Medial superior olive in the rat: Anatomy, sources of input and axonal projections.

Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential aspect of binaural hearing: the ability of animals to localize the sources of low-frequency sounds by detecting the interaural time difference (ITD), that is the difference in the time at which the sound arrives at each ear. In mammals, ITDs are mostly encoded in the medial superior olive (MSO), one of the main nuclei of the superior olivary complex (SOC). Because of their small heads and high frequency hearing range, rats and mice are often considered unable to use ITDs for sound localization. Moreover, their MSO is frequently viewed as too small or insignificant compared to that of mammals that use ITDs to localize sounds, including cats and gerbils. However, recent research has demonstrated remarkable similarities between most morphological and physiological features of mouse MSO neurons and those of MSO neurons of mammals that use ITDs. In this context, we have analyzed the structure and neural afferent and efferent connections of the rat MSO, which had never been studied by injecting neuroanatomical tracers into the nucleus. The rat MSO spans the SOC longitudinally. It is relatively small caudally, but grows rostrally into a well-developed column of stacked bipolar neurons. By placing small, precise injections of the bidirectional tracer biotinylated dextran amine (BDA) into the MSO, we show that this nucleus is innervated mainly by the most ventral and rostral spherical bushy cells of the anteroventral cochlear nucleus of both sides, and by the most ventrolateral principal neurons of the ipsilateral medial nucleus of the trapezoid body. The same experiments reveal that the MSO densely innervates the most dorsolateral region of the central nucleus of the inferior colliculus, the central region of the dorsal nucleus of the lateral lemniscus, and the most lateral region of the intermediate nucleus of the lateral lemniscus of its own side. Therefore, the MSO is selectively innervated by, and sends projections to, neurons that process low-frequency sounds. The structural and hodological features of the rat MSO are notably similar to those of the MSO of cats and gerbils. While these similarities raise the question of what functions other than ITD coding the MSO performs, they also suggest that the rat MSO is an appropriate model for future MSO-centered research.

Afferent and efferent connections of the nucleus prethalamicus in the yellowfin goby Acanthogobius flavimanus.

The nucleus prethalamicus (PTh) receives fibers from the optic tectum and then projects to the dorsal telencephalon in the yellowfin goby Acanthogobius flavimanus. However, it remained unclear whether the PTh is a visual relay nucleus, because the optic tectum receives not only visual but also other sensory modalities. Furthermore, precise telencephalic regions receiving prethalamic input remained unknown in the goby. We therefore investigated the full set of afferent and efferent connections of the PTh by direct tracer injections into the nucleus. Injections into the PTh labeled cells in the optic tectum, ventromedial thalamic nucleus, central and medial parts of the dorsal telencephalon, and caudal lobe of the cerebellum. We found that the somata of most tecto-prethalamic neurons are present in the stratum periventriculare. Their dendrites ascend to reach the major retinorecipient layers of the tectum. The PTh is composed of two subnuclei (medial and lateral) and topographic organization was appreciated only for tectal projections to the lateral subnucleus (PTh-l), which also receives sparse retinal projections. In contrast, the medial subnucleus receives fibers only from the medial tectum. We found that the PTh projects to nine subregions in the dorsal telencephalon and four in the ventral telencephalon. Furthermore, cerebellar injections revealed that cerebello-prethalamic fibers cross the midline twice to innervate the PTh-l on both sides. The present study is the first detailed report on the full set of the connections of PTh, which suggests that the PTh relays visual information from the optic tectum to the telencephalon.

Anatomical evidence for the efferent pathway from the hypothalamus to autonomic innervation in the anterior chamber structures of eyes.

