Optogenetic Stimulation of Basal Forebrain Parvalbumin Neurons Activates the Default Mode Network and Associated Behaviors

AbstractSlow gamma oscillations (30–60 Hz) correlate with retrieval of spatial memory. Altered slow gamma oscillations have been observed in Alzheimer’s disease. Here, we use the J20-APP AD mouse model that displays spatial memory loss as well as reduced slow gamma amplitude and phase-amplitude coupling to theta oscillations phase. To restore gamma oscillations in the hippocampus, we used optogenetics to activate medial septal parvalbumin neurons at different frequencies. We show that optogenetic stimulation of parvalbumin neurons at 40 Hz (but not 80 Hz) restores hippocampal slow gamma oscillations amplitude, and phase-amplitude coupling of the J20 AD mouse model. Restoration of slow gamma oscillations during retrieval rescued spatial memory in mice despite significant plaque deposition. These results support the role of slow gamma oscillations in memory and suggest that optogenetic stimulation of medial septal parvalbumin neurons at 40 Hz could provide a novel strategy for treating memory deficits in AD.

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Basal forebrain contributes to default mode network regulation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712431115 ◽

2018 ◽

Vol 115 (6) ◽

pp. 1352-1357 ◽

Cited By ~ 19

Author(s):

Jayakrishnan Nair ◽

Arndt-Lukas Klaassen ◽

Jozsef Arato ◽

Alexei L. Vyssotski ◽

Michael Harvey ◽

...

Keyword(s):

Default Mode Network ◽

Basal Forebrain ◽

Cognitive Task ◽

Gamma Oscillations ◽

Anterior Cingulate ◽

Gamma Activity ◽

Sensory Stimuli ◽

Quiet Wakefulness ◽

Default Mode ◽

Brain States

The default mode network (DMN) is a collection of cortical brain regions that is active during states of rest or quiet wakefulness in humans and other mammalian species. A pertinent characteristic of the DMN is a suppression of local field potential gamma activity during cognitive task performance as well as during engagement with external sensory stimuli. Conversely, gamma activity is elevated in the DMN during rest. Here, we document that the rat basal forebrain (BF) exhibits the same pattern of responses, namely pronounced gamma oscillations during quiet wakefulness in the home cage and suppression of this activity during active exploration of an unfamiliar environment. We show that gamma oscillations are localized to the BF and that gamma-band activity in the BF has a directional influence on a hub of the rat DMN, the anterior cingulate cortex, during DMN-dominated brain states. The BF is well known as an ascending, activating, neuromodulatory system involved in wake–sleep regulation, memory formation, and regulation of sensory information processing. Our findings suggest a hitherto undocumented role of the BF as a subcortical node of the DMN, which we speculate may be important for switching between internally and externally directed brain states. We discuss potential BF projection circuits that could underlie its role in DMN regulation and highlight that certain BF nuclei may provide potential target regions for up- or down-regulation of DMN activity that might prove useful for treatment of DMN dysfunction in conditions such as epilepsy or major depressive disorder.

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Default mode network connectivity and brain derived neurotrophic factor in brain stimulation of traumatic brain injury patients

Brain Stimulation ◽

10.1016/j.brs.2021.10.146 ◽

2021 ◽

Vol 14 (6) ◽

pp. 1633

Author(s):

Maheen Adamson ◽

M. Windy McNerney ◽

Shan Siddiqi ◽

Girish Swaminath ◽

Lien-Lien Wu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Stimulation ◽

Default Mode Network ◽

Neurotrophic Factor ◽

Network Connectivity ◽

Brain Derived Neurotrophic Factor ◽

Default Mode ◽

Stimulation Of

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Cognitive stimulation of the default-mode network modulates functional connectivity in healthy aging

Brain Research Bulletin ◽

10.1016/j.brainresbull.2015.12.001 ◽

2016 ◽

Vol 121 ◽

pp. 26-41 ◽

Cited By ~ 15

Author(s):

Matteo De Marco ◽

Francesca Meneghello ◽

Davide Duzzi ◽

Jessica Rigon ◽

Cristina Pilosio ◽

...

Keyword(s):

Functional Connectivity ◽

Default Mode Network ◽

Healthy Aging ◽

Cognitive Stimulation ◽

Default Mode ◽

Stimulation Of

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Transcranial Direct Current Stimulation of Default Mode Network Parietal Nodes Decreases Negative Mind-Wandering About the Past

Cognitive Therapy and Research ◽

10.1007/s10608-019-10044-9 ◽

2019 ◽

Vol 44 (1) ◽

pp. 10-20

Author(s):

Tina Chou ◽

Jill M. Hooley ◽

Joan A. Camprodon

Keyword(s):

Direct Current ◽

Default Mode Network ◽

Transcranial Direct Current Stimulation ◽

Mind Wandering ◽

Default Mode ◽

Direct Current Stimulation ◽

The Past ◽

Stimulation Of

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074 Basal Forebrain GABAergic Neurons Promote Arousal by Disinhibiting the Orexin Neurons via Local GABAergic Interneurons

SLEEP ◽

10.1093/sleep/zsab072.073 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A31-A31

Author(s):

Michela Cristofolini ◽

Roberto De Luca ◽

Anne Venner ◽

Loris Ferrari ◽

Kevin Grace ◽

...

