Anatomical delineation of the human amygdaloid complex.
Abstract
The human amygdaloid complex (AC) is associated with the perception of fear and consequent anxiety‐related behaviors, apart from other functions ranging from attention to memory and emotion. The AC is composed of several regions with specific cytoarchitectures, chemistry, and connections that encode different aspects of fear. Detailed understanding of AC cell composition is basic to determining whether cell number alterations coincide with neurological and psychiatric pathologies associated to anxiety imbalances, as well as with changes in brain functionality during aging. Here, we describe quantitative data gathered applying stereological methods to human AC tissue; the amounts of neurons, glial and endothelial cells, as well as of various interneuron subsets that populate the AC regions were noted and compared with those collected in the AC of non‐human primates and rodents. This chapter also addresses the dopaminergic innervation of the AC, which exerts a modulatory effect over the intrinsic AC network and is critical for reward‐related learning and fear conditioning. This innervation is twice as abundant in the main output nuclei as in the principal entry nuclei of the human AC, and this irregularity may indicate functional variations between these entry and output amygdaloid territories.
Keywords
- amygdala
- human
- dopamine
- stereology
- dopamine transporter
- neurons
- glia
- endothelial cells
1. Introduction
The amygdaloid complex (AC) is a heterogeneous structure described for the first time by Burdach as an “almond‐shaped” mass of grey substance located in the anterior part of the temporal lobe [1]. Since then, the various AC nuclei, which have diverse developmental features and functions, have been considered either as part of a single structural unit [2] or a collection of randomly aggregated structures [3]. There have also been many attempts to consistently demarcate the various AC nuclear components and their subdivisions in the human and other non‐human primates, but there is no consensus as yet [3].
The AC receives highly integrated sensory information of all modalities and is needed for the association between each sensory stimulus and its emotional and motivational significance [4, 5]. The AC also contributes to the visceral and somatic expression of endocrine response to these stimuli. Direct stimulation of the AC produces a subjective perception of fear and anxiety, as well as increased heart rate and blood pressure with pupil dilation [6]. A huge number of studies have related the AC with fear perception and the generation of appropriate affective responses to these types of stimuli [7–14]. Other investigations have, nevertheless, demonstrated that the activity of the AC also increases in response to positive emotional stimuli in humans [15–17] and non‐human primates [5]. The AC is crucial to the acquisition, consolidation and extinction of fear memories, as well as to their retrieval after extinction. Therapies known as “exposition therapies” try to produce the extinction of those fear memories that trigger anxiety behaviors [12].
Bilateral lesion of the medial temporal lobes containing the AC produces a visual‐limbic disconnection [18] or a sensory‐affective dissociation [19]. Both alterations seem to be present in Rhesus monkeys affected by the Klüver‐Bucy syndrome [20]. A variety of symptoms including aphasia, amnesia, or dementia have been observed in human patients with a bilateral temporal lobe lesion, and lesions specifically affecting the AC seem to be related to the difficulty in identifying the emotional significance of facial expressions [21].
The dopaminergic innervation received by the AC is intense in rats [22–26], non‐human primates [27–29], and humans [30]. This particular neurochemical input is required to acquire, consolidate or extinguish fear‐related memories, as well as to generate appropriate affective responses toward aversive stimuli [31–36]. A dysfunction of the dopaminergic system is related to psychiatric diseases such as schizophrenia [37, 38] and/or other stress‐related disorders [39, 40]. In addition, the hyperdopaminergic phenotype of transgenic mice lacking the dopamine transporter (DAT) can show the positive symptoms observed in schizophrenic patients [41]. As discussed below, the dopamine in the AC affects projection neurons either directly or through various types of interneurons.
The present chapter will review data collected in recent years in the human AC related to the amount of neurons, glial and endothelial cells, as well as more specific quantitative data on two main AC interneuron populations, which modulate the activity of the projection neurons. The amount, distribution and specific neuronal targets, of the dopaminergic innervation of the human AC will also be addressed.
2. Anatomical delineation and nomenclature of the human amygdaloid complex
Numerous studies have addressed the anatomical nuclear division in the primate AC [2, 42–50], but the lack of well‐defined anatomical limits between the various AC nuclei has complicated any consensus on the delineation of the AC nuclei and their subdivisions. Table 1 shows the most relevant divisions and nomenclature used in the last years to define the AC nuclei in human and non‐human primates. The correct and detailed division of the AC is important because its various nuclei have distinct developmental origins, specific connections, and codify different aspects of fear [7]. The proper delineation of the AC is also necessary to perform accurate quantitative studies such as stereological estimations of cell numbers or nuclear volumes, and the comparisons of such data collected in different studies. For instance, the basolateral group, especially the lateral nucleus, processes the emotional significance of every stimulus, allowing other structures access to this information, and it is involved in the suppression of fear responses and their retrieval after extinction [7, 8, 11]. The central nucleus is activated by the basolateral group and can initiate key defense mechanisms against species‐specific predators representing a danger to an individual given species [7, 8, 13, 51]. The corticomedial group and the lateral nucleus become activated after the presentation of faces expressing fear [52].
Sims and Williams [49] | 1Brady [52] | 2Price et al. [48], Sorvari et al. [58] | Mai et al. [119] | García‐Amado and Prensa [55] |
---|---|---|---|---|
DEEP NUCLEI | BASOLATERAL GROUP (BL) | |||
•External | •Lateral | •Dorsolateral | •External (Lex) | |
•Dorsal | •Medial | •Dorsomedial | •Dorsal (Ld) | |
•Lateral | •Dorsal anterior | •Lateral (Ll) | ||
•Medial | •Intermediate | •Medial (Lm) | ||
•Ventral | ||||
•Lateral | •Magnocellular | •Magnocellular | •Dorsal | •Magnocellular (Bmc) |
•Central | •Intermediate | •Intermediate | •Intermediate | •Intermediate (Bint) |
•Medial | •Parvocellular | •Parvicellular | •Ventromedial | •Parvocellular (Bpc) |
•Ventrolateral | ||||
•Paralaminar | ||||
•Dorsal | •Magnocellular | •Magnocellular | •Dorsomedial | •Dorsal (ABd) |
•Ventral | •Parvocellular | •Parvicellular | •Centromedial | •Ventral (ABv) |
•Ventromedial | •Ventromedial | |||
•Dorsolateral | ||||
•Medial* | ||||
•Lateral* | ||||
•Medial | •Ventral | •Anterior | •Anterior | •Medial (Com) |
•Lateral | •Dorsal | •Posterior | ‐‐ Dorsal portion | •Lateral (Col) |
‐‐ Ventral portion | ||||
•Posterior | ||||
PERIAMIGDALOID CORTEX | •Anterior | |||
LATERAL OLFATORY TRACT NUCLEUS | ||||
•Medial | •Medial | •Medial | •Medial | •Medial (Cem) |
•Lateral | •Lateral | •Lateral | •Lateral | •Lateral (Cel) |
•Dorsolateral | ||||
•Ventrolateral | ||||
•Interstitial | ||||
CORTICO‐AMIGDALOID TRANSITION AREA | CORTICAL TRANSITION AREA | PARAHIPOCAMPAL‐AMIGDALOID | CORTICO‐AMIGDALOID TRANSITION AREA (CTA) | |
TRANSITION AREA | ||||
ANTERIOR AMIGDALOID AREA | ANTERIOR AMIGDALOID AREA | ANTERIOR AMIGDALOID AREA | ANTERIOR AMIGDALOID AREA | PERIAMIGDALOID AREA (PA) |
PREAMIGDALOID CLAUSTRUM | ||||
PERIAMIGDALOID AREA | ||||
INTERCALATED CELLULAR GROUPS | INTERCALATED NEURONS | INTERCALATED NUCLEI | ||
AMYGDALO‐HIPOCAMPAL AREA | AMYGDALO‐HIPOCAMPAL AREA |
One of the first descriptions of the architectonic organization of the AC was made by Völsch [2, 42–50] in primates. Later, Brockhaus published a detailed report of the human AC architecture employing Nissl and myelin staining [47]. However, these classifications were rather complex and Crosby and Humphrey proposed a simpler nomenclature, which is still widely used and based on the one suggested by Johnston [53, 54]. Johnston grouped the amygdaloid nuclei into two groups based on developmental origin and age: the first group included the primitive or little‐modified central, medial, cortical, and nucleus of the lateral olfactory tract; the second group included the more recently evolved basal and lateral nuclei formed by infolding or cell immigration. The basal and lateral nuclei together with the accessory basal nucleus conform the basolateral group of the AC, which has undergone a huge increase of volume in humans [2, 49].
