Cognitive Deficits in Aging Related to Changes in Basal Forebrain Neuronal Activity.

Aging is a physiological process accompanied by a decline in cognitive performance. The cholinergic neurons of the basal forebrain provide projections to the cortex that are directly engaged in many cognitive processes in mammals. In addition, basal forebrain neurons contribute to the generation of different rhythms in the EEG along the sleep/wakefulness cycle. The aim of this review is to provide an overview of recent advances grouped around the changes in basal forebrain activity during healthy aging. Elucidating the underlying mechanisms of brain function and their decline is especially relevant in today's society as an increasingly aged population faces higher risks of developing neurodegenerative diseases such as Alzheimer's disease. The profound age-related cognitive deficits and neurodegenerative diseases associated with basal forebrain dysfunction highlight the importance of investigating the aging of this brain region.

Genomic epidemiology and emergence of SARS-CoV-2 variants of concern in the United Arab Emirates.

Since the declaration of SARS-CoV-2 outbreak as a pandemic, the United Arab Emirates (UAE) public health authorities have adopted strict measures to reduce transmission as early as March 2020. As a result of these measures, flight suspension, nationwide RT-PCR and surveillance of viral sequences were extensively implemented. This study aims to characterize the epidemiology, transmission pattern, and emergence of variants of concerns (VOCs) and variants of interests (VOIs) of SARS-CoV-2 in the UAE, followed by the investigation of mutations associated with hospitalized cases. A total of 1274 samples were collected and sequenced from all seven emirates between the period of 25 April 2020 to 15 February 2021. Phylogenetic analysis demonstrated multiple introductions of SARS-CoV-2 into the UAE in the early pandemic, followed by a local spread of root clades (A, B, B.1 and B.1.1). As the international flight resumed, the frequencies of VOCs surged indicating the January peak of positive cases. We observed that the hospitalized cases were significantly associated with the presence of B.1.1.7 (p < 0.001), B.1.351 (p < 0.001) and A.23.1 (p = 0.009). Deceased cases are more likely to occur in the presence of B.1.351 (p < 0.001) and A.23.1 (p = 0.022). Logistic and ridge regression showed that 51 mutations are significantly associated with hospitalized cases with the highest proportion originated from S and ORF1a genes (31% and 29% respectively). Our study provides an epidemiological insight of the emergence of VOCs and VOIs following the borders reopening and worldwide travels. It provides reassurance that hospitalization is markedly more associated with the presence of VOCs. This study can contribute to understand the global transmission of SARS-CoV-2 variants.

Hypothyroidism confers tolerance to cerebral malaria.

The modulation of the host's metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.

Reduced Insulin-Like Growth Factor-I Effects in the Basal Forebrain of Aging Mouse.

It is known that aging is frequently accompanied by a decline in cognition. Furthermore, aging is associated with lower serum IGF-I levels that may contribute to this deterioration. We studied the effect of IGF-I in neurons of the horizontal diagonal band of Broca (HDB) of young (≤6 months old) and old (≥20-month-old) mice to determine if changes in the response of these neurons to IGF-I occur along with aging. Local injection of IGF-I in the HDB nucleus increased their neuronal activity and induced fast oscillatory activity in the electrocorticogram (ECoG). Furthermore, IGF-I facilitated tactile responses in the primary somatosensory cortex elicited by air-puffs delivered in the whiskers. These excitatory effects decreased in old mice. Immunohistochemistry showed that cholinergic HDB neurons express IGF-I receptors and that IGF-I injection increased the expression of c-fos in young, but not in old animals. IGF-I increased the activity of optogenetically-identified cholinergic neurons in young animals, suggesting that most of the IGF-I-induced excitatory effects were mediated by activation of these neurons. Effects of aging were partially ameliorated by chronic IGF-I treatment in old mice. The present findings suggest that reduced IGF-I activity in old animals participates in age-associated changes in cortical activity.

Corrigendum: The near-infrared autofluorescence fingerprint of the brain.

