Background Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets.
Background: Previous research reported that individual differences in the stress response were moderated by an interaction between individuals' life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response.Results: Compared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66)=3.71, P<.001) and also showed increased global methylation as a function of ELS (r (32)=.45, P=.008) and chronic stress (r (32)=.44, P=.010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41)=-. 31, P=.042) and increased F3 methylation (r (67)=.30, P=.015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r=.41, P<.01), which correlated positively with NR3C1 expression (r (42)=.31, P=.040).Conclusions: Both early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals' stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.
Post-traumatic stress disorder (PTSD) is accompanied by disturbed sleep and an impaired ability to learn and remember extinction of conditioned fear. Following a traumatic event, the full spectrum of PTSD symptoms typically requires several months to develop. During this time, sleep disturbances such as insomnia, nightmares, and fragmented rapid eye movement sleep predict later development of PTSD symptoms. Only a minority of individuals exposed to trauma go on to develop PTSD. We hypothesize that sleep disturbance resulting from an acute trauma, or predating the traumatic experience, may contribute to the etiology of PTSD. Because symptoms can worsen over time, we suggest that continued sleep disturbances can also maintain and exacerbate PTSD. Sleep disturbance may result in failure of extinction memory to persist and generalize, and we suggest that this constitutes one, non-exclusive mechanism by which poor sleep contributes to the development and perpetuation of PTSD. Also reviewed are neuroendocrine systems that show abnormalities in PTSD, and in which stress responses and sleep disturbance potentially produce synergistic effects that interfere with extinction learning and memory. Preliminary evidence that insomnia alone can disrupt sleep-dependent emotional processes including consolidation of extinction memory is also discussed. We suggest that optimizing sleep quality following trauma, and even strategically timing sleep to strengthen extinction memories therapeutically instantiated during exposure therapy, may allow sleep itself to be recruited in the treatment of PTSD and other trauma and stress-related disorders.
There is growing interest in the use of neuroimaging for the direct treatment of mental illness. Here, we present a new framework for such treatment, neurocognitive therapeutics. What distinguishes neurocognitive therapeutics from prior approaches is the use of precise brain-decoding techniques within a real-time feedback system, in order to adapt treatment online and tailor feedback to individuals' needs. We report an initial feasibility study that uses this framework to alter negative attention bias in a small number of patients experiencing significant mood symptoms. The results are consistent with the promise of neurocognitive therapeutics to improve mood symptoms and alter brain networks mediating attentional control. Future work should focus on optimizing the approach, validating its effectiveness, and expanding the scope of targeted disorders.
BACKGROUND:Prior studies suggest that hyperactive insula responding to unpredictable aversiveness is a core feature of anxiety disorders. However, no study to date has investigated the neural correlates of unpredictable aversiveness in those with panic disorder (PD) with comorbid major depressive disorder (MDD). The aim of the current study was to examine group differences in neural responses to unpredictable and predictable aversiveness in 41 adults with either 1) current PD with comorbid MDD (PD-MDD), 2) current MDD with no lifetime diagnosis of an anxiety disorder (MDD-only), or 3) no lifetime diagnosis of psychopathology. All participants completed a functional magnetic resonance imaging (fMRI) scan while viewing temporally predictable or unpredictable negative or neutral images.FINDINGS:The results indicated that individuals with PD-MDD exhibited greater bilateral insula activation to unpredictable aversiveness compared with controls and individuals with MDD-only (who did not differ). There were no group differences in insula activation to predictable aversiveness.CONCLUSIONS:These findings add to a growing literature highlighting the role of the insula in the pathophysiology of anxiety disorders.