In a more recent study, García‐Amado and Prensa suggested a detailed nuclear division and nomenclature for the human AC based on the proposal by Sims and Williams [49] and Ledo‐Varela et al. [56], and that also resembled those used by Schumann and Amaral [57] and Sorvari et al. [58] (Table 1; see [55] for further details). The García‐Amado and Prensa study [55] was focused on providing accurate and objective limits of the entire AC and its various nuclear groups, nuclei, and nuclear subdivisions. The establishment of consistent anatomical limits is essential for making comparisons among quantitative data collected in different studies. To this end, the 2012 García‐Amado and Prensa study did not outline as a single whole the structures with rather fuzzy boundaries like the anterior amygdaloid area described by Sims and Williams [49]. Instead, they only outlined the most lateral part of this region, the periamygdalar area, since this area can be objectively identified by its high content in acetylcholinesterase. Other relevant aspects of the study of García‐Amado and Prensa are the consideration of the dorsal subdivision on the lateral nucleus, whose cells are much smaller and more packed than the ones that populate its three other subdivisions, and the inclusion of the paralaminar region within the parvocellular subdivision of the basal nucleus because the former has unclear limits.
3. Volume of the human AC
The volumes of the AC as a whole and some of its nuclei have been estimated in many studies dealing with psychiatric disorders as well as in others on Alzheimer’s disease [59–64]. The range of AC volume for individuals without any neurological or psychiatric disease varied from 630 to 1380 mm3 depending on the study [59–65]. The variability in the delineation of the AC nuclei and/or the different protocols used to process the human tissue could be responsible for the large range of AC volume reported in normal individuals in the different studies. Similar investigations performed in tissue obtained from schizophrenic and bipolar disorder patients report a decrease in the volume of several AC nuclei, such as the basal and lateral ones [63, 64].
The stereological study by García‐Amado and Prensa [55] of the human AC from individuals without any neurological or psychiatric disease showed that the entire complex reached a volume of approximately 950 mm3 with more than 80% of that volume corresponding to the basolateral group, 10% to the corticomedial group, and 6% to the central group (Table 2; [55]). Overall, these volumes fall within the ranges reported by other authors [59–64]. The volume of the total AC as estimated by García‐Amado and Prensa [55] was smaller than the one reported earlier by Schumann and Amaral [62] due to the unclear limits of particular structures such as the nucleus of the lateral olfactory tract, the anterior amygdaloid area, the periamygdaloid cortex and the amygdalohippocampal area, some of which were not included in the AC by the former study. Nevertheless, the volume estimations for individual AC nuclei reported in these two studies were more alike except for certain minor differences in the lateral and basal nuclei. Chance et al. [61] and Berretta et al. [63] reported smaller volume estimations than García‐Amado and Prensa [55], the disparities being most probably due to the difference in the methods used during tissue processing or to the variations in delineation of the nuclei (see [55] for details).
Schumann and Amaral [62] | Berreta et al. [63] | Kreczmanski et al. [64] | García‐Amado and Prensa [55] | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Region | N | V | Nv | N | V | Nv | N | V | Nv | N | V | Nv |
4 | 452 | 8980 | 2.07 | 243 | 8598 | 4.5 | 400 | 11,000 | 5.48 | 376 | 14,608 | |
3.24 | 343 | 9380 | 1.23 | 151 | 8173 | – | 220 | – | 5.02 | 259 | 19,510 | |
1.28 | 152 | 8600 | 0.59 | 69 | 8519 | – | 60 | – | 1.73 | 123 | 13,770 | |
– | – | – | 0.41 | 44 | 9118 | – | – | – | 1.14 | 69 | 16,210 | |
0.36 | 34 | 10,610 | – | – | – | – | – | – | 0.82 | 60 | 14,720 | |
12.21 | 1380 | 8870 | – | – | – | – | – | – | 15.39 | 956 | 16,088 |
4. Cellular architecture of the human AC
The AC contains three types of cell populations: neurons, glial, and endothelial cells. The morphology, number and density of the first two and the possible changes that they might present in pathologies such as schizophrenia or autism have been discussed in the last years [57, 60, 62–64, 66–68]. There are several morphological neuronal subtypes in the human AC [69]. Some 70% of neurons in the basolateral group show a pyramidal morphology and are thought to be projection neurons; the remaining 30% are interneurons. Cell morphology in the central and medial nuclei is quite variable, but pyramidal cells are not as common as in the basolateral group [70].
Data about the glial cells in the AC are scarce and mostly centered on astrocytes [70, 71]. Certain glial cell populations, such as oligodendrocytes, undergo quantitative changes in major depressive disorder [66, 67]. Further investigations are needed to determine whether other glial cell types (i.e. astrocytes and/or microglia) are involved in this and other psychiatric disorders [72]. The available data on endothelial cells are also very limited and mostly centered on determining the effects on microvasculature that are produced by the antipsychotic treatments or the schizophrenia [73, 74].
4.1. Number and density of neurons, glial, and endothelial cells
The human AC contains approximately 15 million neurons of which 80% are located inside the basolateral group, 10% in the corticomedial group and 5% in the central group [55]. The number of endothelial cells is quite similar to that of neurons, whereas the glial cell number is almost four times higher, and this proportion is maintained in most of the nuclear subdivisions of the AC. This glial/neuron ratio differs from that found in the cerebral cortex, where it ranges from 1.55 to 2.19 depending on the cortical area examined [75], or the one in subcortical structures, which varies from 14 in the mediodorsal thalamic nucleus and ventral pallidum to 3 in the nucleus accumbens [60]. The glial/neuron ratio in the AC increases across species, from rat to human [76], suggesting that the AC is more complex in primates than in rodents.
In terms of neuron number and density in the AC, the estimations of García‐Amado and Prensa [55] (Figure 1) are comparable with, although slightly higher than, those reported in other studies performed in the lateral, basal, accessory basal, and central nuclei [62–64, 66]. Differences in neuron number between studies are due to variations in the delineation of the nuclei whereas differences in neuron density between studies might be the result of different nuclear volume estimations. Particular attention should be given to the work of Dall’Oglio et al. [70], which reported a neuronal and glial cell density in the medial nucleus that was almost 10 times higher than the one reported by García‐Amado and Prensa [55]; this huge difference is probably explained by technical differences in the method used during tissue processing [77] and/or to a different delimitation of the nucleus.
