Optogenetic gamma stimulation rescues memory impairments in an Alzheimer’s disease mouse model

Etter, Guillaume; Veldt, Suzanne van der; Manseau, Frédéric; Zarrinkoub, Iman; Trillaud-Doppia, Émilie; Williams, Sylvain

doi:10.1038/s41467-019-13260-9

Cited by 194 publications

(186 citation statements)

References 70 publications

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“…These results show that AD mice, despite showing aberrant brain dynamics (state 4) at baseline, may return to wild-type-like brain dynamics following theta rhythm optogenetic stimulation of EC. This complements previous evidence that EC stimulation may provide therapeutic benefit in AD 38 , and provides causal evidence of a mechanism that might underpin clinical benefits of EC stimulation.…”

Section: Impaired Multiplexing In Brain Network Dynamics In a Transgesupporting

confidence: 82%

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

Salvan

Lazari

Vidaurre

et al. 2020

Preprint

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An important question in neuroscience is how local activity can be flexibly and selectively routed across the brain network. A proposed mechanism to flexibly route information is frequency division multiplexing: selective readout can be achieved by segregating the signal into non-overlapping frequency bands. Here, in wild-type mice and in a transgenic model (3xTgAD) of Alzheimer's Disease (AD), we use optogenetic activation of the entorhinal cortex, concurrent whole-brain fMRI, and hidden Markov modeling. We demonstrate how inducing neuronal spiking with different theta frequencies causes spatially distinct states of brain network dynamics to emerge and to preferentially respond to one frequency, showing how selective information streams can arise from a single neuronal source of activity. This theta modulation mechanism, however, is impaired in the AD model. This work demonstrates that neuronal multiplexing is a sufficient mechanism to enable flexible brain network communication, and provides insight into the aberrant mechanisms underlying cognitive decline. ResultsOscillations result from the dynamic interaction between cellular and circuit properties. At microscopic scales, oscillatory synchronizations are constrained by axon conduction and synaptic delays; at macroscopic scales, oscillatory synchronizations are thought to be influenced by the architectural properties of the brain network (for review: 8 ). This complex interplay between oscillatory patterns and brain network topology may, therefore, allow neuronal signalling to selectively propagate along distinct subdivisions of anatomical projections or circuits 6 , giving rise to multiple temporal and spatial scales 8 or information streams 4 . From a modeling perspective, it is possible to utilize the sequential nature of BOLD fMRI data in order to characterize transient network states in brain hemodynamic activity. HMMs are well-suited because they provide a time-point-by-time-point description of network activity at the single-trial level, facilitating the characterisation of how such responses may evolve across time 7 or in response to perturbations such as stimulation.While HMMs provide a novel way of interrogating information within fMRI data, their use has not been previously applied to species other than humans. Here, using HMMs, we show that spontaneous hemodynamic fluctuations in the mouse brain at rest are temporally organized in a series of states that mirror well-established resting-state networks 9-11 ( Fig. S1-3 , see Supplementary results). Furthermore, we show that these states are organized in a hierarchical fashion, similar to what has been previously observed in humans 7 . Together, these results show that spontaneous brain network activity in mice is characterized by similar principles of temporal organization as in humans, thus providing further evidence of how the mouse brain is a relevant model to causally study neuronal mechanisms of mammalian brain network dynamics.Single-area evoked neuronal spiking is sufficient to cause spatiall...

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Section: Impaired Multiplexing In Brain Network Dynamics In a Transgesupporting

confidence: 82%

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

Salvan

Lazari

Vidaurre

et al. 2020

Preprint

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“…Other studies showed that alteration gamma with anxiety behaviors (Batashvili et al, 2019;Cruces-Solis et al, 2019;Zhou et al, 2018). Nevertheless, to our knowledge, there is no study showing a systematic effect of aging on magnitude of gamma power, except when degeneration is present (Etter et al, 2019;Goutagny et al, 2013). The lack of theta2 in animals treated with 5-MeO-DMT associated to the lack of anxiety-like behavior also suggest that lack of anxiety rather than aging explain the absence of theta2 in old animals.…”

