Left Basolateral Amygdala Research Articles

Multivariate Neural Patterns of Reward and Anxiety in Adolescents with Anorexia Nervosa.

People with anorexia nervosa (AN) commonly exhibit elevated anxiety and atypical reward responsiveness. To examine multivariate neural patterns associated with reward and the impact of anxiety on reward, we analyzed fMRI data from a monetary reward task using representational similarity analysis, a multivariate approach that measures trial-by-trial consistency of neural responses. Twenty-five adolescent girls with AN and 22 mildly anxious controls lacking any history of AN were presented personalized anxiety-provoking or neutral words before receiving a reward, and neural response patterns in reward regions were analyzed. Consistent with our preregistered hypothesis, AN participants showed lower representational similarity than controls during neutral-word rewarded trials. Within groups, controls showed significant representational similarity in reward circuit regions including the left nucleus accumbens, left basolateral amygdala, and left medial orbitofrontal cortex, which were not observed in AN. Further, reward-related prefrontal cognitive control areas - left ventrolateral prefrontal cortex and left dorsolateral prefrontal cortex - showed significant representational similarity in both groups, but a larger spatial extent in controls. Contrary to predictions, there were no significant between-group differences for the effects of anxiety-words on reward representational similarity, and representational similarity did not predict longitudinal symptom change over six months. Overall, the results demonstrate relatively inconsistent trial-by-trial responses to reward receipt in the neutral state in AN compared with controls in both reward circuit and cognitive control regions, but no significant differential effects of anxiety states on reward responses. These results add to dynamic understandings of reward processing in AN that have potential implications for planning and guiding reward-focused interventions.

Resting-state functional connectivity of amygdala subregions predicts treatment outcome for cognitive behavioral therapy in obsessive-compulsive disorder at a 4-month follow-up

BackgroundCognitive behavioral therapy (CBT) is considered as the first-line treatment for obsessive-compulsive disorder (OCD). However, the underlying neural mechanisms through which CBT exerts its effects in OCD remain unclear. This study aims to investigate whether the improvement of clinical symptoms in OCD patients after CBT treatment is associated with changes in resting-state functional connectivity (FC) of the amygdala subregion, and whether these changes can be served as potential predictors of four-months treatment efficacy. MethodsWe collected resting-state functional magnetic resonance imaging (rs-fMRI) data from 57 OCD patients and 50 healthy subjects at baseline. In the patient group, rs-fMRI was also obtained after completion of an 8-week CBT treatment and 4 months post-treatment. A whole-brain rsFC analysis was conducted using the amygdala subregion as the seed point. We analyzed the FC patterns in relation to 4 months clinical outcomes to elucidate the long-term efficacy of CBT in OCD patients. ResultsTreatment responseat at pre-treatment was found to be associated with reduced rsFC between the left basolateral amygdala(BLA)and left superior temporal gyrus(STG) at baseline. Lower pre-treatment FC were negatively correlated with the severity of OCD symptoms as measured by the Yale-Brown Obsessive Compulsive Severity Scale (Y-BOCS). Moreover, the area under the receiver operating characteristic (ROC) curve for the FC between the left BLA and STG at the end of treatment was 73.0% and 70.4% for the effective-ineffective and remitted or unremitted groups, respectively. At the 4-month follow-up, the area under the ROC curve for the effective-ineffective and remitted or unremitted groups was 83.9% and 76.5%, respectively. ConclusionThese findings suggest that brain functional activity in patients with OCD can predict treatment response to CBT, and longitudinal changes in relevant brain functional activity following CBT treatment are associated with treatment response in OCD.

Lateralization of the 5-HT1A receptors in the basolateral amygdala in metabolic and anxiety responses to chronic restraint stress

