Stria medullaris innervation follows the transcriptomic division of the habenula.

The habenula is a complex neuronal population integrated in a pivotal functional position into the vertebrate limbic system. Its main afference is the stria medullaris and its main efference the fasciculus retroflexus. This neuronal complex is composed by two main components, the medial and lateral habenula. Transcriptomic and single cell RNAseq studies have unveiled the morphological complexity of both components. The aim of our work was to analyze the relation between the origin of the axonal fibers and their final distribution in the habenula. We analyzed 754 tracing experiments from Mouse Brain Connectivity Atlas, Allen Brain Map databases, and selected 12 neuronal populations projecting into the habenular territory. Our analysis demonstrated that the projections into the medial habenula discriminate between the different subnuclei and are generally originated in the septal territory. The innervation of the lateral habenula displayed instead a less restricted distribution from preoptic, terminal hypothalamic and peduncular nuclei. Only the lateral oval subnucleus of the lateral habenula presented a specific innervation from the dorsal entopeduncular nucleus. Our results unveiled the necessity of novel sorts of behavioral experiments to dissect the different functions associated with the habenular complex and their correlation with the distinct neuronal populations that generate them.

Folic acid supplementation rescues valproic acid-induced developmental neurotoxicity and behavioral alterations in zebrafish embryos.

OBJECTIVE: Fetal exposure to the anticonvulsant drug valproic acid (VPA), used to treat certain types of epilepsy, increases the risk for birth defects, including neural tube defects, as well as learning difficulties and behavioral problems. Here, we investigated neurotoxic effects of VPA exposure using zebrafish as a model organism. The capacity of folic acid (FA) supplementation to rescue the VPA-induced neuronal and behavioral perturbations was also examined. METHODS: Zebrafish embryos of different transgenic lines with neuronal green fluorescent protein expression were exposed to increasing concentrations of VPA with or without FA supplementation. Fluorescence microscopy was used to visualize alterations in brain structures and neural progenitor cells, as well as motor neurons and neurite sprouting. A twitching behavioral assay was used to examine the functional consequences of VPA and FA treatment. RESULTS: In zebrafish embryos, VPA exposure caused a decrease in the midbrain size, an increase in the midline gap of the hindbrain, and perturbed neurite sprouting of secondary motor neurons, in a concentration-dependent manner. VPA exposure also decreased the fluorescence intensity of neuronal progenitor cells in early developmental stages, indicating fewer cells. Furthermore, VPA exposure significantly altered embryonic twitching activity, causing hyperactivity in dark and hypoactivity in light. Supplementation of FA rescued the VPA-induced smaller midbrain size and hindbrain midline gap defects. FA treatment also increased the number of neuronal progenitor cells in VPA-treated embryos and salvaged neurite sprouting of the secondary motor neurons. FA rescued the VPA-induced alterations in twitching activity in light but not in dark. SIGNIFICANCE: We conclude that VPA exposure induces specific neurotoxic perturbations in developing zebrafish embryos, and that FA reversed most of the identified defects. The results demonstrate that zebrafish is a promising model to study VPA-induced teratogenesis and to screen for countermeasures.

Human brain transcriptome analysis finds region- and subject-specific expression signatures of GABAAR subunits.

Altered expression of GABA receptors (GABAARs) has been implicated in neurological and psychiatric disorders, but limited information about region-specific GABAAR subunit expression in healthy human brains, heteromeric assembly of major isoforms, and their collective organization across healthy individuals, are major roadblocks to understanding their role in non-physiological states. Here, by using microarray and RNA-Seq datasets-from single cell nuclei to global brain expression-from the Allen Institute, we find that transcriptional expression of GABAAR subunits is anatomically organized according to their neurodevelopmental origin. The data show a combination of complementary and mutually-exclusive expression patterns that delineate major isoforms, and which is highly stereotypical across brains from control donors. We summarize the region-specific signature of GABAR subunits per subject and its variability in a control population sample that can be used as a reference for remodeling changes during homeostatic rearrangements of GABAAR subunits after physiological, pharmacological or pathological challenges.

