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The central extended amygdala (CEA) and ventral pallidum (VP) are involved in diverse motivated behaviors based on rodent models. These structures are conserved, but expanded, in higher primates, including human. Corticotropin releasing factor (CRF), a canonical “stress molecule” associated with the CEA and VP circuitry across species, is dynamically regulated by stress and drugs of abuse and misuse. CRF's effects on circuits critically depend on its colocation with primary “fast” transmitters, making this crucial for understanding circuit effects. We surveyed the distribution and colocalization of CRF-, VGluT2- (vesicular glutamate transporter 2), and VGAT- (vesicular GABA transporter) mRNA in specific subregions of the CEA and VP in young male monkeys. Although CRF-containing neurons were clustered in the lateral central bed nucleus (BSTLcn), the majority were broadly dispersed throughout other CEA subregions, and the VP. CRF/VGAT-only neurons were highest in the BSTLcn, lateral central amygdala nucleus (CeLcn), and medial central amygdala nucleus (CeM) (74%, 73%, and 85%, respectively). In contrast, lower percentages of CRF/VGAT only neurons populated the sublenticular extended amygdala (SLEAc), ventrolateral bed nucleus (BSTLP), and VP (53%, 54%, 17%, respectively), which had higher complements of CRF/VGAT/VGluT2-labeled neurons (33%, 29%, 67%, respectively). Thus, the majority of CRF-neurons at the “poles” (BSTLcn and CeLcn/CeM) of the CEA are inhibitory, while the “extended” BSTLP and SLEAc subregions, and neighboring VP, have a more complex profile with admixtures of “multiplexed” excitatory CRF neurons. CRF's colocalization with its various fast transmitters is likely circuit-specific, and relevant for understanding CRF actions on specific target sites.SIGNIFICANCE STATEMENTThe central extended amygdala (CEA) and ventral pallidum (VP) regulate multiple motivated behaviors through differential downstream projections. The stress neuropeptide corticotropin releasing factor (CRF) is enriched in the CEA, and is thought to “set the gain” through modulatory effects on coexpressed primary transmitters. Using protein and transcript assays in monkey, we found that CRF neurons are broadly and diffusely distributed in CEA and VP. CRF mRNA+neurons colocalize with VGAT (GABA) and VGluT2 (glutamate) mRNAs in different proportions depending on subregion. CRF mRNA was also coexpressed in a subpopulation of VGAT/VGluT2 mRNA (“multiplexed”) cells, which were most prominent in the VP and “pallidal”-like parts of the CEA. Heterogeneous CRF and fast transmitter coexpression across CEA/VP subregions implies circuit-specific effects.

In human and nonhuman primates, the amygdala paralaminar nucleus (PL) contains immature neurons. To explore the PL’s potential for cellular growth during development, we compared PL cells in 1) infant and adolescent macaques (control, maternally-reared), and in 2) infant macaques that experienced separation from their mother in the first month of life. In maternally-reared animals, the adolescent PL had fewer immature neurons, more mature neurons, and larger immature soma volumes compared to infant PL. There were also fewer total neurons (immature plus mature) in adolescent versus infant PL, suggesting that some neurons move out of the PL by adolescence. Maternal separation did not change mean immature or mature neuron counts in infant PL. However, across all infant animals, immature neuron soma volume was strongly correlated with mature neuron counts.tbr-1mRNA, a transcript required for glutamatergic neuron maturation, is significantly reduced in the maternally-separated infant PL (DeCampo et al, 2017), and was also positively correlated with mature neuron counts in infant PL. We conclude that immature neurons gradually mature by adolescence, and that the stress of maternal separation may shift this trajectory, as revealed by correlations between tbr1mRNA and mature neuron numbers across animals.

Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system. This system is comprised of DA and non-DA cells and is divided into specific subregions. Although CRF inputs to the midline A10 nuclei of the DA system are well studied in rodents, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregion. In primates, the central extended amygdala, a rich source of CRF afferents across species, preferentially targets the PBP and A8 fields. We thus sought to characterize CRF terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions at the ultrastructural level using immuno-reactive electron microscopy (EM) for TH and CRF in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted non-DA dendrites in both subregions. Most CRF-positive terminals had inhibitory (symmetric) profiles. In the A8, CRF symmetric (inhibitory) contacts onto non-DA neurons were significantly greater than asymmetric (excitatory) profiles; this pattern was also seen in the PBP, but did not reach statistical significance. No sex differences were found. Hormonal assays suggested that our animals were at similar developmental stages and experienced similar stress levels. Together our findings suggest that at baseline, CRF terminals in the primate PBP and A8 largely regulate DA indirectly through non-DA neurons.

OBJECTIVE:Anorexia nervosa has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom, extreme dietary restriction, remains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with anorexia nervosa avoid food despite emaciation. This study's aim was to examine potential neural insensitivity to these effects of hunger in anorexia nervosa. METHODS:At two scanning sessions scheduled 24 hours apart, one after a 16-hour fast and one after a standardized meal, 26 women who were in remission from anorexia nervosa (to avoid the confounding effects of malnutrition) and 22 matched control women received tastes of sucrose solution or ionic water while functional MRI data were acquired. Within a network of interest responsible for food valuation and transforming taste signals into motivation to eat, the authors compared groups across conditions on blood-oxygen-level-dependent (BOLD) signal and task-based functional connectivity. RESULTS:Participants in the two groups had similar BOLD responses to sucrose and water tastants. A group-by-condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in the control group and the remitted anorexia nervosa group, with an increase and a decrease, respectively, in BOLD response when hungry. Hunger had a similar opposite effect on insula-to-ventral caudal putamen functional connectivity in the remitted anorexia nervosa group compared with the control group. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher scores on harm avoidance among participants in the remitted anorexia nervosa group. CONCLUSIONS:Reduced recruitment of neural circuitry that translates taste stimulation to motivated eating behavior when hungry may facilitate food avoidance and prolonged periods of extremely restricted food intake in anorexia nervosa.