Behavioral and functional studies describe hemispheric asymmetry in anxiety and metabolic behaviors in responses to stress. However, no study has reported serotonergic receptor (the 5-HT1A receptor) lateralization in the basolateral amygdala (BLA) in vivo on anxiety and metabolic behaviors under stress. In the present study, the effect of unilateral and bilateral suppression of the 5-HT1A receptor in the BLA on anxiety, and metabolic responses to chronic restraint stress was assessed. Male Wistar rats 7 days after cannulation into the BLA received chronic restraint stress for 14 consecutive days. 20 minutes before induction of stress, WAY-100–635 (selective 5-HT1A antagonist) or sterile saline (vehicle) was administered either uni- or bi-laterally into the BLA. Behavioral (elevated plus maze; EPM, and open field test), and metabolic parameter studies were performed. Results showed that stress causes a significant increase in weight gain compared to control. In the non-stress condition, the left and bilaterally, and in the stress condition the right, left, and both sides, inhibition of 5-HT1A in the BLA reduced weight gain. In the restraint stress condition, only inhibition of the 5-HT1A receptor in the left BLA led to decreased food intake compared to the control group. In stress conditions, inhibition of the 5-HT1A receptor on the right, left, and bilateral BLA increased water intake compared to the stress group. Inhibition of the 5-HT1A receptor on the left side of the BLA by WAY-100–635 induced anxiety-like behaviors in stressed rats. Similarly, WAY-100–635 on the left BLA effectively caused anxiety-like behaviors in both EPM and open field tests in the control animals. In conclusion, it seems that 5-HT1A receptors in the left BLA are more responsible for anxiety-like behaviors and metabolic changes in responses to stress.

Effects of the suppression of 5-HT1A receptors in the left, right, or bilateral basolateral amygdala on memory consolidation in chronic stress in male rats.

The serotonin-1A receptors (5-HT1A) in the two cerebral hemispheres are differentially involved in memory. The distribution of 5-HT1A receptors in the left and right amygdala is different. Furthermore, evidence shows that the 5-HT1A receptors in the left and right amygdala work differently in memory function. The basolateral amygdala (BLA) also regulates hippocampal long-term potentiation (LTP) during stress. However, which BLA structure in each hemisphere underlies such lateralized function is unclear. The present research investigated the possible involvement of 5-HT1A lateralization in the BLA on stress-induced memory impairment. 5-HT1A receptor antagonist (Way-100-635) was injected into the left, right, or bilateral BLA twenty minutes before chronic restraint stress (CRS) for 14 consecutive days. Results indicated that suppression of 5HT1A-receptors in the BLA plays an essential role in reducing the acquisition of passive avoidance in the shuttle box test and spatial memory in the Barnes maze test in the stress animals. This decrease was significant in the CRS animals with left and bilateral suppressed 5HT1A-receptors in the BLA. Field potential recording results showed that the left, right, and bilateral injection of Way-100-635 into the BLA significantly reduced the slope and amplitude of fEPSP in the CA1 area of the hippocampus in stressed rats. No significant difference was observed in neuronal arborization in the CA1 area of the hippocampus. In conclusion, the 5-HT1A receptor in the left and right sides of BLA nuclei play a different role in memory consolidation in the hippocampus under stress.

Disorganized functional architecture of amygdala subregional networks in obsessive-compulsive disorder

A precise understanding of amygdala-centered subtle networks may help refine neurocircuitry models of obsessive-compulsive disorder (OCD). We applied connectivity-based parcellation methodology to segment the amygdala based on resting-state fMRI data of 92 medication-free OCD patients without comorbidity and 90 matched healthy controls (HC). The amygdala was parcellated into two subregions corresponding to basolateral amygdala (BLA) and centromedial amygdala (CMA). Amygdala subregional functional connectivity (FC) maps were generated and group differences were evaluated with diagnosis-by-subregion flexible factorial ANOVA. We found significant diagnosis × subregion FC interactions in insula, supplementary motor area (SMA), midcingulate cortex (MCC), superior temporal gyrus (STG) and postcentral gyrus (PCG). In HC, the BLA demonstrated stronger connectivity with above regions compared to CMA, whereas in OCD, the connectivity pattern reversed to stronger CMA connectivity comparing to BLA. Relative to HC, OCD patients exhibited hypoconnectivity between left BLA and left insula, and hyperconnectivity between right CMA and SMA, MCC, insula, STG, and PCG. Moreover, OCD patients showed reduced volume of left BLA and right CMA compared to HC. Our findings characterized disorganized functional architecture of amygdala subregional networks in accordance with structural defects, providing direct evidence regarding the specific role of amygdala subregions in the neurocircuitry models of OCD.

