Sublenticular Extended Amygdala Research Articles

Dynamic longitudinal relations between regional brain metabolism and stress-related blood cortisol during the first year of nonhuman primate life

Hypothalamic-pituitary-adrenal(HPA)-activation is critical to the stress response, promoting adaptation and survival. To further understand the developmental time-course of stress-related HPA-activation and its neural correlates in nonhuman primates (NHP), we longitudinally studied infant rhesus monkeys from birth to 1-year. 35 monkeys (24 F/11 M) were assessed 5 times during development (T1-T5; average ages: 11,43,84,168,365 days). At each timepoint, subjects were injected with 18flurodeoxyglucose (FDG) and exposed to 30 minutes of potential threat (No-eye-contact condition of Human Intruder Paradigm, NEC). Subjects were anesthetized, had blood drawn, and underwent a PET scan. We performed timepoint-specific voxel-wise correlations of plasma cortisol levels and FDG-PET metabolism. Threat-induced cortisol levels displayed logarithmic growth across the first year of life (p<0.0002). Cortisol at T1 predicted cortisol levels at T2 and T3 (p<0.001), but not at T4 or T5 (p>0.1). Cortisol levels related to metabolism in different brain regions at each age (p<0.005, uncorrected). At younger ages, higher cortisol levels following NEC were associated with decreased brain metabolism (T1: amygdala; T2: amygdala, anterior hippocampus). At older ages, higher cortisol levels were associated with increased brain metabolism (T4: sublenticular extended amygdala, T5: bed nucleus of stria terminalis, thalamus). These findings demonstrate that the developmental pattern of HPA-activation in young NHPs may be logarithmic in nature. Our findings also indicate changes to the relationship between individual differences in stress-related HPA-activation and regional brain metabolism during this time. Interestingly, cortisol has negative correlations with limbic regions in newborns, later transitioning to adult-like positive correlations with limbic regions.

Somatostatin neurons in the central amygdala mediate anxiety by disinhibition of the central sublenticular extended amygdala.

Fear and anxiety are two defensive emotional states evoked by threats in the environment. Fear can be initiated by either imminent or future threats, but experimentally, it is typically studied as a phasic response initiated by imminent danger that subsides when the threats is removed. In contrast, anxiety is a sustained response, initiated by imagined or potential threats. The central amygdala (CeA) is a key structure active during both fear and anxiety but thought to engage different neural systems. Fear responses are triggered by activation of somatostatin (SOM) expressing neurons in the lateral division of the CeA (CeL), and downstream projections from the medial division. Anxiety responses engage the central extended amygdala that includes the CeA, central sublenticular extended amygdala (SLEAc) and bed nucleus of the stria terminalis, but the nature of connections between these regions is not understood. Here using a combination of tract tracing, electrophysiology, and behavioral analysis in mice, we show that a population of SOM+ neurons in the CeL project to the SLEAc where they inhibit local GABAergic interneurons. Optogenetic activation of this input to the SLEAc has no effect on movement, but is anxiogenic in both open field and elevated plus maze. Our results define the inhibitory connections between CeL and SLEAc and establish a specific CeL to SLEAc projection as a circuit element in mediating anxiety.

Stress-Related Neuronal Clusters in Sublenticular Extended Amygdala of Basal Forebrain Show Individual Differences of Positions.