An Anatomic Characterization of the Midbrain Near Response Neurons in the Macaque Monkey.

Purpose: These experiments were designed to reveal the location of the premotor neurons that have previously been designated physiologically as the midbrain near response cells controlling vergence, lens accommodation, and pupillary constriction in response to target distance. Methods: To identify this population, the fixed N2c strain of rabies virus was injected into the ciliary body of seven Macaca fascicularis monkeys. The virus was trans-synaptically transported to the brain. Following a 58- to 76-hour survival, animals were perfused with formalin fixative. After frozen sectioning, tissue was reacted to reveal the location of the infected populations by use of a monoclonal anti-rabies antibody. Another series of sections was processed to determine which of the rabies-positive cells were cholinergic motoneurons by use of an antibody to choline acetyl transferase. Results: At earlier time points, only cholinergic cells in the preganglionic Edinger-Westphal nucleus ipsilateral to the injection were labeled. At later time points, an additional population of noncholinergic, premotor cells was present. These were most numerous at the caudal end of the supraoculomotor area, where they formed a bilateral band, oriented mediolaterally immediately above the oculomotor nucleus. Rostral to this, a smaller bilateral population was located near the midline within the supraoculomotor area. Conclusions: Most lens preganglionic motoneurons are multipolar cells making up a continuous column within the Edinger-Westphal nucleus. A population of premotor cells that likely represents the midbrain near response cells is located in the supraoculomotor area. These cells are bilaterally distributed relative to the eye they control, and are most numerous caudally.

Modification of a Colliculo-thalamocortical Mouse Brain Slice, Incorporating 3-D printing of Chamber Components and Multi-scale Optical Imaging.

The ability of the brain to process sensory information relies on both ascending and descending sets of projections. Until recently, the only way to study these two systems and how they interact has been with the use of in vivo preparations. Major advances have been made with acute brain slices containing the thalamocortical and cortico-thalamic pathways in the somatosensory, visual, and auditory systems. With key refinements to our recent modification of the auditory thalamocortical slice(1), we are able to more reliably capture the projections between most of the major auditory midbrain and forebrain structures: the inferior colliculus (IC), medial geniculate body (MGB), thalamic reticular nucleus (TRN), and the auditory cortex (AC). With portions of all these connections retained, we are able to answer detailed questions that complement the questions that can be answered with in vivo preparations. The use of flavoprotein autofluorescence imaging enables us to rapidly assess connectivity in any given slice and guide the ensuing experiment. Using this slice in conjunction with recording and imaging techniques, we are now better equipped to understand how information processing occurs at each point in the auditory forebrain as information ascends to the cortex, and the impact of descending cortical modulation. 3-D printing to build slice chamber components permits double-sided perfusion and broad access to networks within the slice and maintains the widespread connections key to fully utilizing this preparation.

The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology.

The eponymous term nucleus of Edinger-Westphal (EW) has come to be used to describe two juxtaposed and somewhat intermingled cell groups of the midbrain that differ dramatically in their connectivity and neurochemistry. On one hand, the classically defined EW is the part of the oculomotor complex that is the source of the parasympathetic preganglionic motoneuron input to the ciliary ganglion (CG), through which it controls pupil constriction and lens accommodation. On the other hand, EW is applied to a population of centrally projecting neurons involved in sympathetic, consumptive, and stress-related functions. This terminology problem arose because the name EW has historically been applied to the most prominent cell collection above or between the somatic oculomotor nuclei (III), an assumption based on the known location of the preganglionic motoneurons in monkeys. However, in many mammals, the nucleus designated as EW is not made up of cholinergic, preganglionic motoneurons supplying the CG and instead contains neurons using peptides, such as urocortin 1, with diverse central projections. As a result, the literature has become increasingly confusing. To resolve this problem, we suggest that the term EW be supplemented with terminology based on connectivity. Specifically, we recommend that 1) the cholinergic, preganglionic neurons supplying the CG be termed the Edinger-Westphal preganglionic (EWpg) population and 2) the centrally projecting, peptidergic neurons be termed the Edinger-Westphal centrally projecting (EWcp) population. The history of this nomenclature problem and the rationale for our solutions are discussed in this review.

Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI.

With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17(-/-)) have anatomical abnormalities in the inferior colliculus (IC)-the auditory midbrain-and minor foliation defects in the cerebellum. In addition, changes in the expression domains of several cortical patterning genes were detected, without overt changes in forebrain morphology. Recently, it has also been reported that Fgf17(-/-) mutants have abnormal vocalization and social behaviors, phenotypes that could reflect molecular changes in the cortex and/or altered auditory processing / perception in these mice. We used manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) to analyze the anatomical phenotype of Fgf17(-/-) mutants in more detail than achieved previously, detecting changes in IC, cerebellum, olfactory bulb, hypothalamus and frontal cortex. We also used MEMRI to characterize sound-evoked activity patterns, demonstrating a significant reduction of the active IC volume in Fgf17(-/-) mice. Furthermore, tone-specific (16- and 40-kHz) activity patterns in the IC of Fgf17(-/-) mice were observed to be largely overlapping, in contrast to the normal pattern, separated along the dorsal-ventral axis. These results demonstrate that Fgf17 plays important roles in both the anatomical and functional development of the auditory midbrain, and show the utility of MEMRI for in vivo analyses of mutant mice with subtle brain defects.

Supracerebellar-supratrochlear and infratentorial-infratrochlear approaches: gravity-dependent variations of the lateral approach over the cerebellum.

OBJECTIVE: Lateral supracerebellar-infratentorial approaches are established for lesions in ambient cistern and posterolateral midbrain, but published surgical experiences do not describe results with this approach in the sitting position. Gravity retraction of the cerebellum opens this surgical corridor and dramatically alters exposure, creating 2 variations of the lateral supracerebellar-infratentorial approach: the supracerebellar-supratrochlear approach and the infratentorial-infratrochlear approach. METHODS: We reviewed our experience treating cavernous malformations and arteriovenous malformations (AVMs) of the posteroinferior thalamus and posterolateral midbrain by use of supracerebellar-supratrochlear and infratentorial-infratrochlear approaches. Microsurgical technique, clinical data, radiographic features, and neurological outcomes were evaluated. RESULTS: During an 11-year surgical experience with 341 cavernous malformation patients and 402 AVM patients, 8 patients were identified, 6 with cavernous malformations and 2 with AVMs. Infratentorial-infratrochlear approaches were used in 4 patients (50%), including 3 with inferolateral midbrain cavernous malformations. Supracerebellar-supratrochlear approaches were used in 4 patients (50%), including 2 with posterior thalamic lesions surfacing on pulvinar. Resections were radiographically complete in all cases. There were no new, permanent neurological deficits, nor were there any medical or surgical complications. There has been no evidence of rebleeding or recurrence. CONCLUSIONS: Gravity retraction of the cerebellum transforms the lateral supracerebellar-infratentorial approach, enhancing exposure and approach trajectories that can be achieved with patients in prone or lateral positions. The increased upward viewing angle of the supracerebellar-supratrochlear approach accesses the posteroinferior thalamus. The increased downward-viewing angle of the infratentorial-infratrochlear approach accesses cerebellomesencephalic fissure and posterolateral midbrain. These approaches open wide corridors for safe surgical resection of symptomatic cavernous malformations and AVMs.

An anatomical assessment of the supracerebellar midline and paramedian approaches to the inferior colliculus for auditory midbrain implants using a neuronavigation model on cadaveric specimens.