Background: The experience of early life stress is a consistently identified risk factor for the development of mood and anxiety disorders. Preclinical research employing animal models of early life stress has made inroads in understanding this association and suggests that the negative sequelae of early life stress may be mediated by developmental disruption of corticolimbic structures supporting stress responsiveness. Work in humans has corroborated this idea, as childhood adversity has been associated with alterations in gray matter volumes of the hippocampus, amygdala, and medial prefrontal cortex. Yet, missing from this body of research is a full understanding of how these neurobiological vulnerabilities may mechanistically contribute to the reported link between adverse childhood experiences and later affective psychopathology.Results: Analyses revealed that self-reported childhood maltreatment was associated with reduced gray matter volumes within the medial prefrontal cortex and left hippocampus. Furthermore, reduced left hippocampal and medial prefrontal gray matter volume mediated the relationship between childhood maltreatment and trait anxiety. Additionally, individual differences in corticolimbic gray matter volume within these same structures predicted the anxious symptoms as a function of life stress 1 year after initial assessment.Conclusions: Collectively, these findings provide novel evidence that reductions in corticolimbic gray matter, particularly within the hippocampus and medial prefrontal cortex, are associated with reported childhood maltreatment and individual differences in adult trait anxiety. Furthermore, our results suggest that these structural alterations contribute to increased affective sensitivity to stress later in life in those that have experienced early adversity. More broadly, the findings contribute to an emerging literature highlighting the critical importance of early stress on the development of corticolimbic structures supporting adaptive functioning later in life.
Background: Aberrant amygdala-prefrontal interactions at rest and during emotion processing are implicated in the pathophysiology of generalized social anxiety disorder (gSAD), a common disorder characterized by fears of potential scrutiny. Cognitive behavioral therapy (CBT) is first-line psychotherapy for gSAD and other anxiety disorders. While CBT is generally effective, there is a great deal of heterogeneity in treatment response. To date, predictors of success in CBT for gSAD include reduced amygdala reactivity and increased activity in prefrontal regulatory regions (e.g., anterior cingulate cortex, ACC)during emotion processing. However, studies have not examined whether tonic (i.e., at rest) coupling of amygdala and these prefrontal regions also predict response to CBT.Results: Twenty-one patients with gSAD participated in resting-state functional magnetic resonance imaging (fMRI) before 12 weeks of CBT. Overall, symptom severity was significantly reduced after completing CBT; however, the patients varied considerably in degree of symptom change. Whole-brain voxel-wise findings showed symptom improvement after CBT was predicted by greater right amygdala-pregenual ACC (pgACC) connectivity and greater left amygdala-pgACC coupling encompassing medial prefrontal cortex. In support of their predictive value, area under receiver operating characteristic curve was significant for the left and right amygdala-pgACC in relation to treatment responders.Conclusions: Improvement after CBT was predicted by enhanced resting-state bilateral amygdala-prefrontal coupling in gSAD. Preliminary results suggest baseline individual differences in a fundamental circuitry that may underlie emotion regulation contributed to variation in symptom change after CBT. Findings offer a new approach towards using a biological measure to foretell who will most likely benefit from CBT. In particular, the departure from neural predictors based on illness-relevant stimuli (e.g., socio-emotional stimuli in gSAD) permits the development of biomarkers that reflect commonalities in the neurobiology of anxiety and mood disorders.
Background: Scientists are beginning to document abnormalities in white matter connectivity in major depressive disorder (MDD). Recent developments in diffusion-weighted image analyses, including tractography clustering methods, may yield improved characterization of these white matter abnormalities in MDD. In this study, we acquired diffusion-weighted imaging data from MDD participants and matched healthy controls. We analyzed these data using two tractography clustering methods: automated fiber quantification (AFQ) and the maximum density path (MDP) procedure. We used AFQ to compare fractional anisotropy (FA; an index of water diffusion) in these two groups across major white matter tracts. Subsequently, we used the MDP procedure to compare FA differences in fiber paths related to the abnormalities in major fiber tracts that were identified using AFQ.Results: FA was higher in the bilateral corticospinal tracts (CSTs) in MDD (p's < 0.002). Secondary analyses using the MDP procedure detected primarily increases in FA in the CST-related fiber paths of the bilateral posterior limbs of the internal capsule, right superior corona radiata, and the left external capsule.Conclusions: This is the first study to implicate the CST and several related fiber pathways in MDD. These findings suggest important new hypotheses regarding the role of CST abnormalities in MDD, including in relation to explicating CST-related abnormalities to depressive symptoms and RDoC domains and constructs.
