Directed Communication between Nucleus Accumbens and Neocortex in Humans Is Differentially Supported by Synchronization in the Theta and Alpha Band.

PubMed

Horschig, Jörn M; Smolders, Ruud; Bonnefond, Mathilde; Schoffelen, Jan-Mathijs; van den Munckhof, Pepijn; Schuurman, P Richard; Cools, Roshan; Denys, Damiaan; Jensen, Ole

2015-01-01

Here, we report evidence for oscillatory bi-directional interactions between the nucleus accumbens and the neocortex in humans. Six patients performed a demanding covert visual attention task while we simultaneously recorded brain activity from deep-brain electrodes implanted in the nucleus accumbens and the surface electroencephalogram (EEG). Both theta and alpha oscillations were strongly coherent with the frontal and parietal EEG during the task. Theta-band coherence increased during processing of the visual stimuli. Granger causality analysis revealed that the nucleus accumbens was communicating with the neocortex primarily in the theta-band, while the cortex was communicating the nucleus accumbens in the alpha-band. These data are consistent with a model, in which theta- and alpha-band oscillations serve dissociable roles: Prior to stimulus processing, the cortex might suppress ongoing processing in the nucleus accumbens by modulating alpha-band activity. Subsequently, upon stimulus presentation, theta oscillations might facilitate the active exchange of stimulus information from the nucleus accumbens to the cortex.

The mammalian neocortex new pyramidal neuron: a new conception.

PubMed

Marín-Padilla, Miguel

2014-01-06

The new cerebral cortex (neocortex) and the new type of pyramidal neuron are mammalian innovations that have evolved for operating their increasing motor capabilities while essentially using analogous anatomical and neural makeups. The human neocortex starts to develop in 6-week-old embryos with the establishment of a primordial cortical organization, which resembles the primitive cortices of amphibian and reptiles. From the 8th to the 15th week of age, new pyramidal neurons, of ependymal origin, are progressively incorporated within this primordial cortex forming a cellular plate that divides its components into those above it (neocortex first layer) and those below it (neocortex subplate zone). From the 16th week of age to birth and postnatally, the new pyramidal neurons continue to elongate functionally their apical dendrite by adding synaptic membrane to incorporate the needed sensory information for operating its developing motor activities. The new pyramidal neuron' distinguishing feature is the capacity of elongating anatomically and functionally its apical dendrite (its main receptive surface) without losing its original attachment to first layer or the location of its soma and, hence, retaining its essential nature. The number of pyramidal cell functional strata established in the motor cortex increases and reflects each mammalian species motor capabilities: the hedgehog needs two pyramidal cell functional strata to carry out all its motor activities, the mouse 3, cat 4, primates 5 and humans 6. The presence of six pyramidal cell functional strata distinguish the human motor cortex from that of others primates. Homo sapiens represent a new evolutionary stage that have transformed his primate brain for operating his unique motor capabilities, such as speaking, writing, painting, sculpturing and thinking as a premotor activity. Words used in language are the motor expression of thoughts and represent sounds produced by maneuvering the column of expiratory air by coordinated motor quivering as it passes through the larynx, pharynx, mouth, tongue, and lips. Homo sapiens cerebrum has developed new motor centers to communicate mental thoughts (and/or intention) through motor actions.

AUDITORY NUCLEI: DISTINCTIVE RESPONSE PATTERNS TO WHITE NOISE AND TONES IN UNANESTHETIZED CATS.

PubMed

GALIN, D

1964-10-09

Electrical responses to "white" noise and tonal stimuli were recorded from unanesthetized cats with permanently implanted bipolar electrodes. The cochlear nucleus, inferior colliculus, and medial geniculate each showed distinctive patterns of evoked activity. White noise and tones produced qualitatively different types of response. A decrease in activity characterized the response of the inferior colliculus to tonal stimuli.

Abundant Occurrence of Basal Radial Glia in the Subventricular Zone of Embryonic Neocortex of a Lissencephalic Primate, the Common Marmoset Callithrix jacchus

PubMed Central

Kelava, Iva; Reillo, Isabel; Murayama, Ayako Y.; Kalinka, Alex T.; Stenzel, Denise; Tomancak, Pavel; Matsuzaki, Fumio; Lebrand, Cécile; Sasaki, Erika; Schwamborn, Jens C.; Okano, Hideyuki; Borrell, Víctor

2012-01-01

Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), glutamate aspartate transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor type. PMID:22114084

Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development

PubMed Central

Mora-Bermúdez, Felipe; Badsha, Farhath; Kanton, Sabina; Camp, J Gray; Vernot, Benjamin; Köhler, Kathrin; Voigt, Birger; Okita, Keisuke; Maricic, Tomislav; He, Zhisong; Lachmann, Robert; Pääbo, Svante; Treutlein, Barbara; Huttner, Wieland B

2016-01-01

Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar. Notably, however, live imaging of apical progenitor mitosis uncovered a lengthening of prometaphase-metaphase in humans compared to chimpanzees that is specific to proliferating progenitors and not observed in non-neural cells. Consistent with this, the small set of genes more highly expressed in human apical progenitors points to increased proliferative capacity, and the proportion of neurogenic basal progenitors is lower in humans. These subtle differences in cortical progenitors between humans and chimpanzees may have consequences for human neocortex evolution. DOI: http://dx.doi.org/10.7554/eLife.18683.001 PMID:27669147

High doses of pseudoephedrine hydrochloride accelerate onset of CNS oxygen toxicity seizures in unanesthetized rats.

PubMed

Pilla, R; Held, H E; Landon, C S; Dean, J B

2013-08-29

Pseudoephedrine (PSE) salts (hydrochloride and sulfate) are commonly used as nasal and paranasal decongestants by scuba divers. Anecdotal reports from the Divers Alert Network suggest that taking PSE prior to diving while breathing pure O₂ increases the risk for CNS oxygen toxicity (CNS-OT), which manifests as seizures. We hypothesized that high doses of PSE reduce the latency time to seizure (LS) in unanesthetized rats breathing 5 atmospheres absolute (ATA) of hyperbaric oxygen. Sixty-three male rats were implanted with radio-transmitters that recorded electroencephalogram activity and body temperature. After ≥7-day recovery, and 2 h before "diving", each rat was administered either saline solution (control) or PSE hydrochloride intragastrically at the following doses (mg PSE/kg): 0, 40, 80, 100, 120, 160, and 320. Rats breathed pure O₂ and were dived to 5ATA until the onset of behavioral seizures coincident with neurological seizures. LS was the time elapsed between reaching 5ATA and exhibiting seizures. We observed a significant dose-dependent decrease in the LS at doses of 100-320 mg/kg, whereas no significant differences in LS from control value were observed at doses ≤80 mg/kg. Our findings showed that high doses of PSE accelerate the onset of CNS-OT seizures in unanesthetized rats breathing 5ATA of poikilocapnic hyperoxia. Extrapolating our findings to humans, we conclude that the recommended daily dose of PSE should not be abused prior to diving with oxygen-enriched gas mixes or pure O₂. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Use of positive reinforcement conditioning to monitor pregnancy in an unanesthetized snow leopard (Uncia uncia) via transabdominal ultrasound.

PubMed

Broder, Jacqueline M; Macfadden, Annabell J; Cosens, Lindsay M; Rosenstein, Diana S; Harrison, Tara M

2008-01-01

Closely monitoring snow leopard (Uncia uncia) fetal developments via transabdominal ultrasound, with minimal stress to the animal, was the goal of this project. The staff at Potter Park Zoo has used the principles of habituation, desensitization, and positive reinforcement to train a female snow leopard (U. uncia). Ultrasound examinations were preformed on an unanesthetized feline at 63 and 84 days. The animal remained calm and compliant throughout both procedures. Fetuses were observed and measured on both occasions. The absence of anesthesia eliminated components of psychologic and physiologic stress associated with sedation. This was the first recorded instance of transabdominal ultrasound being carried out on an unanesthetized snow leopard. It documents the feasibility of detecting pregnancy and monitoring fetal development via ultrasound. Zoo Biol 27:78-85, 2008. (c) 2007 Wiley-Liss, Inc.

Cardiovascular changes in unanesthetized and ketamine-anesthetized Sprague-Dawley rats exposed to 2. 8-GHz radiofrequency radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jauchem, J.R.; Frei, M.R.

1991-01-01

Sprague-Dawley rats were exposed to 2.8-GHz radiofrequency radiation, first while unanesthetized and then while anesthetized with ketamine (150 mg/kg.I.M.). Irradiation at a power density of 60 mW/cm2 (whole-body average specific absorption rate of approximately 14 W/kg) was conducted for sufficient duration to increase colonic temperature from 38.5 to 39.5 degrees C. The time required for the temperature increase was significantly longer in the anesthetized state. During irradiation, heart rate increased significantly both with and without anesthesia, while mean arterial blood pressure increased only when the rats were unanesthetized. The heart rate increase in the anesthetized state contrasts with a lackmore » of change in a previous study of Fischer rats. This difference between anesthetized Sprague-Dawley and Fischer rats should be considered when comparing cardiovascular data obtained from these two strains of rats.« less

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.

PubMed

Colvin, Steven M; Kwan, Kenneth Y

2014-01-01

A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.

Modeling cortical circuits.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rohrer, Brandon Robinson; Rothganger, Fredrick H.; Verzi, Stephen J.

2010-09-01

The neocortex is perhaps the highest region of the human brain, where audio and visual perception takes place along with many important cognitive functions. An important research goal is to describe the mechanisms implemented by the neocortex. There is an apparent regularity in the structure of the neocortex [Brodmann 1909, Mountcastle 1957] which may help simplify this task. The work reported here addresses the problem of how to describe the putative repeated units ('cortical circuits') in a manner that is easily understood and manipulated, with the long-term goal of developing a mathematical and algorithmic description of their function. The approachmore » is to reduce each algorithm to an enhanced perceptron-like structure and describe its computation using difference equations. We organize this algorithmic processing into larger structures based on physiological observations, and implement key modeling concepts in software which runs on parallel computing hardware.« less

Spatiotemporal dynamics of neocortical excitation and inhibition during human sleep.

PubMed

Peyrache, Adrien; Dehghani, Nima; Eskandar, Emad N; Madsen, Joseph R; Anderson, William S; Donoghue, Jacob A; Hochberg, Leigh R; Halgren, Eric; Cash, Sydney S; Destexhe, Alain

2012-01-31

Intracranial recording is an important diagnostic method routinely used in a number of neurological monitoring scenarios. In recent years, advancements in such recordings have been extended to include unit activity of an ensemble of neurons. However, a detailed functional characterization of excitatory and inhibitory cells has not been attempted in human neocortex, particularly during the sleep state. Here, we report that such feature discrimination is possible from high-density recordings in the neocortex by using 2D multielectrode arrays. Successful separation of regular-spiking neurons (or bursting cells) from fast-spiking cells resulted in well-defined clusters that each showed unique intrinsic firing properties. The high density of the array, which allowed recording from a large number of cells (up to 90), helped us to identify apparent monosynaptic connections, confirming the excitatory and inhibitory nature of regular-spiking and fast-spiking cells, thus categorized as putative pyramidal cells and interneurons, respectively. Finally, we investigated the dynamics of correlations within each class. A marked exponential decay with distance was observed in the case of excitatory but not for inhibitory cells. Although the amplitude of that decline depended on the timescale at which the correlations were computed, the spatial constant did not. Furthermore, this spatial constant is compatible with the typical size of human columnar organization. These findings provide a detailed characterization of neuronal activity, functional connectivity at the microcircuit level, and the interplay of excitation and inhibition in the human neocortex.

Evaluation of Veriox as a Skin Decontamination Product after Dermal Exposure to the Nerve Agent VX

DTIC Science & Technology

2016-09-01

in hair -clipped, unanesthetized guinea pigs. Efficacy was established by generating VX dose-lethality curves for each DC product based on 24 survival...This study compared the effectiveness of Veriox® to RSDL when each was used as a DC product 2 min after dermal exposure to VX in hair -clipped...by the dermal LD90 of VX in untreated animals. A LD90 value of 188 μg/kg generated in hair -clipped, unanesthetized guinea pigs (Clarkson, personal

Distribution of neurons expressing tyrosine hydroxylase in the human cerebral cortex

PubMed Central

Benavides-Piccione, Ruth; DeFelipe, Javier

2007-01-01

Since the very first detailed description of the different types of cortical interneurons by Cajal, the tremendous variation in the morphology, physiology and neurochemical properties of these cells has become apparent. However, it still remains unclear whether all types of interneurons are present in all cortical areas and species. Here we have focused on tyrosine hydroxylase (TH)-immunoreactive cortical interneurons, which although only present in certain species, are particularly abundant in the human neocortex. We argue that this type of interneuron is more widespread in the human neocortex than in any other species examined so far and that, therefore, it is probably involved in a larger variety of cortical circuits. In addition, notable regional variation can be seen in relation to these interneurons. These differences further emphasize the variability in the design of microcircuits between cortical areas and species, and they probably reflect an evolutionary adaptation of cortical circuits to particular functions. PMID:17593221

Random Positions of Dendritic Spines in Human Cerebral Cortex

PubMed Central

Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier

2014-01-01

Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits. PMID:25057209

Albumin extravasation rates in tissues of anesthetized and unanesthetized rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renkin, E.M.; Joyner, W.L.; Gustafson-Sgro, M.

Bovine serum albumin (BSA) labeled with /sup 131/I was injected intravenously in chronically prepared, unanesthetized rats and into pentobarbital-anesthetized rats that had received 2 ml 5% BSA to help sustain plasma volume. Initial uptake rates (clearances) in skin, skeletal muscles, diaphragm, and heart (left ventricle) were measured over 1 h. BSA labeled with /sup 125/I was injected terminally to correct for intravascular /sup 131/I-BSA. Observed clearances were in the following order in both groups of animals: heart much greater than diaphragm approximately equal to skin greater than resting skeletal muscles. Differences between unanesthetized and anesthetized animals were small and inconsistentlymore » directed. Our results suggest that the lower albumin clearances reported in the literature for anesthetized rats are not the result of their immobility or any direct effect of anesthesia on albumin transport in these tissues. The lower transport rates appear to result indirectly from changes produced by anesthesia and/or surgery in controllable parameters such as plasma volume and intravascular protein mass.« less

Vestibular short latency responses to pulsed linear acceleration in unanesthetized animals

NASA Technical Reports Server (NTRS)

Jones, T. A.

1992-01-01

Linear acceleration transients were used to elicit vestibular compound action potentials in non-invasively prepared, unanesthetized animals for the first time (chicks, Gallus domesticus, n = 33). Responses were composed of a series of up to 8 dominant peaks occurring within 8 msec of the stimulus. Response amplitudes for 1.0 g stimulus ranged from 1 to 10 microV. A late, slow, triphasic, anesthesia-labile component was identified as a dominant response feature in unanesthetized animals. Amplitudes increased and latencies decreased as stimulus intensity was increased (MANOVA P less than 0.05). Linear regression slope ranges were: amplitudes = 1.0-5.0 microV/g; latencies = -300 to -1100 microseconds/g. Thresholds for single polarity stimuli (0.035 +/- 0.022 g, n = 11) were significantly lower than those of alternating polarity (0.074 +/- 0.028 g, n = 18, P less than 0.001). Bilateral labyrinthectomy eliminated responses whereas bilateral extirpation of cochleae did not significantly change response thresholds. Intense acoustic masking (100/104 dB SL) produced no effect in 2 animals, but did produce small to moderate effects on response amplitudes in 7 others. Changes were attributed to effects on vestibular end organs. Results of unilateral labyrinth blockade (tetrodotoxin) suggest that P1 and N1 preferentially reflect ipsilateral eighth nerve compound action potentials whereas components beyond approximately 2 msec reflect activity from vestibular neurons that depend on both labyrinths. The results demonstrate that short latency vestibular compound action potentials can be measured in unanesthetized, non-invasively prepared animals.

The evolution of the neocortex in mammals: intrinsic and extrinsic contributions to the cortical phenotype.

PubMed

Karlen, Sarah J; Krubitzer, Leah

2006-01-01

The neocortex is that portion of the brain that is involved in volitional motor control, perception, cognition and a number of other complex behaviours exhibited by mammals, including humans. Indeed, the increase in the size of the cortical sheet and cortical field number is one of the hallmarks of human brain evolution. Fossil records and comparative studies of the neocortex indicate that early mammalian neocortices were composed of only a few parts or cortical fields, and that in some lineages such as primates, the neocortex expanded dramatically. More significantly, the number of cortical fields increased and the connectivity between cortical fields became more complex. While we do not know the exact transformation between this type of increase in cortical field number and connectivity; and the emergence of complex behaviours like those mentioned above, we know that species that have large neocorticies with multiple parts generally have more complex behaviours, both overt and covert. Although a number of inroads have been made into understanding how neurons in the neocortex respond to a variety of stimuli, the micro and macro circuitry of particular neocortical fields, and the molecular developmental events that construct current organization, very little is known about how more cortical fields are added in evolution. In particular, we do not know the rules of change, nor the constraints imposed on evolving nervous systems that dictate the particular phenotype that will ultimately emerge. One reason why these issues are unresolved is that the brain is a compromise between existing genetic constraints and the need to adapt. Thus, the functions that the brain generates are absolutely imperfect, although functionally optimized. This makes it very difficult to determine the rules of construction, to generate viable computational models of brain evolution, and to predict the direction of changes that may occur over time. Despite these obstacles, it is still possible to study the evolution of the neocortex. One way is to study the products of the evolutionary process--extant mammal brains-and to make inferences about the process. The second way to study brain evolution is to examine the developmental mechanisms that give rise to complex brains. We have begun to test our theories regarding cortical evolution, generated from comparative studies, by 'tweaking' in a developing nervous system what we believe is naturally being modified in evolution. Our goals are to identify the constraints imposed on the evolving neocortex, to disentangle the genetic and activity dependent mechanisms that give rise to complex brains, and ultimately to produce a cortical phenotype that is consistent with what would naturally occur in evolution.

RANTES modulates the release of glutamate in human neocortex.

PubMed

Musante, Veronica; Longordo, Fabio; Neri, Elisa; Pedrazzi, Marco; Kalfas, Fotios; Severi, Paolo; Raiteri, Maurizio; Pittaluga, Anna

2008-11-19

The effects of the recombinant chemokine human RANTES (hRANTES) on the release of glutamate from human neocortex glutamatergic nerve endings were investigated. hRANTES facilitated the spontaneous release of d [(3)H]D-aspartate ([(3)H]DASP-) by binding Pertussis toxin-sensitive G-protein-coupled receptors (GPCRs), whose activation caused Ca(2+) mobilization from inositol trisphosphate-sensitive stores and cytosolic tyrosine kinase-mediated phosphorylations. Facilitation of release switched to inhibition when the effects of hRANTES on the 12 mM K(+)-evoked [(3)H]D-ASP exocytosis were studied. Inhibition of exocytosis relied on activation of Pertussis toxin-sensitive GPCRs negatively coupled to adenylyl cyclase. Both hRANTES effects were prevented by met-RANTES, an antagonist at the chemokine receptors (CCRs) of the CCR1, CCR3, and CCR5 subtypes. Interestingly, human neocortex glutamatergic nerve endings seem to possess all three receptor subtypes. Blockade of CCR1 and CCR5 by antibodies against the extracellular domain of CCRs prevented both the hRANTES effect on [(3)H]D-ASP release, whereas blockade of CCR3 prevented inhibition, but not facilitation, of release. The effects of RANTES on the spontaneous and the evoked release of [(3)H]D-ASP were also observed in experiments with mouse cortical synaptosomes, which may therefore represent an appropriate animal model to study RANTES-induced effects on neurotransmission. It is concluded that glutamate transmission can be modulated in opposite directions by RANTES acting at distinct CCR receptor subtypes coupled to different transduction pathways, consistent with the multiple and sometimes contrasting effects of the chemokine.

A new subtype of progenitor cell in the mouse embryonic neocortex

PubMed Central

Wang, Xiaoqun; Tsai, Jin-Wu; LaMonica, Bridget; Kriegstein, Arnold R.

2011-01-01

A hallmark of mammalian brain evolution is cortical expansion, which reflects an increase in the number of cortical neurons established by the progenitor cell subtypes present and the number of their neurogenic divisions. Recent studies have revealed a new class of radial glia-like (oRG) progenitor cells in the human brain, which reside in the outer subventricular zone. Expansion of the subventricular zone and appearance of oRG cells may have been essential evolutionary steps leading from lissencephalic to gyrencephalic neocortex. Here we show that oRG-like progenitor cells are present in the mouse embryonic neocortex. They arise from asymmetric divisions of radial glia and undergo self-renewing asymmetric divisions to generate neurons. Moreover, mouse oRG cells undergo mitotic somal translocation whereby centrosome movement into the basal process during interphase preceeds nuclear translocation. Our finding of oRG cells in the developing rodent brain fills a gap in our understanding of neocortical expansion. PMID:21478886

Cortical GABAergic excitation contributes to epileptic activities around human glioma

PubMed Central

Pallud, Johan; Varlet, Pascale; Cresto, Noemie; Baulac, Michel; Duyckaerts, Charles; Kourdougli, Nazim; Chazal, Geneviève; Devaux, Bertrand; Rivera, Claudio; Miles, Richard; Capelle, Laurent; Huberfeld, Gilles

2015-01-01

Rationale Diffuse brain gliomas induce seizures in a majority of patients. As in most epileptic disorders, excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glial tumor cells. Thus the contribution of GABAergic mechanisms which depend on intracellular chloride and which are defective or pro-epileptic in other structural epilepsies merits closer study. Objective We studied in neocortical slices from the peritumoral security margin resected around human brain gliomas, the occurrence, networks, cells and signaling basis of epileptic activities. Results Postoperative glioma tissue from 69% of patients spontaneously generated interictal-like discharges. These events were synchronized, with a high frequency oscillation signature, in superficial layers of neocortex around glioma areas with tumor infiltration. Interictal-like events depended on both glutamatergic transmission and on depolarizing GABAergic signaling. About 65% of pyramidal cells were depolarized by GABA released by interneurons. This effect was related to perturbations in Chloride homeostasis, due to changes in expression of chloride co-transporters: KCC2 was reduced and expression of NKCC1 increased. Ictal-like activities were initiated by convulsant stimuli exclusively in these epileptogenic areas. Conclusions Epileptic activities are sustained by excitatory effects of GABA in the peritumoral human neocortex, as in temporal lobe epilepsies. Glutamate and GABA signaling are involved in oncogenesis and chloride homeostasis is perturbed. These same factors, induce an imbalance between synaptic excitatory and inhibition underly epileptic discharges in tumor patients. PMID:25009229

Random positions of dendritic spines in human cerebral cortex.

PubMed

Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Yuste, Rafael

2014-07-23

Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits. Copyright © 2014 the authors 0270-6474/14/3410078-07$15.00/0.

High-potential defense mechanisms of neocortex in a rat model of transient asphyxia induced cardiac arrest.

PubMed

Keilhoff, Gerburg; Esser, Torben; Titze, Maximilian; Ebmeyer, Uwe; Schild, Lorenz

2017-11-01

Cardiac arrest (CA) is a common cause of disability and mortality and thus an important risk for human health. Circulatory failure has dramatic consequences for the brain as one of the most oxygen-consuming organs. Hippocampus, striatum and neocortex rate among the most vulnerable brain regions. The neocortex is less sensitive to hypoxia/reperfusion in comparison with the hippocampal CA1 region. That implicates the existence of efficient defense mechanisms in the neocortex against hypoxia/reperfusion injury, which we analyzed in a well-established CA rat model. We explored different immunohistochemical markers (NeuN, MAP2, GFAP, IBA1, NOX4, MnSOD, Bax, caspase 3, cfos, nNOS, eNOS, iNOS, TUNEL), amount of mitochondria, activities of respiratory chain complexes and amount/composition of cardiolipin. CA induced a moderate degeneration of cortical neurons. As possible defense mechanisms the study revealed: (i) increased activities of respiratory chain complexes of cortical mitochondria as response to increased energy demand after ACA-induced cell stress; (ii) increase of cardiolipin content as cellular stress response, which might contribute to the promotion of mitochondrial ATP synthesis; (iii) strengthening of the fast, effective and long-lasting mitochondrial MnSOD defense system; (iv) ACA-induced increase in expression of eNOS and nNOS in vasculature being able to reduce ischemic injury by vasodilation. Copyright © 2017 Elsevier B.V. All rights reserved.

Distribution of cholecystokinin mRNA and peptides in the human brain.

PubMed

Lindefors, N; Brené, S; Kopp, J; Lindén, A; Brodin, E; Sedvall, G; Persson, H

1991-01-01

Expression of preprocholecystokinin mRNA was studied in regions of post mortem human brain using RNA blot analysis (Northern blot) and in situ hybridization. Northern blot analysis using a cDNA probe showed high levels of an approximately 0.8 kb preprocholecystokinin mRNA in all regions of neocortex examined. Lower levels of preprocholecystokinin mRNA were detected in amygdaloid body and thalamus. In situ hybridization analysis using the same cDNA probe revealed numerous weakly labelled neurons in different areas of human neocortex and less numerous neurons in hippocampus and amygdaloid body. High-performance liquid-chromatography and gel-chromatography combined with radioimmunoassay of cholecystokinin-like immunoreactivity from human cerebral cortex and caudate nucleus revealed two major forms, one coeluting with sulphated cholecystokinin-8 and the other coeluting with sulphated cholecystokinin-58. Two minor components coeluting with cholecystokinin-4 and cholecystokinin-5 were also detected. The finding of cholecystokinin-like immunoreactivity corresponding to cholecystokinin-8 and cholecystokinin-58 in caudate nucleus where no preprocholecystokinin mRNA was found, indicates the presence of these peptides in afferent nerve terminals.

Endogenous orienting in the archer fish.

PubMed

Saban, William; Sekely, Liora; Klein, Raymond M; Gabay, Shai

2017-07-18

The literature has long emphasized the neocortex's role in volitional processes. In this work, we examined endogenous orienting in an evolutionarily older species, the archer fish, which lacks neocortex-like cells. We used Posner's classic endogenous cuing task, in which a centrally presented, spatially informative cue is followed by a target. The fish responded to the target by shooting a stream of water at it. Interestingly, the fish demonstrated a human-like "volitional" facilitation effect: their reaction times to targets that appeared on the side indicated by the precue were faster than their reaction times to targets on the opposite side. The fish also exhibited inhibition of return, an aftermath of orienting that commonly emerges only in reflexive orienting tasks in human participants. We believe that this pattern demonstrates the acquisition of an arbitrary connection between spatial orienting and a nonspatial feature of a centrally presented stimulus in nonprimate species. In the literature on human attention, orienting in response to such contingencies has been strongly associated with volitional control. We discuss the implications of these results for the evolution of orienting, and for the study of volitional processes in all species, including humans.

Evolution of the amniote pallium and the origins of mammalian neocortex

PubMed Central

Butler, Ann B.; Reiner, Anton; Karten, Harvey J.

2012-01-01

Karten's neocortex hypothesis holds that many component cell populations of the sauropsid dorsal ventricular ridge (DVR) are homologous to particular cell populations in layers of auditory and visual tectofugal-recipient neocortex of mammals (i.e., temporal neocortex), as well as to some amygdaloid populations. The claustroamygdalar hypothesis, based on gene expression domains, proposes that mammalian homologues of DVR are found in the claustrum, endopiriform nuclei, and/or pallial amygdala. Because hypotheses of homology need to account for the totality of the evidence, the available data on multiple forebrain features of sauropsids and mammals are reviewed here. While some genetic data are compatible with the claustroamygdalar hypothesis, and developmental (epigenetic) data are indecisive, hodological, morphological, and topographical data favor the neocortex hypothesis and are inconsistent with the claustroamygdalar hypothesis. Detailed studies of gene signaling cascades that establish neuronal cell-type identity in DVR, tectofugal-recipient neocortex, and claustroamygdala will be needed to resolve this debate about the evolution of neocortex. PMID:21534989

The emergence of mind and emotion in the evolution of neocortex.

PubMed

Freeman, Walter J

2011-01-01

The most deeply transformative concept for the growth of 21st Century psychiatry is the constellation of the chaotic dynamics of the brain. Brains are no longer seen as rational systems that are plagued with emotional disorders reflecting primitives inherited from our animal ancestors. Brains are dynamical systems that continually create patterns by acting intentionally into the environment and shaping themselves in accord with the sensory consequences of their intended actions. Emotions are now seen not as reversions to animal behaviors but as the sources of force and energy that brains require for the actions they take to understand the world and themselves. Humans are unique in experiencing consciousness of their own actions, which they experience as conscience: guilt, shame, pride and joy. Chaotic brain dynamics strives always for unity and harmony, but as a necessary condition for adaptation to a changing world, it repeatedly lapses into disorder. The successes are seen in the normal unity of consciousness; the failures are seen in the disorders that we rightly label the schizophrenias and the less severe character disorders. The foundation for healthy unity is revealed by studies in the evolution of brains, in particular the way in which neocortex of mammals emerged from the primitive allocortex of reptiles. The amazing facts of brain dynamics are now falling into several places. The power-law connectivity of cortex supports the scale-free dynamics of the global workspace in brains ranging from mouse to whale. That dynamics in humans holds the secrets of speech and symbol utilization. By recursive interactions in vast areas of human neocortex the scale-free connectivity supports our unified consciousness. Here in this dynamics are to be sought the keys to understanding and treating the disorders that uniquely plague the human mind.

Light-Addressable Measurement of in Vivo Tissue Oxygenation in an Unanesthetized Zebrafish Embryo via Phase-Based Phosphorescence Lifetime Detection

PubMed Central

Huang, Shih-Hao; Yu, Chu-Hung; Chien, Yi-Lung

2015-01-01

We have developed a digital light modulation system that utilizes a modified commercial projector equipped with a laser diode as a light source for quantitative measurements of in vivo tissue oxygenation in an unanesthetized zebrafish embryo via phase-based phosphorescence lifetime detection. The oxygen-sensitive phosphorescent probe (Oxyphor G4) was first inoculated into the bloodstream of 48 h post-fertilization (48 hpf) zebrafish embryos via the circulation valley to rapidly disperse probes throughout the embryo. The unanesthetized zebrafish embryo was introduced into the microfluidic device and immobilized on its lateral side by using a pneumatically actuated membrane. By controlling the illumination pattern on the digital micromirror device in the projector, the modulated excitation light can be spatially projected to illuminate arbitrarily-shaped regions of tissue of interest for in vivo oxygen measurements. We have successfully measured in vivo oxygen changes in the cardiac region and cardinal vein of a 48 hpf zebrafish embryo that experience hypoxia and subsequent normoxic conditions. Our proposed platform provides the potential for the real-time investigation of oxygen distribution in tissue microvasculature that relates to physiological stimulation and diseases in a developing organism. PMID:25856326

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

PubMed Central

Piekarski, David J.; Johnson, Carolyn; Boivin, Josiah R.; Thomas, A. Wren; Lin, Wan Chen; Delevich, Kristen; Galarce, Ezequiel; Wilbrecht, Linda

2016-01-01

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential. PMID:27590721

Expression of functional neurotransmitter receptors in Xenopus oocytes after injection of human brain membranes

NASA Astrophysics Data System (ADS)

Miledi, Ricardo; Eusebi, Fabrizio; Martínez-Torres, Ataúlfo; Palma, Eleonora; Trettel, Flavia

2002-10-01

The Xenopus oocyte is a very powerful tool for studies of the structure and function of membrane proteins, e.g., messenger RNA extracted from the brain and injected into oocytes leads to the synthesis and membrane incorporation of many types of functional receptors and ion channels, and membrane vesicles from Torpedo electroplaques injected into oocytes fuse with the oocyte membrane and cause the appearance of functional Torpedo acetylcholine receptors and Cl channels. This approach was developed further to transplant already assembled neurotransmitter receptors from human brain cells to the plasma membrane of Xenopus oocytes. Membranes isolated from the temporal neocortex of a patient, operated for intractable epilepsy, were injected into oocytes and, within a few hours, the oocyte membrane acquired functional neurotransmitter receptors to -aminobutyric acid, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and glycine. These receptors were also expressed in the plasma membrane of oocytes injected with mRNA extracted from the temporal neocortex of the same patient. All of this makes the Xenopus oocyte a more useful model than it already is for studies of the structure and function of many human membrane proteins and opens the way to novel pathophysiological investigations of some human brain disorders.

Temperatures Achieved in Human and Canine Neocortex During Intraoperative Passive or Active Focal Cooling

PubMed Central

Han, Rowland H.; Yarbrough, Chester K.; Patterson, Edward E.; Yang, Xiao-Feng; Miller, John W.; Rothman, Steven M.; D'Ambrosio, Raimondo

2015-01-01

Focal cortical cooling inhibits seizures and prevents acquired epileptogenesis in rodents. To investigate the potential clinical utility of this treatment modality, we examined the thermal characteristics of canine and human brain undergoing active and passive surface cooling in intraoperative settings. Four patients with intractable epilepsy were treated in a standard manner. Before the resection of a neocortical epileptogenic focus, multiple intraoperative studies of active (custom-made cooled irrigation-perfused grid) and passive (stainless steel probe) cooling were performed. We also actively cooled the neocortices of two dogs with perfused grids implanted for 2 hours. Focal surface cooling of the human brain causes predictable depth-dependent cooling of the underlying brain tissue. Cooling of 0.6–2°C was achieved both actively and passively to a depth of 10–15 mm from the cortical surface. The perfused grid permitted comparable and persistent cooling of canine neocortex when the craniotomy was closed. Thus, the human cortex can easily be cooled with the use of simple devices such as a cooling grid or a small passive probe. These techniques provide pilot data for the design of a permanently implantable device to control intractable epilepsy. PMID:25902001

Prolonged myelination in human neocortical evolution.

PubMed

Miller, Daniel J; Duka, Tetyana; Stimpson, Cheryl D; Schapiro, Steven J; Baze, Wallace B; McArthur, Mark J; Fobbs, Archibald J; Sousa, André M M; Sestan, Nenad; Wildman, Derek E; Lipovich, Leonard; Kuzawa, Christopher W; Hof, Patrick R; Sherwood, Chet C

2012-10-09

Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelin-related proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees (N = 20) and humans (N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination during childhood, characterized by a delayed period of maturation that extended beyond late adolescence. This comparative research contributes evidence crucial to understanding the evolution of human cognition and behavior, which arises from the unfolding of nervous system development within the context of an enriched cultural environment. Perturbations of normal developmental processes and the decreased expression of myelin-related molecules have been related to psychiatric disorders such as schizophrenia. Thus, these species differences suggest that the human-specific shift in the timing of cortical maturation during adolescence may have implications for vulnerability to certain psychiatric disorders.

Cortical cell and neuron density estimates in one chimpanzee hemisphere.

PubMed

Collins, Christine E; Turner, Emily C; Sawyer, Eva Kille; Reed, Jamie L; Young, Nicole A; Flaherty, David K; Kaas, Jon H

2016-01-19

The density of cells and neurons in the neocortex of many mammals varies across cortical areas and regions. This variability is, perhaps, most pronounced in primates. Nonuniformity in the composition of cortex suggests regions of the cortex have different specializations. Specifically, regions with densely packed neurons contain smaller neurons that are activated by relatively few inputs, thereby preserving information, whereas regions that are less densely packed have larger neurons that have more integrative functions. Here we present the numbers of cells and neurons for 742 discrete locations across the neocortex in a chimpanzee. Using isotropic fractionation and flow fractionation methods for cell and neuron counts, we estimate that neocortex of one hemisphere contains 9.5 billion cells and 3.7 billion neurons. Primary visual cortex occupies 35 cm(2) of surface, 10% of the total, and contains 737 million densely packed neurons, 20% of the total neurons contained within the hemisphere. Other areas of high neuron packing include secondary visual areas, somatosensory cortex, and prefrontal granular cortex. Areas of low levels of neuron packing density include motor and premotor cortex. These values reflect those obtained from more limited samples of cortex in humans and other primates.

Early network activity propagates bidirectionally between hippocampus and cortex.

PubMed

Barger, Zeke; Easton, Curtis R; Neuzil, Kevin E; Moody, William J

2016-06-01

Spontaneous activity in the developing brain helps refine neuronal connections before the arrival of sensory-driven neuronal activity. In mouse neocortex during the first postnatal week, waves of spontaneous activity originating from pacemaker regions in the septal nucleus and piriform cortex propagate through the neocortex. Using high-speed Ca(2+) imaging to resolve the spatiotemporal dynamics of wave propagation in parasagittal mouse brain slices, we show that the hippocampus can act as an additional source of neocortical waves. Some waves that originate in the hippocampus remain restricted to that structure, while others pause at the hippocampus-neocortex boundary and then propagate into the neocortex. Blocking GABAergic neurotransmission decreases the likelihood of wave propagation into neocortex, whereas blocking glutamatergic neurotransmission eliminates spontaneous and evoked hippocampal waves. A subset of hippocampal and cortical waves trigger Ca(2+) waves in astrocytic networks after a brief delay. Hippocampal waves accompanied by Ca(2+) elevation in astrocytes are more likely to propagate into the neocortex. Finally, we show that two structures in our preparation that initiate waves-the hippocampus and the piriform cortex-can be electrically stimulated to initiate propagating waves at lower thresholds than the neocortex, indicating that the intrinsic circuit properties of those regions are responsible for their pacemaker function. © 2015 Wiley Periodicals, Inc.

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

PubMed

Piekarski, David J; Johnson, Carolyn M; Boivin, Josiah R; Thomas, A Wren; Lin, Wan Chen; Delevich, Kristen; M Galarce, Ezequiel; Wilbrecht, Linda

2017-01-01

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

A Child's Brain. Part II. The Human Brain: How Every Single Cell is Organized for Action.

ERIC Educational Resources Information Center

Sylwester, Robert

1982-01-01

The second in a series of three articles concerning children's brain development focuses on the organization of the brain. Aspects of the brain's vertical, neocortex, and temporal organization are discussed and references for further reading are provided. (CJ)

Hypothalamic control of body temperature: insights from the past.

PubMed

Mack, Gary W

2004-11-01

This essay looks at the historical significance of three APS classic papers that are freely available online: Hammel HT, Hardy JD, and Fusco MM. Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am J Physiol 198: 481-486, 1960 (http://ajplegacy.physiology.org/cgi/reprint/198/3/481). Hammel HT, Jackson DC, Stolwijk JAJ, Hardy JD, and Stromme SB. Temperature regulation by hypothalamic proportional control with an adjustable set point. J Appl Physiol 18: 1146-1154, 1963 (http://jap.physiology.org/cgi/reprint/18/6/1146). Hellstrom B and Hammel HT. Some characteristics of temperature regulation in the unanesthetized dog. Am J Physiol 213: 547-556, 1967 (http://ajplegacy.physiology.org/cgi/reprint/213/2/547). Copyright 2004 American Physiological Society

Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering.

PubMed

Dachet, Fabien; Bagla, Shruti; Keren-Aviram, Gal; Morton, Andrew; Balan, Karina; Saadat, Laleh; Valyi-Nagy, Tibor; Kupsky, William; Song, Fei; Dratz, Edward; Loeb, Jeffrey A

2015-02-01

Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

An anatomically comprehensive atlas of the adult human brain transcriptome

PubMed Central

Guillozet-Bongaarts, Angela L.; Shen, Elaine H.; Ng, Lydia; Miller, Jeremy A.; van de Lagemaat, Louie N.; Smith, Kimberly A.; Ebbert, Amanda; Riley, Zackery L.; Abajian, Chris; Beckmann, Christian F.; Bernard, Amy; Bertagnolli, Darren; Boe, Andrew F.; Cartagena, Preston M.; Chakravarty, M. Mallar; Chapin, Mike; Chong, Jimmy; Dalley, Rachel A.; David Daly, Barry; Dang, Chinh; Datta, Suvro; Dee, Nick; Dolbeare, Tim A.; Faber, Vance; Feng, David; Fowler, David R.; Goldy, Jeff; Gregor, Benjamin W.; Haradon, Zeb; Haynor, David R.; Hohmann, John G.; Horvath, Steve; Howard, Robert E.; Jeromin, Andreas; Jochim, Jayson M.; Kinnunen, Marty; Lau, Christopher; Lazarz, Evan T.; Lee, Changkyu; Lemon, Tracy A.; Li, Ling; Li, Yang; Morris, John A.; Overly, Caroline C.; Parker, Patrick D.; Parry, Sheana E.; Reding, Melissa; Royall, Joshua J.; Schulkin, Jay; Sequeira, Pedro Adolfo; Slaughterbeck, Clifford R.; Smith, Simon C.; Sodt, Andy J.; Sunkin, Susan M.; Swanson, Beryl E.; Vawter, Marquis P.; Williams, Derric; Wohnoutka, Paul; Zielke, H. Ronald; Geschwind, Daniel H.; Hof, Patrick R.; Smith, Stephen M.; Koch, Christof; Grant, Seth G. N.; Jones, Allan R.

2014-01-01

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function. PMID:22996553

High-frequency oscillations in human and monkey neocortex during the wake–sleep cycle

PubMed Central

Le Van Quyen, Michel; Muller, Lyle E.; Telenczuk, Bartosz; Halgren, Eric; Cash, Sydney; Hatsopoulos, Nicholas G.; Dehghani, Nima; Destexhe, Alain

2016-01-01

Beta (β)- and gamma (γ)-oscillations are present in different cortical areas and are thought to be inhibition-driven, but it is not known if these properties also apply to γ-oscillations in humans. Here, we analyze such oscillations in high-density microelectrode array recordings in human and monkey during the wake–sleep cycle. In these recordings, units were classified as excitatory and inhibitory cells. We find that γ-oscillations in human and β-oscillations in monkey are characterized by a strong implication of inhibitory neurons, both in terms of their firing rate and their phasic firing with the oscillation cycle. The β- and γ-waves systematically propagate across the array, with similar velocities, during both wake and sleep. However, only in slow-wave sleep (SWS) β- and γ-oscillations are associated with highly coherent and functional interactions across several millimeters of the neocortex. This interaction is specifically pronounced between inhibitory cells. These results suggest that inhibitory cells are dominantly involved in the genesis of β- and γ-oscillations, as well as in the organization of their large-scale coherence in the awake and sleeping brain. The highest oscillation coherence found during SWS suggests that fast oscillations implement a highly coherent reactivation of wake patterns that may support memory consolidation during SWS. PMID:27482084

High-frequency oscillations in human and monkey neocortex during the wake-sleep cycle.

