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Seed-based functional connectivity maps illustrating left and right hemisphere seeds for striatal and cortical regions. Maps are composite statistical maps from the chamber exposure control group at baseline. Regions showing significant functional connectivity with the seed region are displayed (uncorrected threshold, t 2.4, p 0.05). Green arrows indicate the seed region in each map. Each region shows 2 contiguous slices of 12 total coronal slices scanned from rostral to caudal in the brain.
Source publication
Brain imaging studies indicate that chronic cocaine users display altered functional connectivity between prefrontal cortical, thalamic, striatal, and limbic regions; however, the use of cross-sectional designs in these studies precludes measuring baseline brain activity prior to cocaine use. Animal studies can circumvent this limitation by compari...
Contexts in source publication
Context 1
... series fMRI signals were extracted from each ROI based on the atlas-guided seed location (75 bilateral placed seed regions included for 150 total ROIs). Time series for each voxel were averaged per ROI seed, and voxelwise cross-correlations were conducted to create correlation coefficient (Pearson r) maps (Colon- Perez et al., 2016). The first nine images in each functional time series were not used in the cross-correlation step to avoid including unstable fMRI signal intensity variations typical of the initial images. Pearson r coefficients per ROI pairs were subjected to a voxelwise z-transformation and ex- ported for seed-based functional connectivity and net- work analyses in MATLAB (MathWorks). Composite functional connectivity maps were generated in AFNI for cortical and subcortical seed regions to determine the quality and consistency of resting-state correlation data across groups (see Fig. 3, representative group-level sta- tistical map for rats in the chamber exposure control ...
Context 2
... statistical maps of functional connectivity between mesocorticolimbic areas of chamber exposure control rats are shown in Figure 3. These highlight the functional connectivity patterns observed in the baseline presurgical imaging session (i.e., in naïve rats that go on to be chamber exposure controls). Figure 4A-C shows 3D rat brain shells with representations of node strength (spheres) and edge weights (lines connecting spheres) for the chamber exposure control, sucrose and cocaine groups. Connectivity patterns are shown for each group at baseline (before surgery and self-administration) and after 1d Abs and 14d Abs. Although these are qualitative, the maps suggest that chamber exposure control rats showed consistent functional connectivity patterns be- tween sessions at baseline and 1d Abs, but increased connectivity at 14d Abs. In contrast, sucrose and cocaine groups had increased connectivity relative to baseline at 1d Abs, but connectivity was reduced again by 14d ...
Citations
... Furthermore, each factor correlated significantly with its corresponding ERP measure (P3a for bottom-up and P3b for top-down), supporting their reliability as attentional biomarkers. Clinically, the absence of this association in consumers is consistent with previous literature (Ma et al., 2014;Moeller et al., 2010;Orsini et al., 2018;Tomasi et al., 2007;Zhai et al., 2022). Although our cross-sectional study cannot identify vulnerability or drug-derived impairment, these results are clinically relevant for the cognitive treatment of patients with cocaine addiction. ...
... This lack of association is consistent with their lower modulation of ERPs and cognitive performance. This may be attributed to alterations in the prefrontal and parietal cortex among cocaine consumers (Ma et al., 2014;Moeller et al., 2010;Orsini et al., 2018;Tomasi et al., 2007;Zhai et al., 2022), which play a crucial role in All rights reserved. No reuse allowed without permission. ...
Background
Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced modulation of the P3a, while both SCD and IC dependent (ICD) would show reduced modulation of the P3b.
Methods
We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks.
Results
At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. Modulation of P3a and P3b was lower in consumer groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down.
Conclusions
Different routes of administration lead to distinct modulations of attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance abuse.
... In contrast, decreases were observed at 14 days of abstinence, measured by fMRI [205]. Thus, cocaine can significantly change the functional connectivity of brain regions involved in cognition and emotion during withdrawal, particularly early stages. ...
The cognitive decline in people with substance use disorders is well known and can be found during both the dependence and drug abstinence phases. At the clinical level, cognitive decline impairs the response to addiction treatment and increases dropout rates. It can be irreversible, even after the end of drug abuse consumption. Improving our understanding of the molecular and cellular alterations associated with cognitive decline could be essential to developing specific therapeutic strategies for its treatment. Developing animal models to simulate drug abuse-induced learning and memory alterations is critical to continue exploring this clinical situation. The main aim of this review is to summarize the most recent evidence on cognitive impairment and the associated biological markers in patients addicted to some of the most consumed drugs of abuse and in animal models simulating this clinical situation. The available information suggests the need to develop more studies to further explore the molecular alterations associated with cognitive impairment, with the ultimate goal of developing new potential therapeutic strategies.
