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Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.

BACKGROUND: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces. METHODS: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model. RESULTS: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions. CONCLUSIONS: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.

Adolescent↗

Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels.

In a previous positron emission tomography (PET) study of major depression, we demonstrated that cerebral blood flow was increased in the left amygdala in unipolar depressives with familial pure depressive disease (FPDD) relative to healthy controls [J. Neurosci. 12 (1992) 3628.]. These measures were obtained from relatively low-resolution PET images using a stereotaxic method based upon skull X-ray landmarks. The current experiments aimed to replicate and extend these results using higher-resolution glucose metabolism images and magnetic resonance imaging (MRI)-based region-of-interest (ROI) analysis. The specificity of this finding to FPDD was also investigated by assessing depressed samples with bipolar disorder (BD-D) and depression spectrum disease (DSD). Finally, the relationship between amygdala metabolism and plasma cortisol levels obtained during the scanning procedure was assessed. Glucose metabolism was measured using PET and 18F-fluorodeoxyglucose (18FDG) in healthy control (n=12), FPDD (n=12), DSD (n=9) and BD-D (n=7) samples in the amygdala and the adjacent hippocampus. The left amygdala metabolism differed across groups (P<.001), being increased in both the FPDD and BD-D groups relative to the control group. The left amygdala metabolism was positively correlated with stressed plasma cortisol levels in both the unipolar (r=.69; P<.005) and the bipolar depressives (r=0.68;.1<P<.05). In contrast, neither significant main effects of diagnosis nor significant relationships with plasma cortisol were evident in post hoc analyses of metabolism in the right amygdala or the hippocampus. Preliminary assessment of BD subjects imaged during remission suggested that amygdala metabolism is also elevated in remitted subjects who are not taking mood-stabilizing drugs, but within the normal range in subjects taking mood stabilizers. These data confirm our previous finding that neurophysiological activity is abnormally increased in FPDD, and extend it to BD-D. These abnormalities were not accounted for by spilling in of radioactivity from the adjacent hippocampus. The correlation between left amygdala metabolism and stressed plasma cortisol levels may conceivably reflect either the effect of amygdala activity on corticotropin-releasing hormone (CRH) secretion or the effect of cortisol on amygdala function.

Adolescent↗

Differential effects of inferior temporal cortex lesions upon visual and auditory-evoked potentials in the amygdala of the squirrel monkey (Saimiri sciureus).

Visual-evoked potentials (VEPs) and auditory-evoked potentials (AEPs) were elicited from amygdala nuclei and inferior temporal (IT) cortex in chaired, alert squirrel monkeys to diffuse flash and click stimuli. VEPs were recorded from electrodes placed in basalis lateralis amygdalae (BLA) and basalis medialis amygdalae (BMA) while AEPs could also be obtained from additional electrode sites in basalis accessorius medialis (BAM), centralis amygdalae (CeA), and lateralis amygdalae (LA). The amygdala-evoked potentials resulting from stimulation of the two modalities were similar in terms of component configuration. AEPs recorded from the IT cortex had shorter latencies than the amygdala VEPs that were recorded. Both modalities of stimulation elicited potentials with shorter onset latencies in the amygdala than those recorded from the surface of IT cortex. Bilateral ablation of the IT cortex eliminated VEPs recorded from the BMA but not the BLA amygdala region. AEPs recorded from BMA as well as other amygdala areas were not consistently affected by these IT cortical ablations.

Amygdala↗

The pallial amygdala of amniote vertebrates: evolution of the concept, evolution of the structure.

