scholarly journals Inhibition is the hallmark of CA3 intracellular dynamics around awake ripples

2021 ◽  
Author(s):  
Koichiro Kajikawa ◽  
Brad K. Hulse ◽  
Athanassios G. Siapas ◽  
Evgueniy V. Lubenov

ABSTRACTHippocampal ripples are transient population bursts that structure cortico-hippocampal communication and play a central role in memory processing. However, the mechanisms controlling ripple initiation in behaving animals remain poorly understood. Here we combine multisite extracellular and whole cell recordings in awake mice to contrast the brain state and ripple modulation of subthreshold dynamics across hippocampal subfields. We find that entorhinal input to DG exhibits UP and DOWN dynamics with ripples occurring exclusively in UP states. While elevated cortical input in UP states generates depolarization in DG and CA1, it produces persistent hyperpolarization in CA3 neurons. Furthermore, growing inhibition is evident in CA3 throughout the course of the ripple buildup, while DG and CA1 neurons exhibit depolarization transients 100 ms before and during ripples. These observations highlight the importance of CA3 inhibition for ripple generation, while pre-ripple responses indicate a long and orchestrated ripple initiation process in the awake state.

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1118
Author(s):  
Jan Homolak ◽  
Ana Babic Perhoc ◽  
Ana Knezovic ◽  
Jelena Osmanovic Barilar ◽  
Melita Salkovic-Petrisic

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore (i) gastrointestinal homeostasis in the STZ-icv model (ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and (iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and low molecular weight thiols (LMWT), protein sulfhydryls (SH), and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that (i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, (ii) brain GLP-1R signaling is involved in systemic redox regulation, (iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.


2021 ◽  
Author(s):  
Geisa B. Gallardo‐Moreno ◽  
Francisco J. Alvarado‐Rodríguez ◽  
Rebeca Romo‐Vázquez ◽  
Hugo Vélez‐Pérez ◽  
Andrés A. González‐Garrido

2005 ◽  
Vol 25 (12) ◽  
pp. 1586-1595 ◽  
Author(s):  
Olof Bendel ◽  
Tjerk Bueters ◽  
Mia von Euler ◽  
Sven Ove Ögren ◽  
Johan Sandin ◽  
...  

The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.


2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lan Xiao ◽  
Vinay Sharma ◽  
Leila Toulabi ◽  
Xuyu Yang ◽  
Cheol Lee ◽  
...  

Abstract Stress causes release of glucocorticoids from the adrenals which then circulate to the brain. High concentrations glucocorticoid from chronic severe stress results in pathophysiology in the brain, including neuronal degeneration, cell death and cognitive dysfunction, leading to diseases such as Alzheimer Disease and Major Depressive Disorders. Neurotrophic/growth factors such as BDNF, NGF and NT3 have been linked to these pathological conditions. Carboxypeptidase E (CPE), a proneuropeptide/prohormone processing enzyme, also named neurotrophic factor-α1(NFα1) is highly expressed in the stress-vulnerable hippocampal CA3 neurons, and was shown to have neuroprotective activity from in vitro studies. Here we investigated if CPE-NFα1 functions in vivo, independent of its enzymatic activity, and the mechanism underlying its action. We generated knock-in mice expressing a non-enzymatic form of CPE, CPE-E342Q, but not wild-type CPE. The CPE-E342Q mice showed significantly decreased neuropeptide content and exhibited obesity, diabetes and infertility due to lack of prohormone processing activity, similar to CPE-KO mice. However, they showed no hippocampal CA3 degeneration, exhibited neurogenesis in the dentate gyrus, and displayed normal spatial learning and memory, similar to CPE wild-type mice, after weaning stress; unlike CPE-KO mice which showed hippocampal CA3 neuronal degeneration and cognitive deficits. Binding studies showed that radiolabeled CPE bound hippocampal cell membrane specifically, in a saturable manner. Binding of CPE and CPE-E342Q to hippocampal neurons activated Erk signaling and pre-treatment with either of these proteins protected neurons against H2O2- or glutamate-induced neurotoxcity by increasing BCL2 expression. In vitro and in vivo inhibitor studies demonstrated that this neuroprotective effect was independent of tyrosine kinase receptor signaling. Taken together, the data provide evidence that CPE-NFα1 is a unique neurotrophic factor which acts through a non-tyrosine kinase receptor to activate Erk-BCL2 signaling to protect hippocampal CA3 neurons against stress-induced neurodegeneration and maintaining normal cognitive functions in mice.