... This spatial segregation is not as clear in rodents, as some network labels often show spatial overlaps in the rodent frontal cortex [27][28][29]. This cautions against considering only a single circuit/pathway in complex behaviors that have been associated with multiple large-scale networks, such as addiction [30,31]. Considering the urgent need to better understand rodent brain network systems, several pioneering efforts have been made to improve imaging protocols and share databases [32,33]. ...
Alcohol misuse and, particularly adolescent drinking, is a major public health concern. While evidence suggests that adolescent alcohol use affects frontal brain regions that are important for cognitive control over behavior little is known about how acute alcohol exposure alters large-scale brain networks and how sex and age may moderate such effects. Here, we employ a recently developed functional magnetic resonance imaging (fMRI) protocol to acquire rat brain functional connectivity data and use an established analytical pipeline to examine the effect of sex, age, and alcohol dose on connectivity within and between three major rodent brain networks: defaul mode, salience, and lateral cortical network. We identify the intra- and inter-network connectivity differences and establish moderation models to reveal significant influences of age on acute alcohol-induced lateral cortical network connectivity. Through this work, we make brain-wide isotropic fMRI data with acute alcohol challenge publicly available, with the hope to facilitate future discovery of brain regions/circuits that are causally relevant to the impact of acute alcohol use.
... We hypothesized that high sensitizing CC018/UncJ mice would show greater incentive sensitization following cocaine exposure, such that they would lever press more for the CR than the low sensitizing CC027/GeniUncJ mice. As past studies have indicated that repeated intermittent cocaine administration can elicit neuroadaptations in mesocorticolimbic dopamine signaling (Anderson and Pierce 2005;Orsini et al. 2018;Self 2004;Thomas et al. 2009;Wiskerke et al. 2016), as well as provide strong evidence linking dopamine to incentive motivation (Flagel et al. 2011;Salamone et al. 2007;Taylor and Robbins 1986), we also examined aspects of dopamine release in the nucleus accumbens using fast-scan cyclic voltammetry (FSCV) measurements in brain slices taken from these subjects. ...
Rationale
Cocaine use disorder (CUD) is a highly heritable form of substance use disorder, with genetic variation accounting for a substantial proportion of the risk for transitioning from recreational use to a clinically impairing addiction. With repeated exposures to cocaine, psychomotor and incentive sensitization are observed in rodents. These phenomena are thought to model behavioral changes elicited by the drug that contribute to the progression into addiction, but little is known about how genetic variation may moderate these consequences.
Objectives
Here, we describe the use of two Collaborative Cross (CC) recombinant inbred mouse strains that either exhibit high (CC018/UncJ) or no (CC027/GeniUncJ) psychomotor sensitization in response to cocaine to measure phenotypes related to incentive sensitization after repeated cocaine exposures; given the relationship of incentive motivation to nucleus accumbens core (NAc) dopamine release and reuptake, we also assessed these neurochemical mechanisms.
Methods
Adult male and female CC018/UncJ and CC027/GeniUncJ mice underwent Pavlovian conditioning to associate a visual cue with presentation of a palatable food reward, then received five, every-other-day injections of cocaine or vehicle. Following Pavlovian re-training, they underwent testing acquisition of a new operant response for the visual cue, now serving as a conditioned reinforcer. Subsequently, electrically evoked dopamine release was assessed using fast-scan cyclic voltammetry from acute brain slices containing the NAc.
Results
While both strains acquired the Pavlovian association, only CC018/UncJ mice showed conditioned reinforcement and incentive sensitization in response to cocaine, while CC027/GeniUncJ mice did not. Voltammetry data revealed that CC018/UncJ, compared to CC027/GeniUnc, mice exhibited higher baseline dopamine release and uptake. Moreover, chronic cocaine exposure blunted tonic and phasic dopamine release in CC018/UncJ, but not CC027/GeniUncJ, mice.
Conclusions
Genetic background is a moderator of cocaine-induced neuroadaptations in mesolimbic dopamine signaling, which may contribute to both psychomotor and incentive sensitization and indicate a shared biological mechanism of variation.
... In principle, this approach could also be expanded on to assess neuroadaptations to other drugs of abuse. For example, acute and chronic alterations in neurotransmission and functional connectivity of the mesocorticolimbic circuit have been reported for cocaine (69)(70)(71), nicotine (72)(73)(74)(75)(76), and alcohol (77)(78)(79)(80). The current proposal on how to assess and define neuroadaptations in cannabis users would also call for an international, multicenter research effort in order to include large samples of distinct cannabis user groups, ranging from novice and occasional users at the lowest end of the use frequency spectrum to daily, chronic users at the opposite extreme. ...