Regarding neuronal density, the differences among the AC nuclei described in the various studies are consistent [55, 62–64, 66]. The neuronal density in the basal nucleus is considerably higher than that in the rest of the AC nuclei, and this is probably due to the extremely high neuronal density of its parvocellular subdivision [78–80]. The number of neurons in the different AC nuclei and nuclear subdivisions in several non‐human primate species was analyzed by Carlo et al. [81]. Despite the fact that the values reported by these authors are markedly lower than those reported in the human brain by García‐Amado and Prensa [55], the percentages of neurons between nuclei and their subdivisions are roughly similar. Consequently, what Carlo and his colleagues found indicates an increase in the number of neurons in every nucleus of the AC during the evolution of primate species. The percentage of increase in the central nucleus was markedly less than in the rest of AC nuclei.
The reported number and density of glial cells in the AC are consistent in the various studies [65, 66]. The high density of glial cells in the lateral nucleus may be related to the numerous projections from sensory associative cortical structures [82].
The density of neurons and endothelial cells in the AC tends to respectively decrease or increase with age, especially in the basolateral group [55]. In contrast, the number and density of glial cells in the grey matter of AC nuclei tend to increase moderately with age, an observation that could be interpreted as either a compensatory mechanism or a response by the glial cell population to the neuronal loss occurring during aging. Both gliosis and fiber loss have been described as stages of age‐dependent degeneration [83]. The parvocellular subdivision of the basal nucleus is the only AC region that did not show a decrease in the number of neurons over time [55]. The presence of a large number of immature neurons in the paralaminar territory of the basal nucleus in the adult brain might counteract the decrease in neuron number with aging [79, 80]. The increase in the number and density of the AC endothelial cells during aging is considered an adaptation of the brain to maintain the rate of oxygen delivery to this region when the blood flow decreases [84, 85].
4.2. Interneurons in the human AC
Various histochemically and electrophysiologically well‐characterized subsets of interneurons exist in the AC (for review see Ref. [86]). Each of these subsets of AC interneurons is characterized by specific firing patterns, by their targets in discrete subcellular domains of projection neurons, and by their specific modulation by external sensory stimuli [87, 88]. From the functional view point, the AC interneurons exert an important inhibitory effect over the projection neurons of the basolateral nucleus and contribute to generating synchronous theta activity between the amygdala and the hippocampus during the acquisition of emotional memories [87]. The interneurons of the basolateral amygdala are activated by the hippocampal input with theta frequencies that reach the amygdala; this activation causes a transient feedforward inhibition of projection neurons that is followed by the increase of active excitatory synapses and the induction of long‐term potentiation of these synapses during fear memory retrieval [89]. Alterations in the expression of calcium‐binding proteins in some interneuron subsets of the AC [90] or of the cerebral cortex [91–95] have been described in disorders like anxiety in which the extinction of fear memories can be impaired.
As in rodents, four different subsets of interneurons have been determined in primates: (1) parvalbumin (PV) positive (+) interneurons (25% of these also contain calbindin (CB) [86, 96]; (2) CB+ interneurons (30–35% also contain PV) [86, 97, 98]; (3) somatostatin + interneurons [86, 99, 100]; and (4) calretinin (CR) + interneurons [86, 101]. Most of these data were obtained in non‐human primates and the studies performed in humans did not precisely define either the number of AC interneuron subsets or the quantities and percentages of each interneuron population in the various AC nuclei. Nevertheless, PV+ and CR+ interneurons are the most abundant non‐overlapping populations among all the calcium‐binding protein‐containing interneuron populations in the primate AC [86]. Furthermore, these two neurochemically well‐defined interneuron populations are also distinguished by their electrophysiological properties; the PV+ interneurons are associated with “fast” and “burst” firing patterns, whereas the CR+ interneurons show a “regular” firing pattern [102]. PV+ interneurons can innervate the soma, proximal dendrites or the initial axon segment of pyramidal neurons [87, 88], and they receive excitatory inputs from axon collaterals of local pyramidal cells, which form a powerful inhibitory feedback [103].
In terms of their topographic distribution within the AC, the PV+ interneurons are restricted to the basolateral group, whereas CR+, as well as CB+, interneurons are homogeneously distributed through the AC. This means that PV+, CR+ and the CB+ subsets of interneurons exist in the basolateral group, but only CR+ and CB+ subsets of interneurons are present in the corticomedial and the central nuclear groups. CR+ interneurons are especially abundant in the accessory basal nucleus, whereas the PV+ cells abound in the lateral nucleus and gradually diminish toward the more medial regions of the basolateral group [58, 96, 101, 104, 105].
Quantitative data regarding the relative proportion of the PV+ and the CR+ interneuron subtypes with respect to both the total interneuron population and the total neurons in the AC in rodents, primates and humans are already available in the literature. In the basolateral group, the PV+ interneurons represent 19–43% and the CR+ interneurons 17–20% of the total of all interneurons in rodents [106]. In the non‐human primate basolateral group, the PV+ interneurons represent 28–37% of the GABAergic interneurons, while CR+ interneurons represent 23–27% [86]. In rats, PV+ interneurons make up 6% of the total AC neuron population whereas CR+ interneurons are 4% [26]. In the human AC, however, the proportion of PV+ interneurons is lower than that of CR+ interneurons with respect to total AC neurons; PV+ interneurons do not reach 1% in any AC territory whereas CR+ interneurons range from 4 to 23% depending on the AC area studied [105]. Taken together, these data show that the amount of PV+ and CR+ interneurons in the AC decreases and increases, respectively, over the phylogenetic scale, a finding that is in agreement with previous reports made in the striatum, in comparisons of humans with the squirrel monkey and the rat [107].
5. The dopaminergic innervation of the human AC
The AC receives a substantial dopaminergic innervation originating mainly from the A8, A9 and A10 ventral mesencephalic groups [29] and dopamine is a key neurotransmitter in the AC that modulates the entry of information through the basolateral group. Furthermore, this dopaminergic innervation is required for the acquisition, consolidation and extinction of fear memories as well as for generating appropriate affective responses [31–36] and, as mentioned earlier, dysfunctions of this dopaminergic system have been proposed as pathogenic mechanisms in psychiatric diseases such as schizophrenia [37, 38] and stress‐related disorders [39, 40]. Accurate quantitative data regarding the amount of dopaminergic axons and their distribution in the AC from human donors who had not been diagnosed with neurological or psychiatric diseases before their death was collected by García‐Amado and Prensa [108] using DAT immunoreactivity as a marker for the dopaminergic fibers and stereological approaches. Since intrinsic dopamine instability prevents its immunodetection in brain tissue that has not been rapidly fixed by perfusion after the donor’s death, previous studies that were focused on analyzing the dopaminergic innervation of the human AC had used the TH protein to detect dopaminergic profiles. However, TH protein also labels noradrenergic and adrenergic fibers in the AC [109, 110]. Since the AC consists of several nuclear groups with a vast array of interconnections with the cerebral cortex, hippocampal formation, basal ganglia, thalamus, hypothalamus, and brainstem (for review see Refs. [48, 50]), information on the content of dopaminergic axons in each of the nuclear groups is needed to better understand the internal functional organization of this complex.