To understand functional neuronal circuits for emotion in the basal forebrain, patterns of neuronal activation were examined in mice by immunohistochemistry of immediate-early gene products (Zif268/Egr1 and c-Fos). In all mice examined, clusters of 30–50 neurons expressing Zif268 were found on both sides in the area between the extended amygdala (EA) and globus pallidus (GP), generally designated as sublenticular extended amygdala (SLEA). The clusters consisted of 79.9 ± 3.0% of GABAergic neurons in GAD65-mCherry mice. The expression of the cholinergic marker choline acetyltransferase and the GP markers parvalbumin, proenkephalin, and FoxP2 indicated that these neurons were different from known types of neurons in the EA and GP; therefore, we named them the sublenticular extended amygdalar Zif268/Egr1-expressing neuronal cluster (SLEA-zNC). Sublenticular extended amygdalar Zif268/Egr1-expressing neuronal clusters participated in stress processing because increasing numbers of cells were observed in SLEA-zNCs after exposure to restraint stress (RS), the induction of which was suppressed by diazepam treatment. Mapping SLEA-zNCs showed that their positions and arrangement varied individually; SLEA-zNCs were distributed asymmetrically and tended to be situated mainly in the middle region between the anterior commissure (AC) and posterior end of the GP. However, the total cell number in SLEA-zNCs was compatible between the right and left hemispheres after activation by RS. Therefore, SLEA-zNCs were distributed asymmetrically but were not lateralized. Because time courses of activation differed between the Zif268 and c-Fos, the sequential dual treatment of RSs enabled us to differentiate SLEA-zNCs activated by the first and second RS. The results supported that the same SLEA-zNCs responded to both the first and second RS, and this also applied for all SLEA-zNCs. Thus, we concluded that the cluster positions were invariable under RS in each mouse but were distributed differently between individual mice. We name these newly identified neuronal clusters as stress-related neuronal clusters, SLEA-zNCs, which are considered to be novel functional units of “islands of activation.” Moreover, SLEA-zNCs were situated at different positions in all mice examined, showing individual differences in their positions.

Fos expression induced by olanzapine and risperidone in the central extended amygdala

The extended amygdala has been proposed to play an essential role in cognitive and affective processes and in neuropsychiatric disorders. In the present study, we examined the induction of Fos-like nuclei in the central amygdaloid nucleus (CeA), sublenticular extended amygdala (SLEA), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and bed nucleus of the stria terminalis (BSTL) of rodents to improve the knowledge regarding the pharmacological profile, therapeutic efficacy, and side-effects of olanzapine, an atypical antipsychotic drug and risperidone, a mixed atypical/typical antipsychotic drug in the rat brain. In addition, we evaluated the induction of Fos-like-nuclei in areas connected with these structures such as prefrontal cortex (PFCx), and nucleus accumbens shell, and in other important areas including the lateral septum and caudate-putamen that are involved in the therapeutic efficacy or side-effects of antipsychotic drugs. Fos-like-immunoreactivity induced by olanzapine and risperidone was compared with that by the atypical antipsychotic clozapine and typical antipsychotic haloperidol.Regarding the extended amygdala, and similarly to clozapine, olanzapine (5–10 mg/kg) and, with a lower efficacy, risperidone (1–3 mg/kg), induced Fos-like-nuclei in CeA, IPAC, SLEA, and BSTL. Both these drugs increased the induction of Fos-like-nuclei in PFCx, nucleus accumbens shell, lateral septum, and caudate-putamen. On the contrary, the increase of Fos-like-nuclei in the extended amygdala by haloperidol was restricted to IPAC only. These findings, consistent with the important role of extended amygdala in neuropsychiatric disorders characterized by affective disturbances, showed that olanzapine and risperidone, contrary to haloperidol, preferentially activated Fos-expression in these brain areas.

Somatostatin Gene and Protein Expression in the Non-human Primate Central Extended Amygdala

Alterations in central extended amygdala (EAc) function have been linked to anxiety, depression, and anxious temperament (AT), the early-life risk to develop these disorders. The EAc is composed of the central nucleus of the amygdala (Ce), the bed nucleus of the stria terminalis (BST), and the sublenticular extended amygdala (SLEA). Using a non-human primate model of AT and multimodal neuroimaging, the Ce and the BST were identified as key AT-related regions. Both areas are primarily comprised of GABAergic neurons and the lateral Ce (CeL) and lateral BST (BSTL) have among the highest expression of neuropeptides in the brain. Somatostatin (SST) is of particular interest because mouse studies demonstrate that SST neurons, along with corticotropin-releasing factor (CRF) neurons, contribute to a threat-relevant EAc microcircuit. Although the distribution of CeL and BSTL SST neurons has been explored in rodents, this system is not well described in non-human primates. In situ hybridization demonstrated an anterior–posterior gradient of SST mRNA in the CeL but not the BSTL of non-human primates. Triple-labeling immunofluorescence staining revealed that SST protein-expressing cell bodies are a small proportion of the total CeL and BSTL neurons and have considerable co-labeling with CRF. The SLEA exhibited strong SST mRNA and protein expression, suggesting a role for SST in mediating information transfer between the CeL and BSTL. These data provide the foundation for mechanistic non-human primate studies focused on understanding EAc function in neuropsychiatric disorders.

