Microstructural alterations in medial forebrain bundle are associated with interindividual pain sensitivity.

The perception of pain to noxious stimuli, also known as pain sensitivity, varies among individuals. The comprised brain structures and their white matter pathways are complex and elusive. Here, we aimed to investigate whether variation of microstructure of the medial forebrain bundle (MFB), a tract connecting the basal forebrain with the brain stem, is associated with interindividual pain sensitivity. We assessed interindividual pain sensitivity as a rating of pain intensity to heat stimuli (45, 47, and 48.9°C) in 38 healthy men (age: 27.05 ± 5.7 years). We also reconstructed the MFB using multitensor tractography from diffusion magnetic resonance imaging (dMRI) and calculated free-water corrected dMRI measures of fractional anisotropy (FAt ), radial diffusivity (RDt ), and axial diffusivity (ADt ). Lower ratings of interindividual pain intensity correlated with higher FAt and lower RDt of the MFB. As changes in FAt and RDt may reflect abnormalities in myelination, the results might be interpreted as that a lower pain rating is associated with higher degree of myelination of the MFB and could represent an inhibitory pathway of pain. Our results suggest that alteration of microstructure in the MFB contributes to the interindividual variation of pain perception.

Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression.

The medial forebrain bundle (MFB), a key structure of reward-seeking circuitry, remains inadequately characterized in humans despite its vast importance for emotional processing and development of addictions and depression. Using Diffusion Tensor Imaging Fiber Tracking (DTI FT) the authors describe potential converging ascending and descending MFB and anterior thalamic radiation (ATR) that may mediate major brain reward-seeking and punishment functions. Authors highlight novel connectivity, such as supero-lateral-branch MFB and ATR convergence, caudally as well as rostrally, in the anterior limb of the internal capsule and medial prefrontal cortex. These anatomical convergences may sustain a dynamic equilibrium between positive and negative affective states in human mood-regulation and its various disorders, especially evident in addictions and depression.

Microsurgical anatomy of the amygdaloid body and its connections.

The amygdaloid body is a limbic nuclear complex characterized by connections with the thalamus, the brainstem and the neocortex. The recent advances in functional neurosurgery regarding the treatment of refractory epilepsy and several neuropsychiatric disorders renewed the interest in the study of its functional Neuroanatomy. In this scenario, we felt that a morphological study focused on the amygdaloid body and its connections could improve the understanding of the possible  implications in functional neurosurgery. With this purpose we performed a morfological study using nine formalin-fixed human hemispheres dissected under microscopic magnification by using the fiber dissection technique originally described by Klingler. In our results the  amygdaloid body presents two divergent projection systems named dorsal and ventral amygdalofugal pathways connecting the nuclear complex with the septum and the hypothalamus. Furthermore, the amygdaloid body is connected with the hippocampus through the amygdalo-hippocampal bundle, with the anterolateral temporal cortex through the amygdalo-temporalis fascicle, the anterior commissure and the temporo-pulvinar bundle of Arnold, with the insular cortex through the lateral olfactory stria, with the ambiens gyrus, the para-hippocampal gyrus and the basal forebrain through the cingulum, and with the frontal cortex through the uncinate fascicle. Finally, the amygdaloid body is connected with the brainstem through the medial forebrain bundle. Our description of the topographic anatomy of the amygdaloid body and its connections, hopefully represents a useful tool for clinicians and scientists, both in the scope of application and speculation.

Forebrain connections in the goldfish support telencephalic homologies with land vertebrates.

Horseradish peroxidase injections into dorsomedial and dorsolateral regions of the goldfish (Carassius auratus) telencephalon demonstrate, by retrograde cell labeling, that the teleost telencephalon receives a pattern of projections from the thalamus remarkably similar to those of land vertebrates. The evidence provides support for a homology between the dorsomedial region and the corpus striatum of land vertebrates and a homology between two dorsolateral regions and the dorsal and medial pallium of land vertebrates.