The human AC is targeted by widespread DAT‐positive fibers, which are dense and unevenly distributed in every subdivision of this nuclear complex [108] (Figures 2 and 3). Furthermore, their study has yielded accurate information regarding the quantity of DAT‐ir fibers per neuron in each amygdaloid territory. As shown by these authors, the amount of DAT‐ir axons in the human AC varies among the several nuclei of the AC and also varies considerably in the various subdivisions of a given AC nucleus (Figure 2), indicating functional variations among these territories.
One of the most striking gradients in the amount of the DAT‐ir fibers occurred along the mediolateral axis of the lateral nucleus: the total length of DAT‐ir axons range from nearly 300 mm/mm3 in its medial subdivision to nearly 800 mm/mm3 at its external (most lateral) subdivision (Figures 2 and 3). This large variation in the amount of DAT‐ir fibers between the medial and lateral sectors of the lateral nucleus might be related to their differentiated extrinsic and intrinsic connections. Thus, the lateral nucleus would be the main target of sensory information from the external world, and it sends heavy projections to the other amygdaloid nuclei [111]. The external subdivision of the lateral nucleus receives most of these sensory projections (Figures 2 and 3), and the information flows toward the medial side of the nucleus [111, 112]; in addition, this AC region has the shortest latency of conditioned responses elicited by sensory stimuli associated with adverse events in emotional learning tasks [113]. On the other hand, the medial subdivision of the lateral nucleus receives information from higher‐order cortical processing areas [114–117]. In the hippocampus, DAT‐positive axons were present only in the outer two‐thirds of the molecular layer of the dentate gyrus, where the perforant pathway ends [118], indicating that dopamine may potently and selectively regulate the input from the entorhinal cortex and thus the early stages of hippocampus processing, as might be the case for the sensory information entering the AC lateral nucleus.
The central nucleus receives information from the rest of the AC nuclei and is one of the main output nuclei of the AC [111]. Descending projections from the central nucleus terminate in a wide mediolateral region of mesencephalic dopamine cells [120]. In turn, this nucleus receives the heaviest DAT‐positive dopaminergic innervation of all the AC nuclei, however its innervation is not uniformly distributed and markedly decreases along a mediolateral gradient, a finding that agrees with the distribution pattern of TH‐ir fibers [27]. In the basal and accessory basal nuclei of the AC, the content in DAT‐ir fibers decreases from dorsal to ventral sectors, though this gradient is much less marked in the latter than in the former nucleus (see Figure 2A and B) [27–29, 49, 58, 121].
The regulation of extracellular dopamine levels is controlled by distinct mechanisms in different brain areas and is probably related to DAT content. Thus, whereas the dorsal striatum and the nucleus accumbens show an “uptake‐dominated” regulation (i.e. one in which dopamine is quickly recaptured from the extracellular space to end its action), the medial prefrontal cortex and the AC show a “release‐dominated” regulation (i.e. dopamine is maintained in the extracellular space more time) [122]; these findings agree with the observation that there is more DAT in the striatum than in the other two structures [27–29, 49, 58, 121].
The AC is a main target for mesencephalon projections made up of cells from the substantia nigra pars compacta (A9 dopaminergic group), the ventral tegmental area (A10 dopaminergic group) and the retrorubral field (A8 dopaminergic group) [4, 123–125]. In the human mesencephalon, DAT abounds in neurons located in the lateral ventral tegmental area and in the substantia nigra pars compacta and is largely absent from the medial ventral tegmental area [30]. DAT mRNA is more abundant in the A9 ventral tier than in the dorsal tier [125]. The human AC nuclei that contain the most DAT‐ir fibers correspond to those that receive strong projections from the ventral mesencephalon, as also observed in primates [29]. There are, nevertheless, other AC regions showing a high density of DAT‐positive fibers, such as the lateral subdivision of the central nucleus, that do not seem to receive innervation from any part of the ventral midbrain [29]. There are other possible sources of AC dopamine that lie outside the ventral midbrain, but whether they contribute to the DAT‐ir fibers encountered in the AC or not, is not yet clear. The parabrachial nucleus projects to the central and medial nuclei of the AC [29, 123, 124] and it contains putatively dopaminergic neurons that do not carry DAT [126]. Moreover, the neurons of the parabrachial nucleus that project to the AC also lack tyrosine hydroxylase (TH) [29, 123, 124]. The periaqueductal gray substance is another source of input to the AC and it contains dopaminergic neurons (i.e. A11 group) that contain DAT [126] and project to the central and medial AC nuclei [4, 123, 124, 127–129]. This dopaminergic connection is relevant as it specifically targets the lateral subdivision of the central nucleus, a region that sends efferent projections to the medial subdivision of the central nucleus, which in turn projects back to the periaqueductal gray substance handling “
The ultrastructural localization of DAT in the primate AC is unknown at present. In the cerebral cortex, most of the DAT‐labeled profiles correspond to thin unmyelinated axons that rarely form synapses, whereas TH‐labeled profiles vary more in their diameter and TH‐ir varicosities contain abundant vesicles and frequently form synapses [118]. Consequently, Lewis et al. believe that DAT is likely to be restricted to the intervaricose segments [118]. The specific postsynaptic targets of the dopaminergic fibers that reach the human AC are not known. Several studies in rodents have demonstrated that these fibers make synapses with both projection neurons [23, 24, 130] and interneurons [25, 26, 130]. Although projection neurons receive the majority of dopaminergic synapses [130], the CR+ and PV+ interneuron subsets are also innervated by these fibers, especially the ones containing PV [26]. The CR+ interneurons receive only 6% of the dopaminergic synapses, whereas the PV+ cells receive 40% [26]. In the central and basal nuclei, as well as in the paracapsular intercalated groups, the dopaminergic terminals form symmetric synapses more frequently than asymmetric ones [23, 24, 26, 130].
Dopaminergic fibers in the AC form perineuronal nets around the soma of the projection neurons and the PV+ interneurons, and 72% of the contacts that these nets establish with the PV+ interneurons are synaptic [25, 26, 130]. These nets are abundant in some 10–15% of all PV+ interneurons and they appear to avoid other interneuron subsets. These nets are functionally related with the strong inhibition observed in the activity of the projection neurons of the basolateral group after dopamine release [131, 132]. The dopaminergic innervation of the various interneuron populations of the AC could contribute to the induction of long‐term potentiation mechanisms involved in conditioned fear acquisition, which requires suppression of GABAergic interneuron inhibition of projection neurons [35]. Dopamine inhibits the “fast firing” interneurons, which coincide with the PV+ interneurons [102], and reduces the inhibition of projection neurons in the lateral amygdaloid nucleus. More recently, Chu et al. have demonstrated that dopamine blocks GABA release from PV+ interneurons to projection neurons acting on type D2 presynaptic receptors but it does not affect the release of GABA to other interneuron types from this interneuron population [133]. The blockade of both D1 and D2 receptors in the basolateral group prevents fear conditioned acquisition [134–136].
