Efferent Connections Research Articles

Connectivity of the amygdala, piriform, and orbitofrontal cortex during olfactory stimulation

The majority of existing functional MRI studies on olfactory perception have addressed the relationship between stimulus features and the intensity of activity in separate regions considered in isolation. However, anatomical studies as well as neurophysiological recordings in rats and insects suggest that odor features may also be represented in a sparse manner through the simultaneous activity of multiple cortical areas interacting as a network. Here, we aimed to map the interdependence of neural activity among regions of the human brain, representing functional connectivity, during passive smelling. Seventeen healthy participants were scanned while performing a blocked-design task alternating exposure to two unpleasant odorants and breathing fresh air. High efferent connectivity was detected for the piriform cortex and the amygdala bilaterally. By contrast, the medial orbitofrontal cortex was characterized by high afferent connectivity, notably in the absence of an overall change in the intensity of hemodynamic activity during olfactory stimulation. Our results suggest that, even in the context of an elementary task, information on olfactory stimuli is scattered by the amygdala and piriform cortex onto an anatomically sparse representation and then gathered and integrated in the medial orbitofrontal cortex.

Aversive cues fail to activate fos expression in the asymmetric olfactory-habenula pathway of zebrafish

The dorsal habenular nuclei of the zebrafish epithalamus have become a valuable model for studying the development of left-right (L-R) asymmetry and its function in the vertebrate brain. The bilaterally paired dorsal habenulae exhibit striking differences in size, neuroanatomical organization, and molecular properties. They also display differences in their efferent connections with the interpeduncular nucleus (IPN) and in their afferent input, with a subset of mitral cells distributed on both sides of the olfactory bulb innervating only the right habenula. Previous studies have implicated the dorsal habenulae in modulating fear/anxiety responses in juvenile and adult zebrafish. It has been suggested that the asymmetric olfactory-habenula pathway (OB-Ha), revealed by selective labeling from an lhx2a:YFP transgene, mediates fear behaviors elicited by alarm pheromone. Here we show that expression of the fam84b gene demarcates a unique region of the right habenula that is the site of innervation by lhx2a:YFP-labeled olfactory axons. Upon ablation of the parapineal, which normally promotes left habenular identity; the fam84b domain is present in both dorsal habenulae and lhx2a:YFP-labeled olfactory bulb neurons form synapses on the left and the right side. To explore the relevance of the asymmetric olfactory projection and how it might influence habenular function, we tested activation of this pathway using odorants known to evoke behaviors. We find that alarm substance or other aversive odors, and attractive cues, activate fos expression in subsets of cells in the olfactory bulb but not in the lhx2a:YFP expressing population. Moreover, neither alarm pheromone nor chondroitin sulfate elicited fos activation in the dorsal habenulae. The results indicate that L-R asymmetry of the epithalamus sets the directionality of olfactory innervation, however, the lhx2a:YFP OB-Ha pathway does not appear to mediate fear responses to aversive odorants.

Parvalbumin Immunoreactivity Changes during the Maturation of the Thalamic Reticular Nucleus of the Rat

The thalamic reticular nucleus is a thin layer of GABAergic cells located between the external medullary lamina and the internal capsule surrounding the rostolateral surface of the thalamus. It has functionally distinct afferent and efferent connections with thalamic nuclei, the neocortex, the basal forebrain and the brainstem. Parvalbumin is a calcium-binding protein, which is regarded to be a marker for GABAergic neurons. The thalamic reticular neurons are GABAergic, and parvalbumin is always colocalized with GABA in these cells. We have demonstrated the parvalbumin immunoreactivity in the thalamic reticular nucleus at different stages of postnatal development of rats, as well at 1-year-old rats. It was established that the maturation of immunoposive patterns varies in different parts of the nucleus. The intensity of immunostaining decreases with age.