The autonomic innervation in the anterior chamber (AC) structures might play an efferent role in neural intraocular pressure (IOP) regulation, the center of which is thought to be located in the hypothalamus. In this study, we identified the efferent pathway from the hypothalamus to the autonomic innervation in the AC structures. Retrograde trans-multisynaptic pseudorabies virus (PRV) expressing green or red fluorescent protein, PRV531 and PRV724, was injected into the right and left AC of five rats, respectively; PRV531 was injected into the right AC of another five rats, and a non-trans-synaptic tracer, FAST Dil, was injected into the right AC of five rats as a control. Fluorescence signals in autonomic ganglia,the spinal cord and the central nervous system (CNS) were observed. Seven days after FAST Dil right AC injection, FAST Dil-labeled neurons were observed in the ipsilateral autonomic ganglia, including the superior cervical ganglion, pterygopalatine ganglion, and ciliary ganglion, but not in the CNS. Four and a half days after PRV531 injection into the right AC, PRV531-labeled neurons could be observed in the ipsilateral autonomic ganglia and bilateral hypothalamus nuclei, especially in the suprachiasmatic nucleus, paraventricular nucleus, dorsomedial hypothalamus, perifornical hypothalamus and ventral mammillary nucleus. Fluorescence signals of PRV531 mainly located in the ipsilateral autonomic preganglionic nuclei (Edinger-Westphal nucleus, superior salivatory nucleus and intermediolateral nucleus), but not in sensory trigeminal nuclei. Four and a half days after PRV531 right AC injection and PRV724 left AC injection, PRV531-labeled, PRV724-labeled, and double-labeled neurons could be observed in the above mentioned bilateral hypothalamus nuclei; but few contralateral infection-involving neurons (including double-labeled neurons) could be detected in the autonomic preganglionic nuclei. Our results indicate that there exist a both crossed and uncrossed hypothalamo-pre-parasympathetic and -pre-sympathetic tracts in the efferent pathways between the bilateral hypothalamic nuclei and the autonomic innervation of the bilateral AC.

What you learn & when you learn it: Impact of early bilingual & music experience on the structural characteristics of auditory-motor pathways.

Music and language engage the dorsal auditory pathway, linked by the arcuate fasciculus (AF). Sustained practice in these activities can modify brain structure, depending on length of experience but also age of onset (AoO). To study the impact of early experience on brain structure we manually dissected the AF in bilinguals with and without music training (MT) who differed in the AoO of their second language (L2), or MT. We found the usual left-greater-than-right asymmetry in the volume of the long segment (LS) of the AF across all groups. However, simultaneous exposure to two languages from birth enhanced this leftward asymmetry, while early start of MT (≤7) enhanced the right LS macrostructure, reducing the normative asymmetry. Thus, immersive exposure to an L2 in the first year of life can produce long-term plastic effects on the left LS, which is considered to be largely under genetic control, while deliberate music training in early childhood alters the right LS, whose structure appears more open to experience. These findings show that AoO of specific experience plays a key role in a complex gene-environment interaction model where normative brain maturation is differentially impacted by diverse intensive auditory-motor experiences at different points during development.

Pretectal projections to the oculomotor cerebellum in hummingbirds (Calypte anna), zebra finches (Taeniopygia guttata), and pigeons (Columba livia).

In birds, optic flow is processed by a retinal-recipient nucleus in the pretectum, the nucleus lentiformis mesencephali (LM), which then projects to the cerebellum, a key site for sensorimotor integration. Previous studies have shown that the LM is hypertrophied in hummingbirds, and that LM cell response properties differ between hummingbirds and other birds. Given these differences in anatomy and physiology, we ask here if there are also species differences in the connectivity of the LM. The LM is separated into lateral and medial subdivisions, which project to the oculomotor cerebellum and the vestibulocerebellum. In pigeons, the projection to the vestibulocerebellum largely arises from the lateral LM; the projection to the oculomotor cerebellum largely arises from the medial LM. Here, using retrograde tracing, we demonstrate differences in the distribution of projections in these pathways between Anna's hummingbirds (Calypte anna), zebra finches (Taeniopygia guttata), and pigeons (Columba livia). In all three species, the projections to the vestibulocerebellum were largely from lateral LM. In contrast, projections to the oculomotor cerebellum in hummingbirds and zebra finches do not originate in the medial LM (as in pigeons) but instead largely arise from pretectal structures just medial, the nucleus laminaris precommissuralis and nucleus principalis precommissuralis. These species differences in projection patterns provide further evidence that optic flow circuits differ among bird species with distinct modes of flight.

Missing motoric manipulations: rethinking the imaging of the ventral striatum and dopamine in human reward.

Human neuroimaging studies of natural rewards and drugs of abuse frequently assay the brain's response to stimuli that, through Pavlovian learning, have come to be associated with a drug's rewarding properties. This might be characterized as a 'sensorial' view of the brain's reward system, insofar as the paradigms are designed to elicit responses to a reward's (drug's) sight, aroma, or flavor. A different field of research nevertheless suggests that the mesolimbic dopamine system may also be critically involved in the motor behaviors provoked by such stimuli. This brief review and commentary surveys some of the preclinical data supporting this more "efferent" (motoric) view of the brain's reward system, and discusses what such findings might mean for how human brain imaging studies of natural rewards and drugs of abuse are designed.

