Corticolimbic Regions Research Articles

Habenular Involvement in Response to Subcallosal Cingulate Deep Brain Stimulation for Depression.

The habenula (Hb) is a small, evolutionarily conserved epithalamic structure implicated in functions such as reward and mood regulation. Prior imaging work suggests that Hb's structural and functional properties may relate to treatment response in depression and other mood disorders. We used multimodal MRI techniques to investigate the potential involvement of Hb in response to subcallosal cingulate area deep brain stimulation (SCC-DBS) for treatment-resistant mood disorders. Using an automated segmentation technique, we compared Hb volume at baseline and at a subsequent post-operative timepoint (4.4 ± 3.0 years after surgery) in a cohort of 32 patients who received SCC-DBS. Clinical response to treatment (≥50% decrease in HAMD-17 from baseline to 12 months post-operation) was significantly associated with longitudinal Hb volume change: responders tended to have increased Hb volume over time, while non-responders showed decreased Hb volume (t = 2.4, p = 0.021). We additionally used functional MRI (fMRI) in a subcohort of SCC-DBS patients (n = 12) to investigate immediate within-patient changes in Hb functional connectivity associated with SCC-DBS stimulation. Active DBS was significantly associated with increased Hb connectivity to several prefrontal and corticolimbic regions (TFCE-adjusted pBonferroni < 0.0001), many of which have been previously implicated in the neurocircuitry of depression. Taken together, our results suggest that Hb may play an important role in the antidepressant effect of SCC-DBS.

Asymmetric Interaction of Neuropeptidase Activities between Cortico-Limbic Structures, Plasma and Cardiovascular Function after Unilateral Dopamine Depletions of the Nigrostriatal System.

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion.

Longitudinal Changes of Resting-State Networks in Children With Attention-Deficit/Hyperactivity Disorder and Typically Developing Children

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood neurodevelopmental disorder. Given the profound brain changes that occur across childhood and adolescence, it is important to identify functional networks that exhibit differential developmental patterns in children with ADHD. This study sought to examine whether children with ADHD exhibit differential developmental trajectories in functional connectivity compared with typically developing children using a network-based approach. MethodsThis longitudinal neuroimaging study included 175 participants (91 children with ADHD and 84 control children without ADHD) between ages 9 and 14 and up to 3 waves (173 total resting-state scans in children with ADHD and 197 scans in control children). We adopted network-based statistics to identify connected components with trajectories of development that differed between groups. ResultsChildren with ADHD exhibited differential developmental trajectories compared with typically developing control children in networks connecting cortical and limbic regions as well as between visual and higher-order cognitive regions. A pattern of reduction in functional connectivity between corticolimbic networks was seen across development in the control group that was not present in the ADHD group. Conversely, the ADHD group showed a significant decrease in connectivity between predominantly visual and higher-order cognitive networks that was not displayed in the control group. ConclusionsOur findings show that the developmental trajectories in children with ADHD are characterized by a subnetwork involving different trajectories predominantly between corticolimbic regions and between visual and higher-order cognitive network connections. These findings highlight the importance of examining the longitudinal maturational course to understand the development of functional connectivity networks in children with ADHD.

Imaging of astrocytes in posttraumatic stress disorder: A PET study with the monoamine oxidase B radioligand [11C]SL25.1188

Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that results from exposure to traumatic event(s). Decreased astrocyte-related proteins (e.g., glial fibrillary acidic protein, GFAP) and atrophic astrocytes in corticolimbic brain areas implicated in PTSD have been reported in experimental models suggesting that astrocyte pathology may be a feature of this disorder. We used positron emission tomography (PET) of the monoamine oxidase (MAO)-B probe [11C]SL25.1188 to test the hypothesis that levels of MAO-B, an index of astrocyte levels is decreased in PTSD. MAO-B availability ([11C]SL25.1188 distribution volume) was measured in 13 participants with PTSD (∼39 years, 6F) and 17 healthy controls (HC) (∼31 years, 9F). A magnetic resonance image was acquired to delineate 6 cortiolimbic brain regions. PTSD was associated with a trending reduction in [11C]SL25.1188 availability across regions (8-17%; p = 0.067) implicating the ventral striatum (p uncorrected = 0.015) and medial prefrontal cortex (p uncorrected = 0.060). [11C]SL25.1188 availability was ∼30% lower in corticolimbic regions in PTSD with co-morbid major depressive disorder (MDD) (n = 4) vs HC (p = 0.001) and vs PTSD without MDD (p = 0.005). Our preliminary results do not suggest astrogliosis (inferred from elevated availability) in PTSD, but rather point to a loss of astrocytes or an independent downregulation of MAO-B in PTSD with more severe negative affect. These exploratory findings, which are partly in line with preclinical literature and recent PET observations of decreased microglia marker, Translocator Protein, in PTSD, warrant replication in a larger PTSD cohort.