The ventral midbrain is the primary source of dopamine- (DA) expressing neurons in most species. GABA-ergic and glutamatergic cell populations are intermixed among DA-expressing cells and purported to regulate both local and long-range dopamine neuron activity. Most work has been conducted in rodent models, however due to evolutionary expansion of the ventral midbrain in primates, the increased size and complexity of DA subpopulations warrants further investigation. Here, we quantified the number of DA neurons, and their GABA-ergic complement in classic DA cell groups A10 (midline ventral tegmental area nuclei [VTA] and parabrachial pigmented nucleus [PBP]), A9 (substantia nigra, pars compacta [SNc]) and A8 (retrorubral field [RRF]) in the macaque. Because the PBP is a disproportionately expanded feature of the A10 group, and has unique connectional features in monkeys, we analyzed A10 data by dividing it into ‘classic’ midline nuclei and the PBP. Unbiased stereology revealed total putative DA neuron counts to be 210,238 +/− 17,127 (A10 = 110,319 +/− 9,649, A9= 87,399 +/−7,751 and A8=12,520 +/− 827). Putative GABAergic neurons were fewer overall, and evenly dispersed across the DA subpopulations (GAD67= 71,215 +/− 5,663; A10=16,836 +/− 2,743; A9=24,855 +/− 3,144 and A8=12,633 +/− 3,557). Calculating the GAD67/TH ratio for each subregion revealed differential balances of these two cell types across the DA subregions. The A8 subregion had the highest complement of GAD67-positive neurons compared to TH-positive neurons (1:1), suggesting a potentially high capacity for GABAergic inhibition of DA output in this region.HIGHLIGHTSThe A10 subregion expands laterally and caudally in nonhuman primatesThe A10, A9, and A8 comprise 52%, 42% and 6% of DA neurons, respectivelyGABAergic neurons are more evenly dispersed across subregionsThe A8 subpopulation has the highest ratio of GABA: DA neurons

Rodent fear-learning models posit that amygdala–infralimbic connections facilitate extinction while amygdala–prelimbic prefrontal connections mediate fear expression. Analogous amygdala–prefrontal circuitry between rodents and primates is not established. Using paired small volumes of neural tracers injected into the perigenual anterior cingulate cortex (pgACC; areas 24b and 32; a potential homologue to rodent prelimbic cortex) and subgenual anterior cingulate cortex (sgACC, areas 25 and 14c; a potential homologue to rodent infralimbic cortex) in a single hemisphere, we mapped amygdala projections to the pgACC and sgACC within single subjects. All injections resulted in dense retrograde labeling specifically within the intermediate division of the basal nucleus (Bi) and the magnocellular division of the accessory basal nucleus (ABmc). Areal analysis revealed a bias for connectivity with the sgACC, with the ABmc showing a greater bias than the Bi. Double fluorescence analysis revealed that sgACC and pgACC projections were intermingled within the Bi and ABmc, where a proportion were double labeled. We conclude that amygdala inputs to the ACC largely originate from the Bi and ABmc, preferentially connect to the sgACC, and that a subset collaterally project to both sgACC and pgACC. These findings advance our understanding of fear extinction and fear expression circuitry across species.

The subgenual (sgACC) and pregenual (pgACC) anterior cingulate are important afferents of the amygdala, with different cytoarchitecture, connectivity, and function. The sgACC is associated with arousal mechanisms linked to salient cues, while the pgACC is engaged in conflict decision-making, including in social contexts. After placing same-size, small volume tracer injections into sgACC and pgACC of the same hemisphere in male Macaques, we examined anterogradely labeled fiber distribution to understand how these different functional systems communicate in the main amygdala nuclei at both mesocopic and cellular levels. The sgACC has broad-based termination patterns. In contrast, the pgACC has a more restricted pattern which was always nested in sgACC terminals. Terminal overlap occurred in subregions of the accessory basal and basal nuclei, which we termed ‘hotspots’. In triple-labeling confocal studies, the majority of randomly selected CAMKIIα (+) cells (putative amygdala glutamatergic neurons) in ‘hotspots’ received dual contacts from the sgACC and pgACC. The ratio of dual contacts occurred over a surprisingly narrow range, suggesting a consistent, tight balance of afferent contacts on postsynaptic neurons. Large boutons, which are associated with greater synaptic strength, were approximately 3 times more frequent on sgACC versus pgACC axon terminals in ‘hotspots’, consistent with a fast ‘driver’ function. Together, the results reveal a nested interaction in which pgACC (’conflict/social monitoring’) terminals converge with the broader sgACC (’salience’) terminals at both the mesoscopic and cellular level. The pre-synaptic organization in ‘hotspots’ suggest that shifts in arousal states can rapidly, and flexibly influence decision-making functions in the amygdala.Significance statementThe subgenual (sgACC) and perigenual cingulate (pgACC) have distinct structural and functional characteristics and are important afferent modulators of the amygdala. The sgACC is critical for arousal, while the pgACC mediates conflict-monitoring, including in social contexts. Using dual tracer injections in the same monkey, we found that sgACC inputs broadly project in the main amygdala nuclei, whereas pgACC inputs were more restricted and nested in zones containing sgACC terminals (‘hotspots’). The majority of CAMKIIα + (excitatory) amygdala neurons in ‘hotspots’ received converging contacts, which were tightly balanced. pgACC and sgACC afferent streams are therefore highly interdependent in these specific amygdala subregions, permitting ‘internal arousal’ states to rapidly shape responses of amygdala neurons involved in conflict and social monitoring networks.