CaV1.3 channel blockade in the extended amygdala has a delayed effect on the reward efficacy of medial forebrain bundle stimulation

Previous work in our laboratory has shown that stimulating D2 dopamine receptors in the central sublenticular extended amygdala (SLEAc) can render medial forebrain bundle (MFB) stimulation less rewarding. One of the many ways in which D2 stimulation could affect the activity status of SLEAc neurons is by indirectly blocking calcium ion (Ca2+) influx through CaV1.3 channels. He we directly investigate the effects of blocking CaV1.3 channels on the rewarding effect of MFB stimulation. In experiment one, CaV1.3 blockade with the phenylalkylamine verapamil (2.5 and 5.0μg) or the benzothiazepine diltiazem (5.0 and 10.0μg) did not significantly decrease MFB stimulation’s reward efficacy relative to injections of saline. However, there were indications of an unanticipated 24-h-delayed effect of the higher dose of diltiazem – injected ipsilateral to the stimulation site – on the stimulation pulse frequency required to maintain half-maximal response rates (“required frequency”). Experiment two focused on and tracked the time course of this effect. Injections of 10μg of diltiazem decreased required frequency significantly more than did saline injections 24h after injection but not immediately after injection. Required frequency values returned to baseline levels within 48h after injection. This time course is consistent with cellular processes that regulate the insertion of GABA-A receptors in neural membranes. GABA-A-mediated neural communication is implicated in maintaining basal forebrain medium spiny neurons in an excitable state. Therefore, these results may indicate that sustaining SLEAc neurons in an excitable state may be important for MFB stimulation to retain its rewarding properties.

Arborization patterns of amygdalopetal axons from the rat ventral pallidum.

We previously analyzed the arborization patterns of rat ventral pallidal (VP) axons that coursed caudally to innervate the thalamus and brainstem (Tripathi et al. in Brain Struct Funct 218:1133-1157, 2013). Here, we have reconstructed 16 previously undetected axons from the same tracer deposits that follow a more lateral trajectory. Virtually all 16 axons emanating from the different VP compartments collateralized in the extended amygdala system (EAS) and amygdaloid complex. The most frequent targets of axons from the lateral and medial (VPm) VP compartments were the rostral sublenticular extended amygdala, the extended amygdala (EA), the central nucleus of the amygdala and the posterior part of the basolateral amygdaloid nucleus. In contrast, axons from the rostral extension of the VP preferentially innervated the anterior amygdaloid area, the magnocellular preoptic nucleus, and the anterior part of the basomedial amygdaloid nucleus. We additionally found and reconstructed a single corticopetal axon arising from the VPm. The new results show that both direct and indirect projections from the basolateral complex and EAS to the ventral striatopallidal system are reciprocated by VP projections, and suggest that the systems can be activated simultaneously. The results additionally suggest that the amygdaloid complex and cortex are innervated separately from the VP. Finally, the combination of new and previous data indicate that approximately 84% of VP axons (88/105) participate in basal ganglia circuits, 15% (16/105) target the amygdaloid complex, and less than 1% innervate the cortex.

Effect of direct eye contact in women with PTSD related to interpersonal trauma: Psychophysiological interaction analysis of connectivity of an innate alarm system

In healthy individuals, direct eye contact is thought to modulate a cortical route eliciting social cognitive processes via activation of a fast subcortical pathway. This study aimed to examine functional brain connectivity during direct eye contact in women with posttraumatic stress disorder (PTSD) related to childhood abuse as compared with healthy controls. We conducted psychophysiological interaction (PPI) analyses in Statistical Parametric Mapping-8 (SPM8) using the superior colliculus (SC) and locus coeruleus (LC) as seed regions while 16 healthy subjects and 16 patients with a primary diagnosis of PTSD related to childhood maltreatment viewed a functional magnetic resonance imaging (fMRI) paradigm involving direct (D) versus averted (A) gaze (happy, sad, neutral). The PTSD group showed a significantly enhanced connectivity between the SC and the anterior cingulate, and between the LC and the thalamus, caudate, putamen, insula, cingulate gyrus, and amygdala, as compared with healthy individuals. Symptom severity scores on the Clinician-Administered PTSD Scale (CAPS) showed significant positive correlations with superior colliculus connectivity with the perigenual and posterior cingulate, insula, and sublenticular extended amygdala. Functional connectivity data suggest increased recruitment of brain regions involved in emotion processing during direct gaze in PTSD in association with the fast subcortical pathway. The interpretation of eye contact as a signal of threat may require more emotion regulatory capacities in patients with PTSD.