Embryological studies indicate that the amygdala includes pallial structures, namely the cortical amygdala (olfactory and vomeronasal) and the basolateral complex deep to it. In squamate reptiles, the cortical amygdala includes secondary olfactory (the ventral anterior amygdala) and vomeronasal centres (the nucleus sphericus). In birds, the situation is far less clear, due to the relative underdevelopment of the chemosensory systems. The basolateral amygdala of squamate reptiles includes two ventropallial structures: the posterior dorsal ventricular ridge and the lateral amygdala. Like their mammalian counterparts, these centres give rise to glutamatergic projections to the striatal (centromedial) amygdala and the ventromedial hypothalamus. Using the same criteria, the caudal neostriatum and the ventral intermediate archistriatum may represent the ventral pallial amygdala of birds. The basal nucleus of the mammalian amygdala is a lateropallial territory. In reptiles, the lateral pallium includes the dorsolateral amygdala, which, like the mammalian basal nucleus, projects bilaterally to the striatum/accumbens and receives distinct cholinergic and dopaminergic innervations. In the avian brain, the same embryological, hodological, and histochemical criteria are met by the area temporo-parieto-occipitalis, the caudolateral neostriatum and the dorsal intermediate archistriatum. Therefore, the projections from these structures to the paleostriatum and the lobus paraolfactorius are amygdalostriatal, rather than corticostriatal connections.

Amygdala↗

The amygdala and autism: implications from non-human primate studies.

Brothers (1990) has proposed that the amygdala is an important component of the neural network that underlies social behavior. Kemper and Bauman (1993) identified neuropathology in the amygdala of the postmortem autistic brain. These findings, along with recent functional neuroimaging data, have led Baron-Cohen et al. (2000) to propose that dysfunction of the amygdala may be responsible, in part, for the impairment of social behavior that is a hallmark feature of autism. Recent data from studies in our laboratory on the effects of amygdala lesions in the adult and infant macaque monkey do not support a fundamental role for the amygdala in social behavior. If the amygdala is not essential for the component processes of social behavior, as seems to be case in both non-human primates and selected patients with bilateral amygdala damage, then it is unlikely to be the primary substrate for the impaired social behavior of autism. However, damage to the amygdala does have an effect on a monkey's response to normally fear-inducing stimuli, such as snakes, and removes a natural reluctance to engage novel conspecifics in social interactions. These findings lead to the conclusion that an important role for the amygdala is in the detection of threats and mobilizing an appropriate behavioral response, part of which is fear. Interestingly, an important comorbid feature of autism is anxiety (Muris et al. 1998). If the amygdala is pathological in subjects with autism, it may contribute to their abnormal fears and increased anxiety rather than their abnormal social behavior.

Amygdala↗

Involvement of the amygdala in memory storage: interaction with other brain systems.

There is extensive evidence that the amygdala is involved in affectively influenced memory. The central hypothesis guiding the research reviewed in this paper is that emotional arousal activates the amygdala and that such activation results in the modulation of memory storage occurring in other brain regions. Several lines of evidence support this view. First, the effects of stress-related hormones (epinephrine and glucocorticoids) are mediated by influences involving the amygdala. In rats, lesions of the amygdala and the stria terminalis block the effects of posttraining administration of epinephrine and glucocorticoids on memory. Furthermore, memory is enhanced by posttraining intraamygdala infusions of drugs that activate beta-adrenergic and glucocorticoid receptors. Additionally, infusion of beta-adrenergic blockers into the amygdala blocks the memory-modulating effects of epinephrine and glucocorticoids, as well as those of drugs affecting opiate and GABAergic systems. Second, an intact amygdala is not required for expression of retention. Inactivation of the amygdala prior to retention testing (by posttraining lesions or drug infusions) does not block retention performance. Third, findings of studies using human subjects are consistent with those of animal experiments. beta-Blockers and amygdala lesions attenuate the effects of emotional arousal on memory. Additionally, 3-week recall of emotional material is highly correlated with positronemission tomography activation (cerebral glucose metabolism) of the right amygdala during encoding. These findings provide strong evidence supporting the hypothesis that the amygdala is involved in modulating long-term memory storage.

Amygdala↗

Clinical correlates of selective pathology in the amygdala of patients with Parkinson's disease.

The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 )< 0.03; P > 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala subdivisions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson's disease on the amygdala is highly selective and correlates with both early and late clinical features.