2019 ◽  
Author(s):  
Jarno Tuominen ◽  
Sakari Kallio ◽  
Valtteri Kaasinen ◽  
Henry Railo

Can the brain be shifted into a different state using a simple social cue, as tests on highly hypnotisable subjects would suggest? Demonstrating an altered brain state is difficult. Brain activation varies greatly during wakefulness and can be voluntarily influenced. We measured the complexity of electrophysiological response to transcranial magnetic stimulation (TMS) in one “hypnotic virtuoso”. Such a measure produces a response outside the subject’s voluntary control and has been proven adequate for discriminating conscious from unconscious brain states. We show that a single-word hypnotic induction robustly shifted global neural connectivity into a state where activity remained sustained but failed to ignite strong, coherent activity in frontoparietal cortices. Changes in perturbational complexity indicate a similar move toward a more segregated state. We interpret these findings to suggest a shift in the underlying state of the brain, likely moderating subsequent hypnotic responding. [preprint updated 20/02/2020]


2018 ◽  
Vol 25 (11) ◽  
pp. 2832-2843 ◽  
Author(s):  
Amir Segev ◽  
Masaya Yanagi ◽  
Daniel Scott ◽  
Sarah A. Southcott ◽  
Jacob M. Lister ◽  
...  

Abstract Recent findings from in vivo-imaging and human post-mortem tissue studies in schizophrenic psychosis (SzP), have demonstrated functional and molecular changes in hippocampal subfields that can be associated with hippocampal hyperexcitability. In this study, we used a subfield-specific GluN1 knockout mouse with a disease-like molecular perturbation expressed only in hippocampal dentate gyrus (DG) and assessed its association with hippocampal physiology and psychosis-like behaviors. First, we used whole-cell patch-clamp recordings to measure the physiological changes in hippocampal subfields and cFos immunohistochemistry to examine cellular excitability. DG-GluN1 KO mice show CA3 cellular hyperactivity, detected using two approaches: (1) increased excitatory glutamate transmission at mossy fibers (MF)-CA3 synapses, and (2) an increased number of cFos-activated pyramidal neurons in CA3, an outcome that appears to project downstream to CA1 and basolateral amygdala (BLA). Furthermore, we examined psychosis-like behaviors and pathological memory processing; these show an increase in fear conditioning (FC), a reduction in prepulse inhibition (PPI) in the KO animal, along with a deterioration in memory accuracy with Morris Water Maze (MWM) and reduced social memory (SM). Moreover, with DREADD vectors, we demonstrate a remarkably similar behavioral profile when we induce CA3 hyperactivity. These hippocampal subfield changes could provide the basis for the observed increase in human hippocampal activity in SzP, based on the shared DG-specific GluN1 reduction. With further characterization, these animal model systems may serve as targets to test psychosis mechanisms related to hippocampus and assess potential hippocampus-directed treatments.


