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Vertical parasagittal hemispherotomy (VPH) is a well-established surgical treatment which is proposed for children with widespread unilateral onset of intractable epileptic seizures. VPH allows to disconnect from a vertical transventricular approach all white matter fibers of the hemisphere around a central core including the thalamus. We present the case of a girl who underwent VPH for hemimegalencephaly in early infancy. Postoperatively, she developed unexpected seizures of mesio-temporal origin. Stereo-EEG provided arguments for an amygdalar origin. High-resolution MRI with tractography confirmed the presence of the amygdalo-fugal pathway to be responsible of epileptic discharges propagation. She became seizure-free after temporal resection.

С целью выяснения причин необратимых изменений в ЭЭГ гиппокампа после разрушения дорсального амигдалофугального пути, а также участия лимбических структур мозга (амигдала, гипоталамус, ретикулярная формация) в формировании гиппокампального тета-ритма производилась регистрация электрической активности различных ядер гипоталамуса, амигдалы и ретикулярной формации в условиях стимуляции и разрушения дорсального амигдалофугального пути. Полученные данные свидетельствуют о том, что необходимым условием в механизмах регуляции возбудимости нейронов в различных ядрах гипоталамуса, амигдалы и ретикулярной формации является функциональная целостность дорсального амигдалофугального пути.

Introduction The ansa peduncularis is a composite of white matter fiber bundles closely packed together that sweeps around the cerebral peduncle. The exact components of the ansa peduncularis and their anatomical trajectories are still not established firmly in the literature. Objective The aim of this study was to examine the topographical anatomy of the ansa peduncularis and its subcomponents using the fiber dissection and tractography techniques. Methods Ten formalin-fixed brains were prepared according to Klingler’s method and dissected by the fiber dissection technique from the lateral, medial and inferior surfaces. The ansa peduncularis was also traced using high definition fiber tracking (HDFT) from the MRI data of twenty healthy adults and a 1021-subject template from the Human Connectome Project. Results The ventral amygdalofugal pathway system includes white matter fiber bundles with a topographically close relation as they sweep around the cerebral peduncle and contribute to form the ansa peduncularis: amygdaloseptal fibers connect the amygdala and anterior temporal cortex to the septal region and amygdalohypothalamic fibers project from the amygdala to the hypothalamus. Additionally, from the amygdala and anterior temporal cortex, amygdalothalamic fibers project to the medial thalamic region. The ansa lenticularis, which connects the globus pallidus to the thalamus, was not shown in our study. Conclusion The study demonstrated the trajectory of the ansa peduncularis and its subcomponents, based on fiber dissection and tractography, improving our understanding of human brain anatomical connectivity.

The amygdala is a heterogenous set of nuclei with widespread cortical connections that continues to develop postnatally with vital implications for emotional regulation. Using high-resolution anatomical and multi-shell diffusion MRI in conjunction with novel amygdala segmentation, cutting-edge tractography, and Neurite Orientation Dispersion and Density (NODDI) methods, the goal of the current study was to characterize age associations with microstructural properties of amygdala subnuclei and amygdala-related white matter connections across adolescence (N = 61, 26 males; ages of 8–22 years). We found age-related increases in the Neurite Density Index (NDI) in the lateral nucleus (LA), dorsal and intermediate divisions of the basolateral nucleus (BLDI), and ventral division of the basolateral nucleus and paralaminar nucleus (BLVPL). Additionally, there were age-related increases in the NDI of the anterior commissure, ventral amygdalofugal pathway, cingulum, and uncinate fasciculus, with the strongest age associations in the frontal and temporal regions of these white matter tracts. This is the first study to utilize NODDI to show neurite density of basolateral amygdala subnuclei to relate to age across adolescence. Moreover, age-related differences were also notable in white matter microstructural properties along the anterior commissure and ventral amydalofugal tracts, suggesting increased bilateral amygdalae to diencephalon structural connectivity. As these basolateral regions and the ventral amygdalofugal pathways have been involved in associative emotional conditioning, future research is needed to determine if age-related and/or individual differences in the development of these microstructural properties link to socio-emotional functioning and/or risk for psychopathology.

The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)-plays a critical role in triggering fear and anxiety and is implicated in the development of a range of debilitating neuropsychiatric disorders. Although it is widely believed that these disorders reflect the coordinated activity of distributed neural circuits, the functional architecture of the EAc network and the degree to which the BST and the Ce show distinct patterns of functional connectivity is unclear. Here, we used a novel combination of imaging approaches to trace the connectivity of the BST and the Ce in 130 healthy, racially diverse, community-dwelling adults. Multiband imaging, high-precision registration techniques, and spatially unsmoothed data maximized anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala, the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed stronger connectivity with the thalamus, striatum, periaqueductal gray, and several prefrontal territories. The only regions showing stronger functional connectivity with the Ce were neighboring regions of the dorsal amygdala, amygdalohippocampal area, and anterior hippocampus. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and showcase image registration techniques that are likely to be useful for researchers working with "deidentified" neuroimaging data.

The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder., Withdrawal from alcohol activates neurons in the central amygdala (CeA) and increases craving for alcohol. The authors show that these neurons predominantly express CRF and project to the BNST. Inactivation of this pathway reduces the dependence-related escalation of alcohol drinking.

The central extended amygdala (EAc)—including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)—plays a key role in orchestrating states of fear and anxiety and is implicated in the development and maintenance of anxiety disorders, depression, and substance abuse. Although it is widely thought that these disorders reflect the coordinated actions of large-scale functional circuits in the brain, the architecture of the EAc functional network, and the degree to which the BST and the Ce show distinct patterns of intrinsic functional connectivity, remains incompletely understood. Here, we leveraged a combination of approaches to trace the connectivity of the BST and the Ce in 130 psychiatrically healthy, racially diverse, community-dwelling adults with enhanced power and precision. Multiband imaging, high-precision data registration techniques, and spatially unsmoothed data were used to maximize anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala (‘substantia innominata’), the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed significant coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed significantly stronger connectivity with prefrontal territories—including the vmPFC, anterior MCC and pregenual anterior cingulate cortex—as well as the thalamus, striatum, and the periaqueductal gray. The only regions showing stronger functional connectivity with the Ce were located in the anterior hippocampus and dorsal amygdala. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and highlight the value of several new approaches to image registration which may be particularly useful for researchers working with ‘de-identified’ neuroimaging data.GRAPHICAL ABSTRACTIntrinsic functional connectivity of bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce) in 130 psychiatrically healthy adults.HIGHLIGHTSBST and Ce implicated in normal and pathological fear and anxietyTraced the intrinsic functional connectivity of the BST and the Ce in 130 adultsMultiband imaging, high-precision registration, unsmoothed data, newly developed seedsBST and Ce show robust coupling with one another, hippocampus, insula, MCC, and vmPFCBST shows stronger coupling with prefrontal/cingulate territories and brainstem/PAG

The amygdala is one of the anatomical structures that has attracted intensive interest because of its potential involvement in various neuropsychiatric disorders. In recent years, attempts have been made to evaluate the integrity of the axonal connections from and to the amygdala under pathological conditions using MRI. Although the amygdalar pathways have been extensively studied in the past using animal models, the current anatomical references for the human brain are limited to histology-based resources at a small number of slice locations, orientations, and annotations. In this study, we performed high-resolution MRI (250 m) of postmortem samples, followed by serial histology sections. The histology data served as the ground truth to identify amygdalar pathways, and the anatomical delineation of the assigned structures was extended to 3D using the MRI data. We could clearly define the detailed anatomy of the stria terminalis and amygdalofugal pathway, as well as the anatomy of the nearby basal forebrain areas, including the substantia innominata. The results could help us to understand the detailed white matter structures associated with the amygdala and serve as an anatomical reference by which to design and interpret in vivo MRI data.