The inferior colliculus (IC) is an alternative site for electrode placement in neural deafness due to its surgical accessibility and its well-known tonotopic stratification. In patients where tumor surgery has already occurred and the cerebellopontine angle contains scar tissue or tumor-remnants, midline and paramedian supracerebellar approaches are alternative routes. They are often avoided due to concerns regarding the venous drainage of the cerebellum, the electrode trajectory and the course of the electrode cable. We studied these surgical routes in five neuronavigated fixed cadaveric specimens. For paramedian and midline approaches, the transverse sinus was exposed 5.8mm on average. A mean of 1.6 cerebellar veins, with an average diameter of 2.0mm, draining to the tentorium were transected to reach the tentorial notch. Only 0.4 arterial branches were met. We conclude that the supracerebellar midline and paramedian approaches provide a good exposure of the IC and offer safe and viable alternative routes to the IC. Additionally, they provide a wider angle of action for optimal electrode placement.

Sex and regional differences in decrease of estrogen receptor alpha-immunoreactive cells by estrogen in rat hypothalamus and midbrain.

Sensitivity of neurons to estrogen in down-regulation of estrogen receptor alpha (ERalpha) can be thought to make a sex difference in regulatory system of reproductive activities. In this study, to investigate the sex difference of expression of ERalpha in the hypothalamus and midbrain, the number of ERalpha immunoreactive (-ir) cells was counted in orchidectomized (OCX) and ovariectomized (OVX) rats with or without treatment with estrogen. A week after the gonadectomy, 5 rats in each female and male were injected with 1mg estradiol benzoate (EB). The remaining 5 rats in both sexes did not receive EB. The brain was fixed 24h after EB-injection and 50 microm-serial frozen sections were made. After immunohistochemical staining for ERalpha, the number of ERalpha-ir cells was counted in a 0.2-mm2 frame in the anteroventral periventricular nucleus (AVPvN), the ventrolateral part of the ventromedial hypothalamic nucleus (vlVMN), the arcuate nucleus (ARCN), and the lateral mesencephalic central gray (lMCG) in 2 or 3 sections. The total number of ERalpha-ir cells was changed to a density value (number per 1mm3). As the results, in EB-treated rats, the density of ERalpha-ir cells in all regions, except the male AVPvN and male lMCG, were lower than those in untreated rats of both sexes. In the vlVMN, the density of ERalpha-ir cells in OVX rats was higher than in OCX rats. These results suggest that there are sex and regional differences in the mechanisms of down-regulation of ERalpha by estrogen in the rat brain.

Morphometric MRI findings in the thalamus and brainstem in children after moderate to severe traumatic brain injury.

Generalized whole brain volume loss is well documented in moderate to severe traumatic brain injury. Whether this atrophy occurs in the thalamus and brainstem has not been systematically studied in children. Magnetic resonance imaging (MRI) quantitative analysis was used to investigate brain volume loss in the thalamus and brainstem in 16 traumatic brain injury subjects (age range 9-16 years) compared with 16 age and demo-graphically matched controls. Based on multiple analysis of covariance, controlling for age and head size, reduced volume in the thalamus and the midbrain region of the brainstem were found. General linear model analyses revealed a relation between processing speed on a working memory task and midbrain and brain stem volumes. Reduced volume in thalamic and brainstem structures were associated with traumatic brain injury. Reduction in midbrain and thalamic volume is probably a reflection of the secondary effects of diffuse axonal injury and reduction in cortical volume from brain injury.

Neuroanatomical mapping of juvenile rat brain regions with prominent basal signal in [(35)S]GTPgammaS autoradiography.