6. Concluding remarks
The AC is a heterogeneous structure formed by numerous nuclei with diverse morphological and functional features. Numerous neurological or psychiatric diseases are linked to alterations in specific cell populations, as well as neurotransmission systems in the human AC. Understanding how AC dysfunction may be related to the pathogenesis of human disorders or accompany behavioral impairments requires a profound knowledge of the normal anatomy of the human AC. In this sense, several studies performed in the last 5 years have provided accurate quantitative data related to the cellular composition and dopaminergic innervation of the various nuclear complexes and their subdivisions that make up the human amygdala. Data from these studies have revealed, for instance, that the human AC contains approximately 15 million neurons with nearly 80% residing in the basolateral group, 10% in the corticomedial group and 5% in the central group. The number of endothelial cells is similar to the number of neurons whereas the number of glia is approximately four times that of neurons. Most amygdaloid neurons are glutamatergic or GABAergic neurons that project their axons outside the AC. The activity of the AC principal neurons is tightly modulated by local circuit interneurons and this modulation is required for the acquisition of fear memories. The AC interneurons are cataloged into different subsets based on their firing properties, their synaptic inputs and their expression in proteins such as calcium‐binding proteins. Among all the interneurons containing calcium‐binding proteins in the primate AC, the PV+ and the CR+ interneurons are the most abundant, representing 1% and 6–24% of the total neuron population of the human AC, respectively. PV+ interneurons exert robust perisomatic inhibition of principal neurons, but their activity is likely to be mostly concentrated in the basolateral complex, since almost none of these neurons populate other AC territories. In contrast, the CR+ interneurons are, basically, homogeneously distributed through the entire AC. The human AC receives a heterogeneous dopaminergic innervation that mostly originates in the midbrain areas and regulates the activity of the various subsets of AC neurons. Dysfunctions of this dopaminergic system have been described in schizophrenia and stress‐related disorders. Stressful events enhance dopamine release in the AC and this facilitates the formation of fear memories as well as appropriate affective responses. A recent study has demonstrated that the dopaminergic innervation of the human AC is heterogeneous and that the main output nucleus of the AC (i.e. the central nucleus) receives the highest density of dopaminergic axons containing the dopamine transporter, with almost double the density of these fibers compared to the density in the main entrance nucleus of the AC (the basolateral group). The postsynaptic targets of the dopaminergic fibers in the human AC remain unknown, but these fibers make synapses with both projection neurons and interneurons in rodents. The CR+ and the PV+ interneurons of the AC are important targets of the dopaminergic synapses in rodents, but further studies are needed to determine what the main neuronal targets of this neurotransmitter are in the human AC and the role that this innervation has in emotional learning.
Acknowledgments
The project was supported by grants from the
References
- 1.
Burdach KF. Vom Baue und Leben des Gehirns Leipzig. pp. 1819-1822 - 2.
Johnston JB. Further contributions to the study of the evolution of the forebrain. Journal of Comparative Neurology. 1923; 35 (5):337-481 - 3.
Swanson LW, Petrovich GD. What is the amygdala? Trends in Neuroscience. 1998; 21 (8):323-331 - 4.
Aggleton JP, Burton MJ, Passingham RE. Cortical and subcortical afferents to the amygdala of the rhesus monkey ( Macaca mulatta ). Brain Research. 1980;190 (2):347-368 - 5.
Nishijo H, Hori E, Tazumi T, Ono T. Neural correlates to both emotion and cognitive functions in the monkey amygdala. Behavioural Brain Research. 2008; 188 (1):14-23 - 6.
Chapman WP, Schroeder HR, Geyer G, Brazier MA, Fager C, Poppen JL, et al. Physiological evidence concerning importance of the amygdaloid nuclear region in the integration of circulatory function and emotion in man. Science. 1954; 120 (3127):949-950 - 7.
Fanselow MS, Gale GD. The amygdala, fear, and memory. The Annals of the New York Academy of Sciences. 2003; 985 :125-134 - 8.
Maren S, Quirk GJ. Neuronal signalling of fear memory. Nature Reviews Neuroscience. 2004; 5 (11):844-852 - 9.
Falls WA, Miserendino MJ, Davis M. Extinction of fear‐potentiated startle: Blockade by infusion of an NMDA antagonist into the amygdala. Journal of Neuroscience. 1992; 12 (3):854-863 - 10.
Lu KT, Walker DL, Davis M. Mitogen‐activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear‐potentiated startle. Journal of Neuroscience. 2001; 21 (16):RC162 - 11.
Herry C, Ciocchi S, Senn V, Demmou L, Muller C, Luthi A. Switching on and off fear by distinct neuronal circuits. Nature. 2008; 454 (7204):600-606 - 12.
Maren S, Phan KL, Liberzon I. The contextual brain: Implications for fear conditioning, extinction and psychopathology. Nature Reviews Neuroscience. 2013; 14 (6):417-428 - 13.
Ciocchi S, Herry C, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature. 2010; 468 (7321):277-282 - 14.
Pare D, Duvarci S. Amygdala microcircuits mediating fear expression and extinction. Current Opinion in Neurobiology. 2012; 22 (4):717-723 - 15.
Garavan H, Pendergrass JC, Ross TJ, Stein EA, Risinger RC. Amygdala response to both positively and negatively valenced stimuli. Neuroreport. 2001; 12 (12):2779-2783 - 16.
Straube T, Pohlack S, Mentzel HJ, Miltner WH. Differential amygdala activation to negative and positive emotional pictures during an indirect task. Behavioural Brain Research. 2008; 191 (2):285-288 - 17.
Davey CG, Allen NB, Harrison BJ, Yucel M. Increased amygdala response to positive social feedback in young people with major depressive disorder. Biological Psychiatry. 2011; 69 (8):734-741 - 18.
Jones B, Mishkin M. Limbic lesions and the problem of stimulus–reinforcement associations. Experimental Neurology 1972; 36 (2):362-377 - 19.
Geschwind N. Disconnexion syndromes in animals and man. Brain. 1965; 88 :237-294 - 20.
Klüver H, Bucy PC. Preliminary analysis of functions of the temporal lobes in monkeys. Archives of Neurology and Psychiatry. 1939; 42 :979-1000 - 21.
Lilly R, Cummings JL, Benson DF, Frankel M. The human Kluver‐Bucy syndrome. Neurology. 1983; 33 (9):1141-1145 - 22.
Ciliax BJ, Heilman C, Demchyshyn LL, Pristupa ZB, Ince E, Hersch SM, et al. The dopamine transporter: Immunochemical characterization and localization in brain. Journal of Neuroscience. 1995; 15 (3 Pt 1):1714-1723 - 23.
Asan E. Ultrastructural features of tyrosine‐hydroxylase‐immunoreactive afferents and their targets in the rat amygdala. Cell and Tissue Research. 1997; 288 (3):449-469 - 24.
Asan E. The catecholaminergic innervation of the rat amygdala. Advances in Anatomy, Embryology and Cell Biology. 1998; 142 :1-118 - 25.
Brinley‐Reed M, McDonald AJ. Evidence that dopaminergic axons provide a dense innervation of specific neuronal subpopulations in the rat basolateral amygdala. Brain Research. 1999; 850 (1-2):127-135 - 26.
Pinard CR, Muller JF, Mascagni F, McDonald AJ. Dopaminergic innervation of interneurons in the rat basolateral amygdala. Neuroscience. 2008; 157 (4):850-863 - 27.
Sadikot AF, Parent A. The monoaminergic innervation of the amygdala in the squirrel monkey: An immunohistochemical study. Neuroscience. 1990; 36 (2):431-447 - 28.
Freedman LJ, Shi C. Monoaminergic innervation of the macaque extended amygdala. Neuroscience. 2001; 104 (4):1067-1084 - 29.
Cho YT, Fudge JL. Heterogeneous dopamine populations project to specific subregions of the primate amygdala. Neuroscience. 2010; 165 (4):1501-1518 - 30.