Simultaneous stability and sensitivity in model cortical networks is achieved through anti-correlations between the in- and out-degree of connectivity

Neuronal networks in rodent barrel cortex are characterized by stable low baseline firing rates. However, they are sensitive to the action potentials of single neurons as suggested by recent single-cell stimulation experiments that reported quantifiable behavioral responses in response to short spike trains elicited in single neurons. Hence, these networks are stable against internally generated fluctuations in firing rate but at the same time remain sensitive to similarly-sized externally induced perturbations. We investigated stability and sensitivity in a simple recurrent network of stochastic binary neurons and determined numerically the effects of correlation between the number of afferent (“in-degree”) and efferent (“out-degree”) connections in neurons. The key advance reported in this work is that anti-correlation between in-/out-degree distributions increased the stability of the network in comparison to networks with no correlation or positive correlations, while being able to achieve the same level of sensitivity. The experimental characterization of degree distributions is difficult because all pre-synaptic and post-synaptic neurons have to be identified and counted. We explored whether the statistics of network motifs, which requires the characterization of connections between small subsets of neurons, could be used to detect evidence for degree anti-correlations. We find that the sample frequency of the 3-neuron “ring” motif (1→2→3→1), can be used to detect degree anti-correlation for sub-networks of size 30 using about 50 samples, which is of significance because the necessary measurements are achievable experimentally in the near future. Taken together, we hypothesize that barrel cortex networks exhibit degree anti-correlations and specific network motif statistics.

Acute onset of cerebellar ataxia in a spinocerebellar ataxia type 10 patient after use of steroids

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene on chromosome 22q13.31,2. SCA10 gene encodes a 475 KD protein of largely undetermined function. The pathogenic number of ATTCT repeat units ranges from 800 to 4,500 repeats. SCA10 represents a rare form of SCA, described only in Latin America1,2. While clinical manifestations of families described in Brazil are those of a predominantly “pure” cerebellar syndrome, it is often accompanied by epilepsy and occasionally peripheral neuropathy in the Mexican ones1,2. Here, we presented the case of a patient with genetically confirmed SCA10, who developed sudden onset of cerebellar ataxia after a course of corticosteroid therapy. A 34-year-old previously asymptomatic Brazilian woman suddenly developed gait ataxia and dysarthria two weeks after a pulse therapy with methylprednisolone for the treatment of idiopathic thrombocytopenic purpura. The patient was admitted with a clinical picture of body petechiae, gingival bleeding, and hematochezia, which started four days earlier. She had a platelet count of 1,000, which improved with the use of corticosteroids. Neurological assessment revealed gait ataxia, dysarthria, and ocular dysmetria. The Scale for the Assessment and Rating of Ataxia (SARA) was 7.5. Brain magnetic resonance imaging (MRI) showed moderate cerebellar atrophy. Family history was positive for SCA10, including previously reported relatives (aunt and two cousins), whose symptoms were initially manifested during pregnancy3. Interestingly, this same family has also reported the occurrence of cerebellar symptoms triggered by ingestion of small amounts of alcohol, which was previously also published by the authors4. SCA10 is the second most common autosomal dominant cerebellar ataxia in Brazil (after SCA type 3) and in Mexico (after SCA 2). To our knowledge, there is no report of acute cerebellar ataxia development after steroid therapy in patients with SCAs. Based on the case reported here and on family history of onset of symptoms during pregnancy and on postpartum period3, the authors hypothesized that hormonal factors may have a role in the emergence of SCA10 clinical symptoms and signs in previously asymptomatic patients in this family. The mechanisms by which hormones act on cerebellar function and its afferent and efferent connections remain unknown. Previously established genetic variables could be responsible for a lower threshold for manifestation of SCA10 in the course of steroid therapy, and additional studies are necessary to confirm this finding. On the other hand, it is widely known that stress seems to cause acute neuronal death or dysfunction5. Therefore, another possibility is that factors related to stress, involved in acute medical situations, such as pregnancy and postpartum period, could have a pivotal role in the development of acute symptoms of cerebellar ataxia in patients with asymptomatic cerebellar atrophy due to SCA10.

