Induction of an Isoelectric Brain State to Investigate the Impact of Endogenous Synaptic Activity on Neuronal Excitability In Vivo

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

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All-optical electrophysiology reveals brain-state dependent changes in hippocampal subthreshold dynamics and excitability

10.1101/281618 ◽

2018 ◽

Cited By ~ 16

Author(s):

Yoav Adam ◽

Jeong J. Kim ◽

Shan Lou ◽

Yongxin Zhao ◽

Daan Brinks ◽

...

Keyword(s):

High Speed ◽

Near Infrared ◽

Neuronal Excitability ◽

Signal To Noise Ratio ◽

Brain State ◽

Promising Tool ◽

State Dependent ◽

Subthreshold Voltage ◽

Targeted Gene Expression

AbstractA technology to record membrane potential from multiple neurons, simultaneously, in behaving animals will have a transformative impact on neuroscience research1. Parallel recordings could reveal the subthreshold potentials and intercellular correlations that underlie network behavior2. Paired stimulation and recording can further reveal the input-output properties of individual cells or networks in the context of different brain states3. Genetically encoded voltage indicators are a promising tool for these purposes, but were so far limited to single-cell recordings with marginal signal to noise ratio (SNR) in vivo4-6. We developed improved near infrared voltage indicators, high speed microscopes and targeted gene expression schemes which enabled recordings of supra- and subthreshold voltage dynamics from multiple neurons simultaneously in mouse hippocampus, in vivo. The reporters revealed sub-cellular details of back-propagating action potentials, correlations in sub-threshold voltage between multiple cells, and changes in dynamics associated with transitions from resting to locomotion. In combination with optogenetic stimulation, the reporters revealed brain state-dependent changes in neuronal excitability, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behavior.

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Controlling Brain State Prior to Stimulation of Parietal Cortex Prevents Deterioration of Sustained Attention

Cerebral Cortex Communications ◽

10.1093/texcom/tgaa069 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Grace Edwards ◽

Federica Contò ◽

Loryn K Bucci ◽

Lorella Battelli

Keyword(s):

Sustained Attention ◽

Neuronal Excitability ◽

Right Hemisphere ◽

Repetitive Transcranial Magnetic Stimulation ◽

Random Noise ◽

Impact Behavior ◽

Brain State ◽

Functional Compensation ◽

Transcranial Random Noise Stimulation ◽

The Impact

Abstract Sustained attention is a limited resource which declines during daily tasks. Such decay is exacerbated in clinical and aging populations. Inhibition of the intraparietal sulcus (IPS), using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS), can lead to an upregulation of functional communication within the attention network. Attributed to functional compensation for the inhibited node, this boost lasts for tens of minutes poststimulation. Despite the neural change, no behavioral correlate has been found in healthy subjects, a necessary direct evidence of functional compensation. To understand the functional significance of neuromodulatory induced fluctuations on attention, we sought to boost the impact of LF-rTMS to impact behavior. We controlled brain state prior to LF-rTMS using high-frequency transcranial random noise stimulation (HF-tRNS), shown to increase and stabilize neuronal excitability. Using fMRI-guided stimulation protocols combining HF-tRNS and LF-rTMS, we tested the poststimulation impact on sustained attention with multiple object tracking (MOT). While attention deteriorated across time in control conditions, HF-tRNS followed by LF-rTMS doubled sustained attention capacity to 94 min. Multimethod stimulation was more effective when targeting right IPS, supporting specialized attention processing in the right hemisphere. Used in cognitive domains dependent on network-wide neural activity, this tool may cause lasting neural compensation useful for clinical rehabilitation.

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Potential Role of Synaptic Activity to Inhibit LTD Induction in Rat Visual Cortex

Neural Plasticity ◽

10.1155/2016/1401935 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Matthew R. Stewart ◽

Hans C. Dringenberg

Keyword(s):

Visual Cortex ◽

Low Frequency ◽

Synaptic Activity ◽

Brain State ◽

Complex Activity ◽

Intact Brain ◽

Frequency Stimulation ◽

Cortical Synapses

Long-term depression (LTD), a widely studied form of activity-dependent synaptic plasticity, is typically induced by prolonged low-frequency stimulation (LFS). Interestingly, LFS is highly effective in eliciting LTDin vitro, but much less so underin vivoconditions; the reasons for the resistance of the intact brain to express LTD are not well understood. We examined if levels of background electrocorticographic (ECoG) activity influence LTD induction in the thalamocortical visual system of rats under very deep urethane anesthesia, inducing a brain state of reduced spontaneous cortical activity. Under these conditions, LFS applied to the lateral geniculate nucleus resulted in LTD of field postsynaptic potentials (fPSPs) recorded in the primary visual cortex (V1). Pairing LFS with stimulation of the brainstem (pedunculopontine) reticular formation resulted in the appearance of faster, more complex activity in V1 and prevented LTD induction, an effect that did not require muscarinic or nicotinic receptors. Reticular stimulation alone (without LFS) had no effect on cortical fPSPs. These results show that excitation of the brainstem activating system blocks the induction of LTD in V1. Thus, higher levels of neural activity may inhibit depression at cortical synapses, a hypothesis that could explain discrepancies regarding LTD induction in previousin vivoandin vitrowork.

