Organization of primate amygdalar-thalamic pathways for emotions.

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources.

Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism.

Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.

Anterior Cingulate Pathways May Affect Emotions Through Orbitofrontal Cortex.

The anterior cingulate cortex (ACC) and posterior orbitofrontal cortex (pOFC) are associated with emotional regulation. These regions are old in phylogeny and have widespread connections with eulaminate neocortices, intricately linking areas associated with emotion and cognition. The ACC and pOFC have distinct cortical and subcortical connections and are also interlinked, but the pattern of their connections-which may be used to infer the flow of information between them-is not well understood. Here we found that pathways from ACC area 32 innervated all pOFC areas with a significant proportion of large and efficient terminals, seen at the level of the system and the synapse. The pathway from area 32 targeted overwhelmingly elements of excitatory neurons in pOFC, with few postsynaptic sites found on presumed inhibitory neurons. Moreover, pathways from area 32 originated mostly in the upper layers and innervated preferentially the middle-deep layers of the least differentiated pOFC areas, in a pattern reminiscent of feedforward communication. Pathway terminations from area 32 overlapped in the deep layers of pOFC with output pathways that project to the thalamus and the amygdala, and may have cascading downstream effects on emotional and cognitive processes and their disruption in psychiatric disorders.

Mirror trends of plasticity and stability indicators in primate prefrontal cortex.

Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity-stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity-related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases.

Pattern of ventral temporal lobe interconnections in rhesus macaques.

The entorhinal cortex (EC, A28) is linked through reciprocal pathways with nearby perirhinal and visual, auditory, and multimodal association cortices in the temporal lobe, in pathways associated with the flow of information for memory processing. The density and laminar organization of these pathways is not well understood in primates. We studied interconnections within the ventral temporal lobe in young adult rhesus monkeys of both sexes with the aid of neural tracers injected in temporal areas (Ts1, Ts2, TE1, area 36, temporal polar area TPro, and area 28) to determine the density and laminar distribution of projection neurons within the temporal lobe. These temporal areas can be categorized into three different cortical types based on their laminar architecture: the sensory association areas Ts1, Ts2, and TE1 have six layers (eulaminate); the perirhinal limbic areas TPro and area 36 have an incipient layer IV (dysgranular); and area 28 lacks layer IV (agranular). We found that (1) temporal areas that are similar in laminar architecture by cortical type are strongly interconnected, and (2) the laminar pattern of connections is dependent on the difference in cortical laminar structure between linked areas. Thus, agranular A28 is more strongly connected with other agranular/dysgranular areas than with eulaminate cortices. Further, A28 predominantly projected via feedback-like pathways that originated in the deep layers, and received feedforward-like projections from areas of greater laminar differentiation, which emanated from the upper layers. Our results are consistent with the Structural Model, which relates the density and laminar distribution of connections to the relationship of the laminar structure between the linked areas. These connections were viewed in the context of the inhibitory microenvironment of A28, which is the key recipient of pathways from the cortex and of the output of hippocampus. Our findings revealed a higher population of calretinin (CR)-expressing neurons in EC, with a significantly higher density in its lateral division. Medial EC had a higher density of CR neurons in the deep layers, particularly in layer Va. In contrast, parvalbumin (PV) neurons were more densely distributed in the deep layers of the lateral subdivisions of rostral EC, especially in layer Va, whereas the densities of calbindin (CB) neurons in the medial and lateral EC were comparable in all layers, except for layer IIIa, in which medial EC had a higher CB population than the lateral. The pattern of connections in the inhibitory microenvironment of EC, which sends and receives input from the hippocampus, may shed light on signal propagation in this network associated with diverse aspects of memory, and disruptions in neurologic and psychiatric diseases that affect this region.

Low-grade malignant triton tumor in the lumbar spine: a rare variant of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation.

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon type of sarcoma that arises from peripheral nerve sheaths and rarely involves the spinal roots. The origin of this tumor is thought to be Schwann cells or pluripotent cells of the neural crest. The subgroup of tumors in which malignant Schwann cells coexist with malignant rhabdomyoblasts is termed malignant triton tumor (MTT). MPNSTs can show different degrees of malignancy, but overall spinal MTTs are high-grade lesions. We report the exceptional instance of a spinal low-grade MTT in a 39-year-old man treated with total surgical removal followed by local radiation therapy. Histological low grade was based on the lack of necrosis, a low grade of atypia, a low mitotic rate and a Ki-67 labelling index <25%. After 18 months of follow-up the patient is alive with no evidence of disease. A thorough review of the literature yielded 57 well-documented spinal MPNSTs. Ten of them corresponded to MTTs, but none showed low-grade features. An analysis of the clinical, radiological and treatment data was performed to identify factors that might influence the outcome. Overall the 18-month survival rate was 45% but dropped to 0% in the subgroup of spinal MTTs. Besides, a size exceeding 2 cm, extra-spinal extension, association with neurofibromatosis and subtotal removal were all related to a worse outcome. In conclusion, spinal MTTs generally exhibit a more aggressive behavior than conventional MPNSTs. The occurrence of a spinal low-grade MTT with a better prognosis should also be recognized.