PubMed

Le Van Quyen, Michel; Muller, Lyle E; Telenczuk, Bartosz; Halgren, Eric; Cash, Sydney; Hatsopoulos, Nicholas G; Dehghani, Nima; Destexhe, Alain

2016-08-16

Beta (β)- and gamma (γ)-oscillations are present in different cortical areas and are thought to be inhibition-driven, but it is not known if these properties also apply to γ-oscillations in humans. Here, we analyze such oscillations in high-density microelectrode array recordings in human and monkey during the wake-sleep cycle. In these recordings, units were classified as excitatory and inhibitory cells. We find that γ-oscillations in human and β-oscillations in monkey are characterized by a strong implication of inhibitory neurons, both in terms of their firing rate and their phasic firing with the oscillation cycle. The β- and γ-waves systematically propagate across the array, with similar velocities, during both wake and sleep. However, only in slow-wave sleep (SWS) β- and γ-oscillations are associated with highly coherent and functional interactions across several millimeters of the neocortex. This interaction is specifically pronounced between inhibitory cells. These results suggest that inhibitory cells are dominantly involved in the genesis of β- and γ-oscillations, as well as in the organization of their large-scale coherence in the awake and sleeping brain. The highest oscillation coherence found during SWS suggests that fast oscillations implement a highly coherent reactivation of wake patterns that may support memory consolidation during SWS.

Genetics of Cerebellar and Neocortical Expansion in Anthropoid Primates: A Comparative Approach

PubMed Central

Harrison, Peter W.; Montgomery, Stephen H.

2017-01-01

What adaptive changes in brain structure and function underpin the evolution of increased cognitive performance in humans and our close relatives? Identifying the genetic basis of brain evolution has become a major tool in answering this question. Numerous cases of positive selection, altered gene expression or gene duplication have been identified that may contribute to the evolution of the neocortex, which is widely assumed to play a predominant role in cognitive evolution. However, the components of the neocortex co-evolve with other functionally interdependent regions of the brain, most notably in the cerebellum. The cerebellum is linked to a range of cognitive tasks and expanded rapidly during hominoid evolution. Here we present data that suggest that, across anthropoid primates, protein-coding genes with known roles in cerebellum development were just as likely to be targeted by selection as genes linked to cortical development. Indeed, based on currently available gene ontology data, protein-coding genes with known roles in cerebellum development are more likely to have evolved adaptively during hominoid evolution. This is consistent with phenotypic data suggesting an accelerated rate of cerebellar expansion in apes that is beyond that predicted from scaling with the neocortex in other primates. Finally, we present evidence that the strength of selection on specific genes is associated with variation in the volume of either the neocortex or the cerebellum, but not both. This result provides preliminary evidence that co-variation between these brain components during anthropoid evolution may be at least partly regulated by selection on independent loci, a conclusion that is consistent with recent intraspecific genetic analyses and a mosaic model of brain evolution that predicts adaptive evolution of brain structure. PMID:28683440

The multisensory function of the human primary visual cortex.

PubMed

Murray, Micah M; Thelen, Antonia; Thut, Gregor; Romei, Vincenzo; Martuzzi, Roberto; Matusz, Pawel J

2016-03-01

It has been nearly 10 years since Ghazanfar and Schroeder (2006) proposed that the neocortex is essentially multisensory in nature. However, it is only recently that sufficient and hard evidence that supports this proposal has accrued. We review evidence that activity within the human primary visual cortex plays an active role in multisensory processes and directly impacts behavioural outcome. This evidence emerges from a full pallet of human brain imaging and brain mapping methods with which multisensory processes are quantitatively assessed by taking advantage of particular strengths of each technique as well as advances in signal analyses. Several general conclusions about multisensory processes in primary visual cortex of humans are supported relatively solidly. First, haemodynamic methods (fMRI/PET) show that there is both convergence and integration occurring within primary visual cortex. Second, primary visual cortex is involved in multisensory processes during early post-stimulus stages (as revealed by EEG/ERP/ERFs as well as TMS). Third, multisensory effects in primary visual cortex directly impact behaviour and perception, as revealed by correlational (EEG/ERPs/ERFs) as well as more causal measures (TMS/tACS). While the provocative claim of Ghazanfar and Schroeder (2006) that the whole of neocortex is multisensory in function has yet to be demonstrated, this can now be considered established in the case of the human primary visual cortex. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis of Research on Brain Plasticity: The Classroom Environment and Curriculum Enrichment.

ERIC Educational Resources Information Center

Sylwester, Robert

1986-01-01

Outlines research findings on enriched environment investigations on the development of the brain's neocortex. Although the research has been conducted on animal brains, researchers expect to find related patterns in plasticity in humans. The research is important to educators as it challenges them to define, create, and maintain an emotionally…

Dynamic Balance of Excitation and Inhibition in Human and Monkey Neocortex

NASA Astrophysics Data System (ADS)

Dehghani, Nima; Peyrache, Adrien; Telenczuk, Bartosz; Le van Quyen, Michel; Halgren, Eric; Cash, Sydney S.; Hatsopoulos, Nicholas G.; Destexhe, Alain

2016-03-01

Balance of excitation and inhibition is a fundamental feature of in vivo network activity and is important for its computations. However, its presence in the neocortex of higher mammals is not well established. We investigated the dynamics of excitation and inhibition using dense multielectrode recordings in humans and monkeys. We found that in all states of the wake-sleep cycle, excitatory and inhibitory ensembles are well balanced, and co-fluctuate with slight instantaneous deviations from perfect balance, mostly in slow-wave sleep. Remarkably, these correlated fluctuations are seen for many different temporal scales. The similarity of these computational features with a network model of self-generated balanced states suggests that such balanced activity is essentially generated by recurrent activity in the local network and is not due to external inputs. Finally, we find that this balance breaks down during seizures, where the temporal correlation of excitatory and inhibitory populations is disrupted. These results show that balanced activity is a feature of normal brain activity, and break down of the balance could be an important factor to define pathological states.

Generating Adaptive Behaviour within a Memory-Prediction Framework

PubMed Central

Rawlinson, David; Kowadlo, Gideon

2012-01-01

The Memory-Prediction Framework (MPF) and its Hierarchical-Temporal Memory implementation (HTM) have been widely applied to unsupervised learning problems, for both classification and prediction. To date, there has been no attempt to incorporate MPF/HTM in reinforcement learning or other adaptive systems; that is, to use knowledge embodied within the hierarchy to control a system, or to generate behaviour for an agent. This problem is interesting because the human neocortex is believed to play a vital role in the generation of behaviour, and the MPF is a model of the human neocortex. We propose some simple and biologically-plausible enhancements to the Memory-Prediction Framework. These cause it to explore and interact with an external world, while trying to maximize a continuous, time-varying reward function. All behaviour is generated and controlled within the MPF hierarchy. The hierarchy develops from a random initial configuration by interaction with the world and reinforcement learning only. Among other demonstrations, we show that a 2-node hierarchy can learn to successfully play “rocks, paper, scissors” against a predictable opponent. PMID:22272231

Adenosine 2A Receptor Inhibition Enhances Intermittent Hypoxia-Induced Diaphragm but Not Intercostal Long-Term Facilitation

PubMed Central

Navarrete-Opazo, Angela A.; Vinit, Stéphane

2014-01-01

Abstract Acute intermittent hypoxia (AIH) elicits diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF) in normal unanesthetized rats. Although AIH-induced phrenic LTF is serotonin dependent, adenosine constrained in anesthetized rats, this has not been tested in unanesthetized animals. Cervical (C2) spinal hemisection (C2HS) abolishes phrenic LTF because of loss of serotonergic inputs 2 weeks post-injury, but LTF returns 8 weeks post-injury. We tested three hypotheses in unanesthetized rats: (1) systemic adenosine 2aA (A2A) receptor inhibition with intraperitoneal (IP) KW6002 enhances Dia and T2 EIC LTF in normal rats; (2) Dia and T2 EIC LTF are expressed after chronic (8 weeks), but not acute (1 week) C2HS; and (3) KW6002 enhances Dia and T2 EIC LTF after chronic (not acute) C2HS. Electromyography radiotelemetry was used to record Dia and T2 EIC activity during normoxia (21% O2), before and after AIH (10, 5-min 10.5% O2, 5-min intervals). In normal rats, KW6002 enhanced DiaLTF versus AIH alone (33.1±4.6% vs. 22.1±6.4% baseline, respectively; p<0.001), but had no effect on T2 EIC LTF (p>0.05). Although Dia and T2 EIC LTF were not observed 2 weeks post-C2HS, LTF was observed in contralateral (uninjured) Dia and T2 EIC 8 weeks post-C2HS (18.7±2.7% and 34.9±4.9% baseline, respectively; p<0.05), with variable ipsilateral expression. KW6002 had no significant effects on contralateral Dia (p=0.447) or T2 EIC LTF (p=0.796). We conclude that moderate AIH induces Dia and T2 EIC LTF after chronic, but not acute cervical spinal injuries. A single A2A receptor antagonist dose enhances AIH-induced Dia LTF in normal rats, but this effect is not significant in chronic (8 weeks) C2HS unanesthetized rats. PMID:25003645

Accelerated recruitment of new brain development genes into the human genome.

PubMed

Zhang, Yong E; Landback, Patrick; Vibranovski, Maria D; Long, Manyuan

2011-10-01

How the human brain evolved has attracted tremendous interests for decades. Motivated by case studies of primate-specific genes implicated in brain function, we examined whether or not the young genes, those emerging genome-wide in the lineages specific to the primates or rodents, showed distinct spatial and temporal patterns of transcription compared to old genes, which had existed before primate and rodent split. We found consistent patterns across different sources of expression data: there is a significantly larger proportion of young genes expressed in the fetal or infant brain of humans than in mouse, and more young genes in humans have expression biased toward early developing brains than old genes. Most of these young genes are expressed in the evolutionarily newest part of human brain, the neocortex. Remarkably, we also identified a number of human-specific genes which are expressed in the prefrontal cortex, which is implicated in complex cognitive behaviors. The young genes upregulated in the early developing human brain play diverse functional roles, with a significant enrichment of transcription factors. Genes originating from different mechanisms show a similar expression bias in the developing brain. Moreover, we found that the young genes upregulated in early brain development showed rapid protein evolution compared to old genes also expressed in the fetal brain. Strikingly, genes expressed in the neocortex arose soon after its morphological origin. These four lines of evidence suggest that positive selection for brain function may have contributed to the origination of young genes expressed in the developing brain. These data demonstrate a striking recruitment of new genes into the early development of the human brain.

Human cerebral cortex Cajal-Retzius neuron: development, structure and function. A Golgi study.

PubMed

Marín-Padilla, Miguel

2015-01-01

The development, morphology and possible functional activity of the Cajal-Retzius cell of the developing human cerebral cortex are explored herein. The C-RC, of extracortical origin, is the essential neuron of the neocortex first lamina. It receives inputs from afferent fibers that reach the first lamina early in development. Although the origin and function of these original afferent fibers remain unknown, their target is the first lamina sole neuron: the C-RC. This neuron orchestrates the arrival, size and stratification of all pyramidal neurons (of ependymal origin) of the neocortex gray matter. Its axonic terminals spread radially and horizontally throughout the entirety of the first lamina establishing contacts with the dendritic terminals of all gray matter pyramidal cells regardless of size, location and/or eventual functional roles. While the neuron axonic terminals spread radially and horizontally throughout the first lamina, the neuronal' body undergoes progressive developmental dilution and locating any of them in the adult brain become quite difficult. The neuron bodies are probably retained in the older regions of the neocortex while their axonic collaterals will spread throughout its more recent ones and eventually will extend to great majority of the cortical surface. The neocortex first lamina evolution and composition and that of the C-RC are intertwined and mutually interdependent. It is not possible to understand the C-RC evolving morphology without understanding that of the first lamina. The first lamina composition and its structural and functional organizations obtained with different staining methods may be utterly different. These differences have added unnecessary confusion about its nature. The essential emptiness observed in hematoxylin and eosin preparations (most commonly used) contrast sharply with the concentration of dendrites (the cortex' largest) obtained using special (MAP-2) stain for dendrites. Only Golgi preparations demonstrate the numerous dendritic and axonic terminals that compose the first lamina basic structure. High power microscopic views of Golgi preparations demonstrate the intimate anatomical and functional interrelationships among dendritic and axonic terminals as well as synaptic contacts between them. The C-RC' essential morphology does not changes but it is progressively modified by the first lamina increase in thickness and in number of terminal dendrites and their subsequent maturation. This neuron variable morphologic appearance has been the source of controversy. Its morphology depends on the first lamina thickness that may be quite variable among different mammals. In rodents (most commonly used experimental mammal), the first lamina thickness, number and horizontal expansion of dendrites is but a fraction of those in humans. This differences are reflected in the C-RC' morphology among mammals (including humans) and should not be thought as representing new types of neurons.

Perirhinal Cortex Lesions Produce Retrograde Amnesia for Spatial Information in Rats: Consolidation or Retrieval?

ERIC Educational Resources Information Center

Ramos, Juan M. J.

2008-01-01

Several lines of evidence in humans and experimental animals suggest that the hippocampus is critical for the formation and retrieval of spatial memory. However, although the hippocampus is reciprocally connected to adjacent cortices within the medial temporal lobe and they, in turn, are connected to the neocortex, little is known regarding the…

Population dynamics during cell proliferation and neuronogenesis in the developing murine neocortex

NASA Technical Reports Server (NTRS)

Nowakowski, Richard S.; Caviness, Verne S Jr; Takahashi, Takao; Hayes, Nancy L.

2002-01-01

During the development of the neocortex, cell proliferation occurs in two specialized zones adjacent to the lateral ventricle. One of these zones, the ventricular zone, produces most of the neurons of the neocortex. The proliferating population that resides in the ventricular zone is a pseudostratified ventricular epithelium (PVE) that looks uniform in routine histological preparations, but is, in fact, an active and dynamically changing population. In the mouse, over the course of a 6-day period, the PVE produces approximately 95% of the neurons of the adult neocortex. During this time, the cell cycle of the PVE population lengthens from about 8 h to over 18 h and the progenitor population passes through a total of 11 cell cycles. This 6-day, 11-cell cycle period comprises the "neuronogenetic interval" (NI). At each passage through the cell cycle, the proportion of daughter cells that exit the cell cycle (Q cells) increases from 0 at the onset of the NI to 1 at the end of the NI. The proportion of daughter cells that re-enter the cell cycle (P cells) changes in a complementary fashion from 1 at the onset of the NI to 0 at the end of the NI. This set of systematic changes in the cell cycle and the output from the proliferative population of the PVE allows a quantitative and mathematical treatment of the expansion of the PVE and the growth of the cortical plate that nicely accounts for the observed expansion and growth of the developing neocortex. In addition, we show that the cells produced during a 2-h window of development during specific cell cycles reside in a specific set of laminae in the adult cortex, but that the distributions of the output from consecutive cell cycles overlap. These dynamic events occur in all areas of the PVE underlying the neocortex, but there is a gradient of maturation that begins in the rostrolateral neocortex near the striatotelencephalic junction and which spreads across the surface of the neocortex over a period of 24-36 h. The presence of the gradient across the hemisphere is a possible source of positional information that could be exploited during development to establish the areal borders that characterize the adult neocortex.

Different Simultaneous Sleep States in the Hippocampus and Neocortex

PubMed Central

Emrick, Joshua J.; Gross, Brooks A.; Riley, Brett T.; Poe, Gina R.

2016-01-01

Study Objectives: Investigators assign sleep-waking states using brain activity collected from a single site, with the assumption that states occur at the same time throughout the brain. We sought to determine if sleep-waking states differ between two separate structures: the hippocampus and neocortex. Methods: We measured electrical signals (electroencephalograms and electromyograms) during sleep from the hippocampus and neocortex of five freely behaving adult male rats. We assigned sleep-waking states in 10-sec epochs based on standard scoring criteria across a 4-h recording, then analyzed and compared states and signals from simultaneous epochs between sites. Results: We found that the total amount of each state, assigned independently using the hippocampal and neocortical signals, was similar between the hippocampus and neocortex. However, states at simultaneous epochs were different as often as they were the same (P = 0.82). Furthermore, we found that the progression of states often flowed through asynchronous state-pairs led by the hippocampus. For example, the hippocampus progressed from transition-to-rapid eye movement sleep to rapid eye movement sleep before the neocortex more often than in synchrony with the neocortex (38.7 ± 16.2% versus 15.8 ± 5.6% mean ± standard error of the mean). Conclusions: We demonstrate that hippocampal and neocortical sleep-waking states often differ in the same epoch. Consequently, electrode location affects estimates of sleep architecture, state transition timing, and perhaps even percentage of time in sleep states. Therefore, under normal conditions, models assuming brain state homogeneity should not be applied to the sleeping or waking brain. Citation: Emrick JJ, Gross BA, Riley BT, Poe GR. Different simultaneous sleep states in the hippocampus and neocortex. SLEEP 2016;39(12):2201–2209. PMID:27748240

Chronic thinner intoxication: clinico-pathologic report of a human case.

PubMed Central

Escobar, A; Aruffo, C

1980-01-01

A 27 year old Mexican male addicted for 12 years to glue-sniffing and thinner inhalation developed neurological and behavioural disturbances which led to hospital admission and death. Autopsy disclosed diffuse cerebral and cerebellar cortex atrophy and giant axonopathy both central and peripheral. The corpus callosum was atrophic secondarily to neuron loss in the neocortex. Images PMID:7441282

Evolution and development of the mammalian cerebral cortex.

PubMed

Molnár, Zoltán; Kaas, Jon H; de Carlos, Juan A; Hevner, Robert F; Lein, Ed; Němec, Pavel

2014-01-01

Comparative developmental studies of the mammalian brain can identify key changes that can generate the diverse structures and functions of the brain. We have studied how the neocortex of early mammals became organized into functionally distinct areas, and how the current level of cortical cellular and laminar specialization arose from the simpler premammalian cortex. We demonstrate the neocortical organization in early mammals, which helps to elucidate how the large, complex human brain evolved from a long line of ancestors. The radial and tangential enlargement of the cortex was driven by changes in the patterns of cortical neurogenesis, including alterations in the proportions of distinct progenitor types. Some cortical cell populations travel to the cortex through tangential migration whereas others migrate radially. A number of recent studies have begun to characterize the chick, mouse and human and nonhuman primate cortical transcriptome to help us understand how gene expression relates to the development and anatomical and functional organization of the adult neocortex. Although all mammalian forms share the basic layout of cortical areas, the areal proportions and distributions are driven by distinct evolutionary pressures acting on sensory and motor experiences during the individual ontogenies. © 2014 S. Karger AG, Basel.

Selective attention without a neocortex.

PubMed

Krauzlis, Richard J; Bogadhi, Amarender R; Herman, James P; Bollimunta, Anil

2018-05-01

Selective attention refers to the ability to restrict neural processing and behavioral responses to a relevant subset of available stimuli, while simultaneously excluding other valid stimuli from consideration. In primates and other mammals, descriptions of this ability typically emphasize the neural processing that takes place in the cerebral neocortex. However, non-mammals such as birds, reptiles, amphibians and fish, which completely lack a neocortex, also have the ability to selectively attend. In this article, we survey the behavioral evidence for selective attention in non-mammals, and review the midbrain and forebrain structures that are responsible. The ancestral forms of selective attention are presumably selective orienting behaviors, such as prey-catching and predator avoidance. These behaviors depend critically on a set of subcortical structures, including the optic tectum (OT), thalamus and striatum, that are highly conserved across vertebrate evolution. In contrast, the contributions of different pallial regions in the forebrain to selective attention have been subject to more substantial changes and reorganization. This evolutionary perspective makes plain that selective attention is not a function achieved de novo with the emergence of the neocortex, but instead is implemented by circuits accrued and modified over hundreds of millions of years, beginning well before the forebrain contained a neocortex. Determining how older subcortical circuits interact with the more recently evolved components in the neocortex will likely be crucial for understanding the complex properties of selective attention in primates and other mammals, and for identifying the etiology of attention disorders. Published by Elsevier Ltd.

Influence of the upper airway on breathing pattern and expiratory time constant in unanesthetized dog pups.

PubMed

England, S J; Stogryn, H A

1986-11-01

Unanesthetized dog pups (2 to 31 days old) respond to sudden opening of a tracheal cannula to atmospheric pressure with a marked increase in breathing frequency. This response is achieved with a 25% decrease in inspiratory and 40% decrease in expiratory times. Expiratory thyroarytenoid muscle activity increased concomitantly, while inspiratory diaphragmatic and posterior cricoarytenoid muscle activities were reduced. These responses are interpreted as a compensatory mechanism for maintenance of an elevated end-expiratory lung volume with functional loss of the upper airway. The changes in expiratory time and thyroarytenoid muscle activity were not observed when positive pressure was applied at the trachea. The expiratory time constant was assessed during spontaneous breathing. The mean value was twice as long during nasal breathing than during tracheal breathing. The nasal value was substantially increased when the thyroarytenoid muscle was active during expiration.

Activity-dependent ATP-waves in the mouse neocortex are independent from astrocytic calcium waves.

PubMed

Haas, Brigitte; Schipke, Carola G; Peters, Oliver; Söhl, Goran; Willecke, Klaus; Kettenmann, Helmut

2006-02-01

In the corpus callosum, astrocytic calcium waves propagate via a mechanism involving ATP-release but not gap junctional coupling. In the present study, we report for the neocortex that calcium wave propagation depends on functional astrocytic gap junctions but is still accompanied by ATP-release. In acute slices obtained from the neocortex of mice deficient for astrocytic expression of connexin43, the calcium wave did not propagate. In contrast, in the corpus callosum and hippocampus of these mice, the wave propagated as in control animals. In addition to calcium wave propagation in astrocytes, ATP-release was recorded as a calcium signal from 'sniffer cells', a cell line expressing high-affinity purinergic receptors placed on the surface of the slice. The astrocyte calcium wave in the neocortex was accompanied by calcium signals in the 'sniffer cell' population. In the connexin43-deficient mice we recorded calcium signals from sniffer cells also in the absence of an astrocytic calcium wave. Our findings indicate that astrocytes propagate calcium signals by two separate mechanisms depending on the brain region and that ATP release can propagate within the neocortex independent from calcium waves.

Evidence for convergent evolution of a neocortex-like structure in a late Permian therapsid.

PubMed

Laaß, Michael; Kaestner, Anders

2017-08-01

The special sensory, motor, and cognitive capabilities of mammals mainly depend upon the neocortex, which is the six-layered cover of the mammalian forebrain. The origin of the neocortex is still controversial and the current view is that larger brains with neocortex first evolved in late Triassic Mammaliaformes. Here, we report the earliest evidence of a structure analogous to the mammalian neocortex in a forerunner of mammals, the fossorial anomodont Kawingasaurus fossilis from the late Permian of Tanzania. The endocranial cavity of Kawingasaurus is almost completely ossified, which allowed a less hypothetical virtual reconstruction of the brain endocast to be generated. A parietal foramen is absent. A small pit between the cerebral hemispheres is interpreted as a pineal body. The inflated cerebral hemispheres are demarcated from each other by a median sulcus and by a possible rhinal fissure from the rest of the endocast. The encephalization quotient estimated by using the method of Eisenberg is 0.52, which is 2-3 times larger than in other nonmammalian synapsids. Another remarkable feature are the extremely ramified infraorbital canals in the snout. The shape of the brain endocast, the extremely ramified maxillary canals as well as the small frontally placed eyes suggest that special sensory adaptations to the subterranean habitat such as a well developed sense of touch and binocular vision may have driven the parallel evolution of an equivalent of the mammalian neocortex and a mammal-like lemnothalamic visual system in Kawingasaurus. The gross anatomy of the brain endocast of Kawingasaurus supports the Outgroup Hypothesis, according to which the neocortex evolved from the dorsal pallium of an amphibian-like ancestor, which receives sensory projections from the lemnothalamic pathway. The enlarged brain as well as the absence of a parietal foramen may be an indication for a higher metabolic rate of Kawingasaurus compared to other nonmammalian synapsids. © 2017 Wiley Periodicals, Inc.

Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development.

PubMed

Schmouth, Jean-François; Arenillas, David; Corso-Díaz, Ximena; Xie, Yuan-Yun; Bohacec, Slavita; Banks, Kathleen G; Bonaguro, Russell J; Wong, Siaw H; Jones, Steven J M; Marra, Marco A; Simpson, Elizabeth M; Wasserman, Wyeth W

2015-07-24

Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development. In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor. In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development.

The evolution of the complex sensory and motor systems of the human brain.

PubMed

Kaas, Jon H

2008-03-18

Inferences about how the complex sensory and motor systems of the human brain evolved are based on the results of comparative studies of brain organization across a range of mammalian species, and evidence from the endocasts of fossil skulls of key extinct species. The endocasts of the skulls of early mammals indicate that they had small brains with little neocortex. Evidence from comparative studies of cortical organization from small-brained mammals of the six major branches of mammalian evolution supports the conclusion that the small neocortex of early mammals was divided into roughly 20-25 cortical areas, including primary and secondary sensory fields. In early primates, vision was the dominant sense, and cortical areas associated with vision in temporal and occipital cortex underwent a significant expansion. Comparative studies indicate that early primates had 10 or more visual areas, and somatosensory areas with expanded representations of the forepaw. Posterior parietal cortex was also expanded, with a caudal half dominated by visual inputs, and a rostral half dominated by somatosensory inputs with outputs to an array of seven or more motor and visuomotor areas of the frontal lobe. Somatosensory areas and posterior parietal cortex became further differentiated in early anthropoid primates. As larger brains evolved in early apes and in our hominin ancestors, the number of cortical areas increased to reach an estimated 200 or so in present day humans, and hemispheric specializations emerged. The large human brain grew primarily by increasing neuron number rather than increasing average neuron size.

The Evolution of the Brain, the Human Nature of Cortical Circuits, and Intellectual Creativity

PubMed Central

DeFelipe, Javier

2011-01-01

The tremendous expansion and the differentiation of the neocortex constitute two major events in the evolution of the mammalian brain. The increase in size and complexity of our brains opened the way to a spectacular development of cognitive and mental skills. This expansion during evolution facilitated the addition of microcircuits with a similar basic structure, which increased the complexity of the human brain and contributed to its uniqueness. However, fundamental differences even exist between distinct mammalian species. Here, we shall discuss the issue of our humanity from a neurobiological and historical perspective. PMID:21647212

High-Frequency Network Oscillations in Cerebellar Cortex

PubMed Central

Middleton, Steven J.; Racca, Claudia; Cunningham, Mark O.; Traub, Roger D.; Monyer, Hannah; Knöpfel, Thomas; Schofield, Ian S.; Jenkins, Alistair; Whittington, Miles A.

2016-01-01

SUMMARY Both cerebellum and neocortex receive input from the somatosensory system. Interaction between these regions has been proposed to underpin the correct selection and execution of motor commands, but it is not clear how such interactions occur. In neocortex, inputs give rise to population rhythms, providing a spatiotemporal coding strategy for inputs and consequent outputs. Here, we show that similar patterns of rhythm generation occur in cerebellum during nicotinic receptor subtype activation. Both gamma oscillations (30–80 Hz) and very fast oscillations (VFOs, 80–160 Hz) were generated by intrinsic cerebellar cortical circuitry in the absence of functional glutamatergic connections. As in neocortex, gamma rhythms were dependent on GABAA receptor-mediated inhibition, whereas VFOs required only nonsynaptically connected intercellular networks. The ability of cerebellar cortex to generate population rhythms within the same frequency bands as neocortex suggests that they act as a common spatiotemporal code within which corticocerebellar dialog may occur. PMID:18549787

Sensory maps in the claustrum of the cat.

PubMed

Olson, C R; Graybiel, A M

1980-12-04

The claustrum is a telencephalic cell group (Fig. 1A, B) possessing widespread reciprocal connections with the neocortex. In this regard, it bears a unique and striking resemblance to the thalamus. We have now examined the anatomical ordering of pathways linking the claustrum with sensory areas of the cat neocortex and, in parallel electrophysiological experiments, have studied the functional organization of claustral sensory zones so identified. Our findings indicate that there are discrete visual and somatosensory subdivisions in the claustrum interconnected with the corresponding primary sensory areas of the neocortex and that the respective zones contain orderly retinotopic and somatotopic maps. A third claustral region receiving fibre projections from the auditory cortex in or near area Ep was found to contain neurones responsive to auditory stimulation. We conclude that loops connecting sensory areas of the neocortex with satellite zones in the claustrum contribute to the early processing of exteroceptive information by the forebrain.

Epileptogenic networks in nodular heterotopia: A stereoelectroencephalography study.

PubMed

Pizzo, Francesca; Roehri, Nicolas; Catenoix, Hélène; Medina, Samuel; McGonigal, Aileen; Giusiano, Bernard; Carron, Romain; Scavarda, Didier; Ostrowsky, Karine; Lepine, Anne; Boulogne, Sébastien; Scholly, Julia; Hirsch, Edouard; Rheims, Sylvain; Bénar, Christian-George; Bartolomei, Fabrice

2017-12-01

Defining the roles of heterotopic and normotopic cortex in the epileptogenic networks in patients with nodular heterotopia is challenging. To elucidate this issue, we compared heterotopic and normotopic cortex using quantitative signal analysis on stereoelectroencephalography (SEEG) recordings. Clinically relevant biomarkers of epileptogenicity during ictal (epileptogenicity index; EI) and interictal recordings (high-frequency oscillation and spike) were evaluated in 19 patients undergoing SEEG. These biomarkers were then compared between heterotopic cortex and neocortical regions. Seizures were classified as normotopic, heterotopic, or normoheterotopic according to respective values of quantitative analysis (EI ≥0.3). A total of 1,246 contacts were analyzed: 259 in heterotopic tissue (heterotopic cortex), 873 in neocortex in the same lobe of the lesion (local neocortex), and 114 in neocortex distant from the lesion (distant neocortex). No significant difference in EI values, high-frequency oscillations, and spike rate was found comparing local neocortex and heterotopic cortex at a patient level, but local neocortex appears more epileptogenic (p < 0.001) than heterotopic cortex analyzing EI values at a seizure level. According to EI values, seizures were mostly normotopic (48.5%) or normoheterotopic (45.5%); only 6% were purely heterotopic. A good long-term treatment response was obtained in only two patients after thermocoagulation and surgical disconnection. This is the first quantitative SEEG study providing insight into the mechanisms generating seizures in nodular heterotopia. We demonstrate that both the heterotopic lesion and particularly the normotopic cortex are involved in the epileptogenic network. This could open new perspectives on multitarget treatments, other than resective surgery, aimed at modifying the epileptic network. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Different Simultaneous Sleep States in the Hippocampus and Neocortex.

PubMed

Emrick, Joshua J; Gross, Brooks A; Riley, Brett T; Poe, Gina R

2016-12-01

Investigators assign sleep-waking states using brain activity collected from a single site, with the assumption that states occur at the same time throughout the brain. We sought to determine if sleep-waking states differ between two separate structures: the hippocampus and neocortex. We measured electrical signals (electroencephalograms and electromyograms) during sleep from the hippocampus and neocortex of five freely behaving adult male rats. We assigned sleep-waking states in 10-sec epochs based on standard scoring criteria across a 4-h recording, then analyzed and compared states and signals from simultaneous epochs between sites. We found that the total amount of each state, assigned independently using the hippocampal and neocortical signals, was similar between the hippocampus and neocortex. However, states at simultaneous epochs were different as often as they were the same (P = 0.82). Furthermore, we found that the progression of states often flowed through asynchronous state-pairs led by the hippocampus. For example, the hippocampus progressed from transition-to-rapid eye movement sleep to rapid eye movement sleep before the neocortex more often than in synchrony with the neocortex (38.7 ± 16.2% versus 15.8 ± 5.6% mean ± standard error of the mean). We demonstrate that hippocampal and neocortical sleep-waking states often differ in the same epoch. Consequently, electrode location affects estimates of sleep architecture, state transition timing, and perhaps even percentage of time in sleep states. Therefore, under normal conditions, models assuming brain state homogeneity should not be applied to the sleeping or waking brain. © 2016 Associated Professional Sleep Societies, LLC.

Use of implantable telemetry systems for study of cardiovascular phenomena.

NASA Technical Reports Server (NTRS)

Sandler, H.; Fryer, T. B.; Westbrook, R. M.; Stone, H. L.

1972-01-01

Preliminary observations of cardiovascular function have been made in four chimpanzees using multichannel implantable units. Measurements of right- and left-sided pressures were periodically made in these animals over a four-month period, including continuous observations for selected 24-hour periods. Pressures recorded with animals in an awake, unanesthetized, unrestrained state were much lower than pressures reported for restrained animals in similar situations. Diurnal variations of pressure tended to occur, but were not as clear-cut as those reported to occur for humans. The ability to implant a transmitter chronically and receive useful multichannel information in the chimpanzee encourages the future use of such implant devices as part of the control system for an artificial heart or directly for use in man.

From sauropsids to mammals and back: New approaches to comparative cortical development

PubMed Central

Montiel, Juan F.; Vasistha, Navneet A.; Garcia‐Moreno, Fernando

2015-01-01

Abstract Evolution of the mammalian neocortex (isocortex) has been a persisting problem in neurobiology. While recent studies have attempted to understand the evolutionary expansion of the human neocortex from rodents, similar approaches have been used to study the changes between reptiles, birds, and mammals. We review here findings from the past decades on the development, organization, and gene expression patterns in various extant species. This review aims to compare cortical cell numbers and neuronal cell types to the elaboration of progenitor populations and their proliferation in these species. Several progenitors, such as the ventricular radial glia, the subventricular intermediate progenitors, and the subventricular (outer) radial glia, have been identified but the contribution of each to cortical layers and cell types through specific lineages, their possible roles in determining brain size or cortical folding, are not yet understood. Across species, larger, more diverse progenitors relate to cortical size and cell diversity. The challenge is to relate the radial and tangential expansion of the neocortex to the changes in the proliferative compartments during mammalian evolution and with the changes in gene expression and lineages evident in various sectors of the developing brain. We also review the use of recent lineage tracing and transcriptomic approaches to revisit theories and to provide novel understanding of molecular processes involved in specification of cortical regions. J. Comp. Neurol. 524:630–645, 2016. © 2015 The Authors. The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:26234252

The motor cortex: a network tuned to 7-14 Hz

PubMed Central

Castro-Alamancos, Manuel A.

2013-01-01

The neocortex or six layer cortex consists of at least 52 cytoarchitectonically distinct areas in humans, and similar areas can be distinguished in rodents. Each of these areas has a defining set of extrinsic connections, identifiable functional roles, a distinct laminar arrangement, etc. Thus, neocortex is extensively subdivided into areas of anatomical and functional specialization, but less is known about the specialization of cellular and network physiology across areas. The motor cortex appears to have a distinct propensity to oscillate in the 7–14 Hz frequency range. Augmenting responses, normal mu and beta oscillations, and abnormal oscillations or after discharges caused by enhancing excitation or suppressing inhibition are all expressed around this frequency range. The substrate for this activity may be an excitatory network that is unique to the motor cortex or that is more strongly suppressed in other areas, such as somatosensory cortex. Interestingly, augmenting responses are dependent on behavioral state. They are abolished during behavioral arousal. Here, I briefly review this evidence. PMID:23439785

Data mining neocortical high-frequency oscillations in epilepsy and controls

PubMed Central

Stead, Matt; Krieger, Abba; Stacey, William; Maus, Douglas; Marsh, Eric; Viventi, Jonathan; Lee, Kendall H.; Marsh, Richard; Litt, Brian; Worrell, Gregory A.

2011-01-01

Transient high-frequency (100–500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100–250 Hz) and fast ripple (250–500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100–500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value. PMID:21903727

Data mining neocortical high-frequency oscillations in epilepsy and controls.

PubMed

Blanco, Justin A; Stead, Matt; Krieger, Abba; Stacey, William; Maus, Douglas; Marsh, Eric; Viventi, Jonathan; Lee, Kendall H; Marsh, Richard; Litt, Brian; Worrell, Gregory A

2011-10-01

Transient high-frequency (100-500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100-250 Hz) and fast ripple (250-500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100-500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.

Hippocampal Sharp Wave Bursts Coincide with Neocortical "Up-State" Transitions

ERIC Educational Resources Information Center

Battaglia, Francesco P.; Sutherland, Gary R.; McNaughton, Bruce L.

2004-01-01

The sleeping neocortex shows nested oscillatory activity in different frequency ranges, characterized by fluctuations between "up-states" and "down-states." High-density neuronal ensemble recordings in rats now reveal the interaction between synchronized activity in the hippocampus and neocortex: Electroencephalographic sharp…

Subtle changes in brain functions produced by single doses of mevinphos (Phosdrin).

DOT National Transportation Integrated Search

1973-02-01

Mevinphos (Phosdrin) was found to inhibit the amplitude of hippocampal evoked potentials in unanesthetized squirrel monkeys with chronically indwelling electrodes. The threshold dose was 0.050 mg/kg and the maximal dose studied was 0.200 mg/kg. Doses...

Anatomical origin of déjà vu and vivid 'memories' in human temporal lobe epilepsy.

PubMed

Bancaud, J; Brunet-Bourgin, F; Chauvel, P; Halgren, E

1994-02-01

Jackson (Brain 1898; 21: 580-90) observed that seizures arising in the medial temporal lobe may result in a 'dreamy state', consisting of vivid memory-like hallucinations, and/or the sense of having previously lived through exactly the same situation (déjà vu). Penfield demonstrated that the dreamy state can sometimes be evoked by electrical stimulation of the lateral temporal neocortex, especially the superior temporal gyrus. Halgren et al. (Brain 1978; 101: 83-117) showed that the dreamy state can be evoked by stimulation of the hippocampal formation and amygdala and Gloor (Brain 1990; 113: 1673-94) has suggested that it is evoked by lateral stimulation only when the resulting after-discharge spreads medially. In order to resolve the relative importance of these areas, we considered the mental phenomena observed in epileptic patients with electrodes stereotaxically implanted into different brain areas for seizure localization prior to surgical treatment. Sixteen patients, all with seizures involving the temporal lobe, experienced the dreamy state either as a result of spontaneous seizures (nine dreamy states in six patients), or due to electrical stimulation (43 in 14) or to chemical activation (five in three). Déjà vu and hallucinations of scenes were often evoked by different stimulations of the same electrode in the same patient. As Jackson had also observed, the dreamy state could occur alone but was often associated with epigastric phenomena and fear, and followed by loss of contact and oro-alimentary automatisms, and then by simple gestural automatisms, all characteristic of partial seizures beginning in the medial temporal lobe. Furthermore, as also emphasized by Jackson, the dreamy state was seldom associated with sensory illusions. Stimulation of either the neocortex (15 occurrences), anterior hippocampus (17) or amygdala (10) could evoke a dreamy state. However, since fewer hippocampal and amygdala leads were stimulated than temporal neocortical, the proportion of medial temporal electrodes where dreamy states could be evoked was much higher than in the neocortex. Most responsive lateral temporal sites were located in the superior temporal gyrus, rather than the middle temporal gyrus which was significantly less responsive. In 85% of dreamy states evoked by medial temporal lobe stimulation, the discharge spread to the temporal neocortex; and in 53% of dreamy states evoked by lateral temporal stimulation, the discharge spread medially. Considering all dreamy states, the amygdala was involved (as the stimulated structure, or as the site of ictal- or after-discharge) in 73% of cases, the anterior hippocampus in 83% and the temporal neocortex in 88%.(ABSTRACT TRUNCATED AT 400 WORDS)

Respiratory gas exchange as a new aid to monitor acidosis in endotoxemic rats: relationship to metabolic fuel substrates and thermometabolic responses.

PubMed

Steiner, Alexandre A; Flatow, Elizabeth A; Brito, Camila F; Fonseca, Monique T; Komegae, Evilin N

2017-01-01

This study introduces the respiratory exchange ratio (RER; the ratio of whole-body CO 2 production to O 2 consumption) as an aid to monitor metabolic acidosis during the early phase of endotoxic shock in unanesthetized, freely moving rats. Two serotypes of lipopolysaccharide (lipopolysaccharide [LPS] O55:B5 and O127:B8) were tested at shock-inducing doses (0.5-2 mg/kg). Phasic rises in RER were observed consistently across LPS serotypes and doses. The RER rise often exceeded the ceiling of the quotient for oxidative metabolism, and was mirrored by depletion of arterial bicarbonate and decreases in pH It occurred independently of ventilatory adjustments. These data indicate that the rise in RER results from a nonmetabolic CO 2 load produced via an acid-induced equilibrium shift in the bicarbonate buffer. Having validated this new experimental aid, we asked whether acidosis was interconnected with the metabolic and thermal responses that accompany endotoxic shock in unanesthetized rats. Contrary to this hypothesis, however, acidosis persisted regardless of whether the ambient temperature favored or prevented downregulation of mitochondrial oxidation and regulated hypothermia. We then asked whether the substrate that fuels aerobic metabolism could be a relevant factor in LPS-induced acidosis. Food deprivation was employed to divert metabolism away from glucose oxidation and toward fatty acid oxidation. Interestingly, this intervention attenuated the RER response to LPS by 58%, without suppressing other key aspects of systemic inflammation. We conclude that acid production in unanesthetized rats with endotoxic shock results from a phasic activation of glycolysis, which occurs independently of physiological changes in mitochondrial oxidation and body temperature. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Dynamic changes in phrenic motor output following high cervical hemisection in the decerebrate rat.