Growth of prefrontal and limbic brain regions and anxiety disorders in children born very preterm.

Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV (β = -0.461, p = 0.020), TBV (β = -0.503, p = 0.021), left (β = -0.518, p = 0.020) and right hippocampi (β = -0.469, p = 0.020) and left medial orbitofrontal cortex (β = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.

Effects of Mindfulness Training on Emotion Regulation in Patients With Depression: Reduced Dorsolateral Prefrontal Cortex Activation Indexes Early Beneficial Changes.

Mindfulness-based interventions (MBIs) have been found to be a promising approach for the treatment of recurrent courses of depression. However, little is known about their neural mechanisms. This functional magnetic resonance imaging study set out to investigate activation changes in corticolimbic regions during implicit emotion regulation. Depressed patients with a recurrent lifetime history were randomized to receive a 2-week MBI (n = 16 completers) or psychoeducation and resting (PER; n = 22 completers). Before and after, patients underwent functional magnetic resonance imaging while labeling the affect of angry, happy, and neutral facial expressions and completed questionnaires assessing ruminative brooding, the ability to decenter from such thinking, and depressive symptoms. Activation decreased in the right dorsolateral prefrontal cortex (dlPFC) in response to angry faces after MBI (p < .01, voxel-wise family-wise error rate correction, T > 3.282; 56 mm3; Montreal Neurological Institute peak coordinate: 32, 24, 40), but not after PER. This change was highly correlated with increased decentring (r = -0.52, p = .033), decreased brooding (r = 0.60, p = .010), and decreased symptoms (r = 0.82, p = .005). Amygdala activation in response to happy faces decreased after PER (p < .01, family-wise error rate corrected; 392 mm3; Montreal Neurological Institute peak coordinate: 28, -4, -16), whereas the MBI group showed no significant change. The dlPFC is involved in emotion regulation, namely, reappraisal or suppression of negative emotions. Decreased right dlPFC activation might indicate that, after the MBI, patients abstained from engaging in elaboration or suppression of negative affective stimuli; a putatively important mechanism for preventing the escalation of negative mood.Trial Registration: The study is registered at ClinicalTrials.gov (NCT02801513; 16/06/2016).

Addiction-like response in brain and behavior in a rat experimental model of night-eating syndrome

Study objectivesIndividuals ailing from night eating syndrome (NES) consume more than 25% of their daily food intake during the normal sleep time, delaying their sleep or waking up in the middle of the night to eat. This study explored two experimental conditions resembling NES in Wistar rats by offering palatable food during the sleep phase, alone or combined with sleep delay. Also we explored their impact on addiction-like changes in the brain and behavior. MethodsExperiment 1 explored the brain response after a first NES-like event; experiment 2 and 3 explored addiction-like behaviors c-Fos and FosB/ΔFosB in corticolimbic regions after 4 weeks exposition to NES-like conditions and after one week of withdrawal, respectively. For all 3 experiments 6 experimental groups were used: 1. Control; 2. Restricted access (1 h) to high-sugar diet (HSD) or to 3. high-fat diet (HFD); 4., Sleep delay for 4 h (SD) (from ZT0-ZT4, rats using slow rotating wheels); 5. SD + HSD; 6. SD + HFD. ResultsA first event of eating a palatable diet with or without SD was sufficient to stimulate c-Fos and ΔFosB. Along 4 weeks of exposure to the palatable diets rats exhibited escalation and binge eating, which was highest for the HFD. At this stage, SD did not influence behavioral changes nor the neuronal response. After one-week in withdrawal, rats exhibited craving and effort to obtain their palatable diet. The brains of rats previously exposed to sleep delay maintained high levels of FosB/ΔFosB in the accumbens shell and high c-Fos activation in the insular cortex. ConclusionsIn our experimental models of NES-like a HFD in the sleep phase and SD are risk factors to develop binge eating and addiction-like behaviors.