Mobility impairment is associated with reduced microstructural integrity of the inferior and superior cerebellar peduncles in elderly with no clinical signs of cerebellar dysfunction

While the cerebellum plays a critical role in motor coordination and control no studies have investigated its involvement in idiopathic mobility impairment in community-dwelling elderly. In this study we tested the hypothesis that structural changes in the cerebellar peduncles not detected by conventional magnetic resonance imaging are associated with reduced mobility performance. The analysis involved eighty-five subjects (age range: 75–90 years) who had no clinical signs of cerebellar dysfunction. Based on the short physical performance battery (SPPB) score, we defined mobility status of the subjects in the study as normal (score 11–12, n = 26), intermediate (score 9–10, n = 27) or impaired (score < 9, n = 32). We acquired diffusion tensor imaging data to obtain indices of white matter integrity: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Using a parcellation atlas, regional indices within the superior, middle, and inferior cerebellar peduncles (ICP, MCP, SCP) were calculated and their associations with mobility performance were analyzed. Subjects with impaired mobility showed reduced FA and AD values in the ICP and SCP but not in the MCP. The ICP-FA, ICP-AD and SCP-FA indices showed a significant association with the SPPB score. We also observed significant correlation between ICP-FA and walk time (r = − 0.311, p = 0.004), as well as between SCP-AD and self-paced maximum walking velocity (r = 0.385, p = 0.003) and usual walking velocity (r = 0.400, p = 0.002). In logistic regression analysis ICP-FA and ICP-AD together explained 51% of the variability in the mobility status of a sample comprising the normal and impaired subgroups, and correctly classified more than three-quarters of those subjects. Our findings suggest that presence of microstructural damage, likely axonal, in afferent and efferent connections of the cerebellum contributes to the deterioration of motor performance in older people.

Mapping the Hierarchical Layout of the Structural Network of the Macaque Prefrontal Cortex

A consensus on the prefrontal cortex (PFC) holds that it is pivotal for flexible behavior and the integration of the cognitive, affective, and motivational domains. Certain models have been put forth and a dominant model postulates a hierarchical anterior-posterior gradient. The structural connectivity principles of this model dictate that increasingly anterior PFC regions exhibit more efferent connections toward posterior ones than vice versa. Such hierarchical asymmetry principles are thought to pertain to the macaque PFC. Additionally, the laminar patterns of the connectivity of PFC regions can be used for defining hierarchies. In the current study, we formally tested the asymmetry-based hierarchical principles of the anterior-posterior model by employing an exhaustive dataset on macaque PFC connectivity and tools from network science. On the one hand, the asymmetry-based principles and predictions of the hierarchical anterior-posterior model were not confirmed. The wiring of the macaque PFC does not fully correspond to the principles of the model, and its asymmetry-based hierarchical layout does not follow a strict anterior-posterior gradient. On the other hand, our results suggest that the laminar-based hierarchy seems a more tenable working hypothesis for models advocating an anterior-posterior gradient. Our results can inform models of the human PFC.

Altered Parietal-Motor Connections in Alzheimer's Disease Patients

Alzheimer's disease (AD) is characterized by altered functional cortico-cortical connectivity likely due to loss of afferent and efferent connections between different cortical areas. Here we explored parieto-frontal functional connectivity in 15 AD patients and 12 healthy control subjects by means of bifocal transcranial magnetic stimulation (TMS). Conditioning stimuli were applied over the right posterior parietal cortex (PPC) at different intensities (90% and 110% of resting motor threshold, RMT). Motor evoked potentials (MEPs) were then recorded from the ipsilateral primary motor cortex at different interstimulus intervals (ISIs) ranging between 2 and 15 ms. Results showed that in healthy subjects, a conditioning TMS pulse applied over the ipsilateral PPC at 90%, but not at 110%, of RMT intensity was able to increase the excitability of the right M1. This functional interaction peaked at ISI = 6 ms. Conversely, in AD patients the facilitatory pattern of parieto-motor connections was evident only when TMS was delivered at an intensity of 110% of RMT with a peak at ISI = 8 ms. Moreover in AD patients, treatment with cholinesterase inhibitors did not induce any significant modification in the strength of the connection. In subsequent analyses, we found that, in AD patients, the effects induced by PPC conditioning at 110% RMT correlated with neuropsychological measures of episodic memory and executive functions, implying that patients with better cognitive performance had less impaired connectivity. Our findings reveal that parieto-frontal cortico-cortical functional connectivity is altered in AD patients, providing further evidence for a disconnection-based interpretation of AD symptoms.

