Distribution of type I corticotropin‐releasing factor (CRF1) receptors on GABAergic neurons within the basolateral amygdala

The neuropeptide corticotropin‐releasing factor (CRF) plays a critical role in mediating anxiety‐like responses to stressors, and dysfunction of the CRF system has been linked to the etiology of several psychiatric disorders. Extra‐hypothalamic CRF can also modulate learning and memory formation, including amygdala‐dependent learning. The basolateral nucleus of the amygdala (BLA) contains dense concentrations of CRF receptors, yet the distribution of these receptors on specific neuronal subtypes within the BLA has not been characterized. Here, we quantified the expression of CRF receptors on three nonoverlapping classes of GABAergic interneurons: those containing the calcium‐binding protein parvalbumin (PV), and those expressing the neuropeptides somatostatin (SOM) or cholecystokinin (CCK). While the majority of PV+ neurons and roughly half of CCK+ neurons expressed CRF receptors, they were expressed to a much lesser extent on SOM+ interneurons. Knowledge of the distribution of CRF receptors within the BLA can provide insight into how manipulations of the CRF system modulate fear and anxiety‐like behaviors.     

Multiple anxiogenic drugs recruit a parvalbumin-containing subpopulation of GABAergic interneurons in the basolateral amygdala

The basolateral amygdala is a nodal structure within a distributed and interconnected network that regulates anxiety states and anxiety-related behavior. Administration of multiple anxiogenic drugs increases cellular responses (i.e., increases c-Fos expression) in a subregion of the basolateral amygdala, but the neurochemical phenotypes of these cells are not known. The basolateral amygdala contains glutamatergic projection neurons and several populations of γ-aminobutyric acid-synthesizing (GABAergic) interneurons, including a population of parvalbumin (PV)-expressing GABAergic interneurons that co-express the excitatory 5-HT_2A receptor. The role for these PV-expressing GABAergic interneurons in anxiety-states is unclear. In this experiment we examined the effects of multiple anxiogenic drugs including the 5-HT_2C/2A receptor agonist m-chlorophenyl piperazine (mCPP), the adenosine receptor antagonist caffeine, the α₂-adrenoreceptor antagonist yohimbine and the partial inverse agonist at the benzodiazepine allosteric site on the GABA_A receptor, N-methyl-beta-carboline-3-carboxamide (FG-7142), on c-Fos expression in PV-immunoreactive (PV-ir) interneurons in subdivisions of the basolateral amygdala. All drugs with the exception of mCPP increased c-Fos expression in PV-ir neurons in the basolateral amygdaloid nucleus, anterior part (BLA). The numbers of c-Fos-immunoreactive (c-Fos-ir)/PV-ir GABAergic interneurons in the BLA were positively correlated with the numbers of c-Fos-ir serotonergic neurons in the mid-rostrocaudal dorsal raphe nucleus (DR) and with a measure of anxiety-related behavior. All four drugs increased c-Fos expression in non-PV-ir cells in most of the subdivisions of the basolateral amygdala that were sampled, compared with vehicle-injected controls. Together, these data suggest that the PV/5-HT_2A receptor expressing GABAergic interneurons in the basolateral amygdala are part of a DR-basolateral amygdala neuronal circuit modulating anxiety-states and anxiety-related behavior.     

Cortical inputs innervate calbindin‐immunoreactive interneurons of the rat basolateral amygdaloid complex

The present study was undertaken to shed light on the synaptic organization of the rat basolateral amygdala (BLA). The BLA contains multiple types of GABAergic interneurons that are differentially connected with extrinsic afferents and other BLA cells. Previously, it was reported that parvalbumin immunoreactive (PV⁺) interneurons receive strong excitatory inputs from principal BLA cells but very few cortical inputs, implying a prevalent role in feedback inhibition. However, because prior physiological studies indicate that cortical afferents do trigger feedforward inhibition in principal cells, the present study aimed to determine whether a numerically important subtype of interneurons, expressing calbindin (CB⁺), receives cortical inputs. Rats received injections of the anterograde tracer Phaseolus vulgaris‐leucoagglutinin (PHAL) in the perirhinal cortex or adjacent temporal neocortex. Light and electron microscopic observations of the relations between cortical inputs and BLA neurons were performed in the lateral (LA) and basolateral (BL) nuclei. Irrespective of the injection site (perirhinal or temporal neocortex) and target nucleus (LA or BL), ～90% of cortical axon terminals formed asymmetric synapses with dendritic spines of principal BLA neurons, while 10% contacted the dendritic shafts of presumed interneurons, half of which were CB⁺. Given the previously reported pattern of CB coexpression among GABAergic interneurons of the BLA, these results suggest that a subset of PV‐immunonegative cells that express CB, most likely the somatostatin‐positive interneurons, are important mediators of cortically evoked feedforward inhibition in the BLA. J. Comp. Neurol. 522:1915–1928, 2014. © 2013 Wiley Periodicals, Inc.     