Author(s):  
M. Atif Yaqub ◽  
Keum-Shik Hong ◽  
Amad Zafar ◽  
Chang-Seok Kim

Transcranial direct current stimulation (tDCS) has been shown to create neuroplasticity in healthy and diseased populations. The control of stimulation duration by providing real-time brain state feedback using neuroimaging is a topic of great interest. This study presents the feasibility of a closed-loop modulation for the targeted functional network in the prefrontal cortex. We hypothesize that we cannot improve the brain state further after reaching a specific state during a stimulation therapy session. A high-definition tDCS of 1[Formula: see text]mA arranged in a ring configuration was applied at the targeted right prefrontal cortex of 15 healthy male subjects for 10[Formula: see text]min. Functional near-infrared spectroscopy was used to monitor hemoglobin chromophores during the stimulation period continuously. The correlation matrices obtained from filtered oxyhemoglobin were binarized to form subnetworks of short- and long-range connections. The connectivity in all subnetworks was analyzed individually using a new quantification measure of connectivity percentage based on the correlation matrix. The short-range network in the stimulated hemisphere showed increased connectivity in the initial stimulation phase. However, the increase in connection density reduced significantly after 6[Formula: see text]min of stimulation. The short-range network of the left hemisphere and the long-range network gradually increased throughout the stimulation period. The connectivity percentage measure showed a similar response with network theory parameters. The connectivity percentage and network theory metrics represent the brain state during the stimulation therapy. The results from the network theory metrics, including degree centrality, efficiency, and connection density, support our hypothesis and provide a guideline for feedback on the brain state. The proposed neuro-feedback scheme is feasible to control the stimulation duration to avoid overdosage.


Author(s):  
Joseph Levine

There are two basic philosophical problems about colour. The first concerns the nature of colour itself. That is, what sort of property is it? When I say of the shirt that I am wearing that it is red, what sort of fact about the shirt am I describing? The second problem concerns the nature of colour experience. When I look at the red shirt I have a visual experience with a certain qualitative character – a ‘reddish’ one. Thus colour seems in some sense to be a property of my sensory experience, as well as a property of my shirt. What sort of mental property is it? Obviously, the two problems are intimately related. In particular, there is a great deal of controversy over the following question: if we call the first sort of property ‘objective colour’ and the second ‘subjective colour’, which of the two, objective or subjective colour, is basic? Or do they both have an independent ontological status? Most philosophers adhere to the doctrine of physicalism, the view that all objects and events are ultimately constituted by the fundamental physical particles, properties and relations described in physical theory. The phenomena of both objective and subjective colour present problems for physicalism. With respect to objective colour, it is difficult to find any natural physical candidate with which to identify it. Our visual system responds in a similar manner to surfaces that vary along a wide range of physical parameters, even with respect to the reflection of light waves. Yet what could be more obvious than the fact that objects are coloured? In the case of subjective colour, the principal topic of this entry, there is an even deeper puzzle. It is natural to think of the reddishness of a visual experience – its qualitative character – as an intrinsic and categorical property of the experience. Intrinsic properties are distinguished from relational properties in that an object’s possession of the former does not depend on its relation to, or even the existence of, other objects, whereas its possession of the latter does. Categorical properties are distinguished from dispositional ones. A dispositional property is one that an object has by virtue of its tendency to behave in certain ways, or cause certain effects, in particular circumstances. So being brittle is dispositional in that it involves being liable to break under slight pressure, whereas being six feet tall, say, is categorical. If subjective colour is intrinsic and categorical, then it would seem to be a neural property of a brain state. But what sort of neural property could explain the reddishness of an experience? Furthermore, reduction of subjective colour to a neural property would rule out even the possibility that forms of life with different physiological structures, or intelligent robots, could have experiences of the same qualitative type as our experiences of red. While some philosophers endorse this consequence, many find it quite implausible. Neural properties seem best suited to explain how certain functions are carried out, and therefore it might seem better to identify subjective colour with the property of playing a certain functional role within the entire cognitive system realized by the brain. This allows the possibility that structures physically different from human brains could support colour experiences of the same type as our own. However, various puzzles undermine the plausibility of this claim. For instance, it seems possible that two people could agree in all their judgements of relative similarity and yet one sees green where the other sees red. If this ‘inverted spectrum’ case is a genuine logical possibility, as many philosophers advocate, then it appears that subjective colour must not be a matter of functional role, but rather an intrinsic property of experience. Another possibility is that qualitative character is just a matter of features the visual system, in the case of colour, is representing objects in the visual field to have. Reddish experiences are just visual representations of red. But this view too has problems with spectrum-inversion scenarios, and also entails some counterintuitive consequences concerning our knowledge of our own qualitative states. Faced with the dilemmas posed by subjective colour for physicalist doctrine, some philosophers opt for eliminativism, the doctrine that subjective colour is not a genuine, or real, phenomenon after all. On this view the source of the puzzle is a conceptual confusion; a tendency to extend our judgements concerning objective colour, what appear to be intrinsic and categorical properties of the surfaces of physical objects, onto the properties of our mental states. Once we see that nothing qualitative is happening ‘inside’, we will understand why we cannot locate any state or property of the brain with which to identify subjective colour. The controversy over the nature of subjective colour is part of a wider debate about the subjective aspect of conscious experience more generally. How does the qualitative character of experience – what it is like to see, hear and smell – fit into a physicalist scientific framework? At present all of the options just presented have their adherents, and no general consensus exists.