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Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

10.21203/rs.3.rs-41604/v1 ◽

2020 ◽

Author(s):

Eduardo Javier Fernandez-Perez ◽

Braulio Muñoz ◽

Denisse Andrea Bascuñan ◽

Christian Peters ◽

Nicolas Osiel Riffo-Lepe ◽

...

Keyword(s):

Hippocampal Neurons ◽

Neuronal Excitability ◽

Ex Vivo ◽

Synaptic Activity ◽

No Production ◽

Synaptic Currents ◽

Aβ Oligomers ◽

Brain Hyperexcitability

Abstract Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro , ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

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Background Activity Regulates Excitability of Rat Hippocampal CA1 Pyramidal Neurons by Adaptation of a K+ Conductance

Journal of Neurophysiology ◽

10.1152/jn.00220.2005 ◽

2006 ◽

Vol 95 (3) ◽

pp. 2007-2012 ◽

Cited By ~ 11

Author(s):

Ingrid van Welie ◽

Johannes A. van Hooft ◽

Wytse J. Wadman

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Dynamic Range ◽

Background Activity ◽

Hippocampal Slices ◽

Synaptic Activity ◽

Input Output ◽

Ca1 Pyramidal Neurons

In the in vivo brain background synaptic activity has a strong modulatory influence on neuronal excitability. Here we report that in rat hippocampal slices, blockade of endogenous in vitro background activity results in an increased excitability of CA1 pyramidal neurons within tens of minutes. The increase in excitability constitutes a leftward shift in the input–output relationship of pyramidal neurons, indicating a reduced threshold for the induction of action potentials. The increase in excitability results from an adaptive decrease in a sustained K+ conductance, as recorded from somatic cell–attached patches. After 20 min of blockade of background activity, the mean sustained K+ current amplitude in somatic patches was reduced to 46 ± 9% of that in time-matched control patches. Blockade of background activity did not affect fast Na+ conductance. Together, these results suggests that the reduction in K+ conductance serves as an adaptive mechanism to increase the excitability of CA1 pyramidal neurons in response to changes in background activity such that the dynamic range of the input–output relationship is effectively maintained.

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Retrosplenial Cortex Contributes to Network Changes during Seizures in the GAERS Absence Epilepsy Rat Model

Cerebral Cortex Communications ◽

10.1093/texcom/tgab023 ◽

2021 ◽

Author(s):

Lydia Wachsmuth ◽

Maia Datunashvili ◽

Katharina Kemper ◽

Franziska Albers ◽

Henriette Lambers ◽

...

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Local Level ◽

Small World ◽

Resting State Fmri ◽

Absence Epilepsy ◽

Retrosplenial Cortex ◽

Synaptic Activity ◽

Brain State ◽

Cortical Regions

Abstract Resting state-fMRI (rs-fMRI) was performed to explore brain networks in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and in non-epileptic controls (NEC) during monitoring of the brain state by simultaneous optical Ca2+-recordings. Graph theoretical analysis allowed for identification of acute and chronic network changes and revealed preserved small world topology before and after seizure onset. The most prominent acute change in network organization during seizures was the segregation of cortical regions from the remaining brain. Stronger connections between thalamic with limbic regions compared to pre-seizure state indicated network regularization during seizures. When comparing between strains, intra-thalamic connections were prominent in NEC, on local level represented by higher thalamic strengths and hub scores. Subtle differences were observed for retrosplenial cortex (RS), forming more connections beyond cortex in epileptic rats, and showing a tendency to lateralization during seizures. A potential role of RS as hub between subcortical and cortical regions in epilepsy was supported by increased numbers of parvalbumin-positive (PV+) interneurons together with enhanced inhibitory synaptic activity and neuronal excitability in pyramidal neurons. By combining multimodal fMRI data, graph theoretical methods, and electrophysiological recordings we identified the RS as promising target for modulation of seizure activity and/or comorbidities.

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Controlling brain state prior to stimulation of parietal cortex prevents deterioration of sustained attention

10.1101/2020.01.06.896357 ◽

2020 ◽

Author(s):

Grace Edwards ◽

Federica Contò ◽

Loryn K. Bucci ◽

Lorella Battelli

Keyword(s):

