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1.  The von Economo neurons in fronto-insular and anterior cingulate cortex 
The von Economo neurons (VENs) are large bipolar neurons located in fronto-insular cortex (FI) and anterior limbic area (LA) in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week post conception, with numbers increasing during the first eight months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of fronto-temporal dementia implies that they are involved in empathy, social awareness, and self-control, consistent with evidence from functional imaging.
doi:10.1111/j.1749-6632.2011.06011.x
PMCID: PMC3140770  PMID: 21534993
fronto-temporal dementia; autism; schizophrenia; empathy; disgust; self-awareness; hemispheric specialization
2.  Evolutionary appearance of von Economo’s neurons in the mammalian cerebral cortex 
von Economo’s neurons (VENs) are large, spindle-shaped projection neurons in layer V of the frontoinsular (FI) cortex, and the anterior cingulate cortex. During human ontogenesis, the VENs can first be differentiated at late stages of gestation, and increase in number during the first eight postnatal months. VENs have been identified in humans, chimpanzee, bonobos, gorillas, orangutan and, more recently, in the macaque. Their distribution in great apes seems to correlate with human-like social cognitive abilities and self-awareness. VENs are also found in whales, in a number of different cetaceans, and in the elephant. This phylogenetic distribution may suggest a correlation among the VENs, brain size and the “social brain.” VENs may be involved in the pathogenesis of specific neurological and psychiatric diseases, such as autism, callosal agenesis and schizophrenia. VENs are selectively affected in a behavioral variant of frontotemporal dementia in which empathy, social awareness and self-control are seriously compromised, thus associating VENs with the social brain. However, the presence of VENs has also been related to special functions such as mirror self-recognition. Areas containing VENs have been related to motor awareness or sense-of-knowing, discrimination between self and other, and between self and the external environment. Along this line, VENs have been related to the “global Workspace” architecture: in accordance the VENs have been correlated to emotional and interoceptive signals by providing fast connections (large axons = fast communication) between salience-related insular and cingulate and other widely separated brain areas. Nevertheless, the lack of a characterization of their physiology and anatomical connectivity allowed only to infer their functional role based on their location and on the functional magnetic resonance imaging data. The recent finding of VENs in the anterior insula of the macaque opens the way to new insights and experimental investigations.
doi:10.3389/fnhum.2014.00104
PMCID: PMC3953677  PMID: 24672457
insula; cingulate cortex; salience network; self-awareness; prediction; development
3.  Neuroanatomical Correlates of Suicide in Psychosis: The Possible Role of von Economo Neurons 
PLoS ONE  2011;6(6):e20936.
Suicide is the most important incident in psychiatric disorders. Psychological pain and empathy to pain involves a neural network that involves the anterior cingulate cortex (ACC) and the anterior insula (AI). At the neuronal level, little is known about how complex emotions such as shame, guilt, self-derogation and social isolation, all of which feature suicidal behavior, are represented in the brain. Based on the observation that the ACC and the AI contain a large spindle-shaped cell type, referred to as von Economo neuron (VEN), which has dramatically increased in density during human evolution, and on growing evidence that VENs play a role in the pathophysiology of various neuropsychiatric disorders, including autism, psychosis and dementia, we examined the density of VENs in the ACC of suicide victims. The density of VENs was determined using cresyl violet-stained sections of the ACC of 39 individuals with psychosis (20 cases with schizophrenia, 19 with bipolar disorder). Nine subjects had died from suicide. Twenty specimen were available from the right, 19 from the left ACC. The density of VENs was significantly greater in the ACC of suicide victims with psychotic disorders compared with psychotic individuals who died from other causes. This effect was restricted to the right ACC. VEN density in the ACC seems to be increased in suicide victims with psychosis. This finding may support the assumption that VEN have a special role in emotion processing and self-evaluation, including negative self-appraisal.
doi:10.1371/journal.pone.0020936
PMCID: PMC3120769  PMID: 21731632
4.  von Economo neurones are selectively targeted in frontotemporal dementia 
Background
von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population.
Aim
A previous study has shown a selective loss of VEN in FTD above other neurones in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology.
Methods
VEN and neighbouring neurones (NN) were quantified in layers Va and Vb of the right dorsal ACC in 21 cases of bvFTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC).