Adaptation effects of medial forebrain bundle micro-electrical stimulation.

Brain micro-electrical stimulation and its applications are among the most important issues in the field of brain science and neurophysiology. Deep brain stimulation techniques have been used in different theraputic or alternative medicine applications including chronic pain control, tremor control, Parkinson's disease control and depression control. Recently, brain electrical stimulation has been used for tele-control and navigation of small animals such as rodents and birds. Electrical stimulation of the medial forebrain bundle (MFB) area has been reported to induce a pleasure sensation in rat which can be used as a virtual reward for rat navigation. In all cases of electrical stimulation, the temporal adaptation may deteriorate the instantaneous effects of the stimulation. Here, we study the adaptation effects of the MFB electrical stimulation in rats. The animals are taught to press a key in an operant conditioning chamber to self-stimulate the MFB region and receive a virtual reward for each key press. Based on the number of key presses, and statistical analyses the effects of adaptation on MFB stimulation is evaluated. The stimulation frequency were changed from 100 to 400 Hz, the amplitude were changed from 50 to 170 µA and the pulse-width were changed from 180 to 2000 µs. In the frequency of 250 Hz the adaptation effect were observed. The amplitude did not show a significant effect on MFB adaptation. For all values of pulse-widths, the adaptation occurred over two consecutive days, meaning that the number of key presses on the second day was less than the first day.

Ventral tegmental area connections to motor and sensory cortical fields in humans.

In humans, sensorimotor cortical areas receive relevant dopaminergic innervation-although an anatomic description of the underlying fiber projections is lacking so far. In general, dopaminergic projections towards the cortex originate within the ventral tegmental area (VTA) and are organized in a meso-cortico-limbic system. Using a DTI-based global tractography approach, we recently characterized the superolateral branch of the medial forebrain bundle (slMFB), a prominent pathway providing dopaminergic (and other transmitters) innervation for the pre-frontal cortex (Coenen et al., NeuroImage Clin 18:770-783, 2018). To define the connections between VTA and sensory-motor cortical fields that should contain dopaminergic fibers, we use the slMFB as a key structure to lead our fiber selection procedure: using a similar tracking-seed and tractography algorithm, we describe a dorsal extension of this slMFB that covers sensorimotor fields that are dorsally appended to pre-frontal cortical areas. This "motorMFB", that connects the VTA to sensorimotor cortical fields, can be further segregated into three sub-bundles with a seed-based fiber-selection strategy: A PFC bundle that is attendant to the pre-frontal cortex, passes the lateral VTA, runs through the border zone between the posterior and lateral ventral thalamic nucleus, and involves the pre- and postcentral gyrus. An MB bundle that is attendant to the mammillary bodies runs directly through the medial VTA, passes the lateral ventral thalamic nucleus, and involves the pre- and postcentral gyrus as well as the supplementary motor area (SMA) and the dorsal premotor cortex (dPMC). Finally, a BC bundle that is attendant to the brainstem and cerebellum runs through the lateral VTA, passes the anterior ventral thalamic nucleus, and covers the SMA, pre-SMA, and the dPMC. We, furthermore, included a fiber tracking of the well-defined dentato-rubro-thalamic tract (DRT) that is known to lie in close proximity with respect to fiber orientation and projection areas. As expected, the tract is characterized by a decussation at the ponto-mesencephal level and a projection covering the superior-frontal and precentral cortex. In addition to the physiological role of these particular bundles, the physiological and pathophysiological impact of dopaminergic signaling within sensorimotor cortical fields becomes discussed. However, some limitations have to be taken into account in consequence of the method: the transmitter content, the directionality, and the occurrence of interposed synaptic contacts cannot be specified.

The anatomy of the human medial forebrain bundle: Ventral tegmental area connections to reward-associated subcortical and frontal lobe regions.

