Science, Technology and Medicine open access publisher.Publish, read and share novel research. I Akirav, G Richter-levin, 2002Mechanisms of amygdala modulation of hippocampal plasticity. Fink AE & O’Dell TJ2009Short trains of theta frequency stimulation enhance CA1 pyramidal neuron excitability in the absence of synaptic potentiation. Gewirtz JC & Davis M1997Second-order fear conditioning prevented by blocking NMDA receptors in amygdala. Y Gidron, T Barak, A Henik, G Gurman, O Stiener, 2002Implicit learning of emotional information under anesthesia. S Groch, I Wilhelm, S Diekelmann, F Sayk, S Gais, J Born, 2011Contribution of norepinephrine to emotional memory consolidation during sleep. Washington, Jan 28 : The link between amygdala and fear, especially a fear of others unlike us, has gone too far not only in pop culture but also in psychological science, a new study has claimed. The amygdala are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Instead, the amygdala seems to be doing something more subtle - processing events that are related to what a person cares about at the moment. A lot of the time, people really don't know, or won't say, what they're thinking, and it would be nice to be able to look at a picture of their brain and know the answer.
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Fear memory enhances connectivity in cortical and limbic circuits but whether treatments disrupting fear reset connectivity to pre-trauma level is unknown. The present study examines the extent to which β-ARs antagonists, that interfere with fear memory and p-ERK signaling, reinstate pre-trauma levels connectivity in fear-activated neural circuits.
The behavioral protocol was based on the one designed by Debiec and LeDoux (2004) in which TFC takes place in one context (chamber A), while the reactivation trial and the memory test take place in another context (chamber B). On day 5, conditioned mice were injected with saline or propranolol, and pseudo-conditioned mice were injected with saline and immediately after they were submitted to a reactivation trial taking place in chamber B and consisting of a 2-minute habituation period followed by a single CS presentation. Forty-eight hours after the reactivation trial, mice were exposed to four CSs presentations in context B, delivered at a variable inter-tone interval (120 s on average). Behavior during conditioning, reactivation trial, and memory test was recorded by means of a video camera mounted 60 cm above the ceiling of chamber A or B, which was connected to a computer equipped with the Ethovision software (Noldus, The Netherlands).
Punches for western blots were taken 90 min after the memory test from the BLA and the DH of mice experiencing the three conditions (4 mice per group) using a 1 mm punch tool (Fine Science Tools, Foster City, CA) from 1 mm thick sections cut on a frozen brain matrix (ASI Instruments).
Figure 1 shows a cartoon depicting the three phases of the behavioral protocol (Figure 1A) and the freezing scores of the three experimental groups during the conditioning, the reactivation trial, and the memory test (Figure 1B). The time spent freezing in chamber B 48 h after the reactivation trial was then taken as an index of long term fear memory. Western blots were carried out in amygdala and hippocampus homogenates collected 90 min after the memory test and normalized for tubulin levels. Specifically, the amygdala, a tiny little part in the medial temporal lobe of the brain, performs a primary role in memory and emotional response and stores all, ALL, painful and traumatic experiences. Circumcision is inarguably one of those painful and traumatic experiences that is indelibly imprinted upon one's emotional memory.
Conditions such as anxiety, autism, depression, post-traumatic stress disorder, and phobias are suspected of being linked to abnormal functioning of the amygdala, owing to damage, developmental problems, or neurotransmitter imbalance" (Science Daily). The amydala has connections to aggression, sexual orientation, fear and fear response, social response and interactions, alcoholism, anxiety, stress, sexual arousal, and depression.
I am very often accused of being cold and harsh, because I am direct, decisive, and no-nonsense. Executive Function (EF) is a term that describes the way that specific mental processes regulate other cognitive emotional and behavioural functions and actions.
Executive Function is such a large area of brain function that it is valuable to look at some of the physical and neurological aspects involved.
Central to Executive Function is the limbic system in the middle of the brain and its pathways to the “higher” areas of both structure and function. In addition to the general notes about brain structure, and their functions in cognition and emotion, it is useful to look at some of the brain functions associated with music.
The diagram below indicates some of the major pathways to the amygdala, the emotional “centre” of the brain. Given the strong correlations between music perception and emotional regulation, it should not be surprising to note that many autistic people, myself included, have differing emotional relationships with music to the “typical” person. My Brain, My Enemy: There are times when half one's brain doe not obey the direction or requirements of the other half.
Theory of Mind: Theory of Mind is a term that describes the spontaneous abilty to adopt the point of view of another person. Social Communication: Social communication deals with the sharing of affect that forms relationships and oils the wheels of conversation sharing. Colours and Images: The images have been chosen very carefully to enhance the text that they are associated with.
What is Executive Function?: Executive Function is the primary controller of cognitive behaviour. Faces and Bits: Prosopagnosia, or face-blindness, can affect both recognition of people and their nonverbal language. Amygdala of rhesus monkey Macaca mulatta Left, whole brain in sagittal plane and right, amygdala and adjacent regions.
Amygdala and fear response pathwaysLeft, amygdala (in actual coronal brain slice) and its major nuclei. Induction of LTP in the LA in vitroMean baseline EPSP (blue trace) obtained in the presence of 100 ?M PTX by stimulation of cortical inputs into the pyramidal neuron.
Kodirov[1] Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg, Russia[2] I. M Alberini, 2008The role of protein synthesis during the labile phases of memory: Revisiting the skepticism.
