Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis.
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ABSTRACT:
SUBMITTER: Choi Y
PROVIDER: S-EPMC8389495 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionBoth ketamine (KET) and medial prefrontal cortex (mPFC) deep brain stimulation (DBS) are emerging therapies for treatment-resistant depression, yet our understanding of their electrophysiological mechanisms and biomarkers is incomplete. This study investigates aperiodic and periodic spectral parameters, and the signal complexity measure sample entropy, within mPFC local field potentials (LFP) in a chronic corticosterone (CORT) depression model after ketamine and/or mPFC DBS.MethodsMale rats were intraperitoneally administered CORT or vehicle for 21 days. Over the last 7 days, animals receiving CORT were treated with mPFC DBS, KET, both, or neither; then tested across an array of behavioral tasks for 9 days.ResultsWe found that the depression-like behavioral and weight effects of CORT correlated with a decrease in aperiodic-adjusted theta power (5-10 Hz) and an increase in sample entropy during the administration phase, and an increase in theta peak frequency and a decrease in the aperiodic exponent once the depression-like phenotype had been induced. The remission-like behavioral effects of ketamine alone correlated with a post-treatment increase in the offset and exponent, and decrease in sample entropy, both immediately and up to eight days post-treatment. The remission-like behavioral effects of mPFC DBS alone correlated with an immediate decrease in sample entropy, an immediate and sustained increase in low gamma (20-50 Hz) peak width and aperiodic offset, and sustained improvements in cognitive function. Failure to fully induce remission-like behavior in the combinatorial treatment group correlated with a failure to suppress an increase in sample entropy immediately after treatment.ConclusionOur findings therefore support the potential of periodic theta parameters as biomarkers of depression-severity; and periodic low gamma parameters and cognitive measures as biomarkers of mPFC DBS treatment efficacy. They also support sample entropy and the aperiodic spectral parameters as potential cross-modal biomarkers of depression severity and the therapeutic efficacy of mPFC DBS and/or ketamine. Study of these biomarkers is important as objective measures of disease severity and predictive measures of therapeutic efficacy can be used to personalize care and promote the translatability of research across studies, modalities, and species.
| S-EPMC11222339 | biostudies-literature
Project description:Schizophrenia is often marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine exhibit profound social and sensorimotor deficits as previously reported. Using three-dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naïve mice. We then examined the translatome of LS engram neurons and found upregulation of genes encoding potassium inwardly-rectifying channels and solute transporters as well as dysregulation of genes implicated in apoptotic processes, all of which could contribute to the hypoactivation of LS social engram neurons after chronic ketamine exposure. A number of ketamine-induced differentially expressed genes (DEGs), including those involved in mitochondrial function and neuroinflammatory pathways, were shared with human schizophrenia and mouse models of neurodevelopmental disorders.
2024-08-18 | GSE241234 | GEO
Project description:Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.
| S-EPMC4023152 | biostudies-literature
Project description:BackgroundThe medial prefrontal cortex (mPFC) plays an important role in depression and addiction. Previous studies have shown alterations in glutamatergic activity in the mPFC following the administration of ketamine in patients with depression and healthy controls. However, it remains unclear whether chronic, nonmedical use of ketamine affects metabolites in the mPFC.MethodsUsing proton magnetic resonance spectroscopy, we measured metabolites (glutamate and glutamine [Glx]; phosphocreatine and creatine [PCr+Cr]; myo-inositol; N-acetyl-aspartate; and glycerophosphocholine and phosphocholine [GPC+PC]) in the mPFC of chronic ketamine users (n = 20) and healthy controls (n = 43). Among ketamine users, 60% consumed ketamine once per day or more, 10% consumed it every 2 days and 30% consumed it every 3 or more days. Using analysis of covariance, we evaluated between-group differences in the ratios of Glx:PCr+Cr, myo-inositol:PCr+Cr, N-acetyl-aspartate:PCr+Cr and GPC+PC:PCr+Cr.ResultsChronic ketamine users showed significantly higher Glx:PCr+Cr ratios than healthy controls (median 1.05 v. 0.95, p = 0.008). We found no significant differences in myoinositol:PCr+Cr, N-acetyl-aspartate:PCr+Cr or GPC+PC:PCr+Cr ratios between the 2 groups. We found a positive relationship between N-acetyl-aspartate:PCr+Cr and Glx:PCr+Cr ratios in the healthy control group (R = 0.345, p = 0.023), but the ketamine use group failed to show such an association (ρ = 0.197, p = 0.40).LimitationsThe cross-sectional design of this study did not permit causal inferences related to higher Glx:PCr+Cr ratios and chronic ketamine use.ConclusionThis study provides the first evidence that chronic ketamine users have higher glutamatergic activity in the mPFC than healthy controls; this finding may provide new insights relevant to the treatment of depression with ketamine.