Ciliax BJ, Drash GW, Staley JK, Haber S, Mobley CJ, Miller GW, et al. Immunocytochemical localization of the dopamine transporter in human brain. Journal of Comparative Neurology. 1999; 409 (1):38-56 - 31.
Nader K, LeDoux J. The dopaminergic modulation of fear: quinpirole impairs the recall of emotional memories in rats. Behavioral Neuroscience. 1999; 113 (1):152-165 - 32.
Rosenkranz JA, Grace AA. Modulation of basolateral amygdala neuronal firing and afferent drive by dopamine receptor activation in vivo. Journal of Neuroscience. 1999; 19 (24):11027-11039 - 33.
Rosenkranz JA, Grace AA. Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. Journal of Neuroscience. 2001; 21 (11):4090-4103 - 34.
Rosenkranz JA, Grace AA. Dopamine‐mediated modulation of odour‐evoked amygdala potentials during Pavlovian conditioning. Nature. 2002; 417 (6886):282-287 - 35.
Bissiere S, Humeau Y, Luthi A. Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nature Neuroscience. 2003; 6 (6):587-592 - 36.
LeDoux J. The amygdala. Current Biology. 2007; 17 (20):R868-74 - 37.
Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR, et al. Lamina‐specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. The American Journal of Psychiatry 1999; 156 (10):1580-1589 - 38.
Winterer G. Cortical microcircuits in schizophrenia—the dopamine hypothesis revisited. Pharmacopsychiatry. 2006; 39 Suppl. 1:S68‐S71 - 39.
Venator DK, Lewis DA, Finlay JM. Effects of partial dopamine loss in the medial prefrontal cortex on local baseline and stress‐evoked extracellular dopamine concentrations. Neuroscience. 1999; 93 (2):497-505 - 40.
Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, Hedou G, et al. Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience. 2000; 100 (4):749-768 - 41.
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996; 379 (6566):606-612 - 42.
Völsch M. Zur vergleichenden Anatomie des Mandelkerns und seiner Nachbargebilde. I. Teil. Arch f mikr Anat. 1906; 68 :573-683 - 43.
Völsch M. Zur vergleichenden Anatomie des Mandelkerns und seiner Nachbargebilde. II. Teil. Arch f mikr Anat. 1910; 76 :373-523 - 44.
Holmgren P. Points of view concerning forebrain morphology in higuer vertebrates. Acta Zoologica. 1928; 6 :415-477 - 45.
Huber GC, Crosby EC. The nuclei and fibers paths of the avian diencephalon, with consideration of the telencephalic and certain mesencephalic centers and connections. Journal of Comparative Neurology. 1929; 48 :1-186 - 46.
Äriens Kappers CU, Huber G, Crosby EC. The Comparative Anatomy of the Nervous System of Vertebrates, including Man. New York: The Macmillan Company; 1936 - 47.
Brockhaus H. Zur normalen und pathologischen Anatomie des Mandelkerngebiets. Journal of Neurology and Psychology. 1938; 49 :1-136 - 48.
Price JL, Russchen FT, Amaral DG. The limbic region. II. The amygdaloid complex. In: Björkland A, Hökfelt T, Swanson LW, editors. Handbook of Chemical Neuroanatomy. Amsterdam: Elsevier; 1987. pp. 279-381 - 49.
Sims KS, Williams RS. The human amygdaloid complex: A cytologic and histochemical atlas using Nissl, myelin, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate diaphorase staining. Neuroscience. 1990; 36 (2):449-472 - 50.
Amaral DG, Price JL, Pitkanen A, Carmichael ST. Anatomical organization of the primate amygdaloid complex. In: Aggleton JP, editor. The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction. New York: Wiley‐Liss; 1992. pp. 1-66 - 51.
Kapp BS, Frysinger RC, Gallagher M, Haselton JR. Amygdala central nucleus lesions: effect on heart rate conditioning in the rabbit. Physiology & Behavior. 1979; 23 (6):1109-1117 - 52.
Gamer M, Zurowski B, Buchel C. Different amygdala subregions mediate valence‐related and attentional effects of oxytocin in humans. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107 (20):9400-9405 - 53.
Crosby EC, Humphrey T. Studies of the vertebrate telencephalon. II. The nuclear pattern of the anterior olfactory nucleus. Journal of Comparative Neurology. 1941; 74 (2):309-352 - 54.
Brady DR, Carey RG, Mufson EJ. Reduced nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPH‐d) profiles in the amygdala of human and New World monkey ( Saimiri sciureus ). Brain Research. 1992;577 (2):236-248 - 55.
García‐Amado M, Prensa L. Stereological analysis of neuron, glial and endothelial cell numbers in the human amygdaloid complex. PLoS One. 2012; 7 (6):e38692 - 56.
Ledo‐Varela M T, Gimenez‐Amaya J M, Llamas A. The amygdaloid complex and its implication in psychiatric disorders. Anales del Sistema Sanitario de Navarra. 2007; 30 (1):61-74 - 57.
Schumann CM, Amaral DG. Stereological estimation of the number of neurons in the human amygdaloid complex. Journal of Comparative Neurology. 2005; 491 (4):320-329 - 58.
Sorvari H, Soininen H, Paljarvi L, Karkola K, Pitkanen A. Distribution of parvalbumin‐immunoreactive cells and fibers in the human amygdaloid complex. Journal of Comparative Neurology. 1995; 360 (2):185-212 - 59.
Heckers S, Heinsen H, Heinsen YC, Beckmann H. Limbic structures and lateral ventricle in schizophrenia. A quantitative postmortem study. Archives of General Psychiatry. 1990; 47 (11):1016-1022 - 60.
Pakkenberg B. Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Archives of General Psychiatry. 1990; 47 (11):1023-1028 - 61.
Chance SA, Esiri MM, Crow TJ. Amygdala volume in schizophrenia: Post‐mortem study and review of magnetic resonance imaging findings. The British Journal of Psychiatry. 2002; 180 :331-338 - 62.
Schumann CM, Amaral DG. Stereological analysis of amygdala neuron number in autism. Journal of Neuroscience. 2006; 26 (29):7674-7679 - 63.
Berretta S, Pantazopoulos H, Lange N. Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia. Biological Psychiatry. 2007; 62 (8):884-893 - 64.
Kreczmanski P, Heinsen H, Mantua V, Woltersdorf F, Masson T, Ulfig N, et al. Volume, Neuron Density and Total Neuron Number in Five Subcortical Regions in Schizophrenia. Brain. 2007; 130 (Pt 3):678-692 - 65.
Lehericy S, Baulac M, Chiras J, Pierot L, Martin N, Pillon B, et al. Amygdalohippocampal MR volume measurements in the early stages of Alzheimer disease. American Journal of Neuroradiology. 1994; 15 (5):929-237 - 66.
Bowley MP, Drevets WC, Ongur D, Price JL. Low glial numbers in the amygdala in major depressive disorder. Biological Psychiatry. 2002; 52 (5):404-412 - 67.
Hamidi M, Drevets WC, Price JL. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biological Psychiatry. 2004; 55 (6):563-569 - 68.
Bezchlibnyk YB, Sun X, Wang JF, MacQueen GM, McEwen BS, Young LT. Neuron somal size is decreased in the lateral amygdalar nucleus of subjects with bipolar disorder. The Journal of Psychiatry & Neuroscience. 2007; 32 (3):203-210 - 69.
Braak H, Braak E. Neuronal types in the basolateral amygdaloid nuclei of man. Brain Research Bulletin. 1983; 11 (3):349-365 - 70.