The prefrontal cortex (PFC) and insula, amygdala, and striatum form interconnected networks that drive motivated behaviors. We previously found a connectional trend in which granularity of the ventromedial and orbital PFC/insula predicted connections to the amygdala, and also the breadth of amygdalo-striatal efferents, including projections beyond the ’classic’ ventral striatum. To further interrogate connectional relationships among the cortex, amygdala, and striatum, and to further define the ’limbic (amygdala-recipient) striatum’, we conducted tract tracing studies in two cohorts of Macaques (Male n = 14, Female n = 1). We focused on the cortico-amygdalo-striatal (indirect) and cortico-‘limbic’ striatal (direct) paths originating in the entire PFC and insula. Larger data sets and a quantitative approach revealed ’cortical rules’ in which cortical granularity predicts the complexity and location of projections to both the basal nucleus of the amygdala and striatum. Remarkably, projections from ’cortical-like’ basal nucleus to the striatum followed similar patterns. In both ’direct’ and ’indirect’ paths to the ’limbic’ striatum, agranular cortices formed a ’foundational’, broad projection, and were joined by inputs from progressively more differentiated cortices. In amygdalo-striatal paths, the ventral basal nucleus was the ‘foundational’ input, with progressively more dorsal basal nucleus regions gradually adding inputs as the ’limbic striatum’ extended caudally. Together, the ‘indirect’ and ‘direct’ paths followed consistent principles in which cortical granularity dictated the strength and complexity of projections at their targets. Cluster analyses independently confirmed these connectional trends, and also highlighted connectional features that predicted termination in specific subregions of the basal nucleus and ’limbic’ striatum.Significance StatementThe ’limbic system’ broadly refers to brain circuits that coordinate emotional responses. Here, we investigate circuits of the amygdala, which are involved in coding the emotional value of external cues, and their influence on the striatum. Regions of prefrontal cortex and insula form gradients of overlapping inputs to the amygdala’s basal nucleus, which feed forward to the striatum. Direct cortical inputs to these ’amygdala-recipient’ striatal areas are surprisingly organized according to similar principles, but subtly shift from the classic ventral striatum to the caudal ventral striatum. Together, these distinct subsystems—cortico-amygdala-striatal circuits and direct cortico-striatal circuits— provide substantial opportunity for different levels of internal, sensory, and external experiences to be integrated within the striatum, a major motor-behavioral interface.

BackgroundChildren exhibiting extreme anxious temperament (AT) are at an increased risk for developing anxiety and depression. Our previous mechanistic and neuroimaging work in young rhesus monkeys linked the central nucleus of the amygdala to AT and its underlying neural circuit.MethodsHere, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT's molecular underpinnings by focusing on neurons from the lateral division of the central nucleus of the amygdala (CeL). RNA sequencing identified numerous AT-related CeL transcripts, and we used immunofluorescence (n= 3) and tract-tracing (n= 2) methods in a different sample of monkeys to examine the expression, distribution, and projection pattern of neurons expressing one of these transcripts.ResultsWe found 555 AT-related transcripts, 14 of which were confirmed with high statistical confidence (false discovery rate < .10), including protein kinase C delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared its distribution with that of the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis.ConclusionsThese findings demonstrate that CeL PKCδ is associated with primate anxiety, provides evidence of a CeL to laterodorsal bed nucleus of the stria terminalis circuit that may be relevant to understanding human anxiety, and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders.

Corticotropin-releasing factor (CRF) is a neuropeptide that mediates the stress response. Long known to contribute to regulation of the adrenal stress response initiated in the hypothalamic-pituitary axis (HPA), a complex pattern of extrahypothalamic CRF expression is also described in rodents and primates. Cross-talk between the CRF and midbrain dopamine (DA) systems links the stress response to DA regulation. Classically CRF + cells in the extended amygdala and paraventricular nucleus (PVN) are considered the main source of this input, principally targeting the ventral tegmental area (VTA). However, the anatomic complexity of both the DA and CRF system has been increasingly elaborated in the last decade. The DA neurons are now recognized as having diverse molecular, connectional and physiologic properties, predicted by their anatomic location. At the same time, the broad distribution of CRF cells in the brain has been increasingly delineated using different species and techniques. Here, we review updated information on both CRF localization and newer conceptualizations of the DA system to reconsider the CRF-DA interface.

The interactions of anterior temporal structures, and especially the amygdala, with the prefrontal cortex are pivotal to learning, decision-making, and socio-emotional regulation. A clear anatomical description of the organization and dissociation of fiber bundles linking anterior temporal cortex/amygdala and prefrontal cortex in humans is still lacking. Using diffusion imaging techniques, we reconstructed fiber bundles between these anatomical regions in human and macaque brains. First, by studying macaques, we assessed which aspects of connectivity known from tracer studies could be identified with diffusion imaging. Second, by comparing diffusion imaging results in humans and macaques, we estimated the patterns of fibers coursing between human amygdala and prefrontal cortex and compared them with those in the monkey. In posterior prefrontal cortex, we observed a prominent and well-preserved bifurcation of bundles into primarily two fiber systems—an amygdalofugal path and an uncinate path—in both species. This dissociation fades away in more rostral prefrontal regions.