Polygenic risk scores for antisocial behavior in relation to amygdala morphology across an attention deficit hyperactivity disorder case-control sample with and without disruptive behavior

Antisocial and aggressive behaviors show considerable heritability and are central to disruptive behavior disorders (DBDs), but are also frequently observed in attention deficit hyperactivity disorder (ADHD). While the amygdala is implicated as a key neural structure, it remains unclear whether common genetic variants underlie this brain-behavior association. We hypothesized that polygenic (risk) scores for antisocial and aggressive behaviors (ASB-PRS) would be related to amygdala morphology. Using the Broad Antisocial Behavior Consortium genome-wide association study (GWAS; mostly population based cohorts), we calculated ASB-PRS in the NeuroIMAGE I ADHD case-control sample with varying levels of DBD symptomatology (n=679 from 379 families, aged 7 – 29). We first investigated associations of several ASB-PRS p value thresholds with the presence of DBD symptoms and self-reported antisocial behavior (ASB) to determine the threshold for further analyses. This PRS was then related to amygdala volume and shape using regression and vertex-wise analyses. Our results showed associations of ASB-PRS with the presence of DBD symptoms, self-reported ASB, and left basolateral amygdala shape, independent of ADHD symptom severity and ADHD-PRS, with a relative outward displacement of the vertices. No associations of ASB-PRS, DBD symptoms or self-reported ASB with amygdala volume were found. Our results indicate that genetic risk for antisocial and aggressive behaviors is related to amygdala shape alterations, and point to genetic sharing across different DBD and ASB and aggression-related phenotypes as a spectrum of genetically related quantitative traits. Additionally, our findings support the utility of vertex-based shape analyses in genetic studies of ASB, aggression, and DBDs.

Sleep deprivation altered encoding of basolateral amygdala on fear acquisition.

Sleep deprivation (SD) may lead to the development of fear- and anxiety-related emotional disorders. However, the neural mechanisms underlying the effects of SD on fear acquisition are unclear. Here, we tested whether and how SD influences the behavioral and neural manifestations of fear acquisition. We found that subjective fear ratings and objective fear indices (skin conductance response [SCR]) in the SD group were greater than those in the control group during fear acquisition, suggesting that SD facilitated fear acquisition (nSD = 18 and ncontrol = 23 for self-reported rating analysis; nSD = 10 and ncontrol = 10 for SCR analysis). Neuroimaging data showed that the SD group exhibited stronger activity in the left basolateral amygdala (BLA) and left superficial amygdala (SFA). Moreover, the left BLA activity, which positively correlated with the objective fear indices, significantly mediated the effect of SD on fear acquisition. Together, the present findings indicate that SD facilitates fear acquisition by augmenting threat-specific encoding in the BLA, which may be a potential biomarker of the risk of developing fear-related disorders under traumatic and distressing situations.

Oxytocin enhances basolateral amygdala activation and functional connectivity while processing emotional faces: preliminary findings in autistic vs non-autistic women.

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional connectivity of the basolateral amygdala—the brain’s ‘salience detector’—while processing emotional faces vs shapes was tested in 16 autistic and 21 non-autistic women by functional magnetic resonance imaging in a placebo-controlled, within-subject, cross-over design. In the placebo condition, minimal activation differences were observed between autistic and non-autistic women. However, significant drug × group interactions were observed for both basolateral amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35-voxel cluster, Montreal Neurological Institute (MNI) coordinates of peak voxel = −22 −10 −28; mean change = +0.079%, t = 3.159, PTukey = 0.0166) but not among non-autistic women (mean change = +0.003%, t = 0.153, PTukey = 0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not in non-autistic women, attenuating group differences in the placebo condition. Taken together, these findings extend evidence of oxytocin’s effects on the amygdala to specifically include autistic women and specify the subregion of the effect.

Role of Amygdala-Infralimbic Cortex Circuitry in Glucocorticoid-induced Facilitation of Auditory Fear Memory Extinction.