Keyword(s):

Basal Forebrain ◽

Viral Vector ◽

Brain Slices ◽

Nrem Sleep ◽

Gabaergic Neurons ◽

Gabaergic Interneurons ◽

Optogenetic Stimulation ◽

Stimulation Of

Abstract Introduction Optogenetic and chemogenetic studies have shown that activation of basal forebrain (BF) GABAergic neurons rapidly wakes up mice from non-REM (NREM) sleep. These wake-promoting responses have been attributed to BF GABAergic neurons projecting to the cerebral cortex and more specifically to the inhibition of cortical fast-spiking interneurons. Tracing studies have however found that BF GABAergic neurons also densely innervate the lateral hypothalamus (LH) perifornical area, although the role of this pathway in behavioral state control remains mostly unexplored. Methods We conducted in vivo and in vitro optogenetic studies. We selectively expressed channelrhodopsin-2 (ChR2) in BF GABAergic neurons by injecting a cre-dependent viral vector encoding for ChR2 into the BF of VGAT-cre mice. We photostimulated the BF GABAergic input to the LH with optical fibers placed into the LH of EEG instrumented mice. For in vitro recordings we expressed ChR2 in BF GABAergic neurons and we fluorescently labeled orexin or LH GABAergic neurons. We recorded in brain slices from identified orexin neurons or GABA neurons while photostimulating the BF GABAergic input. Results Optogenetic stimulation of the BF GABAergic fibers in the LH produced rapid arousals from NREM sleep. The same stimulation however did not wake up the mice if they were in REM sleep. We conducted additional studies in brain slices to identify the postsynaptic neurons in the LH targeted by the BF GABAergic input. We found that while optogenetic stimulation of the BF GABAergic input did not produce opto-evoked synaptic responses in the orexin neurons, it produced short-latency opto-evoked inhibitory postsynaptic currents (IPSCs) in LH GABAergic neurons. These opto-evoked IPSCs were GABAA receptor-mediated and were maintained in tetrodotoxin (TTX) indicating monosynaptic connectivity. We have previously found that orexin neurons are inhibited by local LH GABAergic neurons. Our hypothesis is that these local GABAergic interneurons are the target of the BF GABAergic arousal input. Conclusion BF GABAergic neurons drive arousal through projections to the LH. We propose that this arousal response is due to the inhibition of local GABAergic interneurons which in turn disinhibit the LH wake-promoting neurons including the orexin neurons. Support (if any) NS091126 and HL149630

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Subcortical Anatomy of the Default Mode Network: a functional and structural connectivity study

10.1101/528679 ◽

2019 ◽

Cited By ~ 1

Author(s):

Pedro Nascimento Alves ◽

Chris Foulon ◽

Vyacheslav Karolis ◽

Danilo Bzdok ◽

Daniel S. Margulies ◽

...

Keyword(s):

Default Mode Network ◽

Basal Forebrain ◽

Diffusion Weighted Imaging ◽

Mammalian Species ◽

Structural Connectivity ◽

Node Degree ◽

Thalamic Nuclei ◽

Subcortical Structures ◽

Default Mode ◽

Unitary Model

AbstractMost existing research into the default-mode network (DMN) has taken a corticocentric approach. Despite the resemblance of the DMN with the unitary model of the limbic system, the anatomy and contribution of subcortical structures to the network may be underappreciated due to methods limitation. Here, we propose a new and more comprehensive neuroanatomical model of the DMN including the basal forebrain and anterior and mediodorsal thalamic nuclei and cholinergic nuclei. This has been achieved by considering functional territories during interindividual brain alignment. Additionally, tractography of diffusion-weighted imaging was employed to explore the structural connectivity of the DMN and revealed that the thalamus and basal forebrain had high importance in term of values of node degree and centrality in the network. The contribution of these neurochemically diverse brain nuclei reconciles previous neuroimaging with neuropathological findings in diseased brain and offers the potential for identifying a conserved homologue of the DMN in other mammalian species.

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Dynamic Subcortical Modulators of Human Default Mode Network Function

10.1101/2021.10.27.466172 ◽

2021 ◽

Author(s):

Ben J Harrison ◽

Christopher G Davey ◽

Hannah S Savage ◽

Alec J Jamieson ◽

Christine A Leonards ◽

...

Keyword(s):

Task Performance ◽

Default Mode Network ◽

Basal Forebrain ◽

Direct Evidence ◽

Cortical Activation ◽

Ultra High Field ◽

Default Mode ◽

Network Function ◽

Cortical Regions ◽

Task Conditions

The brain's 'default mode network' (DMN) enables flexible switching between internally and externally focused cognition. Precisely how this modulation occurs is not well understood, although may involve key subcortical mechanisms, including hypothesized influences from the basal forebrain (BF) and mediodorsal thalamus (MD). Here, we used ultra-high field (7T) functional magnetic resonance imaging to examine the involvement of the BF and MD across states of task-induced DMN activity modulation. Specifically, we mapped DMN activity suppression ('deactivation') when participants transitioned between rest and externally focused task performance, as well as DMN activity engagement ('activation') when task performance was internally (i.e., self) focused. Consistent with recent rodent studies, the BF showed overall activity suppression with DMN cortical regions when comparing the rest to external task conditions. Further analyses, including dynamic causal modelling, confirmed that the BF drove changes in DMN cortical activity during these rest-to-task transitions. The MD, by comparison, was specifically engaged during internally focused cognition and demonstrated a broad excitatory influence on DMN cortical activation. These results provide the first direct evidence in humans of distinct basal forebrain and thalamic circuit influences on the control of DMN function and suggest novel mechanistic avenues for ongoing translational research.

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