A Sensorimotor Pathway via Higher-Order Thalamus.

We now know that sensory processing in cortex occurs not only via direct communication between primary to secondary areas, but also via their parallel cortico-thalamo-cortical (i.e., trans-thalamic) pathways. Both corticocortical and trans-thalamic pathways mainly signal through glutamatergic class 1 (driver) synapses, which have robust and efficient synaptic dynamics suited for the transfer of information such as receptive field properties, suggesting the importance of class 1 synapses in feedforward, hierarchical processing. However, such a parallel arrangement has only been identified in sensory cortical areas: visual, somatosensory, and auditory. To test the generality of trans-thalamic pathways, we sought to establish its presence beyond purely sensory cortices to determine whether there is a trans-thalamic pathway parallel to the established primary somatosensory (S1) to primary motor (M1) pathway. We used trans-synaptic viral tracing, optogenetics in slice preparations, and bouton size analysis in the mouse (both sexes) to document that a circuit exists from layer 5 of S1 through the posterior medial nucleus of the thalamus to M1 with glutamatergic class 1 properties. This represents a hitherto unknown, robust sensorimotor linkage and suggests that the arrangement of parallel direct and trans-thalamic corticocortical circuits may be present as a general feature of cortical functioning.SIGNIFICANCE STATEMENT During sensory processing, feedforward pathways carry information such as receptive field properties via glutamatergic class 1 synapses, which have robust and efficient synaptic dynamics. As expected, class 1 synapses subserve the feedforward projection from primary to secondary sensory cortex, but also a route through specific higher-order thalamic nuclei, creating a parallel feedforward trans-thalamic pathway. We now extend the concept of cortical areas being connected via parallel, direct, and trans-thalamic circuits from purely sensory cortices to a sensorimotor cortical circuit (i.e., primary sensory cortex to primary motor cortex). This suggests a generalized arrangement for corticocortical communication.

Laterality of cerebellar afferent and efferent pathways in a healthy right-handed population: A diffusion tensor imaging study.

The cerebellum communicates with the cerebral cortex through the cortico-ponto-cerebellar tract (CPCT, cerebellar afferent) and the dentato-rubro-thalamo-cortical tract (DRTCT, cerebellar efferent). This study explored the laterality of CPCT and DRTCT in a right-handed population. Forty healthy right-handed subjects (18 males and 22 females with age range of 26-79 years old) who underwent diffusion tensor imaging (DTI) were retrospectively enrolled. Bilateral CPCT, DRTCT, and the corticospinal tract (CST) were reconstructed using probabilistic diffusion tensor tractography (DTT). Tract volume (TV) and fractional anisotropy (FA) were compared between dominant and non-dominant tracts. Subjects were divided into age groups (20-40, 41-60, and 61-80 years), and the DTI-derived parameters of the groups were compared to determine age-related differences. TV and FA of non-dominant CPCT were higher than those of dominant CPCT, and the dominant CST was higher than the non-dominant CST. The TV and FA of DRTCT showed no side-to-side difference. The 61-80 years age group had the highest TV of the dominant and non-dominant DRTCT among the three groups and the highest FA of the non-dominant CPCT and DRTCT. The results revealed the structural characteristics of CPCT and DRTCT using probabilistic DTT. Normal asymmetric patterns and age-related changes in cerebellar white matter tracts may be important to researchers investigating cerebro-cerebellar structural connectivity.

Optogenetic dissection of descending behavioral control in Drosophila.

In most animals, the brain makes behavioral decisions that are transmitted by descending neurons to the nerve cord circuitry that produces behaviors. In insects, only a few descending neurons have been associated with specific behaviors. To explore how descending neurons control an insect's movements, we developed a novel method to systematically assay the behavioral effects of activating individual neurons on freely behaving terrestrial D. melanogaster. We calculated a two-dimensional representation of the entire behavior space explored by these flies, and we associated descending neurons with specific behaviors by identifying regions of this space that were visited with increased frequency during optogenetic activation. Applying this approach across a large collection of descending neurons, we found that (1) activation of most of the descending neurons drove stereotyped behaviors, (2) in many cases multiple descending neurons activated similar behaviors, and (3) optogenetically activated behaviors were often dependent on the behavioral state prior to activation.