Orbital nerve sheath myxoma: a case report.

A 72-year-old man was referred to the Service of Ophthalmology due to a 2-year history of ptosis and a painless mass in the lateral orbital margin of the right eye. Orbital MRI revealed a well-demarcated lesion in the superotemporal quadrant of the orbit. After surgical excision, histopathological examination led to the diagnosis of nerve sheath myxoma, a tumor composed of myxoid nodules separated by fibrous septa with spindle-shaped and stellate cells. Many of these cells were immunostained with antibodies to S-100 protein. This is the first case reported in the literature of such a tumor located in the orbit, and, though extremely rare, it should be considered in the differential diagnosis of orbital tumors.

Parallel Development of Chromatin Patterns, Neuron Morphology, and Connections: Potential for Disruption in Autism.

The phenotype of neurons and their connections depend on complex genetic and epigenetic processes that regulate the expression of genes in the nucleus during development and throughout life. Here we examined the distribution of nuclear chromatin patters in relation to the epigenetic landscape, phenotype and connections of neurons with a focus on the primate cerebral cortex. We show that nuclear patterns of chromatin in cortical neurons are related to neuron size and cortical connections. Moreover, we point to evidence that reveals an orderly sequence of events during development, linking chromatin and gene expression patterns, neuron morphology, function, and connections across cortical areas and layers. Based on this synthesis, we posit that systematic studies of changes in chromatin patterns and epigenetic marks across cortical areas will provide novel insights on the development and evolution of cortical networks, and their disruption in connectivity disorders of developmental origin, like autism. Achieving this requires embedding and interpreting genetic, transcriptional, and epigenetic studies within a framework that takes into consideration distinct types of neurons, local circuit interactions, and interareal pathways. These features vary systematically across cortical areas in parallel with laminar structure and are differentially affected in disorders. Finally, based on evidence that autism-associated genetic polymorphisms are especially prominent in excitatory neurons and connectivity disruption affects mostly limbic cortices, we employ this systematic approach to propose novel, targeted studies of projection neurons in limbic areas to elucidate the emergence and time-course of developmental disruptions in autism.

Age-related epididymis-like intratesticular structures: benign lesions of Wolffian origin that can be misdiagnosed as testicular tumors.

This study aims to characterize the epididymis-like intratesticular structures (ELITSs), a rare lesion found in elderly men. ELITSs were identified in 6 patients from a review of 1442 autopsies and 271 surgical specimens of adult men. Bilateral lesions were seen in 5 cases. The lesion was located in the proximity of the mediastinal rete testis (6 testes) and at the testicular periphery (4 testes), and at both central and peripheral locations in 1 case. The lesion is characterized by a pseudostratified cylindrical epithelium, with a robust pankeratin and 8, 18, and 19 keratin expression, focal vimentin expression, and apical CD 10 expression, similar to what is proper of the normal human epididymidis. The epithelial layer of ELITSs was surrounded by a thin layer of smooth-muscle cells. The adjacent testicular parenchyma was atrophied and the rete testis showed some associated degenerative lesions related to arteriosclerosis. The ELITSs are distinct from atrophic seminiferous tubules with a Sertoli cell-only pattern and from the benign glandular teratomatous component of an involution of a malignant testicular germ cell tumor, the so-called burn-out germ cell tumor. Clinical and histopathological data suggest that this lesion represents a late Wolffian differentiation similar to the initial segment of the epididymal duct, which represents an unusual manifestation of the aging process.

Distinction of Neurons, Glia and Endothelial Cells in the Cerebral Cortex: An Algorithm Based on Cytological Features.