PubMed

Ghali, Michael George Zaki; Marchenko, Vitaliy

2015-09-01

Hemisection of the spinal cord at C2 eliminates ipsilateral descending drive to the phrenic nucleus and causes hemidiaphragmatic paralysis in rats. Phrenic nerve (PhN) or diaphragmatic activity ipsilateral to hemisection can occasionally be induced acutely following hemisection by respiratory stressors (i.e., hypercapnia, asphyxia, contralateral phrenicotomy) and becomes spontaneously active days-to-weeks later. These investigations, however, are potentially confounded by the use of anesthesia, which may suppress spontaneously-active crossed phrenic pathways. Experiments were performed on vecuronium-paralyzed, unanesthetized, decerebrate adult male rats and whole PhN activity recorded continuously before, during, and after high cervical hemisection at the C1 spinal level. Crossed phrenic activity recovered spontaneously over minutes-to-hours with maximal recovery of 11.8 ± 3.1% (m ± SE) in the PhN ipsilateral to hemisection. Additionally, there was a significant increase in PhN activity contralateral to hemisection of 221.0 ± 4 0.4% (m ± SE); since animals were artificially-ventilated, these changes likely represent an increase in central respiratory drive. These results underscore the state-dependence of crossed bulbophrenic projections and suggest that unanesthetized models may be more sensitive in detecting acute recovery of respiratory output following spinal cord injury (SCI). Additionally, our results may suggest an important role for a group of C1-C2 neurons exhibiting respiratory-related activity, spared by the higher level of hemisection. These units may function as relays of polysynaptic bulbophrenic pathways and/or provide excitatory drive to phrenic motoneurons. Our findings provide a new model for investigating acute respiratory recovery following cervical SCI, the high C1-hemisected unanesthetized decerebrate rat and suggest a centrally-mediated increase in central respiratory drive in response to high cervical SCI. Copyright © 2015. Published by Elsevier Inc.

Temporal and spatial tuning of dorsal lateral geniculate nucleus neurons in unanesthetized rats

PubMed Central

Sriram, Balaji; Meier, Philip M.

2016-01-01

Visual response properties of neurons in the dorsolateral geniculate nucleus (dLGN) have been well described in several species, but not in rats. Analysis of responses from the unanesthetized rat dLGN will be needed to develop quantitative models that account for visual behavior of rats. We recorded visual responses from 130 single units in the dLGN of 7 unanesthetized rats. We report the response amplitudes, temporal frequency, and spatial frequency sensitivities in this population of cells. In response to 2-Hz visual stimulation, dLGN cells fired 15.9 ± 11.4 spikes/s (mean ± SD) modulated by 10.7 ± 8.4 spikes/s about the mean. The optimal temporal frequency for full-field stimulation ranged from 5.8 to 19.6 Hz across cells. The temporal high-frequency cutoff ranged from 11.7 to 33.6 Hz. Some cells responded best to low temporal frequency stimulation (low pass), and others were strictly bandpass; most cells fell between these extremes. At 2- to 4-Hz temporal modulation, the spatial frequency of drifting grating that drove cells best ranged from 0.008 to 0.18 cycles per degree (cpd) across cells. The high-frequency cutoff ranged from 0.01 to 1.07 cpd across cells. The majority of cells were driven best by the lowest spatial frequency tested, but many were partially or strictly bandpass. We conclude that single units in the rat dLGN can respond vigorously to temporal modulation up to at least 30 Hz and spatial detail up to 1 cpd. Tuning properties were heterogeneous, but each fell along a continuum; we found no obvious clustering into discrete cell types along these dimensions. PMID:26936980

Hypothalamic supraoptic but not paraventricular nucleus is involved in cardiovascular responses to carbachol microinjected into the bed nucleus of stria terminalis of unanesthetized rats.

PubMed

Alves, Fernando H F; Crestani, Carlos C; Busnardo, Cristiane; Antunes-Rodrigues, José; Gomes, Felipe V; Resstel, Leonardo B M; Corrêa, Fernando M A

2011-06-01

Microinjection of the cholinergic agonist carbachol into the bed nucleus of the stria terminalis (BST) has been reported to cause pressor response in unanesthetized rats, which was shown to be mediated by an acute release of vasopressin into the systemic circulation and followed by baroreflex-mediated bradycardia. In the present study, we tested the possible involvement of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei in the pressor response evoked by carbachol microinjection into the BST of unanesthetized rats. For this, cardiovascular responses following carbachol (1 nmol/100 nL) microinjection into the BST were studied before and after PVN or SON pretreatment, either ipsilateral or contralateral in relation to BST microinjection site, with the nonselective neurotransmission blocker cobalt chloride (CoCl₂, 1 mM/100 nL). Carbachol microinjection into the BST evoked pressor response. Moreover, BST treatment with carbachol significantly increased plasma vasopressin levels, thus confirming previous evidences that carbachol microinjection into the BST evokes pressor response due to vasopressin release into the circulation. SON pretreatment with CoCl₂, either ipsilateral or contralateral in relation to BST microinjection site, inhibited the pressor response to carbachol microinjection into the BST. However, CoCl₂ microinjection into the ipsilateral or contralateral PVN did not affect carbachol-evoked pressor response. In conclusion, our results suggest that pressor response to carbachol microinjection into the BST is mediated by SON magnocellular neurons, without significant involvement of those in the PVN. The results also indicate that responses to carbachol microinjection into the BST are mediated by a neural pathway that depends on the activation of both ipsilateral and contralateral SON. Copyright © 2011 Elsevier B.V. All rights reserved.

The fate of Nissl-stained dark neurons following traumatic brain injury in rats: difference between neocortex and hippocampus regarding survival rate.

PubMed

Ooigawa, Hidetoshi; Nawashiro, Hiroshi; Fukui, Shinji; Otani, Naoki; Osumi, Atsushi; Toyooka, Terushige; Shima, Katsuji

2006-10-01

We studied the fate of Nissl-stained dark neurons (N-DNs) following traumatic brain injury (TBI). N-DNs were investigated in the cerebral neocortex and the hippocampus using a rat lateral fluid percussion injury model. Nissl stain, acid fuchsin stain and immunohistochemistry with phosphorylated extracellular signal-regulated protein kinase (pERK) antibody were used in order to assess posttraumatic neurons. In the neocortex, the number of dead neurons at 24 h postinjury was significantly less than that of the observed N-DNs in the earlier phase. Only a few N-DNs increased their pERK immunoreactivity. On the other hand, in the hippocampus the number of dead neurons was approximately the same number as that of the N-DNs, and most N-DNs showed an increased pERK immunoreactivity. These data suggest that not all N-DNs inevitably die especially in the neocortex after TBI. The fate of N-DNs is thus considered to differ depending on brain subfields.

The evolution of the complex sensory and motor systems of the human brain

PubMed Central

Kaas, Jon H.

2008-01-01

Inferences about how the complex sensory and motor systems of the human brain evolved are based on the results of comparative studies of brain organization across a range of mammalian species, and evidence from the endocasts of fossil skulls of key extinct species. The endocasts of the skulls of early mammals indicate that they had small brains with little neocortex. Evidence from comparative studies of cortical organization from small-brained mammals of the six major branches of mammalian evolution supports the conclusion that the small neocortex of early mammals was divided into roughly 20–25 cortical areas, including primary and secondary sensory fields. In early primates, vision was the dominant sense, and cortical areas associated with vision in temporal and occipital cortex underwent a significant expansion. Comparative studies indicate that early primates had 10 or more visual areas, and somatosensory areas with expanded representations of the forepaw. Posterior parietal cortex was also expanded, with a caudal half dominated by visual inputs, and a rostral half dominated by somatosensory inputs with outputs to an array of seven or more motor and visuomotor areas of the frontal lobe. Somatosensory areas and posterior parietal cortex became further differentiated in early anthropoid primates. As larger brains evolved in early apes and in our hominin ancestors, the number of cortical areas increased to reach an estimated 200 or so in present day humans, and hemispheric specializations emerged. The large human brain grew primarily by increasing neuron number rather than increasing average neuron size. PMID:18331903

Whole genome grey and white matter DNA methylation profiles in dorsolateral prefrontal cortex.

PubMed

Sanchez-Mut, Jose Vicente; Heyn, Holger; Vidal, Enrique; Delgado-Morales, Raúl; Moran, Sebastian; Sayols, Sergi; Sandoval, Juan; Ferrer, Isidre; Esteller, Manel; Gräff, Johannes

2017-06-01

The brain's neocortex is anatomically organized into grey and white matter, which are mainly composed by neuronal and glial cells, respectively. The neocortex can be further divided in different Brodmann areas according to their cytoarchitectural organization, which are associated with distinct cortical functions. There is increasing evidence that brain development and function are governed by epigenetic processes, yet their contribution to the functional organization of the neocortex remains incompletely understood. Herein, we determined the DNA methylation patterns of grey and white matter of dorsolateral prefrontal cortex (Brodmann area 9), an important region for higher cognitive skills that is particularly affected in various neurological diseases. For avoiding interindividual differences, we analyzed white and grey matter from the same donor using whole genome bisulfite sequencing, and for validating their biological significance, we used Infinium HumanMethylation450 BeadChip and pyrosequencing in ten and twenty independent samples, respectively. The combination of these analysis indicated robust grey-white matter differences in DNA methylation. What is more, cell type-specific markers were enriched among the most differentially methylated genes. Interestingly, we also found an outstanding number of grey-white matter differentially methylated genes that have previously been associated with Alzheimer's, Parkinson's, and Huntington's disease, as well as Multiple and Amyotrophic lateral sclerosis. The data presented here thus constitute an important resource for future studies not only to gain insight into brain regional as well as grey and white matter differences, but also to unmask epigenetic alterations that might underlie neurological and neurodegenerative diseases. © 2017 Wiley Periodicals, Inc.

Nogo-receptor gene activity: cellular localization and developmental regulation of mRNA in mice and humans.

PubMed

Josephson, Anna; Trifunovski, Alexandra; Widmer, Hans Ruedi; Widenfalk, Johan; Olson, Lars; Spenger, Christian

2002-11-18

Nogo (reticulon-4) is a myelin-associated protein that is expressed in three different splice variants, Nogo-A, Nogo-B, and Nogo-C. Nogo-A inhibits neurite regeneration in the central nervous system. Messenger RNA encoding Nogo is expressed in oligodendrocytes and central and peripheral neurons, but not in astrocytes or Schwann cells. Nogo is a transmembraneous protein; the extracellular domain is termed Nogo-66, and a Nogo-66-receptor (Nogo-R) has been identified. We performed in situ hybridization in human and mouse nervous tissues to map the cellular distribution of Nogo-R gene activity patterns in fetal and adult human spinal cord and sensory ganglia, adult human brain, and the nervous systems of developing and adult mice. In the human fetus Nogo-R was transcribed in the ventral horn of the spinal cord and in dorsal root ganglia. In adult human tissues Nogo-R gene activity was found in neocortex, hippocampus, amygdala, and a subset of large and medium-sized neurons of the dorsal root ganglia. Nogo-R mRNA was not expressed in the adult human spinal cord at detectable levels. In the fetal mouse, Nogo-R was diffusely expressed in brain, brainstem, trigeminal ganglion, spinal cord, and dorsal root ganglia at all stages. In the adult mouse strong Nogo-R mRNA expression was found in neurons in neocortex, hippocampus, amygdala, habenula, thalamic nuclei, brainstem, the granular cell layer of cerebellum, and the mitral cell layer of the olfactory bulb. Neurons in the adult mouse striatum, the medial septal nucleus, and spinal cord did not express Nogo-R mRNA at detectable levels. In summary, Nogo-66-R mRNA expression in humans and mice was observed in neurons of the developing nervous system Expression was downregulated in the adult spinal cord of both species, and specific expression patterns were seen in the adult brain. Copyright 2002 Wiley-Liss, Inc.

Deriving excitatory neurons of the neocortex from pluripotent stem cells

PubMed Central

Hansen, David V.; Rubenstein, John L.R.; Kriegstein, Arnold R.

2011-01-01

The human cerebral cortex is an immensely complex structure that subserves critical functions that can be disrupted in developmental and degenerative disorders. Recent innovations in cellular reprogramming and differentiation techniques have provided new ways to study the cellular components of the cerebral cortex. Here we discuss approaches to generate specific subtypes of excitatory cortical neurons from pluripotent stem cells. We review spatial and temporal aspects of cortical neuron specification that can guide efforts to produce excitatory neuron subtypes with increased resolution. Finally, we discuss distinguishing features of human cortical development and their translational ramifications for cortical stem cell technologies. PMID:21609822

Neocortical malformation as consequence of nonadaptive regulation of neuronogenetic sequence

NASA Technical Reports Server (NTRS)

Caviness, V. S. Jr; Takahashi, T.; Nowakowski, R. S.

2000-01-01

Variations in the structure of the neocortex induced by single gene mutations may be extreme or subtle. They differ from variations in neocortical structure encountered across and within species in that these "normal" structural variations are adaptive (both structurally and behaviorally), whereas those associated with disorders of development are not. Here we propose that they also differ in principle in that they represent disruptions of molecular mechanisms that are not normally regulatory to variations in the histogenetic sequence. We propose an algorithm for the operation of the neuronogenetic sequence in relation to the overall neocortical histogenetic sequence and highlight the restriction point of the G1 phase of the cell cycle as the master regulatory control point for normal coordinate structural variation across species and importantly within species. From considerations based on the anatomic evidence from neocortical malformation in humans, we illustrate in principle how this overall sequence appears to be disrupted by molecular biological linkages operating principally outside the control mechanisms responsible for the normal structural variation of the neocortex. MRDD Research Reviews 6:22-33, 2000. Copyright 2000 Wiley-Liss, Inc.

Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

NASA Astrophysics Data System (ADS)

Rosenstein, Jeffrey M.

1987-02-01

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

[Correlative interconnections between impulse activity of aminergic neurons of the brainstem and spectral components of electroencephalogram during action of bemitil].

PubMed

Kolotilova, O I; Pavlenko, V B; Koreniuk, I I; Kulychenko, O M; Fokina, Iu O

2007-01-01

Correlative interconnections between frequency of impulse activity of aminergic neurons and neocortex electrical activity during action of bemitil (50 mg/kg) were investigated in 5 cats. It was shown that bemitil affects correlations between frequency of impulses of aminergic neurons and electrical activity of neocortex.

View-Based Models of 3D Object Recognition and Class-Specific Invariance

DTIC Science & Technology

1994-04-01

underlie recognition of geon-like com- ponents (see Edelman, 1991 and Biederman , 1987 ). I(X -_ ta)II1y = (X - ta)TWTW(x -_ ta) (3) View-invariant features...Institute of Technology, 1993. neocortex. Biological Cybernetics, 1992. 14] I. Biederman . Recognition by components: a theory [20] B. Olshausen, C...Anderson, and D. Van Essen. A of human image understanding. Psychol. Review, neural model of visual attention and invariant pat- 94:115-147, 1987 . tern

Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iacopino, A.M.; Christakos, S.

1990-06-01

The present studies establish that there are specific, significant decreases in the neuronal calcium-binding protein (28-kDa calbindin-D) gene expression in aging and in neurodegenerative diseases. The specificity of the changes observed in calbindin mRNA levels was tested by reprobing blots with calmodulin, cyclophilin, and B-actin cDNAs. Gross brain regions of the aging rat exhibited specific, significant decreases in calbindin{center dot}mRNA and protein levels in the cerebellum, corpus striatum, and brain-stem region but not in the cerebral cortex or hippocampus. Discrete areas of the aging human brain exhibited significant decreases in calbindin protein and mRNA in the cerebellum, corpus striatum, andmore » nucleus basalis but not in the neocortex, hippocampus, amygdala, locus ceruleus, or nucleus raphe dorsalis. Comparison of diseased human brain tissue with age- and sex-matched controls yielded significant decreases calbindin protein and mRNA in the substantia nigra (Parkinson disease), in the corpus striatum (Huntington disease), in the nucleus basalis (Alzheimer disease), and in the hippocampus and nucleus raphe dorsalis (Parkinson, Huntington, and Alzheimer diseases) but not in the cerebellum, neocortex, amygdala, or locus ceruleus. These findings suggest that decreased calbindin gene expression may lead to a failure of calcium buffering or intraneuronal calcium homeostasis, which contributes to calcium-mediated cytotoxic events during aging and in the pathogenesis of neurodegenerative diseases.« less

Nitric oxide signaling in the development and evolution of language and cognitive circuits.

PubMed

Funk, Owen H; Kwan, Kenneth Y

2014-09-01

The neocortex underlies not only remarkable motor and sensory capabilities, but also some of our most distinctly human cognitive functions. The emergence of these higher functions during evolution was accompanied by structural changes in the neocortex, including the acquisition of areal specializations such as Broca's speech and language area. The study of these evolutionary mechanisms, which likely involve species-dependent gene expression and function, represents a substantial challenge. These species differences, however, may represent valuable opportunities to understand the molecular underpinnings of neocortical evolution. Here, we discuss nitric oxide signaling as a candidate mechanism in the assembly of neocortical circuits underlying language and higher cognitive functions. This hypothesis was based on the highly specific mid-fetal pattern of nitric oxide synthase 1 (NOS1, previously nNOS) expression in the pyramidal (projection) neurons of two human neocortical areas respectively involved in speech and language, and higher cognition; the frontal operculum (FOp) and the anterior cingulate cortex (ACC). This expression is transiently present during mid-gestation, suggesting that NOS1 may be involved in the development of these areas and the assembly of their neural circuits. As no other gene product is known to exhibit such exquisite spatiotemporal expression, NOS1 represents a remarkable candidate for these functions. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

The effects of stimulation of the anterior cingulate gyrus in cats with freedom of movement

NASA Technical Reports Server (NTRS)

Dapres, G.; Cadilhac, J.; Passouant, P.

1980-01-01

Stimuli of varying strength, frequency and duration were applied to the anterior cingulate gyrus in unanesthetized cats with freedom of movement. The motor, vegetative and electrical effects of these stimuli, although inconstant, lead to a consideration of the role of this structure in the extrapyramidal control of motricity.

In vivo magnetic resonance microscopy of brain structure in unanesthetized flies

NASA Astrophysics Data System (ADS)

Jasanoff, Alan; Sun, Phillip Z.

2002-09-01

We present near-cellular-resolution magnetic resonance (MR) images of an unanesthetized animal, the blowfly Sarcophaga bullata. Immobilized flies were inserted into a home-built gradient probe in a 14.1-T magnet, and images of voxel size (20-40 μm) 3—comparable to the diameter of many neuronal cell bodies in the fly's brain—were obtained in several hours. Use of applied field gradients on the order of 60 G/cm allowed minimally distorted images to be produced, despite significant susceptibility differences across the specimen. The images we obtained have exceptional contrast-to-noise levels; comparison with histology-based anatomical information shows that the MR microscopy faithfully represents patterns of nervous tissue and allows distinct brain regions to be clearly identified. Even at the highest resolutions we explored, morphological detail was pronounced in the apparent absence of instabilities or movement-related artifacts frequently observed during imaging of live animal specimens. This work demonstrates that the challenges of noninvasive in vivo MR microscopy can be overcome in a system amenable to studies of brain structure and physiology.

Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study.

PubMed

Snowdon, D A; Tully, C L; Smith, C D; Riley, K P; Markesbery, W R

2000-04-01

Previous studies suggested that low concentrations of folate in the blood are related to poor cognitive function, dementia, and Alzheimer disease-related neurodegeneration of the brain. Our aim was to determine whether serum folate is inversely associated with the severity of atrophy of the neocortex. Nutrients, lipoproteins, and nutritional markers were measured in the blood of 30 participants in the Nun Study from one convent who later died when they were 78-101 y old (mean: 91 y). At autopsy, several neuropathologic indicators of Alzheimer disease were determined, including the degree of atrophy of 3 lobes of the neocortex (frontal, temporal, and parietal) and the number of neocortical Alzheimer disease lesions (ie, senile plaques and neurofibrillary tangles) as assessed by a neuropathologist. The correlation between serum folate and the severity of atrophy of the neocortex was -0.40 (P = 0.03). Among a subset of 15 participants with significant numbers of Alzheimer disease lesions in the neocortex, the correlation between folate and atrophy was -0.80 (P = 0.0006). Atrophy may be specific to low folate because none of the 18 other nutrients, lipoproteins, or nutritional markers measured in the blood had significant negative correlations with atrophy. Among elderly Catholic sisters who lived in one convent, ate from the same kitchen, and were highly comparable for a wide range of environmental and lifestyle factors, low serum folate was strongly associated with atrophy of the cerebral cortex. Definitive evidence for this relation and its temporal sequence awaits the findings of other studies.

The neocortex of cetartiodactyls. II. Neuronal morphology of the visual and motor cortices in the giraffe (Giraffa camelopardalis).

PubMed

Jacobs, Bob; Harland, Tessa; Kennedy, Deborah; Schall, Matthew; Wicinski, Bridget; Butti, Camilla; Hof, Patrick R; Sherwood, Chet C; Manger, Paul R

2015-09-01

The present quantitative study extends our investigation of cetartiodactyls by exploring the neuronal morphology in the giraffe (Giraffa camelopardalis) neocortex. Here, we investigate giraffe primary visual and motor cortices from perfusion-fixed brains of three subadults stained with a modified rapid Golgi technique. Neurons (n = 244) were quantified on a computer-assisted microscopy system. Qualitatively, the giraffe neocortex contained an array of complex spiny neurons that included both "typical" pyramidal neuron morphology and "atypical" spiny neurons in terms of morphology and/or orientation. In general, the neocortex exhibited a vertical columnar organization of apical dendrites. Although there was no significant quantitative difference in dendritic complexity for pyramidal neurons between primary visual (n = 78) and motor cortices (n = 65), there was a significant difference in dendritic spine density (motor cortex > visual cortex). The morphology of aspiny neurons in giraffes appeared to be similar to that of other eutherian mammals. For cross-species comparison of neuron morphology, giraffe pyramidal neurons were compared to those quantified with the same methodology in African elephants and some cetaceans (e.g., bottlenose dolphin, minke whale, humpback whale). Across species, the giraffe (and cetaceans) exhibited less widely bifurcating apical dendrites compared to elephants. Quantitative dendritic measures revealed that the elephant and humpback whale had more extensive dendrites than giraffes, whereas the minke whale and bottlenose dolphin had less extensive dendritic arbors. Spine measures were highest in the giraffe, perhaps due to the high quality, perfusion fixation. The neuronal morphology in giraffe neocortex is thus generally consistent with what is known about other cetartiodactyls.

Humans use compression heuristics to improve the recall of social networks.

PubMed

Brashears, Matthew E

2013-01-01

The ability of primates, including humans, to maintain large social networks appears to depend on the ratio of the neocortex to the rest of the brain. However, observed human network size frequently exceeds predictions based on this ratio (e.g., "Dunbar's Number"), implying that human networks are too large to be cognitively managed. Here I show that humans adaptively use compression heuristics to allow larger amounts of social information to be stored in the same brain volume. I find that human adults can remember larger numbers of relationships in greater detail when a network exhibits triadic closure and kin labels than when it does not. These findings help to explain how humans manage large and complex social networks with finite cognitive resources and suggest that many of the unusual properties of human social networks are rooted in the strategies necessary to cope with cognitive limitations.

Automatic cortical thickness analysis on rodent brain

NASA Astrophysics Data System (ADS)

Lee, Joohwi; Ehlers, Cindy; Crews, Fulton; Niethammer, Marc; Budin, Francois; Paniagua, Beatriz; Sulik, Kathy; Johns, Josephine; Styner, Martin; Oguz, Ipek

2011-03-01

Localized difference in the cortex is one of the most useful morphometric traits in human and animal brain studies. There are many tools and methods already developed to automatically measure and analyze cortical thickness for the human brain. However, these tools cannot be directly applied to rodent brains due to the different scales; even adult rodent brains are 50 to 100 times smaller than humans. This paper describes an algorithm for automatically measuring the cortical thickness of mouse and rat brains. The algorithm consists of three steps: segmentation, thickness measurement, and statistical analysis among experimental groups. The segmentation step provides the neocortex separation from other brain structures and thus is a preprocessing step for the thickness measurement. In the thickness measurement step, the thickness is computed by solving a Laplacian PDE and a transport equation. The Laplacian PDE first creates streamlines as an analogy of cortical columns; the transport equation computes the length of the streamlines. The result is stored as a thickness map over the neocortex surface. For the statistical analysis, it is important to sample thickness at corresponding points. This is achieved by the particle correspondence algorithm which minimizes entropy between dynamically moving sample points called particles. Since the computational cost of the correspondence algorithm may limit the number of corresponding points, we use thin-plate spline based interpolation to increase the number of corresponding sample points. As a driving application, we measured the thickness difference to assess the effects of adolescent intermittent ethanol exposure that persist into adulthood and performed t-test between the control and exposed rat groups. We found significantly differing regions in both hemispheres.

Brain MR Spectroscopy Biomarkers in a Clinical Trial of PTS Patients With Comorbid AUD

DTIC Science & Technology

2016-05-01

levels in the neocortex of 40 alcohol dependent veterans with posttraumatic stress disorder (PTSD). We propose to perform longitudinal proton magnetic...longitudinal, magnetic resonance spectroscopy, alcohol dependence, posttraumatic stress disorder (PTSD), topiramate, γ-aminobutyric acid (GABA), glutamate, US...the neocortex of alcohol dependent veterans with posttraumatic stress disorder (PTSD). We propose to perform longitudinal proton magnetic resonance

Embodied cognitive evolution and the cerebellum.

PubMed

Barton, Robert A

2012-08-05

Much attention has focused on the dramatic expansion of the forebrain, particularly the neocortex, as the neural substrate of cognitive evolution. However, though relatively small, the cerebellum contains about four times more neurons than the neocortex. I show that commonly used comparative measures such as neocortex ratio underestimate the contribution of the cerebellum to brain evolution. Once differences in the scaling of connectivity in neocortex and cerebellum are accounted for, a marked and general pattern of correlated evolution of the two structures is apparent. One deviation from this general pattern is a relative expansion of the cerebellum in apes and other extractive foragers. The confluence of these comparative patterns, studies of ape foraging skills and social learning, and recent evidence on the cognitive neuroscience of the cerebellum, suggest an important role for the cerebellum in the evolution of the capacity for planning, execution and understanding of complex behavioural sequences--including tool use and language. There is no clear separation between sensory-motor and cognitive specializations underpinning such skills, undermining the notion of executive control as a distinct process. Instead, I argue that cognitive evolution is most effectively understood as the elaboration of specialized systems for embodied adaptive control.

Recruitment and plasticity in diaphragm, intercostal, and abdominal muscles in unanesthetized rats

PubMed Central

Navarrete-Opazo, A.

2014-01-01

Although rats are a frequent model for studies of plasticity in respiratory motor control, the relative capacity of rat accessory respiratory muscles to express plasticity is not well known, particularly in unanesthetized animals. Here, we characterized external intercostal (T2, T4, T5, T6, T7, T8, T9 EIC) and abdominal muscle (external oblique and rectus abdominis) electromyogram (EMG) activity in unanesthetized rats via radiotelemetry during normoxia (Nx: 21% O2) and following acute intermittent hypoxia (AIH: 10 × 5-min, 10.5% O2; 5-min intervals). Diaphragm and T2–T5 EIC EMG activity, and ventilation were also assessed during maximal chemoreceptor stimulation (MCS: 7% CO2, 10.5% O2) and sustained hypoxia (SH: 10.5% O2). In Nx, T2 EIC exhibits prominent inspiratory activity, whereas T4, T5, T6, and T7 EIC inspiratory activity decreases in a caudal direction. T8 and T9 EIC and abdominal muscles show only tonic or sporadic activity, without consistent respiratory activity. MCS increases diaphragm and T2 EIC EMG amplitude and tidal volume more than SH (0.94 ± 0.10 vs. 0.68 ± 0.05 ml/100 g; P < 0.001). Following AIH, T2 EIC EMG amplitude remained above baseline for more than 60 min post-AIH (i.e., EIC long-term facilitation, LTF), and was greater than diaphragm LTF (41.5 ± 1.3% vs. 19.1 ± 2.0% baseline; P < 0.001). We conclude that 1) diaphragm and rostral T2–T5 EIC muscles exhibit inspiratory activity during Nx; 2) MCS elicits greater ventilatory, diaphragm, and rostral T2–T5 EIC muscle activity vs. SH; and 3) AIH induces greater rostral EIC LTF than diaphragm LTF. PMID:24833779

Analysis of Neural Stem Cells from Human Cortical Brain Structures In Vitro.

PubMed

Aleksandrova, M A; Poltavtseva, R A; Marei, M V; Sukhikh, G T

2016-05-01

Comparative immunohistochemical analysis of the neocortex from human fetuses showed that neural stem and progenitor cells are present in the brain throughout the gestation period, at least from week 8 through 26. At the same time, neural stem cells from the first and second trimester fetuses differed by the distribution, morphology, growth, and quantity. Immunocytochemical analysis of neural stem cells derived from fetuses at different gestation terms and cultured under different conditions showed their differentiation capacity. Detailed analysis of neural stem cell populations derived from fetuses on gestation weeks 8-9, 18-20, and 26 expressing Lex/SSEA1 was performed.

Decoding ensemble activity from neurophysiological recordings in the temporal cortex.

PubMed

Kreiman, Gabriel

2011-01-01

We study subjects with pharmacologically intractable epilepsy who undergo semi-chronic implantation of electrodes for clinical purposes. We record physiological activity from tens to more than one hundred electrodes implanted in different parts of neocortex. These recordings provide higher spatial and temporal resolution than non-invasive measures of human brain activity. Here we discuss our efforts to develop hardware and algorithms to interact with the human brain by decoding ensemble activity in single trials. We focus our discussion on decoding visual information during a variety of visual object recognition tasks but the same technologies and algorithms can also be directly applied to other cognitive phenomena.

In vivo multiphoton microscopy beyond 1 mm in the brain

NASA Astrophysics Data System (ADS)

Miller, David R.; Medina, Flor A.; Hassan, Ahmed; Perillo, Evan P.; Hagan, Kristen; Kazmi, S. M. Shams; Zemelman, Boris V.; Dunn, Andrew K.

2017-02-01

We perform high-resolution, non-invasive, in vivo deep-tissue imaging of the mouse neocortex using multiphoton microscopy with a high repetition rate optical parametric amplifier laser source tunable between λ=1,100 and 1,400 nm. We demonstrate an imaging depth of 1,200 μm in vasculature and 1,160 μm in neurons. We also demonstrate deep-tissue imaging using Indocyanine Green (ICG), which is FDA approved and a promising route to translate multiphoton microscopy to human applications.

Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer's-like disease in mice.

PubMed

von Linstow, Christian Ulrich; Waider, Jonas; Grebing, Manuela; Metaxas, Athanasios; Lesch, Klaus Peter; Finsen, Bente

2017-09-12

Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer's disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APP swe /PS1 ΔE9 (APP/PS1) mouse model of AD. We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. Amyloid-β-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aβ42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aβ40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aβ42 and Aβ40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation. Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aβ42 and Aβ40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aβ pathology.

Cardiovascular adaptations during long-term altered gravity

NASA Technical Reports Server (NTRS)

Popovic, V. P.

1982-01-01

Cardiovascular studies were performed on unrestrained, unanesthetized rats and on the same animals in head-down hypokinetic conditions as well as during readaptation of the same animals to free activity. Possible circulatory mechanisms that evolved in mammals during long-lasting gravity exposure are considered. These mechanisms are likely to be affected during exposure to 0-g forces.

Computations in the deep vs superficial layers of the cerebral cortex.

PubMed

Rolls, Edmund T; Mills, W Patrick C

2017-11-01

A fundamental question is how the cerebral neocortex operates functionally, computationally. The cerebral neocortex with its superficial and deep layers and highly developed recurrent collateral systems that provide a basis for memory-related processing might perform somewhat different computations in the superficial and deep layers. Here we take into account the quantitative connectivity within and between laminae. Using integrate-and-fire neuronal network simulations that incorporate this connectivity, we first show that attractor networks implemented in the deep layers that are activated by the superficial layers could be partly independent in that the deep layers might have a different time course, which might because of adaptation be more transient and useful for outputs from the neocortex. In contrast the superficial layers could implement more prolonged firing, useful for slow learning and for short-term memory. Second, we show that a different type of computation could in principle be performed in the superficial and deep layers, by showing that the superficial layers could operate as a discrete attractor network useful for categorisation and feeding information forward up a cortical hierarchy, whereas the deep layers could operate as a continuous attractor network useful for providing a spatially and temporally smooth output to output systems in the brain. A key advance is that we draw attention to the functions of the recurrent collateral connections between cortical pyramidal cells, often omitted in canonical models of the neocortex, and address principles of operation of the neocortex by which the superficial and deep layers might be specialized for different types of attractor-related memory functions implemented by the recurrent collaterals. Copyright © 2017 Elsevier Inc. All rights reserved.

[Neuronal death in the neocortex of drug resistant temporal lobe epilepsy patients].

PubMed

Lorigados Pedre, L; Orozco Suárez, S; Morales Chacón, L; García Maeso, I; Estupiñán Diaz, B; Bender del Busto, J E; Pavón Fuentes, N; Paula Piñero, B; Rocha Arrieta, L

2008-11-01

Introduction. Participation of apoptotic death mechanisms in drug resistant temporal lobe epilepsy (DRTLE) is currently under great debate. We have investigated if there is neuronal loss and the immunodetection to different markers in neocortical tissue death in eigth patients with DRTLE. The neocortexes of five patients deceased due to non-neurological causes, paired in age and gender were evaluated as control tissue. Methods. The evaluation of neuronal loss was made by means of a stereological study and with immunohistochemical techniques with the synaptophysin marker. Immunopositivity to different apoptotic markers (annexin V, caspase 3 and 8, bcl-2 and p53) and detection of deoxyribonucleic acid (DNA) fragmentation (TUNEL) were analyzed and double labeling with synaptophysin was performed in every case. The results were evaluated with confocal microscope and analyzed with the Zeiss LSM 5 Image Browser Program, 2.80.1113 (Germany). Results. A statistically significant decrease in the total number of cells (p < 0.05) and the synaptophysin cells+ (p<0.01) in the neocortex (layer IV) of the patients with DRTLE when compared with the control tissue was found. No significant differences were found in the apoptotic markers bcl-2, p53, caspase 3 and 8 for any of the neocortex layers while there was a statistically significant increase in the number of TUNEL cells+ (p<0.05) and annexin V+ (p<0.05) in the neocortical layer IV of the patients. Conclusions. This group of evidence speaks in favor of the existence of an effect on the neuronal number in the neocortex layer IV that may be associated with noncaspase dependent apoptotic death process, without being able to rule out death by necrosis. Key words: Drug resistant temporal lobe epilepsy. Apoptosis. Necrosis. Neuronal loss. Neurología 2008;23(9):555-565.

Descending pathways to the spinal cord, IV: Some factors related to the amount of cortex devoted to the corticospinal tract.

PubMed

Nudo, R J; Masterton, R B

1990-06-22

In the companion paper to this one (Nudo and Masterton: J. Comp. Neurol. 296:559-583, '90), we have presented data indicating that in each of 22 mammals, there are either 2 or 3 separate regions of neocortex contributing corticospinal fibers. In this paper, we describe the variation in the absolute size of these cortical regions, the total amount of neocortex contributing corticospinal fibers (CST cortex), and the total amount of neocortex (total cortex) in each of the animals. We then use strict statistical tests to examine the relationships between these measures and several other quantitative measures or descriptions of the animals' size, ancestral heritage, motor prowess, and ecological adaptation. The results show that the absolute amount of CST cortex is more closely related to the total amount of neocortex than to any other quantitative measure available. The further variation--that is, the variation in the amount of CST cortex relative to total neocortex--appears to have been random over the inferred ancestral lineages of most animals in the sample, but seems to have been almost absent along the anthropoid lineage. Because this constancy in the relative amount of CST cortex over a very long period of anthropoid ancestry is apparently unusual if not unique among mammals, it may contain a clue to the special role of the corticospinal tract among primates. Finally, the distribution of the CST among the 3 cortical regions in primates was found to be more closely related to their particular mode of ecological adaptation than to their particular combination of digital dexterity and hand-eye coordination.

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

PubMed Central

Palma, E.; Ragozzino, D. A.; Di Angelantonio, S.; Spinelli, G.; Trettel, F.; Martinez-Torres, A.; Torchia, G.; Arcella, A.; Di Gennaro, G.; Quarato, P. P.; Esposito, V.; Cantore, G.; Miledi, R.; Eusebi, F.

2004-01-01

The properties of γ-aminobutyric acid (GABA) type A receptors (GABAA receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABAA receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat α1β2γ2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABAA receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABAA receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABAA-receptor β1, β2, β3, and γ2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABAA receptors. Blockage of phosphatases stabilizes the TLE GABAA receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy. PMID:15218107

Comprehensive transcriptional map of primate brain development

PubMed Central

Bakken, Trygve E.; Miller, Jeremy A.; Ding, Song-Lin; Sunkin, Susan M.; Smith, Kimberly A.; Ng, Lydia; Szafer, Aaron; Dalley, Rachel A.; Royall, Joshua J.; Lemon, Tracy; Shapouri, Sheila; Aiona, Kaylynn; Arnold, James; Bennett, Jeffrey L.; Bertagnolli, Darren; Bickley, Kristopher; Boe, Andrew; Brouner, Krissy; Butler, Stephanie; Byrnes, Emi; Caldejon, Shiella; Carey, Anita; Cate, Shelby; Chapin, Mike; Chen, Jefferey; Dee, Nick; Desta, Tsega; Dolbeare, Tim A.; Dotson, Nadia; Ebbert, Amanda; Fulfs, Erich; Gee, Garrett; Gilbert, Terri L.; Goldy, Jeff; Gourley, Lindsey; Gregor, Ben; Gu, Guangyu; Hall, Jon; Haradon, Zeb; Haynor, David R.; Hejazinia, Nika; Hoerder-Suabedissen, Anna; Howard, Robert; Jochim, Jay; Kinnunen, Marty; Kriedberg, Ali; Kuan, Chihchau L.; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Luong, Lon; Mastan, Naveed; May, Ryan; Melchor, Jose; Mosqueda, Nerick; Mott, Erika; Ngo, Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D.; Parry, Sheana; Pendergraft, Julie; Potekhina, Lydia; Reding, Melissa; Riley, Zackery L.; Roberts, Tyson; Rogers, Brandon; Roll, Kate; Rosen, David; Sandman, David; Sarreal, Melaine; Shapovalova, Nadiya; Shi, Shu; Sjoquist, Nathan; Sodt, Andy J.; Townsend, Robbie; Velasquez, Lissette; Wagley, Udi; Wakeman, Wayne B.; White, Cassandra; Bennett, Crissa; Wu, Jennifer; Young, Rob; Youngstrom, Brian L.; Wohnoutka, Paul; Gibbs, Richard A.; Rogers, Jeffrey; Hohmann, John G.; Hawrylycz, Michael J.; Hevner, Robert F.; Molnár, Zoltán; Phillips, John W.; Dang, Chinh; Jones, Allan R.; Amaral, David G.; Bernard, Amy; Lein, Ed S.

2017-01-01

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny. PMID:27409810

From network heterogeneities to familiarity detection and hippocampal memory management

PubMed Central

Wang, Jane X.; Poe, Gina; Zochowski, Michal

2009-01-01

Hippocampal-neocortical interactions are key to the rapid formation of novel associative memories in the hippocampus and consolidation to long term storage sites in the neocortex. We investigated the role of network correlates during information processing in hippocampal-cortical networks. We found that changes in the intrinsic network dynamics due to the formation of structural network heterogeneities alone act as a dynamical and regulatory mechanism for stimulus novelty and familiarity detection, thereby controlling memory management in the context of memory consolidation. This network dynamic, coupled with an anatomically established feedback between the hippocampus and the neocortex, recovered heretofore unexplained properties of neural activity patterns during memory management tasks which we observed during sleep in multiunit recordings from behaving animals. Our simple dynamical mechanism shows an experimentally matched progressive shift of memory activation from the hippocampus to the neocortex and thus provides the means to achieve an autonomous off-line progression of memory consolidation. PMID:18999453

Cholinesterase inhibitor soman increases inositol trisphosphate in rat brain. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mobley, P.L.

1990-12-31

Studies were conducted to determine the effect of the cholinesterase inhibitor soman on the amount of inositol trisphosphate in the neocortex, striatum, cerebellum, and medulla-pons regions of rat brain in vivo. The studies indicate that treatment with soman increase inositol trisphosphate in the neocortex and striatum, but not in the cerebellum or medulla-pons region. In the neocortex the most pronounced increases were observed in animals with severe poisoning symptoms; however, inositol trisphophate was also found to be elevated in animals with only mild poisoning symptoms. A variety of evidence suggests that the receptor-mediated hydrolysis of phosphatidyl inositol results in themore » formation of inositol trisphosphate (IP3) and diacylglycerol, both of which function as intracellular signal messengers, and that this mechanism represents a major signal transduction system through which extracellular signals can influence intracellular events.« less

Effect of age on pulmonary epithelial permeability in unanesthetized lambs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hutchison, A.A.; McNicol, K.J.; Loughlin, G.M.

