Blunted diurnal interleukin-6 rhythm is associated with amygdala emotional hyporeactivity and depression: a modulating role of gene-stressor interactions.

Background: The immune system has major roles in the brain and related psychopathology. Disrupted interleukin-6 secretion and aberrant amygdala emotional reactivity are well-documented in stress-related mental disorders. The amygdala regulates psychosocial stress-related interleukin-6 affected by related genes. These led us to comprehensively examine the relationship between interleukin-6, amygdala activity, and stress-related mental symptoms under gene-stressor interactions. Methods: One hundred eight nonclinical participants with various levels of anxiety/depression underwent magnetic resonance imaging scans during an emotional face task for amygdala activity and saliva collection (at 10-time points across 2 days) for the total output and diurnal patterns of interleukin-6. Gene-stressor interactions between rs1800796 (C/G) and rs2228145 (C/A) and stressful life events for the biobehavioral measures were explored. Results: The blunting of interleukin-6 diurnal pattern was associated with hypoactivation of the basolateral amygdala in response to fearful (vs. neutral) faces (t = 3.67, FWE-corrected p = 0.003), and was predominantly observed in individuals with rs1800796 C-allele homozygotes and negative life changes in the past year (F = 19.71, p < 0.001). When considered in a comprehensive model, the diminished diurnal pattern predicted greater depressive symptoms (ß = -0.40), modulated by the amygdala hypoactivity (ß = 0.36) and rs1800796-stressor interactions (ß = -0.41; all p < 0.001). Conclusion: Here we show that the blunted interleukin-6 diurnal rhythm predicts depressive symptoms, modulated by amygdala emotional hyporeactivity and gene-stressor interactions. These findings indicate a potential mechanism underlying vulnerability to depressive disorders, suggesting their early detection, prevention, and treatment through the understanding of immune system dysregulation.

The role of basolateral amygdala orexin 1 receptors on the modulation of pain and psychosocial deficits in nitroglycerin-induced migraine model in adult male rats.

BACKGROUND: Migraine headaches have been associated with sensory hyperactivity and anomalies in social/emotional responses. The main objective of this study was to evaluate the potential involvement of orexin 1 receptors (Orx1R) within the basolateral amygdala (BLA) in the modulation of pain and psychosocial dysfunction in a nitroglycerin (NTG)-induced rat model of migraine. METHODS: Adult male Wistar rats were injected with NTG (5 mg/kg, intraperitoneal) every second day over nine days to induce migraine. The experiments were done in the following six groups (6 rats per group): untreated control, NTG, NTG plus vehicle, and NTG groups that were post-treated with intra-BLA microinjection of Orx1R antagonist SB-334867 (10, 20, and 40 nM). Thermal hyperalgesia was assessed using the hot plate and tail-flick tests. Moreover, the elevated plus maze (EPM) and open field (OF) tests were used to assess anxiety-like behaviors. The animals' sociability was evaluated using the three-chamber social task. The NTG-induced photophobia was assessed using a light-dark box. RESULTS: We observed no change in NTG-induced thermal hyperalgesia following administration of SB-334867 (10, 20, and 40 nM). However, SB-334867 (20 and 40 nM) aggravated the NTG-induced anxiogenic responses in both the EPM and OF tasks. The NTG-induced social impairment was overpowered by SB-334867 at all doses. Time spent in the dark chamber of light-dark box was significantly increased in rats treated with SB-334867 (20 and 40 nM/rat). CONCLUSIONS: The findings suggest a role for Orx1R within the BLA in control comorbid affective complaints with migraine in rats.

Restructuring of amygdala subregion apportion across adolescence.

Total amygdala volumes develop in association with sex and puberty, and postmortem studies find neuronal numbers increase in a nuclei specific fashion across development. Thus, amygdala subregions and composition may evolve with age. Our goal was to examine if amygdala subregion absolute volumes and/or relative proportion varies as a function of age, sex, or puberty in a large sample of typically developing adolescents (N = 408, 43 % female, 10-17 years). Utilizing the in vivo CIT168 atlas, we quantified 9 subregions and implemented Generalized Additive Mixed Models to capture potential non-linear associations with age and pubertal status between sexes. Only males showed significant age associations with the basolateral ventral and paralaminar subdivision (BLVPL), central nucleus (CEN), and amygdala transition area (ATA). Again, only males showed relative differences in the proportion of the BLVPL, CEN, ATA, along with lateral (LA) and amygdalostriatal transition area (ASTA), with age. Using a best-fit modeling approach, age, and not puberty, was found to drive these associations. The results suggest that amygdala subregions show unique variations with age in males across adolescence. Future research is warranted to determine if our findings may contribute to sex differences in mental health that emerge across adolescence.

Cholecystokinin immunoreactive neurons in the basolateral amygdala of the rhesus monkey (Macaca mulatta).