White-matter structural connectivity predicts short-term melody and rhythm learning in non-musicians.

Music learning has received increasing attention in the last decades due to the variety of functions and brain plasticity effects involved during its practice. Most previous reports interpreted the differences between music experts and laymen as the result of training. However, recent investigations suggest that these differences are due to a combination of genetic predispositions with the effect of music training. Here, we tested the relationship of the dorsal auditory-motor pathway with individual behavioural differences in short-term music learning. We gathered structural neuroimaging data from 44 healthy non-musicians (28 females) before they performed a rhythm- and a melody-learning task during a single behavioural session, and manually dissected the arcuate fasciculus (AF) in both hemispheres. The macro- and microstructural organization of the AF (i.e., volume and FA) predicted the learning rate and learning speed in the musical tasks, but only in the right hemisphere. Specifically, the volume of the right anterior segment predicted the synchronization improvement during the rhythm task, the FA in the right long segment was correlated with the learning rate in the melody task, and the volume and FA of the right whole AF predicted the learning speed during the melody task. This is the first study finding a specific relation between different branches within the AF and rhythmic and melodic materials. Our results support the relevant function of the AF as the structural correlate of both auditory-motor transformations and the feedback-feedforward loop, and suggest a crucial involvement of the anterior segment in error-monitoring processes related to auditory-motor learning. These findings have implications for both the neuroscience of music field and second-language learning investigations.

Olivocochlear efferents: Their action, effects, measurement and uses, and the impact of the new conception of cochlear mechanical responses.

The anatomy and physiology of olivocochlear (OC) efferents are reviewed. To help interpret these, recent advances in cochlear mechanics are also reviewed. Lateral OC (LOC) efferents innervate primary auditory-nerve (AN) fiber dendrites. The most important LOC function may be to reduce auditory neuropathy. Medial OC (MOC) efferents innervate the outer hair cells (OHCs) and act to turn down the gain of cochlear amplification. Cochlear amplification had been thought to act only through basilar membrane (BM) motion, but recent reports show that motion near the reticular lamina (RL) is amplified more than BM motion, and that RL-motion amplification extends to several octaves below the local characteristic frequency. Data on efferent effects on AN-fiber responses, otoacoustic emissions (OAEs) and human psychophysics are reviewed and reinterpreted in the light of the new cochlear-mechanical data. The possible origin of OAEs in RL motion is considered. MOC-effect measuring methods and MOC-induced changes in human responses are also reviewed, including that ipsilateral and contralateral sound can produce MOC effects with different patterns across frequency. MOC efferents help to reduce damage due to acoustic trauma. Many, but not all, reports show that subjects with stronger contralaterally-evoked MOC effects have better ability to detect signals (e.g. speech) in noise, and that MOC effects can be modulated by attention.

Reactivation or transformation? Motor memory consolidation associated with cerebral activation time-locked to sleep spindles.

Motor memory consolidation is thought to depend on sleep-dependent reactivation of brain areas recruited during learning. However, up to this point, there has been no direct evidence to support this assertion in humans, and the physiological processes supporting such reactivation are unknown. Here, simultaneous electroencephalographic and functional magnetic resonance imaging (EEG-fMRI) recordings were conducted during post-learning sleep to directly investigate the spindle-related reactivation of a memory trace formed during motor sequence learning (MSL), and its relationship to overnight enhancement in performance (reflecting consolidation). We show that brain regions within the striato-cerebello-cortical network recruited during training on the MSL task, and in particular the striatum, were also activated during sleep, time-locked to spindles. Interestingly, the consolidated trace in the striatum was not simply strengthened, but was transformed/reorganized from rostrodorsal (associative) to caudoventral (sensorimotor) subregions. Moreover, the degree of the reactivation was correlated with overnight improvements in performance. Altogether, the present findings demonstrate that striatal reactivation linked to sleep spindles in the post-learning night, is related to motor memory consolidation.

Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei.