The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

Early parental loss is associated with social-emotional dysregulation and amygdala physiologic changes. Previously, we examined whole amygdala gene expression in infant monkeys exposed to early maternal deprivation. Here, we focus on an amygdala region with immature neurons at birth: the paralaminar nucleus (PL). We hypothesized that 1) the normal infant PL is enriched in a subset of neural maturation (NM) genes compared to a nearby amygdala subregion; and 2) maternal deprivation would downregulate expression of NM transcripts (mRNA). mRNAs for bcl2, doublecortin, neuroD1, and tbr1-genes expressed in post-mitotic neurons-were enriched in the normal PL. Maternal deprivation at either 1 week or 1 month of age resulted in PL-specific downregulation of tbr1-a transcription factor necessary for directing neuroblasts to a glutamatergic phenotype. tbr1 expression also correlated with typical social behaviors. We conclude that maternal deprivation influences glutamatergic neuronal development in the PL, possibly influencing circuits mediating social learning.

Background Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT's neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region. Methods Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions. Results Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity. Conclusions This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT's neural circuitry.

The lateral division of the bed nucleus of the stria terminalis (BSTL) and central nucleus of the amygdala (Ce) form the two poles of the 'central extended amygdala', a theorized subcortical macrostructure important in threat-related processing. Our previous work in nonhuman primates, and humans, demonstrating strong resting fMRI connectivity between the Ce and BSTL regions, provides evidence for the integrated activity of these structures. To further understand the anatomical substrates that underlie this coordinated function, and to investigate the integrity of the central extended amygdala early in life, we examined the intrinsic connectivity between the Ce and BSTL in non-human primates using ex vivo neuronal tract tracing, and in vivo diffusion-weighted imaging and resting fMRI techniques. The tracing studies revealed that BSTL receives strong input from Ce; however, the reciprocal pathway is less robust, implying that the primate Ce is a major modulator of BSTL function. The sublenticular extended amygdala (SLEAc) is strongly and reciprocally connected to both Ce and BSTL, potentially allowing the SLEAc to modulate information flow between the two structures. Longitudinal early-life structural imaging in a separate cohort of monkeys revealed that extended amygdala white matter pathways are in place as early as 3weeks of age. Interestingly, resting functional connectivity between Ce and BSTL regions increases in coherence from 3 to 7weeks of age. Taken together, these findings demonstrate a time period during which information flow between Ce and BSTL undergoes postnatal developmental changes likely via direct Ce→BSTL and/or Ce↔SLEAc↔BSTL projections.

Recent studies show that higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa (AN) and overeating in bulimia nervosa (BN). The purpose of this study was to determine whether sensitization effects might underlie pathologic eating behavior when a taste stimulus is administered repeatedly. Recovered AN (RAN, n=14) and BN (RBN, n=15) subjects were studied in order to avoid the confounding effects of altered nutritional state. Functional magnetic resonance imaging (fMRI) measured higher-order brain response to repeated tastes of sucrose (caloric) and sucralose (non-caloric). To test sensitization, the neuronal response to the first and second administration was compared. RAN patients demonstrated a decreased sensitization to sucrose in contrast to RBN patients who displayed the opposite pattern, increased sensitization to sucrose. However, the latter was not as pronounced as in healthy control women (n=13). While both eating disorder subgroups showed increased sensitization to sucralose, the healthy controls revealed decreased sensitization. These findings could reflect on a neuronal level the high caloric intake of RBN during binges and the low energy intake for RAN. RAN seem to distinguish between high energy and low energy sweet stimuli while RBN do not.

The amygdala is a heterogeneous group of nuclei that plays a role in emotional and social learning. As such, there has been increased interest in its development in adolescent animals, a period in which emotional/social learning increases dramatically. While many mechanisms of amygdala development have been studied, the role of cell proliferation during adolescence has received less attention. Using bromodeoxyuridine (BrdU) injections in adolescent and adult rats, we previously found an almost fivefold increase in BrdU-positive cells in the amygdala of adolescents compared to adults. Approximately one third of BrdU-labeled cells in the amygdala contained the putative neural marker doublecortin (DCX), suggesting a potential for neurogenesis. To further investigate this possibility in adolescents, we examined the proliferative dynamics of DCX/BrdU-labeled cells. Surprisingly, DCX/BrdU-positive cells were found to comprise a stable subpopulation of BrdU-containing cells across survivals up to 56 days, and there was no evidence of neural maturation by 28 days after BrdU injection. Additionally, we found that approximately 50% of BrdU+ cells within the adolescent amygdala contain neural-glial antigen (NG2) and are therefore presumptive oligodendrocyte precursors (OPCs). We next characterized the response to a short-lived stressor (3-day repeated variable stress, RVS). The total BrdU-labeled cell number decreased by ∼30% by 13 days following RVS (10 days post-BrdU injection) as assessed by stereologic counting methods, but the DCX/BrdU-labeled subpopulation was relatively resistant to RVS effects. In contrast, NG2/BrdU-labeled cells were strongly influenced by RVS. We conclude that typical neurogenesis is not a feature of the adolescent amygdala. These findings point to several possibilities, including the possibility that DCX/BrdU cells are late-developing neural precursors, or a unique subtype of NG2 cell that is relatively resistant to stress. In contrast, many proliferating OPCs are significantly impacted by a short-lived stressor, suggesting consequences for myelination in the developing amygdala.

The bed nucleus of the stria terminalis (BNST), a portion of the "extended amygdala," is implicated in the pathophysiology of anxiety and addiction disorders. Its small size and connection to other small regions prevents standard imaging techniques from easily capturing it and its connectivity with confidence. Seed-based resting state functional connectivity is an established method for mapping functional connections across the brain from a region of interest. We, therefore, mapped the BNST resting state network with high spatial resolution using 7 Tesla fMRI, demonstrating the in vivo reproduction of many human BNST connections previously described only in animal research. We identify strong BNST functional connectivity in amygdala, hippocampus and thalamic subregions, caudate, periaqueductal gray, hypothalamus, and cortical areas such as the medial PFC and precuneus. This work, which demonstrates the power of ultra-high field for mapping functional connections in the human, is an important step toward elucidating cortical and subcortical regions and subregions of the BNST network.

