Modification of evoked unit activity of the dorsomedial thalamic nucleus following destruction of the basolateral amygdala in rats

Neuronal responses of the dorsomedial thalamic nucleus of anesthetized rats to stimulation of the anterior periamygdalar cortex were compared before and after destruction of the basolateral nuclei of the ipsilateral amygdala. After destruction of the afferent inflow from the nuclei of the amygdala a new type of response appeared, in the form of prolonged generation of bursts of spikes, and also a significant decrease in the number of cells with a phasic activation response and an increase in the number of tonically activated neurons. Destruction of the amygdala was shown to lead to an increase in the number of cells of the dorsomedial nucleus with spontaneous activity. The duration of the tonic spike response in animals undergoing the operation was found to be significantly increased from 142.5±42.4 to 375.4±53.8 msec, whereas the parameters of other types of neuronal responses did not differ statistically significantly.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 16, No. 6, pp. 784–789, November–December, 1984.     

Infusion of methylphenidate into the basolateral nucleus of amygdala or anterior cingulate cortex enhances fear memory consolidation in rats

The psychostimulant methylphenidate (MPD; also called Ritalin) is a blocker of dopamine and norepi-nephrine transporter. It has been clinically used for treatment of Attention Deficit and Hyperactivity Disorder (ADHD). There have been inconsistent reports regarding the effects of systemically adminis-tered MPD on learning and memory, either in animals or humans. In the present study, we investigated the effect of direct infusion of MPD into the basolateral nucleus of amygdala (BLA) or the anterior cin-gulate cortex (ACC) on conditioned fear memory. Rats were trained on a one-trial step-through inhibi-tory avoidance task. MPD was infused bilaterally into the BLA or the ACC, either at ‘0’ or 6 h post-training. Saline was administered as control. Memory retention was tested 48 h post-training. In-tra-BLA or intra-ACC infusion of MPD ‘0’ h but not 6 h post-training significantly improved 48-h memory retention: the MPD-treated rats had significant longer step-through latency than controls. The present results indicate that action of MPD in the BLA or the ACC produces a beneficial effect on the consoli-dation of inhibitory avoidance memory.     

Mitophagy in the basolateral amygdala mediates increased anxiety induced by aversive social experience

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GABAergic circuits of the basolateral amygdala and generation of anxiety after traumatic brain injury

Traumatic brain injury (TBI) has reached epidemic proportions around the world and is a major public health concern in the United States. Approximately 2.8 million individuals sustain a traumatic brain injury and are treated in an Emergency Department yearly in the U.S., and about 50,000 of them die. Persistent symptoms develop in 10–15% of the cases including neuropsychiatric disorders. Anxiety is the second most common neuropsychiatric disorder that develops in those with persistent neuropsychiatric symptoms after TBI. Abnormalities or atrophy in the temporal lobe has been shown in the overwhelming number of TBI cases. The basolateral amygdala (BLA), a temporal lobe structure that consolidates, stores and generates fear and anxiety-based behavioral outputs, is a critical brain region in the anxiety circuitry. In this review, we sought to capture studies that characterized the relationship between human post-traumatic anxiety and structural/functional alterations in the amygdala. We compared the human findings with results obtained with a reproducible mild TBI animal model that demonstrated a direct relationship between the alterations in the BLA and an anxiety-like phenotype. From this analysis, both preliminary insights, and gaps in knowledge, have emerged which may open new directions for the development of rational and more efficacious treatments.

     

Effect of destruction of basolateral nuclei of the amygdala on the character of electrical activity of the dorsomedial thalamic nucleus in rats

Characteristics of slow global and of unit activity in the dorsomedial thalamic nucleus were studied at various times after destruction of nuclei of the basolateral amygdala in semichronic experiments on anesthetized rats. Destruction of this kind was found to cause periodic transformation of the neuronal discharge into rhythmic bursts of spikes, and into the development of bursts of paroxysmal activity in the form of groups of four to six pointed waves with a mean duration of 60.5±20.6 msec, appearing with a frequency of 1.5±0.3 Hz. A change in the coefficient of correlation was found between the duration of bursts and their frequency during the 20–22-sec period of their generation. Interference was demonstrated between bursts and orthodromic focal potentials, evoked by stimulation of the anterior periamygdalar cortex and anterior amygdalar region. Neurons were described with long (up to 1 sec) responses to stimulation of the periamygdalar cortex and amygdalar region, in the form of regular bursts of spikes or tonic activation, correlating with the appearance of a rhythmic after-discharge. Bursts of this kind, which were most marked during the first 3 or 4 days after destruction of the basolateral amygdala, were observed to begin to disappear toward the end of the first postoperative week. It is suggested that one mechanism of the change in the adaptive behavior of animals with destruction of the amygdala is a disturbance, linked with the bursts, of the relay and integrative functions of the dorsomedial thalamic nucleus.     