Clustered Fine Compartmentalization of the Mouse Embryonic Cerebellar Cortex and Its Rearrangement into the Postnatal Striped Configuration

Compartmentalization is essential for a brain area to be involved in different functions through topographic afferent and efferent connections that reflect this organization. The adult cerebellar cortex is compartmentalized into longitudinal stripes, in which Purkinje cells (PCs) have compartment-specific molecular expression profiles. How these compartments form during development is generally not understood. To investigate this process, we focused on the late developmental stages of the cerebellar compartmentalization that occur from embryonic day 17.5 (E17.5), when embryonic compartmentalization is evidently observed, to postnatal day 6 (P6), when adult-type compartmentalization begins to be established. The transformation between these compartmentalization patterns was analyzed by mapping expression patterns of several key molecular markers in serial cerebellar sections in the mouse. A complete set of 54 clustered PC subsets, which had different expression profiles of FoxP2, PLCβ4, EphA4, Pcdh10, and a reporter molecule of the 1NM13 transgenic mouse strain, were distinguished in three-dimensional space in the E17.5 cerebellum. Following individual PC subsets during development indicated that these subsets were rearranged from a clustered and multilayered configuration to a flattened, single-layered and striped configuration by means of transverse slide, longitudinal split, or transverse twist spatial transformations during development. The Purkinje cell-free spaces that exist between clusters at E17.5 become granule cell raphes that separate striped compartments at P6. The results indicate that the ∼50 PC clusters of the embryonic cerebellum will ultimately become the longitudinal compartments of the adult cerebellum after undergoing various peri- and postnatal transformations that alter their relative spatial relationships.

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

The serotonergic (5-HTergic) system arising from the dorsal raphe nucleus (DRN) is implicated in various physiological and behavioral processes, including stress responses. The DRN is comprised of several subnuclei, serving specific functions with distinct afferent and efferent connections. Furthermore, subsets of 5-HTergic neurons are known to coexpress other transmitters, including GABA, glutamate, or neuropeptides, thereby generating further heterogeneity. However, despite the growing evidence for functional variations among DRN subnuclei, relatively little is known about how they map onto neurochemical diversity of 5-HTergic neurons. In the present study, we characterized functional properties of GAD67-expressing 5-HTergic neurons (5-HT/GAD67 neurons) in the rat DRN, and compared with those of neurons expressing 5-HTergic molecules (5-HT neurons) or GAD67 alone. While 5-HT/GAD67 neurons were absent in the dorsomedial (DRD) or ventromedial (DRV) parts of the DRN, they were selectively distributed in the lateral wing of the DRN (DRL), constituting 12% of the total DRL neurons. They expressed plasmalemmal GABA transporter 1, but lacked vesicular inhibitory amino acid transporter. By using whole-cell patch-clamp recording, we found that 5-HT/GAD67 neurons had lower input resistance and firing frequency than 5-HT neurons. As revealed by c-Fos immunohistochemistry, neurons in the DRL, particularly 5-HT/GAD67 neurons, showed higher responsiveness to exposure to an open field arena than those in the DRD and DRV. By contrast, exposure to contextual fear conditioning stress showed no such regional differences. These findings indicate that 5-HT/GAD67 neurons constitute a unique neuronal population with distinctive neurochemical and electrophysiological properties and high responsiveness to innocuous stressor.