2005Effect of LTP-reinforcing paradigms on neurotransmitter release in the dentate gyrus of young and aged rats. F Arnsten, 2007Catecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness.
2003Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. 2003Enhanced human memory consolidation with post-learning stress: Interaction with the degree of arousal at encoding. E Ellis, 1985Amygdala norepinephrine involved in two separate long-term memory retrieval processes.
C Emson, A Bjorklund, O Lindvall, G Paxinos, 1979Contributions of different afferent pathways to the catecholamine and 5-hydroxytryptamine-innervation of the amygdala: A neurochemical and histochemical study.
L Mcgaugh, 2008Involvement of basolateral amygdala ?2-adrenoceptors in modulating consolidation of inhibitory avoidance memory. L Mcgaugh, 1999aBasolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between ?- and ?1-adrenoceptors. L Mcgaugh, 1999bInvolvement of ?1-adrenoceptors in the basolateral amygdala in modulation of memory storage. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.
But it also activates at other times, for example in response to pleasant photographs and happy faces. A lot of people came to the amygdala from the study of fear, says Wil Cunningham of Ohio State University, who co-wrote the new paper with Tobias Brosch of New York University.
This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. In humans, comparisons of EEG signal coherence in adult individuals reporting childhood, adulthood, or no history of traumatic experience points to a positive correlation between connectivity over frontal, central, temporal and parietal areas and intensity of the trauma (Cook et al., 2009).
Importantly, the BLA controls adaptation to stress via a β-ARs-mediated regulation of phosphorylated ERK (Grissom and Bhatnagar, 2011). An ethanol solution (70%) was used to clean the chamber after each mouse underwent the conditioning trial. The time spent freezing (absence of all but respiratory movements) after CS-US presentation was used to score fear during the conditioning and the retrieval while the time spent freezing during the four CSs presentation was averaged and used as a long term fear memory index (Blanchard and Blanchard, 1969).
Brains were dissected and immediately immersed in a Golgi-Cox solution at room temperature for 6 days (Glaser and Van der Loos, 1981). The immunohistochemistry protocol was performed according the manufacturing procedure of ULTRATEK HRP KIT (ScyTek laboratories).
Between-group differences in freezing behavior, spine density, protein levels were estimated by means of a One-Way ANOVA with group as the main factor. Propranolol prevents the increase in spine density observed in basolateral amygdala, but not in CA1 dorsal hippocampus, neurons upon fear memory testing.
Propranolol prevents the increase in p-ERK signaling observed in basolateral amygdala upon fear memory testing.
It is something of an umbrella term and covers more specific aspects such as Local Coherence, Empathy and Emotions, each of which have their own sections in this document. Within the limbic system, the amygdala is actually a pair of almond shaped bodies on the ends of the hippocampus, which in a sense are the “heart” of the brain, as they are largely responsible for our emotional responses. Each of the various structures has specific functions, some of which are indicated here.  Input from the senses is received by the thalamus, in the very middle of the brain, and is distributed to the Cognitive  (cerebral) and emotive (limbic) systems.
Pairing of EPSPs with depolarization-induced action potentials (red) at 2 Hz led to LTP (green).3. 1997Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. U Frey, 2007Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala. L Mcgaugh, 2006Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala.
A Grace, 2007Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of ?-2 and ? receptor activation. E Gold, 2007Amnesia produced by altered release of neurotransmitters after intraamygdala injections of a protein synthesis inhibitor. E Gold, 2008Intra-amygdala injections of CREB antisense impair inhibitory avoidance memory: role of norepinephrine and acetylcholine. 2008Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation. 2009Stimulation of the lateral geniculate, superior colliculus, or visual cortex is sufficient for eyeblink conditioning in rats. Cunningham also thinks many scientists have gotten too attached to a rigid definition of emotions-anger, fear, sadness, happiness, and so on. This intense fear response is associated with a massive increase in dendritic spines and phospho-Erk (p-ERK) signaling in basolateral amygdala (BLA) but neurons.
There is evidence that β-ARs antagonists disrupt fear memory (Soeter and Kindt, 2011), but whether they also block fear-induced phospho-Erk (p-ERK) enhancement has not yet been investigated. This intense freezing response is accompanied by an increase in dendritic spines and p-ERK signaling in BLA neurons.
Chamber B differed from chamber A in shape (trapezoidal shape), color (black walls with a plain gray floor), odor (70% ethanol solution with lemon odor), and light intensity (40 W lamp).
On the seventh day, brains were transferred in a 30% sucrose solution for cryoprotection and then sectioned with a vibratome. The supernatant was collected, and protein content was quantified by Bradford colorimetric assay (Biorad, Milano, Italy). In supplemental experiment 1, differences in freezing behavior during the long term memory test between mice receiving pre-reactivation injections of sotalol or saline were estimated by means of a t-test. Post-hoc comparisons between the two trained groups revealed that although mice injected with propranolol showed less freezing that their saline-injected counterpart, these scores did not differ significantly. Importantly, no difference in spine density was found between the two latter groups (propranolol-injected trained mice vs.