Individuals with bulimia nervosa (BN) engage in episodes of binge eating, marked by loss of control and eating despite fullness. Does altered reward and metabolic state contribute to BN pathophysiology? Normally, hunger increases (and satiety decreases) reward salience to regulate eating. We investigated whether BN is associated with an abnormal response in a neural circuit involved in translating taste signals into motivated behavior, when hungry and fed. Twenty-six women remitted from BN (RBN) and 22 control women (CW) were administered water and sucrose during 2 counterbalanced fMRI visits, following a 16-hr fast or a standardized breakfast. Significant Group × Condition interactions were found in the left putamen, insula, and amygdala. Post hoc analyses revealed CW were significantly more responsive to taste stimuli when hungry versus fed in the left putamen and amygdala. In contrast, RBN response did not differ between conditions. Further, RBN had greater activation in the left amygdala compared with CW when fed. Findings suggest that RBN neural response to rewarding stimuli may not be modulated by metabolic state. Data raise the possibility that disinhibited eating in BN could result from a failure to devalue food reward when fed, resulting in an exaggerated response. (PsycINFO Database Record

The public develops interpretations of physical and mental disabilities through a variety of resources, most notably representations presented by the news media. While disability scholars have long lamented negative portrayals of disabilities in the mass media (e.g., movies, fictional television programs, songs) as dehumanizing and devaluing, studies of news media depictions have been scant. The present study focuses on a salient mental disability—autism—to advance current scholarship about representations of disabilities in the news. Stigmatizing cues and framing techniques from news coverage of autism over a period of approximately 15 years suggest that journalists may be creating a threatening space for autism, particularly through the perpetuation of stigmatic cues in more than two-thirds of news coverage of autism, coupled with the selection of certain news frames. Implications for media and disabilities practice and scholarship are discussed.

Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences.

The lateral bed nucleus of the stria terminalis (BSTL) is involved in mediating anxiety-related behaviors to sustained aversive stimuli. The BSTL forms part of the central extended amygdala, a continuum composed of the BSTL, the amygdala central nucleus, and cell columns running between the two. The central subdivision (BSTLcn) and the juxtacapsular subdivision (BSTLJ) are two BSTL regions that lie above the anterior commissure, near the ventral striatum. The amygdala, a heterogeneous structure that encodes emotional salience, projects to both the BSTL and ventral striatum. We placed small injections of retrograde tracers into the BSTL, focusing on the BSTLcn and BSTLJ, and analyzed the distribution of labeled cells in amygdala subregions. We compared this to the pattern of labeled cells following injections into the ventral striatum. All retrograde results were confirmed by anterograde studies. We found that the BSTLcn receives stronger amygdala inputs relative to the BSTLJ. Furthermore, the BSTLcn is defined by inputs from the corticoamygdaloid transition area and central nucleus, while the BSTLJ receives inputs mainly from the magnocellular accessory basal and basal nucleus. In the ventral striatum, the dorsomedial shell receives inputs that are similar, but not identical, to inputs to the BSTLcn. In contrast, amygdala projections to the ventral shell/core are similar to projections to the BSTLJ. These findings indicate that the BSTLcn and BSTLJ receive distinct amygdala afferent inputs and that the dorsomedial shell is a transition zone with the BSTLcn, while the ventral shell/core are transition zones with the BSTLJ.

Adolescence is characterized by changes in both behavior and neural organization. During this period, the amygdala, a structure that mediates social and emotional behaviors, is changing in terms of neural and glia density. We examined cell proliferation within the amygdala of adolescent (post natal day (PND) 31) and adult (PND 70) male Sprague-Dawley rats using BrdU (bromodeoxyuridine) to label dividing cells. BrdU-labeled cells were distributed throughout the amygdala, often found in fibers surrounding major nuclei. Using two independent cell counting strategies under light and confocal microcopy, respectively, we found significantly more labeled cells in the amygdala in adolescent compared to adult animals (239.3 ± 87.18 vs. 44.75 ± 13.68; n=4/group; p

Gray matter reduction mainly in the anterior cingulate cortex, the basal ganglia, and the cerebellum has been reported in attention-deficit/hyperactivity disorder (ADHD). Yet, respective data remain contradictory and inconclusive. To clarify if structural alteration in these brain areas can be verified in a large cohort of adult patients and if a history of stimulant medication has an effect on brain structure, magnetic resonance imaging was performed in the context of a clinical trial on the efficacy of group psychotherapy, clinical management, methylphenidate, and placebo (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study Trial).Between January 2007 and August 2010, 1480 patients from seven study centers across Germany, aged 18 to 58, were prescreened; 518 were assessed for eligibility; 433 were randomized; and 187 were eligible for neuroimaging. The control group included 121 healthy volunteers. Structural magnetic resonance imaging data sets were acquired. Following strict quality control, 131 patient and 95 control data sets could be analyzed. All patients were unmedicated for at least 6 months. The established method of voxel-based morphometry (VBM8 segmentation and diffeomorphic anatomical registration through exponentiated lie normalization) was used to assess global and regional brain volumes.Patients displayed subtle global cerebral volume reductions. There was no evidence of regional gray matter volume abnormalities. The inattentive ADHD subtype was linked to smaller volumes in the left dorsolateral prefrontal cortex. A history of previous medication did not modulate brain volumes.ADHD in adulthood is associated with global rather than regional volumetric abnormalities. Previous use of stimulant medication does not seem to modify subsequent brain volumes in a significant way.