SSRI-Related Modulation of Sexual Functioning is Predicted by Pre-treatment Resting State Functional Connectivity in Healthy Men

Sexual dysfunction related to treatment with selective serotonin reuptake inhibitors (SSRIs) is a common reason for discontinuation of otherwise effective antidepressant treatment regimens. Thus, identification of subjects at risk for this side effect remains a crucial challenge. After demonstrating task-related neural correlates of impaired sexual functioning under treatment with the SSRI paroxetine (Abler et al., 2011), we studied (1) if resting state brain function before treatment predicts subsequent development of treatment-related modulation of sexual function, and (2) which neural circuits relate to different aspects of the impairment. Effects of paroxetine and bupropion administration over 1week on subjective sexual functioning were investigated in 17 healthy male volunteers in a placebo-controlled, randomized cross-over design using the Massachusetts General Hospital Sexual Function Questionnaire. Data from a 10min eyes-closed resting state scan were used to analyze functional connectivity under placebo in previously identified brain regions, focussing on the sublenticular extended amygdala (SLEA), dopaminergic midbrain, and anterior cingulate cortex. Resting state functional connectivities of the pregenual anterior cingulate cortex (pgACC), midbrain, and insula to the SLEA sufficiently predicted the development of subjective SSRI-related decreased sexual functioning and distinguished vulnerable from resilient subjects. Furthermore, connectivity with the midbrain particularly predicted orgasm-related deficits, while connectivity with pgACC predicted sexual satisfaction. Linking SSRI-related subjective sexual functioning to pre-treatment resting state connectivities in cortico-subcortical network of sexual processing, we demonstrated the potential of novel, non-invasive and passive brain imaging techniques to guide therapeutic decisions and adjust treatment protocols in psychiatric disorders and sexual medicine.

A positron emission tomography study of wind-up pain in chronic postherniotomy pain

Many neuropathic pain conditions are characterized by abnormal responses to noxious or innocuous mechanical stimulation, including wind-up pain. Whereas previous brain imaging studies have explored the cerebral correlates of hyperalgesia and allodynia, no studies are available on mechanical-induced wind-up pain in neuropathic pain patients. We therefore used positron emission tomography (PET) to investigate the cerebral response pattern of mechanical wind-up pain in a homogenous group of 10 neuropathic pain patients with long-standing postherniotomy pain in the groin area. Patients were scanned in the following conditions: (1) rest; (2) wind-up pain, induced by 2 Hz von Frey stimulation in the painful area; (3) non-painful 2 Hz von Frey stimulation in the homologous contralateral area and (4) tonic pressure pain in the homologous contralateral area. A direct comparison between wind-up pain and non-painful von Frey stimulation revealed that the former more strongly activated contralateral secondary somatosensory cortex, insula, anterior cingulate cortex, right dorsolateral prefrontal cortex, thalamus and cerebellum. In addition, wind-up pain also activated the sublenticular extended amygdala (SLEA) and the brain stem. A direct comparison between wind-up pain and pressure pain revealed that both activated a largely overlapping network. Since no de novo brain areas were activated by wind-up pain, our data suggest that the processes specific to wind-up pain do not occur at the cerebral level.