| S-EPMC9343127 | biostudies-literature
Project description:A subanesthetic dose of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine is known to induce a schizophrenia-like phenotype in humans and nonhuman primates alike. The transient behavioral changes mimic the positive, negative, and cognitive symptoms of the disease but the neural mechanisms behind these changes are poorly understood. A growing body of evidence indicates that the cognitive control processes associated with prefrontal cortex (PFC) regions relies on groups of neurons synchronizing at narrow-band frequencies measurable in the local field potential (LFP). Here, we recorded LFPs from the caudo-lateral PFC of 2 macaque monkeys performing an antisaccade task, which requires the suppression of an automatic saccade toward a stimulus and the initiation of a goal-directed saccade in the opposite direction. Preketamine injection activity showed significant differences in a narrow 20-30 Hz beta frequency band between correct and error trials in the postsaccade response epoch. Ketamine significantly impaired the animals' performance and was associated with a loss of the differences in outcome-specific beta-band power. Instead, we observed a large increase in high-gamma-band activity. Our results suggest that the PFC employs beta-band synchronization to prepare for top-down cognitive control of saccades and the monitoring of task outcome.
| S-EPMC4869811 | biostudies-other
Project description:Inhalants, including toluene, target the addiction neurocircuitry and are often one of the first drugs of abuse tried by adolescents. The medial prefrontal cortex (mPFC) is involved in regulating goal-directed/reward-motivated behaviors and different mPFC sub-regions have been proposed to promote (prelimbic, PRL) or inhibit (infralimbic, IL) these behaviors. While this dichotomy has been studied in the context of other drugs of abuse, it is not known whether toluene exposure differentially affects neurons within PRL and IL regions. To address this question, we used whole-cell electrophysiology and determined the intrinsic excitability of PRL and IL pyramidal neurons in adolescent rats 24?h following a brief exposure to air or toluene vapor (10?500?p.p.m.). Prior to exposure, fluorescent retrobeads were injected into the NAc core (NAcc) or shell (NAcs) sub-regions to identify projection-specific mPFC neurons. In toluene treated adolescent rats, layer 5/6 NAcc projecting PRL (PRL5/6) neurons fired fewer action potentials and this was associated with increased rheobase, increased spike duration, and reductions in membrane resistance and amplitude of the Ih current. No changes in excitability were observed in layer 2/3 NAcc projecting PRL (PRL2/3) neurons. In contrast to PRL neurons, layer 5 IL (IL5) and layer 2/3 (IL2/3) NAcc projecting neurons showed enhanced firing in toluene-exposed animals and in IL5 neurons, this was associated with a reduction in rheobase and AHP. For NAcs projecting neurons, toluene exposure significantly decreased firing of IL5 neurons and this was accompanied by an increased rheobase, increased spike duration, and reduced Ih amplitude. The intrinsic excitability of PRL5, PRL2/3, and IL2/3 neurons projecting to the NAcs was not affected by exposure to toluene. The changes in excitability observed 24?h after toluene exposure were not observed when recordings were performed 7 days after the exposure. Finally, there were no changes in intrinsic excitability of any region in rats exposed to toluene as adults. These findings demonstrate that specific projections of the reward circuitry are uniquely susceptible to the effects of toluene during adolescence supporting the idea that adolescence is a critical period of the development that is vulnerable to drugs of abuse.