[(35)S]GTPgammaS autoradiography represents a powerful functional approach to detect receptor-dependent G(i/o) protein activity in anatomically defined brain structures. Inherent to this technique, however, is the notable basal signal evident in several brain regions in the absence of receptor stimulation by exogenously added agonist. In the rat brain, much of this basal labelling derives from tonic activation of adenosine A(1) and lysophosphatidic acid LPA(1) receptors in the gray and white matter regions, respectively. Despite the elimination of the two receptor activities, prominent basal [(35)S]GTPgammaS labelling is still evident in discrete brain structures, possibly reflecting regional enrichment of G(i/o) and/or constitutive receptor activity or the presence of still unknown endogenous ligands activating their orphan receptors. Here, the anatomical distribution of the enhanced basal signal was systematically mapped in brain sections of 4-week-old male Wistar rats. Regions with prominent basal [(35)S]GTPgammaS labelling represented neuroanatomically distinct structures, in particular various thalamic and hypothalamic nuclei. For instance, the paraventricular thalamic nucleus, the bed nucleus of the stria terminalis and the subfornical organ were highly labelled, as were the periaqueductal gray and the nucleus of the solitary tract. Pre-treatment with N-ethylmaleimide (NEM), an alkylating agent preventing all known receptor-driven G protein activity in cryostat sections markedly decreased the basal binding in all examined regions. In preliminary screening, selective antagonists for various brain-enriched G(i/o)-coupled receptors failed to suppress the basal signal in any of the studied regions.

Organization of major telencephalic pathways in an elasmobranch, the thornback ray Platyrhinoidis triseriata.

The forebrain of elasmobranchs is well developed, and in some species the relative brain/body weight is comparable to that in mammals. However, little is known about the organization of major telencephalic pathways. We injected biotinylated dextran amines into the olfactory bulb, lateral pallium, dorsomedial pallium, and the forebrain bundles of the thornback ray, Platyrhinoidis triseriata. Secondary olfactory fibers from the bulb innervate the lateral pallium, the ventral division of the rostral telencephalon and area superficialis basalis. Retrogradely labeled cells were seen exclusively in the lateral periventricular area. The projections of the lateral pallium appeared basically similar to those of the olfactory bulb, but labeling was much denser in the superficial part of area basalis. Some fibers were also seen to innervate the posterior tuberal nucleus. Injections into the dorsomedial pallium revealed a major input from area basalis. Only a few cells were retrogradely labeled in the dorsal thalamus and posterior lateral thalamic nucleus. Major efferents of the dorsomedial pallium appear to reach the contralateral inferior lobe of the hypothalamus and the lateral mesencephalic nucleus. Tracer injections into the forebrain bundles retrogradely labeled many cells in the diencephalon and the mesencephalon and also revealed terminal fields in area superficialis basalis. In addition, a large number of cells were labeled in the dorsomedial pallium. Descending telencephalic fibers innervate heavily the inferior lobes and the lateral mesencephalic nucleus. Our results show that higher order olfactory pathway courses from the lateral pallium through area basalis to the dorsomedial pallium and that ascending non-olfactory input is integrated in area superficialis basalis and the dorsal pallium along with olfactory information, rather than being processed in separate, non-olfactory centers.

The peripeduncular nucleus: a novel target for deep brain stimulation?

The pedunculopontine nucleus, a promising new target for deep brain stimulation in Parkinson's disease, straddles the pontomesencephalic junction--unfamiliar territory to most functional neurosurgeons. This contribution reviews the anatomy of the pedunculopontine and peripeduncular nuclei. Given the reported findings of Mazzone et al. in NeuroReport, the authors postulate that the peripeduncular nucleus might be of previously unexpected clinical relevance.

Binding kinetics of 123I[ADAM] in healthy controls: a selective SERT radioligand.