Section: Discussionmentioning

confidence: 80%

Anxiety-like behavior induced by salicylate depends on age and can be prevented by a single dose of 5-MeO-DMT

Winne

Ciralli

Malfatti

et al. 2020

Experimental Neurology

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Salicylate intoxication is a cause of tinnitus and comorbidly associated with anxiety in humans. In a previous work, we showed that salicylate induces anxiety-like behavior and hippocampal type 2 theta oscillations (theta2) in mice. Here we investigate if the anxiogenic effect of salicylate is dependent on age and previous tinnitus experience. We also tested whether a single dose of DMT can prevent this effect. Using microwire electrode arrays, we recorded local field potential in young (4-5-month-old) and old (11-13-month-old) mice to study the electrophysiological effect of tinnitus in the ventral hippocampus (vHipp) and medial prefrontal cortex (mPFC) in an open field arena and elevated plus maze 1 h after salicylate (300 mg/kg) injection. We found that anxietylike behavior and increase in theta2 oscillations (4-6 Hz), following salicylate pre-treatment, only occurs in young (normal hearing) mice. We also show that theta2 and slow gamma oscillations increase in the vHipp and mPFC in a complementary manner during anxiety tests in the presence of salicylate. Finally, we show that pretreating mice with a single dose of the hallucinogenic 5-MeO-DMT prevents anxiety-like behavior and the increase in theta2 and slow gamma oscillations after salicylate injection in normal hearing young mice. This work further support the hypothesis that anxiety-like behavior after salicylate injection is triggered by tinnitus and require normal hearing. Moreover, our results show that hallucinogenic compounds can be effective in treating tinnitus-related anxiety.

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“…It would be crucial in the future to determine whether optogenetic stimulation of BF PV+ neurons could also modify cognitive functions. A recent study showed that the acute optogenetic induction of low gamma oscillations (but not high gamma) in the hippocampus can rescue memory impairments 26 . Although we did not observe any significant changes in plaque density in the hippocampus, hippocampus-dependent functions may be modified through the modulation of septal activity.…”

Section: Discussionmentioning

confidence: 99%

“…For example, increased or decreased neural firing promotes or suppresses the spread of Amyloid-β (Aβ), respectively 22 , 23 . In particular, the artificial induction of cortical gamma oscillations is an attractive option because it can reduce amyloid load and improve cognitive functions by activating microglia 10 , 11 , 24 , 25 and because optogenetic restoration of hippocampal gamma oscillations can rescue memory impairments 26 .…”

Section: Introductionmentioning

confidence: 99%

Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer’s disease pathology

Wilson

Fouda

Sakata

2020

Sci Rep

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Neuronal activity can modify Alzheimer’s disease pathology. Overexcitation of neurons can facilitate disease progression whereas the induction of cortical gamma oscillations can reduce amyloid load and improve cognitive functions in mouse models. Although previous studies have induced cortical gamma oscillations by either optogenetic activation of cortical parvalbumin-positive (PV+) neurons or sensory stimuli, it is still unclear whether other approaches to induce gamma oscillations can also be beneficial. Here we show that optogenetic activation of PV+ neurons in the basal forebrain (BF) increases amyloid burden, rather than reducing it. We applied 40 Hz optical stimulation in the BF by expressing channelrhodopsin-2 (ChR2) in PV+ neurons of 5xFAD mice. After 1-h induction of cortical gamma oscillations over three days, we observed the increase in the concentration of amyloid-β42 in the frontal cortical region, but not amyloid-β40. Amyloid plaques were accumulated more in the medial prefrontal cortex and the septal nuclei, both of which are targets of BF PV+ neurons. These results suggest that beneficial effects of cortical gamma oscillations on Alzheimer’s disease pathology can depend on the induction mechanisms of cortical gamma oscillations.

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Optogenetic gamma stimulation rescues memory impairments in an Alzheimer’s disease mouse model

Cited by 194 publications

References 70 publications

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

Causal evidence of network communication in whole-brain dynamics through a multiplexed neural code

Anxiety-like behavior induced by salicylate depends on age and can be prevented by a single dose of 5-MeO-DMT

Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer’s disease pathology

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