual cortical map in living humans possible, the question of whether visual cortex remaps inputs that remain after visual loss resulting from retinal disease could be answered. The first study of a patient with loss of central vision due to macular degeneration found no evidence of a reallocation of the visual cortex to the vision that remained8Sunness J.S. Liu T. Yantis S. Retinotopic mapping of the visual cortex using fMRI in a patient with central scotomas from atrophic macular degeneration.Ophthalmology. 2004; 111: 1595-1598Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar. Later work showed that the area of the visual cortex that remained responsive after retinal lesions also caused by macular degeneration was entirely consistent with a stable and not plastic representation9Baseler H.A. Gouws A. Haak K.V. Racey C. Crossland M.D. Tufail A. Rubin G.S. Cornelissen F.W. Morland A.B. Large-scale remapping of visual cortex is absent in adult humans with macular degeneration.Nat. Neurosci. 2011; 14: 649-655Crossref PubMed Scopus (124) Google Scholar. Moreover, when the issue of remapping was revisited in monkeys with both the electrophysiological techniques used in earlier studies and the fMRI studies that can be applied to humans, the results provided no evidence of reorganization of visual cortex4Smirnakis S.M. Brewer A.A. Schmid M.C. Tolias A.S. Schüz A. Augath M. Inhoffen W. Wandell B.A. Logothetis N.K. Lack of long-term cortical reorganization after macaque retinal lesions.Nature. 2005; 435: 300-307Crossref PubMed Scopus (151) Google Scholar. At odds with the findings that visual cortex did not undergo a large scale remapping were contemporaneous studies which showed that when visual stimuli were presented to intact peripheral locations of the retina, the cortical representation of the diseased retina responded robustly in some, but not all, patients similarly affected by retinal disease5Baker C.I. Peli E. Knouf N. Kanwisher N.G. Reorganization of visual processing in macular degeneration.J. Neurosci. 2005; 25: 614-618Crossref PubMed Scopus (197) Google Scholar. The methodology differed from previous studies, however, by using images of faces, other objects and their scrambled counterparts as stimuli, and patients were asked to make a response if the same image was presented in succession (the one-back task). Multiple possible explanations of the result were proposed, including a large-scale reorganization of the cortex, much bigger than those observed in the previous work on animal models, and/or feedback from higher order visual areas of the brain to primary visual cortex5Baker C.I. Peli E. Knouf N. Kanwisher N.G. Reorganization of visual processing in macular degeneration.J. Neurosci. 2005; 25: 614-618Crossref PubMed Scopus (197) Google Scholar. The latter, feedback hypothesis was supported by a subsequent study10Masuda Y. Dumoulin S.O. Nakadomari S. Wandell B.A. V1 projection zone signals in human macular degeneration depend on task, not stimulus.Cereb. Cortex. 2008; 18: 2483-2493Crossref PubMed Scopus (107) Google Scholar performed by some of the authors of the new Masuda et al.6Masuda Y. Takemura H. Terao M. Miyazaki A. Ogawa S. Horiguchi H. Nakadomari S. Matsumoto K. Nakano T. Wandell B.A. Amano K. V1 projection zone signals in human macular degeneration depend on task despite absence of visual stimulus.Curr. Biol. 2021; 31: 406-412Abstract Full Text Full Text PDF Scopus (5) Google Scholar paper. They used a variety of stimuli, including more realistic objects, and had patients view them while doing the task and while simply viewing passively. The results were clear: responses from the regions of the brain that would normally represent areas of lesioned retina only responded when patients were actively engaged in the task. Masuda et al.6Masuda Y. Takemura H. Terao M. Miyazaki A. Ogawa S. Horiguchi H. Nakadomari S. Matsumoto K. Nakano T. Wandell B.A. Amano K. V1 projection zone signals in human macular degeneration depend on task despite absence of visual stimulus.Curr. Biol. 2021; 31: 406-412Abstract Full Text Full Text PDF Scopus (5) Google Scholar addressed a fundamental question — are the responses in representations of lesioned retina present only during visual stimulation or can they be detected during stimulation of other senses? The question has significant theoretical importance because, if responses are found in the absence of any visual stimulation, they largely rule out remapping retinal inputs to visual cortex and instead very much favour feedback as the source of responses in representations of lesioned retina. The authors presented individuals with loss of central vision and controls with tactile and auditory stimuli with and without the task. The results were again clear: responses from the representations of lesioned retina were present only during the task for both tactile and auditory stimuli, while responses from similar locations were uniformly absent in controls. The experiments were first performed with participants’ eyes closed, but the authors followed up with further experiments with participants’ eyes open. As a result, responses were diminished, indicating that input to the visual cortex is sufficient to reduce, in patients, and remove, in controls, modality-independent task-related responses. Taken together the results effectively rule out the possibility of a large-scale rewiring of the primary visual cortex, perhaps through an enlarged version of the lateral spread of axonal connections described in animal models7Yamahachi H. Marik S.A. McManus J.N.J. Denk W. Gilbert C.D. Rapid axonal sprouting and pruning accompany functional reorganization in primary visual cortex.Neuron. 