1985-01-01

Pulmonary epithelial permeability was measured 1) in unanesthetized sheep, and 2) longitudinally in growing lambs. Awake sheep were intubated and a solution of /sup 51/Cr-ethylenediaminetetraacetic acid and /sup 125/I-antipyrine was instilled in the intrathoracic trachea via the nasotracheal tube. Arterial blood was drawn 1-25 minutes after the instillation. The ratios of the counts of /sup 51/Cr to /sup 125/I at 7, 10, and 13 min were calculated and averaged for each animal. Data from six adult sheep showed that the mean +/- SE of the permeability ratio was 0.012 +/- 0.003 and was reproducible over three months. When measured twicemore » within two hours, the second ratio was significantly higher than the first. One hour of general anesthesia with methoxyflurane did not alter the permeability ratio significantly. Ten lambs were studied longitudinally 10 hours and 5, 10, 20, and 30 days after delivery. Within the first 24 hours of life the permeability ratio was, significantly greater than the adult value. At five days there was no significant difference between lambs and adult sheep. Throughout the first month of life, the permeability ratio in lambs remained at at the adult level.« less

Parallel pathways from motor and somatosensory cortex for controlling whisker movements in mice

PubMed Central

Sreenivasan, Varun; Karmakar, Kajari; Rijli, Filippo M; Petersen, Carl C H

2015-01-01

Mice can gather tactile sensory information by actively moving their whiskers to palpate objects in their immediate surroundings. Whisker sensory perception therefore requires integration of sensory and motor information, which occurs prominently in the neocortex. The signalling pathways from the neocortex for controlling whisker movements are currently poorly understood in mice. Here, we delineate two pathways, one originating from primary whisker somatosensory cortex (wS1) and the other from whisker motor cortex (wM1), that control qualitatively distinct movements of contralateral whiskers. Optogenetic stimulation of wS1 drove retraction of contralateral whiskers while stimulation of wM1 drove rhythmic whisker protraction. To map brainstem pathways connecting these cortical areas to whisker motor neurons, we used a combination of anterograde tracing using adenoassociated virus injected into neocortex and retrograde tracing using monosynaptic rabies virus injected into whisker muscles. Our data are consistent with wS1 driving whisker retraction by exciting glutamatergic premotor neurons in the rostral spinal trigeminal interpolaris nucleus, which in turn activate the motor neurons innervating the extrinsic retractor muscle nasolabialis. The rhythmic whisker protraction evoked by wM1 stimulation might be driven by excitation of excitatory and inhibitory premotor neurons in the brainstem reticular formation innervating both intrinsic and extrinsic muscles. Our data therefore begin to unravel the neuronal circuits linking the neocortex to whisker motor neurons. PMID:25476605

Synchronization analysis of voltage-sensitive dye imaging during focal seizures in the rat neocortex

NASA Astrophysics Data System (ADS)

Takeshita, Daisuke; Bahar, Sonya

2011-12-01

Seizures are often assumed to result from an excess of synchronized neural activity. However, various recent studies have suggested that this is not necessarily the case. We investigate synchronization during focal neocortical seizures induced by injection of 4-aminopyridine (4AP) in the rat neocortex in vivo. Neocortical activity is monitored by field potential recording and by the fluorescence of the voltage-sensitive dye RH-1691. After removal of artifacts, the voltage-sensitive dye (VSD) signal is analyzed using the nonlinear dynamics-based technique of stochastic phase synchronization in order to determine the degree of synchronization within the neocortex during the development and spread of each seizure event. Results show a large, statistically significant increase in synchronization during seizure activity. Synchrony is typically greater between closer pixel pairs during a seizure event; the entire seizure region is synchronized almost exactly in phase. This study represents, to our knowledge, the first application of synchronization analysis methods to mammalian VSD imaging in vivo. Our observations indicate a clear increase in synchronization in this model of focal neocortical seizures across a large area of the neocortex; a sharp increase in synchronization during seizure events was observed in all 37 seizures imaged. The results are consistent with a recent computational study which simulates the effect of 4AP in a neocortical neuron model.

Effects of Maternal Dietary Restriction of Vitamin B-6 on Neocortex Development in Rats

NASA Astrophysics Data System (ADS)

Groziak, Susan Marie

The aim of this investigation was to quantitate the effects of a dietary restriction in Vitamin B-6 during gestation or gestation and lactation on neurogenesis, neuron longevity and neuron differentiation in the neocortex of rats. Sprague Dawley female rats were fed, ad libitum, a Vitamin B-6 free diet (AIN 76) supplemented with 0.0 or 0.6 mg pyridoxine (PN)/kg diet during gestation followed by a control level of 7.0 mg PN/kg diet during lactation, or were fed the Vitamin B-6 free diet supplemented with 0.6 or 7.0 mg PN/kg diet throughout gestation and lactation. The neocortex of progeny of these animals were examined at 30 days of age employing light and electron microscopy. Analyses of neurogenesis, neuron longevity and differentiation of neurons (size of somata, dendritic arborization and spine density in Golgi Cox preparations, and synaptic density in E.M. preparations) were conducted. Each of the Vitamin B-6 restricted treatments adversely affected neurogenesis, neuron longevity and neuron differentiation. The degree of adverse effects paralleled the severity (dose or duration) of the restriction imposed. Expressed as percentage reduction from control values, the findings indicated that neuron longevity and differentiation of neurons in the neocortex were more severely affected than neurogenesis by a maternal dietary restriction in Vitamin B-6.

Development of layer 1 neurons in the mouse neocortex.

PubMed

Ma, Jian; Yao, Xing-Hua; Fu, Yinghui; Yu, Yong-Chun

2014-10-01

Layer 1 of the neocortex harbors a unique group of neurons that play crucial roles in synaptic integration and information processing. Although extensive studies have characterized the properties of layer 1 neurons in the mature neocortex, it remains unclear how these neurons progressively acquire their distinct morphological, neurochemical, and physiological traits. In this study, we systematically examined the dynamic development of Cajal-Retzius cells and γ-aminobutyric acid (GABA)-ergic interneurons in layer 1 during the first 2 postnatal weeks. Cajal-Retzius cells underwent morphological degeneration after birth and gradually disappeared from layer 1. The majority of GABAergic interneurons showed clear expression of at least 1 of the 6 distinct neurochemical markers, including Reelin, GABA-A receptor subunit delta (GABAARδ), neuropeptide Y, vasoactive intestinal peptide (VIP), calretinin, and somatostatin from postnatal day 8. Furthermore, according to firing pattern, layer 1 interneurons can be divided into 2 groups: late-spiking (LS) and burst-spiking (BS) neurons. LS neurons preferentially expressed GABAARδ, whereas BS neurons preferentially expressed VIP. Interestingly, both LS and BS neurons exhibited a rapid electrophysiological and morphological development during the first postnatal week. Our results provide new insights into the molecular, morphological, and functional developments of the neurons in layer 1 of the neocortex. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

On the nature and evolution of the neural bases of human language

NASA Technical Reports Server (NTRS)

Lieberman, Philip

2002-01-01

The traditional theory equating the brain bases of language with Broca's and Wernicke's neocortical areas is wrong. Neural circuits linking activity in anatomically segregated populations of neurons in subcortical structures and the neocortex throughout the human brain regulate complex behaviors such as walking, talking, and comprehending the meaning of sentences. When we hear or read a word, neural structures involved in the perception or real-world associations of the word are activated as well as posterior cortical regions adjacent to Wernicke's area. Many areas of the neocortex and subcortical structures support the cortical-striatal-cortical circuits that confer complex syntactic ability, speech production, and a large vocabulary. However, many of these structures also form part of the neural circuits regulating other aspects of behavior. For example, the basal ganglia, which regulate motor control, are also crucial elements in the circuits that confer human linguistic ability and abstract reasoning. The cerebellum, traditionally associated with motor control, is active in motor learning. The basal ganglia are also key elements in reward-based learning. Data from studies of Broca's aphasia, Parkinson's disease, hypoxia, focal brain damage, and a genetically transmitted brain anomaly (the putative "language gene," family KE), and from comparative studies of the brains and behavior of other species, demonstrate that the basal ganglia sequence the discrete elements that constitute a complete motor act, syntactic process, or thought process. Imaging studies of intact human subjects and electrophysiologic and tracer studies of the brains and behavior of other species confirm these findings. As Dobzansky put it, "Nothing in biology makes sense except in the light of evolution" (cited in Mayr, 1982). That applies with as much force to the human brain and the neural bases of language as it does to the human foot or jaw. The converse follows: the mark of evolution on the brains of human beings and other species provides insight into the evolution of the brain bases of human language. The neural substrate that regulated motor control in the common ancestor of apes and humans most likely was modified to enhance cognitive and linguistic ability. Speech communication played a central role in this process. However, the process that ultimately resulted in the human brain may have started when our earliest hominid ancestors began to walk.

BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain

PubMed Central

Teoh, Jia-Jie; Iwano, Tomohiko; Kunii, Masataka; Atik, Nur; Avriyanti, Erda; Yoshimura, Shin-ichiro; Moriwaki, Kenta

2017-01-01

BIG1, an activator protein of the small GTPase, Arf, and encoded by the Arfgef1 gene, is one of candidate genes for epileptic encephalopathy. To know the involvement of BIG1 in epileptic encephalopathy, we analyzed BIG1-deficient mice and found that BIG1 regulates neurite outgrowth and brain development in vitro and in vivo. The loss of BIG1 decreased the size of the neocortex and hippocampus. In BIG1-deficient mice, the neuronal progenitor cells (NPCs) and the interneurons were unaffected. However, Tbr1+ and Ctip2+ deep layer (DL) neurons showed spatial-temporal dependent apoptosis. This apoptosis gradually progressed from the piriform cortex (PIR), peaked in the neocortex, and then progressed into the hippocampus from embryonic day 13.5 (E13.5) to E17.5. The upper layer (UL) and DL order in the neocortex was maintained in BIG1-deficient mice, but the excitatory neurons tended to accumulate before their destination layers. Further pulse-chase migration assay showed that the migration defect was non-cell autonomous and secondary to the progression of apoptosis into the BIG1-deficient neocortex after E15.5. In BIG1-deficient mice, we observed an ectopic projection of corticothalamic axons from the primary somatosensory cortex (S1) into the dorsal lateral geniculate nucleus (dLGN). The thalamocortical axons were unable to cross the diencephalon–telencephalon boundary (DTB). In vitro, BIG1-deficient neurons showed a delay in neuronal polarization. BIG1-deficient neurons were also hypersensitive to low dose glutamate (5 μM), and died via apoptosis. This study showed the role of BIG1 in the survival of DL neurons in developing embryonic brain and in the generation of neuronal polarity. PMID:28414797

Is the social brain theory applicable to human individual differences? Relationship between sociability personality dimension and brain size.

PubMed

Horváth, Klára; Martos, János; Mihalik, Béla; Bódizs, Róbert

2011-06-17

Our study intends to examine whether the social brain theory is applicable to human individual differences. According to the social brain theory primates have larger brains as it could be expected from their body sizes due to the adaptation to a more complex social life. Regarding humans there were few studies about the relationship between theory of mind and frontal and temporal brain lobes. We hypothesized that these brain lobes, as well as the whole cerebrum and neocortex are in connection with the Sociability personality dimension that is associated with individuals' social lives. Our findings support this hypothesis as Sociability correlated positively with the examined brain structures if we control the effects of body size differences and age. These results suggest that the social brain theory can be extended to human interindividual differences and they have some implications to personality psychology too.

Dunbar's number: group size and brain physiology in humans reexamined.

PubMed

de Ruiter, Jan; Weston, Gavin; Lyon, Stephen M

2011-01-01

Popular academic ideas linking physiological adaptations to social behaviors are spreading disconcertingly into wider societal contexts. In this article, we note our skepticism with one particularly popular—in our view, problematic—supposed causal correlation between neocortex size and social group size. The resulting Dunbar's Number, as it has come to be called, has been statistically tested against observed group size in different primate species. Although there may be reason to doubt the Dunbar's Number hypothesis among nonhuman primate species, we restrict ourselves here to the application of such an explanatory hypothesis to human, culture-manipulating populations. Human information process management, we argue, cannot be understood as a simple product of brain physiology. Cross-cultural comparison of not only group size but also relationship-reckoning systems like kinship terminologies suggests that although neocortices are undoubtedly crucial to human behavior, they cannot be given such primacy in explaining complex group composition, formation, or management.

Activity of hippocampal, amygdala, and neocortex during the Rey auditory verbal learning test: an event-related potential study in epileptic patients.

PubMed

Babiloni, Claudio; Vecchio, Fabrizio; Mirabella, Giovanni; Sebastiano, Fabio; Di Gennaro, Giancarlo; Quarato, Pier P; Buffo, Paola; Esposito, Vincenzo; Manfredi, Mario; Cantore, Giampaolo; Eusebi, Fabrizio

2010-08-01

Previous evidence in epileptic subjects has shown that theta (about 4-7Hz) and gamma rhythms (about 40-45Hz) of hippocampus, amygdala, and neocortex were temporally synchronized during the listening of repeated words successfully remembered (Babiloni et al., 2009). Here we re-analyzed those electroencephalographic (EEG) data to test whether a parallel increase in amplitude of late positive event-related potentials takes place. Intracerebral electroencephalographic (EEG) activity had been recorded in five subjects with drug-resistant temporal lobe epilepsy, undergoing pre-surgical evaluation. During the recording of the intracerebral EEG activity, the subjects performed a computerized version of the Rey auditory verbal learning test (RAVLT). They heard the same list of 15 common words for five times. Each time, immediately after the listening of the list, the subjects were required to repeat as many words as they could recall. We found that late positive event-related potentials (ERPs) peaking at about 350ms post-stimulus in amygdala, hippocampus, and occipital-temporal cortex had a higher amplitude during the listening of the repeated words that were subsequently recalled than for those that were not recalled. Late positive ERPs reflect a functional mechanism implemented in a human brain network spanning amygdala, hippocampus, and occipital-temporal cortex which is at the basis of the memorization processes of verbal materials. This ERP component is a promising neuromarker of successful memorization of repeated words in humans. Copyright 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The role of sleep in changing our minds: A psychologist's discussion of papers on memory reactivation and consolidation in sleep

PubMed Central

Cartwright, Rosalind D.

2004-01-01

The group of papers on memory reactivation and consolidation during sleep included in this volume represents cutting edge work in both animals and humans. They support that the two types of sleep serve different necessary functions. The role of slow wave sleep (SWS) is reactivation of the hippocampal-neocortical circuits activated during a waking learning period, while REM sleep is responsible for the consolidation of this new learning into long-term memory. These studies provide further insights into mechanisms involved in brain plasticity. Robeiro has demonstrated the upregulation of an immediate-early gene (IEG zif 268) to waking levels, which occurs only in REM and only in connection with new learning. McNaughton and his group have identified electrical indicators that the hippocampus and neocortex are talking to each other by testing the coactivation of hippocampal sharp wave bursts in SWS and shifts from down to up states of activation in the neocortex. In human studies Smith's group reports work on individual differences such as intelligence and presleep alcohol that affect postsleep performance, and Stickgold and collaborators report that a short nap will improve performance if it contains REM sleep. Payne and Nadel suggest that the recall benefit associated with REM sleep may be due to its association with increased cortisol levels. These papers are important not only in their individual contributions but also in revitalizing the work coordinating waking and sleep. This promises to further the understanding of how our unique capacity to learn from experience and modify our behavior takes place. PMID:15576882

Localization of mRNA for CHRNA7 in human fetal brain.

PubMed

Agulhon, C; Abitbol, M; Bertrand, D; Malafosse, A

1999-08-02

The aim of this study was to determine the regional distribution in situ of the mRNA for the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor in human fetal brain. We found high levels of alpha 7 gene expression in nuclei that receive sensory information, such as those of the neocortex and hippocampus, the thalamic nuclei, the reticular thalamic nucleus, the pontine nuclei and the superior olive complex. These data support a possible regulatory function for alpha 7-containing receptors in sensory processing, which may be involved in the pathological physiology of schizophrenia and autism. Early alpha 7 gene expression is also consistent with a morphogenetic role for alpha 7 receptors in central nervous system development.

Divergent lactate dehydrogenase isoenzyme profile in cellular compartments of primate forebrain structures.

PubMed

Duka, Tetyana; Collins, Zachary; Anderson, Sarah M; Raghanti, Mary Ann; Ely, John J; Hof, Patrick R; Wildman, Derek E; Goodman, Morris; Grossman, Lawrence I; Sherwood, Chet C

2017-07-01

The compartmentalization and association of lactate dehydrogenase (LDH) with specific cellular structures (e.g., synaptosomal, sarcoplasmic or mitochondrial) may play an important role in brain energy metabolism. Our previous research revealed that LDH in the synaptosomal fraction shifts toward the aerobic isoforms (LDH-B) among the large-brained haplorhine primates compared to strepsirrhines. Here, we further analyzed the subcellular localization of LDH in primate forebrain structures using quantitative Western blotting and ELISA. We show that, in cytosolic and mitochondrial subfractions, LDH-B expression level was relatively elevated and LDH-A declined in haplorhines compared to strepsirrhines. LDH-B expression in mitochondrial fractions of the neocortex was preferentially increased, showing a particularly significant rise in the ratio of LDH-B to LDH-A in chimpanzees and humans. We also found a significant correlation between the protein levels of LDH-B in mitochondrial fractions from haplorhine neocortex and the synaptosomal LDH-B that suggests LDH isoforms shift from a predominance of A-subunits toward B-subunits as part of a system that spatially buffers dynamic energy requirements of brain cells. Our results indicate that there is differential subcellular compartmentalization of LDH isoenzymes that evolved among different primate lineages to meet the energy requirements in neocortical and striatal cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

PubMed

Uchida, Sae; Kagitani, Fusako

2017-05-12

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Towards cortex sized artificial neural systems.

PubMed

Johansson, Christopher; Lansner, Anders

2007-01-01

We propose, implement, and discuss an abstract model of the mammalian neocortex. This model is instantiated with a sparse recurrently connected neural network that has spiking leaky integrator units and continuous Hebbian learning. First we study the structure, modularization, and size of neocortex, and then we describe a generic computational model of the cortical circuitry. A characterizing feature of the model is that it is based on the modularization of neocortex into hypercolumns and minicolumns. Both a floating- and fixed-point arithmetic implementation of the model are presented along with simulation results. We conclude that an implementation on a cluster computer is not communication but computation bounded. A mouse and rat cortex sized version of our model executes in 44% and 23% of real-time respectively. Further, an instance of the model with 1.6 x 10(6) units and 2 x 10(11) connections performed noise reduction and pattern completion. These implementations represent the current frontier of large-scale abstract neural network simulations in terms of network size and running speed.

Pharmacokinetics and Pharmacodynamics of Oximes in Unanesthetized Pigs

DTIC Science & Technology

1991-04-01

D-A234 036 U.S. ARMY MEDICAL RESEARCH p INSTITUTE OF CHEMICAL DEFENSE USAMRICD-TR-91-07 PHARMACOKINETICS AND PHARMACODYNAMICS OF OXIMES IN...SUBJECT TERMS (Continue on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP 2-PAM Cl, ICD 467, MMB-4, Pharmacokinetics ...Cardiovascular 06 15 Pharmacodynamics, Oximes06 15 19. ABSTRACT (Continue on reverse if necessary and identify by block number) The pharmacokinetics and

Respiratory Plasticity Following Spinal Injury: Role of Chloride-Dependent Inhibitory Neurotransmission

DTIC Science & Technology

2015-10-01

compensation in unanesthetized rats. 15. SUBJECT TERMS Spinal Injury, Treatment , Intermittent hypoxia, rats, spontaneous recovery, induced recovery, rAIH, PKC...After immunofluoresence for KCC1/NKCC2, confocal z-stacks of cholera - toxin back-labeled phrenic motor neurons were made ipsilateral and contralateral...enhanced excitatory neurotransmission) also did not pan out, we suspect that the timing of rAIH treatment in our studies was not optimal. Indeed

CHAMPION: Intelligent Hierarchical Reasoning Agents for Enhanced Decision Support

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hohimer, Ryan E.; Greitzer, Frank L.; Noonan, Christine F.

2011-11-15

We describe the design and development of an advanced reasoning framework employing semantic technologies, organized within a hierarchy of computational reasoning agents that interpret domain specific information. Designed based on an inspirational metaphor of the pattern recognition functions performed by the human neocortex, the CHAMPION reasoning framework represents a new computational modeling approach that derives invariant knowledge representations through memory-prediction belief propagation processes that are driven by formal ontological language specification and semantic technologies. The CHAMPION framework shows promise for enhancing complex decision making in diverse problem domains including cyber security, nonproliferation and energy consumption analysis.

Heterogeneity of D-Serine Distribution in the Human Central Nervous System

PubMed Central

Suzuki, Masataka; Imanishi, Nobuaki; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu; Sasabe, Jumpei

2017-01-01

D-serine is an endogenous ligand for N-methyl-D-aspartate glutamate receptors. Accumulating evidence including genetic associations of D-serine metabolism with neurological or psychiatric diseases suggest that D-serine is crucial in human neurophysiology. However, distribution and regulation of D-serine in humans are not well understood. Here, we found that D-serine is heterogeneously distributed in the human central nervous system (CNS). The cerebrum contains the highest level of D-serine among the areas in the CNS. There is heterogeneity in its distribution in the cerebrum and even within the cerebral neocortex. The neocortical heterogeneity is associated with Brodmann or functional areas but is unrelated to basic patterns of cortical layer structure or regional expressional variation of metabolic enzymes for D-serine. Such D-serine distribution may reflect functional diversity of glutamatergic neurons in the human CNS, which may serve as a basis for clinical and pharmacological studies on D-serine modulation. PMID:28604057

Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ho, Gideon; Zhang Chunyan; Zhuo Lang

2007-05-15

Gliosis is a universal response of Brain to almost all types of neural insults, including neurotoxicity, neurodegeneration, viral infection, and stroke. A hallmark of gliotic reaction is the up-regulation of the astrocytic biomarker GFAP (glial fibrillary acidic protein), which often precedes the anatomically apparent damages in Brain. In this study, neonatal transgenic mice at postnatal day (PD) 4 expressing GFP (green fluorescent protein) under the control of a widely used 2.2-kb human GFAP promoter in Brain are treated with two model neurotoxicants, 1-methyl-4(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH{sub 3}-MPTP), and kainic acid (KA), respectively, to induce gliosis. Here we show that the neurotoxicant-induced acutemore » gliosis can be non-invasively imaged and quantified in Brain of conscious (un-anesthetized) mice in real-time, at 0, 2, 4, 6, and 8 h post-toxicant dosing. Therefore the current methodology could be a useful tool for studying the developmental aspects of neuropathies and neurotoxicity.« less

Respiratory-related activity in hypoglossal neurons across sleep-waking states in cats.

PubMed

Richard, C A; Harper, R M

1991-02-22

Activity of behaviorally identified neurons in the hypoglossal nuclei supplying the genioglossal muscles was assessed in intact, unanesthetized cats across sleep-wake states. Nineteen of 37 recorded cells discharged on a breath-by-breath or tonic basis with the respiratory cycle in at least one state. Most respiratory-related cells discharged more slowly during quiet sleep, whereas rates during rapid eye movement sleep were similar to those of waking.

Effect on tricaine methanesulfonate (MS-222) on hematocrit values in rainbow trout (Salmo gairdneri)

USGS Publications Warehouse

Reinitz, G.L.; Rix, J.

1977-01-01

1. Anesthesia of rainbow trout (Salmo gairdneri) with 70 ppm tricaine methanesulfonate (MS-222) for 3-9 min resulted in a linear increase in hematocrit.2. Handling of unanesthetized trout caused a higher and more variable hematocrit reading than did exposure to MS-222 for up to 3 min.3. The range and standard error of hematocrit readings was smallest in trout treated with MS-222 for 1 min.

Defective neuronal migration and inhibition of bipolar to multipolar transition of migrating neural cells by Mesoderm-Specific Transcript, Mest, in the developing mouse neocortex.

PubMed

Ji, Liting; Bishayee, Kausik; Sadra, Ali; Choi, Seunghyuk; Choi, Wooyul; Moon, Sungho; Jho, Eek-Hoon; Huh, Sung-Oh

2017-07-04

Brain developmental disorders such as lissencephaly can result from faulty neuronal migration and differentiation during the formation of the mammalian neocortex. The cerebral cortex is a modular structure, where developmentally, newborn neurons are generated as a neuro-epithelial sheet and subsequently differentiate, migrate and organize into their final positions in the cerebral cortical plate via a process involving both tangential and radial migration. The specific role of Mest, an imprinted gene, in neuronal migration has not been previously studied. In this work, we reduced expression of Mest with in utero electroporation of neuronal progenitors in the developing embryonic mouse neocortex. Reduction of Mest levels by shRNA significantly reduced the number of neurons migrating to the cortical plate. Also, Mest-knockdown disrupted the transition of bipolar neurons into multipolar neurons migrating out of the sub-ventricular zone region. The migrating neurons also adopted a more tangential migration pattern upon knockdown of the Mest message, losing their potential to attach to radial glia cells, required for radial migration. The differentiation and migration properties of neurons via Wnt-Akt signaling were affected by Mest changes. In addition, miR-335, encoded in a Mest gene intron, was identified as being responsible for blocking the default tangential migration of the neurons. Our results suggest that Mest and its intron product, miR-335, play important roles in neuronal migration with Mest regulating the morphological transition of primary neurons required in the formation of the mammalian neocortex. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Effect of aging and Alzheimer's disease-like pathology on brain monoamines in mice.

PubMed

Von Linstow, C U; Severino, M; Metaxas, A; Waider, J; Babcock, A A; Lesch, K P; Gramsbergen, J B; Finsen, B

2017-09-01

Aging is the greatest single risk factor of the neurodegenerative disorder Alzheimer's disease (AD). The monoaminergic system, including serotonin (5-HT), dopamine (DA) and noradrenaline (NA) modulates cognition, which is affected in AD. Changes in monoamine levels have been observed in AD, but these can both be age- and/or disease-related. We examined whether brain monoamine levels change as part of physiological aging and/or AD-like disease in APP SWE /PS1 ΔE9 (APP/PS1) transgenic mice. The neocortex, hippocampus, striatum, brainstem and cerebellum of 6-, 12-, 18- and 24-month-old B6C3 wild-type (WT) mice and of 18-month old APP/PS1 and WT mice were analysed for 5-HT, DA and NA contents by high pressure liquid chromatography (HPLC), along with neocortex from 14-month-old APP/PS1 and WT mice. While, we observed no aging effect in WT mice, we detected region-specific changes in the levels of all monoamines in 18-month-old transgenic compared with WT mice. This included reductions in 5-HT (-30%), DA (-47%) and NA (-32%) levels in the neocortex and increases of 5-HT in the brainstem (+18%). No changes were observed in any of the monoamines in the neocortex from 14-month-old APP/PS1 mice. In combination, these findings indicate that aging alone is not sufficient to affect brain monoamine levels, unlike the APP SWE /PS1 ΔE9 genotype. Copyright © 2017 Elsevier Ltd. All rights reserved.

Corpora amylacea in the neocortex in patients with temporal lobe epilepsy and focal cortical dysplasia.

PubMed

Estupiñán-Díaz, B O; Morales-Chacón, L M; García-Maeso, I; Lorigados-Pedre, L; Báez-Martín, M; García-Navarro, M E; Trápaga-Quincoses, O; Quintanal-Cordero, N; Prince-López, J; Bender-del Busto, J E

2015-03-01

Corpora amylacea (CoA) are present in about 60% of atrophic hippocampi resected from patients with drug resistant temporal lobe epilepsy (DRTLE). They have also been described in the lateral temporal neocortex, although less frequently. The objective is to measure the presence, distribution and density of CoA in the lateral temporal lobes of patients with DRTLE and focal cortical dysplasia (FCD), also examining how CoA density may be linked to demographic and clinical traits. Resected tissue from 35 patients was analysed. CoA density was assessed with a semi-quantitative scale according to the criteria established by Cherian et al. Presence of CoA in the neocortex of 9 patients was associated with hippocampal sclerosis (FCD type iiia, 7 cases), disembryoplastic neuroepithelial tumour (FCD type iiib, 1 case), and cavernous angioma (FCD type iiic, 1 case). The meningeal surface (MS) was involved in all cases, and 8 cases displayed CoA in the cerebral parenchyma (white matter) and around blood vessels. CoA density on the MS showed a negative correlation with age at seizure onset (r = -0.828, P<.05) and a positive correlation with disease duration (r = 0.678, P<.05) but not with postoperative clinical outcome. Patients with DRTLE and a primary lesion (hippocampal sclerosis, tumour, vascular malformation) associated with mild FCD were shown to have CoA deposits in the neocortex. No association was found between presence of CoA and clinical outcome one year after surgery. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Face Encoding and Recognition in the Human Brain

NASA Astrophysics Data System (ADS)

Haxby, James V.; Ungerleider, Leslie G.; Horwitz, Barry; Maisog, Jose Ma.; Rapoport, Stanley I.; Grady, Cheryl L.

1996-01-01

A dissociation between human neural systems that participate in the encoding and later recognition of new memories for faces was demonstrated by measuring memory task-related changes in regional cerebral blood flow with positron emission tomography. There was almost no overlap between the brain structures associated with these memory functions. A region in the right hippocampus and adjacent cortex was activated during memory encoding but not during recognition. The most striking finding in neocortex was the lateralization of prefrontal participation. Encoding activated left prefrontal cortex, whereas recognition activated right prefrontal cortex. These results indicate that the hippocampus and adjacent cortex participate in memory function primarily at the time of new memory encoding. Moreover, face recognition is not mediated simply by recapitulation of operations performed at the time of encoding but, rather, involves anatomically dissociable operations.

Genetic and epigenetic contributions to the cortical phenotype in mammals☆

PubMed Central

Larsen, DeLaine D.; Krubitzer, Leah

2008-01-01

One aspect of cortical organization, cortical field size, is variable both within and across species. The observed variability arises from a variety of sources, including genes intrinsic to the neocortex and a number of extrinsic and epigenetic factors. Genes intrinsic to the cortex are directly involved in the development and specification of cortical fields and are regulated from both signaling centers located outside of the neocortex, which secrete diffusible molecules, and the expression of transcription factors within the neocortex. In addition, extrinsic factors such as the type, location and density of sensory receptor arrays and how these receptor arrays are utilized, are also strongly related to cortical field size. Epigenetic factors including the relative activity patterns generated by the different types of physical stimuli in a given environment also contribute to differences in cortical organization, including cortical field size. Since both genetic and epigenetic factors contribute to cortical organization, some aspects of the cortical phenotype evolve, while other aspects of the cortical phenotype persist only if the environment in which an individual develops is relatively stable. PMID:18331904

Memory Consolidation

PubMed Central

Squire, Larry R.; Genzel, Lisa; Wixted, John T.; Morris, Richard G.

2015-01-01

Conscious memory for a new experience is initially dependent on information stored in both the hippocampus and neocortex. Systems consolidation is the process by which the hippocampus guides the reorganization of the information stored in the neocortex such that it eventually becomes independent of the hippocampus. Early evidence for systems consolidation was provided by studies of retrograde amnesia, which found that damage to the hippocampus-impaired memories formed in the recent past, but typically spared memories formed in the more remote past. Systems consolidation has been found to occur for both episodic and semantic memories and for both spatial and nonspatial memories, although empirical inconsistencies and theoretical disagreements remain about these issues. Recent work has begun to characterize the neural mechanisms that underlie the dialogue between the hippocampus and neocortex (e.g., “neural replay,” which occurs during sharp wave ripple activity). New work has also identified variables, such as the amount of preexisting knowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools (e.g., optogenetics) can be expected to further improve understanding of the neural mechanisms underlying consolidation. PMID:26238360

Mu-opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy.

PubMed

Frost, J J; Mayberg, H S; Fisher, R S; Douglass, K H; Dannals, R F; Links, J M; Wilson, A A; Ravert, H T; Rosenbaum, A E; Snyder, S H

1988-03-01

Neurochemical studies in animal models of epilepsy have demonstrated the importance of multiple neurotransmitters and their receptors in mediating seizures. The role of opiate receptors and endogenous opioid peptides in seizure mechanisms is well developed and is the basis for measuring opiate receptors in patients with epilepsy. Patients with complex partial seizures due to unilateral temporal seizure foci were studied by positron emission tomography using 11C-carfentanil to measure mu-opiate receptors and 18F-fluoro-deoxy-D-glucose to measure glucose utilization. Opiate receptor binding is greater in the temporal neocortex on the side of the electrical focus than on the opposite side. Modeling studies indicate that the increase in binding is due to an increase in affinity or the number of unoccupied receptors. No significant asymmetry of 11C-carfentanil binding was detected in the amygdala or hippocampus. Glucose utilization correlated inversely with 11C-carfentanil binding in the temporal neocortex. Increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.

Degenerative changes and cell death in long-living homo- and heterotopic transplants from embryonic germ layers of rat neocortex.

PubMed

Petrova, E S; Otellin, V A

2003-09-01

Morphological study of allotransplants of rat embryonic neocortex 14-18 months after transplantation into the neocortex, lateral cerebral ventricle, and sciatic nerve of adult animals revealed death of nerve and glial cells in the delayed postoperation period independently on the site of transplantation. After heterotopic transplantation the count of degenerated neurons was 2 times higher that after homotopic transplantation. In heterotopic transplants a considerable number of grafted neurons underwent reversible and irreversible degenerative changes accompanied by their premature aging. Neuronal death is probably determined by insufficiency of trophic influence from afferent structures and target tissues. We hypothesized that antiapoptotic preparations can be used for prevention of transplanted cell death. It was also found that degeneration of neurons was associated with impaired vascularization of transplants and pronounced immune reaction of the recipient in late posttransplantation period. Transplantation of embryonic brain structures can serve as a model system in studies concerning involutive and pathological processes in the central nervous system and in the search for factors improving survival of neurons.

The evolution of neocortex in primates

PubMed Central

Kaas, Jon H.

2013-01-01

We can learn about the evolution of neocortex in primates through comparative studies of cortical organization in primates and those mammals that are the closest living relatives of primates, in conjunction with brain features revealed by the skull endocasts of fossil archaic primates. Such studies suggest that early primates had acquired a number of features of neocortex that now distinguish modern primates. Most notably, early primates had an array of new visual areas, and those visual areas widely shared with other mammals had been modified. Posterior parietal cortex was greatly expanded with sensorimotor modules for reaching, grasping, and personal defense. Motor cortex had become more specialized for hand use, and the functions of primary motor cortex were enhanced by the addition and development of premotor and cingulate motor areas. Cortical architecture became more varied, and cortical neuron populations became denser overall than in nonprimate ancestors. Primary visual cortex had the densest population of neurons, and this became more pronounced in the anthropoid radiation. Within the primate clade, considerable variability in cortical size, numbers of areas, and architecture evolved. PMID:22230624

The evolution of neocortex in primates.

PubMed

Kaas, Jon H

2012-01-01

We can learn about the evolution of neocortex in primates through comparative studies of cortical organization in primates and those mammals that are the closest living relatives of primates, in conjunction with brain features revealed by the skull endocasts of fossil archaic primates. Such studies suggest that early primates had acquired a number of features of neocortex that now distinguish modern primates. Most notably, early primates had an array of new visual areas, and those visual areas widely shared with other mammals had been modified. Posterior parietal cortex was greatly expanded with sensorimotor modules for reaching, grasping, and personal defense. Motor cortex had become more specialized for hand use, and the functions of primary motor cortex were enhanced by the addition and development of premotor and cingulate motor areas. Cortical architecture became more varied, and cortical neuron populations became denser overall than in nonprimate ancestors. Primary visual cortex had the densest population of neurons, and this became more pronounced in the anthropoid radiation. Within the primate clade, considerable variability in cortical size, numbers of areas, and architecture evolved. Copyright © 2012 Elsevier B.V. All rights reserved.

Histological evidence for drug diffusion across the cerebral meninges into the underlying neocortex in rats.

PubMed

Ludvig, Nandor; Sheffield, Lynette G; Tang, Hai M; Baptiste, Shirn L; Devinsky, Orrin; Kuzniecky, Ruben I

2008-01-10

Transmeningeal pharmacotherapy has been proposed to treat neurological disorders with localized pathology, such as intractable focal epilepsy. As a step toward understanding the diffusion and intracortical spread of transmeningeally delivered drugs, the present study used histological methods to determine the extent to which a marker compound, N-methyl-D-aspartate (NMDA), can diffuse into the neocortex through the meninges. Rats were implanted with bilateral parietal cortical epidural cups filled with 50 mM NMDA on the right side and artificial cerebrospinal fluid (ACSF) in the contralateral side. After 24 h, the histological effects of these treatments were evaluated using cresyl violet (Nissl) staining. The epidural NMDA exposure caused neuronal loss that in most animals extended from the pial surface through layer V. The area indicated by this neuronal loss was localized to the neocortical region underlying the epidural cup. These results suggest that NMDA-like, water soluble, small molecules can diffuse through the subdural/subarachnoid space into the underlying neocortex and spread in a limited fashion, close to the meningeal penetration site.

Mapping arealisation of the visual cortex of non-primate species: lessons for development and evolution

PubMed Central

Homman-Ludiye, Jihane; Bourne, James A.

2014-01-01

The integration of the visual stimulus takes place at the level of the neocortex, organized in anatomically distinct and functionally unique areas. Primates, including humans, are heavily dependent on vision, with approximately 50% of their neocortical surface dedicated to visual processing and possess many more visual areas than any other mammal, making them the model of choice to study visual cortical arealisation. However, in order to identify the mechanisms responsible for patterning the developing neocortex, specifying area identity as well as elucidate events that have enabled the evolution of the complex primate visual cortex, it is essential to gain access to the cortical maps of alternative species. To this end, species including the mouse have driven the identification of cellular markers, which possess an area-specific expression profile, the development of new tools to label connections and technological advance in imaging techniques enabling monitoring of cortical activity in a behaving animal. In this review we present non-primate species that have contributed to elucidating the evolution and development of the visual cortex. We describe the current understanding of the mechanisms supporting the establishment of areal borders during development, mainly gained in the mouse thanks to the availability of genetically modified lines but also the limitations of the mouse model and the need for alternate species. PMID:25071460

Unravelling Boléro: progressive aphasia, transmodal creativity and the right posterior neocortex.

PubMed

Seeley, William W; Matthews, Brandy R; Crawford, Richard K; Gorno-Tempini, Maria Luisa; Foti, Dean; Mackenzie, Ian R; Miller, Bruce L

2008-01-01

Most neurological lesion studies emphasize performance deficits that result from focal brain injury. Here, we describe striking gains of function in a patient with primary progressive aphasia, a degenerative disease of the human language network. During the decade before her language deficits arose, Anne Adams (AA), a lifelong scientist, developed an intense drive to produce visual art. Paintings from AA's artistic peak revealed her capacity to create expressive transmodal art, such as renderings of music in paint, which may have reflected an increased subjective relatedness among internal perceptual and conceptual images. AA became fascinated with Maurice Ravel, the French composer who also suffered from a progressive aphasia, and painted his best-known work, 'Boléro', by translating its musical elements into visual form. Later paintings, achieved when AA was nearly mute, moved towards increasing photographic realism, perhaps because visual representations came to dominate AA's mental landscape during this phase of her illness. Neuroimaging analyses revealed that, despite severe degeneration of left inferior frontal-insular, temporal and striatal regions, AA showed increased grey matter volume and hyperperfusion in right posterior neocortical areas implicated in heteromodal and polysensory integration. The findings suggest that structural and functional enhancements in non-dominant posterior neocortex may give rise to specific forms of visual creativity that can be liberated by dominant inferior frontal cortex injury.

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

PubMed

Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

2017-11-01

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Theta and Alpha Oscillations Are Traveling Waves in the Human Neocortex.

PubMed

Zhang, Honghui; Watrous, Andrew J; Patel, Ansh; Jacobs, Joshua

2018-06-01

Human cognition requires the coordination of neural activity across widespread brain networks. Here, we describe a new mechanism for large-scale coordination in the human brain: traveling waves of theta and alpha oscillations. Examining direct brain recordings from neurosurgical patients performing a memory task, we found contiguous clusters of cortex in individual patients with oscillations at specific frequencies within 2 to 15 Hz. These oscillatory clusters displayed spatial phase gradients, indicating that they formed traveling waves that propagated at ∼0.25-0.75 m/s. Traveling waves were relevant behaviorally because their propagation correlated with task events and was more consistent when subjects performed the task well. Human traveling theta and alpha waves can be modeled by a network of coupled oscillators because the direction of wave propagation correlated with the spatial orientation of local frequency gradients. Our findings suggest that oscillations support brain connectivity by organizing neural processes across space and time. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparison of Four Skin Decontamination Procedures Using Reactive Skin Decontamination Lotion (RSDL) Following Cutaneous VX Exposure in Guinea Pigs

DTIC Science & Technology

2016-01-01

DC) product following cutaneous exposure to VX was affected by the DC procedure. Fur-clipped, male, unanesthetized guinea pigs were used as subjects...RSDL) Following Cutaneous VX Exposure in Guinea Pigs Irwin Koplovitz Susan Schulz Julia Morgan Robert Reed Edward Clarkson C. Gary Hurst...Decontamination Procedures Using Reactive Skin 5a. CONTRACT NUMBER Decontamination Lotion (RSDL) Following Cutaneous VX Exposure in Guinea Pigs 5b

Hormonal and electrolyte responses to acute isohemic volume expansion in unanesthetized rats

NASA Technical Reports Server (NTRS)

Chenault, V. M.; Morris, M.; Lynch, C. D.; Maultsby, S. J.; Hutchins, P. M.

1993-01-01

This study was undertaken to explore the time course of the metabolic response to isohemic blood volume expansion (30%) in normotensive, unanesthetized Sprague-Dawley rats. Whole blood, drawn from a femoral artery catheter of conscious donor rats, was infused into the jugular vein of recipient rats. Blood samples were drawn from a carotid artery of recipient rats at time points beginning immediately post-volume expansion (IPVE) up through 5 days post-volume expansion (PVE). To characterize the attendant compensatory mechanisms, the plasma concentrations of electrolytes and fluid regulatory hormones were determined. Hematocrit began to raise IPVE and was significantly elevated above control IPVE 20, 30, 40, 60, and 90 min, and 2, 4, 6, 8, 12, and 24 hr PVE. Consistent with our current understanding of the hormonal response to excess volume, atrial natriuretic factor was significantly increased above the prevolume expansion (control) values 0-30 min PVE. Surprisingly, plasma aldosterone levels were significantly increased above control at 20 and 30 min and 6 hr PVE, whereas plasma renin activity was significantly decreased 30-40 min PVE. Plasma sodium was not changed from control values except for a significant increase at 6 hr post-volume expansion. Plasma potassium, osmolality, and arginine vasopressin levels were not altered by the volume expansion. These studies delineate the physiologic time scheme operative in the regulation of fluid volume during acute ischemic volume expansion.

Influence of age, body temperature, GABAA receptor inhibition and caffeine on the Hering-Breuer inflation reflex in unanesthetized rat pups

PubMed Central

Arnal, Ashley V.; Gore, Julie L.; Rudkin, Alison; Bartlett, Donald; Leiter, J.C.

2013-01-01

We measured the duration of apnea induced by sustained end-inspiratory lung inflation (the Hering Breuer Reflex; HBR) in unanesthetized infant rat pups aged 4 days (P4) to P20 at body temperatures of 32°C and 36°C. The expiratory prolongation elicited by the HBR lasted longer in the younger pups and lasted longer at the higher body temperature. Blockade of adenosine receptors by caffeine following injection into the cisterna magna (ICM) significantly blunted the thermal prolongation of the HBR. Blockade of gama-amino-butyric acid A (GABAA) receptors by pre-treatment with ICM bicuculline had no effect on the HBR duration at either body temperature. To test the hypothesis that developmental maturation of GABAergic inhibition of breathing was modifying the response to bicuculline, we pretreated rat pups with systemically administered bumetanide to lower the intracellular chloride concentration, and repeated the bicuculline studies. Bicuculline still did not alter the HBR at either temperature after bumetanide treatment. We administered PSB-36, a selective adenosine A1 receptor antagonist, and this drug treatment did not modify the HBR. We conclude that caffeine blunts the thermal prolongation of the HBR, probably by blocking adenosine A2a receptors. The thermally-sensitive adenosinergic prolongation of the HBR in these intact animals does not seem to depend on GABAA receptors PMID:23318703

The hippocampus and related neocortical structures in memory transformation.