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n = 10); from a larger study on prescription opioid dependent patients (n = 133)] and matched healthy individuals (n = 10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

The neural substrates regulating sensorimotor gating in rodents are studied in order to understand the basis for gating deficits in clinical disorders such as schizophrenia. N-methyl-D-aspartate (NMDA) infusion into the ventral temporal lobe, including caudal parts of the ventral hippocampal region and amygdala, has been shown to disrupt sensorimotor gating in rats, as measured by prepulse inhibition (PPI) of startle. One working model is that reduced PPI after infusion of NMDA into this region is mediated via its efferents to ventral forebrain structures, i.e. medial prefrontal cortex (mPFC) and nucleus accumbens. Yet, PPI-disruptive effects persist after lesions of the precommissural fornix, the principal output pathway of the hippocampal formation. Here, we aimed to characterize non-fornical forebrain projections from this region that might mediate the PPI-disruptive effects of the ventral temporal lobe. Electrolytic lesions of the precommissural fornix in male Sprague-Dawley rats were followed by infusions of fluorogold into the mPFC or by infusions of biotinylated dextan amine into the ventral temporal lobe. Projections from the ventral subiculum and CA1 regions of the ventral hippocampus to the mPFC and accumbens core and shell were interrupted by fornix lesions. Projections to the mPFC and accumbens from other regions of the ventral temporal lobe, particularly the lateral entorhinal cortex and the embedded olfactory and vomeronasal parts of the caudal amygdala, survived fornix lesions. These additional projections coursed rostrally through the amygdala and emerged via the stria terminalis, interstitial nuclei of the posterior limb of the anterior commissure, and the ventral amygdalofugal pathway. PPI-regulatory portions of the ventral temporal lobe innervate the accumbens and mPFC via multiple routes. It remains to be determined which of these non-fornical projections may be responsible for the persistent regulation of PPI after fornix lesions.

The amygdala is known to have a role in core processes regulated by the limbic system such as motivation, memory, emotion, social behavior, self-awareness as well as certain primitive instincts. Several functional studies have investigated some of these brain tasks of the human limbic system. However, the underlying neuronal fiber connectivity of the amygdalo-diencephalon, as part of the limbic system, has not been delineated separately by prior diffusion-weighted imaging studies. The ability to trace the underlying fiber connections individually will be helpful in understanding the neurophysiology of these tracts in different functions. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine connections of the amygdala, hypothalamus, septum or other adjacent limbic structures have yet to be elucidated by diffusion-weighted tractography studies. We therefore aimed to further investigate these fine neuronal connections using fiber tractography and high spatial resolution diffusion tensor imaging on 3T on 15 healthy right-handed male human subjects (age range 24–37 years). The ventral amygdalofugal pathway, anterior commissure and stria terminalis are the three main efferent pathways of the amygdala. We delineated the detailed trajectories of the ventral amygdalofugal tract, anterior commissure and their connections bilaterally in 15 normal adult human brains. Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to demonstrate the trajectory of amygdalofugal tract and its connections to the hypothalamic and septal nuclei. We further revealed, for the first time, the close relationship of the amygdalofugal tract and anterior commissure with the fornix, stria terminalis and uncinate fasciculus bilaterally in 15 healthy adult human brains.

The bed nucleus of the stria terminalis is a key part of a ring of cells extending between the centromedial amygdala and bed nucleus of the stria terminalis referred to as the extended amygdala. The present study describes the architecture of the bed nucleus of the stria terminalis and the connections of subnuclei in posterior bed nucleus of the stria terminalis. The hamster bed nucleus of the stria terminalis is readily allotted to anterior and posterior divisions separated by the fibers of the body of the anterior commissure. The anterior division has four subnuclei: anteromedial, anterointermediate, anterolateral, and anteroventral. Within the posterior division, there are three distinct regions: posteromedial, posterointermediate, and posterolateral. In hamsters, the posterior bed nucleus of the stria terminalis contributes to male sexual behavior, particularly chemoinvestigation. Moreover, the posterior bed nucleus of the stria terminalis is part of a neural circuit essential for mating, including the medial amygdaloid nucleus and medial preoptic area. The connections of bed nucleus of the stria terminalis, posteromedial part, bed nucleus of the stria terminalis, posterointermediate part and bed nucleus of the stria terminalis, posterolateral part were visualized by co-injection of anterograde (Phaseolus vulgaris leucoagglutinin) and retrograde (cholera toxin B) tract tracers. The bed nucleus of the stria terminalis, posterointermediate part and bed nucleus of the stria terminalis, posteromedial part have dense bidirectional connections with medial amygdaloid nucleus and cortical amygdala via the stria terminalis and ventral amygdalofugal pathway. These subnuclei also maintain bidirectional connections with steroid-concentrating areas including lateral septum, medial preoptic area, hypothalamus, and periaqueductal gray. The bed nucleus of the stria terminalis, posterointermediate part and bed nucleus of the stria terminalis, posteromedial part receive projections from the subiculum and send projections to deep mesencephalic nuclei. By contrast, the bed nucleus of the stria terminalis, posterolateral part is connected with the central amygdala, lateral hypothalamus, subthalamic nucleus, nucleus accumbens, substantia innominata, substantia nigra and thalamus. Thus, the bed nucleus of the stria terminalis, posterointermediate part and bed nucleus of the stria terminalis, posteromedial part have similar connections with areas involved in social behaviors. The bed nucleus of the stria terminalis, posterolateral part maintains connections with areas involved in motivational circuits. This supports the concept of distinct circuits within the extended amygdala which differentially link the centromedial amygdala and bed nucleus of the stria terminalis.

In chronic experiments on rabbits, we demonstrated that electrolytic destruction of the stria terminalis results in the intense depression of the integral electrical activity of the hippocampus. Characteristics of the responses induced by electrical and chemostimulation of the hippocampus under the above conditions allowed us to conclude that a significant drop in the excitability of hippocampal neurons themselves, but not changes in the structure and intensity of afferent impulsation from the extrahippocampal structures, underlies such a depression. Morphological changes in neurons and satellite glial cells, such as lysis of the Nissl substance, hyperchromatosis, and wrinkling of the cells after destruction of the stria terminalis, were proof of the correctness of our conclusion. It is postulated that one of the main factors underlying the generalized effects observed in our experiments is probably the disturbance of functional characteristics of the hypothalamo-hypophyseal neurosecretory system induced by destruction of the amygdalofugal connections; this disturbance results in significant pathological shifts of metabolism in the hippocampus.