In the article by J. Lifante et al (doi: 10.1002/jbio.202000154), published in J. Biophotonics 2020;13:e202000154, a spectral feature corresponding to tissue reflectance was mistakenly attributed to autofluorescence. This corrigendum is published to correct the interpretation of the spectral data and images in the manuscript.

The near-infrared autofluorescence fingerprint of the brain.

The brain is a vital organ involved in most of the central nervous system disorders. Their diagnosis and treatment require fast, cost-effective, high-resolution and high-sensitivity imaging. The combination of a new generation of luminescent nanoparticles and imaging systems working in the second biological window (near-infrared II [NIR-II]) is emerging as a reliable alternative. For NIR-II imaging to become a robust technique at the preclinical level, full knowledge of the NIR-II brain autofluorescence, responsible for the loss of image resolution and contrast, is required. This work demonstrates that the brain shows a peculiar infrared autofluorescence spectrum that can be correlated with specific molecular components. The existence of particular structures within the brain with well-defined NIR autofluorescence fingerprints is also evidenced, opening the door to in vivo anatomical imaging. Finally, we propose a rational selection of NIR luminescent probes suitable for low-noise brain imaging based on their spectral overlap with brain autofluorescence.

Ultrafast photochemistry produces superbright short-wave infrared dots for low-dose in vivo imaging.

Optical probes operating in the second near-infrared window (NIR-II, 1,000-1,700 nm), where tissues are highly transparent, have expanded the applicability of fluorescence in the biomedical field. NIR-II fluorescence enables deep-tissue imaging with micrometric resolution in animal models, but is limited by the low brightness of NIR-II probes, which prevents imaging at low excitation intensities and fluorophore concentrations. Here, we present a new generation of probes (Ag2S superdots) derived from chemically synthesized Ag2S dots, on which a protective shell is grown by femtosecond laser irradiation. This shell reduces the structural defects, causing an 80-fold enhancement of the quantum yield. PEGylated Ag2S superdots enable deep-tissue in vivo imaging at low excitation intensities (<10 mW cm-2) and doses (<0.5 mg kg-1), emerging as unrivaled contrast agents for NIR-II preclinical bioimaging. These results establish an approach for developing superbright NIR-II contrast agents based on the synergy between chemical synthesis and ultrafast laser processing.

Rare-earth-doped fluoride nanoparticles with engineered long luminescence lifetime for time-gated in vivo optical imaging in the second biological window.

Biomedicine is continuously demanding new luminescent materials to be used as optical probes for the acquisition of high resolution, high contrast and high penetration in vivo images. These materials, in combination with advanced techniques, could constitute the first step towards new diagnosis and therapy tools. In this work, we report on the synthesis of long lifetime rare-earth-doped fluoride nanoparticles by adopting different strategies: core/shell and dopant engineering. The here developed nanoparticles show intense infrared emission in the second biological window with a long luminescence lifetime close to 1 millisecond. These two properties make the here presented nanoparticles excellent candidates for time-gated infrared optical bioimaging. Indeed, their potential application as optical imaging contrast agents for autofluorescence-free in vivo small animal imaging has been demonstrated, allowing high contrast real-time tracking of gastrointestinal absorption of nanoparticles and transcranial imaging of intracerebrally injected nanoparticles in the murine brain.

Basal Forebrain Nuclei Display Distinct Projecting Pathways and Functional Circuits to Sensory Primary and Prefrontal Cortices in the Rat.