Aged↗

Functional dissociation of amygdala-modulated arousal and cognitive appraisal, in Turner syndrome.

The amygdala is preferentially activated by facial expressions of fear. Right and left amygdala are hypothesized to play distinct, but complementary, roles that influence somatic and cognitive responses to facial expressions. Right amygdala activation is linked to autonomic arousal, and thus indirectly influences left hemisphere cognitive processing centres. Left amygdala activation is more closely associated with cognitive processing and differentiation of facial emotions. A double-dissociation between the functions of left and right amygdala is implied by lesion studies but supportive evidence is inconsistent, partly because patients with structural anteromedial temporal anomalies have experienced variable surgical procedures. A functional dissociation can be demonstrated between arousal and the cognitive appraisal of fearful faces in the condition of X-monosomy or Turner syndrome. Previous research found Turner syndrome women of normal verbal intelligence are seriously impaired in their ability cognitively to differentiate fearful from other facial expressions but they acquire fear conditioning normally, with enhanced autonomic responses. These findings supported the dissociation hypothesis, which was formally tested in a study of 12 X-monosomic and 12 control females who participated in functional magnetic resonance imaging during which simultaneous skin conductance recordings were acquired. Faces depicting fear or neutral emotions were presented to both case and control subjects in random order. Arousal to (fearful-neutral) faces was associated with transiently increased skin conductance responses and bilateral amygdala activation in both groups, but X-monosomic females had proportionately greater--and more persistent--right amygdala activation than controls. In both groups, cognitive accuracy correlated positively with differential activity of left fusiform gyrus. There was a significant correlation between the left fusiform and left medial amygdala activation only in normal females, and only in them did differential SCRs (to fearful-neutral faces) correlate positively with left fusiform responses. Arousal and cognitive appraisal functions of the amygdala can thus be functionally dissociated. X-monosomy selectively impairs explicit recognition of fearful faces in the presence of normal or enhanced autonomic reactivity, and is associated with a functional dissociation of activity in left amygdala and left fusiform gyrus. These findings imply X-linked genes are essential for binding somatic responses to the cognitive appraisal of emotional stimuli.

Adult↗

Effects of Nefiracetam, a novel pyrrolidone-type nootropic agent, on the amygdala-kindled seizures in rats.

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy. METHODS: Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED). RESULTS: In fully amygdala-kindled rats, NEF (25, 50, and 100 mg/kg, p.o.) decreased afterdischarge induction, afterdischarge duration, seizure stage, and motor seizure duration in a dose-dependent manner. LEV (25, 50, and 100 mg/kg, p.o.) had no effects on afterdischarge induction and slightly decreased afterdischarge duration, whereas it markedly decreased seizure stage and motor seizure duration. In contrast to the results in fully amygdala-kindled rats, NEF (25 and 50 mg/kg/day, p.o.) had few or no effects on the development of amygdala-kindled seizures. As well as fully amygdala-kindled seizures, LEV (50 mg/kg/day, p.o.) markedly inhibited the development of behavioral seizures without reducing daily afterdischarge duration. CONCLUSIONS: Although NEF possesses potent anticonvulsant effects on fully amygdala-kindled seizures, it has few or no effects on the development of amygdala-kindled seizures. LEV shows marked anticonvulsant effects on both phases of kindling. In fully amygdala-kindled rats, NEF inhibits both electroencephalographic and behavioral seizures, whereas LEV inhibits only behavioral seizures. This double dissociation suggests that NEF has a distinct anticonvulsant spectrum and mechanisms from those of LEV.

Administration, Oral↗

The amygdala, social behavior, and danger detection.