Fear and stop: A role for the amygdala in motor inhibition by emotional signals

Rapid interruption of ongoing motor actions is crucial to respond to unexpected and potentially threatening situations. Yet, it remains unclear how motor inhibition interacts with emotional processes. Here we used a modified stop-signal task including an emotional component (fearful faces) to investigate whether neural circuits engaged by action suppression are modulated by task-irrelevant threat-related signals. Behavioral performance showed that reaction times were prolonged in the presence of incidental threat information, and this emotional slowing was enhanced when incorrect responses were made following stop signals. However, the speed and efficacy of voluntary inhibition was unaffected by emotion. Brain imaging data revealed that emotional cues during stop trials interacted with activity in limbic regions encompassing the basal amygdala and sublenticular extended amygdala region, as well as with the supplementary motor area (SMA). In addition, successful motor inhibition to threat signals selectively recruited a region in lateral orbitofrontal cortex, distinct from areas in inferior frontal gyrus typically associated with voluntary inhibition. Activity in primary motor cortex was lower when incorrect responses were made on stop signal trials accompanied by a fearful face, relative to neutral, in parallel with the slower response times observed behaviorally. Taken together, our findings suggest that the amygdala may not only promote protective motor reactions in emotionally-significant contexts (such as freezing or defensive behavior) but also influence the execution of ongoing actions by modulating brain circuits involved in motor control, so as to afford quick and adaptive changes in current behavior.

Habitual emotion regulation strategies and depressive symptoms in healthy subjects predict fMRI brain activation patterns related to major depression

The response-focused emotion regulation style ‘Expressive suppression’ has been associated with symptoms of lower psychological well-being and increased function magnetic resonance imaging (fMRI) activation of the sublenticular extended amygdala (SLEA) in patients with major depression. Extending prior studies on active emotion regulation, we were interested in effects of habitual emotion regulation on neurobiology. Thirty subjects with either relatively high or low suppression scores as assessed with the Emotion Regulation Questionnaire without symptoms of clinical depression participated in the study. They were instructed to expect and then perceive emotionally unpleasant, pleasant or neutral stimuli selected from the International Affective Picture System that were announced by a congruent cue during fMRI. In the subjects with high suppression scores, decreased activation of the orbital medial prefrontal cortex (oMFC) when expecting negative pictures and increased activation of the SLEA upon presentation of neutral stimuli were found. Subclinical depression ratings independently of suppression scores in the healthy subjects were positively correlated with brain activation in the SLEA when expecting negative pictures. SLEA hyperactivity may represent an emotional responsivity that involves less successful habitual emotion regulation and a tendency to depressed mood in healthy subjects, as shown in patients with major depression. Decreased anticipatory oMFC activation may parallel a lack of antecedent emotion regulation in subjects with high suppression scores, representing another neurobiological predictor of lower mental well-being.

Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. Patients with Wolfram syndrome display considerable clinical pleiomorphism, and symptoms such as neurological complications and psychiatric disorders are common. In the present study we have characterized Wfs1 expression pattern in the mouse central nervous system by using a combination of immunohistochemistry on wild-type mice and X-Gal staining of Wfs1 knockout mice with targeted insertion of the lacZ reporter. We identified a robust enrichment of Wfs1 protein in the central extended amygdala and ventral striatum. Prominent Wfs1 expression was seen in the hippocampal CA1 region, parasubiculum, superficial part of the second and third layers of the prefrontal cortex and proisocortical areas, hypothalamic magnocellular neurosecretory system, and central auditory pathway. Wfs1 expression was also detected in numerous brainstem nuclei and in laminae VIII and IX of the spinal cord. Wfs1-positive nerve fibers were found in the medial forebrain bundle, reticular part of the substantia nigra, globus pallidus, posterior caudate putamen, lateral lemniscus, alveus, fimbria, dorsal hippocampal commissure, subiculum, and to a lesser extent in the central sublenticular extended amygdala, compact part of substantia nigra, and ventral tegmental area. The neuroanatomical findings suggest that the lack of Wfs1 protein function can be related to several neurological and psychiatric symptoms found in Wolfram syndrome. Enrichment of Wfs1 protein in the central extended amygdala suggests a role in the modulation of anxiety and fear.