In the trained mice, spine density did not significantly differ between those injected with saline or propranolol (p = 0.90, NS) therefore revealing that DH spines were unaffected by the treatment. Current understanding is that the connections to the amygdala from the sensory inputs create “emotional memory”. Note that the thalamus has both a direct connection to the Amygdala and a slower route via the Prefrontal Cortex. Pavlov Department of Physiology, State Research Institute of Experimental Medicine, Russian Academy of Medical Sciences, Saint Petersburg, Russia[3] Department of Molecular Physiology & Biophysics, University of Iowa, Iowa City, USA1. J Hough, H Li, 2004Stress impairs ?1A adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala. In rodents, tone fear conditioning (TFC) drives structural alterations in basolateral amygdala (BLA) neurons consistent with an enhancement in the strength and in the number of synapses. This point is of importance considering that p-ERK regulates the activity of downstream pathways implicated in the synthesis of proteins involved in synaptic plasticity and experience-dependent structural re-arrangements (Sweatt, 2004). Administration of the β-ARs blocker propranolol before, but not immediately after, the reactivation test attenuates fear memory assessed drug-free 48 h later but completely prevents the increase in dendritic spines and of p-ERK signaling in BLA neurons. Coronal sections (100 μm) were collected and stained according to the method described by Gibb and Kolb (1998).
On the next day, frontal 30 um cryostat slices were sectioned from entire brain and immediately prepared for immunohistochemistry.
Section were then washed with PBS and incubated with biotinylated goat antirabbit secondary antibody.
Pre-reactivation injections of sotalol did not decrease freezing during the memory test (sotalol- vs. This includes experiences from very early, preverbal, childhood and experiences that are non-lingual, but have a strong emotive context, such as fear or strong bonding.
IntroductionThe extensive knowledge about the significance and connexions of the amygdala with other brain regions emerged in the early XXth century (Gurdjian, 1928). B Hoffman, 2004Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala. An increase in spines, but not of p-ERK, was also detected in the dorsal hippocampus (DH) of the conditioned mice. The formation of fear memory also promotes an increase in spines, but not of p-ERK levels, in the dorsal hippocampus (DH) of the conditioned mice.
Spine density was analyzed on class I spiny neurons which represent the predominant cell type in the basolateral amygdala nuclei (McDonald, 1982). Pre-reactivation injections of sotalol did not affect freezing during the reactivation trial (sotalol- vs. Pre-reactivation injections of propranolol blocked the increase in spines in BLA but not in CA1 DH neurons.
This is the so-called “paralanguage” including tone and prosody (rhythm, accent and intonation) that carry emotive context and help identify irony and sarcasm and define the difference between a question and a statement. Although it is conceivable that connectivity in fear-activated circuits should be reduced upon fear erasure, whether pharmacological treatments reducing fear memory reset physiological levels of connectivity is unknown.
DH connectivity, however, is unaffected by propranolol suggesting that it plays role in the persistence of a consistent level of fear memory. The two bands corresponding to p-ERK42 and p-ERK44 consistently varied in the same manner and were thus analyzed together. Among the trained mice, those receiving pre-reactivation injections of propranolol showed significantly less freezing during the memory test than those receiving saline injections.

Louis, MO,USA) at the same dose and time-point as propranolol to estimate the respective role of central vs. For light microscopy immunohistochemistry, slices were mounted on superfrost plis slides, air dried, quickly dehydrated, and coverslipped.
The additional nuclei belonging to the amygdala are established as “extended amygdala” (Fig.
Pseudo-conditioning consisted in placing mice in chamber A and exposing them to the tone in the absence of foot-shock. Blots were then incubated with appropriate secondary antibody conjugated to horseradish peroxidase (Chemicon) and developed by ECL Western Blotting Analysis System (GE Healthcare).
In supplemental experiment 2, we compared the effect of propranolol injected immediately before or immediately after the reactivation trial to assess whether attenuation of fear memory can be ascribed to an effect of the drug on retrieval, on reconsolidation, or both. Only protrusions with a clear connection of the head of the spine to the shaft of the dendrite were counted as spines (Horner and Arbuthnott, 1991). However, the majority of studies address the lateral (LA), basolateral (BLA) and central (CeA) amygadala and their role in several emotionally driven responses in organisms. Statistical comparisons were made on single neuron values obtained by averaging the number of spines counted on segments of the same neuron. One of the latter responses is the stress and its circuit initiates in locus coeruleus (LC) after a release of norepinephrine (NE) by noradrenergic neurons. These findings therefore suggest that the effect of the drug on long term fear memory is unlikely to be ascribed to a disruption of memory reconsolidation.
Similar to other catecholamines such as epinephrine (adrenaline) and dopamine (DA), norepinephrine (noradrenaline) is released either into the circulation or locally to brain regions as a response to stress. To control for the regional specificity of fear memory-induced structural changes in the hippocampus, CA1 dorsal (N = 3) and ventral (N = 3) hippocampal neurons were selected within each hemisphere in the same animals, and spine density counts were performed on basal dendrites using to the same quantification method. In the amygdala the content of NE is higher than DA, but comparable to that of serotonin (Niwa et al., 2011). These neurons are distinguished by their positive reaction to DBH ? dopamine ?-hydroxylase, which enables the conversion of DA into NE.
The physiological (endogenous) dynamics or pathological increase of NE occur at terminals originating from the LC (Emson et al., 1979).
In individuals with a history of post-traumatic stress disorder (PTSD) the properties of the amygdala, along the hippocampus and prefrontal cortex, are affected and involve stress hormones such as cortisol and NE (for review see Bremner, 2006).