The anxiogenic β-carboline, FG-7142, produces intense anxiety in humans and anxiety-like behavior in animals. FG-7142 also mimics the effects of exogenous stressors. In cats, FG-7142 lastingly changes defensive and aggressive behavior. Long-term potentiation (LTP) of neural transmission between limbic structures known to modulate feline defensive response to threat accompany behavioral changes. A series of three reports describes experiments designed to test the hypothesis that behavioral changes depend upon an N- methyl-D-aspartate (NMDA) receptor-based LTP of efferent transmission from the amygdala. This first study characterizes the dose and time effects of injection of the NMDA receptor blocker 7-amino-phosphono heptanoic acid (AP7) on efferent transmission from the cat amygdala to the ventromedial hypothalamus (VMH). Effects of doses of 0.5-10 mg/kg (i.v.) of AP7 on potentials evoked in the VMH by single pulse stimulation of the basal amygdala were examined. In order to localize the action of the drug, concurrent measurements were taken of potentials evoked in the VMH by stimulation of the efferent fibers from the amygdala to the VMH (ventral amygdalofugal pathway, VAF). There was a dose-dependent reduction in the amygdalo-VMH evoked potential. The greatest reduction occurred at 5 mg/kg. Effects peaked at 10 min, and persisted for at least 1 h after injection. In contrast, AP7 increased the VAF-VMH-evoked potential at 10 min after injection, with a maximal increase at 5 mg/kg. The data suggest that NMDA receptors intrinsic to the amygdala modulate excitatory efferent transmission from amygdala to VMH in the cat. It is speculated that a glutamatergic projection to γ-aminobutyric acid tonic inhibitory systems in theVMH accounts for theVAF-VMH results.

By virtue of its capacity to prevent apoptosis the proto-oncogene bcl-2 is believed to play a crucial role in CNS development. Studies in rodents have shown that the anti-apoptosis Bcl-2 protein is widely expressed during CNS development, but undergoes a marked down-regulation during maturation and is present only at low concentrations in adult CNS. In contrast, current data suggest that Bcl-2 protein in adult monkey brain results from microglial expression. In the present immunohistochemical study, however, numerous subsets of Bcl-2-immunoreactive neurons were encountered in the amygdala, hippocampus, hypothalamus, limbic cortices and striatum of squirrel monkeys. Of particular interest was the presence in the basal portion of the amygdala and adjoining piriform cortex of numerous intensely immunoreactive cells with long and thick immunopositive processes that ran into the ventral amygdalofugal pathway. At striatal level Bcl-2-positive neurons were strictly confined to calbindin-poor striosomes, which are specifically innervated by limbic cortices. This study has provided the first evidence for the occurrence of Bcl-2 in mature monkey brain. It has further shown that this protein is preferentially expressed in limbic structures in primate forebrain. The sustained expression of this anti-apoptosis protein may protect limbic system neurons from various injuries or neurodegeneration. It may also be involved in the functional and structural changes that occur throughout adulthood in some regions of the primate limbic system.

Chemosensory and hormonal stimuli are essential for mating in the male Syrian hamster. These signals are processed in a neural circuit that includes the medial amygdaloid nucleus (Me), bed nucleus of the stria terminalis (BNST), and medial preoptic area (MPOA). Nitric oxide is implicated in the regulation of male sexual behavior, and nitric oxide synthase (NOS), the enzyme that catalyzes the production of nitric oxide, is present in the limbic system. In this study, the distribution of NOS-containing neurons in mating behavior circuitry of the male Syrian hamster brain was determined using labeling for brain NOS (bNOS) and reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). bNOS and NADPH-d labeled equivalent populations of neurons. NOS-containing neurons were clustered in specific subnuclei within the Me, BNST, and MPOA. NOS-positive fibers and neurons were seen in the stria terminalis and ventral amygdalofugal pathway, which link the Me with BNST and MPOA. Many NOS-positive neurons in the posterior subdivision of the Me, the medial preoptic nucleus (MPN), and the ventral premammillary nucleus contain androgen receptors. Castration reduced NOS-positive neurons in the MPN, implying a selective regulation of NOS by gonadal steroids. Together, these results suggest that NOS may contribute to the regulation of male sexual behavior by influencing the central neural processing of hormonal and chemosensory signals in the hamster limbic system. © 1996 John Wiley & Sons, Inc.

Calretinin is a calcium-binding protein that colocalizes with GABA in the cerebral cortex and hippocampus of the rat and the monkey. In the present study, we investigated the distribution of calretinin-immunoreactive cells and fibers in the human amygdaloid complex. A conspicuous feature was the high density of calretinin neurons in the human amygdala. The highest densities of the calretinin-immunoreactive neurons were observed in the anterior cortical nucleus, accessory basal nucleus, amygdalohippocampal area, and in the nucleus of the lateral olfactory tract. The paralaminar nucleus, central nucleus, medial nucleus, and the periamygdaloid cortex contained the lowest densities of calretinin neurons. In most of the amygdaloid areas, the calretinin cells had the appearance of aspiny or sparsely spiny local circuit neurons. However, in the amygdalohippocampal area, we found also densely spined dendrites. The cortical areas and the central nucleus were characterized by intense neuropil labeling, while the deep nuclei contained a high density of calretinin-immunoreactive fibers and terminals. Calretinin immunoreactivity was also found in the intra-amygdaloid fiber bundles, stria terminalis, and in the ventral amygdalofugal pathway. This suggests that in addition to the local circuit neurons, calretinin immunoreactivity is also located in neurons that connect the amygdaloid complex with the other brain areas. The distribution and morphological characteristics of calretinin-immunoreactive neurons differed from those of another calcium-binding protein, parvalbumin, in the human amygdala (Sorvari et al. [1995] J. Comp. Neurol. 360:185–212). This suggests that these two calcium-binding proteins are located in different populations of neurons. © 1996 Wiley-Liss, Inc.

Calbindin-D28k is a calcium-binding protein located in a variety of neuronal cell types in many regions of the central nervous system. In the present study, we describe the distribution of calbindin-D28k-immunoreactive cells, fibers, and terminals in the monkey amygdaloid complex. Calbindin-D28k-immunoreactive neurons could be divided into four major cell types. Neurons of the first three cell types demonstrated clearly stained dendrites that were either aspiny or had a few spines on their distal portions. Type 1 cells were small, stellate, or multipolar and found throughout the amygdala. Type 2 cells were large, multipolar and were most commonly found in the deep nuclei, particularly in the lateral nucleus, intermediate division of the basal nucleus, accessory basal nucleus and in the periamygdaloid cortex. Type 3 cells were fusiform, of various sizes, and were found throughout the amygdala. Type 4 cells were quite large and lightly stained; the dendrites of these cells were usually unstained. The size, shape, and location of Type 4 labeled cell bodies suggested that they might be the large, modified pyramidal cells that constitute the projection neurons of the amygdala. Type 4 cells were observed primarily in the lateral, basal, and accessory basal nuclei and in the periamygdaloid cortex. Calbindin-D28k-immunoreactive fibers and terminals were difficult to observe in the amygdala partly because of a diffuse, finely granular neuropil labeling that was particularly dense in the anterior cortical and medial nuclei, in the central nucleus, and in the periamygdaloid cortex. The neuropil labeling was substantially lighter in the lateral, basal, and accessory basal nuclei. Conspicuous linear profiles resembling the “calbindin bundles” of the neocortex were evident in large numbers in the accessory basal nucleus, the medial portion of the parvicellular division of the basal nucleus, in the amygdalohippocampal area, and in the periamygdaloid cortex. There were calbindin-D28k-positive fibers in the stria terminalis and in the ventral amygdalofugal pathway. When the distributions of calbindin-D28k and parvalbumin immunoreactivity in the monkey amygdaloid complex were compared, it appeared that the overall distribution of these two calcium-binding proteins was generally complementary rather than overlapping. © 1993 Wiley-Liss, Inc.