Mice with dopaminergic neuron-specific deletion of DTNBP-1 gene show blunted nucleus accumbens dopamine release and associated behaviors

Reduced expression of a schizophrenia-associated gene Dystrobrevin Binding Protein 1 (DTNBP1) and its protein product dysbindin-1, has been reported in the brains of schizophrenia patients. DTNBP1-null mutant Sdy (Sandy) mice exhibit several behavioral features relevant to schizophrenia. Changes in dopaminergic as well as glutamatergic and GABAergic neurotransmission in cortico-limbic regions have been reported in Sdy mice. Since dysbindin-1 is expressed in multiple brain regions, it is not known whether dopamine (DA) changes observed in Sdy null mutants are due to dysbindin-1 deficiency in DAergic neurons specifically. Here, using a mouse line with conditional knockout (cKO) of DTNBP1 in DA neurons, we studied the effects of dysbindin-1 deficiency on DA release and DA-dependent behaviors. Spontaneous locomotor activity of cKO mice in novel environment was significantly reduced initially but was comparable at later time points with littermate controls. However, the locomotion-enhancing effect of a low dose of d-amphetamine (d-AMPH; 2.5 mg/kg, ip) was significantly attenuated in the cKO mice suggesting a dampened mesolimbic DA transmission. Similarly, the prepulse inhibition disrupting effect of d-AMPH was found to be significantly reduced in the mutant mice. No significant differences between the cKO and control mice were observed in tests of anxiety, spatial learning and memory and social interaction. In- vivo microdialysis in the nucleus accumbens (NAc) showed a decrease in d-AMPH-induced extracellular DA release in the cKO mice. No significant alterations in protein levels of DA transporter, phosphorylated CaM kinase-II or Akt308 in the NAc were observed in the cKO mice. Taken together, our data suggest an important role of dysbindin-1 in maintaining mesolimbic DA tone and call for further investigations identifying mechanisms linking dysbindin-1, DA and schizophrenia.

Auditory fear conditioning alters neural gain in the cochlear nucleus: a wireless neural recording study in freely behaving rats.

Anxiety disorders involve distorted perception of the world including increased saliency of stress-associated cues. However, plasticity in the initial sensory regions of the brain following a fearful experience has never been examined. The cochlear nucleus (CN) is the first station in the central auditory system, with heterogeneous collections of neurons that not only project to but also receive projections from cortico-limbic regions, suggesting a potential for experience-dependent plasticity. Using wireless neural recordings in freely behaving rats, we demonstrate for the first time that neural gain in the CN is significantly altered by fear conditioning to auditory sequences. Specifically, the ventral subnuclei significantly increased firing rate to the conditioned tone sequence, while the dorsal subnuclei significantly decreased firing rate during the conditioning session overall. These findings suggest subregion-specific changes in the balance of inhibition and excitation in the CN as a result of conditioning experience. Heart rate was measured as the conditioned response (CR), which showed that while pre-conditioned stimulus (CS) responding did not change across baseline and conditioning sessions, significant changes in heart rate were observed to the tone sequence followed by shock. Heart-rate findings support acquisition of conditioned fear. Taken together, the present study presents first evidence for potential experience-dependent changes in auditory perception that involve novel plasticity within the first site of processing auditory information in the brain.

Maladaptive emotion regulation traits predict altered corticolimbic recovery from psychosocial stress

BackgroundAdaptive recovery from stress promotes healthy cognitive affective functioning, whereas maladaptive recovery is linked to poor psychological outcomes. Neural regions, like the anterior cingulate and hippocampus, play critical roles in psychosocial stress responding and serve as hubs in the corticolimbic neural system. To date, however, it is unknown how cognitive emotion regulation traits (cER), adaptive and maladaptive, influence corticolimbic stress recovery. Here, we examined acute psychosocial stress neural recovery, accounting for cER. MethodsFunctional neuroimaging data were collected while forty-seven healthy participants performed blocks of challenging, time-sensitive, mental calculations. Participants immediately received performance feedback (positive/negative/neutral) and their ranking, relative to fictitious peers. Participants rested for 90 seconds after each feedback, allowing for a neural stress recovery period. Collected before scanning, cER scores were correlated with neural activity during each recovery condition. ResultsNegative feedback recovery yielded increased activity within the dorsomedial prefrontal cortex and amygdala, but this effect was ultimately explained by maladaptive cER (M-cER), like rumination. Isolating positive after-effects (i.e. positive > negative recovery) yielded a significant positive correlation between M-cER and the anterior cingulate, anterior insula, hippocampus, and striatum. ConclusionsWe provide first evidence of M-cER to predict altered neural recovery from positive stress within corticolimbic regions. Positive feedback may be potentially threatening to individuals with poor stress regulation. Identifying positive stress-induced activation patterns in corticolimbic neural networks linked to M-cER creates the possibility to identify these neural responses as risk factors for social-emotional dysregulation subsequent to rewarding social information, often witnessed in affective disorders, like depression.