Electrophysiologic and behavioral changes after destruction of the basolateral nucleus of the amygdala in the rat

In experiments on rats the influence was studied of unilateral destruction of the basolateral amygdala on heterogeneous conditioned reflexes and focal potentials (FPs) of the dorso-medial thalamic nucleus, elicited by stimulation of the peri-amygdalar cortex. It is shown that reduction during 3-4 postsurgery weeks of the number of goal-directed reactions and increase of their latencies are accompanied by suppression of the evoked activity, testifying to disturbance of functional interaction between the structures of limbic and thalamic levels. Changes of FPs parameters, reflecting the establishment of new functional interrelations between the centres of the lesioned system excelled in duration compensatory restoration of properties of conditioned reflexes.     

Similar neural activity during fear and disgust in the rat basolateral amygdala

Much research has focused on how the amygdala processes individual affects, yet little is known about how multiple types of positive and negative affects are encoded relative to one another at the single-cell level. In particular, it is unclear whether different negative affects, such as fear and disgust, are encoded more similarly than negative and positive affects, such as fear and pleasure. Here we test the hypothesis that the basolateral nucleus of the amygdala (BLA), a region known to be important for learned fear and other affects, encodes affective valence by comparing neuronal activity in the BLA during a conditioned fear stimulus (fear CS) with activity during intraoral delivery of an aversive fluid that induces a disgust response and a rewarding fluid that induces a hedonic response. Consistent with the hypothesis, neuronal activity during the fear CS and aversive fluid infusion, but not during the fear CS and rewarding fluid infusion, was more similar than expected by chance. We also found that the greater similarity in activity during the fear- and disgust-eliciting stimuli was specific to a subpopulation of cells and a limited window of time. Our results suggest that a subpopulation of BLA neurons encodes affective valence during learned fear, and furthermore, within this subpopulation, different negative affects are encoded more similarly than negative and positive affects in a time-specific manner.     

Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces

Responses to threat-related stimuli are influenced by conscious and unconscious processes, but the neural systems underlying these processes and their relationship to anxiety have not been clearly delineated. Using fMRI, we investigated the neural responses associated with the conscious and unconscious (backwardly masked) perception of fearful faces in healthy volunteers who varied in threat sensitivity (Spielberger trait anxiety scale). Unconscious processing modulated activity only in the basolateral subregion of the amygdala, while conscious processing modulated activity only in the dorsal amygdala (containing the central nucleus). Whereas activation of the dorsal amygdala by conscious stimuli was consistent across subjects and independent of trait anxiety, activity in the basolateral amygdala to unconscious stimuli, and subjects' reaction times, were predicted by individual differences in trait anxiety. These findings provide a biological basis for the unconscious emotional vigilance characteristic of anxiety and a means for investigating the mechanisms and efficacy of treatments for anxiety.     

Mechanisms regulating GABAergic inhibitory transmission in the basolateral amygdala: implications for epilepsy and anxiety disorders

Summary. The amygdala, a temporal lobe structure that is part of the limbic system, has long been recognized for its central role in emotions and emotional behavior. Pathophysiological alterations in neuronal excitability in the amygdala are characteristic features of certain psychiatric illnesses, such as anxiety disorders and depressive disorders. Furthermore, neuronal excitability in the amygdala, and, in particular, excitability of the basolateral nucleus of the amygdala (BLA) plays a pivotal role in the pathogenesis and symptomatology of temporal lobe epilepsy. Here, we describe two recently discovered mechanisms regulating neuronal excitability in the BLA, by modulating GABAergic inhibitory transmission. One of these mechanisms involves the regulation of GABA release via kainate receptors containing the GluR5 subunit (GluR5KRs). In the rat BLA, GluR5KRs are present on both somatodendritic regions and presynaptic terminals of GABAergic interneurons, and regulate GABA release in an agonist concentration-dependent, bidirectional manner. The relevance of the GluR5KR function to epilepsy is suggested by the findings that GluR5KR agonists can induce epileptic activity, whereas GluR5KR antagonists can prevent it. Further support for an important role of GluR5KRs in epilepsy comes from the findings that antagonism of GluR5KRs is a primary mechanism underlying the antiepileptic properties of the anticonvulsant topiramate. Another mechanism regulating neuronal excitability in the BLA by modulating GABAergic synaptic transmission is the facilitation of GABA release via presynaptic α_1A adrenergic receptors. This mechanism may significantly underlie the antiepileptic properties of norepinephrine. Notably, the α_1A adrenoceptor-mediated facilitation of GABA release is severely impaired by stress. This stress-induced impairment in the noradrenergic facilitation of GABA release in the BLA may underlie the hyperexcitability of the amygdala in certain stress-related affective disorders, and may explain the stress-induced exacerbation of seizure activity in epileptic patients.     