2009; 64: 719-729Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar. A far more likely explanation of the results comes from the existing interconnectivity of the brain. It has been shown, for example, that even in control participants, who were artificially deprived of vision for five days, there were responses to tactile stimuli in visual cortex, presumably arising from the upregulation of existing connections rather than establishing new ones11Merabet L.B. Hamilton R. Schlaug G. Swisher J.D. Kiriakopoulos E.T. Pitskel N.B. Kauffman T. Pascual-Leone A. Rapid and reversible recruitment of early visual cortex for touch.PLoS One. 2008; 3e3046Crossref PubMed Scopus (177) Google Scholar. What connections are there that could generate modality independent task-related responses in primary visual cortex? Masuda et al.6Masuda Y. Takemura H. Terao M. Miyazaki A. Ogawa S. Horiguchi H. Nakadomari S. Matsumoto K. Nakano T. Wandell B.A. Amano K. V1 projection zone signals in human macular degeneration depend on task despite absence of visual stimulus.Curr. Biol. 2021; 31: 406-412Abstract Full Text Full Text PDF Scopus (5) Google Scholar point us to the frontal eye fields, which they show exhibit task-related responses and others have shown influence responses in primary visual cortex12Kastner S. Pinsk M.A. De Weerd P. Desimone R. Ungerleider L.G. Increased activity in human visual cortex during directed attention in the absence of visual stimulation.Neuron. 1999; 22: 751-761Abstract Full Text Full Text PDF PubMed Scopus (1199) Google Scholar. An alternative source of feedback could come from extrastriate areas, which have been shown to not only represent visual information but also capture information from other sensory modalities13Amedi A. Hofstetter S. Maidenbaum S. Heimler B. Task selectivity as a comprehensive principle for brain organization.Trends Cogn. Sci. 2017; 21: 307-310Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar. This seems less likely, however, in the present study as extrastriate responses themselves were frequently smaller than those detected in primary visual cortex5Baker C.I. Peli E. Knouf N. Kanwisher N.G. Reorganization of visual processing in macular degeneration.J. Neurosci. 2005; 25: 614-618Crossref PubMed Scopus (197) Google Scholar. The work of Masuda et al.6Masuda Y. Takemura H. Terao M. Miyazaki A. Ogawa S. Horiguchi H. Nakadomari S. Matsumoto K. Nakano T. Wandell B.A. Amano K. V1 projection zone signals in human macular degeneration depend on task despite absence of visual stimulus.Curr. Biol. 2021; 31: 406-412Abstract Full Text Full Text PDF Scopus (5) Google Scholar shows that we must exhibit caution when interpreting brain responses that arise in one group of individuals whose sensory function is compromised and not in another with intact sensory function. The specific caution is that, while it is tempting to conclude that the human brain is capable of large-scale rewiring, it is essential that the existing wiring properties of the brain are excluded as explanation of the results before doing so14Morland A.B. Organization of the central visual pathways following field defects arising from congenital, inherited, and acquired eye disease.Annu. Rev. Vis. Sci. 2015; 1: 329-350Crossref PubMed Google Scholar. In the study of Masuda et al.6Masuda Y. Takemura H. Terao M. Miyazaki A. Ogawa S. Horiguchi H. Nakadomari S. Matsumoto K. Nakano T. Wandell B.A. Amano K. V1 projection zone signals in human macular degeneration depend on task despite absence of visual stimulus.Curr. Biol. 2021; 31: 406-412Abstract Full Text Full Text PDF Scopus (5) Google Scholar, and likely others too4Smirnakis S.M. Brewer A.A. Schmid M.C. Tolias A.S. Schüz A. Augath M. Inhoffen W. Wandell B.A. Logothetis N.K. Lack of long-term cortical reorganization after macaque retinal lesions.Nature. 2005; 435: 300-307Crossref PubMed Scopus (151) Google Scholar,15Liu T. Cheung S.-H. Schuchard R.A. Glielmi C.B. Hu X. He S. Legge G.E. Incomplete cortical reorganization in macular degeneration.Invest. Ophthalmol. Vis. Sci. 2010; 51: 6826-6834Crossref PubMed Scopus (50) Google Scholar, it is the normal organization of the brain rather than its reorganization that provides the more likely explanation of the results. V1 Projection Zone Signals in Human Macular Degeneration Depend on Task Despite Absence of Visual StimulusMasuda et al.Current BiologyNovember 5, 2020In BriefMasuda et al. show that V1 lesion projection zone of JMD patients responds to tactile and auditory stimuli only in the one-back memory task, not in the passive condition. The modality-independent, task-dependent V1 LPZ responses suggest that V1 LPZ responses reflect task-related feedback signals rather than reorganized feedforward signals. 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Spatial clustering of orientation preference in primary visual cortex of the large rodent agouti.