Currently, the assessment of the neurobehavioral consequences of repeated cannabis use is restricted to studies in which brain function of chronic cannabis users is compared to that of non-cannabis using controls. The assumption of such studies is that changes in brain function of chronic users are caused by repeated and prolonged exposure to acute cannabis intoxication. However, differences in brain function between chronic cannabis users and non-users might also arise from confounding factors such as polydrug use, alcohol use, withdrawal, economic status, or lifestyle conditions. We propose a methodology that highlights the relevance of acute Δ⁹-tetrahydrocannabinol (THC) dosing studies for a direct assessment of neuroadaptations in chronic cannabis users. The approach includes quantification of neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge, as well as stratification of cannabis using groups ranging from occasional to cannabis-dependent individuals. The methodology allows for an evaluation of THC induced neuroadaptive and neurocognitive changes across cannabis use history, that can inform neurobiological models on reward driven, compulsive cannabis use.
... However, experience-dependent changes can also confound interpretations when betweensubjects control comparisons are not included in the study. This point is in part illustrated in previous imaging work by Orsini et al. 65 and Colon-Perez et al., 66 which used a combination of both within-and between-subjects comparisons and observed changes over the course of several imaging sessions that were separated by weeks. In Orsini et al., 65 while drug treatment was observed to lead to increases in functional connectivity (when comparing pre-to post), these changes were not specific to the drug and were observed with a natural reward given for the same amount of time. ...
... This point is in part illustrated in previous imaging work by Orsini et al. 65 and Colon-Perez et al., 66 which used a combination of both within-and between-subjects comparisons and observed changes over the course of several imaging sessions that were separated by weeks. In Orsini et al., 65 while drug treatment was observed to lead to increases in functional connectivity (when comparing pre-to post), these changes were not specific to the drug and were observed with a natural reward given for the same amount of time. In addition, baseline control groups receiving no treatment over the course of the 3 imaging sessions still showed differences when compared to baseline imaging session. ...
... In addition, baseline control groups receiving no treatment over the course of the 3 imaging sessions still showed differences when compared to baseline imaging session. 65 In Colon-Perez et al., 66 the inclusion of an untrained group of rats functionally imaged at the same timepoints as aged and young rats that underwent cognitive training was necessary to demonstrate that in fact training increased rich club organization and node strength. 66 Thus, there are gains in statistical power by including a mixed between/ within-subjects multisession imaging design in TBI research in animal models. ...
Penetrating cortical impact injuries alter neuronal communication beyond the injury epicenter, across regions involved in affective, sensorimotor, and cognitive processing. Understanding how traumatic brain injury reorganizes local and brain wide nodal interactions may provide valuable quantitative parameters for monitoring pathological progression and recovery. To this end, we investigated spontaneous fluctuations in the functional MRI signal obtained at 11.1 Tesla in rats sustaining controlled cortical impact and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12,879 pairwise correlations between functional MRI signals from 162 regions. Our data indicate that on days 2 and 30 post-controlled cortical impact there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic, and basal forebrain areas. Rats imaged on day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality, and participation coefficient track early and late traumatic brain injury effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to controlled cortical impact may be unfavorable to brain wide communication in the early post-injury period.
... Positive edges were included if two nodes had a Pearson's R correlation >0.5. Similar functional network modeling experiments have used a range of edge thresholds spanning from R = 0.3 (Orsini et al., 2018) to R = 0.87 (Wheeler et al., 2013). We chose an edge threshold of R = 0.5 to ensure that all nodes within the network had at least one edge with one other node (Qi et al., 2014;Gao et al., 2019;Kimbrough et al., 2020). ...
Complex social behaviors are governed by a neural network theorized to be the social decision-making network (SDMN). However, this theoretical network is not tested on functional grounds. Here, we assess the organization of regions in the SDMN using c-Fos, to generate functional connectivity models during specific social interactions in a socially monogamous rodent, the prairie voles (Microtus ochrogaster). Male voles displayed robust selective affiliation toward a female partner, while exhibiting increased threatening, vigilant, and physically aggressive behaviors toward novel males and females. These social interactions increased c-Fos levels in eight of the thirteen brain regions of the SDMN. Each social encounter generated a distinct correlation pattern between individual brain regions. Thus, hierarchical clustering was used to characterize interrelated regions with similar c-Fos activity resulting in discrete network modules. Functional connectivity maps were constructed to emulate the network dynamics resulting from each social encounter. Our partner functional connectivity network presents similarities to the theoretical SDMN model, along with connections in the network that have been implicated in partner-directed affiliation. However, both stranger female and male networks exhibited distinct architecture from one another and the SDMN. Further, the stranger-evoked networks demonstrated connections associated with threat, physical aggression, and other aversive behaviors. Together, this indicates that distinct patterns of functional connectivity in the SDMN can be detected during select social encounters.