Hippocampal dendritic spines remodeling and fear memory are modulated by GABAergic signaling within the basolateral amygdala complex

GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long‐term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra‐BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress‐induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory. © 2015 Wiley Periodicals, Inc.     

Physiological and morphological characterization of parvalbumin-containing interneurons of the rat basolateral amygdala

The basolateral amygdala (BLA) is critical for the generation of emotional behavior and the formation of emotional memory. Understanding the neuronal mechanisms that contribute to emotional information processing in the BLA will ultimately require knowledge of the anatomy and physiology of its constituent neurons. Two major cell classes exist in the BLA, pyramidal projection neurons and nonpyramidal interneurons. Although the properties of projection neurons have been studied in detail, little is known about the properties of BLA interneurons. We have used whole-cell patch clamp recording techniques to examine the physiological properties of 48 visually identified putative interneurons from the rat anterior basolateral amygdalar nucleus. Here, we report that BLA interneurons can be differentiated into four electrophysiologically distinct subtypes based on their intrinsic membrane properties and their response to afferent synaptic input. Interneuron subtypes were named according to their characteristic firing pattern generated in response to transient depolarizing current injection and were grouped as follows: 1) burst-firing interneurons (n = 13), 2) regular-firing interneurons (n = 11), 3) fast-firing interneurons (n = 10), and 4) stutter-firing interneurons (n = 14). Post hoc histochemical visualization confirmed that all 48 recorded neurons had morphological properties consistent with their being local circuit interneurons. Moreover, by using triple immunofluorescence (for biocytin, calcium-binding proteins, and neuropeptides) in conjunction with patch clamp recording, we further demonstrated that over 60% of burst-firing and stutter-firing interneurons also expressed the calcium-binding protein parvalbumin (PV(+)). These data demonstrate that interneurons of the BLA show both physiological and neurochemical diversity. Moreover, we demonstrate that the burst- and stutter-firing patterns positively correlate with PV(+) immunoreactivity, suggesting that these neurons may represent functionally distinct subpopulations.     

Parvalbumin-containing interneurons in the basolateral amygdala express high levels of the alpha1 subunit of the GABAA receptor

The basolateral amygdala (ABL) is essential for the amnestic effects of benzodiazepines in aversive learning tasks. Because the alpha1 subunit of the gamma-aminobutyric acid (GABA)(A) receptor is critical for these amnestic actions, knowledge of the neuronal localization of this subunit in the ABL should contribute to an understanding of the candidate neuronal mechanisms involved. To examine this question, we used dual-labeling immunohistochemical techniques to study the localization of the alpha1 subunit in the ABL. Our results suggest that the alpha1 subunit of the GABA(A) receptor is localized primarily in GABAergic interneurons in the ABL at the somal level, although the intense neuropil staining in the lateral nucleus suggests that distal dendrites of pyramidal projection neurons in this nucleus may also contain high levels of the alpha1 subunit. The great majority of alpha1-immunoreactive interneurons also exhibit immunoreactivity for the beta2/3 subunits of the GABA(A) receptor. Parvalbumin-positive (PV+) interneurons are the main interneuronal subpopulation exhibiting alpha1 immunoreactivity, but some calretinin-positive interneurons also express this subunit. These data suggest that certain subpopulations of GABAergic interneurons in the ABL, especially PV+ cells, receive a robust GABAergic innervation. Because the most likely source of this innervation is intrinsic, these results suggest that PV+ interneurons could constitute an important component of interneuronal networks in the ABL. These networks may be critical for the generation of synchronized rhythmic oscillations involved in consolidation of emotional memories. The activation of alpha1-containing GABA(A) receptors in the ABL by benzodiazepines may disrupt rhythmic oscillations critical for memory consolidation.     

Amygdala Inhibitory Circuits Regulate Associative Fear Conditioning

Associative memory formation is essential for an animal’s survival by ensuring adaptive behavioral responses in an ever-changing environment. This is particularly important under conditions of immediate threats such as in fear learning. One of the key brain regions involved in associative fear learning is the amygdala. The basolateral amygdala is the main entry site for sensory information to the amygdala complex, and local plasticity in excitatory basolateral amygdala principal neurons is considered to be crucial for learning of conditioned fear responses. However, activity and plasticity of excitatory circuits are tightly controlled by local inhibitory interneurons in a spatially and temporally defined manner. In this review, we provide an updated view on how distinct interneuron subtypes in the basolateral amygdala contribute to the acquisition and extinction of conditioned fear memories.     

