scholarly journals Mapping Solute Clearance From the Mouse Hippocampus Using a 3D Imaging Cryomicrotome

2021 ◽  
Vol 15 ◽  
Author(s):  
Daphne M. P. Naessens ◽  
Johannes G. G. Dobbe ◽  
Judith de Vos ◽  
Ed VanBavel ◽  
Erik N. T. P. Bakker
Keyword(s):  
Brain Structures ◽  
Small Subset ◽  
Protein Accumulation ◽  
Waste Products ◽  
Molecular Weights ◽  
Interpeduncular Cistern ◽  
Subarachnoid Spaces ◽  
The Brain ◽  
Infusion Period ◽  
Solute Clearance

The hippocampus is susceptible to protein aggregation in neurodegenerative diseases such as Alzheimer’s disease. This protein accumulation is partially attributed to an impaired clearance; however, the removal pathways for fluids and waste products are not fully understood. The aim of this study was therefore to map the clearance pathways from the mouse brain. A mixture of two fluorescently labeled tracers with different molecular weights was infused into the hippocampus. A small subset of mice (n = 3) was sacrificed directly after an infusion period of 10 min to determine dispersion of the tracer due to the infusion, while another group was sacrificed after spreading of the tracers for an additional 80 min (n = 7). Upon sacrifice, mice were frozen and sectioned as a whole by the use of a custom-built automated imaging cryomicrotome. Detailed 3D reconstructions were created to map the tracer spreading. We observed that tracers distributed over the hippocampus and entered adjacent brain structures, such as the cortex and cerebroventricular system. An important clearance pathway was found along the ventral part of the hippocampus and its bordering interpeduncular cistern. From there, tracers left the brain via the subarachnoid spaces in the directions of both the nose and the spinal cord. Although both tracers followed the same route, the small tracer distributed further, implying a major role for diffusion in addition to convection. Taken together, these results reveal an important clearance pathway of solutes from the hippocampus.

scholarly journals Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6071
Author(s):  
Suzanne Gascon ◽  
Jessica Jann ◽  
Chloé Langlois-Blais ◽  
Mélanie Plourde ◽  
Christine Lavoie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factors ◽  
Signaling Pathways ◽  
Brain Structures ◽  
Therapeutic Strategies ◽  
Native Proteins ◽  
Receptor Sites ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

scholarly journals The Brain Resting-State Functional Connectivity Underlying Violence Proneness: Is It a Reliable Marker for Neurocriminology? A Systematic Review

2019 ◽  
Vol 9 (1) ◽  
pp. 11 ◽  
Author(s):  
Ángel Romero-Martínez ◽  
Macarena González ◽  
Marisol Lila ◽  
Enrique Gracia ◽  
Luis Martí-Bonmatí ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Effective Treatment ◽  
Resting State ◽  
Brain Structures ◽  
Prevention Programs ◽  
Angular Gyrus ◽  
Resting State Functional Connectivity ◽  
Treatment And Prevention ◽  
Reliable Marker ◽  
The Brain

Introduction: There is growing scientific interest in understanding the biological mechanisms affecting and/or underlying violent behaviors in order to develop effective treatment and prevention programs. In recent years, neuroscientific research has tried to demonstrate whether the intrinsic activity within the brain at rest in the absence of any external stimulation (resting-state functional connectivity; RSFC) could be employed as a reliable marker for several cognitive abilities and personality traits that are important in behavior regulation, particularly, proneness to violence. Aims: This review aims to highlight the association between the RSFC among specific brain structures and the predisposition to experiencing anger and/or responding to stressful and distressing situations with anger in several populations. Methods: The scientific literature was reviewed following the PRISMA quality criteria for reviews, using the following digital databases: PubMed, PsycINFO, Psicodoc, and Dialnet. Results: The identification of 181 abstracts and retrieval of 34 full texts led to the inclusion of 17 papers. The results described in our study offer a better understanding of the brain networks that might explain the tendency to experience anger. The majority of the studies highlighted that diminished RSFC between the prefrontal cortex and the amygdala might make people prone to reactive violence, but that it is also necessary to contemplate additional cortical (i.e. insula, gyrus [angular, supramarginal, temporal, fusiform, superior, and middle frontal], anterior and posterior cingulated cortex) and subcortical brain structures (i.e. hippocampus, cerebellum, ventral striatum, and nucleus centralis superior) in order to explain a phenomenon as complex as violence. Moreover, we also described the neural pathways that might underlie proactive violence and feelings of revenge, highlighting the RSFC between the OFC, ventral striatal, angular gyrus, mid-occipital cortex, and cerebellum. Conclusions. The results from this synthesis and critical analysis of RSFC findings in several populations offer guidelines for future research and for developing a more accurate model of proneness to violence, in order to create effective treatment and prevention programs.