[123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is a promising radioligand for in-vivo quantification of serotonin transporters (SERT) using single photon emission computed tomography (SPECT) in man. We performed tracer kinetic analysis in various brain regions to determine the optimum equilibrium time for SERT quantification with [123I]ADAM and SPECT. Radiosyntheses of [123I]ADAM were performed at MAP Medical Technologies Oy, Tikkakoski, Finland. Thirty healthy male volunteers (21-41 yr) received between 104 and 163 MBq [123I]ADAM intravenously as a bolus. Consecutively, multiple SPECT scans were performed between 14 and 420 min post-injection (p.i.) using a Siemens Multispect 3 camera. Reconstruction was performed applying filtered back projection with a Butterworth filter (cut-off 0.7, order 7) in 128x128 matrices. Regions of interest (ROI) were drawn manually on the individual T1-weighted magnetic resonance image (MRI) comprising midbrain/hypothalamus for specific binding to SERT, and the cerebellum as reference region. After re-orientation to the MRI, the ROI template was applied to SPECT studies. We generated time-activity curves for the ROI and calculated the ratio countstarget/countscerebellum minus 1 (=V3'') as a measure for specific SERT binding. Counts were corrected for applied activity, acquisition time and body-weight. Peak uptakes were observed between 14 and 50 min after bolus injection. Counts per voxel were highest in the midbrain/hypothalamus, 798 (max. 872, min. 728), whereas 462 counts per voxel (max. 599, min. 412) were measured in the cerebellum at a mean time of 31 min p.i. Stable values for V3'' reached 205-320 min p.i. Mean peak V3'' value was 1.43 (95% CI 171-230) for the midbrain/hypothalamus at 205 min p.i. [123I]ADAM is a useful ligand for in-vivo quantification of human SERT by means of SPECT, with a comparatively better signal-to-noise ratio compared to beta-CIT. Our data suggest that the acquisition time for the SPECT scan is optimally, under pseudo-equilibrium conditions, between 205-320 min post-bolus injection of the tracer.

The pretectum: connections and oculomotor-related roles.

Research over the past two decades in mammals, especially primates, has greatly improved our understanding of the afferent and efferent connections of two retinorecipient pretectal nuclei, the nucleus of the optic tract (NOT) and the pretectal olivary nucleus (PON). Functional studies of these two nuclei have further elucidated some of the roles that they play both in oculomotor control and in relaying oculomotor-related signals to visual relay nuclei. Therefore, following a brief overview of the anatomy and retinal projections to the entire mammalian pretectum, the connections and potential roles of the NOT and the PON are considered in detail. Data on the specific connections of the NOT are combined with data from single-unit recording, microstimulation, and lesion studies to show that this nucleus plays critical roles in optokinetic nystagmus, short-latency ocular following, smooth pursuit eye movements, and adaptation of the gain of the horizontal vestibulo-ocular reflex. Comparable data for the PON show that this nucleus plays critical roles in the pupillary light reflex, light-evoked blinks, rapid eye movement sleep triggering, and modulating subcortical nuclei involved in circadian rhythms.

Neuropeptide B immunoreactivity in the central nervous system of the rat.

Neuropeptide B (NPB) is a recently identified endogenous ligand for the orphan G protein-coupled receptors GPR7 and GPR8. NPB mRNA is expressed in the human, rat, and mouse brain. With the use of an antiserum directed against the rat NPB, immunoreactivity to NPB (irNPB) was detected in several discrete areas of the hypothalamus and midbrain. In the hypothalamus, irNPB cells were present in the medial preoptic area and nucleus, ventromedial preoptic nucleus, retrochiasmatic nucleus, paraventricular hypothalamic nucleus, supraoptic nucleus, accessory neurosecretory nuclei, periventricular hypothalamic nucleus, dorsomedial hypothalamic nucleus, supraoptic retrochiasmatic nucleus, lateral hypothalamic area, posterior hypothalamic area, dorsal hypothalamic area, and zona incerta. A few irNPB perikarya were noted in the arcuate nucleus, whereas a dense network of nerve fibers was present in the median eminence. In the midbrain, irNPB somata were noted in the substantia nigra (compact, reticular, medial, and lateral parts), paranigral nucleus, ventral tegmental area, interfascicular nucleus, and dorsal raphe nucleus. Neurons in the Edinger-Westphal were strongly labeled. Labeled cells were not detected in the cortex, medulla oblongata, and spinal cord; few lightly labeled cells were occasionally seen in the hippocampus. Double labeling the hypothalamic sections with NPB antiserum and vasopressin or oxytocin antibody revealed that a population of vasopressin- but not oxytocin-immunoreactive cells was irNPB. Tyrosine hydroxylase-positive neurons in the midbrain, presumably dopaminergic, were irNPB. The distribution of irNPB neurons in several areas of the hypothalamus and midbrain together with the colocalization with vasopressin or tyrosine hydroxylase suggests that the peptide may subserve neuroendocrine, autonomic, and motor functions.