Results
A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n = 13), VEN/10 000 NN was significantly reduced by 53% compared with NDC (P < 0.001) and 41% compared with AD (P = 0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10 000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups.
Discussion
In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process.
doi:10.1111/nan.12021
PMCID: PMC3749467  PMID: 23346995
anterior cingulate cortex; frontotemporal dementia; frontotemporal lobar degeneration; von Economo neurones
5.  Selective functional, regional, and neuronal vulnerability in frontotemporal dementia 
Current opinion in neurology  2008;21(6):701-707.
Purpose of review
The molecular neuroscience revolution has begun to rekindle interest in fundamental neuroanatomy. Blending these disciplines may prove critical to our understanding of neurodegenerative diseases, which target specific anatomical systems. Recent research on frontotemporal dementia highlights the potential value of these approaches.
Recent findings
The behavioral variant of FTD (bvFTD) leads to progressive social-emotional processing deficits accompanied by anterior cingulate and frontal insular degeneration. These sites form a discrete human neural network and feature a class of Layer 5b projection neurons, von Economo neurons (VENs), found only in large-brained, socially complex mammals. VENs have been shown to represent an early target in bvFTD but not in Alzheimer’s disease.
Summary
Integrative approaches to selective vulnerability may help clarify neurodegenerative disease pathogenesis.
doi:10.1097/WCO.0b013e3283168e2d
PMCID: PMC2909835  PMID: 18989116
frontotemporal dementia; von Economo neuron; anterior cingulate; insula
6.  Selective Frontoinsular von Economo Neuron and Fork Cell Loss in Early Behavioral Variant Frontotemporal Dementia 
Cerebral Cortex (New York, NY)  2011;22(2):251-259.
Behavioral variant frontotemporal dementia (bvFTD) erodes complex social–emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region-specific neuronal targets in early bvFTD.
doi:10.1093/cercor/bhr004
PMCID: PMC3256403  PMID: 21653702
Alzheimer's disease; behavioral variant frontotemporal dementia; fork cell; frontoinsula; von Economo neuron
7.  A volumetric comparison of the insular cortex and its subregions in primates 
Journal of human evolution  2013;64(4):263-279.
The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body’s homeostatic state. We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent = 1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent = 1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.
doi:10.1016/j.jhevol.2012.12.003
PMCID: PMC3756831  PMID: 23466178
Allometry; Brain; Evolution; Frontoinsular cortex; Hominoids
8.  A Case of Semantic Variant Primary Progressive Aphasia with Severe Insular Atrophy 
Neurocase  2011;18(6):450-456.
Insular degeneration has been linked to symptoms of frontotemporal dementia (FTD). Presented in this case is a patient exhibiting semantic variant primary progressive aphasia, behavioral disturbance. Upon autopsy, he was found to have severe insular atrophy. In addition, selective serotonin reuptake inhibitors (SSRIs) were ineffective in reducing symptoms of obsessive-compulsive behaviours or emotional blunting. This case suggests that Seeley et al.'s hypothesis that VEN and fork cell-rich brain regions, particularly in the insula, are targeted in additional subtypes of FTD beyond the behavioral variant.
doi:10.1080/13554794.2011.627343
PMCID: PMC3500405  PMID: 22150361
frontotemporal dementia; MRI; PET; SPECT; insula
9.  Youthful Memory Capacity in Old Brains: Anatomic and Genetic Clues from the Northwestern SuperAging Project 
The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ε4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.
doi:10.1162/jocn_a_00300
PMCID: PMC3541673  PMID: 23198888
10.  Pharmacokinetics of venlafaxine and its major metabolite o-desmethylvenlafaxine in freely moving mice using automated dosing/sampling system 
Indian Journal of Pharmacology  2012;44(1):20-25.
Objective:
To assess the pharmacokinetics of venlafaxine (VEN) and its major metabolite o-desmethylvenlafaxine (ODV) in freely moving mice using automated dosing/infusion (ADI) and automated blood sampling (ABS) systems. In addition, concentration of VEN and its metabolite ODV were also measured in brain by microdialysis.
Materials and Methods:
Venlafaxine was administered directly via jugular vein or gastric catheterization and blood samples were collected through carotid artery. A series of samples with 10 μl of blood was collected from the mouse using ADI/ABS and analyzed with a validated LC-MS/MS system. Extracellular concentrations of VEN and ODV in brain were investigated by using microdialysis procedure.