The basolateral amygdala (BLA) and infralimbic area (IL) of the medial prefrontal cortex (mPFC) are two interconnected brain structures that mediate both fear memory expression and extinction. Besides the well-known role of the BLA in the acquisition and expression of fear memory, projections from IL to BLA inhibit fear expression and have a critical role in fear extinction. However, the details of IL-BLA interaction have remained unclear. Here, we investigated the role of functional reciprocal interactions between BLA and IL in mediating fear memory extinction. Using lidocaine (LID), male rats underwent unilateral or bilateral inactivation of the BLA and then unilateral intra-IL infusion of corticosterone (CORT) prior to extinction training of the auditory fear conditioning paradigm. Freezing behavior was reported as an index for conditioned fear. Infusions were performed before the extinction training, allowing us to examine the effects on fear expression and further extinction memory. Experiments 1-3 investigated the effects of left or right infusion of CORT into IL and LID unilaterally into BLA on fear memory extinction. Intra-IL infusion of CORT in the right hemisphere reduced freezing behavior when administrated before the extinction training. Auditory fear memory extinction was impaired by asymmetric inactivation of BLA and CORT infusion in the right IL; however, the same effect was not observed with symmetric inactivation of BLA. IL-BLA neural circuit may provide additional evidence for the contribution of this circuit to auditory fear extinction. This study demonstrates dissociable roles for right or left BLA in subserving the auditory fear extinction. Our finding also raises the possibility that left BLA-IL circuitry may mediate auditory fear memory extinction via underlying mechanisms. However, further research is required in this area. Corticosterone infusion in the right (but not the left) infralimbic area facilitates auditory fear memory extinction.Corticosterone infusion in the right infralimbic area following symmetric basolateral amygdala inactivation has no effect on auditory fear memory extinction.Asymmetric basolateral amygdala inactivation prior to corticosterone infusion into the right infralimbic area impairs auditory fear memory extinction. Previous studies have established that glucocorticoids, which are released in stressful conditions, enhance fear memory extinction. In this study, we found that corticosterone infusion into the right infralimbic area, but not the left one, facilitates auditory fear memory extinction. The effect of corticosterone infusion in the infralimbic area was not blocked by the intra-basolateral amygdala injections of lidocaine when administrated in the ipsilateral hemisphere. However, asymmetric basolateral amygdala inactivation and corticosterone infusion into the right infralimbic area impairs auditory fear memory extinction.

The mirror neuron system compensates for amygdala dysfunction - associated social deficits in individuals with higher autistic traits

The amygdala is a core node in the social brain which exhibits structural and functional abnormalities in Autism spectrum disorder and there is evidence that the mirror neuron system (MNS) can functionally compensate for impaired emotion processing following amygdala lesions. In the current study, we employed an fMRI paradigm in 241 subjects investigating MNS and amygdala responses to observation, imagination and imitation of dynamic facial expressions and whether these differed in individuals with higher (n = 77) as opposed to lower (n = 79) autistic traits. Results indicated that individuals with higher compared to lower autistic traits showed worse recognition memory for fearful faces, smaller real-life social networks, and decreased left basolateral amygdala (BLA) responses to imitation. Additionally, functional connectivity between the left BLA and the left inferior frontal gyrus (IFG) as well as some other MNS regions was increased in individuals with higher autistic traits, especially during imitation of fearful expressions. The left BLA-IFG connectivity significantly moderated the autistic group differences on recognition memory for fearful faces, indicating that increased amygdala-MNS connectivity could diminish the social behavioral differences between higher and lower autistic trait groups. Overall, findings demonstrate decreased imitation-related amygdala activity in individuals with higher autistic traits in the context of increased amygdala-MNS connectivity which may functionally compensate for amygdala dysfunction and social deficits. Training targeting the MNS may capitalize on this compensatory mechanism for therapeutic benefits in Autism spectrum disorder.

Resting-state functional connectivity of the amygdala subregions in unmedicated patients with obsessive-compulsive disorder before and after cognitive behavioural therapy.