SummaryAll rodents investigated so far possess orientation-selective neurons in the primary visual cortex (V1) but – in contrast to carnivores and primates – no evidence of periodic maps with pinwheel-like structures. Theoretical studies debating whether phylogeny or universal principles determine development of pinwheels point to V1 size as a critical constraint. Thus, we set out to study maps of agouti, a big diurnal rodent with a V1 size comparable to cats'. In electrophysiology, we detected interspersed orientation and direction-selective neurons with a bias for horizontal contours, corroborated by homogeneous activation in optical imaging. Compatible with spatial clustering at short distance, nearby neurons tended to exhibit similar orientation preference. Our results argue against V1 size as a key parameter in determining the presence of periodic orientation maps. They are consistent with a phylogenetic influence on the map layout and development, potentially reflecting distinct retinal traits or interspecies differences in cortical circuitry.

Liraglutide and semaglutide: Pooled post hoc analysis to evaluate risk of dementia in patients with type 2 diabetes

AbstractBackgroundGlucagon‐like peptide 1 receptor agonists (GLP‐1 RA) have previously shown improved measures of memory and reduced phospho‐tau burden in preclinical animal models relevant to progressive cognitive impairment (Hansen. J Alzheimers Dis.2015;46:877‐88; Hansen. Brain Res.2016;1634:158‐70). Liraglutide and semaglutide are structurally similar GLP‐1 RAs associated with potent glucose‐lowering effect, body weight loss and cardiovascular benefits shown in large cardiovascular outcomes trials (CVOTs) (Marso. N Engl J Med.2016;375:311‐22; Marso. N Engl J Med.2016;375:1834‐44; Husain. N Engl J Med.2019;381:841‐51). In order to investigate the potential effects of GLP‐1 RA on dementia in a clinical setting, a post‐hoc analysis was conducted based on pooled data from three CVOTs.MethodLEADER, SUSTAIN 6 and PIONEER 6 were randomised, double‐blind, multicentre, placebo‐controlled CVOTs evaluating the cardiovascular effect of liraglutide or semaglutide vs. placebo, added to standard of care. The trials included patients with type 2 diabetes and established or high risk of cardiovascular disease. A post‐hoc analysis on pooled data from the three CVOTs was considered appropriate due to the similarities in trial design, patient population and treatment effects. Across all trials 15,820 patients with median follow‐up of 3.6 years were included in this analysis. Dementia‐related adverse events (AEs) were identified using Standardised MedDRA (version 21.1) Query for “dementia” narrow search terms. AE data collection across the trials differed in line with the regulatory requirements at the time of trial conduct. In LEADER and PIONEER 6 only serious AEs were systematically collected, while all AEs were collected in SUSTAIN 6. A time‐to‐event analysis based on the Cox proportional‐hazards model using treatment as covariate was used to estimate the hazard ratio for developing dementia.ResultAcross the three CVOTs, 15 GLP‐1 RA‐treated patients and 32 placebo‐treated patients were identified with development of dementia (Figure). Post‐hoc analysis on the pooled data showed a significant estimated hazard ratio of 0.47 [0.25; 0.86]95%CI in favour of the GLP‐1 RA treatment versus placebo.Conclusion Post‐hoc analysis based on pooled data from three double‐blinded CVOTs suggests, albeit with a low number of events, a reduced risk of dementia with liraglutide or semaglutide treatment in patients with type 2 diabetes.