Hippocampal Adult Neurogenesis Is Maintained by Neil3-Dependent Repair of Oxidative DNA Lesions in Neural Progenitor Cells

Accumulation of oxidative DNA damage has been proposed as a potential cause of age-related cognitive decline. The major pathway for removal of oxidative DNA base lesions is base excision repair, which is initiated by DNA glycosylases. In mice, Neil3 is the main DNA glycosylase for repair of hydantoin lesions in single-stranded DNA of neural stem/progenitor cells, promoting neurogenesis. Adult neurogenesis is crucial for maintenance of hippocampus-dependent functions involved in behavior. Herein, behavioral studies reveal learning and memory deficits and reduced anxiety-like behavior in Neil3(-/-) mice. Neural stem/progenitor cells from aged Neil3(-/-) mice show impaired proliferative capacity and reduced DNA repair activity. Furthermore, hippocampal neurons in Neil3(-/-) mice display synaptic irregularities. It appears that Neil3-dependent repair of oxidative DNA damage in neural stem/progenitor cells is required for maintenance of adult neurogenesis to counteract the age-associated deterioration of cognitive performance.

SU-E-I-74: White Matter Tract Disintegrate of Frontal and Limbic Regions in Mild Cognitive Impairment with Depression.

Mild cognitive impairment with depression (MCID) is common and associated with disability and cognitive impairment, with high probability of relapse. Hypothesize that 1) a sign of WM disintegration would be observed in MCID than MCI nondepression (MCIND), especially in frontal and limbic regions and patients with depression would show reduced GM density in the hippocampus, amygdala, anterior gyrus cingulate, and dorsolateral prefrontal cortex (DLPFC) and dorsomedial prefrontal cortex (DMPFC) 2) the abnormalities of long association fiber tracts integrity are correlated with geriatric depression. Forty-two subjects (20 nondepressed, 22 depressed) underwent DTI and cognitive assessment. Depression was initially assessed by means of the Korean version of the 30-item Geriatric Depression Scale (K-GDS). All patients scoring 19 or higher on the K-GDS were screened as depressed. An automated tract-based statistical analysis method was used to derive estimates of fractional anisotropy (FA) for each subject. Group effects and correlations with clinical features on DTI parameters were examined. We found cross-sectional differences in WM tract disintegration on posterior cingulum, splenium of corpus callosum, uncinate fasciculus, genu, thalamus, internal and external capsule of limbic in MCID. These results support changes in the structural integrity of neuronal cells in these specific important brain regions constituting a fronto-limbic-cerebellar network during depressive and in particular during the course of depression. The different parts of the frontal lobes have afferent and efferent connections with other neocortical, limbic, and subcortical regions and participate in the limbic-cortico-striatal-pallidal-thalamic circuits. Findings are suggestive of loss of integrity in WM fiber within frontal, temporal and limbic regions, increasing the evidence that implicates disruptions to the limbic-orbitofrontal networks in the pathogenesis of MCID. These neuroanatomical circuits play an important role in the regulation and modulation of affect and emotion, and contribute to the pathogenesis of late-life depression.

Progression of Idiopathic Late Onset Cerebellar Ataxia (S12.006)

Objective: To analyze the follow-up of idiopathic late onset cerebellar ataxia (ILOCA) patients. Background ILOCA patients represent a group of neurodegenerative diseases of unknown cause affecting the cerebellum and its afferent and efferent connections. Design/Methods: Clinical and laboratory observations of the course of 50 adult patients initially evaluated in an cerebellar ataxia outpatient clinic over 20 years, with a diagnosis of ILOCA, and followed up regularly. The presence of REM sleep behavior disorder (RBD) was evaluated as probable RBD, based on clinical validated criteria, or definite RBD, based on polysomnographic confirmation. Results: From a total of 50 patients with ILOCA (excluding all patients with acquired or genetically defined cerebellar ataxia), 24 subsequently developed criteria for MSA type-C. 26 patients remained with the diagnosis of ILOCA, among them 8 with a probable diagnosis of late cerebellar atrophy of Marie-Foix-Alajouanine syndrome (MFAS). The group of patients with late cerebellar atrophy of MFAS had an older mean age (72.8 years) than MSA-C patients (59.5 years). Neurological examination, including a thorough eye movement assessment did not differentiate patients with MSA-C and ILOCA. Clinically or definite RBD was diagnosed in 46 % of patients. However, patients who developed MSA type C had a highly percentage of probable and definite previously diagnosis of RBD (83.4%). On the other hand, among patients with ILOCA, the percentage of RBD was significantly lower (11.5%, p Conclusions: In this Brazilian series of ILOCA patients, MSA-C was clinically diagnosed in 48 % of cases and 52 % remained with the diagnosis of ILOCA, including a 12 % with the diagnosis of late cerebellar atrophy of MFAS. RBD diagnosis, either clinical or polysomnographic should included as an important tool in the differentiation of MSA type C and ILOCA. Disclosure: Dr. Teive has nothing to disclose. Dr. Munhoz has nothing to disclose. Dr. Arruda has nothing to disclose. Dr. Werneck has nothing to disclose.