Background:Cognitive behavioural therapy (CBT) is considered an effective first-line treatment for obsessive–compulsive disorder (OCD). However, the neural basis of CBT for OCD has not yet been elucidated. The role of the amygdala in OCD and its functional coupling with the cerebral cortex have received increasing attention, and may provide new understanding of the neural basis of CBT for OCD.Methods:We acquired baseline resting-state functional MRI (fMRI) scans from 45 unmedicated patients with OCD and 40 healthy controls; we then acquired another wave of resting-state fMRI scans from the patients with OCD after 12 weeks of CBT. We performed seed-based resting-state functional connectivity analyses of the amygdala subregions to examine changes in patients with OCD as a result of CBT.Results:Compared to healthy controls, patients with OCD showed significantly increased resting-state functional connectivity at baseline between the left basolateral amygdala and the right middle frontal gyrus, and between the superficial amygdala and the right cuneus. In patients with OCD who responded to CBT, we found decreased resting-state functional connectivity after CBT between the amygdala subregions and the visual association cortices and increased resting-state functional connectivity between the amygdala subregions and the right inferior parietal lobe. Furthermore, these changes in resting-state functional connectivity were positively associated with changes in scores on the compulsion or obsession subscales of the Yale–Brown Obsessive–Compulsive Scale.Limitations:Because of the lack of a second scan for healthy controls after 12 weeks, our results may have been confounded by other variables.Conclusion:Our findings yield insights into the pathophysiology of OCD; they also reveal the potential neural changes elicited by CBT, and thus have implications for guiding effective treatment strategies with CBT for OCD.

Dysfunction of Resting-State Functional Connectivity of Amygdala Subregions in Drug-Naïve Patients With Generalized Anxiety Disorder.

Objective: Although previous studies have reported on disrupted amygdala subregional functional connectivity in generalized anxiety disorder (GAD), most of these studies were conducted in GAD patients with comorbidities or with drug treatment. Besides, whether/how the amygdala subregional functional networks were associated with state and trait anxiety is still largely unknown.Methods: Resting-state functional connectivity of amygdala subregions, including basolateral amygdala (BLA) and centromedial amygdala (CMA) as seed, were mapped and compared between 37 drug-naïve, non-comorbidity GAD patients and 31 age- and sex-matched healthy controls (HCs). Relationships between amygdala subregional network dysfunctions and state/trait anxiety were examined using partial correlation analyses.Results: Relative to HCs, GAD patients showed weaker functional connectivity of the left BLA with anterior cingulate/medial prefrontal cortices. Significantly increased functional connectivity of right BLA and CMA with superior temporal gyrus and insula were also identified in GAD patients. Furthermore, these functional connectivities showed correlations with state and trait anxiety scores.Conclusions: These findings revealed abnormal functional coupling of amygdala subregions in GAD patients with regions involved in fear processing and emotion regulation, including anterior cingulate/medial prefrontal cortex and superior temporal gyrus, which provide the unique biological markers for GAD and facilitating the future accurate clinical diagnosis and target treatment.

Short-Term Amygdala Low-Frequency Stimulation Does not Influence Hippocampal Interneuron Changes Observed in the Pilocarpine Model of Epilepsy.

Temporal lobe epilepsy (TLE) is characterized by changes in interneuron numbers in the hippocampus. Deep brain stimulation (DBS) is an emerging tool to treat TLE seizures, although its mechanisms are not fully deciphered. We aimed to depict the effect of amygdala DBS on the density of the most common interneuron types in the CA1 hippocampal subfield in the lithium-pilocarpine model of epilepsy. Status epilepticus was induced in male Wistar rats. Eight weeks later, a stimulation electrode was implanted to the left basolateral amygdala of both pilocarpine-treated (Pilo, n = 14) and age-matched control rats (n = 12). Ten Pilo and 4 control animals received for 10 days 4 daily packages of 50 s 4 Hz regular stimulation trains. At the end of the stimulation period, interneurons were identified by immunolabeling for parvalbumin (PV), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). Cell density was determined in the CA1 subfield of the hippocampus using confocal microscopy. We found that PV+ cell density was preserved in pilocarpine-treated rats, while the NPY+/nNOS+ cell density decreased significantly. The amygdala DBS did not significantly change the cell density in healthy or in epileptic animals. We conclude that DBS with low frequency applied for 10 days does not influence interneuron cell density changes in the hippocampus of epileptic rats.