scholarly journals Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 823
Author(s):  
Ekaterina A. Rudnitskaya ◽  
Tatiana A. Kozlova ◽  
Alena O. Burnyasheva ◽  
Natalia A. Stefanova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Brain Structures ◽  
Time Frame ◽  
Oxys Rats ◽  
Unknown Etiology ◽  
Suitable Model ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

Sporadic Alzheimer’s disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of “neurodevelopmental origin of neurodegenerative disorders”: prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected brain structures (hippocampus and prefrontal cortex) using an immunohistochemical approach in senescence-accelerated OXYS rats, which are considered a suitable model of the most common—sporadic—type of AD. We noticed an additional peak of neurogenesis, which coincides in time with the peak of apoptosis in the hippocampus of OXYS rats on postnatal day three. Besides, we showed signs of delayed migration of neurons to the prefrontal cortex as well as disturbances in astrocytic and microglial support of the hippocampus and prefrontal cortex during the first postnatal week. Altogether, our results point to dysmaturation during early development of the brain—especially insufficient glial support—as a possible “first hit” leading to neurodegenerative processes and AD pathology manifestation later in life.

scholarly journals Consciousness, decision making, and volition: freedom beyond chance and necessity

2021 ◽  
Author(s):  
Hans Liljenström
Keyword(s):  
Decision Making ◽  
Free Will ◽  
Brain Activity ◽  
Brain Structures ◽  
Complex Process ◽  
Neural Information ◽  
Neural Information Processing ◽  
Stochastic Population Model ◽  
The Brain

AbstractWhat is the role of consciousness in volition and decision-making? Are our actions fully determined by brain activity preceding our decisions to act, or can consciousness instead affect the brain activity leading to action? This has been much debated in philosophy, but also in science since the famous experiments by Libet in the 1980s, where the current most common interpretation is that conscious free will is an illusion. It seems that the brain knows, up to several seconds in advance what “you” decide to do. These studies have, however, been criticized, and alternative interpretations of the experiments can be given, some of which are discussed in this paper. In an attempt to elucidate the processes involved in decision-making (DM), as an essential part of volition, we have developed a computational model of relevant brain structures and their neurodynamics. While DM is a complex process, we have particularly focused on the amygdala and orbitofrontal cortex (OFC) for its emotional, and the lateral prefrontal cortex (LPFC) for its cognitive aspects. In this paper, we present a stochastic population model representing the neural information processing of DM. Simulation results seem to confirm the notion that if decisions have to be made fast, emotional processes and aspects dominate, while rational processes are more time consuming and may result in a delayed decision. Finally, some limitations of current science and computational modeling will be discussed, hinting at a future development of science, where consciousness and free will may add to chance and necessity as explanation for what happens in the world.

Intact Priming for Novel Perceptual Representations in Amnesia

1997 ◽  
Vol 9 (6) ◽  
pp. 699-713 ◽  
Author(s):  
Stephan B. Hamann ◽  
Larry R. Squire
Keyword(s):  
Recognition Memory ◽  
Declarative Memory ◽  
Brain Structures ◽  
Perceptual Identification ◽  
Single Exposure ◽  
Memory Representations ◽  
Perceptual Representations ◽  
The Creation ◽  
And Control ◽  
The Brain

Recent studies have challenged the notion that priming for ostensibly novel stimuli such as pseudowords (REAB) reflects the creation of new representations. Priming for such stimuli could instead reflect the activation of familiar memory representations that are orthographically similar (READ) and/or the activation of subparts of stimuli (RE, EX, AR), which are familar because they occur commonly in English. We addressed this issue in three experiments that assessed perceptual identification priming and recognition memory for novel and familiar letter strings in amnesic patients and control subjects. Priming for words, pseudowords, and orthographically illegal nonwords was fully intact in the amnesic patients following a single exposure, whereas recognition memory was impaired for the same items. Thus, priming can occur for stimuli that are unlikely to have preexisting representations. Words and pseudowords exhibited twice as much priming as illegal nonwords, suggesting that activation may contribute to priming for words and wordlike stimuli. Additional results showed that priming for illegal nonwords resulted from the formation of new perceptual associations among the component letters of each nonword rather than the activation of individual letter representations. In summary, the results demonstrate that priming following a single exposure can depend on the creation of new perceptual representations and that such priming is independent of the brain structures essential for declarative memory.

Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice

2021 ◽  
pp. 153537022110568
Author(s):  
Natalia V Bobkova ◽  
Daria Y Zhdanova ◽  
Natalia V Belosludtseva ◽  
Nikita V Penkov ◽  
Galina D Mironova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Memory ◽  
Intranasal Administration ◽  
Brain Structures ◽  
Brain Regions ◽  
Dependent Manner ◽  
Behavioral Experiments ◽  
Hippocampal Cell Culture ◽  
The Brain

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer’s type degeneration. Control OBX mice demonstrated loss of spatial memory tested in the Morris water maze. Immunocytochemical analysis revealed that allogeneic mitochondria colocalized with the markers of astrocytes and neurons in hippocampal cell culture. The results suggest that a non-invasive route intranasal administration of mitochondria may be a promising approach to the treatment of neurodegenerative diseases characterized, like Alzheimer's disease, by mitochondrial dysfunction.

Neural glymphatic system: Clinical implications and potential importance of melatonin

2021 ◽  
Vol 4 (4) ◽  
pp. 551-565
Author(s):  
Ryan D Bitar ◽  
Jorge L Torres-Garza ◽  
Russel J Reiter ◽  
William T Phillips
Keyword(s):  
Lymph Nodes ◽  
Subarachnoid Space ◽  
Slow Wave Sleep ◽  
Lymphatic Vessels ◽  
Amyloid Β ◽  
Secretory Product ◽  
Cervical Lymph Nodes ◽  
Waste Products ◽  
Glymphatic System ◽  
The Brain

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system.  This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively.  The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces.  Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin.  Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia.  Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

Myf5 is a novel early axonal marker in the mouse brain and is subjected to post-transcriptional regulation in neurons

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 319-331 ◽  
Author(s):  
P. Daubas ◽  
S. Tajbakhsh ◽  
J. Hadchouel ◽  
M. Primig ◽  
M. Buckingham
Keyword(s):  
Transcription Factor ◽  
Mouse Brain ◽  
Mrna Translation ◽  
Adult Brain ◽  
Protein Accumulation ◽  
Embryonic Mouse ◽  
Signalling Molecules ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
The Brain

Myf5 is a key basic Helix-Loop-Helix transcription factor capable of converting many non-muscle cells into muscle. Together with MyoD it is essential for initiating the skeletal muscle programme in the embryo. We previously identified unexpected restricted domains of Myf5 transcription in the embryonic mouse brain, first revealed by Myf5-nlacZ(+/)(−) embryos (Tajbakhsh, S. and Buckingham, M. (1995) Development 121, 4077–4083). We have now further characterized these Myf5 expressing neurons. Retrograde labeling with diI, and the use of a transgenic mouse line expressing lacZ under the control of Myf5 regulatory sequences, show that Myf5 transcription provides a novel axonal marker of the medial longitudinal fasciculus (mlf) and the mammillotegmental tract (mtt), the earliest longitudinal tracts to be established in the embryonic mouse brain. Tracts projecting caudally from the developing olfactory system are also labelled. nlacZ and lacZ expression persist in the adult brain, in a few ventral domains such as the mammillary bodies of the hypothalamus and the interpeduncular nucleus, potentially derived from the embryonic structures where the Myf5 gene is transcribed. To investigate the role of Myf5 in the brain, we monitored Myf5 protein accumulation by immunofluorescence and immunoblotting in neurons transcribing the gene. Although Myf5 was detected in muscle myotomal cells, it was absent in neurons. This would account for the lack of myogenic conversion in brain structures and the absence of a neural phenotype in homozygous null mutants. RT-PCR experiments show that the splicing of Myf5 primary transcripts occurs correctly in neurons, suggesting that the lack of Myf5 protein accumulation is due to regulation at the level of mRNA translation or protein stability. In the embryonic neuroepithelium, Myf5 is transcribed in differentiated neurons after the expression of neural basic Helix-Loop-Helix transcription factors. The signalling molecules Wnt1 and Sonic hedgehog, implicated in the activation of Myf5 in myogenic progenitor cells in the somite, are also produced in the viscinity of the Myf5 expression domain in the mesencephalon. We show that cells expressing Wnt1 can activate neuronal Myf5-nlacZ gene expression in dissected head explants isolated from E9.5 embryos. Furthermore, the gene encoding the basic Helix-Loop-Helix transcription factor mSim1 is expressed in adjacent cells in both the somite and the brain, suggesting that signalling molecules necessary for the activation of mSim1 as well as Myf5 are present at these different sites in the embryo. This phenomenon may be widespread and it remains to be seen how many other potentially potent regulatory genes, in addition to Myf5, when activated do not accumulate protein at inappropriate sites in the embryo.

scholarly journals Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Manoj Govindarajulu ◽  
Priyanka D. Pinky ◽  
Jenna Bloemer ◽  
Nila Ghanei ◽  
Vishnu Suppiramaniam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Effects ◽  
Therapeutic Potential ◽  
Protein Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Continuous Increase ◽  
Therapeutic Benefits ◽  
The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

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