大鼠基底外侧杏仁核组蛋白乙酰化对吗啡成瘾记忆的调控作用

为了探索组蛋白乙酰化对吗啡成瘾记忆相关分子表达调控机制,文章选取健康成年雄性SD大鼠34只,随机分为正常对照组(n = 6)及基底外侧杏仁核(Basolateral amygdala, BLA)颅内定位手术组(n =28)。在条件性位置偏爱(Conditioned place preference, CPP)训练阶段,大鼠BLA内给予组蛋白去乙酰化酶抑制剂曲古抑菌素A(Trichostafin A, TSA)并且腹腔注射吗啡溶液(10.0 mg/kg),对照组给予相同体积的10%二甲基亚砜(Dimethyl sulfoxide,DMSO)或盐水。应用蛋白质印记方法,检测吗啡诱导大鼠CPP建立后BLA内组蛋白H3K14乙酰化和脑源性神经营养因子(Brain-derived neurotrophic factor, BDNF)蛋白表达水平。结果显示,腹腔注射10 mg/kg吗啡能成功建立CPP。吗啡、TSA联合给药组大鼠比单纯吗啡给药组大鼠表现出更强烈的CPP(P<0.0001)。吗啡和TSA都能使BLA内的组蛋白H3乙酰化水平和BDNF的表达显著增高(P < 0.0001),同时二者之间具有协同作用。结果表明,大鼠BLA内组蛋白乙酰化水平与吗啡成瘾记忆形成有关,抑制BLA内组蛋白去乙酰化酶(Histone deacetylases, HDACs)的活性可强化吗啡诱导的线索记忆的形成;大鼠BLA内BDNF参与了吗啡诱导的线索记忆的形成并可能受到组蛋白乙酰化的调控。     

Neurons in the amygdala with response-selectivity for anxiety in two ethologically based tests

The amygdala is a key area in the brain for detecting potential threats or dangers, and further mediating anxiety. However, the neuronal mechanisms of anxiety in the amygdala have not been well characterized. Here we report that in freely-behaving mice, a group of neurons in the basolateral amygdala (BLA) fires tonically under anxiety conditions in both open-field and elevated plus-maze tests. The firing patterns of these neurons displayed a characteristic slow onset and progressively increased firing rates. Specifically, these firing patterns were correlated to a gradual development of anxiety-like behaviors in the open-field test. Moreover, these neurons could be activated by any impoverished environment similar to an open-field; and introduction of both comfortable and uncomfortable stimuli temporarily suppressed the activity of these BLA neurons. Importantly, the excitability of these BLA neurons correlated well with levels of anxiety. These results demonstrate that this type of BLA neuron is likely to represent anxiety and/or emotional values of anxiety elicited by anxiogenic environmental stressors.     

Investigating the inhibition of NMDA glutamate receptors in the basolateral nucleus of the amygdala on the pain and inflammation induced by formalin in male Wistar rats

Background

The role of the amygdala in controlling emotional pain has been emphasized in several studies. In this study, the role of the NMDA glutamate receptors in the basolateral nucleus of the amygdala (BLA) in regulating inflammation and emotional pain, induced by formalin, was studied in male rats.

Methods

Male Wistar rats, weighing 250±20 g, were injected with 20 μL of 2% formalin into the paw of the right hind limb. Memantine, at doses of 1 and 5 mg/rat, was injected bilaterally into the BLA five minutes prior to injecting formalin. Following the injection, the pain and inflammation of the paws were measured using Dubbison-Dennis and mercury immersion methods, respectively. The behavior of the animals, including licking time and foot volume, was assessed.

Results

The results showed that the inactivation of the NMDA receptors in the BLA in the acute phase of pain reduced the licking time (the emotional aspect of pain). However, at a high dose (5 μg/rat), memantine exacerbates the pain induced by formalin in the chronic phase. Additionally, the inhibition of the NMDA receptors in the BLA by memantine enhanced the formalin-induced increase in foot volume (inflammation) in a dose-dependent manner.

Conclusion

The study showed that the NMDA glutamate receptors in the BLA are crucial for the emotional pain and inflammation in both chronic and acute phases of formalin-induced pain. However, their roles are more pronounced in the chronic phase than in the acute phase of pain.