The amygdala is a distinctive portion of the anterior temporal lobe that has been implicated in a variety of functions including expression of fear, modulation of memory, and mediation of social communication. While work on the rodent amygdala often deals with emotion, much of the research in nonhuman primates and in man deals with its role in the perception of social signals, such as facial expressions, and the maintenance of social position, such as in primate dominance hierarchies. We have established a program of research that has as its major goal the definition of neural systems that underlie species-typical social communication. A first phase of the program was launched on the premise that the amygdala is essential for species-typical social behavior. We sought to examine in more detail the impairments of social behavior that followed discrete, bilateral lesions of the amygdala. We found, however, that mature rhesus monkeys with bilateral lesions of the amygdala not only were capable of species-typical social behavior, but actually engaged in more affiliative social interactions. The lesioned animals also demonstrated a striking lack of fear of normally fear-inducing stimuli such as replicas of snakes. In a second, ongoing series of studies in the infant rhesus monkey, we are examining whether the amygdala is essential for gaining social knowledge during development. Infant animals that receive bilateral lesions of the amygdala at two weeks of age and are raised by their biological mothers demonstrate all expected social behaviors for their ages. These animals, like the adults, demonstrate a lack of fear of objects such as snakes. However, unlike the adults, they demonstrate more fear when placed into novel social situations. The results from these studies are most consistent with the conclusion that the amygdala is not necessary for species-typical social behavior or for gaining social knowledge during development. We hypothesize that the amygdala is a critical component of a system that evaluates the environment for potential dangers. As such, it has a modulatory role on social behavior-that is, it typically inhibits social interaction with novel conspecifics while they are evaluated as potential adversaries. This perspective predicts that hyperactivity of the amygdala would be associated with increased fear or anxiety and may contribute to disorders such as social phobia.

Affect↗

Lewy bodies in the amygdala increase risk for major depression in subjects with Alzheimer disease.

OBJECTIVE: To determine the relationship between major depression and the presence of Lewy bodies (LBs) in patients with Alzheimer disease (AD). METHODS: The authors examined the presence of major depression in 267 pathologically diagnosed AD cases with Mini-Mental State Examination (MMSE) scores >9. LBs were identified in 142 (53%) patients using alpha-synuclein immunohistochemistry. Subjects were classified according to the Consensus Guidelines for the Clinical and Pathologic Diagnosis of Dementia with LB: 1 to 2 (n = 21), 3 to 6 (n = 26), and 7 to 10 (n = 69). Twenty-six patients had LB only in the amygdala. All cases with LB scores 7 to 10 (or cortical) had amygdala LBs. The association between LBs and major depression was examined with logistic regression analyses, controlled for age at study entry, education level, MMSE scores, antidepressant use, follow-up time, and the presence of cerebrovascular disease. RESULTS: Major depression was present in 11 (9%) AD alone cases, and in 25 (18%) of the AD + LBs cases; amygdala: 8 (31%), scores 1 to 2: 1 (5%), scores 3 to 6: 3 (11.5%), and scores 7 to 10: 13 (14%). Major depression was associated with LBs, in general (relative risk [RR] = 3.06, 95% CI: 1.25 to 7.46), with amygdala only LBs (RR = 8.56 (95% CI: 1.83 to 40.3), and with LB scores 7 to 10 (RR = 3.83, 95% CI: 1.33 to 11.0). There was an association between all amygdala LBs cases (amygdala only LBs + LB scores 7 to 10) and major depression (RR = 4.77, 95% CI: 1.78 to 12.7), but no association was noted between LBs and depression in the absence of amygdala LBs (RR = 0.96, 95% CI: 0.46 to 1.06). CONCLUSION: Lewy bodies (LBs) in the amygdala and in cortical areas increase the risk for major depression in Alzheimer disease. What is common in these two groups is the presence of LBs in the amygdala. That is, all of the cases with cortical LBs also had LBs in the amygdala, making this region the critical area for the development of depression.

Aged↗

Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making.