Specifically, the fear-conditioning paradigm bilaterally increases the activity of the amygdala in those with symptoms of PTSD as a result of abuse. In healthy subjects, such an increase targets the left hemisphere; nevertheless, the left amygdala in the PTSD group is more active compared to the control.
Emotional learning and resultant memories via amygdalaThe amygdala is the main brain region responsible for emotion, at least for its intensity. Emotions, in turn, can influence memory leading to either forgetting – amnesia or stronger (compared to average) remembering – hypermnesia. A particular Pavlovian training or conditioning that has been widely used in research, enables experimental animals to associate the neutral CS with the US of a negative valence. Fear conditioning paradigms are excellent tools for the study of neurobiological substrates of learning and memory. With regard to this, a peculiar interest has been devoted to the role of amygdala in auditory fear conditioning (LeDoux et al., 1984). The learning process in the amygdala and resultant memory undergo multiple steps involving consolidation and re-consolidation. Although the mechanisms underlying these two steps to a greater extent are controversial (Alberini, 2008).
The interplay between information storage and dynamic properties of synapses are complex (Varshney et al., 2006).
The consolidation of recent memories (from the previous day) are processed during sleep within the rapid eye movement (REM) phase, the latter leads to sorting of relatively earlier (then the very recent one) acquired information and its subsequent forgetting (Poe et al., 2000).
Fear memory and circuits related to addiction often function synergistically (Peters et al., 2009).
Fear conditioning and the strength of acquired memory parallel the increased numbers of reactivated neurons (Reijmers et al., 2007) both in the LA and BLA. However, we should consider that not only the amygdala, but also the hippocampus participates in fear response and its subsequent processing (Knierim, 2003). The modulation of cognition by NE is also continuously elucidated in human subjects concurrently with established paradigm.The neuronal excitability is a result of activities and properties of multiple ion channels including hyperpolarization-activated cyclic nucleotide gated non-selective cation (HCN or Ih) channels. It has been established that NE possesses the inverted U shaped dose response effects and targets the ?2A adrenergic receptors (AR) and inhibits HCN channels (for review see Arnsten, 2007). Postsynaptic action potentials and neuronal excitability are required for the plasticity within several inputs.
Clinical experimentsCortisol and NE are considered as a main stress hormones (for literature analyses see Cahill et al., 2003).
Greater amounts of emotionally charged pictures were correctly recalled by CPS group.Stressful events result in activation of the amygdala accompanied by increase in NE levels and surgery counts to this.
Patients who underwent general anesthesia responded faster and provided correct word associations with emotionally negative cues compared to neutral ones (Gidron et al., 2002). This was the case when it concerned the old cues, however in regard to new cues the opposite effects were observed.
Moreover, there was a correlation between the reaction time and spectral edge frequency (SEF) during EEG recordings.
In this study, the noradrenergic response to NE was inhibited by propranolol via blockade of ?-adrenoceptors. Experimentally, the noradrenergic response was enhanced by NE reuptake inhibitor, reboxetine mesilate, a pharmaceutical that is widely used in order to reveal the resultant changes during the exposure to certain experimental paradigms. Such outcomes were observed with both positive and negative oddball stimuli, but not with neutral ones. In fact, the plasma content depends on overall body’s metabolism and prior fasting, as was shown for reboxetine (Hurlemann et al., 2007). Although, emotionally driven retrograde amnesia can occur via modulation of either NE or cortisol signaling, concurrent activation of these systems is perhaps an adequate underlying mechanism. This notion is supported by the magnitudes of recall change under negative emotion contact (E-1) for reboxetine (34 %) and synthetic cortisol (24 %), hydrocortisone, alone.
All these treatment combinations did not alter the von Restroff phenomenon, and the correct recall magnitudes were ~95 % for oddball stimuli.
Oral intake of yohimbine reversibly increases the content of ?-amylase in human saliva (van Stegeren et al., 2010). A cortisol containing pill enhanced the endogenous cortisol level in these subjects abruptly and sustained at plateau for at least 1 h. The performance of these two groups, in terms of (better) recognition and recalling emotional pictures, when compared to neutral ones were similar. Yohimbine was ineffective while cortisol improved recognition and recall responses to both stimuli to similar extent. Endogenous cortisol levels in human subjects vary greatly, and for this reason, experiments are often conducted by assigning two groups with relatively low (~5 nM) and high (~8 nM) contents (van Stegeren et al., 2007). Under placebo the magnitude of amygdalar activation in response to emotional pictures (compared to those of neutral nature) correlated well with the level of cortisol within the groups.
It was suggested that the response of the amygdala underlies an increase in NE levels, since after the intake of 80 mg propranolol such correlations were absent. Oral intake of 3 g metyrapone (cortisol synthesis inhibitor) before the sleep inhibited the plasma level of cortisol during 8 h of sleep in male subjects (Wagner et al., 2005). Metyrapone increased the plasma content of NE during both learning (from ~100 to 120) and retrieval (~130 vs.
These opposing effects of metyrapone on cortisol and NE dynamics correlate and promote the emotionally charged memory formation that occurs within the amygdala.
Emotional memories are consolidated during the slow wave sleep (SWS) and involve NE release. This was verified by intravenous infusion of ?2 agonist clonidine, which inhibits NE release by the LC and decreases the retention of temporal order of emotional stories (Groch et al., 2011). Clonidine inhibited only the REM phase, which consisted of about 5% of total sleep time in tested subjects.
