Somatostatin Peptide Signaling Dampens Cortical Circuits and Promotes Exploratory Behavior

Brockway, Dakota F.; Griffith, Keith R; Aloimonos, Chloe; Clarity, Thomas; Moyer, J. Brody; Smith, Grace C; Dao, Nigel C.; Hossain, Md. Shakhawat; Drew, Patrick J.; Gordon, Joshua A.; Kupferschmit, David A.; Crowley, Nicole A.

doi:10.2139/ssrn.4319532

Cited by 4 publications

(4 citation statements)

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“…A loss of SST interneuron inhibition in depression is implicated by reduced SST expression in human patients postmortem 16,17 , increased anxiety- and depression-like symptoms in rodents with brain-wide SST interneuron silencing 18 , and SST interneuron transcriptome deregulations compared to other cell types following chronic stress in rodents 19 . This is further supported by the joint inhibitory effects and co-release of SST and GABA 20,21 . SST interneurons mediate lateral inhibition through disynaptic loops 22,23 and maintain low Pyr neuron spike rates at baseline 24–26 .…”

Section: Introductionmentioning

confidence: 62%

Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity

Guet-McCreight,

Mazza,

Prevot

et al. 2024

Preprint

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Treatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of α5-GABAA receptors (α5-PAM) offers a promising effective treatment. However, testing the effect of α5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and α5-PAM effects, to simulate EEG of virtual subjects across depression severity and α5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for α5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of α5-PAM treatment to clinical use.

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Section: Introductionmentioning

confidence: 62%

Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity

Guet-McCreight,

Mazza,

Prevot

et al. 2024

Preprint

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“…These effects of AT2R deletion on extinction learning and exploration support our proposed AT2R-somatostatin functional mechanism, as mPFC somatostatin interneurons have been shown to encode fear memory(39–41) and regulate stress in a sex-dependent manner(43). Further, increased somatostatin signaling, which we propose occurs with AT2R deletion, increases exploratory behavior in mice(65).…”

Section: Discussionmentioning

confidence: 84%

“…In both males and females, AT2R primarily colocalized with somatostatin-expressing interneurons, and females had greater co-expression with somatostatin than males across the PL and IL ( Fig. 4 ), indicating that AT2R preferentially modulates the activity of somatostatin interneurons, a key population in regulating cognition(38,65,66) and fear learning(39–41). The minimal levels of AT2R colocalization with other interneuron populations ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent effects of angiotensin type 2 receptor expressing medial prefrontal cortex (mPFC) interneurons in fear extinction learning

Smith,

Yu,

Iyer

et al. 2023

Preprint

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BackgroundThe renin-angiotensin system (RAS) has been identified as a potential therapeutic target for PTSD, though its mechanisms are not well understood. Brain angiotensin type 2 receptors (AT2Rs) are a subtype of angiotensin II receptors located in stress and anxiety-related regions, including the medial prefrontal cortex (mPFC), but their function and mechanism in the mPFC remain unexplored. We therefore used a combination of imaging, cre/lox, and behavioral methods to investigate mPFC-AT2R-expressing neuron involvement in fear learning.MethodsTo characterize mPFC-AT2R-expressing neurons in the mPFC, AT2R-Cre/td-Tomato male and female mice were used for immunohistochemistry (IHC). mPFC brain sections were stained with glutamatergic or interneuron markers, and density of AT2R+cells and colocalization with each marker was quantified. To assess fear-related behaviors in AT2R-flox mice, we selectively deleted AT2R from mPFC neurons using an AAV-Cre virus. Mice then underwent Pavlovian auditory fear conditioning, approach/avoidance, and locomotion testing.ResultsIHC results revealed that AT2R is densely expressed in the mPFC. Furthermore, AT2R is primarily expressed in somatostatin interneurons in females but not males. Following fear conditioning, mPFC-AT2R deletion impaired extinction in female but not male mice. Locomotion was unaltered by mPFC-AT2R deletion in males or females, while AT2R-deleted females had increased exploratory behavior.ConclusionThese results lend support for mPFC-AT2R+ neurons as a novel subgroup of somatostatin interneurons that influence fear extinction in a sex-dependent manner. This furthers underscores the role of mPFC in top-down regulation and a unique role for peptidergic (ie., angiotensin) mPFC regulation of fear and sex differences.

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“…Taken together, these data highlight the fact that SD may disrupt cognitive processes via diverse effects on interneuron populations, which are essential for appropriate memory storage 44 . SST+ interneurons have recently been shown to be essential for optimal hippocampal memory processing 8,45 and neocortical sensory 46 and executive functions 47 . Data from our lab and others suggest that SD-driven changes in the function of neocortical and hippocampal SST+ interneurons may be essential to homeostatic and cognitive responses 8,48,49 .…”

Section: Introductionmentioning

confidence: 99%

Brief sleep disruption alters synaptic structures among hippocampal and neocortical somatostatin-expressing interneurons

Raven,

Medina,

Schmidt

et al. 2024

Preprint

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Brief sleep loss can disrupt cognition, including information processing in neocortex and hippocampus. Recent studies have identified alterations in synaptic structures of principal neurons within these circuits. However, while in vivo recording and bioinformatic data suggest that inhibitory interneurons are more strongly affected by sleep loss, it is unclear how sleep and sleep deprivation affect interneuron synapses. Recent data suggest that activity among hippocampal somatostatin-expressing (SST+) interneurons is selectively increased by experimental sleep disruption. We used Brainbow 3.0 to label SST+ interneurons in the dorsal hippocampus, prefrontal cortex, and visual cortex of SST-CRE transgenic mice, then compared synaptic structures in labeled neurons after a 6-h period of ad lib sleep, or gentle handling sleep deprivation (SD) starting at lights on. We find that dendritic spine density among SST+ interneurons in both hippocampus and neocortex was altered in a subregion-specific manner, with increased overall and thin spine density in CA1, decreased mushroom spine density in CA3, and decreased overall and stubby spine density in V1 after SD. Spine size also changed significantly after SD, with dramatic increases in spine volume and surface area in CA3, and small but significant decreases in CA1, PFC and V1. Together, our data suggest that the synaptic connectivity of SST+ interneurons is significantly altered, in a brain region-specific manner, by a few hours of sleep loss. Further, they suggest that sleep loss can disrupt cognition by altering the balance of excitation and inhibition in hippocampal and neocortical networks.

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Somatostatin Peptide Signaling Dampens Cortical Circuits and Promotes Exploratory Behavior

Cited by 4 publications

References 0 publications

Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity

Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity

Sex-dependent effects of angiotensin type 2 receptor expressing medial prefrontal cortex (mPFC) interneurons in fear extinction learning

Brief sleep disruption alters synaptic structures among hippocampal and neocortical somatostatin-expressing interneurons

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