The somatic marker hypothesis proposes that decision-making is a process that depends on emotion. Studies have shown that damage of the ventromedial prefrontal (VMF) cortex precludes the ability to use somatic (emotional) signals that are necessary for guiding decisions in the advantageous direction. However, given the role of the amygdala in emotional processing, we asked whether amygdala damage also would interfere with decision-making. Furthermore, we asked whether there might be a difference between the roles that the amygdala and VMF cortex play in decision-making. To address these two questions, we studied a group of patients with bilateral amygdala, but not VMF, damage and a group of patients with bilateral VMF, but not amygdala, damage. We used the "gambling task" to measure decision-making performance and electrodermal activity (skin conductance responses, SCR) as an index of somatic state activation. All patients, those with amygdala damage as well as those with VMF damage, were (1) impaired on the gambling task and (2) unable to develop anticipatory SCRs while they pondered risky choices. However, VMF patients were able to generate SCRs when they received a reward or a punishment (play money), whereas amygdala patients failed to do so. In a Pavlovian conditioning experiment the VMF patients acquired a conditioned SCR to visual stimuli paired with an aversive loud sound, whereas amygdala patients failed to do so. The results suggest that amygdala damage is associated with impairment in decision-making and that the roles played by the amygdala and VMF in decision-making are different.

Acoustic Stimulation↗

The amygdala, autism and anxiety.

Brothers has proposed that the amygdala is an important component of the neural network that underlies social cognition. And Bauman and Kemper observed signs of neuropathology in the amygdala of the post-mortem autistic brain. These findings, in addition to recent functional neuroimaging data, have led Baron-Cohen and colleagues to propose that dysfunction of the amygdala may be responsible, in part, for the impairment of social functioning that is a hallmark feature of autism. Recent data from studies in our laboratory on the effects of amygdala lesions in the macaque monkey are at variance with a fundamental role for the amygdala in social behaviour. If the amygdala is not essential for normal social behaviour, as seems to be the case in both non-human primates and selected patients with bilateral amygdala damage, then it is unlikely to be the substrate for the abnormal social behaviour of autism. However, damage to the amygdala does have an effect on a monkey's response to normally fear-inducing stimuli, such as snakes, and removes a natural reluctance to engage novel conspecifics in social interactions. These findings lead to the conclusion that an important role for the amygdala is in the detection of threats and mobilizing an appropriate behavioural response, part of which is fear. If the amygdala is pathological in subjects with autism, it may contribute to their abnormal fears and increased anxiety rather than their abnormal social behaviour.

Amygdala↗

The role of amygdala norepinephrine in memory formation: involvement in the memory enhancing effect of peripheral epinephrine.

The present study examined the roles of amygdala alpha 1 and beta noradrenergic receptors in memory formation as well as their involvement in the memory enhancing effect of peripheral epinephrine (E). Male Sprague-Dawley rats with cannulae implanted into the amygdala were trained on the one-trial inhibitory avoidance task and tested for retention 24 hrs later. Immediately after training, they received various treatments to alter amygdala noradrenergic functions and/or peripheral adrenergic functions. Separate groups of animals were decapitated 10 min after training for assays of monoamine levels in various brain regions by the HPLC-EC method. Results indicated that, when infused into the amygdala immediately after training, isoproterenol and 8-bromo-cAMP enhanced retention, while propranolol impaired retention. On the other hand, phenylephrine or prazosin failed to produce statistically significant effects. Posttraining intra-amygdala infusion of propranolol, but not prazosin, abolished the memory enhancing effects of norepinephrine (NE) infused into the amygdala or E given subcutaneously to the adrenal demedullated rats. Depletion of amygdala NE by the selective neurotoxin DSP-4 also abolished the memory modulatory effects of E. These findings support that amygdala noradrenergic beta, but not alpha 1, receptors are involved in both central and peripheral memory modulatory processes. However, since the postmortem tissue NE levels in the amygdala and other brain regions did not differ among various groups, the inhibitory avoidance training and peripheral E may only activate a transient functional increase in the amygdala NE activity.

Amygdala↗

Amygdala response to fearful faces in anxious and depressed children.