The efferent projections of the anterior and posterodorsal part of the medial nucleus (MePD) in the mouse were studied by means of anterograde axonal tracing using biotinylated dextran amine. The MePD axons ran mainly via the stria terminalis and to a lesser extent via the ventral amygdalofugal pathway. The projections to the forebrain were broadly distributed and varied from very strong to scant. The most significant connections were destined to the bed nucleus of the stria terminalis in which all parts of the medial division were innervated by MePD neurons. Moderate projections reached the limbic striatum (nucleus accumbens), olfactory tubercle and the lateral septal nucleus. The substantia innominata was also innervated by the MePD, and especially the projection to its ventral portion was substantial. The profuse innervation of the medial preoptic nucleus and medial preoptic area indicated significant involvement of the MePD in sexual behavior. Many hypothalamic nuclei were innervated but to a different extent. The very strong innervation of the ventral premammillary nucleus further indicated the involvement of the MePD in the neuronal circuitry for sexual behavior. Substantial projections also reached the anterior hypothalamus and tuber cinereum, while the connections to the lateral hypothalamus were widespread but showed moderate density. MePD strongly innervated the ventrolateral part of the ventromedial hypothalamic nucleus and moderately its remaining parts. The neurosecretory hypothalamic nuclei and the arcuate nucleus contained only a few MePD terminals. The thalamic innervation was very scant and reached the lateral habenular nucleus and the nuclei of the midline. The mesencephalic connections were moderate to sparse and projected to the mesolimbic dopaminergic groups in the ventral tegmental area, the pars lateralis and the dorsal tier of the substantia nigra pars compacta, the periaqueductal gray and the dorsal raphe nucleus. The present results principally resembled data known in other rodent species; however, the efferents of the MePD often differed in extent and/or topical distribution.

We showed recently that conditioned fear to context induces Fos expression in the ventrolateral periaqueductal gray [Neuroscience (1997) 78, 165-177]. Neurons in this region are thought to play an important role in the expression of freezing during conditioned fear. To test the possibility that this activation comes directly from the amygdala, we looked at changes in Fos expression after a unilateral blockade of the ventral amygdalofugal pathway with lidocaine. The pathway contains fibres originating from the central nucleus of the amygdala that project directly and mainly ipsilaterally to the ventrolateral periaqueductal gray. Conditioned fear was evoked by re-exposing rats to the same box in which they had previously received electric footshocks. The test re-exposure was preceded by a unilateral microinjection of lidocaine (2%, 0.5-1 microl; n = 20) or saline (n = 14). Lidocaine was also tested in non-conditioned animals (n = 13). The results show that, when lidocaine was microinjected in the medial part of the central nucleus of the amygdala or along the ventral amygdalofugal pathway of conditioned rats, fear-induced Fos expression in the ventrolateral periaqueductal gray was reduced on the side ipsilateral to the injection (up to 37% reduction in comparison to the contralateral side). Ipsilateral reductions were also observed with saline, but they were weaker (maximum of 27% reduction). Fos expression remained low on both sides in the non-fear-conditioned animals injected with lidocaine. Finally, although freezing was only partly reduced in the conditioned animals unilaterally injected with lidocaine, it was significantly correlated to the ipsilateral reduction in Fos expression. This study provides direct evidence that the projection from the central nucleus of the amygdala to the ventrolateral periaqueductal gray is activated during fear and that it contributes to the Fos response of the ventrolateral periaqueductal gray.

The cholinergic innervation of the rat amygdala was studied immunohistochemically with antibodies against choline acetyltransferase and the low affinity p75 nerve growth factor receptor in normal rats and in rats lesioned with an immunotoxin, 192 IgG-saporin, directed against the p75 nerve growth factor receptor. The density of choline acetyltransferase-positive fibers was high in the nucleus of the lateral olfactory tract, the basolateral nucleus, and the amygdalohippocampal area; medium in the lateral nucleus, the cortical nucleus, the accessory basal nucleus, the periamygdaloid cortex, and the anterior amygdaloid area; and low in the medial and central nuclei. Nerve growth factor receptor-positive fibers were of medium density in the lateral nucleus, the accessory basal nucleus, the cortical nucleus, the anterior amygdaloid area, the periamygdaloid cortex, and the amygdalohippocampal area. The medial nucleus and the central nucleus displayed a low density of nerve growth factor receptor-positive fibers. The basolateral nucleus and the nucleus of the lateral olfactory tract also contained a low density of nerve growth factor receptor-positive fibers even though the two nuclei displayed the highest density of choline acetyltransferase-positive fibers in the amygdala. Injections of 192 IgG-saporin induced a complete loss of cholinergic nerve growth factor receptor-positive neurons in the basal forebrain but spared a subpopulation of nerve growth factor receptor-negative cholinergic neurons in the nucleus basalis-substantia innominata complex. Following 192 IgG-saporin injections, choline acetyltransferase-positive and acetylcholinesterase-positive fibers were essentially unchanged in the nucleus of the lateral olfactory tract and the basolateral nucleus and showed a partial reduction in the remaining nuclei of the amygdaloid complex. Cholinergic fibers emanating from cholinergic cell group 4 neurons reached the amygdala via the stria terminalis and the ventral amygdalofugal pathway. These observations indicate that two amygdaloid nuclei, the nucleus of the lateral olfactory tract and the basolateral nucleus, receive their cholinergic projections predominantly, if not exclusively, from nerve growth factor receptor-negative cholinergic neurons whereas all remaining amygdaloid regions receive fibers from nerve growth factor receptor-negative as well as nerve growth factor receptor-positive cholinergic neurons.