PubMed

Sekeres, Melanie J; Winocur, Gordon; Moscovitch, Morris

2018-05-04

Episodic memories are multifaceted and malleable, capable of being transformed with time and experience at both the neural level and psychological level. At the neural level, episodic memories are transformed from being dependent on the hippocampus to becoming represented in neocortical structures, such as the medial prefrontal cortex (mPFC), and back again, while at the psychological level, detailed, perceptually rich memories, are transformed to ones retaining only the gist of an experience or a schema related to it. Trace Transformation Theory (TTT) initially proposed that neural and psychological transformations are linked and proceed in tandem. Building on recent studies on the neurobiology of memory transformation in rodents and on the organization of the hippocampus and its functional cortical connectivity in humans, we present an updated version of TTT that is more precise and detailed with respect to the dynamic processes and structures implicated in memory transformation. At the heart of the updated TTT lies the long axis of the hippocampus whose functional differentiation and connectivity to neocortex make it a hub for memory formation and transformation. The posterior hippocampus, connected to perceptual and spatial representational systems in posterior neocortex, supports fine, perceptually rich, local details of memories; the anterior hippocampus, connected to conceptual systems in anterior neocortex, supports coarse, global representations that constitute the gist of a memory. Notable among the anterior structures is the medial prefrontal cortex which supports representation of schemas that code for common aspects of memories across different episodes. Linking the aHPC with mPFC is the entorhinal cortex (EC) which conveys information needed for the interaction/translation between gist and schemas. Thus, the long axis of the hippocampus, mPFC and EC provide the representational gradient, from fine to coarse and from perceptual to conceptual, that can implement processes implicated in memory transformation. Each of these representations of an episodic memory can co-exist with one another and be in dynamic flux as they interact with one another throughout the memory's lifetime, going from detailed to schematic and possibly back again, all mediated by corresponding changes in neural representation. Copyright © 2018 Elsevier B.V. All rights reserved.

Very low concentrations of ethanol suppress excitatory synaptic transmission in rat visual cortex.

PubMed

Luong, Lucas; Bannon, Nicholas M; Redenti, Andrew; Chistiakova, Marina; Volgushev, Maxim

2017-05-01

Ethanol is one of the most commonly used substances in the world. Behavioral effects of alcohol are well described, however, cellular mechanisms of its action are poorly understood. There is an apparent contradiction between measurable behavioral changes produced by low concentrations of ethanol, and lack of evidence of synaptic changes at these concentrations. Furthermore, effects of ethanol on synaptic transmission in the neocortex are poorly understood. Here, we set to determine effects of ethanol on excitatory synaptic transmission in the neocortex. We show that 1-50 mm ethanol suppresses excitatory synaptic transmission to layer 2/3 pyramidal neurons in rat visual cortex in a concentration-dependent manner. To the best of our knowledge, this is the first demonstration of the effects of very low concentrations of ethanol (from 1 mm) on synaptic transmission in the neocortex. We further show that a selective antagonist of A 1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), blocks effects of 1-10 mm ethanol on synaptic transmission. However, the reduction in excitatory postsynaptic potential amplitude by 50 mm ethanol was not affected by DPCPX. We propose that ethanol depresses excitatory synaptic transmission in the neocortex by at least two mechanisms, engaged at different concentrations: low concentrations of ethanol reduce synaptic transmission via A 1 R-dependent mechanism and involve presynaptic changes, while higher concentrations activate additional, adenosine-independent mechanisms with predominantly postsynaptic action. Involvement of adenosine signaling in mediating effects of low concentrations of ethanol may have important implications for understanding alcohol's effects on brain function, and provide a mechanistic explanation to the interaction between alcohol and caffeine. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction.

PubMed

Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz; Crews, Fulton T

2016-07-01

Adolescence is characterized by considerable brain maturation that coincides with the development of adult behavior. Binge drinking is common during adolescence and can have deleterious effects on brain maturation because of the heightened neuroplasticity of the adolescent brain. Using an animal model of adolescent intermittent ethanol [AIE; 5.0 g/kg, intragastric, 20 percent EtOH w/v; 2 days on/2 days off from postnatal day (P)25 to P55], we assessed the adult brain structural volumes and integrity on P80 and P220 using diffusion tensor imaging (DTI). While we did not observe a long-term effect of AIE on structural volumes, AIE did reduce axial diffusivity (AD) in the cerebellum, hippocampus and neocortex. Radial diffusivity (RD) was reduced in the hippocampus and neocortex of AIE-treated animals. Prior AIE treatment did not affect fractional anisotropy (FA), but did lead to long-term reductions of mean diffusivity (MD) in both the cerebellum and corpus callosum. AIE resulted in increased anxiety-like behavior and diminished object recognition memory, the latter of which was positively correlated with DTI measures. Across aging, whole brain volumes increased, as did volumes of the corpus callosum and neocortex. This was accompanied by age-associated AD reductions in the cerebellum and neocortex as well as RD and MD reductions in the cerebellum. Further, we found that FA increased in both the cerebellum and corpus callosum as rats aged from P80 to P220. Thus, both age and AIE treatment caused long-term changes to brain structural integrity that could contribute to cognitive dysfunction. © 2015 Society for the Study of Addiction.

Transiently increased colocalization of vesicular glutamate transporters 1 and 2 at single axon terminals during postnatal development of mouse neocortex: a quantitative analysis with correlation coefficient.

PubMed

Nakamura, Kouichi; Watakabe, Akiya; Hioki, Hiroyuki; Fujiyama, Fumino; Tanaka, Yasuyo; Yamamori, Tetsuo; Kaneko, Takeshi

2007-12-01

Vesicular glutamate transporter 1 (VGLUT1) and VGLUT2 show complementary distribution in neocortex; VGLUT1 is expressed mainly in axon terminals of neocortical neurons, whereas VGLUT2 is located chiefly in thalamocortical axon terminals. However, we recently reported a frequent colocalization of VGLUT1 and VGLUT2 at a subset of axon terminals in postnatal developing neocortex. We here quantified the frequency of colocalization between VGLUT1 and VGLUT2 immunoreactivities at single axon terminals by using the correlation coefficient (CC) as an indicator in order to determine the time course and spatial extent of the colocalization during postnatal development of mouse neocortex. The colocalization was more frequent in the primary somatosensory (S1) area than in both the primary visual (V1) and the motor areas; of area S1 cortical layers, colocalization was most evident in layer IV barrels at postnatal day (P) 7 and in adulthood. CC in layer IV showed a peak at P7 in area S1, and at P10 in area V1 though the latter peak was much smaller than the former. These results suggest that thalamocortical axon terminals contained not only VGLUT2 but also VGLUT1, especially at P7-10. Double fluorescence in situ hybridization confirmed coexpression of VGLUT1 and VGLUT2 mRNAs at P7 in the somatosensory thalamic nuclei and later in the thalamic dorsal lateral geniculate nucleus. As VGLUT1 is often used in axon terminals that show synaptic plasticity in adult brain, the present findings suggest that VGLUT1 is used in thalamocortical axons transiently during the postnatal period when plasticity is required.

A Synaptic Basis for Memory Storage in the Cerebral Cortex

NASA Astrophysics Data System (ADS)

Bear, Mark F.

1996-11-01

A cardinal feature of neurons in the cerebral cortex is stimulus selectivity, and experience-dependent shifts in selectivity are a common correlate of memory formation. We have used a theoretical ``learning rule,'' devised to account for experience-dependent shifts in neuronal selectivity, to guide experiments on the elementary mechanisms of synaptic plasticity in hippocampus and neocortex. These experiments reveal that many synapses in hippocampus and neocortex are bidirectionally modifiable, that the modifications persist long enough to contribute to long-term memory storage, and that key variables governing the sign of synaptic plasticity are the amount of NMDA receptor activation and the recent history of cortical activity.

Alzheimer disease.

PubMed

Calderon-Garcidueñas, Ana Laura; Duyckaerts, Charles

2017-01-01

Alzheimer disease neuropathology is characterized by the extracellular accumulation of Aβ peptide and intracellular aggregation of hyperphosphorylated tau. With the progression of the disease, macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. The locus coeruleus is depigmented. The deposition of Aβ is first made of diffuse deposits. Amyloid focal deposits constitute the core of the senile plaque which also comprises a corona of tau-positive neurites. Aβ deposits are found successively in the neocortex, the hippocampus, the striatum, the mesencephalon, and finally the cerebellum together with the pontine nuclei (Thal phases). Tau pathology affects in a stereotyped order some specific nuclei of the brainstem, the entorhinal area, the hippocampus, and the neocortex - first the associative areas and secondarily the primary cortices (Braak stages). Loss of synapses is observed in association with tau and Aβ pathology; neuronal loss occurs in the most affected areas. Granulovacuolar degeneration and perisomatic granules are also linked to Alzheimer disease pathology. The physiopathology of Alzheimer disease remains unknown. Familial cases suggest that Aβ deposition is the initial step, but tau pathology appears early in the course and seems to be better correlated with the symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

Activation patterns in superficial layers of neocortex change between experiences independent of behavior, environment, or the hippocampus.

PubMed

Takehara-Nishiuchi, Kaori; Insel, Nathan; Hoang, Lan T; Wagner, Zachary; Olson, Kathy; Chawla, Monica K; Burke, Sara N; Barnes, Carol A

2013-09-01

Previous work suggests that activation patterns of neurons in superficial layers of the neocortex are more sensitive to spatial context than activation patterns in deep cortical layers. A possible source of this laminar difference is the distribution of contextual information to the superficial cortical layers carried by hippocampal efferents that travel through the entorhinal cortex and subiculum. To evaluate the role that the hippocampus plays in determining context sensitivity in superficial cortical layers, behavior-induced expression of the immediate early gene Arc was examined in hippocampus-lesioned and control rats after exposing them to 2 distinct contexts. Contrary to expectations, hippocampal lesions had no observable effect on Arc expression in any neocortical layer relative to controls. Furthermore, another group of intact animals was exposed to the same environment twice, to determine the reliability of Arc-expression patterns across identical contextual and behavioral episodes. Although this condition included no difference in external input between 2 epochs, the significant layer differences in Arc expression still remained. Thus, laminar differences in activation or plasticity patterns are not likely to arise from hippocampal sources or differences in external inputs, but are more likely to be an intrinsic property of the neocortex.

Voltage-sensitive dye imaging of mouse neocortex during a whisker detection task

PubMed Central

Kyriakatos, Alexandros; Sadashivaiah, Vijay; Zhang, Yifei; Motta, Alessandro; Auffret, Matthieu; Petersen, Carl C. H.

2016-01-01

Abstract. Sensorimotor processing occurs in a highly distributed manner in the mammalian neocortex. The spatiotemporal dynamics of electrical activity in the dorsal mouse neocortex can be imaged using voltage-sensitive dyes (VSDs) with near-millisecond temporal resolution and ∼100-μm spatial resolution. Here, we trained mice to lick a water reward spout after a 1-ms deflection of the C2 whisker, and we imaged cortical dynamics during task execution with VSD RH1691. Responses to whisker deflection were highly dynamic and spatially highly distributed, exhibiting high variability from trial to trial in amplitude and spatiotemporal dynamics. We differentiated trials based on licking and whisking behavior. Hit trials, in which the mouse licked after the whisker stimulus, were accompanied by overall greater depolarization compared to miss trials, with the strongest hit versus miss differences being found in frontal cortex. Prestimulus whisking decreased behavioral performance by increasing the fraction of miss trials, and these miss trials had attenuated cortical sensorimotor responses. Our data suggest that the spatiotemporal dynamics of depolarization in mouse sensorimotor cortex evoked by a single brief whisker deflection are subject to important behavioral modulation during the execution of a simple, learned, goal-directed sensorimotor transformation. PMID:27921068

Human Genomic Signatures of Brain Oscillations During Memory Encoding.

PubMed

Berto, Stefano; Wang, Guang-Zhong; Germi, James; Lega, Bradley C; Konopka, Genevieve

2018-05-01

Memory encoding is an essential step for all learning. However, the genetic and molecular mechanisms underlying human memory encoding remain poorly understood, and how this molecular framework permits the emergence of specific patterns of brain oscillations observed during mnemonic processing is unknown. Here, we directly compare intracranial electroencephalography recordings from the neocortex in individuals performing an episodic memory task with human gene expression from the same areas. We identify genes correlated with oscillatory memory effects across 6 frequency bands. These genes are enriched for autism-related genes and have preferential expression in neurons, in particular genes encoding synaptic proteins and ion channels, supporting the idea that the genes regulating voltage gradients are involved in the modulation of oscillatory patterns during successful memory encoding across brain areas. Memory-related genes are distinct from those correlated with other forms of cognitive processing and resting state fMRI. These data are the first to identify correlations between gene expression and active human brain states as well as provide a molecular window into memory encoding oscillations in the human brain.

Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis.

PubMed

Fiddes, Ian T; Lodewijk, Gerrald A; Mooring, Meghan; Bosworth, Colleen M; Ewing, Adam D; Mantalas, Gary L; Novak, Adam M; van den Bout, Anouk; Bishara, Alex; Rosenkrantz, Jimi L; Lorig-Roach, Ryan; Field, Andrew R; Haeussler, Maximilian; Russo, Lotte; Bhaduri, Aparna; Nowakowski, Tomasz J; Pollen, Alex A; Dougherty, Max L; Nuttle, Xander; Addor, Marie-Claude; Zwolinski, Simon; Katzman, Sol; Kriegstein, Arnold; Eichler, Evan E; Salama, Sofie R; Jacobs, Frank M J; Haussler, David

2018-05-31

Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Influence of Route and Pattern of Exposure on the Pharmacokinetics and Hepatotoxicity of Carbon Tetrachloride

DTIC Science & Technology

1990-05-30

metabolize the chemical is limited [16]. Also, in high doses, CC14 can cause liver injury and thereby inhibit its own metabolism I23] If ingested CC...to clarify whether the liver is actually at greater risk of injury upon oral exposure to CC!4 . As cumulative uptaL. (Le, the systemically absorbed...the unanesthetized animals by means of an indwelling arterial cannula and analyzed for CC14 by headspace gas chromatography. Blood and liver samples

Human brain somatostatin release from isolated cortical nerve endings and its modulation through GABAB receptors.

PubMed Central

Bonanno, G.; Gemignani, A.; Schmid, G.; Severi, P.; Cavazzani, P.; Raiteri, M.

1996-01-01

1. The release of somatostatin-like immunoreactivity (SRIF-LI) in the human brain was studied in synaptosomal preparations from fresh neocortical specimens obtained from patients undergoing neurosurgery to remove deeply sited tumours. 2. The basal outflow of SRIF-LI from superfused synaptosomes was increased about 3 fold during exposure to a depolarizing medium containing 15 mM KCl. The K(+)-evoked overflow of SRIF-LI was almost totally dependent on the presence of Ca2+ in the superfusion medium. 3. The GABAB receptor agonist, (-)-baclofen (0.3 - 100 microM), inhibited the overflow of SRIF-LI in a concentration-dependent manner (EC50 = 1.84 +/- 0.20 microM; maximal effect: about 50%). The novel GABAB receptor ligand, 3-aminopropyl(difluoromethyl)phosphinic acid (CGP 47656) mimicked (-)-baclofen in inhibiting the SRIF-LI overflow (EC50 = 3.06 +/- 0.52 microM; maximal effect: about 50%), whereas the GABAA receptor agonist, muscimol, was ineffective up to 100 microM. 4. The inhibition by 10 microM (-)-baclofen of the K(+)-evoked SRIF-LI overflow was concentration-dependently prevented by two selective GABAB receptor antagonists, 3-amino-propyl (diethoxymethyl)-phosphinic acid (CGP 35348) (IC50 = 24.40 +/- 2.52 microM) and [3-[[(3,4-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic acid (CGP 52432) (IC50 = 0.06 +/- 0.005 microM). 5. The inhibition of SRIF-LI overflow caused by 10 microM CGP 47656 was abolished by 1 microM CGP 52432. 6. When human synaptosomes were labelled with [3H]-GABA and depolarized in superfusion with 15 mM KCl, the inhibition by 10 microM (-)-baclofen of the depolarization-evoked [3H]-GABA overflow was largely prevented by 10 microM CGP 47656 which therefore behaved as an autoreceptor antagonist. 7. In conclusion: (a) the characteristics of SRIF-LI release from synaptosomal preparations of human neocortex are compatible with a neuronal origin; (b) the nerve terminals releasing the neuropeptide possess inhibitory receptors of the GABAB type; (c) these receptors differ pharmacologically from the GABAB autoreceptors present on human neocortex nerve terminals since the latter have been shown to be CGP 35348-insensitive but can be blocked by CGP 47656. PMID:8832070

Canonical Genetic Signatures of the Adult Human Brain

PubMed Central

Hawrylycz, Michael; Miller, Jeremy A.; Menon, Vilas; Feng, David; Dolbeare, Tim; Guillozet-Bongaarts, Angela L.; Jegga, Anil G.; Aronow, Bruce J.; Lee, Chang-Kyu; Bernard, Amy; Glasser, Matthew F.; Dierker, Donna L.; Menche, Jörge; Szafer, Aaron; Collman, Forrest; Grange, Pascal; Berman, Kenneth A.; Mihalas, Stefan; Yao, Zizhen; Stewart, Lance; Barabási, Albert-László; Schulkin, Jay; Phillips, John; Ng, Lydia; Dang, Chinh; Haynor, David R.; Jones, Allan; Van Essen, David C.; Koch, Christof; Lein, Ed

2015-01-01

The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure, and function. We applied a correlation-based metric of “differential stability” (DS) to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing meso-scale genetic organization. The highest DS genes are highly biologically relevant, with enrichment for brain-related biological annotations, disease associations, drug targets, and literature citations. Using high DS genes we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components, and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely-patterned genes displayed dramatic shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry. PMID:26571460

Neocortical glial cell numbers in human brains.

PubMed

Pelvig, D P; Pakkenberg, H; Stark, A K; Pakkenberg, B

2008-11-01

Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex.

Evolution of Osteocrin as an activity-regulated factor in the primate brain

PubMed Central

Ataman, Bulent; Boulting, Gabriella L.; Harmin, David A.; Yang, Marty G.; Baker-Salisbury, Mollie; Yap, Ee-Lynn; Malik, Athar N.; Mei, Kevin; Rubin, Alex A.; Spiegel, Ivo; Durresi, Ershela; Sharma, Nikhil; Hu, Linda S.; Pletikos, Mihovil; Griffith, Eric C.; Partlow, Jennifer N.; Stevens, Christine R.; Adli, Mazhar; Chahrour, Maria; Sestan, Nenad; Walsh, Christopher A.; Berezovskii, Vladimir K.; Livingstone, Margaret S.; Greenberg, Michael E.

2017-01-01

Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates. PMID:27830782

Functional subregions of the human entorhinal cortex

PubMed Central

Maass, Anne; Berron, David; Libby, Laura A; Ranganath, Charan; Düzel, Emrah

2015-01-01

The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC. DOI: http://dx.doi.org/10.7554/eLife.06426.001 PMID:26052749

Transcriptional architecture of the primate neocortex.

PubMed

Bernard, Amy; Lubbers, Laura S; Tanis, Keith Q; Luo, Rui; Podtelezhnikov, Alexei A; Finney, Eva M; McWhorter, Mollie M E; Serikawa, Kyle; Lemon, Tracy; Morgan, Rebecca; Copeland, Catherine; Smith, Kimberly; Cullen, Vivian; Davis-Turak, Jeremy; Lee, Chang-Kyu; Sunkin, Susan M; Loboda, Andrey P; Levine, David M; Stone, David J; Hawrylycz, Michael J; Roberts, Christopher J; Jones, Allan R; Geschwind, Daniel H; Lein, Ed S

2012-03-22

Genome-wide transcriptional profiling was used to characterize the molecular underpinnings of neocortical organization in rhesus macaque, including cortical areal specialization and laminar cell-type diversity. Microarray analysis of individual cortical layers across sensorimotor and association cortices identified robust and specific molecular signatures for individual cortical layers and areas, prominently involving genes associated with specialized neuronal function. Overall, transcriptome-based relationships were related to spatial proximity, being strongest between neighboring cortical areas and between proximal layers. Primary visual cortex (V1) displayed the most distinctive gene expression compared to other cortical regions in rhesus and human, both in the specialized layer 4 as well as other layers. Laminar patterns were more similar between macaque and human compared to mouse, as was the unique V1 profile that was not observed in mouse. These data provide a unique resource detailing neocortical transcription patterns in a nonhuman primate with great similarity in gene expression to human. Copyright © 2012 Elsevier Inc. All rights reserved.

Attention Drives Synchronization of Alpha and Beta Rhythms between Right Inferior Frontal and Primary Sensory Neocortex

PubMed Central

Sacchet, Matthew D.; LaPlante, Roan A.; Wan, Qian; Pritchett, Dominique L.; Lee, Adrian K.C.; Hämäläinen, Matti; Moore, Christopher I.; Kerr, Catherine E.

2015-01-01

The right inferior frontal cortex (rIFC) is specifically associated with attentional control via the inhibition of behaviorally irrelevant stimuli and motor responses. Similarly, recent evidence has shown that alpha (7–14 Hz) and beta (15–29 Hz) oscillations in primary sensory neocortical areas are enhanced in the representation of non-attended stimuli, leading to the hypothesis that allocation of these rhythms plays an active role in optimal inattention. Here, we tested the hypothesis that selective synchronization between rIFC and primary sensory neocortex occurs in these frequency bands during inattention. We used magnetoencephalography to investigate phase synchrony between primary somatosensory (SI) and rIFC regions during a cued-attention tactile detection task that required suppression of response to uncertain distractor stimuli. Attentional modulation of synchrony between SI and rIFC was found in both the alpha and beta frequency bands. This synchrony manifested as an increase in the alpha-band early after cue between non-attended SI representations and rIFC, and as a subsequent increase in beta-band synchrony closer to stimulus processing. Differences in phase synchrony were not found in several proximal control regions. These results are the first to reveal distinct interactions between primary sensory cortex and rIFC in humans and suggest that synchrony between rIFC and primary sensory representations plays a role in the inhibition of irrelevant sensory stimuli and motor responses. PMID:25653364

Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain

PubMed Central

Pilaz, Louis-Jan; Silver, Debra L.

2015-01-01

The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. During corticogenesis, neural stem cells generate distinct populations of progenitors and excitatory neurons. These new neurons migrate radially in the cortex, eventually forming neuronal layers and establishing synaptic connections with other neurons both within and outside the cortex. Perturbations to corticogenesis can result in severe neurodevelopmental disorders, thus emphasizing the need to better understand molecular regulation of brain development. Recent studies in both model organisms and humans have collectively highlighted roles for post-transcriptional regulation in virtually all steps of corticogenesis. Genomic approaches have revealed global RNA changes associated with spatial and temporal regulation of cortical development. Additionally, genetic studies have uncovered RNA-binding proteins (RBPs) critical for cell proliferation, differentiation, and migration within the developing neocortex. Many of these same RBPs play causal roles in neurodevelopmental pathologies. In the developing neocortex, RBPs influence diverse steps of mRNA metabolism, including splicing, stability, translation, and localization. With the advent of new technologies, researchers have begun to uncover key transcripts regulated by these RBPs. Given the complexity of the developing mammalian cortex, a major challenge for the future will be to understand how dynamic RNA regulation occurs within heterogeneous cell populations, across space and time. In sum, post-transcriptional regulation has emerged as a critical mechanism for driving corticogenesis and exciting direction of future research. PMID:26088328

Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

PubMed

Buzhdygan, Tetyana; Lisinicchia, Joshua; Patel, Vipulkumar; Johnson, Kenneth; Neugebauer, Volker; Paessler, Slobodan; Jennings, Kristofer; Gelman, Benjamin

2016-06-01

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients.

Cardiovascular responses to microinjection of L-glutamate into the NTS in AV3V-lesioned rats.

PubMed

Vieira, Alexandre Antonio; Colombari, Eduardo; De Luca, Laurival A; de Almeida Colombari, Débora Simões; Menani, José V

2004-10-29

The excitatory amino acid L-glutamate injected into the nucleus of the solitary tract (NTS) in unanesthetized rats similar to peripheral chemoreceptor activation increases mean arterial pressure (MAP) and reduces heart rate. In this study, we investigated the effects of acute (1 day) and chronic (15 days) electrolytic lesions of the preoptic-periventricular tissue surrounding the anteroventral third ventricle (AV3V region) on the pressor and bradycardic responses induced by injections of L-glutamate into the NTS or peripheral chemoreceptor activation in unanesthetized rats. Male Holtzman rats with sham or electrolytic AV3V lesions and a stainless steel cannula implanted into the NTS were used. Differently from the pressor responses (28+/-3 mm Hg) produced by injections into the NTS of sham-lesioned rats, L-glutamate (5 nmol/100 nl) injected into the NTS reduced MAP (-26+/-8 mm Hg) or produced no effect (2+/-7 mm Hg) in acute and chronic AV3V-lesioned rats, respectively. The bradycardia to l-glutamate into the NTS and the cardiovascular responses to chemoreflex activation with intravenous potassium cyanide or to baroreflex activation with intravenous phenylephrine or sodium nitroprusside were not modified by AV3V lesions. The results show that the integrity of the AV3V region is essential for the pressor responses to L-glutamate into the NTS but not for the pressor responses to chemoreflex activation, suggesting dissociation between the central mechanisms involved in these responses.

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines.

PubMed

ElMallah, Mai K; Pagliardini, Silvia; Turner, Sara M; Cerreta, Anthony J; Falk, Darin J; Byrne, Barry J; Greer, John J; Fuller, David D

2015-09-01

Pompe disease results from a mutation in the acid α-glucosidase gene leading to lysosomal glycogen accumulation. Respiratory insufficiency is common, and the current U.S. Food and Drug Administration-approved treatment, enzyme replacement, has limited effectiveness. Ampakines are drugs that enhance α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses and can increase respiratory motor drive. Recent work indicates that respiratory motor drive can be blunted in Pompe disease, and thus pharmacologic stimulation of breathing may be beneficial. Using a murine Pompe model with the most severe clinical genotype (the Gaa(-/-) mouse), our primary objective was to test the hypothesis that ampakines can stimulate respiratory motor output and increase ventilation. Our second objective was to confirm that neuropathology was present in Pompe mouse medullary respiratory control neurons. The impact of ampakine CX717 on breathing was determined via phrenic and hypoglossal nerve recordings in anesthetized mice and whole-body plethysmography in unanesthetized mice. The medulla was examined using standard histological methods coupled with immunochemical markers of respiratory control neurons. Ampakine CX717 robustly increased phrenic and hypoglossal inspiratory bursting and reduced respiratory cycle variability in anesthetized Pompe mice, and it increased inspiratory tidal volume in unanesthetized Pompe mice. CX717 did not significantly alter these variables in wild-type mice. Medullary respiratory neurons showed extensive histopathology in Pompe mice. Ampakines stimulate respiratory neuromotor output and ventilation in Pompe mice, and therefore they have potential as an adjunctive therapy in Pompe disease.

Influence of age, body temperature, GABAA receptor inhibition and caffeine on the Hering-Breuer inflation reflex in unanesthetized rat pups.

PubMed

Arnal, Ashley V; Gore, Julie L; Rudkin, Alison; Bartlett, Donald; Leiter, J C

2013-03-01

We measured the duration of apnea induced by sustained end-inspiratory lung inflation (the Hering Breuer Reflex, HBR) in unanesthetized infant rat pups aged 4 days (P4) to P20 at body temperatures of 32°C and 36°C. The expiratory prolongation elicited by the HBR lasted longer in the younger pups and lasted longer at the higher body temperature. Blockade of adenosine receptors by caffeine following injection into the cisterna magna (ICM) significantly blunted the thermal prolongation of the HBR. Blockade of gama-amino-butyric acid A (GABAA) receptors by pre-treatment with ICM bicuculline had no effect on the HBR duration at either body temperature. To test the hypothesis that developmental maturation of GABAergic inhibition of breathing was modifying the response to bicuculline, we pretreated rat pups with systemically administered bumetanide to lower the intracellular chloride concentration, and repeated the bicuculline studies. Bicuculline still did not alter the HBR at either temperature after bumetanide treatment. We administered PSB-36, a selective adenosine A1 receptor antagonist, and this drug treatment did not modify the HBR. We conclude that caffeine blunts the thermal prolongation of the HBR, probably by blocking adenosine A2a receptors. The thermally sensitive adenosinergic prolongation of the HBR in these intact animals does not seem to depend on GABAA receptors. Copyright © 2013 Elsevier B.V. All rights reserved.

Analysis of stability and bifurcations of fixed points and periodic solutions of a lumped model of neocortex with two delays

PubMed Central

2012-01-01

A lumped model of neural activity in neocortex is studied to identify regions of multi-stability of both steady states and periodic solutions. Presence of both steady states and periodic solutions is considered to correspond with epileptogenesis. The model, which consists of two delay differential equations with two fixed time lags is mainly studied for its dependency on varying connection strength between populations. Equilibria are identified, and using linear stability analysis, all transitions are determined under which both trivial and non-trivial fixed points lose stability. Periodic solutions arising at some of these bifurcations are numerically studied with a two-parameter bifurcation analysis. PMID:22655859

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation.

PubMed

Miller, Jonathan; Watrous, Andrew J; Tsitsiklis, Melina; Lee, Sang Ah; Sheth, Sameer A; Schevon, Catherine A; Smith, Elliot H; Sperling, Michael R; Sharan, Ashwini; Asadi-Pooya, Ali Akbar; Worrell, Gregory A; Meisenhelter, Stephen; Inman, Cory S; Davis, Kathryn A; Lega, Bradley; Wanda, Paul A; Das, Sandhitsu R; Stein, Joel M; Gorniak, Richard; Jacobs, Joshua

2018-06-21

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1-3-Hz "low theta" band increases when viewing subsequently remembered object-location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.

Cycle-Triggered Cortical Stimulation during Slow Wave Sleep Facilitates Learning a BMI Task: A Case Report in a Non-Human Primate

PubMed Central

Rembado, Irene; Zanos, Stavros; Fetz, Eberhard E.

2017-01-01

Slow wave sleep (SWS) has been identified as the sleep stage involved in consolidating newly acquired information. A growing body of evidence has shown that delta (1–4 Hz) oscillatory activity, the characteristic electroencephalographic signature of SWS, is involved in coordinating interaction between the hippocampus and the neocortex and is thought to take a role in stabilizing memory traces related to a novel task. This case report describes a new protocol that uses neuroprosthetics training of a non-human primate to evaluate the effects of surface cortical electrical stimulation triggered from SWS cycles. The results suggest that stimulation phase-locked to SWS oscillatory activity promoted learning of the neuroprosthetic task. This protocol could be used to elucidate mechanisms of synaptic plasticity underlying off-line learning during sleep and offers new insights into the role of brain oscillations in information processing and memory consolidation. PMID:28450831

Propagation of cortical spreading depression into the hippocampus: The role of the entorhinal cortex.

PubMed

Martens-Mantai, Tanja; Speckmann, Erwin-Josef; Gorji, Ali

2014-07-22

Propagation of cortical spreading depression (CSD) to the subcortical structures could be the underlying mechanism of some neurological deficits in migraine with aura. The entorhinal cortex (EC) as a gray matter bridge between the neocortex and subcortical regions plays an important role in this propagation. In vitro combined neocortex-hippocampus brain slices were used to study the propagation pattern of CSD between the neocortex and the hippocampus. The effects of different compounds as well as tetanic electrical stimulations in the EC on propagation of CSD to the hippocampus were investigated. Repetitive induction of CSD by KCl injection in the somatosensory cortex enhanced the probability of CSD entrance to the hippocampus via EC. Local application of AMPA receptor blocker CNQX and cannabinoid receptor agonist WIN 55212-2 in EC facilitated the propagation of CSD to the hippocampus, whereas application of NMDA receptor blocker APV and GABA A receptor blocker bicuculline in this region reduced the probability of CSD penetration to the hippocampus. Application of tetanic stimulation in EC also facilitated the propagation of CSD entrance to the hippocampus. Our data suggest the importance of synaptic plasticity of EC in filtering the propagation of CSD into subcortical structures and possibly the occurrence of concomitant neurological deficits. Synapse, 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

Disturbances in the positioning, proliferation, and apoptosis of neural progenitors contribute to subcortical band heterotopia formation

PubMed Central

Fitzgerald, MP; Covio, M; Lee, KS

2011-01-01

Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic model of subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental events underlying SBH formation in the neocortex. Our results demonstrate that Pax6+ and Tbr2+ progenitors are mislocalized in tish+/− and tish−/− neocortex throughout neurogenesis. In addition, mislocalized tish−/− progenitors possess a longer cell cycle than wildtype or normally-positioned tish−/− progenitors, owing to a lengthened G2+M+G1 time. This mislocalization is not associated with adherens junction breakdown or loss of radial glial polarity in the ventricular zone, as assessed by immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ, and Par3. However, vimentin immunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish−/− heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish−/− neocortex demonstrate that mislocalized progenitors do not retain contact with the ventricular surface and that ventricular/subventricular zone progenitors produce neurons that migrate into both the heterotopia and cortical plate. Taken together, these findings define a series of developmental errors contributing to SBH formation that differs fundamentally from a primary error in neuronal migration. PMID:21145942

Direction of Amygdala-Neocortex Interaction During Dynamic Facial Expression Processing.

PubMed

Sato, Wataru; Kochiyama, Takanori; Uono, Shota; Yoshikawa, Sakiko; Toichi, Motomi

2017-03-01

Dynamic facial expressions of emotion strongly elicit multifaceted emotional, perceptual, cognitive, and motor responses. Neuroimaging studies revealed that some subcortical (e.g., amygdala) and neocortical (e.g., superior temporal sulcus and inferior frontal gyrus) brain regions and their functional interaction were involved in processing dynamic facial expressions. However, the direction of the functional interaction between the amygdala and the neocortex remains unknown. To investigate this issue, we re-analyzed functional magnetic resonance imaging (fMRI) data from 2 studies and magnetoencephalography (MEG) data from 1 study. First, a psychophysiological interaction analysis of the fMRI data confirmed the functional interaction between the amygdala and neocortical regions. Then, dynamic causal modeling analysis was used to compare models with forward, backward, or bidirectional effective connectivity between the amygdala and neocortical networks in the fMRI and MEG data. The results consistently supported the model of effective connectivity from the amygdala to the neocortex. Further increasing time-window analysis of the MEG demonstrated that this model was valid after 200 ms from the stimulus onset. These data suggest that emotional processing in the amygdala rapidly modulates some neocortical processing, such as perception, recognition, and motor mimicry, when observing dynamic facial expressions of emotion. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A New Transgenic Mouse Model for Studying the Neurotoxicity of Spermine Oxidase Dosage in the Response to Excitotoxic Injury

PubMed Central

Cervelli, Manuela; Bellavia, Gabriella; D'Amelio, Marcello; Cavallucci, Virve; Moreno, Sandra; Berger, Joachim; Nardacci, Roberta; Marcoli, Manuela; Maura, Guido; Piacentini, Mauro; Amendola, Roberto; Cecconi, Francesco; Mariottini, Paolo

2013-01-01

Spermine oxidase is a FAD-containing enzyme involved in polyamines catabolism, selectively oxidizing spermine to produce H2O2, spermidine, and 3-aminopropanal. Spermine oxidase is highly expressed in the mouse brain and plays a key role in regulating the levels of spermine, which is involved in protein synthesis, cell division and cell growth. Spermine is normally released by neurons at synaptic sites where it exerts a neuromodulatory function, by specifically interacting with different types of ion channels, and with ionotropic glutamate receptors. In order to get an insight into the neurobiological roles of spermine oxidase and spermine, we have deregulated spermine oxidase gene expression producing and characterizing the transgenic mouse model JoSMOrec, conditionally overexpressing the enzyme in the neocortex. We have investigated the effects of spermine oxidase overexpression in the mouse neocortex by transcript accumulation, immunohistochemical analysis, enzymatic assays and polyamine content in young and aged animals. Transgenic JoSMOrec mice showed in the neocortex a higher H2O2 production in respect to Wild-Type controls, indicating an increase of oxidative stress due to SMO overexpression. Moreover, the response of transgenic mice to excitotoxic brain injury, induced by kainic acid injection, was evaluated by analysing the behavioural phenotype, the immunodistribution of neural cell populations, and the ultrastructural features of neocortical neurons. Spermine oxidase overexpression and the consequently altered polyamine levels in the neocortex affects the cytoarchitecture in the adult and aging brain, as well as after neurotoxic insult. It resulted that the transgenic JoSMOrec mouse line is more sensitive to KA than Wild-Type mice, indicating an important role of spermine oxidase during excitotoxicity. These results provide novel evidences of the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. PMID:23840306

Acetylation of histones in neocortex and hippocampus of rats exposed to different modes of hypobaric hypoxia: Implications for brain hypoxic injury and tolerance.

PubMed

Samoilov, Mikhail; Churilova, Anna; Gluschenko, Tatjana; Vetrovoy, Oleg; Dyuzhikova, Natalia; Rybnikova, Elena

2016-03-01

Acetylation of nucleosome histones results in relaxation of DNA and its availability for the transcriptional regulators, and is generally associated with the enhancement of gene expression. Although it is well known that activation of a variety of pro-adaptive genes represents a key event in the development of brain hypoxic/ischemic tolerance, the role of epigenetic mechanisms, in particular histone acetylation, in this process is still unexplored. The aim of the present study was to investigate changes in acetylation of histones in vulnerable brain neurons using original well-standardized model of hypobaric hypoxia and preconditioning-induced tolerance of the brain. Using quantitative immunohistochemistry and Western blot, effects of severe injurious hypobaric hypoxia (SH, 180mm Hg, 3h) and neuroprotective preconditioning mode (three episodes of 360mm Hg for 2h spaced at 24h) on the levels of the acetylated proteins and acetylated H3 Lys24 (H3K24ac) in the neocortex and hippocampus of rats were studied. SH caused global repression of the acetylation processes in the neocortex (layers II-III, V) and hippocampus (CA1, CA3) by 3-24h, and this effect was prevented by the preconditioning. Moreover, hypoxic preconditioning remarkably increased the acetylation of H3K24 in response to SH in the brain areas examined. The preconditioning hypoxia without subsequent SH also stimulated acetylation processes in the neocortex and hippocampus. The moderately enhanced expression of the acetylated proteins in the preconditioned rats was maintained for 24h, whereas acetylation of H3K24 was intense but transient, peaked at 3h. The novel data obtained in the present study indicate that large activation of the acetylation processes, in particular acetylation of histones might be essential for the development of brain hypoxic tolerance. Copyright © 2015 Elsevier GmbH. All rights reserved.

[Effect of arecoline on neuronal activity in the posterior hypothalamus of rabbits with experimental fever].

PubMed

Gurin, V N; Fitton, A G; Tsariuk, V V

1983-11-01

It has been found in experiments on unanesthetized rabbits that arecoline administered to the lateral ventricle of the brain produced an action which was opposite to that of leukocytic pyrogen. It inhibited the activity of individual neurons of the posterior hypothalamus and decreased the body temperature, with this decrease being attended by the signs of intensified heat emission. Arecoline injection coupled with the central action of PGE2 was followed by an increase in the neuronal activity in the posterior hypothalamus and reduction of hyperthermal response.

Low Dose Isoflurane Exerts Opposing Effects on Neuronal Network Excitability in Neocortex and Hippocampus

PubMed Central

Ranft, Andreas; von Meyer, Ludwig; Zieglgänsberger, Walter; Kochs, Eberhard; Dodt, Hans-Ulrich

2012-01-01

The anesthetic excitement phase occurring during induction of anesthesia with volatile anesthetics is a well-known phenomenon in clinical practice. However, the physiological mechanisms underlying anesthetic-induced excitation are still unclear. Here we provide evidence from in vitro experiments performed on rat brain slices that the general anesthetic isoflurane at a concentration of about 0.1 mM can enhance neuronal network excitability in the hippocampus, while simultaneously reducing it in the neocortex. In contrast, isoflurane tissue concentrations above 0.3 mM expectedly caused a pronounced reduction in both brain regions. Neuronal network excitability was assessed by combining simultaneous multisite stimulation via a multielectrode array with recording intrinsic optical signals as a measure of neuronal population activity. PMID:22723999

Attention as an effect not a cause

PubMed Central

Krauzlis, Richard J.; Bollimunta, Anil; Arcizet, Fabrice; Wang, Lupeng

2014-01-01

Attention is commonly thought to be important for managing the limited resources available in sensory areas of neocortex. Here we present an alternative view that attention arises as a byproduct of circuits centered on the basal ganglia involved in value-based decision-making. The central idea is that decision-making depends on properly estimating the current state of the animal and its environment, and that the weighted inputs to the currently prevailing estimate give rise to the filter-like properties of attention. After outlining this new framework, we describe findings from physiology, anatomy, computational and clinical work that support this point of view. We conclude that the brain mechanisms responsible for attention employ a conserved circuit motif that predates the emergence of the neocortex. PMID:24953964

Memory processes during sleep: beyond the standard consolidation theory.

PubMed

Axmacher, Nikolai; Draguhn, Andreas; Elger, Christian E; Fell, Juergen

2009-07-01

Two-step theories of memory formation suggest that an initial encoding stage, during which transient neural assemblies are formed in the hippocampus, is followed by a second step called consolidation, which involves re-processing of activity patterns and is associated with an increasing involvement of the neocortex. Several studies in human subjects as well as in animals suggest that memory consolidation occurs predominantly during sleep (standard consolidation model). Alternatively, it has been suggested that consolidation may occur during waking state as well and that the role of sleep is rather to restore encoding capabilities of synaptic connections (synaptic downscaling theory). Here, we review the experimental evidence favoring and challenging these two views and suggest an integrative model of memory consolidation.

Responses of single cells in cat visual cortex to prolonged stimulus movement: neural correlates of visual aftereffects.