Sex Differences in the Development of the Rodent Corticolimbic System.

In recent years, a growing body of research has shown sex differences in the prevalence and symptomatology of psychopathologies, such as depression, anxiety, and fear-related disorders, all of which show high incidence rates in early life. This has highlighted the importance of including female subjects in animal studies, as well as delineating sex differences in neural processing across development. Of particular interest is the corticolimbic system, comprising the hippocampus, amygdala, and medial prefrontal cortex. In rodents, these corticolimbic regions undergo dynamic changes in early life, and disruption to their normative development is believed to underlie the age and sex-dependent effects of stress on affective processing. In this review, we consolidate research on sex differences in the hippocampus, amygdala, and medial prefrontal cortex across early development. First, we briefly introduce current principles on sexual differentiation of the rodent brain. We then showcase corticolimbic regional sex differences in volume, morphology, synaptic organization, cell proliferation, microglia, and GABAergic signaling, and explain how these differences are influenced by perinatal and pubertal gonadal hormones. In compiling this research, we outline evidence of what and when sex differences emerge in the developing corticolimbic system, and illustrate how temporal dynamics of its maturational trajectory may differ in male and female rodents. This will help provide insight into potential neural mechanisms underlying sex-specific critical windows for stress susceptibility and behavioral emergence.

Region-specific brain area reductions and increased cholecystokinin\xa0positive neurons in diabetic OLETF rats: implication for anxiety-like behavior

Metabolic disorders can induce psychiatric comorbidities. Both brain and neuronal composition imbalances reportedly induce an anxiety-like phenotype. We hypothesized that alterations of localized brain areas and cholecystokinin (CCK) and parvalbumin (PV) expression could induce anxiety-like behavior in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Twenty-week-old OLETF and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were used. The areas of corticolimbic regions were smaller in OLETF rats. The densities of CCK positive neurons in the lateral and basolateral amygdala, hippocampal cornu ammonis area 2, and prelimbic cortex were higher in OLETF rats. The densities of PV positive neurons were comparable between OLETF and LETO rats. Locomotion in the center zone in the open field test was lower in OLETF rats. These results suggest that imbalances of specific brain region areas and neuronal compositions in emotion-related areas increase the prevalence of anxiety-like behaviors in OLETF rats.

Energy sensors in drug addiction: A potential therapeutic target.

Addiction is defined as the repeated exposure and compulsive seek of psychotropic drugs that, despite the harmful effects, generate relapse after the abstinence period. The psychophysiological processes associated with drug addiction (acquisition/expression, withdrawal, and relapse) imply important alterations in neurotransmission and changes in presynaptic and postsynaptic plasticity and cellular structure (neuroadaptations) in neurons of the reward circuits (dopaminergic neuronal activity) and other corticolimbic regions. These neuroadaptation mechanisms imply important changes in neuronal energy balance and protein synthesis machinery. Scientific literature links drug-induced stimulation of dopaminergic and glutamatergic pathways along with presence of neurotrophic factors with alterations in synaptic plasticity and membrane excitability driven by metabolic sensors. Here, we provide current knowledge of the role of molecular targets that constitute true metabolic/energy sensors such as AMPK, mTOR, ERK, or KATP in the development of the different phases of addiction standing out the main brain regions (ventral tegmental area, nucleus accumbens, hippocampus, and amygdala) constituting the hubs in the development of addiction. Because the available treatments show very limited effectiveness, evaluating the drug efficacy of AMPK and mTOR specific modulators opens up the possibility of testing novel pharmacotherapies for an individualized approach in drug abuse.

Frontal-executive and corticolimbic structural brain circuitry in older people with remitted depression, mild cognitive impairment, Alzheimer's dementia, and normal cognition.