CART mRNA expression in rat monkey and human brain: Relevance to cocaine abuse

The neuropeptide CART (cocaine and amphetamine regulated transcript) is suggested to be regulated by psychostimulant administration. We review here the localization of CART mRNA expression in the human brain and its possible relevance to human cocaine abuse. Except for strong hypothalamic expression, the CART transcript is predominately expressed in target regions of the mesocorticolimbic dopamine system, such as the nucleus accumbens shell, amygdala complex, extended amygdala and orbitofrontal, enthorhinal and piriform cortices. The discrete limbic localization strongly implies involvement in reward and reinforcement behaviors. We therefore examined CART mRNA expression in both Sprague Dawley rats and Rhesus monkeys that had self-administered cocaine. Cocaine self-administration in the rat (1.5 mg/kg/inj, on a fixed ratio 1 schedule of reinforcement for 1 week) and monkey (0.03 or 0.3 mg/kg/inj on a fixed 3 min interval schedule of reinforcement for 5 or 100 days) did not alter transcript levels in CART expressing nucleus accumbens (monkey not studied), amygdala nuclei or cortical areas. However, in the monkey sublenticular extended amygdala, low dose cocaine self-administration resulted in increased CART transcript levels after both 5 and 100 days of self-administration, whereas no difference was found after high dose self-administration. In conclusion, we found no substantial alterations CART mRNA expression during cocaine self-administration, but this neuropeptide has the anatomical and functional potential to modulate brain areas relevant for cocaine abuse. Further studies are needed to evaluate the involvement of CART in other components of the cocaine abuse cycle.

Neuroimaging Studies of Emotional Responses in PTSD

Neuroimaging research offers a powerful and noninvasive means to understand healthy as well as dysregulated emotional processing in healthy subjects and PTSD patients. Functional neuroimaging findings suggest specific roles for subregions of the medial prefrontal (mPFC), orbito frontal (OFC), anterior cingulate (ACC), and insular cortices as well as the sublenticular extended amygdala (SLEA) and hippocampus in various components of emotional processing. Some of the same regions appear to be associated with emotional response to trauma, and with symptom formation in PTSD. Neuroimaging findings of emotional processing in healthy subjects and PTSD patients are discussed, addressing the specific roles of cortical regions like mPFC, ACC, and insula, and their potential contribution to PTSD pathophysiology. Processes of cognitive-emotional interactions and social emotions are discussed in an attempt to synthesize the prefrontal findings in healthy subjects and PTSD patients. Further links between functional neuroanatomy of emotional responses and neuroendocrine stress regulation are proposed.

Activation of the medial prefrontal cortex and extended amygdala by individual ratings of emotional arousal: a fMRI study

Background Significant differences between individual responses to emotional stimuli can be important for the study of emotion. We investigated whether incorporating individual ratings of emotional arousal in the analysis of functional magnetic resonance imaging (fMRI) data improves the detection of activation in the medial prefrontal cortex (MPFC) and sublenticular extended amygdala (SLEA), areas implicated in the processing of emotional salience. Methods Healthy subjects viewed counterbalanced blocks of aversive, nonaversive, and blank images. Outside the scanner, they rated the intensity of emotional arousal (salience) of each presented picture. Results Incorporating the subject’s response to each stimulus by using individualized regressors produced more robust activations within MPFC and SLEA compared with a simple boxcar regressor, identical for all subjects. Conclusions Our findings demonstrate that individual behavioral data are useful in improving detection of activation in block-design functional imaging studies.

Bed nucleus of the stria terminalis and extended amygdala inputs to dopamine subpopulations in primates.

The 'extended amygdala', a forebrain continuum implicated in complex motivational responses, is comprised of the bed nucleus of the stria terminalis and its sublenticular extension into the centromedial amygdala. Dopamine is also involved in motivated behavior, and is increased in several brain regions by emotionally relevant stimuli. To examine how the extended amygdala influences the dopamine cells, we determined the organization of inputs from subdivisions of the bed nucleus of the stria terminalis and sublenticular extended amygdala to the dopamine subpopulations in monkeys. Inputs from the bed nucleus of the stria terminalis and corresponding regions of the sublenticular extended amygdala are differentially organized. The medial bed nucleus of the stria terminalis and its medial sublenticular extension have a mediolateral organization with the densest inputs to the medial substantia nigra, pars compacta, and relatively few inputs to the central and lateral substantia nigra. In contrast, the lateral bed nucleus of the stria terminalis (and its continuation into the sublenticular extended amygdala) projects across the mediolateral extent of the substantia nigra. The subnuclei of the lateral bed nucleus of the stria terminalis also have differential projections to the dopamine cells. While the central core of the lateral bed nucleus of the stria terminalis has restricted inputs, the surrounding dorsolateral, capsular and juxtacapsular subdivisions project strongly to the dorsal tier dopamine neurons. The posterior subdivision of the lateral bed nucleus of the stria terminalis and its continuation into the central sublenticular extended amygdala project more broadly to both the dorsal tier and densocellular region of the ventral tier. From these results we suggest that specific subdivisions of the bed nucleus of the stria terminalis have differential influences on the dopamine subpopulations, influencing dopamine responses in diverse brain regions.