Subtypes of substance P receptor immunoreactive interneurons in the rat basolateral amygdala

Local injections of the neurotoxin SP-saporin into the basolateral amygdala (BLA) are reported to specifically lesion substance P receptor immunoreactive (SPR-IR) interneurons, and to reduce anxiety related behavior. Hence, this technique might provide a means to study how defined interneuron populations regulate neuronal activity in the BLA. However, what interneuron subgroups in the BLA might be targeted by SP-saporin lesions has not been established. This study has used dual-labeling immunofluorescence in the rat BLA to examine SPR-IR neurons for their colocalization with the calcium-binding proteins; calbindin-D28k (CB), parvalbumin (PV), and calretinin (CR); and the neuropeptides somatostatin (SOM) and neuropeptide Y (NPY). We found that all NPY-IR neurons and 45% of SOM-IR interneurons expressed SPR-IR, and that 50% and 51% of the SPR-IR interneuron population expressed NPY- and SOM-IR, respectively. Previous studies have reported that approximately a third of SOM-IR interneurons also express NPY, which suggests a large degree of overlap between the NPY, SOM and SPR expressing neurons in the BLA. We also found that the majority of SPR-IR cells were CB-IR (62%), but that these interneurons represented only 2.8% of the total CB-IR population. Moreover, SPR-IR interneurons did not express either PV-or CR- IR. Hence, SP-saporin lesions would ablate all interneurons in the BLA that contain NPY, but leave the majority of the CB-IR cells intact, and have no effect on the CR- and PV-IR populations. Consequently, these results support the use of SP-saporin lesions as a useful technique to study the role of NPY-IR interneurons in the BLA.     

Cell‐specific expression of neuropeptide Y Y1 receptor immunoreactivity in the rat basolateral amygdala

Activation of neuropeptide Y (NPY) Y1 receptors (Y1r) in the rat basolateral nuclear complex of the amygdala (BLA) produces anxiolysis and interferes with the generation of conditioned fear. NPY is important in regulating the output of the BLA, yet the cell types involved in mediating this response are currently unknown. The current studies employed multiple label immunocytochemistry to determine the distribution of Y1r‐immunoreactivity (‐ir) in glutamatergic pyramidal and GABAergic cell populations in the BLA using scanning laser confocal stereology. Pyramidal neurons were identified by expression of calcium‐calmodulin dependent kinase II (CaMKII‐ir) and functionally distinct interneuron subpopulations were distinguished by peptide (cholecystokinin, somatostatin) or calcium‐binding protein (parvalbumin, calretinin) content. Throughout the BLA, Y1r‐ir was predominately on soma with negligible fiber staining. The high degree of coexpression of Y1r‐ir (99.9%) in CaMKII‐ir cells suggests that these receptors colocalize on pyramidal cells and that NPY could influence BLA output by directly regulating the activity of these projection neurons. Additionally, Y1r‐ir was also colocalized with the interneuronal markers studied. Parvalbumin‐ir interneurons, which participate in feedforward inhibition of BLA pyramidal cells, represented the largest number of Y1r expressing interneurons in the BLA (≈4% of the total neuronal population). The anatomical localization of NPY receptors on different cell populations within the BLA provides a testable circuit whereby NPY could modulate the activity of the BLA via actions on both projection cells and interneuronal cell populations. J. Comp. Neurol. 517:166–176, 2009. © 2009 Wiley‐Liss, Inc.     

Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons

Stress‐sensitive psychopathologies such as post‐traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex‐to‐BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non‐conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress‐related disorders.     

Effects of context‐drug learning on synaptic connectivity in the basolateral nucleus of the amygdala in rats

Context‐drug learning produces structural and functional synaptic changes in the circuitry of the basolateral nucleus of the amygdala (BLA). However, how the synaptic changes translated to the neuronal targets was not established. Thus, in the present study, immunohistochemistry with a cell‐specific marker and the stereological quantification of synapses was used to determine if context‐drug learning increases the number of excitatory and inhibitory/modulatory synapses contacting the gamma‐aminobutyric acid (GABA) interneurons and/or the pyramidal neurons in the BLA circuitry. Amphetamine‐conditioned place preference increased the number of asymmetric (excitatory) synapses contacting the spines and dendrites of pyramidal neurons and the number of multisynaptic boutons contacting pyramidal neurons and GABA interneurons. Context‐drug learning increased asymmetric (excitatory) synapses onto dendrites of GABA interneurons and increased symmetric (inhibitory or modulatory) synapses onto dendrites but not perikarya of these same interneurons. The formation of context–drug associations alters the synaptic connectivity in the BLA circuitry, findings that have important implications for drug‐seeking behavior.     