Mouse brain organization revealed through direct genome-scale TF expression analysis.

In the developing brain, transcription factors (TFs) direct the formation of a diverse array of neurons and glia. We identifed 1445 putative TFs in the mouse genome. We used in situ hybridization to map the expression of over 1000 of these TFs and TF-coregulator genes in the brains of developing mice. We found that 349 of these genes showed restricted expression patterns that were adequate to describe the anatomical organization of the brain. We provide a comprehensive inventory of murine TFs and their expression patterns in a searchable brain atlas database.

Incentive-elicited brain activation in adolescents: similarities and differences from young adults.

Brain motivational circuitry in human adolescence is poorly characterized. One theory holds that risky behavior in adolescence results in part from a relatively overactive ventral striatal (VS) motivational circuit that readily energizes approach toward salient appetitive cues. However, other evidence fosters a theory that this circuit is developmentally underactive, in which adolescents approach more robust incentives (such as risk taking or drug experimentation) to recruit this circuitry. To help resolve this, we compared brain activation in 12 adolescents (12-17 years of age) and 12 young adults (22-28 years of age) while they anticipated the opportunity to respond to obtain monetary gains as well as to avoid monetary losses. In both age groups, anticipation of potential gain activated portions of the VS, right insula, dorsal thalamus, and dorsal midbrain, where the magnitude of VS activation was sensitive to gain amount. Notification of gain outcomes (in contrast with missed gains) activated the mesial frontal cortex (mFC). Across all subjects, signal increase in the right nucleus accumbens during anticipation of responding for large gains independently correlated with both age and self-rated excitement about the high gain cue. In direct comparison, adolescents evidenced less recruitment of the right VS and right-extended amygdala while anticipating responding for gains (in contrast with anticipation of nongains) compared with young adults. However, brain activation after gain outcomes did not appreciably differ between age groups. These results suggest that adolescents selectively show reduced recruitment of motivational but not consummatory components of reward-directed behavior.

Brain afferents to the lateral caudal ventrolateral medulla: a retrograde and anterograde tracing study in the rat.

The ventrolateral medulla (VLM) modulates autonomic functions, motor reactions and pain responses. The lateralmost part of the caudal VLM (VLMlat) was recently shown to be the VLM area responsible for pain modulation. In the present study, the brain sources of VLMlat afferent fibers were determined by tract-tracing techniques. Following injection of cholera toxin subunit B into the VLMlat, retrogradely labeled neurons in the forebrain occurred at the somatosensory, insular, motor, limbic and infralimbic cortices, and at the central amygdaloid nucleus. Retrogradely labeled neurons in diencephalic regions were observed in the lateral hypothalamus, posterior hypothalamus and paraventricular nucleus. In the brainstem, retrograde labeling occurred at the periaqueductal gray, red nucleus, parabrachial area, nucleus raphe magnus, nucleus tractus solitarii, lateral reticular nucleus and dorsal and ventral medullary reticular formation. In the cerebellum, retrogradely labeled neurons occurred at the lateral nucleus. Following injections of the anterograde tracer biotinylated dextran amine (BDA) into the lateral hypothalamus or paraventricular nucleus, anterogradely labeled fibers were mainly observed in the VLMlat. Injections of BDA into the periaqueductal gray, red nucleus or lateral nucleus of the cerebellum resulted in anterograde labeling in the VLMlat and lateral reticular nucleus. The present study gives an account of the brain regions putatively involved in triggering the modulatory actions elicited from the VLMlat. These include areas committed to somatosensory processing, autonomic control, somatic and visceral motor activity and affective reactions. The findings suggest that the VLMlat may play a major homeostatic role in the integration of nociception with other brain functions.