... Therefore, dopamine transporter can act as a master regulator of dopaminergic networks through regulation of dopaminergic signaling. Additionally, this provides a direct pharmacological target that may be able to revert dopaminergic networks with dysfunctional properties, such as those found in Parkinson's disease (Fischer et al., 2019) and addiction (Tomasi et al., 2009;Ding et al., 2013;Orsini et al., 2018). However, as the experiments were performed in a cocktail of antagonists, future experiments will be necessary to provide more nuanced interpretations to the regulation of dopaminergic networks through simultaneous polypharmacy approaches of multiple targets that have been shown to alter network synchrony (Li et al., 2011). ...
Dopaminergic neurons of the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here, we used live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis, in DAT-cre/loxP-GCaMP6f mice of either sex, when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC or VTA networks. Neuronal loss in the SNC increased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by decreasing network clustering in the VTA. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions.
SIGNIFICANCE STATEMENT In this work, we begin to untangle the differences in complex network properties between the substantia nigra pars compacta (SNC) and VTA, that may underlie differential sensitivity between regions. The methods and analysis employed provide a springboard for investigations of network topology in multiple deep brain structures and disorders.
... The present study was conducted with only a single isoflurane treatment session using a specific concentration (1.8%), a fixed exposure time (3 h), and a single waiting period between the isoflurane treatment and the readouts. Interestingly, Orsini and co-workers ( Orsini et al., 2018 ) demonstrated increased cortical connectivity at 1 month, but not after 2 weeks, following 0.5% isoflurane/medetomidine anesthesia. Clearly, additional studies are needed to evaluate functional changes in response to different isoflurane concentrations, exposure times, and various readout points after the treatment. ...
Isoflurane, the most commonly used preclinical anesthetic, induces brain plasticity and long-term cellular and molecular changes leading to behavioral and/or cognitive consequences. These changes are most likely associated with network-level changes in brain function. To elucidate the mechanisms underlying long-term effects of isoflurane, we investigated the influence of a single isoflurane exposure on functional connectivity, brain electrical activity, and gene expression.
Male Wistar rats (n=22) were exposed to 1.8% isoflurane for 3 h. Control rats (n=22) spent 3 h in the same room without exposure to anesthesia. After 1 month, functional connectivity was evaluated with resting-state functional magnetic resonance imaging (fMRI; n=6+6) and local field potential measurements (n=6+6) in anesthetized animals. A whole genome expression analysis (n=10+10) was also conducted with mRNA-sequencing from cortical and hippocampal tissue samples.
Isoflurane treatment strengthened thalamo-cortical and hippocampal-cortical functional connectivity. Cortical low-frequency fMRI power was also significantly increased in response to the isoflurane treatment. The local field potential results indicating strengthened hippocampal-cortical alpha and beta coherence were in good agreement with the fMRI findings. Furthermore, altered expression was found in 20 cortical genes, several of which are involved in neuronal signal transmission, but no gene expression changes were noted in the hippocampus.
Isoflurane induced prolonged changes in thalamo-cortical and hippocampal-cortical function and expression of genes contributing to signal transmission in the cortex. Further studies are required to investigate whether these changes are associated with the postoperative behavioral and cognitive symptoms commonly observed in patients and animals.
... Therefore, dopamine transporter can act as a master regulator of dopaminergic networks through regulation of dopaminergic signalling. Additionally, this provides a direct pharmacological target that may be able to revert dopaminergic networks with dysfunctional properties, such as those found in Parkinson's disease 138 and addiction [139][140][141] . However, as the experiments were performed in a cocktail of antagonists, future experiments will be necessary to provide more nuanced interpretations to the regulation of dopaminergic networks through simultaneous polypharmacy approaches of multiple targets that have been shown to . ...
Dopaminergic neurons of the substantia nigra (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here we utilized live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC dopamine neurons than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC, or VTA networks. Neuronal loss in the SNC decreased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by increasing network clustering in the VTA. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions.