1989 ◽  
Vol 62 (4) ◽  
pp. 882-895 ◽  
Author(s):  
E. Cherubini ◽  
Y. Ben-Ari ◽  
K. Krnjevic

1. The reversible blocking effect of brief anoxia (2-4 min) on synaptic transmission was studied in submerged hippocampal slices (kept mostly at 34 degrees), obtained from adult (greater than 120 g) and very young (6-50 g) Wistar rats. Excitatory postsynaptic potentials (EPSPs) were recorded with extra- and intracellular electrodes, sometimes simultaneously: in CA1, they were evoked by stratum radiation stimulation, in CA3 by hilar stimulation. 2. In slices from adults, EPSPs in CA1 were depressed by 90% after 2 min of anoxia, and postanoxic recovery was relatively slow (one-half recovery times 4.0 +/- 0.23 min, mean +/- SE). EPSPs in CA3 were consistently more resistant, especially those generated by mossy fibers; after 2 min of anoxia, these were reduced by only 14.7 +/- 5.4%. 3. In newborn animals (PN1-4), both intra- and extracellular EPSPs (but no population spikes) could be recorded in CA1. Although smaller and more fatigable than in the adult, they were much more resistant to anoxia, after 2 min being reduced by only 44.1 +/- 8.8%; and they were not abolished even after 6-7 min. On the other hand, postanoxic recovery was very rapid, being one-half complete in 2.4 +/- 0.48 min. Only large and very prolonged (giant) depolarizing PSPs [probably inhibitory postsynaptic potentials (IPSPs)] could be recorded in CA3 neurons; they were rapidly blocked by anoxia. 4. In older pups (PN6-21), the CA1 EPSPs became progressively more sensitive to anoxia. At the end of the second week, they were as rapidly blocked as in slices from adults; but postanoxic recovery remained quicker throughout this period. In CA3, EPSPs could now be evoked that were as resistant to anoxia as in adult slices. 5. In both CA1 and CA3 neurons from adult rats, anoxia (for 2-3 min) reduced the input resistance (RN) by 45.7 +/- 6.25%. In CA1 neurons, there was most often some hyperpolarization (-7.2 +/- 1.8 mV), which was less consistent in CA3 cells. The return of O2 typically led to a second (postanoxic) phase of hyperpolarization (-7.9 +/- 1.93 mV). 6. At PN1-4, the resting potential (Vm) of most cells had to be maintained by current injection; the input resistance (RN) of CA1 neurons was 70% higher than in mature cells, and there was little time-dependent inward rectification. Anoxia produced no regular changes in Vm, and reductions in RN were very small (by only 9.6 +/- 5.0%). A postanoxic hyperpolarization was seen in only 2 neurons out of 11.(ABSTRACT TRUNCATED AT 400 WORDS)


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