Introduction: Despite their importance in reward, motivation, and learning there is only sparse anatomical knowledge about the human medial forebrain bundle (MFB) and the connectivity of the ventral tegmental area (VTA). A thorough anatomical and microstructural description of the reward related PFC/OFC regions and their connection to the VTA - the superolateral branch of the MFB (slMFB) - is however mandatory to enable an interpretation of distinct therapeutic effects from different interventional treatment modalities in neuropsychiatric disorders (DBS, TMS etc.). This work aims at a normative description of the human MFB (and more detailed the slMFB) anatomy with respect to distant prefrontal connections and microstructural features. Methods and material: Healthy subjects (n = 55; mean age ±â€¯SD, 40 ±â€¯10 years; 32 females) underwent high resolution anatomical magnetic resonance imaging including diffusion tensor imaging. Connectivity of the VTA and the resulting slMFB were investigated on the group level using a global tractography approach. The Desikan/Killiany parceling (8 segments) of the prefrontal cortex was used to describe sub-segments of the MFB. A qualitative overlap with Brodmann areas was additionally described. Additionally, a pure visual analysis was performed comparing local and global tracking approaches for their ability to fully visualize the slMFB. Results: The MFB could be robustly described both in the present sample as well as in additional control analyses in data from the human connectome project. Most VTA- connections reached the superior frontal gyrus, the middel frontal gyrus and the lateral orbitofrontal region corresponding to Brodmann areas 10, 9, 8, 11, and 11m. The projections to these regions comprised 97% (right) and 98% (left) of the total relative fiber counts of the slMFB. Discussion: The anatomical description of the human MFB shows far reaching connectivity of VTA to reward-related subcortical and cortical prefrontal regions - but not to emotion-related regions on the medial cortical surface - realized via the superolateral branch of the MFB. Local tractography approaches appear to be inferior in showing these far-reaching projections. Since these local approaches are typically used for surgical targeting of DBS procedures, the here established detailed map might - as a normative template - guide future efforts to target deep brain stimulation of the slMFB in depression and other disorders related to dysfunction of reward and reward-associated learning.

Tractography Study of Deep Brain Stimulation of the Anterior Cingulate Cortex in Chronic Pain: Key to Improve the Targeting.

BACKGROUND: Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a new treatment for alleviating intractable neuropathic pain. However, it fails to help some patients. The large size of the ACC and the intersubject variability make it difficult to determine the optimal site to position DBS electrodes. The aim of this work was therefore to compare the ACC connectivity of patients with successful versus unsuccessful DBS outcomes to help guide future electrode placement. METHODS: Diffusion magnetic resonance imaging (dMRI) and probabilistic tractography were performed preoperatively in 8 chronic pain patients (age 53.4 ± 6.1 years, 2 females) with ACC DBS, of whom 6 had successful (SO) and 2 unsuccessful outcomes (UOs) during a period of trialing. RESULTS: The number of patients was too small to demonstrate any statistically significant differences. Nevertheless, we observed differences between patients with successful and unsuccessful outcomes in the fiber tract projections emanating from the volume of activated tissue around the electrodes. A strong connectivity to the precuneus area seems to predict unsuccessful outcomes in our patients (UO: 160n/SO: 27n), with (n), the number of streamlines per nonzero voxel. On the other hand, connectivity to the thalamus and brainstem through the medial forebrain bundle (MFB) was only observed in SO patients. CONCLUSIONS: These findings could help improve presurgical planning by optimizing electrode placement, to selectively target the tracts that help to relieve patients' pain and to avoid those leading to unwanted effects.

The Structural Connectome of the Human Central Homeostatic Network.

Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy.

An anatomic review of thalamolimbic fiber tractography: ultra-high resolution direct visualization of thalamolimbic fibers anterior thalamic radiation, superolateral and inferomedial medial forebrain bundles, and newly identified septum pellucidum tract.