Evolutionary plasticity of habenular asymmetry with a conserved efferent connectivity pattern.

The vertebrate habenulae (Hb) is an evolutionary conserved dorsal diencephalic nuclear complex that relays information from limbic and striatal forebrain regions to the ventral midbrain. One key feature of this bilateral nucleus is the presence of left-right differences in size, cytoarchitecture, connectivity, neurochemistry and/or gene expression. In teleosts, habenular asymmetry has been associated with preferential innervation of left-right habenular efferents into dorso-ventral domains of the midbrain interpeduncular nucleus (IPN). However, the degree of conservation of this trait and its relation to the structural asymmetries of the Hb are currently unknown. To address these questions, we performed the first systematic comparative analysis of structural and connectional asymmetries of the Hb in teleosts. We found striking inter-species variability in the overall shape and cytoarchitecture of the Hb, and in the frequency, strength and to a lesser degree, laterality of habenular volume at the population level. Directional asymmetry of the Hb was either to the left in D. rerio, E. bicolor, O. latipes, P. reticulata, B. splendens, or to the right in F. gardneri females. In contrast, asymmetry was absent in P. scalare and F. gardneri males at the population level, although in these species the Hb displayed volumetric asymmetries at the individual level. Inter-species variability was more pronounced across orders than within a single order, and coexisted with an overall conserved laterotopic representation of left-right habenular efferents into dorso-ventral domains of the IPN. These results suggest that the circuit design involving the Hb of teleosts promotes structural flexibility depending on developmental, cognitive and/or behavioural pressures, without affecting the main midbrain connectivity output, thus unveiling a key conserved role of this connectivity trait in the function of the circuit. We propose that ontogenic plasticity in habenular morphogenesis underlies the observed inter-species variations in habenular asymmetric morphology.

Noise-induced increase in human auditory evoked fields

Background noise is usually detrimental to auditory perception. However, psychophysical studies have shown that in some circumstances low levels of broadband noise may improve signal detection. Here, we measured auditory evoked fields (AEFs) while participants listened passively (no response required) to stimuli embedded in low or moderate levels of continuous Gaussian noise. As a control condition, the stimuli were also presented without background noise. The AEFs were modeled with a pair of dipoles in the superior temporal plane and the effects of noise on the amplitude and latency of the resulting source waveforms were examined. The results show that low-level background noise enhanced AEF amplitude. The effects of continuous low level Gaussian noise on AEF amplitudes were comparable for young and older adults. Possible explanations for the noise-induced increase in AEF amplitude are a lengthening of the temporal integration window and/or efferent feedback connections between the auditory cortex and lower auditory centers to enhance the signal-to-noise ratio.

Neural regulation of inflammation: no neural connection from the vagus to splenic sympathetic neurons

The 'inflammatory reflex' acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7-9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue-labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic-projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.