Acute Neurofunctional Effects of Escitalopram in Pediatric Anxiety: A Double-Blind, Placebo-Controlled Trial

Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD). Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed. Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F= 17.79, p= .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p< .001) but not placebo (p= .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p= .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA)-VLPFC (F= 19.64, p< .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F= 22.92, p= .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment. In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development. Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Resting functional connectivity in the semantic appraisal network predicts accuracy of emotion identification

ObjectiveStructural and task-based functional studies associate emotion reading with frontotemporal brain networks, though it remains unclear whether functional connectivity (FC) alone predicts emotion reading ability. The predominantly frontotemporal salience and semantic appraisal (SAN) networks are selectively impacted in neurodegenerative disease syndromes like behavioral-variant frontotemporal dementia (bvFTD) and semantic-variant primary progressive aphasia (svPPA). Accurate emotion identification diminishes in some of these patients, but studies investigating the source of this symptom in patients have predominantly examined structural rather than functional brain changes. Thus, we investigated the impact of altered connectivity on their emotion reading. MethodsOne-hundred-eighty-five participants (26 bvFTD, 21 svPPA, 24 non-fluent variant PPA, 24 progressive supranuclear palsy, 49 Alzheimer’s disease, 41 neurologically healthy older controls) underwent task-free fMRI, and completed the Emotion Evaluation subtest of The Awareness of Social Inference Test (TASIT-EET), watching videos and selecting labels for actors’ emotions. ResultsAs expected, patients averaged significantly worse on emotion reading, but with wide inter-individual variability. Across all groups, lower mean FC in the SAN, but not other ICNs, predicted worse TASIT-EET performance. Node-pair analysis revealed that emotion identification was predicted by FC between 1) right anterior temporal lobe (RaTL) and right anterior orbitofrontal (OFC), 2) RaTL and right posterior OFC, and 3) left basolateral amygdala and left posterior OFC. ConclusionEmotion reading test performance predicts FC in specific SAN regions mediating socioemotional semantics, personalized evaluations, and salience-driven attention, highlighting the value of emotion testing in clinical and research settings to index neural circuit dysfunction in patients with neurodegeneration and other neurologic disorders.

The Effect of Deep Brain Stimulation on High Frequency Oscillations in a Chronic Epilepsy Model

Abstract Temporal lobe epilepsy (TLE) is a severe neurological disease which is often pharmacoresistant. Deep brain stimulation (DBS) is a novel method for treating epilepsy; however, its mechanism of action is not fully understood. We aimed to study the effect of amygdala DBS in the pilocarpine model of TLE. Status epilepticus was induced by pilocarpine in male Wistar rats, and spontaneous seizures occurred after a latency period. A stimulating electrode was inserted into the left basolateral amygdala and two recording electrodes into the left and right hippocampus. A stimulus package consisted of 0.1 ms-long biphasic pulses applied regularly at 4 Hz for 50 seconds. This package was repeated four times a day, with 5-minute pauses, for 10 days. We also used an age-matched healthy control group of stimulated animals and another one of sham-operated rats. From the hippocampal local field potentials high frequency oscillations (HFOs) were analyzed as these are promising epilepsy biomarkers. HFOs are short oscillatory events between 80-600 Hz which were detected offline using an open-source application of MATLAB, the RIPPLELAB system. We found that the HFO rate was significantly higher in pilocarpine-treated rats compared to the control groups (0.41 ± 0.14 HFO/min vs. 0.006 ± 0.003 in the stimulated control group and no HFO in the sham-operated group). In the pilocarpine group an instantaneous decrease in HFO rate was observed while the stimulation was on (0.44 ± 0.15 HFO/min vs 0.07 ± 0.03 HFO/min, p=0.017). The effect was short-lived because the frequency of HFOs did not change significantly in the time windows between stimulus packages or during the ten-day stimulation period. The difference of HFO rates between epileptic and control groups could be used in the electrographic assessment of epilepsy. The decreased frequency of HFOs during stimulation may be useful to study the efficacy of DBS.

Amygdala Low-Frequency Stimulation Reduces Pathological Phase-Amplitude Coupling in the Pilocarpine Model of Epilepsy.