BACKGROUND: Images obtained through ultra-high-field 7.0-tesla magnetic resonance imaging with track-density imaging provide clear, high-resolution tractograms that have been hitherto unavailable, especially in deep brain areas such as the limbic and thalamic regions. This study is a largely pictorial description of the deep fiber tracts in the brain using track-density images obtained with 7.0-T diffusion-weighted imaging. METHODS: To identify the fiber tracts, we selected 3 sets of tractograms and performed interaxis correlation between them. These tractograms offered an opportunity to extract new information in areas that have previously been difficult to examine using either in vivo or in vitro human brain tractography. RESULTS: With this new technique, we identified 4 fiber tracts that have not previously been directly visualized in vivo: septum pellucidum tract, anterior thalamic radiation, superolateral medial forebrain bundle, and inferomedial forebrain bundle. CONCLUSIONS: We present the high-resolution images as a tool for researchers and clinicians working with neurodegenerative and psychiatric diseases, such as Parkinson disease, Alzheimer disease, and depression, in which the accurate positioning of deep brain stimulation is essential for precise targeting of nuclei and fiber tracts.

Limbic connections to the lateral preoptic area: a horseradish peroxidase study in the rat.

Horseradish peroxidase, 13% Sigma Type VI, was administered iontophoretically to the lateral preoptic area (LPA) of male hooded rats. Animals were perfused intracardially on the following day and brains were removed and sliced in the coronal plane into 50 microns sections. Alternate sections were processed with DAB and BDH for the brown and blue reaction products and later examined by bright and dark field microscopy for the presence and location of retrogradely labeled neurons. Results indicate that there are a significant number of limbic efferent connections to the LPA. Afferents to the LPA originate in the prefrontal corex, nucleus accumbens, diagonal band and olfactory structures, lateral and medial septum, stria hypothalamic tract and stria terminalis, the magnocellular and medial preoptic nuclei, along the extent of the medial forebrain bundle in the LPA and LH, anterior and basolateral amygdala, ventromedial caudate-putamen, stria medullaris and lateral habenula, the stellatocellular-periventricular, ventromedial, arcuate and anterior hypothalamic nuclei, the perifornical area, zona incerta, ventral medial thalamic area, ventral tegmental area of Tsai, interpeduncular nucleus, reticular zone of the substantia nigra, mesencephalic periaqueductal gray and reticular formation, all aspects of the raphe nuclei and the locus coeruleus. Results are discussed in terms of known anatomical and neurophysiological data and the similar limbic inputs observed for lateral hypothalamic neurons which are found along the extent of the medial forebrain bundle.

Projections of the medial preoptic nucleus: a Phaseolus vulgaris leucoagglutinin anterograde tract-tracing study in the rat.

The projections of the medial preoptic nucleus (MPN) were examined by making injections of the anterogradely transported lectin Phaseolus vulgaris leucoagglutinin (PHA-L) into the MPN and charting the distribution of labeled fibers. The evidence indicates that the MPN projects extensively to widely distributed regions in both the forebrain and brainstem, most of which also supply inputs to the nucleus. An important neuroendocrine role for the MPN is underscored by its extensive projections to almost all parts of the periventricular zone of the hypothalamus, including the anteroventral periventricular, anterior part of the periventricular, paraventricular (PVH), and arcuate nuclei, and a role in autonomic mechanisms is indicated by projections to such regions as the dorsal and lateral parvicellular parts of the PVH, the lateral parabrachial nucleus, and the nucleus of the solitary tract. Other projections of the MPN suggest participation in the initiation of specific motivated behaviors. For example, inputs to two nuclei of the medial zone of the hypothalamus, the ventromedial and dorsomedial nuclei, may be related to the control of reproductive and ingestive behaviors, respectively, although the possible functional significance of a strong projection to the ventral premammillary nucleus is presently unclear. The execution of these behaviors may involve activation of somatomotor regions via projections to the substantia innominata, zona incerta, ventral tegmental area, and pedunculopontine nucleus. Similarly, inputs to other regions that project directly to the spinal cord, such as the periaqueductal gray, the laterodorsal tegmental nucleus, certain medullary raphe nuclei, and the magnocellular reticular nucleus may also be involved in modulating somatic and/or autonomic reflexes. Finally, the MPN may influence a wide variety of physiological mechanisms and behaviors through its massive projections to areas like the ventral part of the lateral septal nucleus, the bed nucleus of the stria terminalis, the lateral hypothalamic area, the supramammillary nucleus, and the ventral tegmental area, all of which have extensive connections with regions along the medial forebrain bundle. Although the PHA-L method does not allow a clear demonstration of possible differential projections from each subdivision of the MPN, our results suggest that each of them does give rise to a unique pattern of outputs.(ABSTRACT TRUNCATED AT 400 WORDS)