Dall’Oglio A, Xavier LL, Hilbig A, Ferme D, Moreira JE, Achaval M, et al. Cellular components of the human medial amygdaloid nucleus. Journal of Comparative Neurology. 2012; 521 (3):589-611 - 71.
Johnson RT, Schneider A, DonCarlos LL, Breedlove SM, Jordan CL. Astrocytes in the rat medial amygdala are responsive to adult androgens. Journal of Comparative Neurology. 2012; 520 (11):2531-2544 - 72.
Öngür D, Bechtholt AJ, Carlezon Jr WA, Cohen BM. Glial abnormalities in mood disorders. Harvard Review of Psychiatry. 2014; 22 (6):334-337 - 73.
Konopaske GT, Dorph‐Petersen KA, Pierri JN, Wu Q, Sampson AR, Lewis DA. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology. 2007; 32 (6):1216-1223 - 74.
Kreczmanski P, Heinsen H, Mantua V, Woltersdorf F, Masson T, Ulfig N, et al. Microvessel length density, total length, and length per neuron in five subcortical regions in schizophrenia. Acta Neuropathologica. 2009; 117 (4):409-421 - 75.
Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, et al. Evolution of increased glia‐neuron ratios in the human frontal cortex. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103 (37):13606-13611 - 76.
Chareyron LJ, Banta Lavenex P, Amaral DG, Lavenex P. Stereological analysis of the rat and monkey amygdala. Journal of Comparative Neurology. 2011; 519 (16):3218-3239 - 77.
Dorph‐Petersen KA, Nyengaard JR, Gundersen HJ. Tissue shrinkage and unbiased stereological estimation of particle number and size. Journal of Microscopy. 2001; 204 (Pt 3):232-246 - 78.
Decampo DM, Fudge JL. Where and what is the paralaminar nucleus? A review on a unique and frequently overlooked area of the primate amygdala. Neuroscience & Biobehavioral Reviews. 2012; 36 :520-535 - 79.
Yachnis AT, Roper SN, Love A, Fancey JT, Muir D. Bcl‐2 immunoreactive cells with immature neuronal phenotype exist in the nonepileptic adult human brain. Journal of Neuropathology & Experimental Neurology. 2000; 59 (2):113-119 - 80.
Zhang X‐M, Cai Y, Chu Y, Chen E‐Y, Feng J‐C, Luo X‐G, et al. Doublecortin‐expressing cells persist in the associative cerebral cortex and amygdala in aged nonhuman primates. Frontiers in Neuroanatomy. 2009; 3 :17. doi: 10.3389/neuro.05.017.2009. eCollection 2009 - 81.
Carlo CN, Stefanacci L, Semendeferi K, Stevens CF. Comparative analyses of the neuron numbers and volumes of the amygdaloid complex in old and new world primates. Journal of Comparative Neurology. 2010; 518 (8):1176-1198 - 82.
Price JL. Comparative aspects of amygdala connectivity. Annals of the New York Academy of Sciences. 2003; 985 :50-58 - 83.
Beach TG, Walker R, McGeer EG. Patterns of gliosis in Alzheimer’s disease and aging cerebrum. Glia. 1989; 2 (6):420-436 - 84.
LaManna JC, Chavez JC, Pichiule P. Structural and functional adaptation to hypoxia in the rat brain. Journal of Experimental Biology. 2004; 207 (Pt 18):3163-3169 - 85.
Asllani I, Habeck C, Borogovac A, Brown TR, Brickman AM, Stern Y. Separating function from structure in perfusion imaging of the aging brain. Human Brain Mapping. 2009; 30 (9):2927-2935 - 86.
Mascagni F, Muly EC, Rainnie DG, McDonald AJ. Immunohistochemical characterization of parvalbumin‐containing interneurons in the monkey basolateral amygdala. Neuroscience 2009; 158 (4):1541-1550 - 87.
Bienvenu TC, Busti D, Magill PJ, Ferraguti F, Capogna M. Cell‐type‐specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo. Neuron. 2012; 74 (6):1059-1074 - 88.
Vereczki VK, Veres JM, Muller K, Nagy GA, Racz B, Barsy B, et al. Synaptic organization of perisomatic GABAergic inputs onto the principal cells of the mouse basolateral amygdala. Frontiers in Neuroanatomy. 2016; 10 :20 - 89.
Bazelot M, Bocchio M, Kasugai Y, Fischer D, Dodson PD, Ferraguti F, et al. Hippocampal theta input to the amygdala shapes feedforward inhibition to gate heterosynaptic plasticity. Neuron. 2015; 87 (6):1290-1303 - 90.
Yilmazer‐Hanke DM, Faber‐Zuschratter H, Linke R, Schwegler H. Contribution of amygdala neurons containing peptides and calcium‐binding proteins to fear‐potentiated startle and exploration‐related anxiety in inbred Roman high‐ and low‐avoidance rats. European Journal of Neuroscience. 2002; 15 (7):1206-1218 - 91.
Lewis DA. GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Research Reviews. 2000; 31 (2-3):270-276 - 92.
Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nature Reviews Neuroscience. 2005; 6 (4):312-324 - 93.
Helmeke C, Ovtscharoff W, Jr., Poeggel G, Braun K. Imbalance of immunohistochemically characterized interneuron populations in the adolescent and adult rodent medial prefrontal cortex after repeated exposure to neonatal separation stress. Neuroscience. 2008; 152 (1):18-28 - 94.
Maciag D, Hughes J, O’Dwyer G, Pride Y, Stockmeier CA, Sanacora G, et al. Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biological Psychiatry. 2010; 67 (5):465-470 - 95.
Hashemi E, Ariza J, Rogers H, Noctor SC, Martinez‐Cerdeno V. The number of parvalbumin‐expressing interneurons is decreased in the medial prefrontal cortex in autism. Cerebral Cortex. 2016; 27 (3): 1931-1943 - 96.
Pantazopoulos H, Lange N, Hassinger L, Berretta S. Subpopulations of neurons expressing parvalbumin in the human amygdala. Journal of Comparative Neurology. 2006; 49 6(5):706-722 - 97.
Pitkanen A, Amaral DG. Distribution of calbindin‐D28k immunoreactivity in the monkey temporal lobe: the amygdaloid complex. Journal of Comparative Neurology. 1993; 331 (2):199-224 - 98.
Sorvari H, Soininen H, Pitkanen A. Calbindin‐D28K‐immunoreactive cells and fibres in the human amygdaloid complex. Neuroscience. 1996; 75 (2):421-443 - 99.
Amaral DG, Avendano C, Benoit R. Distribution of somatostatin‐like immunoreactivity in the monkey amygdala. Journal of Comparative Neurology. 1989; 284 (2):294-313 - 100.
McDonald AJ, Mascagni F, Augustine JR. Neuropeptide Y and somatostatin‐like immunoreactivity in neurons of the monkey amygdala. Neuroscience. 1995; 66 (4):959-982 - 101.
Sorvari H, Soininen H, Pitkanen A. Calretinin‐immunoreactive cells and fibers in the human amygdaloid complex. Journal of Comparative Neurology. 1996; 369 (2):188-208 - 102.
Rainnie DG, Mania I, Mascagni F, McDonald AJ. Physiological and morphological characterization of parvalbumin‐containing interneurons of the rat basolateral amygdala. Journal of Comparative Neurology. 2006; 498 (1):142-161 - 103.