Results:
The bioavailability of VEN was 11.6%. The percent AUC ratios of ODV to VEN were 18% and 39% following intravenous and intragastric administration, respectively. The terminal half-life of venlafaxine was about two hours. Extracellular concentration of VEN contributed 3.4% of the blood amount, while ODV was not detected in dialysate.
Conclusion:
This study suggests that besides rapid absorption of VEN, the first-pass metabolism is likely to contribute for its lower bioavailability in the mouse. The proposed automated technique can be used easily to conduct pharmacokinetic studies and is applicable to high-throughput manner in mouse model.
doi:10.4103/0253-7613.91861
PMCID: PMC3271533  PMID: 22345864
Pharmacokinetics; microdialysis; O-desmethylvenlafaxine; venlafaxine
11.  Predictors of nonresponse to cognitive behavioural therapy or venlafaxine using glucose metabolism in major depressive disorder 
Background
Longitudinal neuroimaging investigations of antidepressant treatment offer the opportunity to identify potential baseline biomarkers associated with poor outcome.
Methods
To explore the neural correlates of nonresponse to cognitive behavioural therapy (CBT) or venlafaxine (VEN), we compared pretreatment (18)F-fluoro-2-deoxy-d-glucose positron emission tomography scans of participants with major depressive disorder responding to either 16 weeks of CBT (n = 7) or VEN treatment (n = 9) with treatment nonresponders (n = 8).
Results
Nonresponders to CBT or VEN, in contrast to responders, exhibited pretreatment hypermetabolism at the interface of the pregenual and subgenual cingulate cortices.
Limitations
Limitations of our study include the small sample sizes and the absence of both arterial sampling to determine absolute glucose metabolism and high-resolution structural magnetic resonance imaging coregistration for region-of-interest analyses.
Conclusion
Our current findings are consistent with those reported in previous studies of relative hyperactivity in the ventral anterior cingulate cortex in treatment-resistant populations.
PMCID: PMC2674969  PMID: 19448846
12.  Posterior parahippocampal gyrus pathology in Alzheimer’s disease 
Neuroscience  2008;154(2):667-676.
The posterior parahippocampal gyrus (PPHG) of the non-human primate brain has a distinct dual role in cortical neural systems. On the one hand, it is a critical link in providing the entorhinal cortex and hippocampal formation with cortical input, while on the other hand it receives output from these structures and projects widely by disseminating the medial temporal lobe output to the cortex. Layer III of TF and TH areas (temporal areas F, H of von Economo and Koskinas (1925) and von Bonin and Bailey (1947) largely mediate the former (input) while layer V mediates the latter (output). We have examined areas TF and TH in the normal human brain and in Alzheimer’s disease (AD) using pathological stains (Nissl, Thioflavin S) and phenotype specific stains non-phosphorylated neurofilament protein (SMI-32) and parvalbumin (PV). Seven clinically and pathologically confirmed AD cases have been studied along with six age-compatible normal cases. Our observations reveal that neurofibrillary tangles (NFTs) heavily invest the area TF and TH neurons that form layers III and V. In both cortical areas, the large pyramids that form layer V contain a greater number of NFTs. These changes, and possibly, pyramidal cell loss, greatly alter the cytoarchitectural picture and diminish SMI-32 staining patterns. Layer III of area TH loses the majority of SMI-32 immunoreactivity, whereas this change is more conspicuous in layer V of area TF. PV-staining in both areas is largely unaffected. Normal cases contained no evidence of pathology or altered cytoarchitecture. These observations reveal a further disruption of memory related temporal neural systems in AD where pathology selectively alters both the input to the hippocampal formation and its output to the cortex.
doi:10.1016/j.neuroscience.2008.03.077
PMCID: PMC2517248  PMID: 18486350
Alzheimer’s disease; neurofibrillary tangles; posterior parahippocampal gyrus; hippocampal formation; memory; laminar pattern
13.  Brain and aviation: on the 80th anniversary of Constantin von Economo’s (1876–1931) death 
Neurological Sciences  2012;34(3):387-391.