BACKGROUND: Alterations in amygdala function have been implicated in the pathophysiological characteristics of adult anxiety and depressive disorders. Studies with healthy adults and children, as well as with adults who have amygdala lesions, have found facial expressions of emotion to be useful probes of amygdala activity. Our study examined the amygdala response to fearful and neutral facial expressions in healthy, anxious, and depressed children. We hypothesized that children with anxiety and depression may show atypical amygdala responses to emotional stimuli. METHODS: Twelve children (8-16 years of age) with generalized anxiety or panic disorder and 12 healthy comparison children underwent noninvasive functional magnetic resonance imaging while viewing photographs of fearful and neutral facial expressions. In a second comparison, 5 girls with major depressive disorder were compared with 5 anxious and 5 healthy girls from the previous sample. RESULTS: Children with anxiety disorders showed an exaggerated amygdala response to fearful faces compared with healthy children, whereas depressed children showed a blunted amygdala response to these faces. In addition, the magnitude of the amygdala's signal change between fearful and neutral faces was positively correlated with the severity of everyday anxiety symptoms. CONCLUSIONS: Our results suggest that amygdala function is affected in both anxiety and depression during childhood and adolescence. Moreover, this disruption appears to be specific to the child's own rating of everyday anxiety.

Adolescent↗

Organization of the ophidian amygdala: chemosensory pathways to the hypothalamus.

Although recent studies in squamate reptiles have importantly clarified how chemical information is processed in the reptilian brain, how the amygdala relays chemosensory inputs to the hypothalamus to influence chemically guided behaviors is still poorly documented. To identify these chemosensory pathways, the amygdalo-hypothalamic projections, intra-amygdaloid circuitry and afferents from the lateral cortex (LC) to the amygdala were investigated by injecting conjugated dextran-amines into the hypothalamus, amygdala, and LC of garter snakes. The amygdala was divided into olfactory recipient (ventral anterior and external amygdalae), vomeronasal recipient (nucleus sphericus, NS, and medial amygdala, MA), and nonchemosensory (e.g., posterior dorsal ventricular ridge, PDVR, and dorsolateral amygdaloid nucleus, DLA) subdivisions. Rostroventral (LCrv) and dorsocaudal subdivisions of the LC were distinguished. In addition to receiving afferents from the main olfactory bulb, the olfactory amygdala receives afferents from NS and projects to the NS, PDVR, and dorsal hypothalamus. The NS has only a minor projection to the lateral hypothalamus, whereas the MA, which receives afferents from the LCrv and NS, has projections to the ventromedial hypothalamic (VMH) and lateral posterior hypothalamic nuclei. Among the nonchemosensory amygdaloid structures, the PDVR receives afferents from the LCrv and the olfactory amygdala and projects to the VMH, whereas DLA receives afferents from the LCrv and NS, and projects to the periventricular hypothalamus. These results substantially clarify the olfactory and vomeronasal tertiary connections and demonstrate that parts of the nonchemosensory amygdala play a major role in relaying chemosensory information to the hypothalamus.

Amygdala↗

Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity.