BACKGROUND:It has long been suggested that feedback signals from facial muscles influence emotional experience. The recent surge in use of botulinum toxin (BTX) to induce temporary muscle paralysis offers a unique opportunity to directly test this "facial feedback hypothesis." Previous research shows that the lack of facial muscle feedback due to BTX-induced paralysis influences subjective reports of emotional experience, as well as brain activity associated with the imitation of emotional facial expressions. However, it remains to be seen whether facial muscle paralysis affects brain activity, especially the amygdala, which is known to be responsive to the perception of emotion in others. Further, it is unknown whether these neural changes are permanent or whether they revert to their original state after the effects of BTX have subsided. The present study sought to address these questions by using functional magnetic resonance imaging to measure neural responses to angry and happy facial expressions in the presence or absence of facial paralysis.RESULTS:Consistent with previous research, amygdala activity was greater in response to angry compared to happy faces before BTX treatment. As predicted, amygdala activity in response to angry faces was attenuated when the corrugator/procerus muscles were paralyzed via BTX injection but then returned to its original state after the effects of BTX subsided. This preliminary study comprises a small sample size and no placebo condition; however, the A-B-A design affords the present sample to serve as its own control.CONCLUSIONS:The current demonstration that amygdala responses to facial expressions were influenced by facial muscle paralysis offers direct neural support for the facial feedback hypothesis. Specifically, the present findings offer preliminary causal evidence that amygdala activity is sensitive to facial feedback during the perception of the facial expressions of others. More broadly, these data confirm the utility of using BTX to address the effect of facial feedback on neural responses associated with the perception, in addition to the experience or expression of emotion.
BACKGROUND:Childhood onset of anxiety disorders is associated with greater functional impairment and burden across the lifespan. Recent work suggests that generalized anxiety disorder (GAD) is characterized by dysfunctional connectivity in amygdala-based circuits at rest in adolescents, consistent with adults. However, neural mechanisms underlying a broad spectrum of often-comorbid anxiety disorders in children remains unclear and understudied. The current study examines amygdala functional connectivity at rest in children and adolescents across comorbid anxiety disorders (ADs) including youth with primary diagnoses of GAD and social phobia (SP).RESULTS:Compared with healthy controls (HCs), AD youth exhibited hyperconnectivity between the right amygdala and the insula and hypoconnectivity between the left amygdala and the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Within the AD group, connectivity was not correlated with anxiety severity and only the amygdala-PCC connectivity was positively correlated with age.CONCLUSIONS:Our findings indicate that youth with comorbid ADs demonstrate aberrant connectivity in the anterior limbic network (ALN) as well as the PCC at rest. This extends upon previous work suggesting alterations in amygdala circuits underlying fear learning, emotion regulation, and the processing of interoceptive states. Presence of these findings within this young, comorbid sample points to underlying common mechanisms across ADs and illuminates future targets for prevention and intervention in childhood.
In this article, I argue for a reconceptualization of major depressive disorder (major depression) as an infectious disease. I suggest that major depression may result from a parasitic, bacterial, or viral infection and present examples that illustrate possible pathways by which these microorganisms could contribute to the etiology of major depression. I also argue that the reconceptualization of the human body as an ecosystem for these microorganisms and the human genome as a host for non-human exogenous sequences may greatly amplify the opportunity to discover genetic links to the illness. Deliberately speculative, this article is intended to stimulate novel research approaches and expand the circle of researchers taking aim at this vexing illness.