The fear-potentiated startle paradigm has proven to be a useful system with which to analyze neural systems involved in fear and anxiety. This test measures conditioned fear by an increase in the amplitude of a simple reflex (the acoustic startle reflex) in the presence of a cue previously paired with a shock. Fear-potentiated startle is sensitive to a variety of drugs such as diazepam, morphine, and buspirone that reduce anxiety in people and can be measured reliably in humans when the eyeblink component of startle is elicited at a time when they are anticipating a shock. Electrical stimulation techniques suggest that a visual conditioned stimulus ultimately alters acoustic startle at a specific point along the acoustic startle pathway. The lateral, basolateral and central amygdaloid nuclei and the caudal branch of the ventral amygdalofugal pathway projecting to the brainstem are necessary for potentiated startle to occur. The central nucleus of the amygdala projects directly to one of the brainstem nuclei critical for startle and electrical stimulation of this nucleus increases startle amplitude. Chemical or electrolytic lesions of either the central nucleus or the lateral and basolateral nuclei of the amygdala block the expression of fear-potentiated startle. The perirhinal cortex, which projects directly to the lateral and basolateral amygdaloid nuclei, plays a critical role in the expression of fear-potentiated startle using either visual or auditory conditioned stimuli. These latter amygdaloid nuclei may actually be the site of plasticity for fear conditioning, because local infusion of the NMDA antagonist AP5 into these nuclei blocks the acquisition of fear-potentiated startle. On the other hand, the expression of fear-potentiated startle is blocked by local infusion of the non-NMDA ionotropic antagonist CNQX or the G-protein inactivating toxin, pertussis toxin, but not by AP5. Finally, we have begun to investigate brain systems that might be involved in the inhibition of fear. Local infusion of AP5 into the amygdala was found to block the acquisition of experimental extinction, a prototypical method for reducing fear. We have also established a reliable procedure for producing both external and conditioned inhibition of fear-potentiated startle and hope to eventually understand the neural systems involved in these phenomena.

The magnocellular nuclei of the basal forebrain (MNBF) consist of several groups of cholinergic and non-cholinergic cells scattered through the septum, substantia innominata, peripallidum and preoptic region. Although anatomically confusing, this distribution is understandable if it is realized that all of the groups are situated within and along the major fiber pathways of the ventral forebrain. Thus, the nuclei of the diagonal band and the medial septal nucleus are arrayed along the vertical and horizontal limbs of the diagonal band (of Broca), and continue back into the rostral part of the medial forebrain bundle. The nucleus basalis is partially situated along the medial forebrain bundle, but is also related to the ventral amygdalofugal pathway, the ansa lenticularis and (in primates) the medullary laminae of the globus pallidus. As seen with the Golgi method, all these nuclei are made up of multipolar cells with long radiating, spine-free dendrites that extend across the fiber bundles, apparently receiving synaptic inputs from a large number of fibers. Thus, based on their anatomical configuration, cells throughout the MNBF appear to have the capacity to sample and integrate diverse information passing between structures such as the orbito-medial prefrontal cortex, septum, amygdaloid complex, hypothalamus and brainstem. This information may be presumed to shape the functional outputs that the MNBF sends to the cerebral cortex and other telencephalic structures.

The basal forebrain contains a seemingly heterogeneous collection of structures including nucleus accumbens, olfactory tubercle, septum, diagonal band nuclei, bed nucleus of stria terminalis, substantia innominata, olfactory cortex, hippocampus formation and amygdaloid body. It is also traversed by a number of large fiber tracts, e.g. fornix, stria terminalis, diagonal band of Broca, medial forebrain bundle, inferior thalamic peduncle, and ventral amygdalofugal pathway, to which the various basal forebrain structures contribute axons in order to establish connections between themselves and with other parts of the brain. Hypothalamus, the main diencephalic component of the basal forebrain, is one such region closely related to many of the telencephalic basal forebrain structures and fiber tracts. These intimate relations to the hypothalamus provided much of the anatomical rationale to bring the above-mentioned basal forebrain structures together as integral parts of the “limbic system”. This has contributed to the popular view of forebrain organization in which the neocortex is related to the basal ganglia or the “extrapyramidal motor system” through the well-known cortico-striato-pallidal pathways, while so-called limbic structures, e.g. septum, nucleus accumbens, amygdaloid body and allocortical areas like hippocampus and olfactory cortex are characterized foremost by their relation to the hypothalamus, a major regulator of autonomic and endocrine functions.

These experiments examined the role of two major amygdala afferent-efferent pathways--the stria terminalis (ST) and the ventral amygdalofugal pathway (VAF)--in mediating the effects, on memory storage, of post-training intra-amygdala injections of norepinephrine (NE) and subcutaneous (s.c.) injections of epinephrine (E). Rats with either ST lesions or VAF transections and sham-operated rats were trained on a one-trial step-through inhibitory avoidance task and immediately after training received intra-amygdala injections of NE or a buffer solution. Other groups of VAF-transected animals received post-training s.c. injections of E or saline. ST lesions blocked the memory-enhancing effect of intra-amygdala injections of a low dose of NE (0.2 microgram) as well as the amnestic effect of a high dose of NE (5.0 microgram). In contrast, VAF transections did not block the memory-enhancing effect of NE (0.2 microgram). However, VAF transections attenuated the memory-enhancing effect of s.c. injections of E: the effective dose of E was shifted from 0.1 to 0.5 mg/kg. These findings, considered together with previous evidence that ST lesions block the memory-enhancing effect of peripheral E injections, suggest that the VAF is involved in mediating the central influence of peripheral E on amygdala functioning, while the ST is involved in mediating amygdala influences on memory storage elsewhere in the brain.

Amygdaloid and pontine projections to the feline ventromedial nucleus of the hypothalamus (HVM) were studied with retrograde transport of horseradish peroxidase (HRP) and anterograde transport of tritiated amino acids. Following injections of HRP into HVM, amygdaloid neurons were labeled in the ipsilateral cortical and medial nuclei and the ventral portion of the parvocellular part of the basal nucleus. In experiments in which HRP was injected into the tuberal hypothalamus following stria terminalis lesions, it was determined that amygdaloid neurons projecting to HVM by way of the stria terminalis were located in the cortical and medial nuclei while those projecting through another route, presumably the ventral amygdalofugal pathway, were found in the rostral part of the medial nucleus and the parvocellular basal nucleus. Following HRP injection into lateral hypothalamus at the level of HVM, labeled neurons were seen in the magnocellular basal nucleus. After preoptic injections, neurons containing the HRP reaction product were in cortical and medial nuclei and magnocellular and parvocellular parts of the basal nucleus. In addition to cells in the amygdala, rostral pontine neurons were labeled after HRP injections into HVM. The cells were located ipsilateral to the injection, mostly in the dorsal nucleus of the lateral lemniscus, lateral and dorsolateral to the brachium conjunctivum. The pontine cells labeled following HVM injections of HRP were different from those labeled following lateral hypothalamic and preoptic region injections. The pontine projection to HVM was confirmed using axoplasmic transport autoradiography. A mixture of tritiated leucine and tritiated proline was injected into the lateral pontine region labeled after HRP injections into HVM. Labeled axons ascending in the medial forebrain bundle terminated throughout the rostro-caudal extent of HVM.

Lesions of the stria terminalis in the rat brain indicate that neuropeptide Y, a recently isolated peptide of the pancreatic polypeptide family, projects rostrally in an efferent pathway from the amygdaloid complex. Marked depletions of NPY-immunoreactivity observed by immunocytochemistry were apparent in the laterobasal septum and suprachiasmatic nucleus of the hypothalamus, but most markedly in rostrolateral regions of the bed nucleus of the strial terminalis.

A series of studies investigated the role of the amygdala, and its connections with hypothalamic areas, in gastric pathology induced by immobilization. Results showed that lesions in the medial amygdala and the ventral amygdalofugal pathway reduced the stomach pathology induced by restraint. Lesions in the stria terminalis, on the other hand, increased the severity of stomach pathology. It is concluded that the lesions in the medial nuclei and the ventral pathway attenuated the effectiveness of the noxious stimulus to produce gastrointestinal abnormalities whereas the lesions in the stria terminalis interfered with inhibitory effects.