The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR) and caudal dorsal raphe nucleus (DRC), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions or the MnR and additionally examined the transmitter phenotype of major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques. Besides receiving inputs from MHb and also LHb, we found that IP is reciprocally interconnected mainly with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and laterodorsal tegmental nucleus. The bidirectional connections between IP and MnR proved to be primarily GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas major ascending projections, including focal projections to ventral hippocampus, ventrolateral septum, and LHb originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures that modulate hippocampal theta activity and forms a node linking MHb and LHb with this network, and the hippocampus. Moreover, they support a cardinal role of GABAergic IP/MnR interconnections in the behavioral response to nicotine.

Vagal neurocircuitry and its influence on gastric motility.

A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

Anatomical basis of the coordination between smooth and striated urethral and anal sphincters: loops of regulation between inferior hypogastric plexus and pudendal nerve. Immuno-histological study with 3D reconstruction.

PURPOSE: (1) Describe both nervous pathways to the sphincters, and highlight the anatomical support of their coordination. (2) Obtain a 3D representation of this complex innervation system. METHODS: A computer-assisted anatomical dissection technique was used. Serial histological sections were cut in the pelvis of four female human foetuses (aged 19-32 weeks of gestation). The sections were treated with conventional staining, and with seven different immunostainings. The sections were digitalized and, finally, a 3D representation was built from the corresponding images. RESULTS: Myelinated and sensory fibres were detected at the inferior hypogastric plexus (IHP) level. Our analysis showed that most of the afferent sensory fibres come from the urinary and anal sphincters through the anterior and posterior branches of the IHP respectively. A highly positive nitrergic (anti-NOS1) and sensitive (anti-CGRP) labelling was found in the external layer of the urethral sphincter. The 3D representation allowed describing the two components of the innervation system. A sensory-motor regulation loop was found for both sphincters. CONCLUSION: A 3D description of the components of both nervous pathways to the sphincters has been established. Our findings on the innervation of the sphincters tend to question the classical infra/supra levatorian muscle description. The coordinated work of the internal and external layers of the anal and urethral sphincter is probably mediated by multiple roles regulation.

Commentary on: Efferent connections of the parabrachial nucleus in the rat. C.B. Saper and A.D. Loewy, Brain Research 197:291-317, 1980.

By the late 1970׳s, the pathways had been identified from neurons in the nucleus of the solitary tract that control visceral sensory inflow and from the paraventricular nucleus and lateral hypothalamus that directly innervate the autonomic preganglionic neurons, thereby controlling autonomic outflow. However, the connections between the two were not yet clear. This paper identified the parabrachial nucleus as a key intermediary, receiving the bulk of outflow from the nucleus of the solitary tract and distributing it to a set of brainstem and forebrain sites that constituted a central autonomic control network. This work also identified the insular cortex as a key visceral sensory cortical area. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation.

OBJECT The dentatorubrothalamic tract (DRTT) is the major efferent cerebellar pathway arising from the dentate nucleus (DN) and decussating to the contralateral red nucleus (RN) and thalamus. Surprisingly, hemispheric cerebellar output influences bilateral limb movements. In animals, uncrossed projections from the DN to the ipsilateral RN and thalamus may explain this phenomenon. The aim of this study was to clarify the anatomy of the dentatorubrothalamic connections in humans. METHODS The authors applied advanced deterministic fiber tractography to a template of 488 subjects from the Human Connectome Project (Q1-Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dissection of cadaveric brains prepared according to Klingler's method. RESULTS The authors identified the "classic" decussating DRTT and a corresponding nondecussating path (the nondecussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentatorubro tract and the nondecussating dentatorubro tract. The left nd-DRTT encompasses 21.7% of the tracts and 24.9% of the volume of the left superior cerebellar peduncle, and the right nd-DRTT encompasses 20.2% of the tracts and 28.4% of the volume of the right superior cerebellar peduncle. CONCLUSIONS The connections of the DN with the RN and thalamus are bilateral, not ipsilateral only. This affords a potential anatomical substrate for bilateral limb motor effects originating in a single cerebellar hemisphere under physiological conditions, and for bilateral limb motor impairment in hemispheric cerebellar lesions such as ischemic stroke and hemorrhage, and after resection of hemispheric tumors and arteriovenous malformations. Furthermore, when a lesion is located on the course of the dentatorubrothalamic system, a careful preoperative tractographic analysis of the relationship of the DRTT, nd-DRTT, and the lesion should be performed in order to tailor the surgical approach properly and spare all bundles.

Combining task-evoked and spontaneous activity to improve pre-operative brain mapping with fMRI.

