Subsystem macroarchitecture of the intrinsic midbrain neural network and its tectal and tegmental subnetworks.

The midbrain is the smallest of three primary vertebrate brain divisions. Here we use network science tools to reveal the global organizing principles of intramidbrain axonal circuitry before adding extrinsic connections with the remaining nervous system. Curating the experimental neuroanatomical literature yielded 17,248 connection reports for 8,742 possible connections between the 94 gray matter regions forming the right and left midbrain. Evidence for the existence of 1,676 connections suggests a 19.2% connection density for this network, similar to that for the intraforebrain network [L. W. Swanson et al., Proc. Natl. Acad. Sci. U.S.A. 117, 31470-31481 (2020)]. Multiresolution consensus cluster analysis parceled this network into a hierarchy with 6 top-level and 30 bottom-level subsystems. A structure-function model of the hierarchy identifies midbrain subsystems that play specific functional roles in sensory-motor mechanisms, motivation and reward, regulating complex reproductive and agonistic behaviors, and behavioral state control. The intramidbrain network also contains four bilateral region pairs designated putative hubs. One pair contains the superior colliculi of the tectum, well known for participation in visual sensory-motor mechanisms, and the other three pairs form spatially compact right and left units (the ventral tegmental area, retrorubral area, and midbrain reticular nucleus) in the tegmentum that are implicated in motivation and reward mechanisms. Based on the core hypothesis that subsystems form functionally cohesive units, the results provide a theoretical framework for hypothesis-driven experimental analysis of neural circuit mechanisms underlying behavioral responses mediated in part by the midbrain.

Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep.

Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.

Efferent Axonal Projections of the Habenular Complex in the Fire-Bellied Toad Bombina orientalis.

The habenular complex and its associated axonal pathways are often thought of as phylogenetically conserved features of the brain among vertebrates despite the fact that detailed studies of this brain region are limited to a few species. Here, the gross morphology and axonal projection pattern of the habenular complex of an anuran amphibian, the fire-bellied toad Bombina orientalis, was studied to allow comparison with the situation in other vertebrates. Axonal pathways were traced using biocytin applications in dissected brain preparations. The results show that the rostral part of the left dorsal nucleus is enlarged in this species, while the rostral ventral nucleus and caudal parts do not show left-right size differences. Biocytin applications revealed widespread axonal projections of the habenular complex to the posterior tuberculum/dorsal hypothalamic region, ventral tegmentum, interpeduncular nucleus (IPN), and raphe median. Additionally, axons targeting the lateral hypothalamus originated from the ventral habenular nuclei. The results also suggest an asymmetrical pattern of projection to the IPN in the rostral part of the habenular complex, where the left habenula preferentially targeted the dorsal IPN while the right habenula preferentially targeted the ventral IPN. The caudal habenular nuclei showed no asymmetry of projections as both sides targeted the ventral IPN. Comparison of the habenular complex axonal connectivity across vertebrates argues against strong phylogenetic conservation of the axonal projection patterns of different habenular nuclei.

Pain. Part 2a: Trigeminal Anatomy Related to Pain.

In order to understand the underlying principles of orofacial pain it is important to understand the corresponding anatomy and mechanisms. Paper 1 of this series explains the central nervous and peripheral nervous systems relating to pain. The trigeminal nerve is the 'great protector' of the most important region of our body. It is the largest sensory nerve of the body and over half of the sensory cortex is responsive to any stimulation within this system. This nerve is the main sensory system of the branchial arches and underpins the protection of the brain, sight, smell, airway, hearing and taste, underpinning our very existence. The brain reaction to pain within the trigeminal system has a significant and larger reaction to the threat of, and actual, pain compared with other sensory nerves. We are physiologically wired to run when threatened with pain in the trigeminal region and it is a 'miracle' that patients volunteer to sit in a dental chair and undergo dental treatment. Clinical Relevance: This paper aims to provide the dental and medical teams with a review of the trigeminal anatomy of pain and the principles of pain assessment.

[THE ORGANIZATION OF PROJECTIONS OF MIDBRAIN LATERAL TEGMENTAL NUCLEI THE TO BRAIN BASAL GANGLIA IN DOGS].