The present study investigated the response characteristics of individual neurons in the amygdala following stimulation of the substantia innominata (SI), and compared these responses with those elicited by stimulation of insular and temporal polar cortices and the lateral olfactory tract (LOT). Recordings were made from single units within the medial, central, basal, and lateral amygdaloid nuclei of anesthetized, male cats. Stimulating electrodes were located in the SI, LOT, and sylvian cortex (SG). Unit responses were classified as either excitation or inhibition. Excitatory responses were further divided into fixed latency excitation (FLE) and variable latency excitation (VLE) based on the variability of the onset latency of the response. The majority of responses to SI stimulation were of the FLE type, implying a direct orthodromic, monosynaptic activation of amygdaloid units. Proportionally more FLE responses were recorded laterally, especially in the magnocellular basal nucleus, compared to VLE responses which were common in the medial and central nuclei. SI stimulation consistently affected the activity of many more units than did SG or LOT stimulation. The onset latencies of the population of cells exhibiting excitatory responses elicited by SI stimulation were distributed bimodally, and this may reflect a dual projection pathway of amygdaloid afferents from this basal forebrain region. This correlates with anatomical descriptions indicating that SI projections to amygdala pass via the ventral amygdalofugal pathway as well as in the stria terminalis. Excitatory onset latencies of responses to SI stimulation were the shortest in the lateral and magnocellular basal nuclei and the longest in the parvocellular basal nucleus. Amygdaloid units exhibited convergent input from the stimulus sites. A clear topographical distribution of units was not demonstrated. The data suggests that units receiving a convergent input were rarely driven monosynaptically by more than one stimulus site. The basal nucleus contained the smallest fraction of units exhibiting a convergent input. A small population of antidromic responses was recorded and indicates that within the system studied the caudal aspect of the basal nucleus is a major source of amygdaloid efferents. Antidromically driven units did not exhibit transynaptic responses following stimulation of any of the test sites.

The rat brain contains a large number of vasopressin (VP) immunoreactive fibers, the sites of origin of which have not yet been established completely. For instance, the sources of VP fiber systems in the amygdala, ventral hippocampus (VH), mediodorsal thalamic nucleus, ventral tegmental area, and dorsal raphe yet remain obscure. These VP fibers may originate in any of the recently described extrahypothalamic VP cell groups, viz., medial amygdaloid nucleus (AME), dorsomedial hypothalamic nucleus, or locus coeruleus, since VP efferents from these cells still remain to be demonstrated. In search of AME VP efferents three approaches were followed: (1) the Phaseolus vulgaris anterograde tracing method, (2) immunocytochemistry after AME lesioning, and (3) retrograde transport of a fluorescent dye in combination with immunofluorescence. The results demonstrate that VP cells in the AME project to (1) the lateral septum (LS) by the ventral amygdalofugal pathway and (2) the VH via the amygdalohippocampal transition zone. In addition, the VP projection from the bed nucleus of the stria terminalis (BST) to the LS was confirmed. There was no indication that VP cells in the AME project through the amygdalotegmental pathway to the medulla oblongata and spinal cord. The results support the possibility that the BST and AME are an anatomical entity that may be part of the central loci controlling sexual processes in the rat.

Vibra tome sections of male hamster brains were treated immunohistochemically with LHRH antiserum, and the anatomical distribution of LHRH immunoreactive cells and nerve fibers was assessed. LHRH-cell bodies are found in the ventral hypothalamus that includes its preoptic, anterior and central parts, in the septum, the olfactory tubercle, the main and accessory olfactory bulb, and the prepiriform cortex. In addition, extracerebral LHRH-neurons and ganglia exist in LHRH-positive nerves at the ventromedial surface of the olfactory tubercle and bulb as well as in olfactory nerves. Dense networks of LHRH-immunoreactive fibers are found in all regions where LHRH-cell bodies exist. Intraseptal connections reach the organum vasculosum of the lamina terminalis, the subfornical organ, and the lateral ventricle. Dorsolateral projections from the septum can be traced via the fimbria hippocampi and alveus to the ventral hippocampus, via the stria terminalis to the amygdala and piriform cortex. Ventrolateral projections extend from the level of the olfactory tubercle and preoptic-anterior hypothalamic area via the ventral amygdalofugal pathway to the prepiriform and piriform cortex as well as the amygdala. Dorsal supracallosal projections via the stria longitudinalis are seen in the induseum griseum and the cingulate cortex. Caudal efferents reach the habenula, interpeduncular nucleus, midbrain raphe, and central gray of the rostral fourth ventricle via the stria medullaris and fasciculus retroflexus and by a ventral projection via the periventricular and subventricular hypothalamus. A major portion of this ventrocaudal projection gives rise to a dense network in the median eminence. Anatomical relationships of LHRH-fibers to certain regions of the inner ventricular and outer brain surface are noted.

The destruction of th central amygdaloid nucleus (Ce), which contains a large group of neurons with leucine-enkephalin (L-ENK)-like immunoreactivity (L-ENKI), resulted in a marked ipsilateral reduction of these fibers in the bed nucleus of the stria terminalis (BST) suggesting that L-ENKI neurons in the Ce project ipsilaterally to the BST. This was supported by the finding that injection of biotin-wheat germ agglutinin into the BST labeled many neurons in the Ce. Simultaneous staining with antiserum showed that some of these neurons are L-ENKI. The L-ENKI fibers from the Ce reach the BST via two pathways; one from the ventral amygdalofugal pathway (VA), which terminate in the ventral subdivision of the BST pars lateralis (BSTL), and the other from the stria terminalis (ST), which terminates in the lateral subdivision of the BSTL, because (1) accumulation of L-ENKI structures appeared in the axons of these two systems on the amygdaloid side, (2) transection or destruction of the ST alone caused only a slight reduction of ENKI fibers in the lateral subdivision of the BSTL ipsilaterally and (3) transection or destruction of VA alone markedly reduced the number of L-ENKI fibers in the ventral subdivision of the ipsilateral BSTL. Thus, the VA L-ENKI fiber system is the major source of L-ENKI fibers in the ventral subdivision, while the ST L-ENKI fiber system is a minor source of the L-ENKI fibers in the lateral subdivision. The presence of an intrinsic L-ENKI system in the BST which may innervate the lateral subdivision was also suggested.

In 22 squirrel monkeys ( Saimiri sciureus ) vocalization-eliciting electrodes were implanted into the amygdala and along the trajectory of the stria terminals. Then, lesions were placed in the stria terminals, its bed nucleus, the ventral amygdalofugal pathway and several di- and mesencephalic structures in order to find out the pathways along which the amygdala exerts its vocalization-controlling influence. It was found that different call types are controlled by different pathways. Purring and chattering calls, which express a self-confident, challenging attitude and an attempt to recruit fellow-combatants in intra-specific mobbing, respectively, are controlled via the stria terminalis; alarm peep and groaning calls, in contrast, which indicate flight motivation and resentment, respectively, are triggered via the ventral amygdalofugal fibre bundle. Both pathways traverse the dorsolateral and dorsomedial hypothalamus, respectively, and unite in the periaqueducctal grey of the midbrain.

