Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE161626 | GEO | 2021/02/24
REPOSITORIES: GEO
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Project description:Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice
| PRJNA678963 | ENA
Project description:Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics' enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics' long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.
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Project description:Acute traumatic event exposure is a direct cause of post-traumatic stress disorder (PTSD). Amygdala is suggested to be associated with the development of PTSD. In our previous findings, different activation patterns of GABAergic neurons and glutamatergic neurons in early or late stages after stress were found. However, the neural plastic mechanism underlying the role of basolateral amygdala (BLA) in post-traumatic stress disorder remains unclear. Therefore, this study mainly aimed at investigating time-dependent morphologic and electrophysiological changes in BLA during the development of PTSD. We used single prolonged stress (SPS) procedure to establish PTSD model of rats. The rats showed no alterations in anxiety behavior as well as in dendritic spine density or synaptic transmission in BLA 1 day after SPS. However, 10 days after SPS, rats showed enhancement of anxiety behavior, and spine density and frequency of miniature excitatory and inhibitory postsynaptic currents in BLA. Our results suggested that after traumatic stress, BLA displayed delayed increase in both spinogenesis and synaptic transmission, which seemed to facilitate the development of PTSD.
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Project description:Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer's disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.
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Project description:We examined the effects of antipsychotic medications on the cell-specific epigenomics and transcriptomics in the frontal cortex of schizophrenic subjects.
2021-11-05 | GSE174407 | GEO
Project description:Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
| S-EPMC7772211 | biostudies-literature
Project description:Psychedelics hold promising potential as alternate treatments for neuropsychiatric disorders. However, the neural mechanisms by which they drive adaptive behavioral effects remain unclear. We isolated the specific neurons modulated by a psychedelic to determine their role in driving behavior. Using a light- and calcium-dependent activity integrator, we genetically tagged psychedelic-responsive neurons in the medial prefrontal cortex (mPFC) of mice. Single-nucleus RNA sequencing revealed that the psychedelic drove network-level activation of multiple cell-types, beyond those expressing 5-hydroxytryptamine 2A receptors. We labeled psychedelic-responsive mPFC neurons with an excitatory channelrhodopsin to enable their targeted manipulation. We found that reactivation of these cells recapitulated the anxiolytic effects of the psychedelic, without driving its hallucinogenic-like effects. These findings reveal essential insight into the cell-type specific mechanisms underlying psychedelic-induced behavioral states.
2024-11-04 | GSE278644 | GEO
Project description:Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.
| S-EPMC4648633 | biostudies-literature
Project description:Many aspects of the brain's design can be understood as the result of evolutionary drive toward metabolic efficiency. In addition to the energetic costs of neural computation and transmission, experimental evidence indicates that synaptic plasticity is metabolically demanding as well. As synaptic plasticity is crucial for learning, we examine how these metabolic costs enter in learning. We find that when synaptic plasticity rules are naively implemented, training neural networks requires extremely large amounts of energy when storing many patterns. We propose that this is avoided by precisely balancing labile forms of synaptic plasticity with more stable forms. This algorithm, termed synaptic caching, boosts energy efficiency manifold and can be used with any plasticity rule, including back-propagation. Our results yield a novel interpretation of the multiple forms of neural synaptic plasticity observed experimentally, including synaptic tagging and capture phenomena. Furthermore, our results are relevant for energy efficient neuromorphic designs.
| S-EPMC7082127 | biostudies-literature
Project description:To investigate the gene program activated by serotonergic hallucinogens in mouse somatosensory cortex, the effects of the 5-HT2A agonist (±)2,5-dimethoxy 4-iodoamphetamine (DOI) on gene expression was studied. The 5-HT2A serotonin receptor is a member of the 5-HT2 receptor subfamily of G protein–coupled receptors. The 5-HT2A receptor is thought to modulate processes related to cognition, appetite, mood, anxiety, sleep, and sexual behavior. Abnormal function of this receptor has been implicated in neuropsychiatric disorders such as major depression and schizophrenia. In particular, the 5-HT2A receptor has been implicated in the modulation of the mechanisms related to psychosis. We compared gene response patterns in the somatosensory cortical brain area, which has a high density of 5-HT2A receptors and has been implicated in the action of hallucinogenic drugs. Mice (strain 129Sv) were injected with DOI (2 mg/kg or 10 mg/kg) or vehicle, animals were sacrificed after 1 h, and somatosensory cortex samples dissected on ice for RNA extraction. Seven independent microarray hybridizations from seven different DOI- or vehicle-treated mouse pairs were performed. Keywords: other
2003-04-29 | GSE138 | GEO