A history of depression is a risk factor for dementia. Despite strong epidemiologic evidence, the pathways linking depression and dementia remain unclear. We assessed structural brain alterations in white and gray matter of frontal-executive and corticolimbic circuitries in five groups of older adults putatively at-risk for developing dementia-remitted depression (MDD), non-amnestic MCI (naMCI), MDD+naMCI, amnestic MCI (aMCI), and MDD+aMCI. We also examined two other groups: non-psychiatric ("healthy") controls (HC) and individuals with Alzheimer's dementia (AD). Magnetic resonance imaging (MRI) data were acquired on the same 3T scanner. Following quality control in these seven groups, from diffusion-weighted imaging (n = 300), we compared white matter fractional anisotropy (FA), mean diffusivity (MD), and from T1-weighted imaging (n = 333), subcortical volumes and cortical thicknessin frontal-executive and corticolimbic regions of interest (ROIs). We also used exploratory graph theory analysis to compare topological properties of structural covariance networks and hub regions. We found main effects for diagnostic group in FA, MD, subcortical volume, and cortical thickness. These differences were largely due to greater deficits in the AD group and to a lesser extent aMCI compared with other groups. Graph theory analysis revealed differences in several global measures among several groups. Older individuals with remitted MDD and naMCI did not have the same white or gray matter changes in the frontal-executive and corticolimbic circuitries as those with aMCI or AD, suggesting distinct neural mechanisms in these disorders. Structural covariance global metrics suggested a potential difference in brain reserve among groups.

Systemic inflammation is associated with differential neural reactivity and connectivity to affective images.

Systemic inflammation is increasingly appreciated as a predictor of health and well-being. Further, inflammation has been shown to influence and be influenced by affective experiences. Although prior work has substantiated associations between inflammatory and affective processes, fewer studies have investigated the neurobiological correlates that underlie links between systemic, low-grade inflammation and affective reactivity. Thus, the current study examined whether markers of systemic inflammation (i.e. interleukin-6, C-reactive protein) are associated with differential patterns of neural activation and connectivity in corticolimbic regions in response to affective images. We investigated this question in a sample of 66 adults (44 women, M age = 54.98 years, range = 35–76) from the Midlife in the United States study. Higher levels of inflammation were associated with lower activity in limbic regions (i.e. amygdala, hippocampus, anterior insula, temporal pole) when viewing positive (vs neutral) images. Higher levels of inflammation were also associated with greater connectivity between the hippocampus and the medial prefrontal cortex in response to positive images. Inflammatory markers were not associated with significant differences in activation or connectivity to negative images. These findings highlight the utility of health neuroscience approaches in demonstrating that physiological processes such as inflammation are related to how our brains respond to affective information.

The pontine-driven somatic gaze tract contributes to affective processing in humans

The relevance of subcortical structures for affective processing is not fully understood. Inspired by the gerbil retino-raphe pathway that has been shown to regulate affective behavior and previous human work showing that the pontine region is important for processing emotion, we asked whether well-established tracts in humans traveling between the eye and the brain stem contribute to functions beyond their conventionally understood roles. Here we report neuroimaging findings showing that optic chiasm-brain stem diffusivity predict responses reflecting perceived arousal and valence. Analyses of subsequent task-evoked connectivity further revealed that visual affective processing implicates the brain stem, particularly the pontine region at an early stage of the cascade, projecting to cortico-limbic regions in a feedforward manner. The optimal model implies that all intrinsic connections between the regions of interest are unidirectional and outwards from the pontine region. These findings suggest that affective processing implicates regions outside the cortico-limbic network. The involvement of a phylogenetically older locus in the pons that has consequences in oculomotor control may imply adaptive consequences of affect detection.

Structural brain networks in remitted psychotic depression.

Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique-non-negative matrix factorization-and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.

Acute alcohol intake alters resting state functional connectivity of nucleus accumbens with pain-related corticolimbic structures

BackgroundThe nucleus accumbens (NAc) is a ventral striatal structure underlying reward, reinforcement, and motivation, with extensive anatomic and functional connections to a wide range of affective processing structures (medial prefrontal cortex (mPFC), amygdala, and insula). Characterizing how acute alcohol intake affects resting state functional connectivity (rsFC) between the nucleus accumbens (NAc) and these regions will improve mechanistic understanding of alcohol’s neurobehavioral effects, including the neural overlap between acute alcohol effects and pain processing. MethodsFifteen healthy social drinkers (10 women; age: 25–45 years) were included in the study. Participants completed one session in which they consumed an alcohol dose targeting a breath alcohol concentration of 0.08 g/dL, and in a second a placebo beverage. Nine-minute resting state fMRI scans were acquired 30−35 min after beverage administration during each session. rsFC between NAc and a priori corticolimbic regions of interest (mPFC, amgydala, and insula), were compared between beverage conditions. We also conducted an exploratory whole-brain seed-to-voxel analysis of NAc FC. ResultsAlcohol intake reduced rsFC between NAc and mPFC, as well as NAc and amygdala. Alcohol also reduced rsFC between NAc and a 97-voxel cluster including bilateral paracingulate cortex and anterior cingulate cortex. ConclusionsFindings suggest that acute alcohol intake reduces rsFC between NAc and several structures, including mPFC, amygdala, and rostral ACC in healthy social drinkers. These structures underlie reward, motivated behavior, and emotion regulation, and may provide mechanistic insight to how alcohol affects related processes, including pain.

Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1)

Environmental factors, including substance abuse and stress, cause long-lasting changes in the regulation of gene expression in the brain via epigenetic mechanisms, such as DNA methylation. We examined genome-wide DNA methylation patterns in the prefrontal cortex (PFC, BA10) of 25 pairs of control and individuals with alcohol use disorder (AUD), using the Infinium® MethylationEPIC BeadChip. We identified 5254 differentially methylated CpGs (pnominal < 0.005). Bioinformatic analyses highlighted biological processes containing genes related to stress adaptation, including the glucocorticoid receptor (encoded by NR3C1). Considering that alcohol is a stressor, we focused our attention on differentially methylated regions of the NR3C1 gene and validated the differential methylation of several genes in the NR3C1 network. Chronic alcohol drinking results in a significant increased methylation of the NR3C1 exon variant 1H, with a particular increase in the levels of 5-hydroxymethylcytosine over 5-methylcytosine. These changes in DNA methylation were associated with reduced NR3C1 mRNA and protein expression levels in PFC, as well as other cortico-limbic regions of AUD subjects when compared with controls. Furthermore, we show that the expression of several stress-responsive genes (e.g., CRF, POMC, and FKBP5) is altered in the PFC of AUD subjects. These stress-response genes were also changed in the hippocampus, a region that is highly susceptible to stress. These data suggest that alcohol-dependent aberrant DNA methylation of NR3C1 and consequent changes in other stress-related genes might be fundamental in the pathophysiology of AUD and lay the groundwork for treatments targeting the epigenetic mechanisms regulating NR3C1 in AUD.

Adenosine-to-Inosine RNA Editing Within Corticolimbic Brain Regions Is Regulated in Response to Chronic Social Defeat Stress in Mice.

Adenosine-to-inosine (A-to-I) RNA editing is a co-/posttranscriptional modification of double-stranded RNA, catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes, which results in recognition of inosine as guanosine by translational and splicing machinery causing potential recoding events in amino acid sequences. A-to-I editing is prominent within brain-specific transcripts, and dysregulation of editing at several well-studied loci (e.g., Gria2, Htr2c) has been implicated in acute and chronic stress in rodents as well as neurological (e.g., Alzheimer’s) and psychopathological disorders such as schizophrenia and major depressive disorder. However, only a small fraction of recoding sites has been investigated within the brain following stress, and our understanding of the role of RNA editing in transcriptome regulation following environmental stimuli remains poorly understood. Thus, we aimed to investigate A-to-I editing at hundreds of loci following chronic social defeat stress (CSDS) in mice within corticolimbic regions responsive to chronic stress regulation. Adult male mice were subjected to CSDS or control conditions for 21 days and dynamic regulation of A-to-I editing was investigated 2 and 8 days following the final defeat within both the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). Employing a targeted resequencing approach, which utilizes microfluidics-based multiplex polymerase chain reaction (PCR) coupled with next-generation sequencing, we analyzed A-to-I editing at ∼100 high-confidence editing sites within the mouse brain. CSDS resulted in acute regulation of transcripts encoding several ADAR enzymes, which normalized 8 days following the final defeat and was specific for susceptible mice. In contrast, sequencing analysis revealed modest and dynamic regulation of A-to-I editing within numerous transcripts in both the mPFC and BLA of resilient and susceptible mice at both 2 and 8 days following CSDS with minimal overlap between regions and time points. Editing within the Htr2c transcript and relative abundance of Htr2c messenger RNA (mRNA)variants were also observed within the BLA of susceptible mice 2 days following CSDS. These results indicate dynamic RNA editing within discrete brain regions following CSDS in mice, further implicating A-to-I editing as a stress-sensitive molecular mechanism within the brain of potential relevance to resiliency and susceptibility to CSDS.