The projections of the hypothalamus to the amygdala have been studied autoradiographically in a series of eleven cynomolgus monkeys (Macaca fascicularis) in which injections of [3H]amino acids had been made in different regions of the caudal two-thirds of the hypothalamus. The most prominent projection arises from the ventromedial nucleus of the hypothalamus and terminates most heavily in the medial, magnocellular division of the central nucleus. Injections confined to the ventromedial nucleus also result in labeling of the piriform cortex, the periamygdaloid cortex, the anterior amygdaloid area, the medial amygdaloid nucleus and the parvocellular divisions of both the basal and basal accessory nuclei. All these projections are bilateral (although the contralateral component is much smaller) and show evidence of a rostro-caudal topographic organization. Isotope injections that involve the caudal part of the lateral hypothalamic area label projections to the medial division of the central amygdaloid nucleus, to the medial and cortical nuclei and to the anterior amygdaloid area. When such caudally placed injections also involved the lateral mamillary nucleus, the lateral division of the central amygdaloid nucleus was additionally labeled. Although the medial mamillary nucleus does not project to the amygdala, there is evidence for a minor projection from the supramamillary region to the medial amygdaloid nucleus. The ventral tegmental area appears to project to the lateral division of the central nucleus and the medial portion of the substantia nigra has a small projection to both divisions of the central nucleus. All of these projections reach the amygdala by way of the so-called ventral amygdalofugal pathway, but at least some of the fibers that arise in the ventromedial nucleus run in the stria terminalis.

The efferent projections of the lateral hypothalamic area (LHA) at mid-tuberal levels were examined with the autoradiographic tracing method. Connections were observed to widespread regions of the brain, from the telencephalon to the medulla. Ascending fibers course through LHA and the lateral preoptic area and lie lateral to the diagonal band of Broca. Fibers sweep dorsally into the lateral septal nucleus, cingulum bundle and medial cortex. Although sparse projections are found to the ventromedial hypothalamic nucleus, a prominent pathway courses to the dorsal and medial parvocellular subnuclei of the paraventricular nucleus. Labeled fibers in the stria medullaris project to the lateral habenular nucleus. The central nucleus of the amygdala is encapsulated by fibers from the stria terminalis and the ventral amygdalofugal pathway. The substantia innominate, nucleus paraventricularis of the thalamus, and bed nucleus of the stria terminalis also receive LHA fibers. Three descending pathways course to the brainstem: (1) periventricular system, (2) central tegmental tract (CTT), and (3) medial forebrain bundle (MFB). Periventricular fibers travel to the ventral and lateral parts of the midbrain central gray, dorsal raphe nucleus, and laterodorsal tegmental nucleus of the pens. Dorsally coursing fibers of CTT enter the central tegmental field and the lateral and medial parabrachial nuclei. The intermediate and deep layers of the superior colliculus receive some fibers. Fibers from CTT leave the parabranchial region by descending in the ventrolateral pontine and medullary reticular formation; some of these fibers sweep dorsomedially into the nucleus tractus solitarius, dorsal motor nucleus of the vagus, and nucleus commissuralis. From MFB, fibers descend into the ventral tegmental area and to the border of the median raphe and raphe magnus nuclei.

The efferent fiber connections of the nuclei of the amygdaloid complex with subcortical structures in the basal telencephalon, hypothalamus, midbrain, and pons have been studied in the rat and cat, using the autoradiographic method for tracing axonal connections. The cortical and thalamic projections of these nuclei have been described in previous papers (Krettek and Price, ′77b,c). Although the subcortical connections of the amygdaloid nuclei are widespread within the basal forebrain and brain stem, the projections of each nucleus have been found to be well defined, and distinct from those of the other amygdaloid nuclei. The basolateral amygdaloid nucleus projects heavily to the lateral division of the bed nucleus of the stria terminalis (BNST), to the caudal part of the substantia innominata, and to the ventral part of the corpus striatum (nucleus accumbens and ventral putamen) and the olfactory tubercle; it projects more lightly to the lateral hypothalamus. The central nucleus also projects to the lateral division of the BNST and the lateral hypothalamus, but in addition it sends fibers to the lateral part of the substantia nigra and the marginal nucleus of the brachium conjunctivum. The basomedial nucleus has projections to the ventral striatum and olfactory tubercle which are similar to those of the basolateral nucleus, but it also projects to the core of the ventromedial hypothalamic nucleus and the premammillary nucleus, and to a central zone of the BNST which overlaps the medial and lateral divisions. The medial nucleus also projects to the core of the ventromedial nucleus and the premammillary nucleus, but sends fibers to the medial division of the BNST and does not project to the ventral striatum. The posterior cortical nucleus projects to the premammillary nucleus and to the medial division of the BNST, but a projection from this nucleus to the ventromedial nucleus has not been demonstrated. Projections to the “shell” of the ventromedial nucleus have been found only from the ventral part of the subiculum and from a structure at the junction of the amygdala and the hippocampal formation, which has been termed the amygdalo-hippocampal area (AHA). The AHA also sends fibers to the medial part of the BNST and the premammillary nucleus. Virtually no subcortical projections outside the amygdala itself have been demonstrated from the lateral nucleus, or from the olfactory cortical areas around the amygdala (the anterior cortical nucleus, the periamygdaloid cortex, and the posterior prepiriform cortex). However, portions of the endopiriform nucleus deep to the prepiriform cortex project to the ventral putamen, and to the lateral hypothalamus.

The spread of ventral hippocampal afterdischarge activity to nuclei of the basal diencephalon was studied in rats with fornix lesions and combined lesions of the fornix and stria terminalis. The results indicate that a major hippocampal influence on specific hypothalamic, preoptic and basal forebrain structures is conveyed by way of the amygdala's stria terminalis. An additional hippocampal influence on certain basal forebrain nuclei is consistent with projections via the ventral amygdalofugal pathway.

The participation of amygdaloid and striatal structures in the various signs of morphine withdrawal syndrome (MWS) has been investigated using two complementary approaches: intracerebral application of naloxone in various nuclei of dependent rats and effects of various lesions and transections on systemically induced MWS. In morphine dependent rats local application of naloxone (10 micrograms in 0.1 microliter solution) in the vicinity of either the central nucleus of the amygdala or the lateral anterior nucleus but not in adjacent amygdaloid or striatal nuclei elicited the jump sign. Diarrhea was more frequently elicited by application of naloxone in the striatum or centromedial amygdala than the basolateral parts of the complex. In contrast, there was no specific anatomical correlates to the remaining signs including wet shakes, paw tremor, teeth chattering and chewing. Bilateral electrolytic lesion of the central amygdala or combined transection of the stria terminalis and so-called ventral amygdalofugal pathway eliminated the jump without affecting the remaining signs. In contrast a large bilateral destruction of the entire striatrum did not significantly affect the various signs. Bilateral transection of the stria terminalis reduced only the occurrence of the wet shakes. Also, a transection of the medial forebrain bundle considerably reduced the 3 main signs, i.e. jump, wet shakes and diarrhea. These results suggest that, in analogy to the acute actions of morphine, MWS should not be considered as a unitary phenomenon but as an ensemble of signs which probably reflect the intense activation induced by naloxone in a number of brain sites consequent to the abrupt interruption of opioid actions in a dependent animal. The significance of these results is discussed with reference to previous anatomical, biochemical and behavioural studies performed on the amygdala.