Woodruff AR, Sah P. Inhibition and synchronization of basal amygdala principal neuron spiking by parvalbumin‐positive interneurons. Journal of Neurophysiology. 2007; 98 (5):2956-2961 - 104.
Sorvari H, Miettinen R, Soininen H, Pitkanen A. Parvalbumin‐immunoreactive neurons make inhibitory synapses on pyramidal cells in the human amygdala: a light and electron microscopic study. Neuroscience Letters. 1996; 217 (2-3):93-96 - 105.
Garcia‐Amado M, Prensa L. A quantitative study of the percentage of parvalbumin‐positive interneurons and the dopaminergic fiber length density in the nuclear subdivisions of the human basolateral amygdaloid complex. In: Planner NM. 40th Annual Meeting of the Society for Neuroscience; November; San Diego, California, EEUU 2010. p. Program 909.24/LLL29 - 106.
Kemppainen S, Pitkanen A. Distribution of parvalbumin, calretinin, and calbindin‐D(28k) immunoreactivity in the rat amygdaloid complex and colocalization with gamma‐aminobutyric acid. Journal of Comparative Neurology. 2000; 426 (3):441-467 - 107.
Wu Y, Parent A. Striatal interneurons expressing calretinin, parvalbumin or NADPH‐diaphorase: A comparative study in the rat, monkey and human. Brain Research. 2000; 863 (1-2):182-191 - 108.
García‐Amado M, Prensa L. Distribution of dopamine transporter immunoreactive fibers in the human amygdaloid complex. European Journal of Neuroscience. 2013; 38 (11):3589-3601 - 109.
Goldstein M, Freedman LS, Ebstein RP, Park DH. Studies on dopamine‐beta‐hydroxylase in mental disorders. Journal of Psychiatric Research. 1974; 11 :205-210 - 110.
Farley IJ, Hornykiewicz O. Noradrenaline distribution in subcortical areas of the human brain. Brain Research. 1977; 126 (1):53-62 - 111.
Pitkanen A, Savander V, LeDoux JE. Organization of intra‐amygdaloid circuitries in the rat: An emerging framework for understanding functions of the amygdala. Trends in Neurosciences. 1997; 20 (11):517-523 - 112.
Pitkanen A, Amaral DG. Organization of the intrinsic connections of the monkey amygdaloid complex: Projections originating in the lateral nucleus. Journal of Comparative Neurology. 1998; 398 (3):431-458 - 113.
Quirk GJ, Repa C, LeDoux JE. Fear conditioning enhances short‐latency auditory responses of lateral amygdala neurons: Parallel recordings in the freely behaving rat. Neuron. 1995; 15 (5):1029-1039 - 114.
Ottersen OP. Connections of the amygdala of the rat. IV: Corticoamygdaloid and intraamygdaloid connections as studied with axonal transport of horseradish peroxidase. Journal of Comparative Neurology. 1982; 205 (1):30-48 - 115.
Berendse HW, Galis‐de Graaf Y, Groenewegen HJ. Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. Journal of Comparative Neurology. 1992; 316 (3):314-347 - 116.
Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral Neuroscience. 1992; 106 (2):274-285 - 117.
Romanski LM, LeDoux JE. Information cascade from primary auditory cortex to the amygdala: Corticocortical and corticoamygdaloid projections of temporal cortex in the rat. Cerebral Cortex. 1993; 3 (6):515-532 - 118.
Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A. Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. Journal of Comparative Neurology. 2001; 432 (1):119-136 - 119.
Mai JK, Assheuer J, Paxinos G. Atlas of the Human Brain. 2nd ed. San Diego, California: Elsevier Academic Press; 2004 - 120.
Price JL, Amaral DG. An autoradiographic study of the projections of the central nucleus of the monkey amygdala. Journal of Neuroscience. 1981; 1 (11):1242-1259 - 121.
Marcellino D, Frankowska M, Agnati L, Perez de la Mora M, Vargas‐Barroso V, Fuxe K, et al. Intercalated and paracapsular cell islands of the adult rat amygdala: A combined rapid‐Golgi, ultrastructural, and immunohistochemical account. Neuroscience. 2012; 226 :324-347 - 122.
Garris PA, Wightman RM. Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: An in vivo voltammetric study. Journal of Neuroscience. 1994; 14 (1):442-450 - 123.
Mehler WR. Subcortical afferent connections of the amygdala in the monkey. Journal of Comparative Neurology. 1980; 190 (4):733-762 - 124.
Norita M, Kawamura K. Subcortical afferents to the monkey amygdala: An HRP study. Brain Research. 1980; 190 (1):225-230 - 125.
Haber SN, Ryoo H, Cox C, Lu W. Subsets of midbrain dopaminergic neurons in monkeys are distinguished by different levels of mRNA for the dopamine transporter: Comparison with the mRNA for the D2 receptor, tyrosine hydroxylase and calbindin immunoreactivity. Journal of Comparative Neurology. 1995; 362 (3):400-410 - 126.
Sanchez‐Gonzalez MA, Garcia‐Cabezas MA, Rico B, Cavada C. The primate thalamus is a key target for brain dopamine. Journal of Neuroscience. 2005; 25 (26):6076-6083 - 127.
Arsenault MY, Parent A, Seguela P, Descarries L. Distribution and morphological characteristics of dopamine‐immunoreactive neurons in the midbrain of the squirrel monkey ( Saimiri sciureus ). Journal of Neuroscience. 1988;267 (4):489-506 - 128.
Kitahama K, Ikemoto K, Jouvet A, Nagatsu I, Sakamoto N, Pearson J. Aromatic L‐amino acid decarboxylase‐ and tyrosine hydroxylase‐immunohistochemistry in the adult human hypothalamus. Journal of Chemical Neuroanatomy. 1998; 16 (1):43-55 - 129.
Hasue RH, Shammah‐Lagnado SJ. Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: a combined retrograde tracing and immunohistochemical study in the rat. Journal of Comparative Neurology. 2002; 454 (1):15-33 - 130.
Muller JF, Mascagni F, McDonald AJ. Dopaminergic innervation of pyramidal cells in the rat basolateral amygdala. Brain Structure & Function. 2009; 213 (3):275-288 - 131.
Ben‐Ari Y, Kelly JS. Dopamine evoked inhibition of single cells of the feline putamen and basolateral amygdala. Journal of Physiology. 1976; 256 (1):1-21 - 132.
Loretan K, Bissiere S, Luthi A. Dopaminergic modulation of spontaneous inhibitory network activity in the lateral amygdala. Neuropharmacology. 2004; 47 (5):631-639 - 133.
Chu HY, Ito W, Li J, Morozov A. Target‐specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine. Journal of Neuroscience. 2012; 32 (42):14815-14820 - 134.
Greba Q, Gifkins A, Kokkinidis L. Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear‐potentiated startle. Brain Research. 2001; 899 (1-2):218-26 - 135.
Greba Q, Kokkinidis L. Peripheral and intraamygdalar administration of the dopamine D1 receptor antagonist SCH 23390 blocks fear‐potentiated startle but not shock reactivity or the shock sensitization of acoustic startle. Behavioral Neuroscience. 2000; 114 (2):262-272 - 136.
Guarraci FA, Frohardt RJ, Falls WA, Kapp BS. The effects of intra‐amygdaloid infusions of a D2 dopamine receptor antagonist on Pavlovian fear conditioning. Behavioral Neuroscience. 2000; 114 (3):647-651