Functional imaging of neural responses to expectancy and experience of monetary gains and losses.

Neural responses accompanying anticipation and experience of monetary gains and losses were monitored by functional magnetic resonance imaging. Trials comprised an initial "prospect" (expectancy) phase, when a set of three monetary amounts was displayed, and a subsequent "outcome" phase, when one of these amounts was awarded. Hemodynamic responses in the sublenticular extended amygdala (SLEA) and orbital gyrus tracked the expected values of the prospects, and responses to the highest value set of outcomes increased monotonically with monetary value in the nucleus accumbens, SLEA, and hypothalamus. Responses to prospects and outcomes were generally, but not always, seen in the same regions. The overlap of the observed activations with those seen previously in response to tactile stimuli, gustatory stimuli, and euphoria-inducing drugs is consistent with a contribution of common circuitry to the processing of diverse rewards.

Differential Induction of Fos-Like-Immunoreactivity in the Extended Amygdala after Haloperidol and Clozapine

The extended amygdala is composed of the central and medial amygdaloid nucleus which through the sublenticular extended amygdala (SLEA) and the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) merge into the bed nucleus of stria terminals (BST). Based on anatomical connections with limbic areas, the extended amygdala has been proposed to play an important role in cognitive and affective processes. This study examines the effect of the atypical antipsychotic clozapine and the classical antipsychotic haloperidol on Fos-like-immunoreactivity (FLI) induction in areas belonging to the extended amygdala. Acute administration of clozapine (10–20 mg/kg) induced FLI in the central amygdaloid nucleus, IPAC, SLEA, and BST lateral division and, as previously described, in areas connected to the extended amygdala, such as the prefrontal cortex and nucleus accumbens shell. In contrast, acute administration of haloperidol (0.1–1 mg/kg) failed to induce FLI in the BST lateral division and SLEA but increased FLI in the IPAC. A small increase in FLI was observed in the central amygdaloid nucleus after 0.1 but not after 1 mg/kg of haloperidol. The present results, showing a preferential influence of clozapine, as compared to haloperidol, in the extended amygdala propose a new brain structure involved in the pharmacological effects of atypical antipsychotics.

Functional magnetic resonance imaging of brain reward circuitry in the human.

To produce behavior, motivational states necessitate at least three fundamental operations, including (1) selection of objectives focused on goal-objects, (2) compilation of goal-object information, and (3) determination of physical plans for securing goal-objects. The second of these general operations has been theorized to involve three subprocesses: (a) feature detection and other perceptual processing of putative goal-object "rewards," (b) valuation of goal-object worth in the context of potential hedonic deficit states, and (c) extraction of incidence and temporal data regarding the goal-object. A number of subcortical brain regions appear to be involved in these three informational subprocesses, in particular, the amygdala, sublenticular extended amygdala (SLEA) of the basal forebrain, and nucleus accumbens/subcallosal cortex (NAc/SCC). Components of the amygdala, SLEA, and NAc/SCC together constitute the larger anatomic structure of the extended amygdala. Functional magnetic resonance imaging (fMRI) studies of humans have recently begun to localize these subcortical regions within the extended amygdala during specific experimental conditions. In this manuscript, two human cocaine- infusion studies and one cognitive psychology experiment are reviewed in relation to their pattern of fMRI activation within regions of the extended amygdala. Activation in the NAc/SCC, in particular, is evaluated in relation to a hypothesis that one function of the NAc/SCC and associated brain regions is the evaluation of goal-object incidence data for the computation of conditional probabilities regarding goal-object availability. Further work is warranted to test hypothesized functions for all regions within the extended amygdala and integrate them toward an understanding of motivated behavior.