Sustained Attention ◽

Neuronal Excitability ◽

Right Hemisphere ◽

Random Noise ◽

Cognitive Domain ◽

Impact Behavior ◽

Brain State ◽

Functional Compensation ◽

Transcranial Random Noise Stimulation ◽

The Impact

AbstractSustained attention is a limited resource which declines during daily tasks. Such decay is exacerbated in clinical and aging populations. Recent research has demonstrated that inhibition of the intraparietal sulcus (IPS) using low-frequency transcranial magnetic stimulation (LF-rTMS) can lead to an upregulation of functional communication within the attention network. Attributed to functional compensation for the inhibited node, this boost outlasts the stimulation for tens of minutes. Despite the neural change, no behavioral correlate has been found in healthy subjects, a necessary direct evidence of functional compensation. To understand the functional significance of neuromodulatory induced fluctuations on attention, we sought to boost the impact of LF-rTMS through controlling neural excitability prior to LF-rTMS, with the goal to impact behavior. Brain state was controlled using high-frequency transcranial random noise stimulation (HF-tRNS), shown to increase and stabilizes neuronal excitability. Using fMRI-guided stimulation protocols combining HF-tRNS and LF-rTMS, we tested the post-stimulation impact on sustained attention via a multiple object tracking task (MOT). Whilst attention deteriorated across time in the control conditions, HF-tRNS followed by LF-rTMS maintained attention performance up to 94 minutes, doubling the length of successful sustained attention. Multimethod stimulation was also more effective when targeting right IPS, supporting the notion of specialized attention processing in the right hemisphere. Used in a cognitive domain dependent on network-wide neural activity, this tool may be effective in causing lasting neural compensation important for clinical rehabilitation.

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Impact of Spontaneous Synaptic Activity on the Resting Properties of Cat Neocortical Pyramidal Neurons In Vivo

Journal of Neurophysiology ◽

10.1152/jn.1998.79.3.1450 ◽

1998 ◽

Vol 79 (3) ◽

pp. 1450-1460 ◽

Cited By ~ 270

Author(s):

Denis Paré ◽

Eric Shink ◽

Hélène Gaudreau ◽

Alain Destexhe ◽

Eric J. Lang

Keyword(s):

Cortical Neurons ◽

Pyramidal Neurons ◽

Brain Slices ◽

Synaptic Activity ◽

Intact Brain ◽

Lower Temperature ◽

The Impact ◽

Neocortical Pyramidal Neurons

Paré, Denis, Eric Shink, Hélène Gaudreau, Alain Destexhe, and Eric J. Lang. Impact of spontaneous synaptic activity on the resting properties of cat neocortical pyramidal neurons in vivo. J. Neurophysiol. 79: 1450–1460, 1998. The frequency of spontaneous synaptic events in vitro is probably lower than in vivo because of the reduced synaptic connectivity present in cortical slices and the lower temperature used during in vitro experiments. Because this reduction in background synaptic activity could modify the integrative properties of cortical neurons, we compared the impact of spontaneous synaptic events on the resting properties of intracellularly recorded pyramidal neurons in vivo and in vitro by blocking synaptic transmission with tetrodotoxin (TTX). The amount of synaptic activity was much lower in brain slices (at 34°C), as the standard deviation of the intracellular signal was 10–17 times lower in vitro than in vivo. Input resistances ( R ins) measured in vivo during relatively quiescent epochs (“control R ins”) could be reduced by up to 70% during periods of intense spontaneous activity. Further, the control R ins were increased by ∼30–70% after TTX application in vivo, approaching in vitro values. In contrast, TTX produced negligible R in changes in vitro (∼4%). These results indicate that, compared with the in vitro situation, the background synaptic activity present in intact networks dramatically reduces the electrical compactness of cortical neurons and modifies their integrative properties. The impact of the spontaneous synaptic bombardment should be taken into account when extrapolating in vitro findings to the intact brain.

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The Ethanol Metabolite Acetic Acid Activates Mouse Nucleus Accumbens Shell Medium Spiny Neurons

Journal of Neurophysiology ◽

10.1152/jn.00659.2020 ◽

2021 ◽

Author(s):

Andrew D. Chapp ◽

Paul G Mermelstein ◽

Mark J Thomas

Keyword(s):

Acetic Acid ◽

Nucleus Accumbens ◽

Neuronal Excitability ◽

Ethanol Consumption ◽

Synaptic Activity ◽

Medium Spiny Neurons ◽

Nucleus Accumbens Shell ◽

Spiny Neurons ◽

The Impact ◽

Reward Circuit

While ethanol consumption leads to an array of neurophysiological alterations involving the neural circuits for reward, the underlying mechanisms remain unclear. Acetic acid is a major metabolite of ethanol with high bioactivity and potentially significant pharmacological importance in regulating brain function. Yet the impact of acetic acid on reward circuit function has not been well explored. Given the rewarding properties associated with ethanol consumption, we investigated the acute effects of ethanol and/or acetic acid on the neurophysiological function of medium spiny neurons of the nucleus accumbens shell, a key node in the mammalian reward circuit. We find that acetic acid, but not ethanol, provided a rapid and robust boost in neuronal excitability at physiologically relevant concentrations, while both compounds enhanced glutamatergic synaptic activity. These effects were consistent across both sexes in C57BL/6J mice. Overall, our data suggest acetic acid is a promising candidate mediator for ethanol effects on mood and motivation that deserves further investigation.

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