The primate amygdala is composed of multiple subnuclei that play distinct roles in amygdala function. While some nuclei have been areas of focused investigation, others remain virtually unknown. One of the more obscure regions of the amygdala is the paralaminar nucleus (PL). The PL in humans and non-human primates is relatively expanded compared to lower species. Long considered to be part of the basal nucleus, the PL has several interesting features that make it unique. These features include a dense concentration of small cells, high concentrations of receptors for corticotropin releasing hormone and benzodiazepines, and dense innervation of serotonergic fibers. More recently, high concentrations of immature-appearing cells have been noted in the primate PL, suggesting special mechanisms of neural plasticity. Following a brief overview of amygdala structure and function, this review will provide an introduction to the history, embryology, anatomical connectivity, immunohistochemical and cytoarchitectural properties of the PL. Our conclusion based on the following information, is that the PL is a unique subregion of the amygdala that may yield important clues about the normal growth and function of the amygdala, particularly in higher species.

In times of crisis or natural disaster, there is an intense demand from the public for information about the who, what, when, where, why, and how of the crisis (Smith & Price, 2005), and pressure o...

Individuals with anorexia nervosa have a relentless preoccupation with dieting and weight loss that results in severe emaciation and sometimes death. It is controversial whether such symptoms are secondary to psychosocial influences, are a consequence of obsessions and anxiety or reflect a primary disturbance of brain appetitive circuits. New brain imaging technology provides insights into ventral and dorsal neural circuit dysfunction - perhaps related to altered serotonin and dopamine metabolism - that contributes to the puzzling symptoms found in people with eating disorders. For example, altered insula activity could explain interoceptive dysfunction, and altered striatal activity might shed light on altered reward modulation in people with anorexia nervosa.

It is possible that disturbances of systems modulating reward may contribute to a vulnerability to develop an eating disorder.This hypothesis was tested by assessing functional magnetic resonance brain imaging response to a monetary reward task known to activate the anterior ventral striatum (AVS), a region implicated in motivational aspects toward stimuli. To avoid the confounding effects of malnutrition, 10 women who had recovered from bulimia nervosa (BN) were compared with 10 healthy comparison women (CW).For the AVS, CW distinguished positive and negative feedback, whereas recovered BN women had similar responses to both conditions. In addition, these groups had similar patterns of findings for the dorsal caudate.We have previously shown that individuals recovered from anorexia nervosa (AN) also had altered striatal responses and difficulties in differentiating positive and negative feedback. Thus BN and AN individuals may share a difficulty in discriminating the emotional significance of a stimulus.

Adolescence is the transition period that prepares individuals for fulfilling their role as adults. Most conspicuous in this transition period is the peak level of risk-taking behaviors that characterize adolescent motivated behavior. Significant neural remodeling contributes to this change. This review focuses on the functional neuroanatomy underlying motivated behavior, and how ontogenic changes can explain the typical behavioral patterns in adolescence. To help model these changes and provide testable hypotheses, a neural systems-based theory is presented. In short, the Triadic Model proposes that motivated behavior is governed by a carefully orchestrated articulation among three systems, approach, avoidance and regulatory. These three systems map to distinct, but overlapping, neural circuits, whose representatives are the striatum, the amygdala and the medial prefrontal cortex. Each of these system-representatives will be described from a functional anatomy perspective that includes a review of their connectivity and what is known of their ontogenic changes.

In rats and primates, the central nucleus of the amygdala (CeN) is most known for its role in responses to fear stimuli. Recent evidence also shows that the CeN is required for directing attention and behaviors when the salience of competing stimuli is in flux. To examine how information flows through this key output region of the primate amygdala, we first placed small injections of retrograde tracers into the subdivisions of the central nucleus in Old world primates, and examined inputs from specific amygdaloid nuclei. The amygdalostriatal area and interstitial nucleus of the posterior limb of the anterior commissure (IPAC) were distinguished from the CeN using histochemical markers, and projections to these regions were also described. As expected, the basal nucleus and accessory basal nucleus are the main afferent connections of the central nucleus and transition zones. The medial subdivision of the central nucleus (CeM) receives a significantly stronger input from all regions compared to the lateral core subdivision (CeLcn). The corticoamygdaloid transition zone (a zone of confluence of the medial parvicellular basal nucleus, paralaminar nucleus, and the sulcal periamygdaloid cortex) provides the main input to the CeLcn. The IPAC and amygdalostriatal area can be divided in medial and lateral subregions, and receive input from the basal and accessory basal nucleus, with differential inputs according to subdivision. The piriform cortex and lateral nucleus, two important sensory interfaces, send projections to the transition zones. In sum, the CeM receives broad inputs from the entire amygdala, whereas the CeLcn receives more restricted inputs from the relatively undifferentiated corticoamygdaloid transition region. Like the CeN, the transition zones receive most of their input from the basal nucleus and accessory basal nucleus, however, inputs from the piriform cortex and lateral nucleus, and a lack of input from the parvicellular accessory basal nucleus, are distinguishing afferent features.

Anorexia nervosa (AN) is an illness characterized by aversion to ingestion of normally palatable foods. We examined whether there is a primary disturbance of taste processing and experience of pleasure using a sucrose/water task in conjunction with functional magnetic resonance imaging (fMRI). To avoid confounding effects of illness, 16 women recovered from restricting-type AN were compared to 16 control women (CW). We used a region of interest-based fMRI approach to test the idea that individuals with AN have differential neural activation in primary and secondary taste cortical regions after sucrose and water administration. Compared to CW, individuals recovered from AN showed a significantly lower neural activation of the insula, including the primary cortical taste region, and ventral and dorsal striatum to both sucrose and water. In addition, insular neural activity correlated with pleasantness ratings for sucrose in CW, but not in AN subjects. Altered taste processing may occur in AN, based on differences in activity in insular-striatal circuits. These data provide the first evidence that individuals with AN process taste stimuli differently than controls, based on differences in neural activation patterns.