PubMed

Vautin, R G; Berkley, M A

1977-09-01

1. The activity of single cortical cells in area 17 of anesthetized and unanesthetized cats was recorded in response to prolonged stimulation with moving stimuli. 2. Under the appropriate conditions, all cells observed showed a progressive response decrement during the stimulation period, regardless of cell classification, i.e., simple, complex, or hypercomplex. 3. The observed response decrement was shown to be largely cortical in origin and could be adequately described with an exponential function of the form R = Rf +(R1-Rf)e-t/T. Time constants derived from such calculations yielded values ranging from 1.92 to 12.45 s under conditions of optimal-stimulation. 4. Most cells showed poststimulation effects, usually a brief period of reduced responsiveness that recovered exponentially. Recovery was essentially complete in about 5-35 s. 5. The degree to which stimuli were effective at inducing response was shown to have significant effects on the magnitude of the response decrement. 6. Several cells showed neural patterns of response and recovery that suggested the operation of intracortical inhibitory mechanisms. 7. A simple two-process model that adequately describes the behavior of all the studied cells is presented. 8. Because the properties of the cells studied correlate well with human psychophysical measures of contour and movement adaptation and recovery, a causal relationship to similar neural mechanisms in humans is suggested.

Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma

PubMed Central

Takahashi, D. Koji; Isabel, Feng Gu; Parada, Shri Vyas; Prince, David A.

2016-01-01

Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation (“undercut” or “UC”) leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3 days post UC injury (Graber and Prince, 1999, 2004; Li et al., 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3 days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments. PMID:26956396

Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma.

PubMed

Takahashi, D Koji; Gu, Feng; Parada, Isabel; Vyas, Shri; Prince, David A

2016-07-01

Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation ("undercut" or "UC") leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3days post UC injury (Graber and Prince 1999, 2004; Li et al. 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments. Copyright © 2016 Elsevier Inc. All rights reserved.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

PubMed Central

Eagleson, Kathie L.; Xie, Zhihui; Levitt, Pat

2016-01-01

People with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy - the influence of one gene on distinct phenotypes - raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multi-functional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain, and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with ASD, reduces transcription and disrupts socially-relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways, and has a complex protein interactome that is enriched in ASD and other NDD candidates. The interactome is co-regulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, impacting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. PMID:27837921

High-peak-power microwave pulses: effects on heart rate and blood pressure in unanesthetized rats.

PubMed

Jauchem, J R; Frei, M R

1995-10-01

Exposure sources capable of generating high-peak-power microwave pulses, with relatively short pulse widths, have recently been developed. Studies of the effect of these sources on the cardiovascular systems of animals have not been reported previously. We exposed 14 unanesthetized male Sprague-Dawley rats to 10 high-peak-power microwave pulses generated by a transformer-energized megawatt pulsed output (TEMPO) microwave source, at frequencies ranging from 1.2-1.8 GHz. Peak power densities were as high as 51.6 kW/cm2. At 14 d prior to irradiation, the animals were implanted with chronic aortic cannulae. With appropriate shielding of the transducer, blood pressure recordings were obtained during microwave pulsing. In a preliminary series of exposures at 1.7-1.8 GHz (peak power density 3.3-6.5 kW/cm2), an immediate but transient increase in mean arterial blood pressure (significant) and decrease in heart rate (non-significant) were observed. A loud noise was associated with each pulse produced by the TEMPO; this factor was subsequently attenuated. In a second series of exposures at 1.2-1.4 GHz (peak power density 14.6-51.6 kW/cm2), there were no significant changes in mean arterial blood pressure or heart rate during microwave exposure. The earlier significant increase in blood pressure that occurred during microwave exposure appeared to be related to the sharp noise produced by the TEMPO source. After appropriate sound attenuation, there were no significant effects of exposure to the microwave pulses.

Central Connections of the Lacrimal Functional Unit.

PubMed

Willshire, Catherine; Buckley, Roger J; Bron, Anthony J

2017-08-01

To study the contribution of each eye to the reflex tear response, after unilateral and bilateral topical anesthesia. A closed-eye, modified Schirmer test was performed bilaterally in 8 normal subjects, in a controlled environment chamber set to 23°C, 45% relative humidity, and 0.08 m/s airflow. Eye drops were instilled into each eye 10 minutes before the Schirmer test. Experiments were as follows: 1) bilateral saline (control), 2) unilateral anesthesia (ipsilateral anesthetic; contralateral saline), and 3) bilateral anesthesia. There was no difference in between-eye wetting lengths in the saline control eyes (P = 0.394) or the bilaterally anesthetized eyes (P = 0.171). The wetting length was reduced in both eyes after bilateral anesthesia compared with saline controls (P = 0.001; P ≤ 0.0005). After unilateral anesthesia, the wetting length was reduced in the anesthetized eye compared with its saline control by 51.4% (P ≤ 0.0005) and compared with its fellow, unanesthetized eye (P = 0.005). The fellow eye value was also reduced compared with its saline control (P = 0.06). The wetting length was reduced by topical anesthesia, when instilled bilaterally and ipsilaterally. The latter response implies an ipsilateral, reflex sensory drive to lacrimal secretion. In the unanesthetized fellow eye, the reduction compared with its saline control was not quite significant. This implies a relative lack of central, sensory, reflex cross-innervation, although the possibility cannot entirely be ruled out. These results are relevant to the possibility of reflex lacrimal compensation from a normal fellow eye, in cases of unilateral corneal anesthesia.

How do neurons work together? Lessons from auditory cortex.

PubMed

Harris, Kenneth D; Bartho, Peter; Chadderton, Paul; Curto, Carina; de la Rocha, Jaime; Hollender, Liad; Itskov, Vladimir; Luczak, Artur; Marguet, Stephan L; Renart, Alfonso; Sakata, Shuzo

2011-01-01

Recordings of single neurons have yielded great insights into the way acoustic stimuli are represented in auditory cortex. However, any one neuron functions as part of a population whose combined activity underlies cortical information processing. Here we review some results obtained by recording simultaneously from auditory cortical populations and individual morphologically identified neurons, in urethane-anesthetized and unanesthetized passively listening rats. Auditory cortical populations produced structured activity patterns both in response to acoustic stimuli, and spontaneously without sensory input. Population spike time patterns were broadly conserved across multiple sensory stimuli and spontaneous events, exhibiting a generally conserved sequential organization lasting approximately 100 ms. Both spontaneous and evoked events exhibited sparse, spatially localized activity in layer 2/3 pyramidal cells, and densely distributed activity in larger layer 5 pyramidal cells and putative interneurons. Laminar propagation differed however, with spontaneous activity spreading upward from deep layers and slowly across columns, but sensory responses initiating in presumptive thalamorecipient layers, spreading rapidly across columns. In both unanesthetized and urethanized rats, global activity fluctuated between "desynchronized" state characterized by low amplitude, high-frequency local field potentials and a "synchronized" state of larger, lower-frequency waves. Computational studies suggested that responses could be predicted by a simple dynamical system model fitted to the spontaneous activity immediately preceding stimulus presentation. Fitting this model to the data yielded a nonlinear self-exciting system model in synchronized states and an approximately linear system in desynchronized states. We comment on the significance of these results for auditory cortical processing of acoustic and non-acoustic information. © 2010 Elsevier B.V. All rights reserved.

Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.

PubMed

Porcellotti, Sara; Fanelli, Francesca; Fracassi, Anna; Sepe, Sara; Cecconi, Francesco; Bernardi, Cinzia; Cimini, AnnaMaria; Cerù, Maria Paola; Moreno, Sandra

2015-01-01

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes.

Amelioration of improper differentiation of somatostatin-positive interneurons by triiodothyronine in a growth-retarded hypothyroid mouse strain.

PubMed

Uchida, Katsuya; Taguchi, Yusuke; Sato, Chika; Miyazaki, Hidetaka; Kobayashi, Kenichi; Kobayashi, Tetsuya; Itoi, Keiichi

2014-01-24

Thyroid hormone (TH) plays an important role in brain development, and TH deficiency during pregnancy or early postnatal periods leads to neurological disorders such as cretinism. Hypothyroidism reduces the number of parvalbumin (PV)-positive interneurons in the neocortex and hippocampus. Here we used a mouse strain (growth-retarded; grt) that shows growth retardation and hypothyroidism to examine whether somatostatin (Sst)-positive interneurons that are generated from the same pool of neural progenitor cells as PV-positive cells are also altered by TH deficiency. The number of PV-positive interneurons was significantly decreased in the neocortex and hippocampus of grt mice as compared with normal control mice. In contrast to the decrease in the number of PV neurons, the number of Sst-positive interneurons in grt mice was increased in the stratum oriens of the hippocampus and the hilus of the dentate gyrus, although their number was unchanged in the neocortex. These changes were reversed by triiodothyronine administration from postnatal day (PD) 0 to 20. TH supplementation that was initiated after PD21 did not, however, affect the number of PV- or Sst-positive cells. These results suggest that during the first three postnatal weeks, TH may be critical for the generation of subpopulations of interneurons. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

RECURRENT NEONATAL SEIZURES RESULT IN LONG-TERM INCREASE OF NEURONAL NETWORK EXCITABILITY IN THE RAT NEOCORTEX

PubMed Central

Isaeva, Elena; Isaev, Dmytro; Savrasova, Alina; Khazipov, Rustem; Holmes, Gregory L.

2011-01-01

Neonatal seizures are associated with a high likelihood of adverse neurological outcomes, including mental retardation, behavioral disorders, and epilepsy. Early seizures typically involve the neocortex, and post-neonatal epilepsy is often of neocortical origin. However, our understanding of the consequences of neonatal seizures for neocortical function is limited. In the present study, we show that neonatal seizures induced by flurothyl result in markedly enhanced susceptibility of the neocortex to seizure-like activity. This change occurs in young rats studied weeks after the last induced seizure and in adult rats studied months after the initial seizures. Neonatal seizures resulted in reductions in the amplitude of spontaneous inhibitory postsynaptic currents and the frequency of miniature inhibitory postsynaptic currents, and significant increases in the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in pyramidal cells of layer 2/3 of the somatosensory cortex. The selective N-methyl-d-aspartate (NMDA) receptor antagonist d-2-amino-5-phosphon-ovalerate eliminated the differences in amplitude and frequency of sEPSCs and mEPSCs in the control and flurothyl groups, suggesting that NMDA receptors contribute significantly to the enhanced excitability seen in slices from rats that experienced recurrent neonatal seizures. Taken together, our results suggest that recurrent seizures in infancy result in a persistent enhancement of neocortical excitability. PMID:20384780

Aggrecan-based extracellular matrix shows unique cortical features and conserved subcortical principles of mammalian brain organization in the Madagascan lesser hedgehog tenrec (Echinops telfairi Martin, 1838).

PubMed

Morawski, M; Brückner, G; Jäger, C; Seeger, G; Künzle, H; Arendt, T

2010-02-03

The Madagascan tenrecs (Afrotheria), an ancient mammalian clade, are characterized by unique brain anatomy. Striking features are an expanded paleocortex but a small and poorly differentiated neocortex devoid of a distinct granular layer IV. To investigate the organization of cortical areas we analyzed extracellular matrix components in perineuronal nets (PNs) using antibodies to aggrecan, lectin staining and hyaluronan-binding protein. Selected subcortical regions were studied to correlate the cortical patterns with features in evolutionary conserved systems. In the neocortex, paleocortex and hippocampus PNs were associated with nonpyramidal neurons. Quantitative analysis in the cerebral cortex revealed area-specific proportions and laminar distribution patterns of neurons ensheathed by PNs. Cortical PNs showed divergent structural phenotypes. Diffuse PNs forming a cotton wool-like perisomatic rim were characteristic of the paleocortex. These PNs were associated with a dense pericellular plexus of calretinin-immunoreactive fibres. Clearly contoured PNs were devoid of a calretinin-positive plexus and predominated in the neocortex and hippocampus. The organization of the extracellular matrix in subcortical nuclei followed the widely distributed mammalian type. We conclude that molecular properties of the aggrecan-based extracellular matrix are conserved during evolution of mammals; however, the matrix scaffold is adapted to specific wiring patterns of cortical and subcortical neuronal networks. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Early remodeling of the neocortex upon episodic memory encoding

PubMed Central

Bero, Adam W.; Meng, Jia; Cho, Sukhee; Shen, Abra H.; Canter, Rebecca G.; Ericsson, Maria; Tsai, Li-Huei

2014-01-01

Understanding the mechanisms by which long-term memories are formed and stored in the brain represents a central aim of neuroscience. Prevailing theory suggests that long-term memory encoding involves early plasticity within hippocampal circuits, whereas reorganization of the neocortex is thought to occur weeks to months later to subserve remote memory storage. Here we report that long-term memory encoding can elicit early transcriptional, structural, and functional remodeling of the neocortex. Parallel studies using genome-wide RNA sequencing, ultrastructural imaging, and whole-cell recording in wild-type mice suggest that contextual fear conditioning initiates a transcriptional program in the medial prefrontal cortex (mPFC) that is accompanied by rapid expansion of the synaptic active zone and postsynaptic density, enhanced dendritic spine plasticity, and increased synaptic efficacy. To address the real-time contribution of the mPFC to long-term memory encoding, we performed temporally precise optogenetic inhibition of excitatory mPFC neurons during contextual fear conditioning. Using this approach, we found that real-time inhibition of the mPFC inhibited activation of the entorhinal–hippocampal circuit and impaired the formation of long-term associative memory. These findings suggest that encoding of long-term episodic memory is associated with early remodeling of neocortical circuits, identify the prefrontal cortex as a critical regulator of encoding-induced hippocampal activation and long-term memory formation, and have important implications for understanding memory processing in healthy and diseased brain states. PMID:25071187

An Architectonic Study of the Neocortex of the Short-Tailed Opossum (Monodelphis domestica)

PubMed Central

Wong, Peiyan; Kaas, Jon H.

2013-01-01

Short-tailed opossums (Monodelphis domestica) belong to the branch of marsupial mammals that diverged from eutherian mammals approximately 180 million years ago. They are small in size, lack a marsupial pouch, and may have retained more morphological characteristics of early marsupial neocortex than most other marsupials. In the present study, we used several different histochemical and immunochemical procedures to reveal the architectonic characteristics of cortical areas in short-tailed opossums. Subdivisions of cortex were identified in brain sections cut in the coronal, sagittal, horizontal or tangential planes and processed for a calcium-binding protein, parvalbumin (PV), neurofilament protein epitopes recognized by SMI-32, the vesicle glutamate transporter 2 (VGluT2), myelin, cytochrome oxidase (CO), and Nissl substance. These different procedures revealed similar boundaries among areas, suggesting that functionally relevant borders were detected. The results allowed a fuller description and more precise demarcation of previously identified sensory areas, and the delineation of additional subdivisions of cortex. Area 17 (V1) was especially prominent, with a densely populated layer 4, high myelination levels, and dark staining of PV and VGluT2 immunopositive terminations. These architectonic features were present, albeit less pronounced, in somatosensory and auditory cortex. The major findings support the conclusion that short-tailed opossums have fewer cortical areas and their neocortex is less distinctly laminated than most other mammals. PMID:19546531

[A cross-correlational analysis of the background neuronal pulse trains in surviving slices of the guinea pig neocortex].

PubMed

Bortnik, A T; Iakupova, L P

1991-01-01

Cross-correlation analysis of interdependence of the background spike activity was carried out for pairs of adjacent neurons simultaneously recorded in the incubated slices of the neocortex of guinea-pig. Statistical correlation of spike discharges was detected in 16 out of 26 recorded pairs of the neurons. Significant correlation was observed mainly in the range of +/- 100 ms from the null point. Cross-correlation had symmetric or asymmetric maxima up to 150 ms long and negative shifts up to 200 ms long. More complex positive-negative types of cross-correlations were also obtained. The data were compared to those known from other authors for the intact brain. The contribution of intrinsic intracortical interactions and extrinsic afferent influences in these correlations of activity is discussed.

Odor from a chemical perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wray, T.K.

1995-06-01

Early odor-detection measurements categorized chemicals according to odor quality. Recent methods focus on the odor threshold, or the quantitative amount of a chemical in air that can be detected by the human sense of smell. Researchers characterize and quantify odor using an array of sensory and analytical procedures. Humans possess one of the dullest mammalian senses of smell; however, they can recognize about 10,000 distinct odors at concentrations ranging from less than 1 part per billion to several hundred thousand parts per million. Each time humans inhale, they chemically analyze microscopic pieces of the environment that make physical contact withmore » the nerves in their noses. Individual molecules travel up the nose to a sheet of moist, mucus-bathed tissue that consists of about 5 million smell-sensing, olfactory neurons. After dissolving in the mucus, odor molecules ``float`` into appropriately shaped receptor pockets. A series of cellular reactions then transmit impulses to the limbic system, hippocampus and, finally, the neocortex. Odor detection is an important defense mechanism. The author presents the odor thresholds for selected organic compounds, and other hazardous chemicals.« less

Endogenous orienting in the archer fish

PubMed Central

Sekely, Liora; Klein, Raymond M.; Gabay, Shai

2017-01-01

The literature has long emphasized the neocortex’s role in volitional processes. In this work, we examined endogenous orienting in an evolutionarily older species, the archer fish, which lacks neocortex-like cells. We used Posner’s classic endogenous cuing task, in which a centrally presented, spatially informative cue is followed by a target. The fish responded to the target by shooting a stream of water at it. Interestingly, the fish demonstrated a human-like “volitional” facilitation effect: their reaction times to targets that appeared on the side indicated by the precue were faster than their reaction times to targets on the opposite side. The fish also exhibited inhibition of return, an aftermath of orienting that commonly emerges only in reflexive orienting tasks in human participants. We believe that this pattern demonstrates the acquisition of an arbitrary connection between spatial orienting and a nonspatial feature of a centrally presented stimulus in nonprimate species. In the literature on human attention, orienting in response to such contingencies has been strongly associated with volitional control. We discuss the implications of these results for the evolution of orienting, and for the study of volitional processes in all species, including humans. PMID:28673997

Neurogenic radial glia in the outer subventricular zone of human neocortex.

PubMed

Hansen, David V; Lui, Jan H; Parker, Philip R L; Kriegstein, Arnold R

2010-03-25

Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.

Effects of pharmacological agents on subcortical resistance shifts

NASA Technical Reports Server (NTRS)

Klivington, K. A.

1975-01-01

Microliter quantities of tetrodotoxin, tetraethylammonium chloride, and picrotoxin injected into the inferior colliculus and superior olive of unanesthetized cats differentially affect the amplitude and waveform of click-evoked potentials and evoked resistance shifts. Tetrodotoxin simultaneously reduces the negative phase of the evoked potential and eliminates the evoked resistance shift. Tetraethylammonium enhances the negative evoked potential component, presumably of postsynaptic origin, without significantly altering evoked resistance shift amplitude. Picrotoxin also enhances the negative evoked potential wave but increases evoked resistance shift amplitude. These findings implicate events associated with postsynaptic membrane depolarization in the production of the evoked resistance shift.

Cornu Ammonis Regions–Antecedents of Cortical Layers?

PubMed Central

Mercer, Audrey; Thomson, Alex M.

2017-01-01

Studying neocortex and hippocampus in parallel, we are struck by the similarities. All three to four layered allocortices and the six layered mammalian neocortex arise in the pallium. All receive and integrate multiple cortical and subcortical inputs, provide multiple outputs and include an array of neuronal classes. During development, each cell positions itself to sample appropriate local and distant inputs and to innervate appropriate targets. Simpler cortices had already solved the need to transform multiple coincident inputs into serviceable outputs before neocortex appeared in mammals. Why then do phylogenetically more recent cortices need multiple pyramidal cell layers? A simple answer is that more neurones can compute more complex functions. The dentate gyrus and hippocampal CA regions—which might be seen as hippocampal antecedents of neocortical layers—lie side by side, albeit around a tight bend. Were the millions of cells of rat neocortex arranged in like fashion, the surface area of the CA pyramidal cell layers would be some 40 times larger. Even if evolution had managed to fold this immense sheet into the space available, the distances between neurones that needed to be synaptically connected would be huge and to maintain the speed of information transfer, massive, myelinated fiber tracts would be needed. How much more practical to stack the “cells that fire and wire together” into narrow columns, while retaining the mechanisms underlying the extraordinary precision with which circuits form. This demonstrably efficient arrangement presents us with challenges, however, not the least being to categorize the baffling array of neuronal subtypes in each of five “pyramidal layers.” If we imagine the puzzle posed by this bewildering jumble of apical dendrites, basal dendrites and axons, from many different pyramidal and interneuronal classes, that is encountered by a late-arriving interneurone insinuating itself into a functional circuit, we can perhaps begin to understand why definitive classification, covering every aspect of each neurone's structure and function, is such a challenge. Here, we summarize and compare the development of these two cortices, the properties of their neurones, the circuits they form and the ordered, unidirectional flow of information from one hippocampal region, or one neocortical layer, to another. PMID:29018334

Developmental Markers Expressed in Neocortical Layers Are Differentially Exhibited in Olfactory Cortex

PubMed Central

Brunjes, Peter C.; Osterberg, Stephen K.

2015-01-01

Neurons in the cerebral cortex stratify on the basis of their time of origin, axonal terminations and the molecular identities assigned during early development. Olfactory cortices share many feature with the neocortex, including clear lamination and similar cell types. The present study demonstrates that the markers differentially expressed in the projection neurons of the cerebral cortex are also found in olfactory areas. Three of the four regions examined (pars principalis of the anterior olfactory nucleus: AONpP, anterior and posterior piriform cortices: APC, PPC, and the olfactory tubercle) expressed transcription factors found in deep or superficial neurons in the developing neocortex, though large differences were found between areas. For example, while the AONpP, APC and PPC all broadly expressed the deep cortical marker CTIP2, NOR1 (NR4a3) levels were higher in AONpP and DAARP-32 was more prevalent in the APC and PPC. Similar findings were encountered for superficial cortical markers: all three regions broadly expressed CUX1, but CART was only observed in the APC and PPC. Furthermore, regional variations were observed even within single structures (e.g., NOR1 was found primarily in in the dorsal region of AONpP and CART expression was observed in a discrete band in the middle of layer 2 of both the APC and PPC). Experiments using the mitotic marker EDU verified that the olfactory cortices and neocortex share similar patterns of neuronal production: olfactory cells that express markers found in the deep neocortex are produced earlier than those that express superficial makers. Projection neurons were filled by retrograde tracers injected into the olfactory bulb to see if olfactory neurons with deep and superficial markers had different axonal targets. Unlike the cerebral cortex, no specificity was observed: neurons with each of the transcription factors examined were found to be labelled. Together the results indicate that olfactory cortices are complex: they differ from each other and each is formed from a variable mosaic of neurons. The results suggest that the olfactory cortices are not merely a remnant architype of the primordial forebrain but varied and independent regions. PMID:26407299

Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid.

PubMed

Rinaldi, Tania; Silberberg, Gilad; Markram, Henry

2008-04-01

Exposure to valproic acid (VPA) during embryogenesis can cause several teratogenic effects, including developmental delays and in particular autism in humans if exposure occurs during the third week of gestation. We examined the postnatal effects of embryonic exposure to VPA on microcircuit properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. The study of the biophysical properties of these connections revealed weaker excitatory synaptic responses. A marked decrease of the intrinsic excitability of pyramidal neurons was also observed. Furthermore, we demonstrate a diminished number of putative synaptic contacts in connection between layer 5 pyramidal neurons. Local hyperconnectivity may render cortical modules more sensitive to stimulation and once activated, more autonomous, isolated, and more difficult to command. This could underlie some of the core symptoms observed in humans prenatally exposed to valproic acid.

Visual Functions of the Thalamus

PubMed Central

Usrey, W. Martin; Alitto, Henry J.

2017-01-01

The thalamus is the heavily interconnected partner of the neocortex. All areas of the neocortex receive afferent input from and send efferent projections to specific thalamic nuclei. Through these connections, the thalamus serves to provide the cortex with sensory input, and to facilitate interareal cortical communication and motor and cognitive functions. In the visual system, the lateral geniculate nucleus (LGN) of the dorsal thalamus is the gateway through which visual information reaches the cerebral cortex. Visual processing in the LGN includes spatial and temporal influences on visual signals that serve to adjust response gain, transform the temporal structure of retinal activity patterns, and increase the signal-to-noise ratio of the retinal signal while preserving its basic content. This review examines recent advances in our understanding of LGN function and circuit organization and places these findings in a historical context. PMID:28217740

Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor.

PubMed

Benekareddy, Madhurima; Nair, Amrita R; Dias, Brian G; Suri, Deepika; Autry, Anita E; Monteggia, Lisa M; Vaidya, Vidita A

2013-03-01

Exposure to stress and hallucinogens in adulthood evokes persistent alterations in neurocircuitry and emotional behaviour. The structural and functional changes induced by stress and hallucinogen exposure are thought to involve transcriptional alterations in specific effector immediate early genes. The immediate early gene, activity regulated cytoskeletal-associated protein (Arc), is important for both activity and experience dependent plasticity. We sought to examine whether trophic factor signalling through brain-derived neurotrophic factor (BDNF) contributes to the neocortical regulation of Arc mRNA in response to distinct stimuli such as immobilization stress and the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Acute exposure to either immobilization stress or DOI induced Arc mRNA levels within the neocortex. BDNF infusion into the neocortex led to a robust up-regulation of local Arc transcript expression. Further, baseline Arc mRNA expression in the neocortex was significantly decreased in inducible BDNF knockout mice with an adult-onset, forebrain specific BDNF loss. The induction of Arc mRNA levels in response to both acute immobilization stress or a single administration of DOI was significantly attenuated in the inducible BDNF knockout mice. Taken together, our results implicate trophic factor signalling through BDNF in the regulation of cortical Arc mRNA expression, both under baseline conditions and following stress and hallucinogen exposure. These findings suggest the possibility that the regulation of Arc expression via BDNF provides a molecular substrate for the structural and synaptic plasticity observed following stimuli such as stress and hallucinogens.

Neural cell adhesion molecule, NCAM, regulates thalamocortical axon pathfinding and the organization of the cortical somatosensory representation in mouse

PubMed Central

Enriquez-Barreto, Lilian; Palazzetti, Cecilia; Brennaman, Leann H.; Maness, Patricia F.; Fairén, Alfonso

2012-01-01

To study the potential role of neural cell adhesion molecule (NCAM) in the development of thalamocortical (TC) axon topography, wild type, and NCAM null mutant mice were analyzed for NCAM expression, projection, and targeting of TC afferents within the somatosensory area of the neocortex. Here we report that NCAM and its α-2,8-linked polysialic acid (PSA) are expressed in developing TC axons during projection to the neocortex. Pathfinding of TC axons in wild type and null mutant mice was mapped using anterograde DiI labeling. At embryonic day E16.5, null mutant mice displayed misguided TC axons in the dorsal telencephalon, but not in the ventral telencephalon, an intermediate target that initially sorts TC axons toward correct neocortical areas. During the early postnatal period, rostrolateral TC axons within the internal capsule along the ventral telencephalon adopted distorted trajectories in the ventral telencephalon and failed to reach the neocortex in NCAM null mutant animals. NCAM null mutants showed abnormal segregation of layer IV barrels in a restricted portion of the somatosensory cortex. As shown by Nissl and cytochrome oxidase staining, barrels of the anterolateral barrel subfield (ALBSF) and the most distal barrels of the posteromedial barrel subfield (PMBSF) did not segregate properly in null mutant mice. These results indicate a novel role for NCAM in axonal pathfinding and topographic sorting of TC axons, which may be important for the function of specific territories of sensory representation in the somatosensory cortex. PMID:22723769

Neocortical arealization: evolution, mechanisms, and open questions.

PubMed

Alfano, Christian; Studer, Michèle

2013-06-01

The mammalian neocortex is a structure with no equals in the vertebrates and is the seat of the highest cerebral functions, such as thoughts and consciousness. It is radially organized into six layers and tangentially subdivided into functional areas deputed to the elaboration of sensory information, association between different stimuli, and selection and triggering of voluntary movements. The process subdividing the neocortical field into several functional areas is called "arealization". Each area has its own cytoarchitecture, connectivity, and peculiar functions. In the last century, several neuroscientists have investigated areal structure and the mechanisms that have led during evolution to the rising of the neocortex and its organization. The extreme conservation in the positioning and wiring of neocortical areas among different mammalian families suggests a conserved genetic program orchestrating neocortical patterning. However, the impressive plasticity of the neocortex, which is able to rewire and reorganize areal structures and connectivity after impairments of sensory pathways, argues for a more complex scenario. Indeed, even if genetics and molecular biology helped in identifying several genes involved in the arealization process, the logic underlying the neocortical bauplan is still beyond our comprehension. In this review, we will introduce the present knowledge and hypotheses on the ontogenesis and evolution of neocortical areas. Then, we will focus our attention on some open issues, which are still unresolved, and discuss some recent studies that might open new directions to be explored in the next few years. Copyright © 2012 Wiley Periodicals, Inc.

Expression of SHANK3 in the Temporal Neocortex of Patients with Intractable Temporal Epilepsy and Epilepsy Rat Models.

PubMed

Zhang, Yanke; Gao, Baobing; Xiong, Yan; Zheng, Fangshuo; Xu, Xin; Yang, Yong; Hu, Yida; Wang, Xuefeng

2017-07-01

SH3 and multiple ankyrin (ANK) repeat domain 3 (SHANK3) is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. SHANK3 plays an important role in the formation and maturation of excitatory synapses. In the brain, SHANK3 directly or indirectly interacts with various synaptic molecules including N-methyl-D-aspartate receptor, the metabotropic glutamate receptor (mGluR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Previous studies have shown that Autism spectrum disorder is a result of mutations of the main SHANK3 isoforms, which may be due to deficit in excitatory synaptic transmission and plasticity. Recently, accumulating evidence has demonstrated that overexpression of SHANK3 could induce seizures in vivo. However, little is known about the role of SHANK3 in refractory temporal lobe epilepsy (TLE). Therefore, we investigated the expression pattern of SHANK3 in patients with intractable temporal lobe epilepsy and in pilocarpine-induced models of epilepsy. Immunofluorescence, immunohistochemistry, and western blot analysis were used to locate and determine the expression of SHANK3 in the temporal neocortex of patients with epilepsy, and in the hippocampus and temporal lobe cortex of rats in a pilocarpine-induced epilepsy model. Double-labeled immunofluorescence showed that SHANK3 was mainly expressed in neurons. Western blot analysis confirmed that SHANK3 expression was increased in the neocortex of TLE patients and rats. These results indicate that SHANK3 participates in the pathology of epilepsy.

Progressive brain damage, synaptic reorganization and NMDA activation in a model of epileptogenic cortical dysplasia.

PubMed

Colciaghi, Francesca; Finardi, Adele; Nobili, Paola; Locatelli, Denise; Spigolon, Giada; Battaglia, Giorgio Stefano

2014-01-01

Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.

The missing link: evolution of the primate cerebellum.

PubMed

MacLeod, Carol

2012-01-01

The cerebellum has too often been seen as the "little brain," subservient to the "big brain," the cerebrum. That is changing, as neuroimaging uncovers the cerebellum as the "missing link" in the neurological underpinnings of many cognitive domains. Connections between the neocortex and the cerebellum are now more precisely defined, with functionally localized areas of cerebellar cortex understood for cognitive tasks in humans. Comparative volumetric studies of the primate cerebellum have isolated some elements of circuitry, and our field is moving toward a better integration with the neurosciences in a systematic comparative framework. The next decade may show great advances, as relatively noninvasive techniques of neuroimaging have the potential to build a comparative model of the evolution of primate neurocircuitry. Copyright © 2012 Elsevier B.V. All rights reserved.

Parcellations and Hemispheric Asymmetries of Human Cerebral Cortex Analyzed on Surface-Based Atlases

PubMed Central

Glasser, Matthew F.; Dierker, Donna L.; Harwell, John; Coalson, Timothy

2012-01-01

We report on surface-based analyses that enhance our understanding of human cortical organization, including its convolutions and its parcellation into many distinct areas. The surface area of human neocortex averages 973 cm2 per hemisphere, based on cortical midthickness surfaces of 2 cohorts of subjects. We implemented a method to register individual subjects to a hybrid version of the FreeSurfer “fsaverage” atlas whose left and right hemispheres are in precise geographic correspondence. Cortical folding patterns in the resultant population-average “fs_LR” midthickness surfaces are remarkably similar in the left and right hemispheres, even in regions showing significant asymmetry in 3D position. Both hemispheres are equal in average surface area, but hotspots of surface area asymmetry are present in the Sylvian Fissure and elsewhere, together with a broad pattern of asymmetries that are significant though small in magnitude. Multiple cortical parcellation schemes registered to the human atlas provide valuable reference data sets for comparisons with other studies. Identified cortical areas vary in size by more than 2 orders of magnitude. The total number of human neocortical areas is estimated to be ∼150 to 200 areas per hemisphere, which is modestly larger than a recent estimate for the macaque. PMID:22047963

Cardiorespiratory effects of gap junction blockade in the locus coeruleus in unanesthetized adult rats.

PubMed

Patrone, Luis G A; Bícego, Kênia Cardoso; Hartzler, Lynn K; Putnam, Robert W; Gargaglioni, Luciane H

2014-01-01

The locus coeruleus (LC) plays an important role in central chemoreception. In young rats (P9 or younger), 85% of LC neurons increase firing rate in response to hypercapnia vs. only about 45% of neurons from rats P10 or older. Carbenoxolone (CARB - gap junction blocker) does not affect the % of LC neurons responding in young rats but it decreases the % responding by half in older animals. We evaluated the participation of gap junctions in the CO2 ventilatory response in unanesthetized adult rats by bilaterally microinjecting CARB (300μM, 1mM or 3mM/100nL), glycyrrhizic acid (GZA, CARB analog, 3mM) or vehicle (aCSF - artificial cerebrospinal fluid) into the LC of Wistar rats. Bilateral gap junction blockade in LC neurons did not affect resting ventilation; however, the increase in ventilation produced by hypercapnia (7% CO2) was reduced by ∼25% after CARB 1mM or 3mM injection (1939.7±104.8mLkg(-1)min(-1) for the aCSF group and 1468.3±122.2mLkg(-1)min(-1) for 1mM CARB, P<0.05; 1939.7±104.8mLkg(-1)min(-1) for the aCSF group and 1540.9±68.4mLkg(-1)min(-1) for the 3mM CARB group, P<0.05) due largely to a decrease in respiratory frequency. GZA injection or CARB injection outside the LC (peri-LC) had no effect on ventilation under any conditions. The results suggest that gap junctions in the LC modulate the hypercapnic ventilatory response of adult rats. Copyright © 2013 Elsevier B.V. All rights reserved.

Measurement of growth hormone-releasing hormone and somatostatin in hypothalamic-portal plasma of unanesthetized sheep. Spontaneous secretion and response to insulin-induced hypoglycemia.

PubMed Central

Frohman, L A; Downs, T R; Clarke, I J; Thomas, G B

1990-01-01

To elucidate the role of growth hormone (GH)-releasing hormone (GRH) and somatostatin (SRIH) in the regulation of the growth hormone (GH) secretory pattern, we collected portal blood from five unanesthetized ovariectomized ewes for repeated measurements of GRH and SRIH simultaneous with those of peripheral GH. Hormones were measured at 10-min intervals for 5.5 h and their interrelationships analyzed. Mean portal GRH was 20.4 +/- 6.7 (SD) pg/ml and the estimated overall secretion rate was 13 pg/min. GRH secretion was pulsatile with peaks of 25-40 pg/ml and a mean pulse interval of 71 min. Mean portal SRIH was 72 +/- 33 pg/ml and the estimated overall secretion rate was 32 pg/min. SRIH secretion was also pulsatile with peaks of 65-160 pg/ml and a mean pulse interval of 54 min. The GH pulse interval was 62 min. A significant association was present between GRH and GH secretory peaks though not between GRH and SRIH or SRIH and GH. Insulin hypoglycemia resulted in a rapid and brief stimulation of SRIH secretion followed by a decline in GH levels. No effect was observed on GRH secretion until 90 min, when a slight increase occurred. The results suggest (a) the presence of an independent neural rhythmicity of GRH and SRIH secretion with a primary role of GRH in determining pulsatile GRH secretion, and (b) that the inhibitory effects of insulin hypoglycemia on GH in this species are attributable to a combination of enhanced SRIH secretion and possibly other factors, though without significant inhibition of GRH. PMID:1973173

Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.

PubMed

Snapper, J R; Hutchison, A A; Ogletree, M L; Brigham, K L

1983-07-01

The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.

Acid-base balance in the developing marsupial: from ectotherm to endotherm.

PubMed

Andrewartha, Sarah J; Cummings, Kevin J; Frappell, Peter B

2014-05-01

Marsupial joeys are born ectothermic and develop endothermy within their mother's thermally stable pouch. We hypothesized that Tammar wallaby joeys would switch from α-stat to pH-stat regulation during the transition from ectothermy to endothermy. To address this, we compared ventilation (Ve), metabolic rate (Vo2), and variables relevant to blood gas and acid-base regulation and oxygen transport including the ventilatory requirements (Ve/Vo2 and Ve/Vco2), partial pressures of oxygen (PaO2), carbon dioxide (PaCO2), pHa, and oxygen content (CaO2) during progressive hypothermia in ecto- and endothermic Tammar wallabies. We also measured the same variables in the well-studied endotherm, the Sprague-Dawley rat. Hypothermia was induced in unrestrained, unanesthetized joeys and rats by progressively dropping the ambient temperature (Ta). Rats were additionally exposed to helox (80% helium, 20% oxygen) to facilitate heat loss. Respiratory, metabolic, and blood-gas variables were measured over a large body temperature (Tb) range (∼15-16°C in both species). Ectothermic joeys displayed limited thermogenic ability during cooling: after an initial plateau, Vo2 decreased with the progressive drop in Tb. The Tb of endothermic joeys and rats fell despite Vo2 nearly doubling with the initiation of cold stress. In all three groups the changes in Vo2 were met by changes in Ve, resulting in constant Ve/Vo2 and Ve/Vco2, blood gases, and pHa. Thus, although thermogenic capability was nearly absent in ectothermic joeys, blood acid-base regulation was similar to endothermic joeys and rats. This suggests that unlike some reptiles, unanesthetized mammals protect arterial blood pH with changing Tb, irrespective of their thermogenic ability and/or stage of development.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

PubMed

Eagleson, Kathie L; Xie, Zhihui; Levitt, Pat

2017-03-01

People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

TrpM8-mediated somatosensation in mouse neocortex.

PubMed

Beukema, Patrick; Cecil, Katherine L; Peterson, Elena; Mann, Victor R; Matsushita, Megumi; Takashima, Yoshio; Navlakha, Saket; Barth, Alison L

2018-06-15

Somatosensation is a complex sense mediated by more than a dozen distinct neural subtypes in the periphery. Although pressure and touch sensation have been mapped to primary somatosensory cortex in rodents, it has been controversial whether pain and temperature inputs are also directed to this area. Here we use a well-defined somatosensory modality, cool sensation mediated by peripheral TrpM8-receptors, to investigate the neural substrate for cool perception in the mouse neocortex. Using activation of cutaneous TrpM8 receptor-expressing neurons, we identify candidate neocortical areas responsive for cool sensation. Initially, we optimized TrpM8 stimulation and determined that menthol, a selective TrpM8 agonist, was more effective than cool stimulation at inducing expression of the immediate-early gene c-fos in the spinal cord. We developed a broad-scale brain survey method for identification of activated brain areas, using automated methods to quantify c-fos immunoreactivity (fos-IR) across animals. Brain areas corresponding to the posterior insular cortex and secondary somatosensory (S2) show elevated fos-IR after menthol stimulation, in contrast to weaker activation in primary somatosensory cortex (S1). In addition, menthol exposure triggered fos-IR in piriform cortex, the amygdala, and the hypothalamus. Menthol-mediated activation was absent in TrpM8-knock-out animals. Our results indicate that cool somatosensory input broadly drives neural activity across the mouse brain, with neocortical signal most elevated in the posterior insula, as well as S2 and S1. These findings are consistent with data from humans indicating that the posterior insula is specialized for somatosensory information encoding temperature, pain, and gentle touch. © 2018 Wiley Periodicals, Inc.

Neurochemical Mechanisms Mediating Recovery of Function.

DTIC Science & Technology

1984-11-01

and hippocampus following physical ( electrocoagulation ) and chemical (ibotenic acid) destruction of the Ch neurons in the nucleus basalis...contains magnocellular Ch neurons which project primarily to ipsilateral neocortex (14). The destruction of these Ch neurons by electrocoagulation (16

The Microcircuit Concept Applied to Cortical Evolution: from Three-Layer to Six-Layer Cortex

PubMed Central

Shepherd, Gordon M.