Several distinct subpopulations of interneurons (INs) in the amygdalar basolateral nuclear complex (BNC) of the rat can be recognized on the basis of their expression of calcium-binding proteins and neuropeptides, including parvalbumin (PV), somatostatin (SOM), calretinin (CR), and cholecystokinin (CCK). In the rat BNC CCK is expressed in two separate IN subpopulations, termed large (CCKL ) and small (CCKS ). These subpopulations exhibit distinct connections indicative of discrete functional roles in the circuitry of the BNC. Although there have been several studies of PV+, SOM+, and CR+ INs in the primate BNC, there is almost no information regarding CCK+ INs in these species. Therefore, in the present study the distribution and morphology of CCK+ INs and their axon terminals in the BNC of the monkey was investigated. CCK immunoreactivity in the BNC was observed in somata and proximal dendrites of nonpyramidal neurons, as well as in axon terminals. A moderate density of CCK+ INs was found in all nuclei of the BNC. CCK+ INs in the BNC were morphologically heterogeneous, with both small and large varieties observed. All CCK+ somata gave rise to 2-4 dendrites that branched sparingly and were aspiny. CCK+ axon terminals in the BNC were found both in the neuropil and forming pericellular baskets contacting somata of pyramidal cells. In addition, many CCK+ neurons were contacted by multiple CCK+ terminals, indicative of the existence of a CCK interneuronal network. These data indicate that the morphology of CCK+ INs in the monkey is very similar to that of the rat.

Morphologic Alterations in Amygdala Subregions of Adult Patients with Bipolar Disorder

OBJECTIVES: Previous studies have revealed inconsistent results on amygdala volume in adult bipolar disorder (BD) patients compared to healthy controls (HC). Since the amygdala encompasses multiple subregions, the subtle volume changes in each amygdala nucleus might have not been fully reflected in the measure of the total amygdala volume, causing discrepant results. Thus, we aimed to investigate volume changes in each amygdala subregion and their association with subtypes of BD, lithium use and clinical status of BD. METHODS: Fifty-five BD patients and 55 HC underwent T1-weighted structural magnetic resonance imaging. We analyzed volumes of the whole amygdala and each amygdala subregion, including the anterior amygdaloid area, cortico-amygdaloid transition area, basal, lateral, accessory basal, central, cortical, medial and paralaminar nuclei using the atlas in the FreeSurfer. The volume difference was analyzed using a one-way analysis of covariance with individual volumes as dependent variables, and age, sex, and total intracranial volume as covariates. RESULTS: The volumes of whole right amygdala and subregions including basal nucleus, accessory basal nucleus, anterior amygdaloid area, and cortico-amygdaloid transition area in the right amygdala of BD patients were significantly smaller for the HC group. No significant volume difference between bipolar I disorder and bipolar II disorder was found after the Bonferroni correction. The trend of larger volume in medial nucleus with lithium treatment was not significant after the Bonferroni correction. No significant correlation between illness duration and amygdala volume, and insignificant negative correlation were found between right central nucleus volume and depression severity. CONCLUSIONS: Significant volume decrements of the whole amygdala, basal nucleus, accessory basal nucleus, anterior amygdaloid area, and cortico-amygdaloid transition area were found in the right hemisphere in adult BD patients, compared to HC group. We postulate that such volume changes are associated with altered functional activity and connectivity of amygdala nuclei in BD.

Effect of amitriptyline on phosphorylation of HDAC5 in basolateral amygdale of rats with neuropathic pain / 中华麻醉学杂志

Objective To evaluate the effect of amitriptyline on the phosphorylation of histone deacetylase 5 (HDAC5) in the basolateral amygdala (BLA) of rats with neuropathic pain.Methods Thirty healthy male Wistar rats,weighing 250-300 g,were divided into 3 groups (n=10 each) using a random number table method:sham operation group (S group),neuropathic pain group (NP group) and amitriptyline group (A group).Spared nerve injury was produced by exposing the sciatic nerve and its branches and ligation and transection of tibial nerve and common fibular nerve in anesthetized rats.Amitriptyline 10 mg/kg was intraperitoneally injected every day on 14-35 days after establishing the model in group A,while the equal volume of normal saline was given instead of amitriptyline in S and NP groups.The mechanical paw withdrawal threshold (MWT) was measured on 3,7,14,21,28 and 35 days after establishing the model in each group.The forced swimming test was performed on day 36 after establishing the model,and immobility time,climbing time and swimming time were recorded.The rats were then sacrificed,and brain tissues in BLA were obtained for determination of the expression of HDAC5 and phosphorylated HDAC5 (p-HDAC5) (by Western blot) and expressionof HDAC5 mRNA (by real-time quantitative polymerase chain reaction).Results Compared with group S,the MWT was significantly decreased at each time point,the immobility time was prolonged,and the swimming time and climbing time were shortened in group NP,and the MWT was significantly decreased on days 14,21 and 28 after establishing the model,the expression of p-HDAC5 was down-regulated,and the expression of HDAC5 mRNA was up-regulated in group A (P＜0.05).Compared with group NP,the MWT was significantly increased on days 21,28 and 35 after establishing the model,the immobility time was shortened,the climbing time was prolonged,the expression of p-HDAC5 was up-regulated,and the expression of HDAC5 mRNA was down-regulated in group A (P＜0.05or 0.01).Conclusion The mechanism by which amitriptyline improves depression is associated with promoting the phosphorylation of HDAC5 in BLA of rats with NP.