2011 marks the 80th anniversary of the death of Constantin Alexander von Economo who conducted advanced research on the cytoarchitectonics of the brain. This Austrian neurologist and the pioneer of aviation described encephalitis lethargica, discovered the spindle neurons, and postulated the existence of the sleep and wakefulness centre in the brain. What is more he realized two of the biggest dreams of humankind: conquering space and getting to know the secrets of the human brain.
doi:10.1007/s10072-012-1111-0
PMCID: PMC3586395  PMID: 22569570
Constantin von Economo; History of neurology; von Economo neurons; Encephalitis lethargica; Brain
14.  The Human Parahippocampal Region: I. Temporal Pole Cytoarchitectonic and MRI Correlation 
Cerebral Cortex (New York, NY)  2010;20(9):2198-2212.
The temporal pole (TP) is the rostralmost portion of the human temporal lobe. Characteristically, it is only present in human and nonhuman primates. TP has been implicated in different cognitive functions such as emotion, attention, behavior, and memory, based on functional studies performed in healthy controls and patients with neurodegenerative diseases through its anatomical connections (amygdala, pulvinar, orbitofrontal cortex). TP was originally described as a single uniform area by Brodmann area 38, and von Economo (area TG of von Economo and Koskinas), and little information on its cytoarchitectonics is known in humans. We hypothesize that 1) TP is not a homogenous area and we aim first at fixating the precise extent and limits of temporopolar cortex (TPC) with adjacent fields and 2) its structure can be correlated with structural magnetic resonance images. We describe here the macroscopic characteristics and cytoarchitecture as two subfields, a medial and a lateral area, that constitute TPC also noticeable in 2D and 3D reconstructions. Our findings suggest that the human TP is a heterogeneous region formed exclusively by TPC for about 7 mm of the temporal tip, and that becomes progressively restricted to the medial and ventral sides of the TP. This cortical area presents topographical and structural features in common with nonhuman primates, which suggests an evolutionary development in human species.
doi:10.1093/cercor/bhp289
PMCID: PMC2923216  PMID: 20064939
cytoarchitecture; humans; MRI; temporal pole; temporopolar cortex
15.  EVIDENCE OF CELL-NONAUTONOMOUS CHANGES IN DENDRITE AND DENDRITIC SPINE MORPHOLOGY IN THE MET-SIGNALING DEFICIENT MOUSE FOREBRAIN 
The Journal of comparative neurology  2010;518(21):4463-4478.
Human genetic findings and murine neuroanatomical expression mapping have intersected to implicate Met receptor tyrosine kinase signaling in the development of forebrain circuits controlling social and emotional behaviors that are atypical in autism spectrum disorders (ASD). To clarify roles for Met signaling during forebrain circuit development in vivo, we generated mutant mice (Emx1Cre/Metfx/fx) with an Emx1-Cre-driven deletion of signaling-competent Met in dorsal pallially-derived forebrain neurons. Morphometric analyses of Lucifer Yellow-injected pyramidal neurons in postnatal day 40 anterior cingulate cortex (ACC) revealed no statistically significant changes in total dendritic length, but a selective reduction in apical arbor length distal to the soma in Emx1Cre/Metfx/fx neurons relative to wild type, consistent with a decrease in the total tissue volume sampled by individual arbors in the cortex. The effects on dendritic structure appear to be circuit-selective, as basal arbor length was increased in Emx1Cre/Metfx/fx layer 2/3 neurons. Spine number was not altered on Emx1Cre/Metfx/fx pyramidal cell populations studied, but spine head volume was significantly increased (~20%). Cell-nonautonomous, circuit-level influences of Met signaling on dendritic development were confirmed by studies of medium spiny neurons (MSN), which do not express Met, but receive Met-expressing corticostriatal afferents during development. Emx1Cre/Metfx/fx MSN exhibited robust increases in total arbor length (~20%). Like in the neocortex, average spine head volume was also increased (~12%). These data demonstrate that a developmental loss of presynaptic Met receptor signaling can affect postsynaptic morphogenesis and suggest a mechanism whereby attenuated Met signaling could disrupt both local and long-range connectivity within circuits relevant to ASD.
doi:10.1002/cne.22467
PMCID: PMC2952412  PMID: 20853516
16.  Different evolutionary pathways underlie the morphology of wrist bones in hominoids 
Background
The hominoid wrist has been a focus of numerous morphological analyses that aim to better understand long-standing questions about the evolution of human and hominoid hand use. However, these same analyses also suggest various scenarios of complex and mosaic patterns of morphological evolution within the wrist and potentially multiple instances of homoplasy that would benefit from require formal analysis within a phylogenetic context.