Background: Obsessive-compulsive disorder (OCD) is a common and debilitating neuropsychiatric illness thought to involve abnormal connectivity of widespread brain networks, including frontal-striatal-thalamic circuits. At least half of OCD cases arise in childhood and their underlying neuropathology may differ at least in part from that of adult-onset OCD. Yet, only a few studies have examined brain white matter (WM) integrity in childhood-onset OCD using diffusion tensor imaging (DTI), and none have examined potential associations with age at onset.Results: In this study, 17 youth with OCD and 19 healthy control subjects, ages 10 to 19 years, underwent DTI on a 3T Siemens scanner. DSM-IV diagnoses were established with standardized interviews, and OCD symptom severity was evaluated using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Voxel-wise analyses were conducted on data processed with tract-based spatial statistics (TBSS) to derive measures of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). OCD patients had significantly lower FA in seven WM clusters, with over 80% of significant voxels in bilateral frontal cortex and corpus callosum (CC). There were no regions of significantly higher FA in patients compared with controls. Patients also had significantly higher RD in right frontal cortex and right body of the CC. Earlier age at onset of OCD correlated significantly with lower FA in the right thalamus and with higher RD in the right CC. FA and RD were not significantly associated with symptom severity.Conclusions: These findings point to compromised WM integrity and reduced myelination in some brain regions of children with OCD, particularly the CC and fiber tracts that connect the frontal lobes to widespread cortical and subcortical targets. They also suggest that age at onset may be a moderator of some of the WM changes in pediatric OCD.
BACKGROUND:Premenstrual dysphoric disorder (PMDD), characterized by luteal phase-induced negative affect and loss of impulse control, often results in compromised social interactions. Although amygdala activation is generally linked to negative affect, increased amygdala reactivity to aversive stimuli in the luteal phase has not been consistently reported in PMDD. We tested the hypothesis that amygdala hyper-reactivity in PMDD is symptom specific, rather than generalized, and linked to socially relevant stimuli. Blood oxygenation level dependent signal changes during exposure to negative images with social and non-social content were evaluated in the mid-follicular and late luteal phase of the menstrual cycle. Fourteen women with PMDD and 13 healthy controls participated.RESULTS:When compared with healthy controls, women with PMDD in the luteal phase had enhanced reactivity to social stimuli compared to non-social stimuli in the amygdala and insula, but attenuated reactivity in the anterior cingulate cortex. Functional couplings between emotion processing and controlling areas were significantly different, being positive in women with PMDD and negative in healthy controls. Changes in progesterone levels in women with PMDD correlated positively with altered amygdala reactivity.CONCLUSIONS:Socially relevant aversive stimulation elicited enhanced activity in affective processing brain regions that were functionally coupled to compromised activity in cognitive control areas. Because increased reactivity correlated positively with alterations in ovarian steroid levels, data preliminary support the hypothesis that enhanced progesterone sensitivity in PMDD affects corticolimbic processing of social emotions.
Background: Social anxiety has been associated with potentiated negative affect and, more recently, with diminished positive affect. It is unclear how these alterations in negative and positive affect are represented neurally in socially anxious individuals and, further, whether they generalize to non-social stimuli. To explore this, we used a monetary incentive paradigm to explore the association between social anxiety and both the anticipation and consumption of non-social incentives. Eighty-four individuals from a longitudinal community sample underwent functional magnetic resonance imaging (fMRI) while participating in a monetary incentive delay (MID) task. The MID task consisted of alternating cues indicating the potential to win or prevent losing varying amounts of money based on the speed of the participant's response. We examined whether self-reported levels of social anxiety, averaged across approximately 7 years of data, moderated brain activity when contrasting gain or loss cues with neutral cues during the anticipation and outcome phases of incentive processing. Whole brain analyses and analyses restricted to the ventral striatum for the anticipation phase and the medial prefrontal cortex for the outcome phase were conducted.Results: Social anxiety did not associate with differences in hit rates or reaction times when responding to cues. Further, socially anxious individuals did not exhibit decreased ventral striatum activity during anticipation of gains or decreased MPFC activity during the outcome of gain trials, contrary to expectations based on literature indicating blunted positive affect in social anxiety. Instead, social anxiety showed positive associations with extensive regions implicated in default mode network activity (for example, precuneus, posterior cingulate cortex, and parietal lobe) during anticipation and receipt of monetary gain. Social anxiety was further linked with decreased activity in the ventral striatum during anticipation of monetary loss.Conclusions: Socially anxious individuals may increase default mode network activity during reward processing, suggesting high self-focused attention even in relation to potentially rewarding stimuli lacking explicit social connotations. Additionally, social anxiety may relate to decreased ventral striatum reactivity when anticipating potential losses.