Early parental loss is associated with social–emotional dysregulation and amygdala physiologic changes. Previously, we examined whole amygdala gene expression in infant monkeys exposed to early maternal deprivation. Here, we focus on an amygdala region with immature neurons at birth: the paralaminar nucleus (PL). We hypothesized that 1) the normal infant PL is enriched in a subset of neural maturation (NM) genes compared to a nearby amygdala subregion; and 2) maternal deprivation would downregulate expression of NM transcripts (mRNA). mRNAs for bcl2, doublecortin, neuroD1, and tbr1—genes expressed in post-mitotic neurons—were enriched in the normal PL. Maternal deprivation at either 1 week or 1 month of age resulted in PL-specific downregulation of tbr1—a transcription factor necessary for directing neuroblasts to a glutamatergic phenotype. tbr1 expression also correlated with typical social behaviors. We conclude that maternal deprivation influences glutamatergic neuronal development in the PL, possibly influencing circuits mediating social learning.

The central extended amygdala is an evolutionarily conserved set of interconnected brain regions that play an important role in threat processing to promote survival. Two core components of the central extended amygdala, the central nucleus of the amygdala (Ce) and the lateral bed nucleus of the stria terminalis (BST) are highly similar regions that serve complimentary roles by integrating fear- and anxiety-relevant information. Survival depends on the ability of the central extended amygdala to rapidly integrate and respond to threats that vary in their immediacy, proximity, and characteristics. Future studies will benefit from understanding alterations in central extended amygdala function in relation to stress-related psychopathology.

Oxytocin (OT) is a neuropeptide synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) in the hypothalamus. Although OT is more commonly known for its role in the milk-ejection reflex, in recent years research has indicated that OT participates in the expression of social behavior, memory processing, modulation of fear, and stress responses. The demonstration that OT influences affiliative behaviors, such as parental care and reproduction, and decreases anxiety has lead to speculations that it may have a role in mood disorders. Evidence from pharmacologic studies, pointing out the modulation of the OT system by serotonin, has argued in favor of OT as a mediator of serotonin reuptake inhibitors (SSRIs) antidepressant properties. In the present study, we investigated the distribution and overlap of OT-labeled cells and serotonin transporter (5-HTT) immunoreactive (IR) fibers in the Macaque hypothalamus, utilizing immunocytochemical and double-immunofluorescent techniques. Consistent with previous reports, the distribution of OT-labeled cells in the hypothalamus is confined to the PVN and SON. In these nuclei, we demonstrate that the distribution of 5-HTT-labeled fibers follows the distribution of OT-labeled cells. Overlap of OT-labeled neurons and 5-HTT-IR fibers occurs in the parvicellular, magnocellular, dorsal, and posterior subdivisions of the PVN. In the SON, 5-HTT-labeled fibers and OT-labeled cells overlap in the ventromedial subdivision and in the 'capsular' part of the dorsolateral SON. These findings provide neuroanatomic support for the idea that SSRIs' therapeutic effects on social affiliation and anxiety may be mediated in part through components of the OT system.

Background The serotonin transporter 5-HTT mediates responses to serotonin reuptake inhibitors (SSRIs), a mainstay treatment in mood disorders. The amygdala, a key emotional processing center, has functional abnormalities in mood disorders, which resolve following successful SSRI treatment. To better understand the effects of SSRIs in mood disorders, we examined the distribution of 5-HTT labeled fibers relative to specific nuclear groups in the amygdala. Methods Immunocytochemical techniques were used to chart 5-HTT labeled fibers in the amygdala in coronal sections through the brain of six adult Macaques. Nissl staining was used to define nuclear groups in the amygdala. Results The serotonin transporter 5-HTT is distributed heterogeneously in the primate amygdala, with the lateral subdivision of the central nucleus, intercalated cell islands, amygdalohippocampal area, and the paralaminar nucleus showing the heaviest concentrations. Conclusions 5HTT-labeled fibers are very densely concentrated in output regions of the amygdala. High concentrations of 5-HTT-positive fibers in the central nucleus indicate that tight regulation of serotonin is critical in modulating fear responses mediated by this nucleus. High concentrations of 5-HTT-labeled fibers in the intercalated islands and parvicellular basal nucleus/paralaminar nucleus, which contain immature -appearing neurons, suggest a potential trophic role for serotonin in these subregions.

The widespread use of the selective serotonin reuptake inhibitors (SSRIs) has been accompanied by numerous reports describing a potential association with hyperprolactinemia. Antipsychotics are commonly known to elevate serum prolactin (PRL) through blockade of dopamine receptors in the pituitary. However, there is little awareness of the mechanisms by which SSRIs stimulate PRL release. Hyperprolactinemia may result in overt symptoms such as galactorrhea, which may be accompanied by impaired fertility. Long-term clinical sequelae include decreased bone density and the possibility of an increased risk of breast cancer. Through literature review, we explore the possible pathways involved in serotonin-induced PRL release. While the classic mechanism of antipsychotic-induced hyperprolactinemia directly involves dopamine cells in the tuberoinfundibular pathway, SSRIs may act on this system indirectly through GABAergic neurons. Alternate pathways involve serotonin stimulation of vasoactive intestinal peptide (VIP) and oxytocin (OT) release. We conclude with a comprehensive review of clinical sequelae associated with hyperprolactinemia, and the potential role of SSRIs in this phenomenon.