We identify morphological features that principally characterize primate – and, in particular, hominoid (apes, including humans) - wrist evolution and reveal the rate, process and evolutionary timing of patterns of morphological change on individual branches of the primate tree of life. Linear morphological variables of five wrist bones – the scaphoid, lunate, triquetrum, capitate and hamate – are analyzed in a diverse sample of extant hominoids (12 species, 332 specimens), Old World (8 species, 43 specimens) and New World (4 species, 26 specimens) monkeys, fossil Miocene apes (8 species, 20 specimens) and Plio-Pleistocene hominins (8 species, 18 specimens).
Result
Results reveal a combination of parallel and synapomorphic morphology within haplorrhines, and especially within hominoids, across individual wrist bones. Similar morphology of some wrist bones reflects locomotor behaviour shared between clades (scaphoid, triquetrum and capitate) while others (lunate and hamate) indicate clade-specific synapomorphic morphology. Overall, hominoids show increased variation in wrist bone morphology compared with other primate clades, supporting previous analyses, and demonstrate several occurrences of parallel evolution, particularly between orangutans and hylobatids, and among hominines (extant African apes, humans and fossil hominins).
Conclusions
Our analyses indicate that different evolutionary processes can underlie the evolution of a single anatomical unit (the wrist) to produce diversity in functional and morphological adaptations across individual wrist bones. These results exemplify a degree of evolutionary and functional independence across different wrist bones, the potential evolvability of skeletal morphology, and help to contextualize the postcranial mosaicism observed in the hominin fossil record.
doi:10.1186/1471-2148-13-229
PMCID: PMC4015765  PMID: 24148262
Carpal; Functional morphology; Locomotion; Phylogeny; Variable rates estimation
17.  Effects of social disruption in elephants persist decades after culling 
Frontiers in Zoology  2013;10:62.
Background
Multi-level fission-fusion societies, characteristic of a number of large brained mammal species including some primates, cetaceans and elephants, are among the most complex and cognitively demanding animal social systems. Many free-ranging populations of these highly social mammals already face severe human disturbance, which is set to accelerate with projected anthropogenic environmental change. Despite this, our understanding of how such disruption affects core aspects of social functioning is still very limited.
Results
We now use novel playback experiments to assess decision-making abilities integral to operating successfully within complex societies, and provide the first systematic evidence that fundamental social skills may be significantly impaired by anthropogenic disruption. African elephants (Loxodonta africana) that had experienced separation from family members and translocation during culling operations decades previously performed poorly on systematic tests of their social knowledge, failing to distinguish between callers on the basis of social familiarity. Moreover, elephants from the disrupted population showed no evidence of discriminating between callers when age-related cues simulated individuals on an increasing scale of social dominance, in sharp contrast to the undisturbed population where this core social ability was well developed.
Conclusions
Key decision-making abilities that are fundamental to living in complex societies could be significantly altered in the long-term through exposure to severely disruptive events (e.g. culling and translocation). There is an assumption that wildlife responds to increasing pressure from human societies only in terms of demography, however our study demonstrates that the effects may be considerably more pervasive. These findings highlight the potential long-term negative consequences of acute social disruption in cognitively advanced species that live in close-knit kin-based societies, and alter our perspective on the health and functioning of populations that have been subjected to anthropogenic disturbance.
doi:10.1186/1742-9994-10-62
PMCID: PMC3874604  PMID: 24152378
Social behaviour; Human disturbance; Anthropogenic disruption; Cognitive abilities; Playback experiment; Large-brained mammals; Social organisation; Loxodonta africana; Fission-fusion society; Vocal communication; Matriarch
18.  Assessing the Molecular Genetics of the Development of Executive Attention in Children: Focus on Genetic Pathways Related to the Anterior Cingulate Cortex and Dopamine 
Neuroscience  2009;164(1):241-246.
It is well-known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and fronto-striatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to-date that employs both adult and child-friendly versions of the Attention Network Task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention.
doi:10.1016/j.neuroscience.2009.01.029
PMCID: PMC2792745  PMID: 19344637
19.  Measurements of Salivary Alpha Amylase and Salivary Cortisol in Hominoid Primates Reveal Within-Species Consistency and Between-Species Differences 
PLoS ONE  2013;8(4):e60773.