BACKGROUND:Previous functional imaging studies using symptom provocation in patients with social anxiety disorder (SAD) reported inconsistent findings, which might be at least partially related to different time-dependent activation profiles in different brain areas. In the present functional magnetic resonance imaging study, we used a novel video-based symptom provocation design in order to investigate the magnitude and time course of activation in different brain areas in 20 SAD patients and 20 healthy controls.RESULTS:The disorder-related videos induced increased anxiety in patients with SAD as compared to healthy controls. Analyses of brain activation to disorder-related versus neutral video clips revealed amygdala activation during the first but not during the second half of the clips in patients as compared to controls. In contrast, the activation in the insula showed a reversed pattern with increased activation during the second but not during the first half of the video clips. Furthermore, a cluster in the anterior dorsal anterior cingulate cortex showed a sustained response for the entire duration of the videos.CONCLUSIONS:The present findings suggest that different regions of the fear network show differential temporal response patterns during video-induced symptom provocation in SAD. While the amygdala is involved during initial threat processing, the insula seems to be more involved during subsequent anxiety responses. In accordance with cognitive models of SAD, a medial prefrontal region engaged in emotional-cognitive interactions is generally hyperactivated.
Background: Animal studies have suggested that the hippocampus may play an important role in anxiety as part of the Behavioural Inhibition System (BIS), which mediates reactivity to threat and punishment and can predict an individual's response to anxiety-relevant cues in a given environment. The aim of the present structural magnetic resonance imaging (MRI) study was to examine the relationship between individual differences in BIS and hippocampal structure, since this has not received sufficient attention in non-clinical populations. Thirty healthy right-handed participants with no history of alcohol or drug abuse, neurological or psychiatric disorders, or traumatic brain injury were recruited (16 male, 14 female, age 18 to 32 years). T1-weighted structural MRI scans were used to derive estimates of total intracranial volume, and hippocampal and amygdala gray matter volume using FreeSurfer. To relate brain structure to Gray's BIS, participants completed the Sensitivity to Punishment questionnaire. They also completed questionnaires assessing other measures potentially associated with hippocampal volume (Beck Depression Inventory, Negative Life Experience Survey), and two other measures of anxiety (Spielberger Trait Anxiety Inventory and the Beck Anxiety Inventory).Results: We found that high scores on the Sensitivity to Punishment scale were positively associated with hippocampal volume, and that this phenomenon was lateralized to the right side. In other words, greater levels of behavioural inhibition (BIS) were positively associated with right hippocampal volume.Conclusions: Our data suggest that hippocampal volume is related to the cognitive and affective dimensions of anxiety indexed by the Sensitivity to Punishment, and support the idea that morphological differences in the hippocampal formation may be associated with behavioural inhibition contributions to anxiety.