The amygdala and hippocampus are key limbic structures of the temporal lobe, and are implicated in the pathology of mood disorders. Bcl-2, an intracellular protein, has recently been identified in the primate amygdala and hippocampus, and is now recognized as an intracellular target of mood stabilizing drugs. However, there are few data on the cellular phenotypes of bcl-2-expressing cells, or their distribution in specific subregions of the amygdala and hippocampus. We used a number of histochemical markers to define specific subregions of the primate amygdala and hippocampus, and examined phenotype-specific distributions of bcl-2 immunoreactive cells within each subregion. Immature-appearing bcl-2 labeled neurons, which co-contain class III beta-tubulin immunoreactivity, are found in distinct subregions in each structure. In the amygdala, bcl-2 positive neurons with an immature morphology are densely distributed in the paralaminar nucleus and intercalated cell islands, the parvicellular basal nucleus, and the ventral periamygdaloid cortex and amygdalohippocampal area. In the hippocampus, immature-appearing bcl-2-labeled cells are confined to the polymorph layer (subgranular zone), and base of the granule cell layer in the dentate gyrus. Well-differentiated neurons also express bcl-2. In the amygdala, labeled cells with mature phenotypes are concentrated in the parvicellular basal nucleus, the accessory basal nucleus, and the periamygdaloid cortex. The medial nucleus and central extended amygdala also contain many well-differentiated bcl-2 positive cells. In the hippocampus, the dentate gyrus and Ammon's horn contain many bcl-2 immunoreactive nonpyramidal cells. These are preferentially distributed in the rostral hippocampus. CA3 and CA2 contain relatively higher concentrations of bcl-2-labeled cells than CA1 and the subiculum. Bcl-2 is thus important in intrinsic circuitry of the hippocampus, and in amygdaloid subregions modulated by the hippocampus. In addition, the extended amygdala, a key amygdaloid output, is richly endowed with bcl-2 positive cells. This distribution suggests a role for bcl-2 in circuits mediating emotional learning and memory which may be targets of mood stabilizing drugs.

The dopamine system (DA) has long been associated with the pathophysiology of psychosis. The DA theory of schizophrenia continues to find support in neuroreceptor imaging and ligand-binding studies that show excess DA transmission in patients, as compared to controls. The pathways which regulate the primate DA system, however, have yet to be fully elucidated. The amygdala, including its extended amygdala component, is involved in evaluating the emotional value of sensory stimuli. Since emotionally relevant sensory stimuli are distorted during psychotic episodes, we hypothesize that amygdaloid influences are likely to be significant modulators of the DA system. We reviewed evidence for direct projections from the central extended amygdala to specific subpopulations of DA neurons, and we discussed how these pathways may serve as important conduits of emotionally relevant information that can have immediate and long-term effects on DA regulation.

BACKGROUND: Hunger enhances sensitivity to reward, yet individuals with anorexia nervosa (AN) are not motivated to eat when starved. This study investigated brain response to rewards during hunger and satiated states to examine whether diminished response to reward could underlie food restriction in AN. METHODS: Using a delay discounting monetary decision task known to discriminate brain regions contributing to processing of immediate rewards and cognitive control important for decision making regarding future rewards, we compared 23 women remitted from AN (RAN group; to reduce the confounding effects of starvation) with 17 healthy comparison women (CW group). Monetary rewards were used because the rewarding value of food may be confounded by anxiety in AN. RESULTS: Interactions of Group (RAN, CW) 3 Visit (hunger, satiety) revealed that, for the CW group, hunger significantly increased activation in reward salience circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during processing of immediate reward, whereas satiety increased activation in cognitive control circuitry (ventrolateral prefrontal cortex, insula) during decision making. In contrast, brain response in reward and cognitive neurocircuitry did not differ during hunger and satiety in the RAN group. A main effect of group revealed elevated response in the middle frontal gyrus for the RAN group compared with the CW group. CONCLUSIONS: Women remitted from AN failed to increase activation of reward valuation circuitry when hungry and showed elevated response in cognitive control circuitry independent of metabolic state. Decreased sensitivity to the motivational drive of hunger may explain the ability of individuals with AN to restrict food when emaciated. Difficulties in valuating emotional salience may contribute to inabilities to appreciate the risks inherent in this disorder.

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.

Clinical manifestations in diseases affecting the dopamine system include deficits in emotional, cognitive, and motor function. Although the parallel organization of specific corticostriatal pathways is well documented, mechanisms by which dopamine might integrate information across different cortical/basal ganglia circuits are less well understood. We analyzed a collection of retrograde and anterograde tracing studies to understand how the striatonigrostriatal (SNS) subcircuit directs information flow between ventromedial (limbic), central (associative), and dorsolateral (motor) striatal regions. When viewed as a whole, the ventromedial striatum projects to a wide range of the dopamine cells and receives a relatively small dopamine input. In contrast, the dorsolateral striatum (DLS) receives input from a broad expanse of dopamine cells and has a confined input to the substantia nigra (SN). The central striatum (CS) receives input from and projects to a relatively wide range of the SN. The SNS projection from each striatal region contains three substantia nigra components: a dorsal group of nigrostriatal projecting cells, a central region containing both nigrostriatal projecting cells and its reciprocal striatonigral terminal fields, and a ventral region that receives a specific striatonigral projection but does not contain its reciprocal nigrostriatal projection. Examination of results from multiple tracing experiments simultaneously demonstrates an interface between different striatal regions via the midbrain dopamine cells that forms an ascending spiral between regions. The shell influences the core, the core influences the central striatum, and the central striatum influences the dorsolateral striatum. This anatomical arrangement creates a hierarchy of information flow and provides an anatomical basis for the limbic/cognitive/motor interface via the ventral midbrain.