| S-EPMC5809778 | biostudies-literature
Project description:BackgroundAcute treatment with subanaesthetic doses of NMDA receptor antagonists, such as ketamine, provides a translational model with relevance to many of the symptoms of schizophrenia. Previous studies have focused specifically on the prefrontal cortex (PFC) because this region is implicated in many of the functional deficits associated with this disorder and shows reduced activity (hypofrontality) in schizophrenia patients. Chronic NMDA antagonist treatment in rodents can also induce hypofrontality, although paradoxically acute NMDA receptor antagonist administration induces metabolic hyperfrontality.MethodsIn this study, we use 2-deoxyglucose imaging data in mice to characterize acute ketamine-induced alterations in regional functional connectivity, a deeper analysis of the consequences of acute NMDA receptor hypofunction.ResultsWe show that acute ketamine treatment increases PFC metabolic activity while reducing metabolic activity in the dorsal reticular thalamic nucleus (dRT). This is associated with abnormal functional connectivity between the PFC and multiple thalamic nuclei, including the dRT, mediodorsal (MDthal), and anteroventral (AVthal) thalamus. In addition, we show that acute NMDA receptor blockade alters the functional connectivity of the serotonergic (dorsal raphe [DR]), noradrenergic (locus coeruleus [LC]), and cholinergic (vertical limb of the diagonal band of broca [VDB]) systems.ConclusionsTogether with other emerging data, these findings suggest that the reticular nucleus of the thalamus, along with the diffusely projecting subcortical aminergic/cholinergic systems, represent a primary site of action for ketamine in reproducing the diverse symptoms of schizophrenia. Our results also demonstrate the added scientific insight gained by characterizing the functional connectivity of discrete brain regions from brain imaging data gained in a preclinical context.
| S-EPMC3576175 | biostudies-literature
Project description:Subanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamine's effects remains elusive, but ketamine may broadly modulate brain plasticity processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces downregulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons in vitro and in vivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus, ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia.
| S-EPMC7925140 | biostudies-literature
Project description:Anatomical alterations in the medial prefrontal cortex (mPFC) are associated with hypothalamopituitary adrenal (HPA) axis dysregulation, altered stress hormone levels, and psychiatric symptoms of stress-related mental illnesses. Functional imaging studies reveal impairment and shrinkage of the mPFC in such conditions, and these findings are paralleled by experimental studies showing dendritic retraction and spine loss following repeated stress in rodents. Here we extend this characterization to how repeated stress affects dendritic spine morphology in mPFC through the utilization of an automated approach that rapidly digitizes, reconstructs three dimensionally, and calculates geometric features of neurons. Rats were perfused after being subjected to 3 weeks of daily restraint stress (6 hours/day), and intracellular injections of Lucifer Yellow were made in layer II/III pyramidal neurons in the dorsal mPFC. To reveal spines in all angles of orientation, deconvolved high-resolution confocal laser scanning microscopy image stacks of dendritic segments were reconstructed and analyzed for spine volume, surface area, and length using a Rayburst-based automated approach (8,091 and 8,987 spines for control and stress, respectively). We found that repeated stress results in an overall decrease in mean dendritic spine volume and surface area, which was most pronounced in the distal portion of apical dendritic fields. Moreover, we observed an overall shift in the population of spines, manifested by a reduction in large spines and an increase in small spines. These results suggest a failure of spines to mature and stabilize following repeated stress and are likely to have major repercussions on function, receptor expression, and synaptic efficacy.
| S-EPMC2796421 | biostudies-literature
Project description:Current theories of deliberative decision making suggest that deliberative decisions arise from imagined simulations that require interactions between the prefrontal cortex and hippocampus. In rodent navigation experiments, hippocampal theta sequences advance from the location of the rat ahead to the subsequent goal. To examine the role of the medial prefrontal cortex (mPFC) on the hippocampus, we disrupted the mPFC with DREADDs (designer receptors exclusively activated by designer drugs). Using the Restaurant Row foraging task, we found that mPFC disruption resulted in decreased vicarious trial and error behavior, reduced the number of theta sequences, and impaired theta sequences in hippocampus. mPFC disruption led to larger changes in the initiation of the hippocampal theta sequences that represent the current location of the rat rather than to the later portions that represent the future outcomes. These data suggest that the mPFC likely provides an important component to the initiation of deliberative sequences and provides support for an episodic-future thinking, working memory interpretation of deliberation. NEW & NOTEWORTHY The medial prefrontal cortex (mPFC) and hippocampus interact during deliberative decision making. Disruption of the mPFC impaired hippocampal processes, including the local and nonlocal representations of space along each theta cycle and the initiation of hippocampal theta sequences, while sparing place cell firing characteristics and phase precession. mPFC disruption reduced the deliberative behavioral process vicarious trial and error and improved economic behaviors on this task.
| S-EPMC6620703 | biostudies-literature