2011-01-01

Understanding the principles of organization of the cerebral cortex requires insight into its evolutionary history. This has traditionally been the province of anatomists, but evidence regarding the microcircuit organization of different cortical areas is providing new approaches to this problem. Here we use the microcircuit concept to focus first on the principles of microcircuit organization of three-layer cortex in the olfactory cortex, hippocampus, and turtle general cortex, and compare it with six-layer neocortex. From this perspective it is possible to identify basic circuit elements for recurrent excitation and lateral inhibition that are common across all the cortical regions. Special properties of the apical dendrites of pyramidal cells are reviewed that reflect the specific adaptations that characterize the functional operations in the different regions. These principles of microcircuit function provide a new approach to understanding the expanded functional capabilities elaborated by the evolution of the neocortex. PMID:21647397

Electrical coupling regulates layer 1 interneuron microcircuit formation in the neocortex

PubMed Central

Yao, Xing-Hua; Wang, Min; He, Xiang-Nan; He, Fei; Zhang, Shu-Qing; Lu, Wenlian; Qiu, Zi-Long; Yu, Yong-Chun

2016-01-01

The coexistence of electrical and chemical synapses among interneurons is essential for interneuron function in the neocortex. However, it remains largely unclear whether electrical coupling between interneurons influences chemical synapse formation and microcircuit assembly during development. Here, we show that electrical and GABAergic chemical connections robustly develop between interneurons in neocortical layer 1 over a similar time course. Electrical coupling promotes action potential generation and synchronous firing between layer 1 interneurons. Furthermore, electrically coupled interneurons exhibit strong GABA-A receptor-mediated synchronous synaptic activity. Disruption of electrical coupling leads to a loss of bidirectional, but not unidirectional, GABAergic connections. Moreover, a reduction in electrical coupling induces an increase in excitatory synaptic inputs to layer 1 interneurons. Together, these findings strongly suggest that electrical coupling between neocortical interneurons plays a critical role in regulating chemical synapse development and precise formation of circuits. PMID:27510304

Prenatal Organophosphates Exposure Alternates the Cleavage Plane Orientation of Apical Neural Progenitor in Developing Neocortex

PubMed Central

Chen, Xiao-Ping; Chen, Wei-Feng; Wang, Da-Wei

2014-01-01

Prenatal organophosphate exposure elicits long-term brain cytoarchitecture and cognitive function impairments, but the mechanism underlying the onset and development of neural progenitors remain largely unclear. Using precise positioned brain slices, we observed an alternated cleavage plane bias that emerged in the mitotic neural progenitors of embryonal neocortex with diazinion (DZN) and chlorpyrifos (CPF) pretreatment. In comparison with the control, DZN and CPF treatment induced decrease of vertical orientation, increase of oblique orientation, and increase of horizontal orientation. That is, the cleavage plane orientation bias had been rotated from vertical to horizontal after DZN and CPF treatment. Meanwhile, general morphology and mitotic index of the progenitors were unchanged. Acephate (ACP), another common organophosphate, had no significant effects on the cleavage plane orientation, cell morphology and mitotic index. These results represent direct evidence for the toxicity mechanism in onset multiplication of neural progenitors. PMID:24740262

Coding principles of the canonical cortical microcircuit in the avian brain

PubMed Central

Calabrese, Ana; Woolley, Sarah M. N.

2015-01-01

Mammalian neocortex is characterized by a layered architecture and a common or “canonical” microcircuit governing information flow among layers. This microcircuit is thought to underlie the computations required for complex behavior. Despite the absence of a six-layered cortex, birds are capable of complex cognition and behavior. In addition, the avian auditory pallium is composed of adjacent information-processing regions with genetically identified neuron types and projections among regions comparable with those found in the neocortex. Here, we show that the avian auditory pallium exhibits the same information-processing principles that define the canonical cortical microcircuit, long thought to have evolved only in mammals. These results suggest that the canonical cortical microcircuit evolved in a common ancestor of mammals and birds and provide a physiological explanation for the evolution of neural processes that give rise to complex behavior in the absence of cortical lamination. PMID:25691736

The thalamus as a monitor of motor outputs.

PubMed Central

Guillery, R W; Sherman, S M

2002-01-01

Many of the ascending pathways to the thalamus have branches involved in movement control. In addition, the recently defined, rich innervation of 'higher' thalamic nuclei (such as the pulvinar) from pyramidal cells in layer five of the neocortex also comes from branches of long descending axons that supply motor structures. For many higher thalamic nuclei the clue to understanding the messages that are relayed to the cortex will depend on knowing the nature of these layer five motor outputs and on defining how messages from groups of functionally distinct output types are combined as inputs to higher cortical areas. Current evidence indicates that many and possibly all thalamic relays to the neocortex are about instructions that cortical and subcortical neurons are contributing to movement control. The perceptual functions of the cortex can thus be seen to represent abstractions from ongoing motor instructions. PMID:12626014

Caffeine Controls Glutamatergic Synaptic Transmission and Pyramidal Neuron Excitability in Human Neocortex

PubMed Central

Kerkhofs, Amber; Xavier, Ana C.; da Silva, Beatriz S.; Canas, Paula M.; Idema, Sander; Baayen, Johannes C.; Ferreira, Samira G.; Cunha, Rodrigo A.; Mansvelder, Huibert D.

2018-01-01

Caffeine is the most widely used psychoactive drug, bolstering attention and normalizing mood and cognition, all functions involving cerebral cortical circuits. Whereas studies in rodents showed that caffeine acts through the antagonism of inhibitory A1 adenosine receptors (A1R), neither the role of A1R nor the impact of caffeine on human cortical neurons is known. We here provide the first characterization of the impact of realistic concentrations of caffeine experienced by moderate coffee drinkers (50 μM) on excitability of pyramidal neurons and excitatory synaptic transmission in the human temporal cortex. Moderate concentrations of caffeine disinhibited several of the inhibitory A1R-mediated effects of adenosine, similar to previous observations in the rodent brain. Thus, caffeine restored the adenosine-induced decrease of both intrinsic membrane excitability and excitatory synaptic transmission in the human pyramidal neurons through antagonism of post-synaptic A1R. Indeed, the A1R-mediated effects of endogenous adenosine were more efficient to inhibit synaptic transmission than neuronal excitability. This was associated with a distinct affinity of caffeine for synaptic versus extra-synaptic human cortical A1R, probably resulting from a different molecular organization of A1R in human cortical synapses. These findings constitute the first neurophysiological description of the impact of caffeine on pyramidal neuron excitability and excitatory synaptic transmission in the human temporal cortex, providing adequate ground for the effects of caffeine on cognition in humans. PMID:29354052

[Pathological neocortical findings in patients with medication-resistant medial temporal lobe epilepsy submitted to surgery].

PubMed

Estupiñán-Díaz, B; Morales-Chacón, L M; Lorigados-Pedre, L; García-Maeso, I; Bender-del Busto, J E; Trápaga-Quincoses, O; Hidalgo-Portal, L; García-Navarro, M E; Sánchez-Coroneaux, A; Orozco-Suárez, S

The dual pathology consisting of hippocampal sclerosis plus focal cortical dysplasia (FCD) is often reported in patients with medication-resistant medial temporal lobe epilepsy (MTLE). To determine the histopathological changes that take place in the neocortex of patients with medication-resistant MTLE submitted to surgery and to evaluate the relation between the histopathological changes, pathological background and the clinical course of patients who had received surgical treatment. Tissue obtained by en bloc resection from the neocortex of 18 patients with MTLE refractory to medical treatment was processed histologically and a tailored temporal lobectomy was performed with electrocorticography. Dual pathology was diagnosed in 13 patients (72.2%). Imaging studies confirmed the existence of mesial sclerosis of the temporal in 100% of cases and there was no evidence of neocortical lesions. Histologically, 46.15% and 38.46% of the patients were diagnosed as belonging to FCD type 1a and FCD type 1b, respectively. Only one patient presented FCD type 2a. A statistically significant relation was found between the presence of dual pathology and the existence of an early precipitating injury (p = 0.04). One year after surgery, 72.7% (8/11) patients with dual pathology were classified as belonging to Engel class I. In patients with MTLE there are microscopic FCD-type alterations in the neocortex. There is an association between these alterations and the existence of an initial precipitating injury. Complete resection of the epileptogenic area, which is guaranteed by the lobectomy tailored by electrocorticography, allows patients to enjoy a favourable post-surgical progression one year after surgery.

The Role Of Basal Forebrain Cholinergic Neurons In Fear and Extinction Memory

PubMed Central

Knox, Dayan

2016-01-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. PMID:27264248

Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis.

PubMed

Batista, Sonia; Zivadinov, Robert; Hoogs, Marietta; Bergsland, Niels; Heininen-Brown, Mari; Dwyer, Michael G; Weinstock-Guttman, Bianca; Benedict, Ralph H B

2012-01-01

Information-processing speed (IPS) slowing is a primary cognitive deficit in multiple sclerosis (MS). Basal ganglia, thalamus and neocortex are thought to have a key role for efficient information-processing, yet the specific relative contribution of these structures for MS-related IPS impairment is poorly understood. To determine if basal ganglia and thalamus atrophy independently contribute to visual and auditory IPS impairment in MS, after controlling for the influence of neocortical volume, we enrolled 86 consecutive MS patients and 25 normal controls undergoing 3T brain MRI and neuropsychological testing. Using Sienax and FIRST software, neocortical and deep gray matter (DGM) volumes were calculated. Neuropsychological testing contributed measures of auditory and visual IPS using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), respectively. MS patients exhibited significantly slower IPS relative to controls and showed reduction in neocortex, caudate, putamen, globus pallidus, thalamus and nucleus accumbens volume. SDMT and PASAT were significantly correlated with all DGM regions. These effects were mitigated by controlling for the effects of neocortical volume, but all DGM volumes remained significantly correlated with SDMT, putamen (r = 0.409, p < 0.001) and thalamus (r = 0.362, p < 0.001) having the strongest effects, whereas for PASAT, the correlation was significant for putamen (r = 0.313, p < 0.01) but not for thalamus. We confirm the significant role of thalamus atrophy in MS-related IPS slowing and find that putamen atrophy is also a significant contributor to this disorder. These DGM structures have independent, significant roles, after controlling for the influence of neocortex atrophy.

PDGF-responsive progenitors persist in the subventricular zone across the lifespan

PubMed Central

Moore, Lisamarie; Bain, Jennifer M.; Loh, Ji Meng; Levison, Steven W.

2013-01-01

The SVZ (subventricular zone) contains neural stem cells and progenitors of various potentialities. Although initially parsed into A, B, and C cells, this germinal zone is comprised of a significantly more diverse population of cells. Here, we characterized a subset of postnatal PRPs (PDGF-AA-responsive precursors) that express functional PDGFα and β receptors from birth to adulthood. When grown in PDGF-AA, dissociated neonatal rat SVZ cells divided to produce non-adherent clusters of progeny. Unlike the self-renewing EGF/FGF-2-responsive precursors that produce neurospheres, these PRPs failed to self-renew after three passages; therefore, we refer to the colonies they produce as spheroids. Upon differentiation these spheroids could produce neurons, type 1 astrocytes and oligodendrocytes. When maintained in medium supplemented with BMP-4 they also produced type 2 astrocytes. Using lineage tracing methods, it became evident that there were multiple types of PRPs, including a subset that could produce neurons, oligodendrocytes, and type 1 and type 2 astrocytes; thus some of these PRPs represent a unique population of precursors that are quatropotential. Spheroids also could be generated from the newborn neocortex and they had the same potentiality as those from the SVZ. By contrast, the adult neocortex produced less than 20% of the numbers of spheroids than the adult SVZ and spheroids from the adult neocortex only differentiated into glial cells. Interestingly, SVZ spheroid producing capacity diminished only slightly from birth to adulthood. Altogether these data demonstrate that there are PRPs that persist in the SVZ that includes a unique population of quatropotential PRPs. PMID:24367913

S-phase duration is the main target of cell cycle regulation in neural progenitors of developing ferret neocortex.

PubMed

Turrero García, Miguel; Chang, YoonJeung; Arai, Yoko; Huttner, Wieland B

2016-02-15

The evolutionary expansion of the neocortex primarily reflects increases in abundance and proliferative capacity of cortical progenitors and in the length of the neurogenic period during development. Cell cycle parameters of neocortical progenitors are an important determinant of cortical development. The ferret (Mustela putorius furo), a gyrencephalic mammal, has gained increasing importance as a model for studying corticogenesis. Here, we have studied the abundance, proliferation, and cell cycle parameters of different neural progenitor types, defined by their differential expression of the transcription factors Pax6 and Tbr2, in the various germinal zones of developing ferret neocortex. We focused our analyses on postnatal day 1, a late stage of cortical neurogenesis when upper-layer neurons are produced. Based on cumulative 5-ethynyl-2'-deoxyuridine (EdU) labeling as well as Ki67 and proliferating cell nuclear antigen (PCNA) immunofluorescence, we determined the duration of the various cell cycle phases of the different neocortical progenitor subpopulations. Ferret neocortical progenitors were found to exhibit longer cell cycles than those of rodents and little variation in the duration of G1 among distinct progenitor types, also in contrast to rodents. Remarkably, the main difference in cell cycle parameters among the various progenitor types was the duration of S-phase, which became shorter as progenitors progressively changed transcription factor expression from patterns characteristic of self-renewal to those of neuron production. Hence, S-phase duration emerges as major target of cell cycle regulation in cortical progenitors of this gyrencephalic mammal. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

A unified theory for systems and cellular memory consolidation.

PubMed

Dash, Pramod K; Hebert, April E; Runyan, Jason D

2004-04-01

The time-limited role of the hippocampus for explicit memory storage has been referred to as systems consolidation where learning-related changes occur first in the hippocampus followed by the gradual development of a more distributed memory trace in the neocortex. Recent experiments are beginning to show that learning induces plasticity-related molecular changes in the neocortex as well as in the hippocampus and with a similar time course. Present memory consolidation theories do not account for these findings. In this report, we present a theory (the C theory) that incorporates these new findings, provides an explanation for the length of time for hippocampal dependency, and that can account for the apparent longer consolidation periods in species with larger brains. This theory proposes that a process of cellular consolidation occurs in the hippocampus and in areas of the neocortex during and shortly after learning resulting in long-term memory storage in both areas. For a limited time, the hippocampus is necessary for memory retrieval, a process involving the coordinated reactivation of these areas. This reactivation is later mediated by longer extrahippocampal connectivity between areas. The delay in hippocampal-independent memory retrieval is the time it takes for gene products in these longer extrahippocampal projections to be transported from the soma to tagged synapses by slow axonal transport. This cellular transport event defines the period of hippocampal dependency and, thus, the duration of memory consolidation. The theoretical description for memory consolidation presented in this review provides alternative explanations for several experimental observations and presents a unification of the concepts of systems and cellular memory consolidation.

Virology, Immunology and Pathology of Human Rabies During Treatment

PubMed Central

Caicedo, Yolanda; Paez, Andres; Kuzmin, Ivan; Niezgoda, Michael; Orciari, Lillian A.; Yager, Pamela A.; Recuenco, Sergio; Franka, Richard; Velasco-Villa, Andres; Willoughby, Rodney E.

2016-01-01

Background Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus. The first human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005. We report a second unvaccinated patient who showed early recovery from rabies and then died accidentally during convalescence, providing an unparalleled opportunity to examine the histopathology as well as immune and virological correlates of early recovery from human rabies. Methods Case report, rapid fluorescent focus inhibition test, enzyme-linked immunosorbent assay, indirect and direct fluorescent antibody assays, reverse-transcriptase polymerase chain reaction, phylogenetic reconstruction, isolation in tissue culture, pathology and immunohistochemistry. Results The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by cat bite. Antibody response in serum and cerebrospinal fluid was robust and associated with severe cerebral edema. No rabies virus was cultured at autopsy. Rabies virus antigen was atypical in size and distribution. Rabies virus genome was present in neocortex but absent in brainstem. Conclusions Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious rabies virus in the central nervous system by 76 days but not clearance of detectable viral subcomponents such as nucleoprotein antigen or RNA in brain. PMID:25405805

Cortical and subcortical innervation of band heterotopia after developmental thyroid hormone insufficiency

EPA Science Inventory

The characteristic laminated cytoarchitecture of the neocortex emerges from the orderly proliferation and migration of neurons during corticogenesis. Not surprisingly, developmental disorders affecting the laminar positioning of cortical neurons can have dramatic affects on cogni...

Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer's mouse model: Implication of TLR4 signaling in disease progression.

PubMed

Go, Michelle; Kou, Jinghong; Lim, Jeong-Eun; Yang, Junling; Fukuchi, Ken-Ichiro

2016-10-14

Microglia-mediated clearance of amyloid beta-protein (Aβ) via Toll-like receptor 4 (TLR4) signaling may play an important role in the pathogenesis of Alzheimer's disease (AD). However, as the disease progresses, activated microglia appear to become incapable of clearing Aβ deposits. Because repeated exposure to a TLR4 ligand leads to a diminished response of monocytes/macrophages to lipopolysaccharide (LPS) and because aggregated Aβ is a TLR4 ligand, we hypothesize that chronic exposure of microglia to Aβ deposits may induce a state of Toll-like receptor (TLR) signaling dysfunction, leading to decreased Aβ clearance and accelerated disease progression. LPS or phosphate-buffered saline (PBS) was injected into the hippocampus of AD-model (TgAPP/PS1) and wild-type (non-Tg) mice before and after the onset of Aβ deposition, at age 2 and 12 months, respectively. Brain specimens were collected 7 days post-injection and analyzed for microglial activation and Aβ load. While LPS-injected 2-month-old non-Tg mice showed 48-fold and 11-fold greater Iba1 immunoreactivity in the neocortex and hippocampus, respectively, compared with PBS-injected mice, LPS-injected 2-month-old TgAPP/PS1 mice had 61-fold and 13-fold increases in the neocortex and hippocampus, respectively. LPS injection activated microglia more strongly in TgAPP/PS1 mice than in non-Tg mice at 2 months of age. In contrast, at 12 months of age, Iba1 immunoreactivity of microglia was increased 541-fold and 38-fold in the neocortex and hippocampus, respectively, in LPS-injected non-Tg mice and 2.7-fold and 3.3-fold in the neocortex and hippocampus, respectively, in LPS-injected TgAPP/PS1 mice. Surprisingly, LPS injection decreased CD45 immunoreactivity in TgAPP/PS1 mice but increased it in non-Tg mice at 12 months. Although microglia in 12-month-old non-Tg mice showed stronger response to LPS than 2-month-old non-Tg mice, microglia in TgAPP/PS1 mice exhibited diminished immune response to LPS during aging. Our data indicate that microglial TLR4 signaling is altered in an AD mouse model and suggest that altered TLR4 signaling may contribute to Aβ accumulation in the brain. Copyright © 2016 Elsevier Inc. All rights reserved.

Exploring emotions using invasive methods: review of 60 years of human intracranial electrophysiology

PubMed Central

Guillory, Sean A.

2014-01-01

Over the past 60 years, human intracranial electrophysiology (HIE) has been used to characterize seizures in patients with epilepsy. Secondary to the clinical objectives, electrodes implanted intracranially have been used to investigate mechanisms of human cognition. In addition to studies of memory and language, HIE methods have been used to investigate emotions. The aim of this review is to outline the contribution of HIE (electrocorticography, single-unit recording and electrical brain stimulation) to our understanding of the neural representations of emotions. We identified 64 papers dating back to the mid-1950s which used HIE techniques to study emotional states. Evidence from HIE studies supports the existence of widely distributed networks in the neocortex, limbic/paralimbic regions and subcortical nuclei which contribute to the representation of emotional states. In addition, evidence from HIE supports hemispheric dominance for emotional valence. Furthermore, evidence from HIE supports the existence of overlapping neural areas for emotion perception, experience and expression. Lastly, HIE provides unique insights into the temporal dynamics of neural activation during perception, experience and expression of emotional states. In conclusion, we propose that HIE techniques offer important evidence which must be incorporated into our current models of emotion representation in the human brain. PMID:24509492

The organization and neural substrates of human memory.

PubMed

Squire, L R

The neurology of memory has been illuminated by parallel studies of patients with circumscribed memory impairment and animal models of human amnesia. Human amnesia can occur as an isolated cognitive deficit that impairs the ability to learn new facts and episodes. In addition, memory can be affected for material learned many years prior to the onset of amnesia. The finding that some memory abilities are intact in amnesia (e.g., skill learning, word priming, and adaptation-level effects) has suggested that memory can be divided into two or more separate processes. Declarative memory affords the ability to store information explicitly and to retrieve it later as a conscious recollection. This form of memory depends on the integrity of the structures damaged in amnesia. Other, non-declarative kinds of memory afford the ability to change as the result of experience, but the information is available only through performance. Recent studies of a favorable human case provided strong evidence that the hippocampus is a critical component of the declarative memory system. Extensive convergent and divergent projections link the hippocampus to many areas of neocortex where processing and storage of new information is likely to occur. It is perhaps by way of these connections that the hippocampus operates upon and participates in declarative representations.

Bayesian Networks Predict Neuronal Transdifferentiation.

PubMed

Ainsworth, Richard I; Ai, Rizi; Ding, Bo; Li, Nan; Zhang, Kai; Wang, Wei

2018-05-30

We employ the language of Bayesian networks to systematically construct gene-regulation topologies from deep-sequencing single-nucleus RNA-Seq data for human neurons. From the perspective of the cell-state potential landscape, we identify attractors that correspond closely to different neuron subtypes. Attractors are also recovered for cell states from an independent data set confirming our models accurate description of global genetic regulations across differing cell types of the neocortex (not included in the training data). Our model recovers experimentally confirmed genetic regulations and community analysis reveals genetic associations in common pathways. Via a comprehensive scan of all theoretical three-gene perturbations of gene knockout and overexpression, we discover novel neuronal trans-differrentiation recipes (including perturbations of SATB2, GAD1, POU6F2 and ADARB2) for excitatory projection neuron and inhibitory interneuron subtypes. Copyright © 2018, G3: Genes, Genomes, Genetics.

THE NEUROTOXICANT TRIMETHYLTIN STIMULATES APOPTOSIS VIA OXIDATIVE STRESS, CASPASE ACTIVATION AND P38 PROTEIN KINASE.

EPA Science Inventory

Acute exposure to the tri-substituted organotin trimethyltin (TMT) causes neuronal degeneration in the hippocampus, amygdala, pyriform cortex, and neocortex. Developmental exposure to TMT impairs later learning and memory. Despite extensive efforts elucidating neuropathological...

High-throughput RNA sequencing reveals structural differences of orthologous brain-expressed genes between western lowland gorillas and humans.

PubMed

Lipovich, Leonard; Hou, Zhuo-Cheng; Jia, Hui; Sinkler, Christopher; McGowen, Michael; Sterner, Kirstin N; Weckle, Amy; Sugalski, Amara B; Pipes, Lenore; Gatti, Domenico L; Mason, Christopher E; Sherwood, Chet C; Hof, Patrick R; Kuzawa, Christopher W; Grossman, Lawrence I; Goodman, Morris; Wildman, Derek E

2016-02-01

The human brain and human cognitive abilities are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure differences accounted for a total of 134 amino acids in proteins found in the gorilla that were absent from protein products of the orthologous human genes. Proteins varying in structure between human and gorilla were involved in immunity and energy metabolism, suggesting their relevance to phenotypic differences. This gorilla neocortical transcriptome comprises an empirical, not homology- or prediction-driven, resource for orthologous gene comparisons between human and gorilla. These findings provide a unique repository of the sequences and structures of thousands of genes transcribed in the gorilla brain, pointing to candidate genes that may contribute to the traits distinguishing humans from other closely related great apes. © 2015 Wiley Periodicals, Inc.

Rapid and automatic speech-specific learning mechanism in human neocortex.

PubMed

Kimppa, Lilli; Kujala, Teija; Leminen, Alina; Vainio, Martti; Shtyrov, Yury

2015-09-01

A unique feature of human communication system is our ability to rapidly acquire new words and build large vocabularies. However, its neurobiological foundations remain largely unknown. In an electrophysiological study optimally designed to probe this rapid formation of new word memory circuits, we employed acoustically controlled novel word-forms incorporating native and non-native speech sounds, while manipulating the subjects' attention on the input. We found a robust index of neurolexical memory-trace formation: a rapid enhancement of the brain's activation elicited by novel words during a short (~30min) perceptual exposure, underpinned by fronto-temporal cortical networks, and, importantly, correlated with behavioural learning outcomes. Crucially, this neural memory trace build-up took place regardless of focused attention on the input or any pre-existing or learnt semantics. Furthermore, it was found only for stimuli with native-language phonology, but not for acoustically closely matching non-native words. These findings demonstrate a specialised cortical mechanism for rapid, automatic and phonology-dependent formation of neural word memory circuits. Copyright © 2015. Published by Elsevier Inc.

Structure-activity comparison of organotin species: dibutyltin is a developmental neurotoxicant in vitro and in vivo.

PubMed

Jenkins, Scott M; Ehman, Kimberly; Barone, Stanley

2004-07-19

Human exposure to the organotins can occur due to their use as polyvinyl chloride heat stabilizers and as marine biocides. The consequences of this exposure for human health are unknown. We initially compared the toxicity of monomethyltin, dimethyltin, and dibutyltin to the known neurotoxicant trimethyltin using an in vitro model of neuronal development in PC12 cells. Dibutyltin, a compound traditionally thought to target the immune system, was the most potent neurotoxicant. Dibutyltin significantly inhibited neurite outgrowth and caused cell death at concentrations approximately 40-fold lower than the lowest toxic concentrations of trimethyltin. Dimethyltin was less potent than trimethyltin and monomethyltin was not toxic at any concentration examined. These results suggested the importance of prioritizing in vivo neurotoxicity testing with dibutyltin. To accomplish this, pregnant rats were dosed orally with low levels of dibutyltin from gestational day 6 through weaning. In response to developmental dibutyltin exposure, the incidence of apoptotic cell death, measured by DNA fragmentation and TUNEL staining, was increased in the neocortex and hippocampus of postnatal day 38 offspring. No effect was observed at other ages examined.

3D Culture for Self-Formation of the Cerebellum from Human Pluripotent Stem Cells Through Induction of the Isthmic Organizer.

PubMed

Muguruma, Keiko

2017-01-01

Pluripotent stem cells (PSCs) possess self-organizing abilities in 3D culture. This property has been demonstrated in recent studies, including the generation of various neuroectodermal and endodermal tissues. For example, PSCs are able to differentiate into specific type of neural tissues, such as the neocortex and the optic cup, in response to local positional information brought about by signals during embryogenesis. In contrast, the generation of cerebellar tissue from PSCs requires a secondary induction by a signaling center, called the isthmic organizer, which first appears in the cell aggregate in 3D culture. Such developmental complexity of cerebellum has hampered establishment of effective differentiation culture system from PSCs, thus far.We recently reported that cerebellar neurons are generated from human PSCs (hPSCs). In this chapter, we describe an efficient protocol for differentiation of 3D cerebellar neuroepithelium from hPSCs. We also describe the protocols for further differentiation into specific neurons in the cerebellar cortex, such as Purkinje cells and the granule cells.

Hippocampal memory consolidation during sleep: a comparison of mammals and birds

PubMed Central

Rattenborg, Niels C.; Martinez-Gonzalez, Dolores; Roth, Timothy C.; Pravosudov, Vladimir V.

2010-01-01

The transition from wakefulness to sleep is marked by pronounced changes in brain activity. The brain rhythms that characterize the two main types of mammalian sleep, slow-wave sleep (SWS) and rapid eye movement (REM) sleep, are thought to be involved in the functions of sleep. In particular, recent theories suggest that the synchronous slow-oscillation of neocortical neuronal membrane potentials, the defining feature of SWS, is involved in processing information acquired during wakefulness. According to the Standard Model of memory consolidation, during wakefulness the hippocampus receives input from neocortical regions involved in the initial encoding of an experience and binds this information into a coherent memory trace that is then transferred to the neocortex during SWS where it is stored and integrated within preexisting memory traces. Evidence suggests that this process selectively involves direct connections from the hippocampus to the prefrontal cortex (PFC), a multimodal, high-order association region implicated in coordinating the storage and recall of remote memories in the neocortex. The slow-oscillation is thought to orchestrate the transfer of information from the hippocampus by temporally coupling hippocampal sharp-wave/ripples (SWRs) and thalamocortical spindles. SWRs are synchronous bursts of hippocampal activity, during which waking neuronal firing patterns are reactivated in the hippocampus and neocortex in a coordinated manner. Thalamocortical spindles are brief 7–14 Hz oscillations that may facilitate the encoding of information reactivated during SWRs. By temporally coupling the readout of information from the hippocampus with conditions conducive to encoding in the neocortex, the slow-oscillation is thought to mediate the transfer of information from the hippocampus to the neocortex. Although several lines of evidence are consistent with this function for mammalian SWS, it is unclear whether SWS serves a similar function in birds, the only taxonomic group other than mammals to exhibit SWS and REM sleep. Based on our review of research on avian sleep, neuroanatomy, and memory, although involved in some forms of memory consolidation, avian sleep does not appear to be involved in transferring hippocampal memories to other brain regions. Despite exhibiting the slow-oscillation, SWRs and spindles have not been found in birds. Moreover, although birds independently evolved a brain region – the caudolateral nidopallium (NCL) – involved in performing high-order cognitive functions similar to those performed by the PFC, direct connections between the NCL and hippocampus have not been found in birds, and evidence for the transfer of information from the hippocampus to the NCL or other extra-hippocampal regions is lacking. Although based on the absence of evidence for various traits, collectively, these findings suggest that unlike mammalian SWS, avian SWS may not be involved in transferring memories from the hippocampus. Furthermore, it suggests that the slow-oscillation, the defining feature of mammalian and avian SWS, may serve a more general function independent of that related to coordinating the transfer of information from the hippocampus to the PFC in mammals. Given that SWS is homeostatically regulated (a process intimately related to the slow-oscillation) in mammals and birds, functional hypotheses linked to this process may apply to both taxonomic groups. PMID:21070585

Hippocampal memory consolidation during sleep: a comparison of mammals and birds.

PubMed

Rattenborg, Niels C; Martinez-Gonzalez, Dolores; Roth, Timothy C; Pravosudov, Vladimir V

2011-08-01

The transition from wakefulness to sleep is marked by pronounced changes in brain activity. The brain rhythms that characterize the two main types of mammalian sleep, slow-wave sleep (SWS) and rapid eye movement (REM) sleep, are thought to be involved in the functions of sleep. In particular, recent theories suggest that the synchronous slow-oscillation of neocortical neuronal membrane potentials, the defining feature of SWS, is involved in processing information acquired during wakefulness. According to the Standard Model of memory consolidation, during wakefulness the hippocampus receives input from neocortical regions involved in the initial encoding of an experience and binds this information into a coherent memory trace that is then transferred to the neocortex during SWS where it is stored and integrated within preexisting memory traces. Evidence suggests that this process selectively involves direct connections from the hippocampus to the prefrontal cortex (PFC), a multimodal, high-order association region implicated in coordinating the storage and recall of remote memories in the neocortex. The slow-oscillation is thought to orchestrate the transfer of information from the hippocampus by temporally coupling hippocampal sharp-wave/ripples (SWRs) and thalamocortical spindles. SWRs are synchronous bursts of hippocampal activity, during which waking neuronal firing patterns are reactivated in the hippocampus and neocortex in a coordinated manner. Thalamocortical spindles are brief 7-14 Hz oscillations that may facilitate the encoding of information reactivated during SWRs. By temporally coupling the readout of information from the hippocampus with conditions conducive to encoding in the neocortex, the slow-oscillation is thought to mediate the transfer of information from the hippocampus to the neocortex. Although several lines of evidence are consistent with this function for mammalian SWS, it is unclear whether SWS serves a similar function in birds, the only taxonomic group other than mammals to exhibit SWS and REM sleep. Based on our review of research on avian sleep, neuroanatomy, and memory, although involved in some forms of memory consolidation, avian sleep does not appear to be involved in transferring hippocampal memories to other brain regions. Despite exhibiting the slow-oscillation, SWRs and spindles have not been found in birds. Moreover, although birds independently evolved a brain region--the caudolateral nidopallium (NCL)--involved in performing high-order cognitive functions similar to those performed by the PFC, direct connections between the NCL and hippocampus have not been found in birds, and evidence for the transfer of information from the hippocampus to the NCL or other extra-hippocampal regions is lacking. Although based on the absence of evidence for various traits, collectively, these findings suggest that unlike mammalian SWS, avian SWS may not be involved in transferring memories from the hippocampus. Furthermore, it suggests that the slow-oscillation, the defining feature of mammalian and avian SWS, may serve a more general function independent of that related to coordinating the transfer of information from the hippocampus to the PFC in mammals. Given that SWS is homeostatically regulated (a process intimately related to the slow-oscillation) in mammals and birds, functional hypotheses linked to this process may apply to both taxonomic groups. © 2010 The Authors. Biological Reviews © 2010 Cambridge Philosophical Society.

GESTATIONAL EXPOSURE TO CHLORPYRIFOS: QUALITATIVE AND QUANTITATIVE NEUROPATHOLOGICAL CHANGES IN THE FETAL NEOCORTEX.

EPA Science Inventory

This study investigated the qualitative and quantitative neuropathological changes that occur in the fetal brain following gestational exposure to chlorpyrifos [(O,O'diethyl O-3,5,6-trichloro-2-pyridyl) phosphorothionate], a commonly used organophosphorus insecticide. Two cohort...

Thyroid Hormone Disruption Effects Lamination of the Neocortex but not the Cerebellum in a Model of Developmental Hypothyroidism and Hypothyroxinemia

EPA Science Inventory

Introduction: Research on neurodevelopmental changes resulting from thyroid hormone (TH) disruption has important basic and clinical implications. We previously demonstrated, in a rodent model, that developmental hypothyroidism or hypothyroxinemia can cause ...

Diluted connectivity in pattern association networks facilitates the recall of information from the hippocampus to the neocortex.

PubMed

Rolls, Edmund T

2015-01-01

The recall of information stored in the hippocampus involves a series of corticocortical backprojections via the entorhinal cortex, parahippocampal gyrus, and one or more neocortical stages. Each stage is considered to be a pattern association network, with the retrieval cue at each stage the firing of neurons in the previous stage. The leading factor that determines the capacity of this multistage pattern association backprojection pathway is the number of connections onto any one neuron, which provides a quantitative basis for why there are as many backprojections between adjacent stages in the hierarchy as forward projections. The issue arises of why this multistage backprojection system uses diluted connectivity. One reason is that a multistage backprojection system with expansion of neuron numbers at each stage enables the hippocampus to address during recall the very large numbers of neocortical neurons, which would otherwise require hippocampal neurons to make very large numbers of synapses if they were directly onto neocortical neurons. The second reason is that as shown here, diluted connectivity in the backprojection pathways reduces the probability of more than one connection onto a receiving neuron in the backprojecting pathways, which otherwise reduces the capacity of the system, that is the number of memories that can be recalled from the hippocampus to the neocortex. For similar reasons, diluted connectivity is advantageous in pattern association networks in other brain systems such as the orbitofrontal cortex and amygdala; for related reasons, in autoassociation networks in, for example, the hippocampal CA3 and the neocortex; and for the different reason that diluted connectivity facilitates the operation of competitive networks in forward-connected cortical systems. © 2015 Elsevier B.V. All rights reserved.

Columnar interactions determine horizontal propagation of recurrent network activity in neocortex

PubMed Central

Wester, Jason C.; Contreras, Diego

2012-01-01

The cortex is organized in vertical and horizontal circuits that determine the spatiotemporal properties of distributed cortical activity. Despite detailed knowledge of synaptic interactions among individual cells in the neocortex, little is known about the rules governing interactions among local populations. Here we used self-sustained recurrent activity generated in cortex, also known as up-states, in rat thalamocortical slices in vitro to understand interactions among laminar and horizontal circuits. By means of intracellular recordings and fast optical imaging with voltage sensitive dyes, we show that single thalamic inputs activate the cortical column in a preferential L4→L2/3→L5 sequence, followed by horizontal propagation with a leading front in supra and infragranular layers. To understand the laminar and columnar interactions, we used focal injections of TTX to block activity in small local populations, while preserving functional connectivity in the rest of the network. We show that L2/3 alone, without underlying L5, does not generate self-sustained activity and is inefficient propagating activity horizontally. In contrast, L5 sustains activity in the absence of L2/3 and is necessary and sufficient to propagate activity horizontally. However, loss of L2/3 delays horizontal propagation via L5. Finally, L5 amplifies activity in L2/3. Our results show for the first time that columnar interactions between supra and infragranular layers are required for the normal propagation of activity in the neocortex. Our data suggest that supra and infragranular circuits with their specific and complex set of inputs and outputs, work in tandem to determine the patterns of cortical activation observed in vivo. PMID:22514308

The Construction of Semantic Memory: Grammar-Based Representations Learned from Relational Episodic Information

PubMed Central

Battaglia, Francesco P.; Pennartz, Cyriel M. A.

2011-01-01

After acquisition, memories underlie a process of consolidation, making them more resistant to interference and brain injury. Memory consolidation involves systems-level interactions, most importantly between the hippocampus and associated structures, which takes part in the initial encoding of memory, and the neocortex, which supports long-term storage. This dichotomy parallels the contrast between episodic memory (tied to the hippocampal formation), collecting an autobiographical stream of experiences, and semantic memory, a repertoire of facts and statistical regularities about the world, involving the neocortex at large. Experimental evidence points to a gradual transformation of memories, following encoding, from an episodic to a semantic character. This may require an exchange of information between different memory modules during inactive periods. We propose a theory for such interactions and for the formation of semantic memory, in which episodic memory is encoded as relational data. Semantic memory is modeled as a modified stochastic grammar, which learns to parse episodic configurations expressed as an association matrix. The grammar produces tree-like representations of episodes, describing the relationships between its main constituents at multiple levels of categorization, based on its current knowledge of world regularities. These regularities are learned by the grammar from episodic memory information, through an expectation-maximization procedure, analogous to the inside–outside algorithm for stochastic context-free grammars. We propose that a Monte-Carlo sampling version of this algorithm can be mapped on the dynamics of “sleep replay” of previously acquired information in the hippocampus and neocortex. We propose that the model can reproduce several properties of semantic memory such as decontextualization, top-down processing, and creation of schemata. PMID:21887143

Spatiotemporal alterations of cortical network activity by selective loss of NOS-expressing interneurons.

PubMed

Shlosberg, Dan; Buskila, Yossi; Abu-Ghanem, Yasmin; Amitai, Yael

2012-01-01

Deciphering the role of GABAergic neurons in large neuronal networks such as the neocortex forms a particularly complex task as they comprise a highly diverse population. The neuronal isoform of the enzyme nitric oxide synthase (nNOS) is expressed in the neocortex by specific subsets of GABAergic neurons. These neurons can be identified in live brain slices by the nitric oxide (NO) fluorescent indicator diaminofluorescein-2 diacetate (DAF-2DA). However, this indicator was found to be highly toxic to the stained neurons. We used this feature to induce acute phototoxic damage to NO-producing neurons in cortical slices, and measured subsequent alterations in parameters of cellular and network activity. Neocortical slices were briefly incubated in DAF-2DA and then illuminated through the 4× objective. Histochemistry for NADPH-diaphorase (NADPH-d), a marker for nNOS activity, revealed elimination of staining in the illuminated areas following treatment. Whole cell recordings from several neuronal types before, during, and after illumination confirmed the selective damage to non-fast-spiking (FS) interneurons. Treated slices displayed mild disinhibition. The reversal potential of compound synaptic events on pyramidal neurons became more positive, and their decay time constant was elongated, substantiating the removal of an inhibitory conductance. The horizontal decay of local field potentials (LFPs) was significantly reduced at distances of 300-400 μm from the stimulation, but not when inhibition was non-selectively weakened with the GABA(A) blocker picrotoxin. Finally, whereas the depression of LFPs along short trains of 40 Hz stimuli was linearly reduced with distance or initial amplitude in control slices, this ordered relationship was disrupted in DAF-treated slices. These results reveal that NO-producing interneurons in the neocortex convey lateral inhibition to neighboring columns, and shape the spatiotemporal dynamics of the network's activity.

The role of basal forebrain cholinergic neurons in fear and extinction memory.

PubMed

Knox, Dayan

2016-09-01

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Excitatory signal flow and connectivity in a cortical column: focus on barrel cortex.

PubMed

Lübke, Joachim; Feldmeyer, Dirk

2007-07-01

A basic feature of the neocortex is its organization in functional, vertically oriented columns, recurring modules of signal processing and a system of transcolumnar long-range horizontal connections. These columns, together with their network of neurons, present in all sensory cortices, are the cellular substrate for sensory perception in the brain. Cortical columns contain thousands of neurons and span all cortical layers. They receive input from other cortical areas and subcortical brain regions and in turn their neurons provide output to various areas of the brain. The modular concept presumes that the neuronal network in a cortical column performs basic signal transformations, which are then integrated with the activity in other networks and more extended brain areas. To understand how sensory signals from the periphery are transformed into electrical activity in the neocortex it is essential to elucidate the spatial-temporal dynamics of cortical signal processing and the underlying neuronal 'microcircuits'. In the last decade the 'barrel' field in the rodent somatosensory cortex, which processes sensory information arriving from the mysticial vibrissae, has become a quite attractive model system because here the columnar structure is clearly visible. In the neocortex and in particular the barrel cortex, numerous neuronal connections within or between cortical layers have been studied both at the functional and structural level. Besides similarities, clear differences with respect to both physiology and morphology of synaptic transmission and connectivity were found. It is therefore necessary to investigate each neuronal connection individually, in order to develop a realistic model of neuronal connectivity and organization of a cortical column. This review attempts to summarize recent advances in the study of individual microcircuits and their functional relevance within the framework of a cortical column, with emphasis on excitatory signal flow.

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.

PubMed

Sawicka, Kirsty; Pyronneau, Alexander; Chao, Miranda; Bennett, Michael V L; Zukin, R Suzanne

2016-10-11

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.

Hippocampal, amygdala, and neocortical synchronization of theta rhythms is related to an immediate recall during rey auditory verbal learning test.

PubMed

Babiloni, Claudio; Vecchio, Fabrizio; Mirabella, Giovanni; Buttiglione, Maura; Sebastiano, Fabio; Picardi, Angelo; Di Gennaro, Giancarlo; Quarato, Pier P; Grammaldo, Liliana G; Buffo, Paola; Esposito, Vincenzo; Manfredi, Mario; Cantore, Giampaolo; Eusebi, Fabrizio

2009-07-01

It is well known that theta rhythms (3-8 Hz) are the fingerprint of hippocampus, and that neural activity accompanying encoding of words differs according to whether the items are later remembered or forgotten ["subsequent memory effect" (SME)]. Here, we tested the hypothesis that temporal synchronization of theta rhythms among hippocampus, amygdala, and neocortex is related to immediate memorization of repeated words. To address this issue, intracerebral electroencephalographic (EEG) activity was recorded in five subjects with drug-resistant temporal lobe epilepsy (TLE), under presurgical monitoring routine. During the recording of the intracerebral EEG activity, the subjects performed a computerized version of Rey auditory verbal learning test (RAVLT), a popular test for the clinical evaluation of the immediate and delayed memory. They heard the same list of 15 common words for five times. Each time, immediately after listening the list, the subjects were required to repeat as many words as they could recall. Spectral coherence of the intracerebral EEG activity was computed in order to assess the temporal synchronization of the theta (about 3-8 Hz) rhythms among hippocampus, amygdala, and temporal-occipital neocortex. We found that theta coherence values between amygdala and hippocampus, and between hippocampus and occipital-temporal cortex, were higher in amplitude during successful than unsuccessful immediate recall. A control analysis showed that this was true also for a gamma band (40-45 Hz). Furthermore, these theta and gamma effects were not observed in an additional (control) subject with drug-resistant TLE and a wide lesion to hippocampus. In conclusion, a successful immediate recall to the RAVLT was associated to the enhancement of temporal synchronization of the theta (gamma) rhythms within a cerebral network including hippocampus, amygdala, and temporal-occipital neocortex. Copyright 2009 Wiley-Liss, Inc

The pathways connecting the hippocampal formation, the thalamic reuniens nucleus and the thalamic reticular nucleus in the rat.