Mapping pain activation and connectivity of the human habenula

The habenula, located in the posterior thalamus, is implicated in a wide array of functions. Animal anatomical studies have indicated that the structure receives inputs from a number of brain regions (e.g., frontal areas, hypothalamic, basal ganglia) and sends efferent connections predominantly to the brain stem (e.g., periaqueductal gray, raphe, interpeduncular nucleus). The role of the habenula in pain and its anatomical connectivity are well-documented in animals but not in humans. In this study, for the first time, we show how high-field magnetic resonance imaging can be used to detect habenula activation to noxious heat. Functional maps revealed significant, localized, and bilateral habenula responses. During pain processing, functional connectivity analysis demonstrated significant functional correlations between the habenula and the periaqueductal gray and putamen. Probabilistic tractography was used to assess connectivity of afferent (e.g., putamen) and efferent (e.g., periaqueductal gray) pathways previously reported in animals. We believe that this study is the first report of habenula activation by experimental pain in humans. Since the habenula connects forebrain structures with brain stem structures, we suggest that the findings have important implications for understanding sensory and emotional processing in the brain during both acute and chronic pain.

Kölliker–Fuse neurons send collateral projections to multiple hypoxia-activated and nonactivated structures in rat brainstem and spinal cord.

The Kölliker–Fuse nucleus (KFN) in dorsolateral pons has been implicated in many physiological functions via its extensive efferent connections. Here, we combine iontophoretic anterograde tracing with posthypoxia c-Fos immunohistology to map KFN axonal terminations among hypoxia-activated/nonactivated brain stem and spinal structures in rats. Using a set of stringent inclusion/exclusion criteria to align visualized axons across multiple coronal brain sections, we were able to unequivocally trace axonal trajectories over a long rostrocaudal distance perpendicular to the coronal plane. Structures that were both richly innervated by KFN axonal projections and immunopositive to c-Fos included KFN (contralateral side), ventrolateral pontine area, areas ventral to rostral compact/subcompact ambiguus nucleus, caudal (lateral) ambiguus nucleus, nucleus retroambiguus, and commissural–medial subdivisions of solitary tract nucleus. The intertrigeminal nucleus, facial and hypoglossal nuclei, retrotrapezoid nucleus, parafacial region and spinal cord segment 5 were also richly innervated by KFN axonal projections but were only weakly (or not) immunopositive to c-Fos. The most striking finding was that some descending axons from KFN sent out branches to innervate multiple (up to seven) pontomedullary target structures including facial nucleus, trigeminal sensory nucleus, and various parts of ambiguus nucleus and its surrounding areas. The extensive axonal fan-out from single KFN neurons to multiple brainstem and spinal cord structures("one-to-many relationship"’) provides anatomical evidence that KFN may coordinate diverse physiological functions including hypoxic and hypercapnic respiratory responses, respiratory pattern generation and motor output,diving reflex, modulation of upper airways patency,coughing and vomiting abdominal expiratory reflex, as well as cardiovascular regulation and cardiorespiratory coupling.

Diversity of Neuronal Elements and Circuitry in the Cerebellar Nuclei

The afferent and efferent synaptic connections of the cerebellar nuclei (CN) place them in a key position where they can integrate sensory signals with the output from cerebellar cortex and to provide the main efferent pathway of the cerebellum. While this conclusion can be derived based on purely anatomical knowledge, it remains unknown in which manner the CN contributes to the generation of cerebellar output signals that are involved in creating timing signals and temporal patterns. As a first step towards understanding the role neuronal circuits of the CN, the major CN neuronal types are now identified based on expression patterns of neurotransmitters (GABA and glycine) and characterized both in electrophysiological and morphological manner. The classification-likely to be refined in the future-consists of six types: four classes of projection and two classes of local neurons. The classification is a combination of electrophysiological and morphological methods with the expression pattern of GAD67 and GlyT2, markers for GABAergic and glycinergic neurons, respectively (Uusisaari et al. J Neurophysiol 97:901-911, 2007; Uusisaari and Knöpfel, Cerebellum 10(4):637-46, 2010).

Profound gastroparesis after bilateral posterior inferior cerebellar artery territory infarcts

The afferent and efferent connections between medullary uclei, the esophagus, and the stomach that are essential in reglation of gastric relaxation and motility are well-described [1]. owever, reports of specific damage to these circuits resulting from cute injury to the central nervous system are rare. We describe a atient who developed severe gastroparesis after sustaining bilatral posterior inferior cerebellar artery (PICA) territory infarction.