In case of polymorphism in the COMT gene, the substitution of valine by methionine occurs at amino acid 158 (val158met). In healthy subjects, the particular allele of the COMT gene is associated with emotional memory formation in the amygdala (Smolka et al., 2005). The unpleasant stimulus (pictures) was found to activate the right human amygdala as revealed by blood oxygen level-dependent (BOLD) response during fMRI scanning. Propranalol slightly increased the baseline heart rate (HR) compared to placebo group, but it significantly decreased before and after the fMRI procedure. Both groups similarly distinguished the emotional intensity of presented pictures by comparing them to prior images. The responses to gradually increased emotional intensity of pictures correlated with the pattern of activity in the amygdala. The latter activity was decreased by propranolol, but to significant extent only at intermediate intensity.
In females, the amygdala exhibited about two fold less activation and higher resistance to propranolol compared to males. Male and female subjects also rated the pictures of similar intensity differently, especially former identified a greater number of images of neutral nature, while the latter rated them as emotionally intense pictures. Interestingly, propranolol did not affect the response of subjects exposed to pictures of highest emotional intensity. In vivo studies – behaviorThe memory performance and related behaviour in rodents can be analyzed by employing multiple trainings and tests.
Studies revealing the enhancement of memory by NESince moderate stress promotes memory formation and this event is accompanied by the release of NE, it is logical to expect similar effects on retention by this substance alone. By increasing the training time to 10 min, one would observe the resultant retention even after 24 h (Roozendaal et al., 2008). The latter study revealed that the NE administration into the BLA immediately after 3 min training improved the retention that lasted at least 24 h. However, the NE was effective only at lower doses up to 1 ?g and declined abruptly at 3 ?g.
Direct exposure of BLA to propranolol resulted in impairment of retention in those rats trained during 10 min. The enhancement of fear memory by bilateral injection of NE into the BLA is reversed by prior exposure to context (Huff et al., 2005). In this regard, the latter study also provides some clarifications addressing controversial arguments in several studies. The dose response was not classical as judged by three different concentration of NE, and a clear effect was evident only at 1 ?g, since at 3 ?g, the freezing response – memory for fear, among tested rats declined and was not significant compared to control group. Injection of propranolol into the BLA immediately after training abolishes the enhancement of object recognition memory by corticosterone (Roozendaal et al., 2006b). The blockade of this memory via ?–adrenoceptors was selective to the amygdala, since similar procedures (albeit even higher concentration of antagonist) targeting the hippocampus did not alter the discrimination index.
One of them is DSP-4 [N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine] with selective effects on DBH positive cells of the amygdala and LC as demonstrated 10 days after i.p. One week after the injection, animals underwent the habituation and training sessions, and active avoidance responses to US were analyzed.
The majority of DSP-4 treated rats were unable to avoid the foot-shock within the 5 s consequently receiving 25 s long US. The same tendency was found also after additional seven training sessions in subsequent days and correlated with the decrease in NE neurons.
The DBH positive neurons in BLA are also immunoreactive to choline acetyltransferase (ChAT). The immediate mean release after the shock was estimated around two-fold compared to baseline. The three-fold peak increase in NE level occurred after 15 min and then gradually declined, but did not reach baseline during up to 2 h and remained at ~1.5 fold. Interestingly, the identical stimulus delivered via the grid in the bottom of the holding cage evoked a small NE release that lasted ~15 min. In some rats, the content of NE reached the highest level (~7.5 fold), and there was to some extent a correlation between the level of NE and the latency to enter the dark compartment during inhibitory avoidance (IA) test in particular animals. Interestingly, this procedure resulted in a transient two-fold increase in NE level in BLA and Arc expression in the hippocampus; the latter effects were observed only in trained rats.
In fractioned synaptoneurosome, the expression of PSD-95 was higher than in total homogenate from hippocampus. Direct injection of propranolol into the BLA decreased the Arc density in synaptoneurosome preparation. These results support the notion that amygdala and hippocampus may act in synergy during cognitive behavior. The authors compared these effects with those resulting after escapable foot-shock in these two groups.
The 1 s foot-shock with the intensity of 0.8 mA caused only a slight NE increase in of groups, but differences appeared not to be significant. The NE increase was concluded to take place in amygdalar terminals of nucleus tractus solitarius (NTS) neurons. The latter was confirmed recently, since experimentally NE release could be also achieved in BNST ? extended amygdala ? by stimulating (60 Hz) the fibers of NTS.
Such stimulation evokes higher NE release in rats intraperitoneally injected with either idazoxan (selective ?2 adrenergic receptor antagonist) or desipramine (NE reuptake inhibitor).
The evoked release is distinctly modulated by averse and pleasant stimuli (Park et al., 2011), thereby it is either increased or decreased in response to intra-oral delivery of quinine and sucrose (palatable food). Both substances affected the magnitude of NE release into the BNST to similar extent (±20 nM) with the time course of around 9 s. The content of NE metabolite, MHPG (3-methoxy-4-hydroxyphenylglycol), also changes in those areas of brain that possess noradrenergic terminals. The ratio of MHPG to NE is significantly increased within BNST when animals are fear conditioned (Onaka & Yagi, 1998).
The post-training injection of NE into the BLA enhanced the retention of contextual fear conditioning (CFC) revealed by freezing time during the Y-maze test (LaLumiere et al., 2003).