Salivary alpha amylase (sAA) is the most abundant enzyme in saliva. Studies in humans found variation in enzymatic activity of sAA across populations that could be linked to the copy number of loci for salivary amylase (AMY1), which was seen as an adaptive response to the intake of dietary starch. In addition to diet dependent variation, differences in sAA activity have been related to social stress. In a previous study, we found evidence for stress-induced variation in sAA activity in the bonobos, a hominoid primate that is closely related to humans. In this study, we explored patterns of variation in sAA activity in bonobos and three other hominoid primates, chimpanzee, gorilla, and orangutan to (a) examine if within-species differences in sAA activity found in bonobos are characteristic for hominoids and (b) assess the extent of variation in sAA activity between different species. The results revealed species-differences in sAA activity with gorillas and orangutans having higher basal sAA activity when compared to Pan. To assess the impact of stress, sAA values were related to cortisol levels measured in the same saliva samples. Gorillas and orangutans had low salivary cortisol concentrations and the highest cortisol concentration was found in samples from male bonobos, the group that also showed the highest sAA activity. Considering published information, the differences in sAA activity correspond with differences in AMY1 copy numbers and match with general features of natural diet. Studies on sAA activity have the potential to complement molecular studies and may contribute to research on feeding ecology and nutrition.
doi:10.1371/journal.pone.0060773
PMCID: PMC3629192  PMID: 23613746
20.  NEURAL PROCESSING OF GUSTATORY INFORMATION IN INSULAR CIRCUITS 
Current opinion in neurobiology  2012;22(4):709-716.
The insular cortex is the primary cortical site devoted to taste processing. A large body of evidence is available for how insular neurons respond to gustatory stimulation in both anesthetized and behaving animals. Most of the reports describe broadly tuned neurons that are involved in processing the chemosensory, physiological and psychological aspects of gustatory experience. However little is known about how these neural responses map onto insular circuits. Particularly mysterious is the functional role of the three subdivisions of the insular cortex: the granular, the dysgranular and the agranular insular cortices. In this article we review data on the organization of the local and long-distance circuits in the three subdivisions. The functional significance of these results is discussed in light of the latest electrophysiological data. A view of the insular cortex as a functionally integrated system devoted to processing gustatory, multimodal, cognitive and affective information is proposed.
doi:10.1016/j.conb.2012.04.001
PMCID: PMC3438322  PMID: 22554880
21.  Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits 
Nicotine is the principle addictive agent delivered via cigarette smoking. The addictive activity of nicotine is due to potent interactions with nicotinic acetylcholine receptors (nAChRs) on neurons in the reinforcement and reward circuits of the brain. Beyond its addictive actions, nicotine is thought to have positive effects on performance in working memory and short-term attention-related tasks. The brain areas involved in such behaviors are part of an extensive cortico-limbic network that includes relays between prefrontal cortex (PFC) and cingulate cortex (CC), hippocampus, amygdala, ventral tegmental area (VTA) and the nucleus accumbens (nAcc). Nicotine activates a broad array of nAChRs subtypes that can be targeted to pre- as well as peri- and post-synaptic locations in these areas. Thereby, nicotine not only excites different types of neurons, but it also perturbs baseline neuronal communication, alters synaptic properties and modulates synaptic plasticity.
In this review we focus on recent findings on nicotinic modulation of cortical circuits and their targets fields, which show that acute and transient activation of nicotinic receptors in cortico-limbic circuits triggers a series of events that affects cognitive performance in a long lasting manner. Understanding how nicotine induces long-term changes in synapses and alters plasticity in the cortico-limbic circuits is essential to determining how these areas interact in decoding fundamental aspects of cognition and reward.