Some telencephalic connections in the frog, Rana pipiens.

Some afferent, efferent and intrinsic connections of the telencephalon of Rana pipiens were studied using a horseradish peroxidase method. Afferents to the telencephalon from thalamic and brain stem cell groups were demonstrated. These findings, taken together with the results of previous studies, indicate that separate thalamic cell groups project visual, auditory and somatosensory information onto the striatum. A separate thalamic cell group projects to the medial telencephalic wall and probably conveys visual and somatosensory information. These telencephalic afferent systems do not appear to be directly comparable to those of birds and reptiles. Additionally, some telencephalic afferents demonstrated in previous studies using anterograde degeneration techniques were confirmed, and some intratelencephalic connections were identified.

An autoradiographic study of the efferent connections of the lateral hypothalamic area in the rat.

The efferent connections of the lateral hypothalamic area (LHA) have been analyzed in a series of 30 rat brains with injections of 3H-amino acids into different parts of the area and the surrounding regions. Our findings indicate that all parts of the LHA contribute ascending and descending fibers to the medial forebrain bundle, and also project medially to certain of the adjoining hypothalamic nuclei. All levels of the LHA appear to send some fibers to a continuous group of structures that extends from the medial septal-diagonal band complex rostrally, through the lateral preoptic and lateral hypothalamic areas to the mammillary complex and the ventral tegmental area caudally. In addition, it is evident that cells at different levels within the LHA may have differential projections. Thus, the anterior and lateral parts of the LHA also appear to project substantially to the anterior hypothalamic area, the ventromedial and dorsomedial hypothalamic nuclei, the parataenial and paraventricular nuclei of the thalamus, and the medial part of the lateral habenular nucleus. Similarly, cells in the tuberal and posterior parts of the LHA project to the central gray, the longest projections from the posterior region reaching as far caudally as the central tegmental field, the parabrachial nucleus, the locus coeruleus, and the superior central and dorsal nuclei of the raphe. Viewed as a whole, the LHA is therefore well-suited to integrate inputs from the limbic system and brainstem and to relay them on the one hand to the medial zone of the hypothalamus and on the other to virtually every structure closely associated with the medial forebrain bundle and to the nuclei of origin of the major ascending monoaminergic systems.

The morphology and connections of the posterior hypothalamus in the cynomolgus monkey (Macaca fascicularis). I. Cytoarchitectonic organization.

The cytoarchitectonic organization of the posterior hypothalamus of the cynomolgus monkey (Macaca fascicularis) was analyzed in Nissl, Golgi, acetylcholinesterase, and reduced silver preparations. The region consists of a number of cell masses that differ considerably in their discreteness and in the homogeneity of their neuronal populations. The nuclei identified include: the medial mamillary nucleus (in which at least three distinct subdivisions can be recognized--a pars medialis, a pars lateralis, and a pars basalis); the small-celled nucleus intercalatus; the large-celled lateral mamillary nucleus; a single premamillary nucleus; the tuberomamillary nucleus; the posterior hypothalamic nucleus; the caudal extension of the lateral hypothalamic area; the supramamillary area; and the paramamillary nucleus (which appears to correspond to the nucleus of the ansa lenticularis of other workers). As a basis for the subsequent experimental study of the efferent connections of the posterior hypothalamus, the location of each of these cell masses is described and illustrated in a series of low-power photomicrographs, as are the form and distribution of the resident neuronal populations of the various components of the mamillary complex as seen in Golgi preparations.