Previous reports indicate that the midbrain periaqueductal gray and the central nucleus of the amygdala are interconnected but the organization of these projections has not been characterized. We have analyzed this reciprocal circuitry using anterograde and retrograde tracing methods and image analysis. Our findings reveal that innervation of periaqueductal gray from the central nucleus of the amygdala is extensive and discretely organized along the rostrocaudal axis of periaqueductal gray. In addition, the reciprocal projection from periaqueductal gray to the central nucleus of the amygdala is more extensive and more highly organized than previously suggested. Multiple or single discrete injections of wheatgerm agglutinin-horseradish peroxidase into several rostrocaudal levels of periaqueductal gray retrogradely labeled a substantial population of neurons, predominantly located in the medial division of the central nucleus of the amygdala. Tracer injections into the central nucleus revealed a high degree of spatial organization in the projection from this nucleus to periaqueductal gray. Two discrete longitudinally directed columns in dorsomedial and lateral/ventrolateral periaqueductal gray are heavily targeted by central amygdalar inputs throughout the rostral one-half to two-thirds of periaqueductal gray. Beginning at the level of dorsal raphe and continuing caudally, inputs from the central nucleus terminate more uniformly throughout the ventral half of periaqueductal gray. In addition, a substantial population of periaqueductal gray neurons were retrogradely labeled from the central nucleus of the amygdala; these were heterogeneously distributed along the rostrocaudal axis of periaqueductal gray, and included both raphe and non-raphe neurons. Thus, the present study demonstrates that periaqueductal gray receives heavy, highly organized projections from the central nucleus of the amygdala and, in turn, has reciprocal connections with the central nucleus. Previous studies have demonstrated that longitudinally organized columns of output neurons located in dorsomedial and lateral/ventrolateral periaqueductal gray project to the ventral medulla. Thus, there may be considerable overlap between the two longitudinally organized terminal input columns from the central nucleus of the amygdala and the two longitudinal columns of descending projection neurons from periaqueductal gray to the ventral medulla. The central nucleus of the amygdala has been implicated in a variety of emotional/cognitive functions ranging from fear and orienting responses, defensive and aversive reactions, associative conditioning, cardiovascular regulation, and antinociception. Many of these same functions are strongly represented in the periaqueductal gray. It is noteworthy that the present results demonstrate that lateral periaqueductal gray, a preeminent central trigger site for behavioral and autonomic components of the defense/aversion response, is heavily targeted by inputs from the central nucleus of the amygdala at all levels of periaqueductal gray.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗

Connections of the posterior nucleus of the amygdala.

The connections of a relatively homogeneous band of neurons in the caudal amygdala have been examined with anterograde and retrograde axonal tracing methods in the rat. This region, called here the posterior nucleus of the amygdala (PA), corresponds in part to an area that has been referred to as the cortico-amygdaloid transition area, posterior part of the medial nucleus of the amygdala, amygdalo-hippocampal transition area, and posteromedial basal nucleus. Experiments with fluorogold and phaseolus vulgaris leucoagglutinin (PHAL) indicate that the major neuronal input to the PA arises in the ventral premammillary nucleus, and that substantial projections also arise in olfactory-related areas such as the medial nucleus of the amygdala, bed nucleus of the accessory olfactory tract, and posterior cortical nucleus of the amygdala, as well as in the ventral subiculum and adjacent parts of hippocampal field CA1. Other seemingly minor inputs, including cholinergic fibers from the substantia innominata, dopaminergic fibers from the ventral tegmental area, and serotoninergic fibers from the dorsal nucleus of the raphe, were also identified. The efferent projections of the PA as determined with the PHAL method appear to follow five major routes: 1) a relatively small group of laterally directed fibers innervates the dorsal endopiriform nucleus, and a few of these fibers reach cortical area TR and the lateral entorhinal area; 2) another small group of fibers courses medially to innervate the ventral subiculum and adjacent parts of field CA1; 3) many fibers course ventrally to innervate the outer molecular layer of the medial part of the posterior cortical nucleus of the amygdala; 4) a moderate group of fibers courses rostrally to innervate primarily the posterodorsal part of the medial nucleus of the amygdala, although some fibers continue on to end less densely in rostral parts of the medial nucleus of the amygdala before leaving the amygdala through the ansa peduncularis; and 5) the major output of the PA courses through the stria terminalis. One branch of this pathway massively innervates the principal nucleus of the bed nuclei of the stria terminalis before entering the medial hypothalamus, where it ends massively in the anteroventral periventricular and medial preoptic nuclei, ventrolateral part of the ventromedial nucleus and adjacent parts of the basal lateral hypothalamic area, and ventral premammillary nucleus. The other branch sends fibers to the ventral lateral septal nucleus, nucleus accumbens, olfactory tubercle, and infralimbic area of the prefrontal cortex.(ABSTRACT TRUNCATED AT 400 WORDS)

Amygdala↗