The organization of the projections of midbrain lateral tegmental nuclei (peripeduncular nucleus, paralemniscal nucleus, nucleus of the brachium of inferior colliculus) to functionally diverse nuclei of the basal ganglia system was studied in dogs (n = 34) by the method of retrograde axonal transport of horse-radish peroxidase. It was found that the midbrain nuclei studied were involved in functionally different circuits, containing the basal ganglia as their components. These nuclei innervate the regions of the putamen, globus pallidus, cuneate nucleus, subcuneate nucleus, which are the motor or the limbic structures on the basis of their predominant connections with the motor or the limbic brain nuclei, and also regions of the caudate nucleus, nucleus accumbens, entopeduncular nucleus, compact part of the pedunculopontine nucleus, which receive the projections from the functionally various structures. The analysis of Nissl-stained frontal sections allowed to refine the anatomical topography of the individual nuclei of the midbrain lateral tegmentum. The cholinergic nature of their neurons was demonstrated based on of the positive histochemical reaction to NADPH diaphorase.

Allometric scaling of the optic tectum in cartilaginous fishes.

In cartilaginous fishes (Chondrichthyes; sharks, skates and rays (batoids), and holocephalans), the midbrain or mesencephalon can be divided into two parts, the dorsal tectum mesencephali or optic tectum (analogous to the superior colliculus of mammals) and the ventral tegmentum mesencephali. Very little is known about interspecific variation in the relative size and organization of the components of the mesencephalon in these fishes. This study examined the relative development of the optic tectum and the tegmentum in 75 chondrichthyan species representing 32 families. This study also provided a critical assessment of attempts to quantify the size of the optic tectum in these fishes volumetrically using an idealized half-ellipsoid approach (method E), by comparing this method to measurements of the tectum from coronal cross sections (method S). Using species as independent data points and phylogenetically independent contrasts, relationships between the two midbrain structures and both brain and mesencephalon volume were assessed and the relative volume of each brain area (expressed as phylogenetically corrected residuals) was compared among species with different ecological niches (as defined by primary habitat and lifestyle). The relatively largest tecta and tegmenta were found in pelagic coastal/oceanic and oceanic sharks, benthopelagic reef sharks, and benthopelagic coastal sharks. The smallest tecta were found in all benthic sharks and batoids and the majority of bathyal (deep-sea) species. These results were consistent regardless of which method of estimating tectum volume was used. We found a highly significant correlation between optic tectum volume estimates calculated using method E and method S. Taxon-specific variation in the difference between tectum volumes calculated using the two methods appears to reflect variation in both the shape of the optic tectum relative to an idealized half-ellipsoid and the volume of the ventricular cavity. Because the optic tectum is the principal termination site for retinofugal fibers arising from the retinal ganglion cells, the relative size of this brain region has been associated with an increased reliance on vision in other vertebrate groups, including bony fishes. The neuroecological relationships between the relative size of the optic tectum and primary habitat and lifestyle we present here for cartilaginous fishes mirror those established for bony fishes; we speculate that the relative size of the optic tectum and tegmentum similarly reflects the importance of vision and sensory processing in cartilaginous fishes.

Mammillotegmental tract in the human brain: diffusion tensor tractography study.

INTRODUCTION: Several animal studies have been conducted for the identification of the mammillotegmental tract (MTT); however, no study has been reported in the human brain. METHODS: In the current study, using diffusion tensor tractography (DTT), we attempted to identify the MTT in the human brain. We recruited 31 healthy volunteers for this study. Diffusion tensor images were acquired using 1.5 T, and the MTT was obtained using a probabilistic tractography method based on a multi-fiber model. Values of fractional anisotropy, mean diffusivity, and tract volume of the MTT were measured. RESULTS: MTTs of all subjects, which originated from the mammillary body, ascended posteriorly to the bicommissural level along the third ventricle and then turned caudally and terminated at the tegmentum of the midbrain. No significant differences were observed in terms of fractional anisotropy, mean diffusivity, and tract volume according to hemisphere and sex (P < 0.05). Using DTT, we identified the MTT in the human brain. CONCLUSION: We believe that the methodology and results of this study would be helpful in research on the MTT in the human brain.