Afferent and efferent connections of small nuclei in the posterolateral hypothalamus of the cat.

Four separate neuronal groups, termed the anterior, dorsal, ventral, and posterior nuclei of the juxtamamillary complex, were labeled retrogradely from the thalamic lateral posterior nucleus with horseradish peroxidase. The retrograde labeling was predominantly ipsilateral in the anterior, dorsal, and ventral nuclei, while it was predominantly contralateral in the posterior nucleus. The anterior, dorsal, and posterior nuclei could be detected clearly in Nissl sections; the ventral nucleus was only identified by horseradish peroxidase transport. The distribution of afferents to the juxtamamillary nuclei was investigated with the Fink-Heimer technique. Following lesions of the olfactory tubercle and underlying structures, degenerating fibers in the medial forebrain bundle terminated discretely in the juxtamamillary nuclei. The dense terminal pattern conformed to the borders of the nuclei and was sometimes visible macroscopically. This pattern resembles that of medial forebrain bundle afferents to nuclei gemini in the rabbit and rat. Since the anatomical portions of these nuclei are also similar, it was concluded that the nuclei of the cat are comparable with the nuclei gemini in the rabbit and rat.

Ascending projections of the mammillary region in the pigeon: emphasis on telencephalic connections.

The ascending projections of the mammillary region of the hypothalamus and adjacent posterolateral hypothalamus were investigated by autoradiographic and horseradish peroxidase histochemical techniques. Analysis of the anterograde data revealed that the main contingent of mammillary fibers ascends in the medial forebrain bundle (MFB) in the lateral hypothalamic area. These fibers distribute to a number of telencephalic regions via three pathways. (1) Fibers course dorsomedially into the medial and lateral parts of the septum and continue into the hippocampus with a dense terminal field in the parahippocampal area. (2) Laterally coursing fibers project to area corticoidea dorsolateralis, area temporo-parieto-occipitalis, cortex piriformis, and the posterior part of archistriatum. (3) The fibers remaining in the MFB ascend into the "ventral paleostriatum," olfactory tubercle, and into the lateral and ventral borders of the rostral portion of lobus parolfactorius (LPO). Numerous fibers leave the LPO region and course dorsally into the deep layer of the Wulst, hyperstriatum dorsale (HD). Many fibers continue dorsolaterally through the HD and enter an unnamed region of the dorsolateral telencephalon (lateral to the vallecula) at the level of the olfactory bulb. Retrograde transport experiments revealed that the perikarya of origin-of-fiber projections to the parahippocampal area and to the rostral, dorsolateral telencephalon reside not only in nucleus mammillaris lateralis but also in posterolateral hypothalamic cells rostral and dorsal to this nucleus. The projection of these hypothalamic cells to the hippocampal formation and many other telencephalic regions in birds suggests that these cells are similar to the mammalian supramammillary nucleus and posterolateral hypothalamus rather than the mammillary nuclei.

Distribution and projections of cholecystokinin-immunoreactive neurons in the hypothalamic paraventricular nucleus of rat.

Analysis of coronal sections from colchicine-treated rat brains reveals that CCK-immunoreactivity (CCK-ir) is present in two distinguishable neuronal systems in the paraventricular nucleus (PVN). More than 60% of these cells were found to be typical parvicellular neurons; the remainder were magnocellular neurons. The magnocellular CCK-ir neurons were concentrated in the medial magnocellular subdivision, while more caudally they formed a ring around a zone of unstained magnocellular neurons. Immunostained parvicellular neurons predominate in medial and periventricular parvicellular subdivisions. The efferent projections of CCK-ir neurons were investigated by looking for retrograde accumulation of CCK-ir in cell bodies after selective knife cuts. A parasagittal cut of the lateral retrochiasmatic area as well as transection of the rostral median eminence resulted in an accumulation of CCK-ir material in a large number of both parvi- and magnocellular neurons. After pituitary stalk lesions, however, increased staining was only seen in magnocellular neurons. It is inferred that the magnocellular (presumed oxytocin-CCK) cells send their axons to the pituitary, whereas axons of CCK-ir parvicellular neurons appear to terminate in the median eminence. After transection of the medial forebrain bundle (MFB), immunostaining increased in a small number of scattered transected fibers proximal to the knife cut and in a few perikarya in the PVN, indicating that very few CCK cells may send descending fibers to the lower brainstem.