The pattern of response to two different concentrations was similar when the latency of both freezing and entry into the shock arm were analyzed. The CFC could be performed also by using the straight alley test and analyzing the avoidance (latency) of rats to enter the dark shock compartment. The enhancement of retention by 1 ?g NE was comparable to that in the Y-maze, but slightly less pronounced (~3 vs. Finally, the improvement of the retention is also observed during antagonism of ?2 adrenoceptors by idazoxan (Ferry & McGaugh, 2008). Thus, idazoxan injected into the BLA 20 min prior to IA test increased the retention latency from ~120 to 180 s, which was significantly longer (~260 s) when introduced immediately after foot-shock.
The dose-dependent effects of idazoxan in these two experiments were similar and the peak identically occurred at 0.3 ?g demonstrating the narrow bell-shaped effects. The subcutaneous injection of hormone corticosterone decreased the conditioned auditory-cue fear response (Roozendall et al., 2006a). The effect of corticosterone was reversed by injection of ?1-adrenoceptor antagonist atenolol (0.5 ?g) into the BLA.
Atenolol alone was ineffective and both agents’ effects occur only when they were administered immediately after pairing of tone with the shock, but not before it.
Studies revealing the impairment of memory by NEMost evidently, severe stress negatively impacts the memory and correlated amount of NE released during this period may exert such effects.

A dramatic release of multiple neurotransmitters including NE (1200 %) is observed also after bilateral injection of antibiotic anisomycin into the amygdala.
Under both conditions, the NE release was a transient event lasting ~60 and 45 min in former and latter cases. Another difference was seen in samples from anisomycin treated group that showed a rebound decrease almost to 0 % below the normalized 100 % baseline level. A rebound decrease was not observed in vehicle-injected animals, and after a transient increase, the NE levels returned to baseline values. 15 min above), the transient increase was less pronounced in the anisomycin group, while it disappeared in the vehicle one. The rebound decrease in NE release was consistently present in anisomycin treated animals and remained at 50 % despite the prolonged experiments; baseline recovery occurred after 48 h.
Amnesia by anisomycin involves the noradrenergic receptors, since either the prior injection of propranolol or subsequent administration of clenbuterol (?2 agonist) resulted in significantly lower impairment of memory in both groups of experiments. The lidocaine (Na+ channel blocker) prevents NE release that is evoked by intra-amygdalar injection of anisomycin (Sadowski et al., 2011). The latter correlated with the reversal (to some extent) of memory impairment achieved by anisomycin. Furthermore, anisomycin attenuated c-Fos (cellular FBJ osteosarcoma oncogene) immunoreactivity (assessed by application of foot-shocks) by inhibiting the protein synthesis in BLA, and thereby providing some possible challenges for required de novo synthesis for long-term memory generation. The activity of c-Fos within several major nuclei of amygdala was up to 10 fold higher after 2 h of contextual fear training (Murchison et al., 2011).
However, upon reexposure to context 1 d after conditioning the immunoreactivity was highest among tested nuclei including the LA.
Stress can be introduced to laboratory animals with paradigms closely resembling those occurring in the nature: social isolation, maternal separation or both. The combination of latter factors in mice between postnatal day 15 (P15) and P21 reduced the social interaction time by two-fold, measured during adulthood (Niwa et al., 2011). Thus, these mice were more anxious and show a decreased short-term memory (STM) compared to the control group, which is improved with antipsychotic drug clozapine.
The NE content shows a tendency to decrease, but statistical analyses perhaps did not reveal a degree of significance contrary to that of the frontal cortex. Note that the overall level of NE in the frontal cortex was higher compared to the amygdala.
Nevertheless, injection of NE into the right BLA immediately after the CFC decreases the freezing behavior in a dose-dependent manner (Berlau and McGaugh, 2006). However, this U-shaped response was narrow as judged by three logarithmic concentrations (0.3?3 ?g) and show peak effects at 1 ?g.
The pain perception was found to be lower in two lines of transgenic mice that lack ?2A adrenergic receptors (Davies et al., 2004). The odexmedetomidine in ?2A AR mice did not affect the flinch response, while in D97N mice it increased the threshold (0.18 vs. In WT mice the freezing response was decreased, when odexmedetomidine was injected 30 min prior to fear conditioning, but not immediately after. This procedure also reduced the number of both P-CREB (phosphorylated) and c-Fos positive neurons in all three major nuclei of amygdala: LA, BLA and CeA. In vivo studies – electrophysiologyElectrophysiological studies in vivo provided interesting results on brain structures and neurobiological processes underlying learning and memory. It was shown that amygdala modulates the LTP in dentate gyrus (DG) and the effects are derived selectively by LA and BLA nuclei, but not CeA (Akirav & Richter-Levin, 2002).
Moreover, the effects of ipsilateral (same hemisphere) activation of two former nuclei on LTP in DG depend on timing between the two stimulations sites.