The estimation of the number or density of neurons and types of glial cells and their relative proportions in different brain areas are at the core of rigorous quantitative neuroanatomical studies. Unfortunately, the lack of detailed, updated, systematic and well-illustrated descriptions of the cytology of neurons and glial cell types, especially in the primate brain, makes such studies especially demanding, often limiting their scope and broad use. Here, following an extensive analysis of histological materials and the review of current and classical literature, we compile a list of precise morphological criteria that can facilitate and standardize identification of cells in stained sections examined under the microscope. We describe systematically and in detail the cytological features of neurons and glial cell types in the cerebral cortex of the macaque monkey and the human using semithin and thick sections stained for Nissl. We used this classical staining technique because it labels all cells in the brain in distinct ways. In addition, we corroborate key distinguishing characteristics of different cell types in sections immunolabeled for specific markers counterstained for Nissl and in ultrathin sections processed for electron microscopy. Finally, we summarize the core features that distinguish each cell type in easy-to-use tables and sketches, and structure these key features in an algorithm that can be used to systematically distinguish cellular types in the cerebral cortex. Moreover, we report high inter-observer algorithm reliability, which is a crucial test for obtaining consistent and reproducible cell counts in unbiased stereological studies. This protocol establishes a consistent framework that can be used to reliably identify and quantify cells in the cerebral cortex of primates as well as other mammalian species in health and disease.

Large cell neuroendocrine carcinoma of the parotid gland: case report and literature review.

A 74-year-old male presented with a large polinodular mass in the neck. Fine needle aspiration cytology (FNAC) showed an undifferentiated large cell carcinoma. Computed tomography (CT) showed a large parotid mass with multiple satelite nodules. The remaining radiological studies were normal. Radical parotidectomy was performed. The tumor was a large cell carcinoma with neuroendocrine features and positive immunostain for neuroendocrine markers. The patient received postoperative radiotherapy and was free of tumor eight months later. Only four cases of large cell neuroendocrine carcinoma (LCNEC) of the salivary gland have been communicated. All of them have involved the parotid gland. This tumor presents in elderly patients as a large infiltrating parotid mass. Fine needle aspiration cytology serves to recognize the carcinoma, but it fails in recognizing the neuroendocrine features of the tumor. The histopathological features of this tumor are the same as in other organs. Chromogranin and synaptophysin are useful immunohistochemical markers. A primary location of the tumor in another organ, specially the lung, should be ruled out. Surgery is the main treatment modality and can be complemented with postoperative radiotherapy. The prognosis seems to be poor. More studies are needed to better define the therapeutical alternatives and prognostic factors of these rare tumors.

Motor cortex layer 4: less is more.

The stratified motor cortex is variously thought to either lack or contain layer 4. Yamawaki et al. described a functional layer 4 in mouse motor cortex with properties and connections similar to layer 4 in sensory areas. Their results bolster a theoretical framework suggesting all primary cortical areas are equivalent.

Microlithiasis of the epididymis and the rete testis.

Testicular microlithiasis is a well-defined clinical and pathologic entity easily diagnosed through testicular echography; however, its association with cancer and infertility is now under debate. Many efforts have been done in recent years to clarify the spectrum of lesions observed in testicular microlithiasis, but no published data as to the existence of a possible microlithiasis of the epididymis and the rete testis have been found. We have observed microlithiasis of the epididymis and the rete testis in surgical (8 epididymis and 6 testis) and autopsy specimens (12 cases). In decreased order of frequency, microliths of the proximal spermatic way were seen in rete testis, epididymal duct, and efferent ducts. Intraluminal, subepithelial, and interstitial microliths were localized along these segments of the spermatic way. Subepithelial microliths were the most frequently found. A granulomatous reaction around the interstitial epididymal microliths, mimicking malacoplakia, was observed in 1 case. The differential diagnosis of microliths includes corpora amilacea, Michaelis-Gutmann bodies, calcium deposits, hyaline globules, and parasites, like the giant kidney worm Dioctophyme renale. In infants and young adults, microlithiasis of the epididymis and the rete testis is frequently associated with alterations in the development of the proximal spermatic way. In elderly adults, it is related to ischemia and obstruction of the spermatic way.

A direct anterior cingulate pathway to the primate primary olfactory cortex may control attention to olfaction.

Behavioral and functional studies in humans suggest that attention plays a key role in activating the primary olfactory cortex through an unknown circuit mechanism. We report that a novel pathway from the anterior cingulate cortex, an area which has a key role in attention, projects directly to the primary olfactory cortex in rhesus monkeys, innervating mostly the anterior olfactory nucleus. Axons from the anterior cingulate cortex formed synapses mostly with spines of putative excitatory pyramidal neurons and with a small proportion of a neurochemical class of inhibitory neurons that are thought to have disinhibitory effect on excitatory neurons. This novel pathway from the anterior cingulate is poised to exert a powerful excitatory effect on the anterior olfactory nucleus, which is a critical hub for odorant processing via extensive bilateral connections with primary olfactory cortices and the olfactory bulb. Acting on the anterior olfactory nucleus, the anterior cingulate may activate the entire primary olfactory cortex to mediate the process of rapid attention to olfactory stimuli.

CX3CL1 promotes breast cancer via transactivation of the EGF pathway.

Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was not a consequence of CX3CL1-induced metastatic dissemination of the primary tumor, although CX3CL1 induced epithelial-to-mesenchymal transition in breast cancer cells in vitro. Instead, CX3CL1 triggered cell proliferation by induction of ErbB receptors through the proteolytic shedding of an ErbB ligand. This effect was important insofar as mammary tumorigenesis was delayed and tumor multiplicity was reduced by genetic deletion of CX3CL1 in HER2/neu mice, but not in polyoma middle T-antigen oncomice. Our findings support the conclusion that CX3CL1 acts as a positive modifier of breast cancer in concert with ErbB receptors.

Peripheral primitive neuroectodermal tumour of the orbit.

Peripheral primitive neuroectodermal tumours (pPNETs) are a group of soft-tissue tumours of neuroepithelial origin that arise outside the central and sympathetic nervous system. Orbital location is infrequent, and to the best of the authors' knowledge only 16 cases have been reported in the literature. With this article, the authors report the demographics and clinical characteristics, diagnostic features, differential diagnosis, prognosis and therapeutic options of primary orbital peripheral primitive neuroectodermal tumour, based on their patients and on the cases reported in the literature to date. A differential diagnosis should be made with other small round cell tumours; immunohistochemical and ultrastructural techniques are essential for this purpose. Although bone invasion and extraorbital extension are possible, systemic metastases are uncommon in the cases of orbital pPNETs. Surgery has been the initial treatment in most cases; chemotherapy with or without radiotherapy is considered the best additional treatment. The orbital pPNET could be less aggressive than other forms of pPNETs, since most of the patients reported were alive after the follow-up period (at least 6 months).

Inter-hemispheric asymmetry of nigrostriatal dopaminergic lesion: a possible compensatory mechanism in Parkinson's disease.

The onset of Parkinson's disease (PD) is characterized by focal motor features in one body part, which are usually correlated with greater dopaminergic depletion in the contralateral posterior putamen. The role of dopamine (DA) hemispheric differences in the onset and progression of motor symptoms of PD, however, remains undefined. Previous studies have demonstrated that unilateral manipulations of one nigrostriatal system affect contralateral DA turnover, indicating a functional and compensatory inter-dependence of the two nigrostriatal systems. In preliminary data obtained by our group from asymmetric PD patients, a higher asymmetry index as measured by 6-[(18)F]fluoro-L-dopa ((18) F-DOPA) positron emission tomography (PET) was associated with a higher threshold (i.e., greater dopaminergic loss) for the onset of motor symptoms in the less-affected side. To further elucidate the underlying basis for this, we carried out a complementary study in monkeys using PET to assess and correlate the degree of dopaminergic striatal depletion with motor activity. Control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys with symmetrical lesions were characterized behaviorally and with (18)F-DOPA PET. In parallel, an acute lesion was inflicted in the nigrostriatal projection unilaterally in one monkey, generating a 30% dopaminergic depletion in the ipsilateral striatum, which was not associated with any noticeable parkinsonian feature or deficit. The monkey remained asymptomatic for several months. Subsequently, this monkey received systemic MPTP, following which motor behavior and PET were repeatedly evaluated during progression of parkinsonian signs. The brains of all monkeys were processed using immunohistochemical methods. Our results suggest that the onset of motor signs is related to and influenced by the dopaminergic status of the less-affected, contralateral striatum. Although this work is still preliminary, the study agrees with our general hypothesis of hemispheric inter-dependence in the compensation of striatal DA deficit in PD.

Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain).

Reactive Oxygen Species (ROS) result from cell metabolism as well as from extracellular processes. ROS exert some functions necessary for cell homeostasis maintenance. When produced in excess they play a role in the causation of cancer. ROS mediated lipid peroxides are of critical importance because they participate in chain reactions that amplify damage to biomolecules including DNA. DNA attack gives rise to mutations that may involve tumor suppressor genes or oncogenes, and this is an oncogenic mechanism. On the other hand, ROS production is a mechanism shared by many chemotherapeutic drugs due to their implication in apoptosis control. The ROS mediated cell responses depend on the duration and intensity of the cells exposing to the increased ROS environment. Thus the status redox is of great importance for oncogenetic process activation and it is also implicated in tumor susceptibility to specific chemotherapeutic drugs. Phospholipid Hydroperoxide Glutathione Peroxidase (PH-GPx) is an antioxidant enzyme that is able to directly reduce lipid peroxides even when they are bound to cellular membranes. This article will review the relevance of oxidative stress, particularly of lipid peroxidation, in cell response with special focus in carcinogenesis and cancer therapy that suggests PH-GPx as a potentially important enzyme involved in the control of this processes.