Temporal-lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and warrants the development of new therapies, such as deep-brain stimulation (DBS). DBS was applied to different brain regions for patients with epilepsy; however, the mechanisms of action are not fully understood. Therefore, we tried to characterize the effect of amygdala DBS on hippocampal electrical activity in the lithium-pilocarpine model in male Wistar rats. After status epilepticus (SE) induction, seizure patterns were determined based on continuous video recordings. Recording electrodes were inserted in the left and right hippocampus and a stimulating electrode in the left basolateral amygdala of both Pilo and age-matched control rats 10 weeks after SE. Daily stimulation protocol consisted of 4 × 50 s stimulation trains (4-Hz, regular interpulse interval) for 10 days. The hippocampal electroencephalogram was analyzed offline: interictal epileptiform discharge (IED) frequency, spectral analysis, and phase-amplitude coupling (PAC) between delta band and higher frequencies were measured. We found that the seizure rate and duration decreased (by 23% and 26.5%) and the decrease in seizure rate correlated negatively with the IED frequency. PAC was elevated in epileptic animals and DBS reduced the pathologically increased PAC and increased the average theta power (25.9% ± 1.1 vs. 30.3% ± 1.1; p < 0.01). Increasing theta power and reducing the PAC could be two possible mechanisms by which DBS may exhibit its antiepileptic effect in TLE; moreover, they could be used to monitor effectiveness of stimulation.

Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression

Chronic treatment with fluoxetine (FLX) is required for its antidepressant effects, but the role of serotonin (5-HT) axonal plasticity in FLX action is unknown. To address this, we examined mice with a stroke in the left medial prefrontal cortex (mPFC) resulting in persistent anxiety-like and depression-like behaviors and memory deficits as a model of post-stroke depression. Chronic treatment with FLX (but not exercise) completely reversed the behavioral phenotype and partially reversed changes in FosB-labeled cells in the mPFC, nucleus accumbens, septum, hippocampus, basolateral amygdala (BLA), and dorsal raphe. In these regions, 5-HT or norepinephrine (NE) innervation was quantified by staining for 5-HT or NE transporters, respectively. 5-HT synapses and synaptic triads were identified as synaptophysin-stained sites on 5-HT axons located proximal to gephyrin-stained or PSD95-stained spines. A week after stroke, 5-HT innervation was greatly reduced at the stroke site (left cingulate gyrus (CG) of the mPFC) and the left BLA. Chronically, 5-HT and NE innervation was reduced at the left CG, nucleus accumbens, and BLA, with no changes in other regions. In these areas, pre-synaptic and post-synaptic 5-HT synapses and triads to inhibitory (gephyrin+) sites were reduced, while 5-HT contacts at excitatory (PSD95+) sites were reduced in the CG and prelimbic mPFC. Chronic FLX, but not exercise, reversed these reductions in 5-HT innervation but incompletely restored NE projections. Changes in 5-HT innervation were verified using YFP staining in mice expressing YFP-tagged channelrhodopsin in 5-HT neurons. Thus, FLX-induced 5-HT axonal neuroplasticity of forebrain projections may help mediate recovery from brain injury.

It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress.

Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons in vitro in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms.SIGNIFICANCE STATEMENT Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders.

Neurobiological evidence of sexual dimorphism in limbic circuitry of US Veterans

BackgroundFemale Veterans are an increasing patient population in the Department of Veterans Affairs and may have distinct clinical and neurobiological features compared to males. MethodsNineteen female and 19 male Veterans who met diagnostic criteria for depression/posttraumatic stress disorder (MDD/PTSD) completed diagnostic interviews, symptom measures, and resting-state neuroimaging. Participants completed clinical measures of mood and aggression in addition to magnetic resonance imaging on a 3.0 Tesla Siemens scanner. ResultsFemales showed increased functional connectivity between the left and right basolateral amygdala (BLA) and the left and right cerebellar and occipital lobes. Sex differences also were evident in the relationship between affective and clinical symptoms with BLA connectivity. Females showed a correlation between revenge planning and decreased connectivity between the left BLA and left occipital lobe and also a correlation between aggression and decreased connectivity between the right BLA and right mid cingulate, right and left medial frontal lobe, and right frontal lobe. Males evidenced a relationship between increased depressive symptoms and increased connectivity between the left BLA and right and left occipital lobe, left calcarine, and other areas associated with visual memory and processing, and interpretation of sensory information. Additionally, males reported higher levels of physical aggression and revenge planning compared to females. LimitationsThis study included neuroimaging and self-report clinical measures. Further studies will benefit from multimodal measures, including behavioral measures of aggression. ConclusionsResults suggest that male Veterans report more aggression than females and symptoms of aggression and mood are differentially related to BLA connectivity by sex.