The stimulation of the BLA just 30 s prior to the perforant path (PP) activation enhances LTP, while 2 h intervals decrease it. Although, also the contralateral (opposite hemisphere) priming of BLA exhibits similar effects, it was not derived by NE and corticosterone release. Note that the electrical stimulation of BLA decreases the NE release in DG (Almaguer-Melian et al., 2005). The injection of ~7 nM propranolol into the DG five minute prior to the BLA reinforcing paradigm decreases the LTP in DG achieved by PP stimulation (Bergado et al., 2007). The magnitudes of initial potentiation caused by PP stimulation in both groups were almost identical. Note that the control group comprises data obtained after the NaCl injections into the BLA, LC and medial septum and figure legend states that propranolol was delivered into the BLA. Figure 2.Amygdala and fear response pathwaysLeft, amygdala (in actual coronal brain slice) and its major nuclei. In vitro studies – cellular counterpart of learning and memory in rodentsThe potentiation of synaptic responses underlies the learning and memory at neuronal level. Characteristics of LA and BLA cells involved in plasticityDiverse cells have been observed in the amygdala, but the majority is comprised of two types. In recent years, the attempt to recognize both types of cells by usage of biological marker ? green fluorescent protein (GFP) ? are starting to emerge. The interneurons in the BLA are apparently similar to other brain regions, because they express glutamate decarboxylase ? 67 (GAD-67). In the BLA a single glutamatergic and three distinct GABAergic types of neurons have been distinguished (Kaneko et al., 2008). Although, this study is substantial, the characterized cell types warrant some skepticism, since in presented micrographs there are too many GFP+ (GABAergic) cells, the soma of several neurons is pyramidal-like, and finally the size of GFP- (glutamatergic, if those black spots are intact neurons, but not damaged ones) cells are comparable to those of GFP+. Even during targeted recordings one would not encounter that amount of GABAergic cells in such a close proximity within the amygdala. This study is actually contrary to current dogma, since principal cells “exclusively showed regular spiking” and only about half of studied cells possess pyramidal soma.
Plasticity in the amygdala and the role of NENE release can be also triggered in brain slices by excessive depolarization using higher concentrations of K+. This procedure enables an increase (by 10-15 %) in NE content compared to basal magnitude in the amygdala (Lonart et al., 2008). In Rab3 interacting molecule 1 alpha (Rim1?) KO animals the identical approach evoked considerably lower NE release in BLA. Although in one of presented experiments, NE release from the CeA may have decreased, but the average data was not significant.
The magnitude and response pattern of NE release in LA were indistinguishable from those of WT mice. Interestingly, in all these cases the peak release appeared with identical latencies of six minutes. In control mice, NE gradually increases the frequency of spontaneous inhibitory postsynaptic currents (sIPSC) in pyramidal neurons of the BLA according to applied concentration (Braga et al., 2004). The selective ?1A agonist A61603 increased both the rate and amplitude of sIPSC, and these effects were not observed in the presence of selective antagonist WB4101.
NE at 10 ?M had opposite effects on evoked IPSC, and note that the inhibition was not complete, but reversible and perhaps rather targeted only to those with the highest amplitude. The results became more complicated, since a blockade of GABAB receptors (although their activation was not experimentally shown) changed the effects of NE on evoked IPSC.
However, because of large diapason of values in individual experiments, the effects can not be considered significant.
In some of the latter neurons, NE slightly decreased the tonic GABAergic currents, while the parameters of phasic ones were not altered. Amygdala, placticity and fear learningAn increase in synaptic strength within the amygdalar fear circuit comprises the plasticity.
Memory formation in the LA can easily be demonstrated, since synapses can undergo LTP (Fig.
Figure 3.Induction of LTP in the LA in vitroMean baseline EPSP (blue trace) obtained in the presence of 100 ?M PTX by stimulation of cortical inputs into the pyramidal neuron. Picrotoxin (PTX) facilitates the induction of LTP of excitatory postsynaptic potentials (EPSP) in the amygdala (Kodirov et al., 2006) by inhibiting the GABAA receptors. However, via the same mechanism, it can block the induction of another form of plasticity (Fink & O’Dell, 2009) known as EPSP–spike (E–S) potentiation in cornu ammonis 1 (CA1). Under both of these circumstances, PTX decreases the level of inhibition of the principal cells during high frequency synaptic activation.
The LTP time course can be subdivided into different components and subsequent early and late phases can be distinguished (Dong et al., 2008). The early phase of LTP (E?LTP) in vitro corresponds to short-term memory and the late phase (L?LTP) to long-term memory in vivo. LTP in the amygdala occurs at both the thalamic and cortical synapses into the pyramidal neurons. Recently, the NE effects on LTP at thalamic inputs into the LA were revealed (Tully et al., 2007). Note that under these conditions, the synapses at thalamic inputs into the LA are not prone to LTP.
Therefore, NE rather enables the induction of LTP, and its effects on maintenance remains to be elucidated. Under facilitated excitatory drive, which is commonly achieved in the presence of up to 100 µM PTX, there was a tendency for enhanced LTP by NE, however, not to a significant level. Furthermore, the amplitudes of both components of glutamatergic currents remain unaltered in the presence of NE. However, two opposite effects were observed when prior to NE either ?2? (yohimbine) or ?–adrenoreceptors (propranolol) antagonists were applied.
During the priming with yohimbine NE increased the amplitude of evoked excitatory postsynaptic currents (EPSC), while with propranolol NE decreased it. The latency was shorter and magnitude was greater in the former situation compared to the second one.
Both effects were to some extent reversible after application of either yohimbine or propranolol. It has previously been shown that the NE effects vary depending on targeted influence on the latter two receptors (Ferry et al., 1999a). Therefore, perhaps just by using either yohimbine or propranolol one could observe the corresponding drug induced LTP in those experiments in the LA. Intrinsic excitability of neurons can be attributed per se to learning and memory in vivo and either the ability or disability of neurons to regulate this activity results in either memory formation or its impairment (Kaczorowski & Disterhoft, 2009).