Neuronal responses were recorded extracellularly in the preoptic region of 11 male castrate cats following stimulation in the 'medial' group of amygdalar nuclei (medial, basomedial, basolateral). The latency of responses varied with the site of stimulation and could be explained if connections to the preoptic region were made through both the stria terminalis and the ventral amygdalofugal pathway. Projection of 13% of orthodromically excited preoptic units to the medial basal hypothalamus was established by collision tests following stimulation in these regions. The amygdalar excitation was probably exerted through the amygdalofugal pathway. In 5/6 cats the amygdalar stimulation was successfully used to raise plasma LH levels. In one cat no preoptic units projecting to the medial basal hypothalamus were found and in the cat which failed to increase plasma LH in response to amygdala stimulation, 5 such units were found. We conclude the pathway from the amygdala through the preoptic region to the hypothalamus may not be the way in which amygdalar stimulation affects LH release in the cat. Projection of 10% of orthodromically excited preoptic units in the medial forebrain bundle was established by collision tests in 3 cats. These identified units were driven from amygdalar sites thought to project to the preoptic region by ventral amygdalofugal pathways.

Bipolar electrical stimulation of the medial amygdala, primarily the central nucleus, produced gastric ulcers and hemorrhages in rats. Prior lesions of the ventral amygdalofugal pathway prevented the pathology, whereas lesions in the stria terminalis did not. Neuroanatomical circuits which may mediate these effects are described.

The present study investigated the involvement of two amygdala pathways, the stria terminalis (ST) and the ventral amygdalofugal pathway (VAF), in the effect of post-training electrical stimulation of the amygdala on retention. Rats with implanted amygdaloid electrodes and ST lesions, VAF transections or sham pathway operations, were trained on an inhibitory avoidance task and an active avoidance task. Electrical stimulation of the amygdala was given immediately after training and retention was tested 24 h later. In rats with sham ST lesions, post-training amygdaloid stimulation impaired retention in both tasks. Lesions of the ST did not significantly affect retention in the unstimulated rats. However, the ST lesions attenuated the amnestic effect of amygdaloid stimulation. In rats with sham VAF transections, stimulation of the amygdala impaired retention in the inhibitory avoidance task but enhanced retention in the active avoidance task. Transecting the VAF impaired retention performance of the unstimulated rats in the inhibitory avoidance task. However, the VAF transections did not alter the effect of amygdaloid stimulation: in both tasks, the retention performance of stimulated rats with VAF transections did not differ from that of stimulated rats with sham transections. These findings suggest that the ST may be involved in mediating the influences of the stimulated amygdala in modulating memory storage processing in the brain.

Bilateral electrolytic lesions in the dorsal aspect of the central amygdaloid nucleus of the rat produced aphagia and adipsia which was similar to but not as severe as or identical to that observed with lesions of the lateral hypothalamus. After tube-feeding to recovery these animals showed permanent deficits in motor coordination as well as in their ability to respond normally to external stimuli. Lesions in the same lateral plane but more ventral or posterior produced none of these changes. An immediate mild, transient hyperphagia was produced by lesioning the ventral posterior aspect of the lateral amygdala, and an impaired neophobic response was observed by lesioning the dorsal aspect of the lateral amgdala. These studies show that it is possible to localize discrete areas in the amygdala which have specific effects on ingestive behaviors. It is suggested that the amygdala modulates on-going hypothalamic activity via the stria terminalis from the dorsomedial area and the ventral amygdalofugal pathway from the ventral and lateral amygdala.

Extracellular action potentials were recorded from spontaneously active septopreoptic neurones responding to amygdala stimulation in the urethane-anaesthetized rat. Initial responses were either excitation or inhibition. All responses contained an inhibitory component and were characterized according to postinhibitory excitation. Response characteristics or firing rates were not altered by ipsilateral or bilateral lesion of the stria terminalis (ST). It is suggested that impulses from the amygdala that influence ovulation, as well as several other functions, may travel in the ventral amygdalofugal pathway (VAF).

Publisher Summary Fibre degeneration resulting from coagulations in the amygdaloid complex and anterior amygdaloid area was traced by means of the Nauta–Gygax method to the following structures: posterior pole of the claustrum via capsula externa; lateral parts of the anterior amygdaloid area, rostra1 to the lesion, and prepiriform area via lateral components of the ventral amygdalofugal system; lateral preoptic region and medial part of the anterior amygdaloid area via medial components of the ventral amygdalofugal pathway; medial preoptic region, base of the septum, nucleus accumbens septi and diagonal band of Broca via stria terminalis; lateral hypothalamus and subthalamic nucleus via stria terminalis-medial forebrain bundle; posteromedial part of the dorsomedial thalamic nucleus via ansa lenticularis-inferior thalamic peduncle. Some Golgi observations on the forebrain of the mouse are presented. Several components of the medial forebrain bundle are discussed pointing out the existence throughout the lateral hypothalamus of a system of short linked cells forming the so called “bed nucleus of the medial forebrain bundle”. The chapter concludes that the three projecting systems—namely, the stria terminalis, the ventral-amygdalofugal system, and the amygdalo-thalamo-orbitofrontal system converge upon the basal forebrain region wherein they articulate with the short-linked system of cells of the medial forebrain bundle.

SummaryAfter injection of a physiologic dose of 3H-estradiol into female and male rats, radioactive labeling was found in certain neurons of the amygdala, while not in others. Labeled neurons were concentrated in the nucleus medialis; nucleus centralis; nucleus lateralis, pars anterior; nucleus basalis, pars medialis; and nucleus corticalis. In the ventroanterior portion of the hippocampus, close to the lateral ventricle, weakly labeled neurons were found. The stria terminalis, the ventral amygdalofugal pathway, and the medial corticohypothalamic tract are considered interlinking pathways for estrogen-neuron systems in the amygdala and diencephalon. Estrogen-neuron systems seem to constitute a major component of what has been regarded the “sex center” or “sex centers” in the brain.

The fields of origin of the amygdalofugal pathways in the albino rat were studied by using the Fink-Heimer technique to stain degenerating fibers and terminals in brains of animals sacrificed four and seven days after small unilateral lesions of the amygdale. A surprisingly restricted field of origin was found for the supracommissural stria terminalis — the component projecting to the ventromedial nucleus of the hypothalamus Only a lesion in the most posterior part of the cortical nucleus produced degeneration in this pathway. The postcommissural stria terminalis which apparently distributes to the bed nucleus of the stria terminalis and preoptic area originates in a more widespread area including parts of both the basolateral and corticomedial complexes. Although intense terminal degeneration could be seen within the amygdala following all lesions, long fibers projecting into the anterior amygdaloid area, lateral preoptic area and lateral hypothalamus were found only after lesions in which fibers of passage from periamygdaloid cortex could have been interrupted. Convincing evidence, therefore, of a long axon ventral amygdalofugal pathway of the rat was not found in this study.