Internuclear synapse in the amygdala is not facilitated in fear conditioning

The amygdala is essential for fear learning and memory. Synaptic transmission is enhanced in two pathways in the amygdala in fear conditioning. In this study we examined whether lateral (LA) to basolateral (BLA) amygdala synapses are potentiated and participate in intra-amygdala plasticity during the maintenance of fear memory. Our data showed that synaptic strength from the LA (ventrolateral) to the BLA (parvicellular) pathway was not increased after fear conditioning and suggests that this pathway does not integrate information relevant to the coding of memories in auditory fear learning.     

Evidence for a perisomatic innervation of parvalbumin-containing interneurons by individual pyramidal cells in the basolateral amygdala

The basolateral amygdala (ABL) contains pyramidal projection neurons (PNs) and several discrete subpopulations of nonpyramidal interneurons. Interneurons containing the calcium-binding protein parvalbumin (PV) constitute about half of all ABL interneurons, and provide a robust innervation of the perisomatic domain of PNs. Although it is known that PNs reciprocate this projection by innervating PV interneurons, little is known about the details of these connections. In the present study, we investigated the innervation of PV interneurons by individual PNs in rat amygdalar slices. PNs in the basolateral nucleus, identified in vitro by their distinctive electrophysiological characteristics in whole cell patch-clamp recordings, were filled with biocytin by diffusion from the patch electrode. PV interneurons and biocytin-labeled PNs were visualized with a two-color immunoperoxidase procedure using nickel-enhanced DAB (black) for biocytin and non-enhanced DAB (brown) for PV. In slices with well-stained PN axons and PV neurons, light microscopy revealed numerous synapse-like contacts between these structures. The main PV+ targets of PN axons were the somata and proximal dendrites of PV neurons, although there were also contacts with more distal PV dendrites. In many cases, the PN axons ran along PV somata and/or proximal dendrites, forming multiple contacts. However, the great majority the PN axon terminals did not contact PV neurons. These observations suggest that there are robust reciprocal perisomatic PN-to-PV connections that may be important for the precise timing of rhythmic activity in the basolateral amygdala.     

Pyramidal cells of the rat basolateral amygdala: synaptology and innervation by parvalbumin-immunoreactive interneurons

The generation of emotional responses by the basolateral amygdala is determined largely by the balance of excitatory and inhibitory inputs to its principal neurons, the pyramidal cells. The activity of these neurons is tightly controlled by gamma-aminobutyric acid (GABA)-ergic interneurons, especially a parvalbumin-positive (PV(+)) subpopulation that constitutes almost half of all interneurons in the basolateral amygdala. In the present semiquantitative investigation, we studied the incidence of synaptic inputs of PV(+) axon terminals onto pyramidal neurons in the rat basolateral nucleus (BLa). Pyramidal cells were identified by using calcium/calmodulin-dependent protein kinase II (CaMK) immunoreactivity as a marker. To appreciate the relative abundance of PV(+) inputs compared with excitatory inputs and other non-PV(+) inhibitory inputs, we also analyzed the proportions of asymmetrical (presumed excitatory) synapses and symmetrical (presumed inhibitory) synapses formed by unlabeled axon terminals targeting pyramidal neurons. The results indicate that the perisomatic region of pyramidal cells is innervated almost entirely by symmetrical synapses, whereas the density of asymmetrical synapses increases as one proceeds from thicker proximal dendritic shafts to thinner distal dendritic shafts. The great majority of synapses with dendritic spines are asymmetrical. PV(+) axon terminals form mainly symmetrical synapses. These PV(+) synapses constitute slightly more than half of the symmetrical synapses formed with each postsynaptic compartment of BLa pyramidal cells. These data indicate that the synaptology of basolateral amygdalar pyramidal cells is remarkably similar to that of cortical pyramidal cells and that PV(+) interneurons provide a robust inhibition of both the perisomatic and the distal dendritic domains of these principal neurons.     