The facilitated excitability of neurons by NE may contribute to the induction of LTP (if it occurs at least in part via inhibition of GABAergic or potentiation of glutamatergic neurotransmission, which can lead to increased postsynaptic depolarization during pairing with the presynaptic stimulation (Bissiere et al., 2003).
At thalamic inputs, terazosin decreased the amplitude of disynaptically induced inhibitory currents at 10 µM concentration, which did not alter the excitatory ones that were evoked in response to the first pulse (Lazzaro et al., 2010).
Interestingly, the amplitude of excitatory currents evoked during application of second pulse was increased by terazosin (Lazzaro et al., 2010), thus resulting in paired-pulse facilitation (PPF).
Note that no PPF at both synapses was observed under control conditions, although employing the ISI of 50 ms usually results in PPF when the single pulses are applied. Interestingly, the thalamo-amygdalar synapses exhibit LTP that decay with time, but in the presence of PTX it persisted steadily at least up to 1.5 h. However, it is not clear when terazosin was applied, since the descriptions in both text and figures are contradictory. One pitfall during LTP experiments is the difficulty of comparing the potency of compounds, including NE.
Nevertheless, at these inputs the LTP was more pronounced in the presence of terazosin compared to PTX. Molecular substrate of LTPThe Pavlovian paradigm also alters the expression of multiple genes in amygdala. Under control conditions, freezing response was observed in ~20 %, which was increased to ~80 % rats measured after 24 h of one trial of fear conditioning ? pairing tone with foot-shock (Ploski et al., 2010). The expresion of Arc, Nr4a2, Per1 genes decreased by 90 min while those of remaining three increased. Among additional genes the highest increase at 30 min time point was revealed for Fos, although the degree of associated change is unclear (~3 fold in the graph vs. The latter perhaps is not a reflection of data normalizations, since the magnitude of corresponding genes in the naive group was considered either as 0 or 1, respectively.
There are more molecular substrates potentially involved in LTP, and the active-zone scaffolding protein (RIM1?) is one of them (Fourcaudot et al., 2008). We have encountered that the PPF at cortical inputs into the LA occurs less compared to other regions of the brain (Kodirov et al., 2009). However, the average data is perhaps inadequately presented by subtracting the PPF of baseline from that of heterosynaptic associative LTP (LTPHA – evoked by the simultaneous stimulation of cortical and thalamic inputs), thus resulting in negative paired-pulse ratios (PPR). Comparing PPF before and after the paradigm would be sufficient in order to conclude whether or not the expression of LTP is presynaptic. Moreover, it is not clear that “changes in PPR could also involve postsynaptic mechanisms” and “induction of LTPHA depends on presynaptic, but not postsynaptic, NMDA receptors”.
The PPF ratio was reduced by 50 ?M forskolin and the identical concentration rapidly (~2 min) increases the EPSP reaching within four minutes the plateau and thus induces potentiation lasting at least 20 min. Its amplitude (~150 % of baseline) was comparable with LTP triggered by the stimulation of cortical inputs. ConclusionNE influences memory performance either via interplay between the ?- and ?-adrenergic receptors or by co-activation of both (Ferry et al., 1999a, b).
The memory promoting effects of NE via amygdala may occur also by the activation of principal neurons in the NTS and involve epinephrine (Williams et al., 1998). Amygdala dependent fear learning involves NE as a main neurotransmitter, since the post-training intracranial injection of 1 ?g NE led to amnesia in rats 24 h after passive avoidance task (Kesner & Ellis, 1983).
The pathological release of catecholamine NE in mammals including humans occurs in comparable manner to invertebrates (Kodirov, 2011). The above outlined dual effects of NE on memory (impairment and enhancement) possibly underly the distinct BLA single neuronal response, since iontophoretic injection of NE in some cells increased and others decreased the spontaneous firings in vivo (Buffalari & Grace, 2007). The fact that these neurons could be subdivided clearly into two groups is valuable, however identifying cells with higher rate as projecting ones (even based on their antidromic response to the stimulation of entorhinal cortex), is against the properties of neurons. The projection cells should not fire high frequency APs compared to other neurons within this structure, e.g.
Nevertheless, the experiments are precise, since the recording and 200 ?M NE application was performed via the single multi-barrelled electrode at the same time.
In the LA the proportion of neurons with inhibitory response to NE was higher than in the BLA, but those with excitatory ones similar.
Upon the termination of injection, the neurons continued to fire at baseline frequencies, therefore in the same neuron it was revealed that the NE inhibitory effects occur via ?2 AR, since the latter was mimicked by 50 ?M clonidine. The excitatory effects of NE on BLA neurons may occur via ? AR (for discussions see Buffalari & Grace, 2007).
Similar dual effects were observed also upon the stimulation of LC, but the baseline frequencies of two groups were only slightly apart.
Although the extent of inhibition was similar after foot-shock or NE injection, the excitation was greater in the former case. Eventually, such results in the future could specify the role of plasticity related genes more precisely (in terms of their associations to certain neurotransmitters including NE), which then potentially could serve as a target points during diagnosis and the search for potential cure.
Even in this century “how memory processing would be coded at the receptor [or gene] level remains unknown” (Ellis, 1985).AcknowledgementIn this instance, I would like to acknowledge contributions of authors, which I was not able to review because of either length limitations or many of them were discussed elsewhere recently.

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