The neuroimaging literature of Major Depressive Disorder (MDD) has grown substantially over the last several decades, facilitating great advances in the identification of specific brain regions, neurotransmitter systems and networks associated with depressive illness. Despite this progress, fundamental questions remain about the pathophysiology and etiology of MDD. More importantly, this body of work has yet to directly influence clinical practice. It has long been a goal for the fields of clinical psychology and psychiatry to have a means of making objective diagnoses of mental disorders. Frustratingly little movement has been achieved on this front, however, and the 'gold-standard' of diagnostic validity and reliability remains expert consensus. In light of this challenge, the focus of the current review is to provide a critical summary of key findings from different neuroimaging approaches in MDD research, including structural, functional and neurochemical imaging studies. Following this summary, we discuss some of the current conceptual obstacles to better understanding the pathophysiology of depression, and conclude with recommendations for future neuroimaging research.
BACKGROUND:Recent studies examining the interaction between the 5-HTTLPR locus in the serotonin transporter gene and life stress in predicting depression have yielded equivocal results, leading some researchers to question whether 5-HTTLPR variation indeed regulates depressive responses to stress. Two possible sources of inconsistent data in this literature are imprecise stress assessment methodologies and a restricted focus on depression phenotypes as the outcome of interest, as opposed to transdiagnostic emotional symptoms such as internalizing and externalizing dimensions. The present study aimed to address these critical limitations in prior research by examining how 5-HTTLPR acts in concert with idiographically assessed daily life stress to predict transdiagnostic emotional outcomes.RESULTS:One hundred and four healthy young adults genotyped for 5-HTTLPR reported on their life stress exposure and internalizing and externalizing experiences for 14 consecutive days. As hypothesized, daily stress levels were associated with severity of internalizing symptoms, but only for 5-HTTLPR S allele carriers. Additional analyses revealed that these interactive effects of 5-HTTLPR and daily life stress on internalizing symptoms extended to both the distress and fear subdomains of internalizing symptoms.CONCLUSIONS:Considered together, these results support the validity of the 5-HTTLPR stress sensitivity hypothesis and suggest for the first time that variation at 5-HTTLPR moderates the effects of daily life stress on broadband symptom profiles.
Background: Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice.Results: CRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed.Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls.Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT1A receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact.Conclusions: These results suggest that CRFR2 are required for proper functionality of 5-HT1A receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration.
Background: Early adverse experiences, especially those involving disruption of the mother-infant relationship, are detrimental for proper socioemotional development in primates. Humans with histories of childhood maltreatment are at high risk for developing psychopathologies including depression, anxiety, substance abuse, and behavioral disorders. However, the underlying neurodevelopmental alterations are not well understood. Here we used a nonhuman primate animal model of infant maltreatment to study the long-term effects of this early life stress on brain white matter integrity during adolescence, its behavioral correlates, and the relationship with early levels of stress hormones.Methods: Diffusion tensor imaging and tract based spatial statistics were used to investigate white matter integrity in 9 maltreated and 10 control animals during adolescence. Basal plasma cortisol levels collected at one month of age (when abuse rates were highest) were correlated with white matter integrity in regions with group differences. Total aggression was also measured and correlated with white matter integrity.Results: We found significant reductions in white matter structural integrity (measured as fractional anisotropy) in the corpus callosum, occipital white matter, external medullary lamina, as well as in the brainstem of adolescent rhesus monkeys that experienced maternal infant maltreatment. In most regions showing fractional anisotropy reductions, opposite effects were detected in radial diffusivity, without changes in axial diffusivity, suggesting that the alterations in tract integrity likely involve reduced myelin. Moreover, in most regions showing reduced white matter integrity, this was associated with elevated plasma cortisol levels early in life, which was significantly higher in maltreated than in control infants. Reduced fractional anisotropy in occipital white matter was also associated with increased social aggression.Conclusions: These findings highlight the long-term impact of infant maltreatment on brain white matter structural integrity, particularly in tracts involved in visual processing, emotional regulation, and somatosensory and motor integration. They also suggest a relationship between elevations in stress hormones detected in maltreated animals during infancy and long-term brain white matter structural effects.