Recent evidence supports that specific projections between different basal forebrain (BF) nuclei and their cortical targets are necessary to modulate cognitive functions in the cortex. We tested the hypothesis of the existence of specific neuronal populations in the BF linking with specific sensory, motor, and prefrontal cortices in rats. Neuronal tracing techniques were performed using retrograde tracers injected in the primary somatosensory (S1), auditory (A1), and visual (V1) cortical areas, in the medial prefrontal cortex (mPFC) as well as in BF nuclei. Results indicate that the vertical and horizontal diagonal band of Broca (VDB/HDB) nuclei target specific sensory cortical areas and maintains reciprocal projections with the prelimbic/infralimbic (PL/IL) area of the mPFC. The basal magnocellular nucleus (B nucleus) has more widespread targets in the sensory-motor cortex and does not project to the PL/IL cortex. Optogenetic stimulation was used to establish if BF neurons modulate whisker responses recorded in S1 and PL/IL cortices. We drove the expression of high levels of channelrhodopsin-2, tagged with a fluorescent protein (ChR2-eYFP) by injection of a virus in HDB or B nuclei. Blue-light pulses were delivered to the BF through a thin optic fiber to stimulate these neurons. Blue-light stimulation directed toward the HDB facilitated whisker responses in S1 cortex through activation of muscarinic receptors. The same optogenetic stimulation of HDB induced an inhibition of whisker responses in mPFC by activation of nicotinic receptors. Blue-light stimulation directed toward the B nucleus had lower effects than HDB stimulation. Our findings pointed the presence of specific neuronal networks between the BF and the cortex that may play different roles in the control of cortical activity.

Bilateral Pathways from the Basal Forebrain to Sensory Cortices May Contribute to Synchronous Sensory Processing.

Sensory processing in the cortex should integrate inputs arriving from receptive fields located on both sides of the body. This role could be played by the corpus callosum through precise projections between both hemispheres. However, different studies suggest that cholinergic projections from the basal forebrain (BF) could also contribute to the synchronization and integration of cortical activities. Using tracer injections and optogenetic techniques in transgenic mice, we investigated whether the BF cells project bilaterally to sensory cortical areas, and have provided anatomical evidence to support a modulatory role for the cholinergic projections in sensory integration. Application of the retrograde tracer Fluor-Gold or Fast Blue in both hemispheres of the primary somatosensory (S1), auditory or visual cortical areas showed labeled neurons in the ipsi- and contralateral areas of the diagonal band of Broca and substantia innominata. The nucleus basalis magnocellularis only showed ipsilateral projections to the cortex. Optogenetic stimulation of the horizontal limb of the diagonal band of Broca facilitated whisker responses in the S1 cortex of both hemispheres through activation of muscarinic cholinergic receptors and this effect was diminished by atropine injection. In conclusion, our findings have revealed that specific areas of the BF project bilaterally to sensory cortices and may contribute to the coordination of neuronal activity on both hemispheres.

Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated pools of neurons that may modulate specific cortical areas.

Corticofugal projections induce long-lasting effects on somatosensory responses in the trigeminal complex of the rat.

The sensory information flow at subcortical relay stations is controlled by the action of topographic connections from the neocortex. To determinate the functional properties of the somatosensory corticofugal projections to the principal (Pr5) and caudal spinal (Sp5C) trigeminal nuclei, we performed unitary recordings in anesthetized rats. To examine the effect of these cortical projections we used tactile stimulation of the whisker and electrical stimulation of somatosensory cortices. Corticofugal anatomical projections to Pr5 and Sp5C nuclei were detected by using retrograde fluorescent tracers. Neurons projecting exclusively to Pr5 were located in the cingulate cortex while neurons projecting to both Sp5C and Pr5 nuclei were located in the somatosensory and insular cortices (>75% of neurons). Physiological results indicated that primary somatosensory cortex produced a short-lasting facilitating or inhibiting effects (<5 min) of tactile responses in Pr5 nucleus through activation of NMDA glutamatergic or GABAA receptors since effects were blocked by iontophoretically application of APV and bicuculline, respectively. In contrast, stimulation of secondary somatosensory cortex did not affect most of the Pr5 neurons; however both cortices inhibited the nociceptive responses in the Sp5C nucleus through activation of glycinergic or GABAA receptors because effects were blocked by iontophoretically application of strychnine and bicuculline, respectively. These and anatomical results demonstrated that the somatosensory cortices projects to Pr5 nucleus to modulate tactile responses by excitatory and inhibitory actions, while projections to the Sp5C nucleus control nociceptive sensory transmission by only inhibitory effects. Thus, somatosensory cortices may modulate innocuous and noxious inputs simultaneously, contributing to the perception of specifically tactile or painful sensations.