Rac1 Signaling in Amygdala Astrocytes Regulates Fear Memory Acquisition and Retrieval

The importance of astrocytes in behavior control is increasingly appreciated, but little is known about the effects of their dynamic activity in regulating learning and memory. In the present study, we constructed AAVs of photoactivatable and photoinactivatable Ras-related C3 botulinum toxin substrate 1 (Rac1) under the mGFAP promoter, which enabled the manipulation of Rac1 activity in astrocytes by optical stimulation in free-moving mice. We found that both up-regulation and down-regulation of astrocytic Rac1 activity in the basolateral amygdala (BLA) attenuated memory acquisition in a fear conditioning mouse model. Meanwhile, neuronal activation in the BLA induced by memory acquisition was inhibited under both the up- and down-regulation of astrocytic Rac1 activity during training. In terms of the impact on fear memory retrieval, we found both up- and down-regulation of BLA astrocytic Rac1 activity impaired memory retrieval of fear conditioning and memory retrieval-induced neuronal activation. Notably, the effect of astrocytic Rac1 on memory retrieval was reversible. Our results demonstrate that the normal activity of astrocytic Rac1 is necessary for the activation of neurons and memory formation. Both activation and inactivation of astrocytic Rac1 activity in the BLA reduced the excitability of neurons, and thereby impaired fear memory acquisition and retrieval.     

Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala

Whereas the neuronal substrates underlying the acquisition of auditory fear conditioning have been widely studied, the substrates and mechanisms mediating the acquisition of fear extinction remain largely elusive. Previous reports indicate that consolidation of fear extinction depends on the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) signalling pathway and on protein synthesis in the medial prefrontal cortex (mPFC). Based on experiments using the fear-potentiated startle paradigm suggesting a role for neuronal plasticity in the basolateral amygdala (BLA) during fear extinction, we directly addressed whether MAPK/ERK signalling in the basolateral amygdala is necessary for the acquisition of fear extinction using conditioned freezing as a read-out. First, we investigated the regional and temporal pattern of MAPK/ERK activation in the BLA following extinction learning in C57Bl/6J mice. Our results indicate that acquisition of extinction is associated with an increase of phosphorylated MAPK/ERK in the BLA. Moreover, we found that inhibition of the MAPK/ERK signalling pathway by intrabasolateral amygdala infusion of the MEK inhibitor, U0126, completely blocks acquisition of extinction. Thus, our results indicate that the MAPK/ERK signalling pathway is required for extinction of auditory fear conditioning in the BLA, and support a role for neuronal plasticity in the BLA during the acquisition of fear extinction.     

Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons

Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information affects newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear-conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits.     

Role of amygdala oscillations in the consolidation of emotional memories.

Much evidence indicates that emotional arousal generally improves memory and that the amygdala is responsible for this effect. The available data suggest that stress hormones and neuromodulators released in emotionally arousing conditions alter the activity of basolateral amygdala (BLA) neurons in the hours after the learning episode. In turn, these changes would facilitate synaptic plasticity elsewhere in the brain; however, the biological mechanisms underlying the facilitation of memory consolidation by the BLA remain unknown. This article focuses on data suggesting that synchronized oscillatory BLA activity promotes synaptic plasticity by facilitating interactions between neocortical and temporal lobe areas involved in declarative memory.     

Basolateral amygdala,nicotinic cholinergic receptors,and nicotine: Pharmacological effects and addiction in animal models and humans

The amygdala is involved in processing incoming information about rewarding stimuli and emotions that denote danger such as anxiety and fear. Bi‐directional neural connections between basolateral amygdala (BLA) and brain regions such as nucleus accumbens, prefrontal cortex, hippocampus, and hindbrain regions regulate motivation, cognition, and responses to stress. Altered local regulation of BLA excitability is pivotal to the behavioral disturbances characteristic of posttraumatic stress disorder, and relapse to drug use induced by stress. Herein, we review the physiological regulation of BLA by cholinergic inputs, emphasizing the role of BLA nicotinic receptors. We review BLA‐dependent effects of nicotine on cognition, motivated behaviors, and emotional states, including memory, taking and seeking drugs, and anxiety and fear in humans and animal models. The alterations in BLA activity observed in animal studies inform human behavioral and brain imaging research by enabling a more exact understanding of altered BLA function. Converging evidence indicates that cholinergic signaling from basal forebrain projections to local nicotinic receptors is an important physiological regulator of BLA and that nicotine alters BLA function. In essence, BLA is necessary for behavioral responses to stimuli that evoke anxiety and fear; reinstatement of cue‐induced drug seeking; responding to second‐order cues conditioned to abused drugs; reacquisition of amplified nicotine self‐administration due to chronic stress during abstinence; and to promote responding for natural reward.