The morphology and connections of the posterior hypothalamus in the cynomolgus monkey (Macaca fascicularis). II. Efferent connections.

The efferent connections of the posterior hypothalamus have been analyzed autoradiographically in a series of eight cynomolgus monkey (Macaca fascicularis) brains with injections of 3H-amino acids in different regions of the mamillary complex and the surrounding areas. The medial mamillary nucleus was found to project through the mamillothalamic tract to the ipsilateral anteroventral, anteromedial, and interanteromedial nuclei, and by way of the mamillotegmental tract principally to the deep tegmental nucleus (of Gudden). It also appears to contribute fibers to the medial forebrain bundle, some of which reach as far rostrally as the medial septal nucleus. The lateral mamillary nucleus projects through the mamillothalamic tract bilaterally upon the anterodorsal nuclei of the thalamus, and through the mamillotegmental system to the dorsal tegmental nucleus; it also appears to contribute fibers to the medial forebrain bundle. The supramamillary area has extensive ascending and descending connections that are distributed with the medial forebrain bundle to the hypothalamus and rostral midbrain; in addition, it gives rise to an unusually well-defined projection to field CA2 of the hippocampus and to a narrow zone overlying the outer part of the granule cell layer and the adjoining part of the molecular layer of the dentate gyrus. We have not been able to distinguish the connections of the posterior hypothalamic nucleus from those of the caudal part of the lateral hypothalamic area: they both appear to contribute substantially to the ascending components of the medial forebrain bundle, and through its descending projection to the tegmental fields of the midbrain, the nucleus centralis superior of the raphe complex, the locus coeruleus, and the central gray as far caudally as the facial nerve. Their further projections to the spinal cord were not examined. Viewed broadly, and in the light of previous work, our observations confirm, once again, the constancy of the connections of the hypothalamus in the mammalian brain, and the pivotal position that the posterior hypothalamus occupies in the elaborate system of connections that links the limbic areas of the forebrain with the complex of structures that Nauta has aptly designated the "midbrain limbic region."

Origins of substance P-containing fibers in the lateral septal area of young rats: immunohistochemical analysis of experimental manipulations.

The majority of substance P-like immunoreactive (SPLI) fibers in the lateral septal area (LS) are supplied by SPLI cells in the area (BAL) between the anterior hypothalamic nucleus and the lateral hypothalamus, and by those in the nucleus latero-dorsalis tegmenti (TLD). These conclusions are based on following: (1) Unilateral destruction of the BAL resulted in an ipsilateral decrease in the septal SPLI fibers similar to that seen after the destruction of the TLD, and (2) simultaneous destruction of the BAL and TLD caused a marked reduction of SPLI fibers in the LS on the operated side. The possibility that the destruction of the BAL affected the ascending SPLI system from the TLD seems to be excluded, because (1) the destruction of the TLD resulted in a decrease in SPLI fibers in the ipsilateral medial forebrain bundle (MFB), but failed to reduce the number of SPLI fibers in the BAL, and (2) the destruction of the BAL caused a decrease in SPLI fibers in the perifornical area rostral to the lesion, but failed to reduce the number of SPLI fibers in the MFB. These facts further suggest that ascending SPLI fibers from the BAL travel in the perifornical area and those from the TLD pass through the MFB. It should be noted that a few SPLI fibers remained intact following the simultaneous destruction of the BAL and TLD. The present study suggests that these remaining SPLI fibers might be innervated by intrinsic SPLI cells. In support of this, several SPLI cells were detected in the septal area after colchicine pretreatment.