     

选择性5-HT1A受体拮抗剂WAY-100635增加6-羟多巴胺损毁大鼠杏仁基底外侧核的神经活动

本文采用玻璃微电极细胞外记录法,观察正常大鼠和6-羟多巴胺(6-hydroxydopamine,6-OHDA)损毁黑质致密部大鼠杏仁基底外侧核(basolateral nucleus,BL)神经元电活动的变化,以及体循环给予选择性5-HT1A受体拮抗剂WAY-100635对神经元电活动的影响.结果显示,正常大鼠BL投射神经元和中间神经元的放电频率分别足(O.39±0.04)Hz和(0.83±0.16)Hz,6-OHDA损毁大鼠BL投射神经元和中间神经元的放电频率分别足(0.32±0.04)Hz和(0.53±0.12)Hz,与正常大鼠相比无显著差异.在正常大鼠,所有投射神经元呈现爆发式放电;94%的中间神经元为爆发式放电,6%为不规则放电.在6.OHDA损毁大鼠,85%的投射神经元呈现爆发式放电,15%为不规则放电;86%的中间神经元为爆发式放电,14%为不规则放电,与正常大鼠相比无显著差别.静脉给予0.1 mg/kg体重的WAY-100635不改变正常大鼠和6-OHDA损毁人鼠BL投射神经元和中间神经元的放电频率.然而,0.5 mg/kg体重的WAY-100635却显著降低正常大鼠BL投射神经元的平均放电频率(P<0.01),明显增加6-OHDA损毁大鼠BL投射神经元的平均放电频率(P<0.004).高剂量WAY-100635不影响正常大鼠和6-OHDA损毁大鼠BL中间神经元的平均放电频率.结果表明,黑质多巴胺能损毁后内在和外在的传入调节BL神经元的活动,在正常大鼠和6-OHDA损毁大鼠5-HT1A 受体调节投射神经元的活动,并且在6-OHDA损毁大鼠WAY-100635诱发投射神经元平均放电频率增加.结果提示,5-HT1A 受体在帕金森病情感性症状的产生中起重要作用.     

Paradoxical facilitation of working memory after basolateral amygdala damage

Working memory is a vital cognitive capacity without which meaningful thinking and logical reasoning would be impossible. Working memory is integrally dependent upon prefrontal cortex and it has been suggested that voluntary control of working memory, enabling sustained emotion inhibition, was the crucial step in the evolution of modern humans. Consistent with this, recent fMRI studies suggest that working memory performance depends upon the capacity of prefrontal cortex to suppress bottom-up amygdala signals during emotional arousal. However fMRI is not well-suited to definitively resolve questions of causality. Moreover, the amygdala is neither structurally or functionally homogenous and fMRI studies do not resolve which amygdala sub-regions interfere with working memory. Lesion studies on the other hand can contribute unique causal evidence on aspects of brain-behaviour phenomena fMRI cannot "see". To address these questions we investigated working memory performance in three adult female subjects with bilateral basolateral amygdala calcification consequent to Urbach-Wiethe Disease and ten healthy controls. Amygdala lesion extent and functionality was determined by structural and functional MRI methods. Working memory performance was assessed using the Wechsler Adult Intelligence Scale-III digit span forward task. State and trait anxiety measures to control for possible emotional differences between patient and control groups were administered. Structural MRI showed bilateral selective basolateral amygdala damage in the three Urbach-Wiethe Disease subjects and fMRI confirmed intact functionality in the remaining amygdala sub-regions. The three Urbach-Wiethe Disease subjects showed significant working memory facilitation relative to controls. Control measures showed no group anxiety differences. Results are provisionally interpreted in terms of a 'cooperation through competition' networks model that may account for the observed paradoxical functional facilitation effect.     

Hyperpolarization-activated currents control the excitability of principal neurons in the basolateral amygdala

Anxiety is thought to be influenced by neuronal excitability in basolateral nucleus of the amygdala (BLA). However, molecules that are critical for regulating excitability of BLA neurons are yet to be determined. In the present study, we have examined whether hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which mediate the depolarizing cation current, can control the neuronal excitability. HCN channel-like activity appeared to be detected in BLA principal neurons. ZD7288, a specific blocker for HCN channels, increased the input resistance of membrane, hyperpolarized resting membrane potential, and enhanced action potential firing in BLA principal neurons. The blockade of HCN channels facilitated temporal summation of repetitively evoked excitatory postsynaptic potentials, suggesting that suppression of HCN channel activity in principal neurons can accelerate the propagation of synaptic responses onto the axon hillock. Thus, our findings have laid foundation for studies to reveal how HCN channel activity in BLA principal neurons regulates anxiety in vivo.