Whole-brain mapping of monosynaptic inputs to midbrain cholinergic neurons.

The cholinergic midbrain is involved in a wide range of motor and cognitive processes. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental nucleus (LDT) send long-ranging axonal projections that target sensorimotor and limbic areas in the thalamus, the dopaminergic midbrain and the striatal complex following a topographical gradient, where they influence a range of functions including attention, reinforcement learning and action-selection. Nevertheless, a comprehensive examination of the afferents to PPN and LDT cholinergic neurons is still lacking, partly due to the neurochemical heterogeneity of this region. Here we characterize the whole-brain input connectome to cholinergic neurons across distinct functional domains (i.e. PPN vs LDT) using conditional transsynaptic retrograde labeling in ChAT::Cre male and female rats. We reveal that input neurons are widely distributed throughout the brain but segregated into specific functional domains. Motor related areas innervate preferentially the PPN, whereas limbic related areas preferentially innervate the LDT. The quantification of input neurons revealed that both PPN and LDT receive similar substantial inputs from the superior colliculus and the output of the basal ganglia (i.e. substantia nigra pars reticulata). Notably, we found that PPN cholinergic neurons receive preferential inputs from basal ganglia structures, whereas LDT cholinergic neurons receive preferential inputs from limbic cortical areas. Our results provide the first characterization of inputs to PPN and LDT cholinergic neurons and highlight critical differences in the connectome among brain cholinergic systems thus supporting their differential roles in behavior.

Adenosine A1 and A2A receptors are not upstream of caffeine's dopamine D2 receptor-dependent aversive effects and dopamine-independent rewarding effects.

Caffeine is widely consumed throughout the world, but little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversion to caffeine, but also reveals dopamine blockade-induced conditioned place preferences. These aversive effects are mediated by the dopamine D(2) receptor, as knockout mice showed conditioned place preferences in response to doses of caffeine that C57Bl/6 mice found aversive. Furthermore, these aversive responses appear to be centrally mediated, as a quaternary analog of caffeine failed to produce conditioned place aversion. Although the adenosine A(2A) receptor is important for caffeine's physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A(2A) receptor knockout mice showed stronger dopamine-dependent aversive responses to caffeine than did C57Bl/6 mice, which partially obscured the dopamine-independent and A(2A) receptor-independent preferences. Additionally, the A(1) receptor, alone or in combination with the A(2A) receptor, does not seem to be important for caffeine's rewarding or aversive effects. Finally, excitotoxic lesions of the tegmental pedunculopontine nucleus revealed that this brain region is not involved in dopamine blockade-induced caffeine reward. These data provide surprising new information on the mechanism of action of caffeine, indicating that adenosine receptors do not mediate caffeine's appetitive and aversive effects. We show that caffeine has an atypical reward mechanism, independent of the dopaminergic system and the tegmental pedunculopontine nucleus, and provide additional evidence in support of a role for the dopaminergic system in aversive learning.

The regional distribution of T2-relaxation times in MR images of the substantia nigra and crus cerebri.

INTRODUCTION: When scanning the size of the substantia nigra (SN), for example in Parkinson's disease, it is important to precisely locate its true anatomic location. The hypointense areas on T2-weighted magnetic resonance images (T2w) at the level of the upper midbrain are usually labeled as the SN. Recent studies showed that the line of demarcation between the SN and the crus cerebri (CC) in T2w images seems not to be clear. The purpose of our study was to evaluate the depiction of the SN and the CC on calculated R2 maps by analyzing the regional distribution of T2 values in both regions. METHODS: In 36 healthy subjects, triple echo turbo spin echo were obtained at 1.5 T and R2 maps calculated. Proton density-weighted turbo spin echo images (PDw) were used as reference. The CC and SN were manually traced on PDw sections (CCP and SNP) and also the hyperintense areas on the R2 maps, suggestive of the SN (DT2). The obtained volumes were evaluated in terms of total size, intersections size, and residual areas, as well as the corresponding T2 values. RESULTS: DT2 corresponded to anterolateral parts of the SNP and showed an extension to anteromedial part of the CC. The intersections between DT2 and CCP and DT2 and SNP presented both decreased but different T2 values (102 +/- 5 and 95 +/- 4 ms). CONCLUSION: An exact differentiation of the SN from the CC is not possible on the basis of T2w images but rather on the basis of the underlying calculated T2 values from the triple echo sequence.