Noninvasive localization of brain function is used to understand and treat neurological disease, exemplified by pre-operative fMRI mapping prior to neurosurgical intervention. The principal approach for generating these maps relies on brain responses evoked by a task and, despite known limitations, has dominated clinical practice for over 20years. Recently, pre-operative fMRI mapping based on correlations in spontaneous brain activity has been demonstrated, however this approach has its own limitations and has not seen widespread clinical use. Here we show that spontaneous and task-based mapping can be performed together using the same pre-operative fMRI data, provide complimentary information relevant for functional localization, and can be combined to improve identification of eloquent motor cortex. Accuracy, sensitivity, and specificity of our approach are quantified through comparison with electrical cortical stimulation mapping in eight patients with intractable epilepsy. Broad applicability and reproducibility of our approach are demonstrated through prospective replication in an independent dataset of six patients from a different center. In both cohorts and every individual patient, we see a significant improvement in signal to noise and mapping accuracy independent of threshold, quantified using receiver operating characteristic curves. Collectively, our results suggest that modifying the processing of fMRI data to incorporate both task-based and spontaneous activity significantly improves functional localization in pre-operative patients. Because this method requires no additional scan time or modification to conventional pre-operative data acquisition protocols it could have widespread utility.

The centrally projecting Edinger-Westphal nucleus--I: Efferents in the rat brain.

The oculomotor accessory nucleus, often referred to as the Edinger-Westphal nucleus [EW], was first identified in the 17th century. Although its most well known function is the control of pupil diameter, some controversy has arisen regarding the exact location of these preganglionic neurons. Currently, the EW is thought to consist of two different parts. The first part [termed the preganglionic EW-EWpg], which controls lens accommodation, choroidal blood flow and pupillary constriction, primarily consists of cholinergic cells that project to the ciliary ganglion. The second part [termed the centrally projecting EW-EWcp], which is involved in non-ocular functions such as feeding behavior, stress responses, addiction and pain, consists of peptidergic neurons that project to the brainstem, the spinal cord and prosencephalic regions. However, in the literature, we found few reports related to either ascending or descending projections from the EWcp that are compatible with its currently described functions. Therefore, the objective of the present study was to systematically investigate the ascending and descending projections of the EW in the rat brain. We injected the anterograde tracer biotinylated dextran amine into the EW or the retrograde tracer cholera toxin subunit B into multiple EW targets as controls. Additionally, we investigated the potential EW-mediated innervation of neuronal populations with known neurochemical signatures, such as melanin-concentrating hormone in the lateral hypothalamic area [LHA] and corticotropin-releasing factor in the central nucleus of the amygdala [CeM]. We observed anterogradely labeled fibers in the LHA, the reuniens thalamic nucleus, the oval part of the bed nucleus of the stria terminalis, the medial part of the central nucleus of the amygdala, and the zona incerta. We confirmed our EW-LHA and EW-CeM connections using retrograde tracers. We also observed moderate EW-mediated innervation of the paraventricular nucleus of the hypothalamus and the posterior hypothalamus. Our findings provide anatomical bases for previously unrecognized roles of the EW in the modulation of several physiologic systems.

In vivo characterization of the connectivity and subcomponents of the human globus pallidus.

Projections from the substantia nigra and striatum traverse through the pallidum on the way to their targets. To date, in vivo characterization of these pathways remains elusive. Here we used high angular resolution diffusion imaging (N=138) to study the characteristics and structural subcompartments of the human pallidum. Our central result shows that the diffusion orientation distribution functions within the pallidum are asymmetrically oriented in a dorsal to dorsolateral direction, consistent with the orientation of underlying fiber systems. We also observed systematic differences in the diffusion signal between the two pallidal segments. Compared to the outer pallidal segment, the internal segment has more peaks in the diffusion orientation distribution and stronger anisotropy in the primary fiber direction, consistent with known cellular differences between the underlying nuclei. These differences in orientation, complexity, and degree of anisotropy are sufficiently robust to automatically segment the pallidal nuclei using diffusion properties. We characterize these patterns in one data set using diffusion spectrum imaging and replicate in a separate sample of subjects imaged using multi-shell imaging, highlighting the reliability of these diffusion patterns within pallidal nuclei. Thus the gray matter diffusion signal can be useful as an in vivo measure of the collective efferent pathways running through the human pallidum.