doi:10.1016/j.semcdb.2009.01.007
PMCID: PMC2742626  PMID: 19560048
Nicotine; Cognition; Limbic; Acetylcholine; Synaptic plasticity
22.  Evidence for evolutionary specialization in human limbic structures 
Increasingly, functional and evolutionary research has highlighted the important contribution emotion processing makes to complex human social cognition. As such, it may be asked whether neural structures involved in emotion processing, commonly referred to as limbic structures, have been impacted in human brain evolution. To address this question, we performed an extensive evolutionary analysis of multiple limbic structures using modern phylogenetic tools. For this analysis, we combined new volumetric data for the hominoid (human and ape) amygdala and 4 amygdaloid nuclei, hippocampus, and striatum, collected using stereological methods in complete histological series, with previously published datasets on the amygdala, orbital and medial frontal cortex, and insula, as well as a non-limbic structure, the dorsal frontal cortex, for contrast. We performed a parallel analysis using large published datasets including many anthropoid species (human, ape, and monkey), but fewer hominoids, for the amygdala and 2 amygdaloid subdivisions, hippocampus, schizocortex, striatum, and septal nuclei. To address evolutionary change, we compared observed human values to values predicted from regressions run through (a) non-human hominoids and (b) non-human anthropoids, assessing phylogenetic influence using phylogenetic generalized least squares regression. Compared with other hominoids, the volumes of the hippocampus, the lateral nucleus of the amygdala, and the orbital frontal cortex were, respectively, 50, 37, and 11% greater in humans than predicted for an ape of human hemisphere volume, while the medial and dorsal frontal cortex were, respectively, 26 and 29% significantly smaller. Compared with other anthropoids, only human values for the striatum fell significantly below predicted values. Overall, the data present support for the idea that regions involved in emotion processing are not necessarily conserved or regressive, but may even be enhanced in recent human evolution.
doi:10.3389/fnhum.2014.00277
PMCID: PMC4033018  PMID: 24904348
emotion; human brain evolution; hippocampus; amygdala; frontal cortex; comparative neuroanatomy; ape; hominoid
23.  Synapses with inhibitory neurons differentiate anterior cingulate from dorsolateral prefrontal pathways associated with cognitive control 
Neuron  2009;61(4):609-620.
Summary
The primate dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) focus attention on relevant signals and suppress noise in cognitive tasks. However, their synaptic interactions and unique roles in cognitive control are unknown. We report that two distinct pathways to DLPFC area 9, one from the neighboring area 46 and the other from the functionally distinct ACC, similarly innervate excitatory neurons associated with selecting relevant stimuli. However, ACC has more prevalent and larger synapses with inhibitory neurons and preferentially innervates calbindin inhibitory neurons, which reduce noise by inhibiting excitatory neurons. In contrast, area 46 mostly innervates calretinin inhibitory neurons, which disinhibit excitatory neurons. These synaptic specializations suggest that ACC has a greater impact in reducing noise in dorsolateral areas during challenging cognitive tasks involving conflict, error, or reversing decisions, mechanisms that are disrupted in schizophrenia. These observations highlight the unique roles of the DLPFC and ACC in cognitive control.
doi:10.1016/j.neuron.2009.01.006
PMCID: PMC2804928  PMID: 19249280
Macaca mulatta; anterior cingulate; dorsolateral prefrontal; calbindin; calretinin; parvalbumin; inhibitory neurons
24.  Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis 
Neuropsychopharmacology  2011;36(8):1754-1768.
In the search for antidepressants' (ADs') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI- and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.
doi:10.1038/npp.2011.57
PMCID: PMC3138654  PMID: 21508931
autophagosome; lysosome; amitriptyline; class-III PI3 kinase; mitochondria; antidepressants; second messengers; molecular and cellular neurobiology; depression; unipolar/bipolar; autophagosome; lysosome; amitriptyline; citalopram; mitochondria
25.  Emotional communication in primates: implications for neurobiology 
Current opinion in neurobiology  2005;15(6):716-720.
The social brain hypothesis proposes that large neocortex size in Homonoids evolved to cope with the increasing demands of complex group living and greater numbers of interindividual relationships. Group living requires that individuals communicate effectively about environmental and internal events. Recent data have highlighted the complexity of chimpanzee communication, including graded facial expressions and referential vocalizations. Among Hominoids, elaborate facial communication is accompanied by specializations in brain areas controlling facial movement. Finally, the evolution of empathy, or emotional awareness, might have a neural basis in specialized cells in the neocortex, that is, spindle cells that have been associated with self-conscious emotions, and mirror neurons that have recently been shown to activate in response to communicative facial gestures.
doi:10.1016/j.conb.2005.10.017
PMCID: PMC2826104  PMID: 16274983

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