Perineuronal nets and subtypes of GABAergic cells differentiate auditory and multisensory nuclei in the intercollicular area of the midbrain.

The intercollicular region, which lies between the inferior and superior colliculi in the midbrain, contains neurons that respond to auditory, visual, and somatosensory stimuli. Golgi studies have been used to parse this region into three distinct nuclei: the intercollicular tegmentum (ICt), the rostral pole of the inferior colliculus (ICrp), and the nucleus of the brachium of the IC (NBIC). Few reports have focused on these nuclei, especially the ICt and the ICrp, possibly due to lack of a marker that distinguishes these areas and is compatible with modern methods. Here, we found that staining for GABAergic cells and perineuronal nets differentiates these intercollicular nuclei in guinea pigs. Further, we found that the proportions of four subtypes of GABAergic cells differentiate intercollicular nuclei from each other and from adjacent inferior collicular subdivisions. Our results support earlier studies that suggest distinct morphology and functions for intercollicular nuclei, and provide staining methods that differentiate intercollicular nuclei and are compatible with most modern techniques. We hope that this will help future studies to further characterize the intercollicular region.

Organization of ventral tegmental area projections to the ventral tegmental area-nigral complex in the rat.

The ventral tegmental area (VTA) is a nodal link in reward circuitry. Based on its striatal output, it has been subdivided in a caudomedial part which targets the ventromedial striatum, and a lateral part which targets the ventrolateral striatum [Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 56:27-78]. Whether these two VTA parts are interconnected and to what extent the VTA innervates the substantia nigra compacta (SNc) and retrorubral nucleus (RR) are critical issues for understanding information processing in the basal ganglia. Here, VTA projections to the VTA-nigral complex were examined in rats, using Phaseolus vulgaris leucoagglutinin (PHA-L) as anterograde tracer. The results show that the dorsolateral VTA projects to itself, as well as to the dorsal tier of the SNc and RR, largely avoiding the caudomedial VTA. The ventrolateral VTA innervates mainly the interfascicular nucleus. The components of the caudomedial VTA (the interfascicular, paranigral and caudal linear nuclei) are connected with each other. In addition, the caudomedial VTA (especially the paranigral and caudal linear nuclei) innervates the lateral VTA, and, to a lesser degree, the SNc and RR. The caudal pole of the VTA sends robust, bilateral projections to virtually all the VTA-nigral complex, which terminate in the dorsal and ventral tiers. Modest inputs from the medial supramammillary nucleus to ventromedial parts of the VTA-nigral complex were also identified. In double-immunostained sections, PHA-L-labeled varicosities were sometimes found apposed to tyrosine hydroxylase-positive neurons in the ventral mesencephalon. Overall, the results underscore that VTA projections to the VTA-nigral complex are substantial and topically organized. In general, these projections, like the spiralated striato-nigro-striatal loops, display a medial-to-lateral organization. This anatomical arrangement conceivably permits the ventromedial striatum to influence the activity of the lateral striatum. The caudal pole of the VTA appears to be a critical site for a global recruitment of the mesotelencephalic system.

Evaluation of the somatotopic organization of corticospinal tracts in the internal capsule and cerebral peduncle: results of diffusion-tensor MR tractography.

OBJECTIVE: We have used diffusion tensor tractography (DTT) for the evaluation of the somatotopic organization of corticospinal tracts (CSTs) in the posterior limb of the internal capsule (PLIC) and cerebral peduncle (CP). MATERIALS AND METHODS: We imaged the brains of nine healthy right-handed subjects. We used a spin-echo echo-planar imaging (EPI) sequence with 12 diffusion-sensitized directions. DTT was calculated with an angular threshold of 35 degrees and a fractional anistropy (FA) threshold of 0.25. We determined the location of the CSTs by using two regions of interest (ROI) at expected areas of the pons and expected areas of the lateral half of the PLIC, in the left hemisphere of the brain. Fiber tracts crossing these two ROIs and the precentral gyrus (PCG) were defined as CSTs. Four new ROIs were then defined for the PCG, from the medial to lateral direction, as ROI 1 (medial) to ROI 4 (lateral). Finally, we defined each fiber tract of the CSTs between the pons and each ROI in the PCG by using two ROIs methods. RESULTS: In all subjects, the CSTs were organized along the long axis of the PLIC, and the hand fibers were located anterior to the foot fibers. The CSTs showed transverse orientation in the CP, and the hand fibers were located usually medial to the foot fibers. CONCLUSION: Corticospinal tracts are organized along the long axis of the PLIC and the horizontal direction of the CP.

Surgical anatomy of the pedunculopontine and peripeduncular nuclei.

The pedunculopontine nucleus is a promising new target for deep brain stimulation (DBS) in Parkinsonian patients with gait disturbance and postural instability refractory to other treatment modalities. This region of the brain is unfamiliar territory to most functional neurosurgeons and has been the subject of inaccurate descriptions and representations. This contribution reviews the anatomy of the human pedunculopontine nucleus as well as that of another brainstem nucleus that carries a vaguely similarly sounding name and with which the former has been confused--the peripeduncular nucleus. The stereotactic coordinates for both structures are reviewed, as are methods of anatomical localization in surgical practice. The precise understanding and use of anatomical terminology together with accurate postoperative lead localization are essential when reporting on the clinical effects of novel DBS targets.

An assessment of the contributions of the pedunculopontine tegmental and cuneiform nuclei to anxiety and neophobia.

The pedunculopontine tegmental and cuneiform nuclei are adjacent structures in the mesopontine tegmentum. The pedunculopontine has attracted interest because of its extensive reciprocal connections with corticostriatal systems and possible role in complex behavioral and cognitive processes; the cuneiform is thought to be part of a neural system important for organizing defensive behaviors. Excitotoxic lesions of the pedunculopontine have been shown to affect a variety of complex functions, including learning and attention, but it has been suggested that a consequence of lesions here is the production of an anxiety-like state. We present experiments to clarify the relative role of the pedunculopontine and cuneiform nuclei in anxiety-like states in rats, measured using the elevated plus maze, food neophobia and palatability tests, and by open field behavior. In addition, we measured (through Fos expression) the effect that being on the elevated plus maze had on the pedunculopontine and cuneiform nuclei. Bilateral ibotenate lesions of cuneiform increased anxiety-like responses on the elevated plus maze, food neophobia and open field tests. Bilateral ibotenate lesions of pedunculopontine that spared cuneiform did not produce anxiety-like behavior, but did disinhibit performance in all the tests. Lesions directed at the pedunculopontine produced anxiety-like effects only when there was also significant damage in the cuneiform. The data are discussed in terms of the relationships these nuclei have with different neural systems: pedunculopontine can be understood in terms of its hierarchical relationships with forebrain systems, while cuneiform is understood best in terms of its role in regulating responses to threatening stimuli.

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.

Origins of spinal cholinergic pathways in amphibians demonstrated by retrograde transport and choline acetyltransferase immunohistochemistry.

The existence of propriospinal cholinergic pathways and the origin of supraspinal cholinergic descending projections have been investigated in anuran and urodele amphibians. Retrograde tract tracing techniques with dextran amines injected in the spinal cord at different levels were combined with immunohistochemistry for choline acetyltransferase (ChAT). The analysis of the brachial, thoracic and lumbar spinal cord demonstrated that doubly labeled cells were present only close to the injection site. Thus, the participation of the spinal cholinergic cells in distant intersegmental connections is not present, or is very limited, in amphibians. In anurans, tracer applications to the brachial cord revealed cholinergic cells of origin of spinal projections located in four distinct brain nuclei. The most rostrally located cells were found bilaterally in the preoptic area, among the magnocellular cells. In the ipsilateral isthmic region, the laterodorsal tegmental nucleus also showed doubly labeled cells. Throughout the brainstem, abundant codistribution was observed but actual coexistence of the tracer and ChAT was only found in the nucleus of the solitary tract and the inferior reticular nucleus. In the case of the urodele, abundant codistribution between retrogradely labeled cells and ChAT-positive neurons in zones like the suprachiasmatic nucleus, the isthmic region and the rhombencephalic reticular formation was observed, but the only doubly labeled cells were the Mauthner neurons. The present results in amphibians contrast with previous data in mammals in which is striking the presence of a widespread intrinsic cholinergic innervation of the spinal cord and the virtual absence of cholinergic projections descending from the brainstem.

Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

Barosensory cells in the nucleus tractus solitarius receive convergent input from group III muscle afferents and central command.

Some neural mechanism must prevent the full expression of the baroreceptor reflex during static exercise because arterial blood pressure increases even though the baroreceptors are functioning. Two likely candidates are central command and input from the thin fiber muscle afferents evoking the exercise pressor reflex. Recently, activation of the mesencephalic locomotor region, an anatomical locus for central command, was found to inhibit the discharge of nucleus tractus solitarius cells that were stimulated by arterial baroreceptors in decerebrated cats. In contrast, the effect of thin fiber muscle afferent input on the discharge of nucleus tractus solitarius cells stimulated by baroreceptors is not known. Consequently in decerebrated unanesthetized cats, we examined the responses of barosensory nucleus tractus solitarius cells to stimulation of thin fiber muscle afferents and to stimulation of the mesencephalic locomotor region, a maneuver which evoked fictive locomotion. We found that electrical stimulation of either the mesencephalic locomotor region or the gastrocnemius nerve at current intensities that recruited group III afferents inhibited the discharge of nucleus tractus solitarius cells receiving baroreceptor input. We also found that the inhibitory effects of both gastrocnemius nerve stimulation and mesencephalic locomotor region stimulation converged onto the same barosensory nucleus tractus solitarius cells. We conclude that the nucleus tractus solitarius is probably the site whereby input from both central command and thin fiber muscle afferents function to reset the baroreceptor reflex during exercise.

Injections of urocortin 1 into the basolateral amygdala induce anxiety-like behavior and c-Fos expression in brainstem serotonergic neurons.

The amygdala plays a key role in emotional processing and anxiety-related physiological and behavioral responses. Previous studies have shown that injections of the anxiety-related neuropeptide corticotropin-releasing factor or the related neuropeptide urocortin 1 into the region of the basolateral amygdaloid nucleus induce anxiety-like behavior in several behavioral paradigms. Brainstem serotonergic systems in the dorsal raphe nucleus and median raphe nucleus may be part of a distributed neural system that, together with the basolateral amygdala, regulates acute and chronic anxiety states. We therefore investigated the effect of an acute bilateral injection of urocortin 1 into the basolateral amygdala on behavior in the social interaction test and on c-Fos expression within serotonergic neurons in the dorsal raphe nucleus and median raphe nucleus. Male rats were implanted with bilateral cannulae directed at the region of the basolateral amygdala; 72 h after surgery, rats were injected with urocortin 1 (50 fmol/100 nl) or vehicle (100 nl of 1% bovine serum albumin in distilled water). Thirty minutes after injection, a subgroup of rats from each experimental group was exposed to the social interaction test; remaining animals were left in the home cage. Two hours after injection rats were perfused with paraformaldehyde and brains were removed and processed for immunohistochemistry. Acute injection of urocortin 1 had anxiogenic effects in the social interaction test, reducing total interaction time without affecting locomotor activity or exploratory behavior. These behavioral effects were associated with increases in c-Fos expression within brainstem serotonergic neurons. In home cage rats and rats exposed to the social interaction test, urocortin 1 treatment increased the number of c-Fos-immunoreactive serotonergic neurons within subdivisions of both the dorsal raphe nucleus and median raphe nucleus. These results are consistent with the hypothesis that the basolateral amygdala and serotonergic neurons within the midbrain raphe complex are part of an integrated neural system modulating anxiety state.