PubMed

Cavdar, Safiye; Onat, Filiz Y; Cakmak, Yusuf Ozgür; Yananli, Hasan R; Gülçebi, Medine; Aker, Rezzan

2008-03-01

Most dorsal thalamic nuclei send axons to specific areas of the neocortex and to specific sectors of the thalamic reticular nucleus; the neocortex then sends reciprocal connections back to the same thalamic nucleus, directly as well indirectly through a relay in the thalamic reticular nucleus. This can be regarded as a 'canonical' circuit of the sensory thalamus. For the pathways that link the thalamus and the hippocampal formation, only a few comparable connections have been described. The reuniens nucleus of the thalamus sends some of its major cortical efferents to the hippocampal formation. The present study shows that cells of the hippocampal formation as well as cells in the reuniens nucleus are retrogradely labelled following injections of horseradish peroxidase or fluoro-gold into the rostral part of the thalamic reticular nucleus in the rat. Within the hippocampal formation, labelled neurons were localized in the subiculum, predominantly on the ipsilateral side, with fewer neurons labelled contralaterally. Labelled neurons were seen in the hippocampal formation and nucleus reuniens only after injections made in the rostral thalamic reticular nucleus (1.6-1.8 mm caudal to bregma). In addition, the present study confirmed the presence of afferent connections to the rostral thalamic reticular nucleus from cortical (cingulate, orbital and infralimbic, retrosplenial and frontal), midline thalamic (paraventricular, anteromedial, centromedial and mediodorsal thalamic nuclei) and brainstem structures (substantia nigra pars reticularis, ventral tegmental area, periaqueductal grey, superior vestibular and pontine reticular nuclei). These results demonstrate a potential for the thalamo-hippocampal circuitry to influence the functional roles of the thalamic reticular nucleus, and show that thalamo-hippocampal connections resemble the circuitry that links the sensory thalamus and neocortex.

The pathways connecting the hippocampal formation, the thalamic reuniens nucleus and the thalamic reticular nucleus in the rat

PubMed Central

Çavdar, Safiye; Onat, Filiz Y; Çakmak, Yusuf Özgür; Yananli, Hasan R; Gülçebi, Medine; Aker, Rezzan

2008-01-01

Most dorsal thalamic nuclei send axons to specific areas of the neocortex and to specific sectors of the thalamic reticular nucleus; the neocortex then sends reciprocal connections back to the same thalamic nucleus, directly as well indirectly through a relay in the thalamic reticular nucleus. This can be regarded as a ‘canonical’ circuit of the sensory thalamus. For the pathways that link the thalamus and the hippocampal formation, only a few comparable connections have been described. The reuniens nucleus of the thalamus sends some of its major cortical efferents to the hippocampal formation. The present study shows that cells of the hippocampal formation as well as cells in the reuniens nucleus are retrogradely labelled following injections of horseradish peroxidase or fluoro-gold into the rostral part of the thalamic reticular nucleus in the rat. Within the hippocampal formation, labelled neurons were localized in the subiculum, predominantly on the ipsilateral side, with fewer neurons labelled contralaterally. Labelled neurons were seen in the hippocampal formation and nucleus reuniens only after injections made in the rostral thalamic reticular nucleus (1.6–1.8 mm caudal to bregma). In addition, the present study confirmed the presence of afferent connections to the rostral thalamic reticular nucleus from cortical (cingulate, orbital and infralimbic, retrosplenial and frontal), midline thalamic (paraventricular, anteromedial, centromedial and mediodorsal thalamic nuclei) and brainstem structures (substantia nigra pars reticularis, ventral tegmental area, periaqueductal grey, superior vestibular and pontine reticular nuclei). These results demonstrate a potential for the thalamo-hippocampal circuitry to influence the functional roles of the thalamic reticular nucleus, and show that thalamo-hippocampal connections resemble the circuitry that links the sensory thalamus and neocortex. PMID:18221482

Distribution of CaMKIIα expression in the brain in vivo, studied by CaMKIIα-GFP mice

PubMed Central

Wang, Xinjun; Zhang, Chunzhao; Szábo, Gábor; Sun, Qian-Quan

2013-01-01

To facilitate the study of the CaMKIIα function in vivo, a CaMKIIα-GFP transgenic mouse line was generated. Here, our goal is to provide the first neuroanatomical characterization of GFP expression in the CNS of this line of mouse. Overall, CaMKIIα -GFP expression is strong and highly heterogeneous, with the dentate gyrus of the hippocampus as the most abundantly expressed region. In the hippocampus, around 70% of granule and pyramidal neurons expressed strong GFP. In the neocortex, presumed pyramidal neurons were GFP positive: around 32% of layer II/III and 35% of layer VI neurons expressed GFP, and a lower expression rate was found in other layers. In the thalamus and hypothalamus, strong GFP signals were detected in the neuropil. GFP-positive cells were also found in many other regions such as the spinal trigeminal nucleus, cerebellum and basal ganglia. We further compared the GFP expression with specific antibody staining for CaMKIIα and GABA. We found that GFP+ neurons were mostly positive for CaMKIIα-IR throughout the brain, with some exceptions throughout the brain, especially in the deeper layers of neocortex. GFP and GABA-IR marked distinct neuronal populations in most brain regions with the exception of granule cells in the olfactory bulb, purkinje cells in the cerebellar, and some layer I cells in neocortex. In conclusion, GFP expression in the CaMKIIα-GFP mice is similar to the endogenous expression of CaMKIIα protein, thus these mice can be used in in vivo and in vitro physiological studies in which visualization of CaMKIIα- neuronal populations is required. PMID:23632380

Effects of hypoxic preconditioning on expression of transcription factor NGFI-A in the rat brain after unavoidable stress in the "learned helplessness" model.

PubMed

Baranova, K A; Rybnikova, E A; Mironova, V I; Samoilov, M O

2010-07-01

We report here our immunocytochemical studies establishing that the development of a depression-like state in rats following unavoidable stress in a "learned helplessness" model is accompanied by stable activation of the expression of transcription factor NGFI-A in the dorsal hippocampus (field CA1) and the magnocellular paraventricular nucleus of the hypothalamus, along with an early wave of post-stress expression, which died down rapidly, in the ventral hippocampus (the dentate gyrus) and a long period of up to five days of high-level expression in the neocortex. In rats subjected to three sessions of preconditioning consisting of moderate hypobaric hypoxia (360 mmHg, 2 h, with intervals of 24 h), which did not form depression in these circumstances, there were significant changes in the dynamics of immunoreactive protein content in the hippocampus, with a stable increase in expression in the ventral hippocampus and only transient and delayed (by five days) expression in field CA1. In the neocortex (layer II), preconditioning eliminated the effects of stress, preventing prolongation of the first wave of NGFI-A expression to five days, while in the magnocellular hypothalamus, conversely, preconditioning stimulated a second (delayed) wave of the expression of this transcription factor. The pattern of NGFI-A expression in the hippocampus, neocortex, and hypothalamus seen in non-preconditioned rats appears to reflect the pathological reaction to aversive stress, which, rather than adaptation, produced depressive disorders. Post-stress modification of the expression of the product of the early gene NGFI-A in the brain induced by hypoxic preconditioning probably plays an important role in increased tolerance to severe psychoemotional stresses and is an important component of antidepressant mechanisms.

S‐phase duration is the main target of cell cycle regulation in neural progenitors of developing ferret neocortex

PubMed Central

Turrero García, Miguel; Chang, YoonJeung; Arai, Yoko

2016-01-01

ABSTRACT The evolutionary expansion of the neocortex primarily reflects increases in abundance and proliferative capacity of cortical progenitors and in the length of the neurogenic period during development. Cell cycle parameters of neocortical progenitors are an important determinant of cortical development. The ferret (Mustela putorius furo), a gyrencephalic mammal, has gained increasing importance as a model for studying corticogenesis. Here, we have studied the abundance, proliferation, and cell cycle parameters of different neural progenitor types, defined by their differential expression of the transcription factors Pax6 and Tbr2, in the various germinal zones of developing ferret neocortex. We focused our analyses on postnatal day 1, a late stage of cortical neurogenesis when upper‐layer neurons are produced. Based on cumulative 5‐ethynyl‐2′‐deoxyuridine (EdU) labeling as well as Ki67 and proliferating cell nuclear antigen (PCNA) immunofluorescence, we determined the duration of the various cell cycle phases of the different neocortical progenitor subpopulations. Ferret neocortical progenitors were found to exhibit longer cell cycles than those of rodents and little variation in the duration of G1 among distinct progenitor types, also in contrast to rodents. Remarkably, the main difference in cell cycle parameters among the various progenitor types was the duration of S‐phase, which became shorter as progenitors progressively changed transcription factor expression from patterns characteristic of self‐renewal to those of neuron production. Hence, S‐phase duration emerges as major target of cell cycle regulation in cortical progenitors of this gyrencephalic mammal. J. Comp. Neurol. 524:456–470, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:25963823

Prevention of thiopental and thiopental/halothane cardiac sensitization to epinephrine in the sheep.

PubMed Central

Rezakhani, A; Edjtehadi, M; Szabuniewicz, M

1977-01-01

The effects of epinephrine (5 microgram/kg of body weight) on ten unanesthetized sheep were experimentally tested: all sheep displayed serious arrhythmias. Sheep anesthetized with thiopental and thiopental/halothane combination displayed cardiac arrhythmias of the order of 10% and 20% respectively. Challenge injections of epinephrine (5 microgram/kg of body weight) to ten sheep anesthetized with thiopental, and to the same number of animals after 45 minutes of anesthesia with thiopental/halothane, produced serious arrhythmias. However, following preanesthetic treatment with acepromazine maleate (0.5 mg/kg) to 15 sheep, serious arrhythmias were prevented in all of them when they were given arrhythmic doses of epinephrine. Images Fig. 2. PMID:922556

Pressor and hemodilution responses compensate for acute hemorrhage in bluefish.

PubMed

Ogilvy, C S; Tremml, P G; DuBois, A B

1988-01-01

1. After hemorrhage of 21% blood volume (0.9% body weight) blood pressure (BP) and heart rate (H.R.) of unanesthetized bluefish (Pomatomus saltatrix) recovered within 5 min. 2. Phentolamine blocked this recovery. 3. Atropine increased control H.R. from 48 to 87 per min, and to 108 after hemorrhage, with delay of BP recovery to 10 min. 4. With small, repeated hemorrhages every 20 min, hemodilution and recovery of BP occurred between hemorrhages. Removal of 27% blood volume resulted in only temporary recovery. 5. Thirty min after hemorrhage, plasma epinephrine was 5 x and norepinephrine 8 x control. 6. Thus, bluefish tolerate hemorrhage with initial vasoconstriction via alpha-adrenergic pathways, and hemodilution.

A Genomic Analysis of Subclinical Hypothyroidism in Hippocampus and Neocortex of the Developing Brain -- JN

EPA Science Inventory

Hypothyroidism during pregnancy and the early postnatal period has severe neurological consequences for the developing offspring. The impact of milder degrees of perturbation of the thyroid axis, typically considered subclinical, however, has not been established. Thyroid hormo...

Electrical activity controls area-specific expression of neuronal apoptosis in the mouse developing cerebral cortex.

PubMed

Blanquie, Oriane; Yang, Jenq-Wei; Kilb, Werner; Sharopov, Salim; Sinning, Anne; Luhmann, Heiko J

2017-08-21

Programmed cell death widely but heterogeneously affects the developing brain, causing the loss of up to 50% of neurons in rodents. However, whether this heterogeneity originates from neuronal identity and/or network-dependent processes is unknown. Here, we report that the primary motor cortex (M1) and primary somatosensory cortex (S1), two adjacent but functionally distinct areas, display striking differences in density of apoptotic neurons during the early postnatal period. These differences in rate of apoptosis negatively correlate with region-dependent levels of activity. Disrupting this activity either pharmacologically or by electrical stimulation alters the spatial pattern of apoptosis and sensory deprivation leads to exacerbated amounts of apoptotic neurons in the corresponding functional area of the neocortex. Thus, our data demonstrate that spontaneous and periphery-driven activity patterns are important for the structural and functional maturation of the neocortex by refining the final number of cortical neurons in a region-dependent manner.

Pretraining Cortical Thickness Predicts Subsequent Perceptual Learning Rate in a Visual Search Task.

PubMed

Frank, Sebastian M; Reavis, Eric A; Greenlee, Mark W; Tse, Peter U

2016-03-01

We report that preexisting individual differences in the cortical thickness of brain areas involved in a perceptual learning task predict the subsequent perceptual learning rate. Participants trained in a motion-discrimination task involving visual search for a "V"-shaped target motion trajectory among inverted "V"-shaped distractor trajectories. Motion-sensitive area MT+ (V5) was functionally identified as critical to the task: after 3 weeks of training, activity increased in MT+ during task performance, as measured by functional magnetic resonance imaging. We computed the cortical thickness of MT+ from anatomical magnetic resonance imaging volumes collected before training started, and found that it significantly predicted subsequent perceptual learning rates in the visual search task. Participants with thicker neocortex in MT+ before training learned faster than those with thinner neocortex in that area. A similar association between cortical thickness and training success was also found in posterior parietal cortex (PPC). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Convallis Rule for Unsupervised Learning in Cortical Networks

PubMed Central

Yger, Pierre; Harris, Kenneth D.

2013-01-01

The phenomenology and cellular mechanisms of cortical synaptic plasticity are becoming known in increasing detail, but the computational principles by which cortical plasticity enables the development of sensory representations are unclear. Here we describe a framework for cortical synaptic plasticity termed the “Convallis rule”, mathematically derived from a principle of unsupervised learning via constrained optimization. Implementation of the rule caused a recurrent cortex-like network of simulated spiking neurons to develop rate representations of real-world speech stimuli, enabling classification by a downstream linear decoder. Applied to spike patterns used in in vitro plasticity experiments, the rule reproduced multiple results including and beyond STDP. However STDP alone produced poorer learning performance. The mathematical form of the rule is consistent with a dual coincidence detector mechanism that has been suggested by experiments in several synaptic classes of juvenile neocortex. Based on this confluence of normative, phenomenological, and mechanistic evidence, we suggest that the rule may approximate a fundamental computational principle of the neocortex. PMID:24204224

GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia

PubMed Central

Gonzalez-Burgos, Guillermo; Lewis, David A.

2008-01-01

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical γ-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type–specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value. PMID:18586694

GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.

PubMed

Gonzalez-Burgos, Guillermo; Lewis, David A

2008-09-01

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical gamma-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type-specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.

Identified Cellular Correlates of Neocortical Ripple and High-Gamma Oscillations during Spindles of Natural Sleep.

PubMed

Averkin, Robert G; Szemenyei, Viktor; Bordé, Sándor; Tamás, Gábor

2016-11-23

Ultra-high-frequency network events in the hippocampus are instrumental in a dialogue with the neocortex during memory formation, but the existence of transient ∼200 Hz network events in the neocortex is not clear. Our recordings from neocortical layer II/III of freely behaving rats revealed field potential events at ripple and high-gamma frequencies repeatedly occurring at troughs of spindle oscillations during sleep. Juxtacellular recordings identified subpopulations of fast-spiking, parvalbumin-containing basket cells with epochs of firing at ripple (∼200 Hz) and high-gamma (∼120 Hz) frequencies detected during spindles and centered with millisecond precision at the trough of spindle waves in phase with field potential events but phase shifted relative to pyramidal cell firing. The results suggest that basket cell subpopulations are involved in spindle-nested, high-frequency network events that hypothetically provide repeatedly occurring neocortical temporal reference states potentially involved in mnemonic processes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A natural history of the human mind: tracing evolutionary changes in brain and cognition

PubMed Central

Sherwood, Chet C; Subiaul, Francys; Zawidzki, Tadeusz W

2008-01-01

Since the last common ancestor shared by modern humans, chimpanzees and bonobos, the lineage leading to Homo sapiens has undergone a substantial change in brain size and organization. As a result, modern humans display striking differences from the living apes in the realm of cognition and linguistic expression. In this article, we review the evolutionary changes that occurred in the descent of Homo sapiens by reconstructing the neural and cognitive traits that would have characterized the last common ancestor and comparing these with the modern human condition. The last common ancestor can be reconstructed to have had a brain of approximately 300–400 g that displayed several unique phylogenetic specializations of development, anatomical organization, and biochemical function. These neuroanatomical substrates contributed to the enhancement of behavioral flexibility and social cognition. With this evolutionary history as precursor, the modern human mind may be conceived as a mosaic of traits inherited from a common ancestry with our close relatives, along with the addition of evolutionary specializations within particular domains. These modern human-specific cognitive and linguistic adaptations appear to be correlated with enlargement of the neocortex and related structures. Accompanying this general neocortical expansion, certain higher-order unimodal and multimodal cortical areas have grown disproportionately relative to primary cortical areas. Anatomical and molecular changes have also been identified that might relate to the greater metabolic demand and enhanced synaptic plasticity of modern human brain's. Finally, the unique brain growth trajectory of modern humans has made a significant contribution to our species’ cognitive and linguistic abilities. PMID:18380864

A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels

PubMed Central

Martínez-Martínez, Maria Ángeles; De Juan Romero, Camino; Fernández, Virginia; Cárdenas, Adrián; Götz, Magdalena; Borrell, Víctor

2016-01-01

The outer subventricular zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species such as human and ferret, where it contains abundant basal radial glia cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident downregulation of Cdh1 and Trnp1, and their upregulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease. PMID:27264089

Social networks in primates: smart and tolerant species have more efficient networks.

PubMed

Pasquaretta, Cristian; Levé, Marine; Claidière, Nicolas; van de Waal, Erica; Whiten, Andrew; MacIntosh, Andrew J J; Pelé, Marie; Bergstrom, Mackenzie L; Borgeaud, Christèle; Brosnan, Sarah F; Crofoot, Margaret C; Fedigan, Linda M; Fichtel, Claudia; Hopper, Lydia M; Mareno, Mary Catherine; Petit, Odile; Schnoell, Anna Viktoria; di Sorrentino, Eugenia Polizzi; Thierry, Bernard; Tiddi, Barbara; Sueur, Cédric

2014-12-23

Network optimality has been described in genes, proteins and human communicative networks. In the latter, optimality leads to the efficient transmission of information with a minimum number of connections. Whilst studies show that differences in centrality exist in animal networks with central individuals having higher fitness, network efficiency has never been studied in animal groups. Here we studied 78 groups of primates (24 species). We found that group size and neocortex ratio were correlated with network efficiency. Centralisation (whether several individuals are central in the group) and modularity (how a group is clustered) had opposing effects on network efficiency, showing that tolerant species have more efficient networks. Such network properties affecting individual fitness could be shaped by natural selection. Our results are in accordance with the social brain and cultural intelligence hypotheses, which suggest that the importance of network efficiency and information flow through social learning relates to cognitive abilities.

Social networks in primates: smart and tolerant species have more efficient networks

PubMed Central

Pasquaretta, Cristian; Levé, Marine; Claidière, Nicolas; van de Waal, Erica; Whiten, Andrew; MacIntosh, Andrew J. J.; Pelé, Marie; Bergstrom, Mackenzie L.; Borgeaud, Christèle; Brosnan, Sarah F.; Crofoot, Margaret C.; Fedigan, Linda M.; Fichtel, Claudia; Hopper, Lydia M.; Mareno, Mary Catherine; Petit, Odile; Schnoell, Anna Viktoria; di Sorrentino, Eugenia Polizzi; Thierry, Bernard; Tiddi, Barbara; Sueur, Cédric

2014-01-01

Network optimality has been described in genes, proteins and human communicative networks. In the latter, optimality leads to the efficient transmission of information with a minimum number of connections. Whilst studies show that differences in centrality exist in animal networks with central individuals having higher fitness, network efficiency has never been studied in animal groups. Here we studied 78 groups of primates (24 species). We found that group size and neocortex ratio were correlated with network efficiency. Centralisation (whether several individuals are central in the group) and modularity (how a group is clustered) had opposing effects on network efficiency, showing that tolerant species have more efficient networks. Such network properties affecting individual fitness could be shaped by natural selection. Our results are in accordance with the social brain and cultural intelligence hypotheses, which suggest that the importance of network efficiency and information flow through social learning relates to cognitive abilities. PMID:25534964

Late onset neurodegeneration in the Cln3-/- mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation.

PubMed

Pontikis, Charlie C; Cella, Claire V; Parihar, Nisha; Lim, Ming J; Chakrabarti, Shubhodeep; Mitchison, Hannah M; Mobley, William C; Rezaie, Payam; Pearce, David A; Cooper, Jonathan D

2004-10-15

Mouse models of neuronal ceroid lipofuscinosis (NCL) exhibit many features of the human disorder, with widespread regional atrophy and significant loss of GABAergic interneurons in the hippocampus and neocortex. Reactive gliosis is a characteristic of all forms of NCL, but it is unclear whether glial activation precedes or is triggered by neuronal loss. To explore this issue we undertook detailed morphological characterization of the Cln3 null mutant (Cln3(-/-)) mouse model of juvenile NCL (JNCL) that revealed a delayed onset neurodegenerative phenotype with no significant regional atrophy, but with widespread loss of hippocampal interneurons that was first evident at 14 months of age. Quantitative image analysis demonstrated upregulation of markers of astrocytic and microglial activation in presymptomatic Cln3(-/-) mice at 5 months of age, many months before significant neuronal loss occurs. These data provide evidence for subtle glial responses early in JNCL pathogenesis.

Cortical topography of intracortical inhibition influences the speed of decision making.

PubMed

Wilimzig, Claudia; Ragert, Patrick; Dinse, Hubert R

2012-02-21

The neocortex contains orderly topographic maps; however, their functional role remains controversial. Theoretical studies have suggested a role in minimizing computational costs, whereas empirical studies have focused on spatial localization. Using a tactile multiple-choice reaction time (RT) task before and after the induction of perceptual learning through repetitive sensory stimulation, we extend the framework of cortical topographies by demonstrating that the topographic arrangement of intracortical inhibition contributes to the speed of human perceptual decision-making processes. RTs differ among fingers, displaying an inverted U-shaped function. Simulations using neural fields show the inverted U-shaped RT distribution as an emergent consequence of lateral inhibition. Weakening inhibition through learning shortens RTs, which is modeled through topographically reorganized inhibition. Whereas changes in decision making are often regarded as an outcome of higher cortical areas, our data show that the spatial layout of interaction processes within representational maps contributes to selection and decision-making processes.

Cortical topography of intracortical inhibition influences the speed of decision making

PubMed Central

Wilimzig, Claudia; Ragert, Patrick; Dinse, Hubert R.

2012-01-01

The neocortex contains orderly topographic maps; however, their functional role remains controversial. Theoretical studies have suggested a role in minimizing computational costs, whereas empirical studies have focused on spatial localization. Using a tactile multiple-choice reaction time (RT) task before and after the induction of perceptual learning through repetitive sensory stimulation, we extend the framework of cortical topographies by demonstrating that the topographic arrangement of intracortical inhibition contributes to the speed of human perceptual decision-making processes. RTs differ among fingers, displaying an inverted U-shaped function. Simulations using neural fields show the inverted U-shaped RT distribution as an emergent consequence of lateral inhibition. Weakening inhibition through learning shortens RTs, which is modeled through topographically reorganized inhibition. Whereas changes in decision making are often regarded as an outcome of higher cortical areas, our data show that the spatial layout of interaction processes within representational maps contributes to selection and decision-making processes. PMID:22315409

A Neuroscience Perspective on Learning

ERIC Educational Resources Information Center

Sloan, Dendy; Norrgran, Cynthia

2016-01-01

We briefly discuss memory types and three modern principles of neuroscience: 1) Protein growth at the synapse, 2) the three-brain theory, and 3) the interplay of the hippocampus, the neocortex, and the prefrontal cortex. To illustrate the potential of this perspective, four applications of these principles are provided.

Immediate and Long-Term Outcome of Acute H2S Intoxication Induced Coma in Unanesthetized Rats: Effects of Methylene Blue

PubMed Central

Sonobe, Takashi; Chenuel, Bruno; Cooper, Timothy K.; Haouzi, Philippe

2015-01-01

Background Acute hydrogen sulfide (H2S) poisoning produces a coma, the outcome of which ranges from full recovery to severe neurological deficits. The aim of our study was to 1- describe the immediate and long-term neurological effects following H2S-induced coma in un-anesthetized rats, and 2- determine the potential benefit of methylene blue (MB), a compound we previously found to counteract acute sulfide cardiac toxicity. Methods NaHS was administered IP in un-sedated rats to produce a coma (n = 34). One minute into coma, the rats received MB (4 mg/kg IV) or saline. The surviving rats were followed clinically and assigned to Morris water maze (MWM) and open field testing then sacrificed at day 7. Results Sixty percent of the non-treated comatose rats died by pulseless electrical activity. Nine percent recovered with neurological deficits requiring euthanasia, their brain examination revealed major neuronal necrosis of the superficial and middle layers of the cerebral cortex and the posterior thalamus, with variable necrosis of the caudate putamen, but no lesions of the hippocampus or the cerebellum, in contrast to the typical distribution of post-ischemic lesions. The remaining animals displayed, on average, a significantly less effective search strategy than the control rats (n = 21) during MWM testing. Meanwhile, 75% of rats that received MB survived and could perform the MWM test (P<0.05 vs non-treated animals). The treated animals displayed a significantly higher occurrence of spatial search than the non-treated animals. However, a similar proportion of cortical necrosis was observed in both groups, with a milder clinical presentation following MB. Conclusion In conclusion, in rats surviving H2S induced coma, spatial search patterns were used less frequently than in control animals. A small percentage of rats presented necrotic neuronal lesions, which distribution differed from post-ischemic lesions. MB dramatically improved the immediate survival and spatial search strategy in the surviving rats. PMID:26115032

A method for measuring brain partial pressure of oxygen in unanesthetized unrestrained subjects: the effect of acute and chronic hypoxia on brain tissue PO(2).

PubMed

Ortiz-Prado, E; Natah, Siraj; Srinivasan, Sathyanarayanan; Dunn, Jeff F

2010-11-30

The level of tissue oxygenation provides information related to the balance between oxygen delivery, oxygen utilization, tissue reactivity and morphology during physiological conditions. Tissue partial pressure of oxygen (PtO(2)) is influenced by the use of anesthesia or restraint. These factors may impact the absolute level of PtO(2). In this study we present a novel fiber optic method to measure brain PtO(2). This method can be used in unanesthetized, unrestrained animals, provides absolute values for PO(2), has a stable calibration, does not consume oxygen and is MRI compatible. Brain PtO(2) was studied during acute hypoxia, as well as before and after 28 days of high altitude acclimatization. A sensor was chronically implanted in the frontal cortex of eight Wistar rats. It is comprised of a fiber optic probe with a tip containing material that fluoresces with an oxygen dependent lifetime. Brain PtO(2) declines by 80% and 76% pre- and post-acclimatization, respectively, when the fraction of inspired oxygen declines from 0.21 to 0.08. In addition, a linear relationship between brain PtO(2) and inspired O(2) levels was demonstrated r(2)=0.98 and r(2)=0.99 (pre- and post-acclimatization). Hypoxia acclimatization resulted in an increase in the overall brain PtO(2) by approximately 35%. This paper demonstrates the use of a novel chronically implanted fiber optic based sensor for measuring absolute PtO(2). It shows a very strong linear relationship in awake animals between inspired O(2) and tissue O(2), and shows that there is a proportional increase in PtO(2) over a range of inspired values after exposure to chronic hypoxia. Copyright © 2010 Elsevier B.V. All rights reserved.

Oxotremorine-induced cerebral hyperemia does not predict infarction volume in spontaneously hypertensive or stroke-prone rats.

PubMed

Harukuni, I; Takahashi, H; Traystman, R J; Bhardwaj, A; Kirsch, J R

2000-01-01

We tested the following hypotheses: a) spontaneously hypertensive stroke-prone rats (SHR-SP) have more brain injury than spontaneously hypertensive rats (SHR) and normotensive controls (Wistar-Kyoto rats [WKY]) when exposed to transient focal ischemia; b) infarction size is not correlated with baseline blood pressure; and c) infarction size is inversely related to the cerebral hyperemic response to oxotremorine, a muscarinic agonist that increases cerebral blood flow (CBF) by stimulating endothelial nitric oxide synthase. In vivo study. Animal laboratory in a university teaching hospital. Adult age-matched male WKY, SHR, and SHR-SP. Rats were instrumented under halothane anesthesia. Transient focal cerebral ischemia was produced for 2 hrs with the intravascular suture technique. Cerebral perfusion, estimated with laser Doppler flowmetry (LD-CBF), in response to intravenous oxotremorine, was measured in one cohort of rats to estimate endothelial nitric oxide synthase function. Infarction volume was measured at 22 hrs of reperfusion with 2,3,5-triphenyltetrazolium chloride staining. Infarction volume in the striatum of SHR-SP (42+/-4 mm3) was greater than in SHR (29+/-6 mm3) or WKY (1+/-1 mm3) (n = 9 rats/strain). Resting (unanesthetized) mean arterial blood pressure was similar in SHR-SP (177+/-5 mm Hg) and SHR (170+/-5 mm Hg) despite a greater infarction volume in SHR-SP (n = 4) compared with SHR (n = 5). The percentage increase in LD-CBF signal in response to oxotremorine was similar for both groups (SHR, 64%+/-22% [n = 10]; SHR-SP, 69%+/-22% [n = 8]). However, in this cohort, cortical infarction volume was less in SHR (30%+/-4% of ipsilateral cortex) than in SHR-SP (49%+/-2% of ipsilateral cortex). Although SHR-SP have greater infarction volume than SHR, the mechanism of injury does not appear to be related to a difference in unanesthetized baseline mean arterial blood pressure or to an alteration in endothelium-produced nitric oxide.

Immediate and Long-Term Outcome of Acute H2S Intoxication Induced Coma in Unanesthetized Rats: Effects of Methylene Blue.

PubMed

Sonobe, Takashi; Chenuel, Bruno; Cooper, Timothy K; Haouzi, Philippe

2015-01-01

Acute hydrogen sulfide (H2S) poisoning produces a coma, the outcome of which ranges from full recovery to severe neurological deficits. The aim of our study was to 1--describe the immediate and long-term neurological effects following H2S-induced coma in un-anesthetized rats, and 2--determine the potential benefit of methylene blue (MB), a compound we previously found to counteract acute sulfide cardiac toxicity. NaHS was administered IP in un-sedated rats to produce a coma (n = 34). One minute into coma, the rats received MB (4 mg/kg i.v.) or saline. The surviving rats were followed clinically and assigned to Morris water maze (MWM) and open field testing then sacrificed at day 7. Sixty percent of the non-treated comatose rats died by pulseless electrical activity. Nine percent recovered with neurological deficits requiring euthanasia, their brain examination revealed major neuronal necrosis of the superficial and middle layers of the cerebral cortex and the posterior thalamus, with variable necrosis of the caudate putamen, but no lesions of the hippocampus or the cerebellum, in contrast to the typical distribution of post-ischemic lesions. The remaining animals displayed, on average, a significantly less effective search strategy than the control rats (n = 21) during MWM testing. Meanwhile, 75% of rats that received MB survived and could perform the MWM test (P<0.05 vs non-treated animals). The treated animals displayed a significantly higher occurrence of spatial search than the non-treated animals. However, a similar proportion of cortical necrosis was observed in both groups, with a milder clinical presentation following MB. In conclusion, in rats surviving H2S induced coma, spatial search patterns were used less frequently than in control animals. A small percentage of rats presented necrotic neuronal lesions, which distribution differed from post-ischemic lesions. MB dramatically improved the immediate survival and spatial search strategy in the surviving rats.

Role of maternal thyroid hormones in the developing neocortex and during human evolution

PubMed Central

Stenzel, Denise; Huttner, Wieland B.

2013-01-01

The importance of thyroid hormones during brain development has been appreciated for many decades. In humans, low levels of circulating maternal thyroid hormones, e.g., caused by maternal hypothyroidism or lack of iodine in diet, results in a wide spectrum of severe neurological defects, including neurological cretinism characterized by profound neurologic impairment and mental retardation, underlining the importance of the maternal thyroid hormone contribution. In fact, iodine intake, which is essential for thyroid hormone production in the thyroid gland, has been related to the expansion of the brain, associated with the increased cognitive capacities during human evolution. Because thyroid hormones regulate transcriptional activity of target genes via their nuclear thyroid hormone receptors (THRs), even mild and transient changes in maternal thyroid hormone levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Here we summarize how thyroid hormones may have influenced human brain evolution through the adaptation to new habitats, concomitant with changes in diet and, therefore, iodine intake. Further, we review the current picture we gained from experimental studies in rodents on the function of maternal thyroid hormones during developmental neurogenesis. We aim to evaluate the effects of maternal thyroid hormone deficiency as well as lack of THRs and transporters on brain development and function, shedding light on the cellular behavior conducted by thyroid hormones. PMID:23882187

Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke

PubMed Central

Miyamoto, Michiyuki; Yamauchi, Tomohiro; Kawabori, Masahito; Osanai, Toshiya; Sasaki, Tasuku; Houkin, Kiyohiro; Kuroda, Satoshi

2018-01-01

Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans. PMID:29765415

Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke.

PubMed

Miyamoto, Michiyuki; Nakamura, Kentaro; Shichinohe, Hideo; Yamauchi, Tomohiro; Ito, Masaki; Saito, Hisayasu; Kawabori, Masahito; Osanai, Toshiya; Sasaki, Tasuku; Houkin, Kiyohiro; Kuroda, Satoshi

2018-01-01

Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans.

Exceptional Evolutionary Expansion of Prefrontal Cortex in Great Apes and Humans.

PubMed

Smaers, Jeroen B; Gómez-Robles, Aida; Parks, Ashley N; Sherwood, Chet C

2017-03-06

One of the enduring questions that has driven neuroscientific enquiry in the last century has been the nature of differences in the prefrontal cortex of humans versus other animals [1]. The prefrontal cortex has drawn particular interest due to its role in a range of evolutionarily specialized cognitive capacities such as language [2], imagination [3], and complex decision making [4]. Both cytoarchitectonic [5] and comparative neuroimaging [6] studies have converged on the conclusion that the proportion of prefrontal cortex in the human brain is greatly increased relative to that of other primates. However, considering the tremendous overall expansion of the neocortex in human evolution, it has proven difficult to ascertain whether this extent of prefrontal enlargement follows general allometric growth patterns, or whether it is exceptional [1]. Species' adherence to a common allometric relationship suggests conservation through phenotypic integration, while species' deviations point toward the occurrence of shifts in genetic and/or developmental mechanisms. Here we investigate prefrontal cortex scaling across anthropoid primates and find that great ape and human prefrontal cortex expansion are non-allometrically derived features of cortical organization. This result aligns with evidence for a developmental heterochronic shift in human prefrontal growth [7, 8], suggesting an association between neurodevelopmental changes and cortical organization on a macroevolutionary scale. The evolutionary origin of non-allometric prefrontal enlargement is estimated to lie at the root of great apes (∼19-15 mya), indicating that selection for changes in executive cognitive functions characterized both great ape and human cortical organization. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synchrony of clonal cell proliferation and contiguity of clonally related cells: production of mosaicism in the ventricular zone of developing mouse neocortex

NASA Technical Reports Server (NTRS)

Cai, L.; Hayes, N. L.; Nowakowski, R. S.

1997-01-01

We have analyzed clonal cell proliferation in the ventricular zone (VZ) of the early developing mouse neocortex with a replication-incompetent retrovirus encoding human placental alkaline phosphatase (AP). The retrovirus was injected into the lateral ventricles on embryonic day 11 (E11), i.e., at the onset of neuronogenesis. Three days postinjection, on E14, a total of 259 AP-labeled clones of various sizes were found in 7 fetal brains. There are approximately 7 cell cycles between E11 and E14 (), and there is a 1-2 cell cycle delay between retroviral injection and the production of a retrovirally labeled "founder" cell; thus, we estimate that the "age" of the clones was about 5-6 cell cycles. Almost one-half of the clones (48.3%) identified were pure proliferating clones containing cells only in the VZ. Another 18.5% contained both proliferating and postproliferative cells, and 33.2% contained only postproliferative cells. It was striking that over 90% of the clonally related proliferating cells occurred in clusters of two or more apparently contiguous cells, and about 73% of the proliferating cells occurred in clusters of three or more cells. Regardless of the number of cells in the clone, these clusters were tightly packed and confined to a single level of the VZ. This clustering of proliferating cells indicates that clonally related cells maintain neighbor-neighbor relationships as they undergo interkinetic nuclear migration and progress through several cell cycles, and, as a result, the ventricular zone is a mosaic of small clusters of clonally related and synchronously cycling cells. In addition, cells in the intermediate zone and the cortical plate were also frequently clustered, indicating that they became postproliferative at a similar time and that the output of the VZ is influenced by its mosaic structure.

Nicotinic Acetylcholine Receptors in Sensory Cortex

ERIC Educational Resources Information Center

Metherate, Raju

2004-01-01

Acetylcholine release in sensory neocortex contributes to higher-order sensory function, in part by activating nicotinic acetylcholine receptors (nAChRs). Molecular studies have revealed a bewildering array of nAChR subtypes and cellular actions; however, there is some consensus emerging about the major nAChR subtypes and their functions in…

Repeated Stimulation of Cultured Networks of Rat Cortical Neurons Induces Parallel Memory Traces

ERIC Educational Resources Information Center

le Feber, Joost; Witteveen, Tim; van Veenendaal, Tamar M.; Dijkstra, Jelle

2015-01-01

During systems consolidation, memories are spontaneously replayed favoring information transfer from hippocampus to neocortex. However, at present no empirically supported mechanism to accomplish a transfer of memory from hippocampal to extra-hippocampal sites has been offered. We used cultured neuronal networks on multielectrode arrays and…

Repair of Neocortex in a Model of Cortical Dysplasia

DTIC Science & Technology

2007-03-27

236. Dang L, Yoon K, Wang M, Gaiano N. 2006. Notch3 signaling promotes radial glial/progenitor character in the Mammalian telencephalon. Dev Neurosci...2006) Notch3 signaling promotes radial glial/progenitor character in the Mammalian telencephalon. Dev Neurosci 28:58- 69. Desai AR, McConnell SK (2000

Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue.

PubMed

Brené, S; Lindefors, N; Ehrlich, M; Taubes, T; Horiuchi, A; Kopp, J; Hall, H; Sedvall, G; Greengard, P; Persson, H

1994-03-01

In this study we have isolated and sequenced human cDNAs for the phosphoproteins DARPP-32, ARPP-21, and ARPP-16/19, and have compared these sequences to previously characterized bovine and rat cDNAs. In situ hybridization and Northern blot analysis with the human cDNA probes were used to study the expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human postmortem brain tissue. In situ hybridization was performed using horizontal whole hemisphere sections. Five representative levels of the brain ranging from 71 mm to 104 mm ventral to vertex were examined. All three probes showed distinct hybridization patterns in the caudate nucleus, putamen, nucleus accumbens, and the amygdaloid complex. For ARPP-16/19 mRNA, a hybridization signal comparable to the signal in caudate nucleus, putamen, and nucleus accumbens was also detected in the neocortex. ARPP-21 and DARPP-32 mRNA, on the other hand, were present in lower levels in neocortical regions. DARPP-32 mRNA was abundant in the cerebellar cortex at the level of the Purkinje cell layer. High levels of ARPP-16/19 and ARPP-21 mRNA were also found in the cerebellar cortex, where they were confined to deeper layers. The present result demonstrate that mRNAs for the three phosphoproteins are expressed in overlapping, but also distinct, areas of the human brain that in many cases coincide with previously described distribution of the dopamine D1 receptor.

A multichannel implantable telemetry system for flow, pressure, and ECG measurements

NASA Technical Reports Server (NTRS)

Fryer, T. B.; Sandler, H.; Freund, W.; Mccutcheon, E. P.; Carlson, E. L.

1975-01-01

The design, principles of operation, and performance of an implantable miniaturized (48 cu cm in volume) multiplex telemetry system for simultaneous measurement of up to eight physiological parameters (including cardiovascular data) are described. Integrated circuits are used to reduce the size, complexity, and cost of fabrication. Power consumption is reduced using recently developed complementary MOS devices. PWM technique is selected as it is relatively easy to implement, lends itself to ICs, and provides an accurate means of transmitting data. The system is totally implantable within the chest of a test animal, with no wire penetrating through the skin. It is shown that the described system permits repeated measurement of the physiological effects of a variety of interventions in awake unanesthetized animals.

CYP3A5 Mediates Effects of Cocaine on Human Neocorticogenesis: Studies using an In Vitro 3D Self-Organized hPSC Model with a Single Cortex-Like Unit.

PubMed

Lee, Chun-Ting; Chen, Jia; Kindberg, Abigail A; Bendriem, Raphael M; Spivak, Charles E; Williams, Melanie P; Richie, Christopher T; Handreck, Annelie; Mallon, Barbara S; Lupica, Carl R; Lin, Da-Ting; Harvey, Brandon K; Mash, Deborah C; Freed, William J

2017-02-01

Because of unavoidable confounding variables in the direct study of human subjects, it has been difficult to unravel the effects of prenatal cocaine exposure on the human fetal brain, as well as the cellular and biochemical mechanisms involved. Here, we propose a novel approach using a human pluripotent stem cell (hPSC)-based 3D neocortical organoid model. This model retains essential features of human neocortical development by encompassing a single self-organized neocortical structure, without including an animal-derived gelatinous matrix. We reported previously that prenatal cocaine exposure to rats during the most active period of neural progenitor proliferation induces cytoarchitectural changes in the embryonic neocortex. We also identified a role of CYP450 and consequent oxidative ER stress signaling in these effects. However, because of differences between humans and rodents in neocorticogenesis and brain CYP metabolism, translation of the research findings from the rodent model to human brain development is uncertain. Using hPSC 3D neocortical organoids, we demonstrate that the effects of cocaine are mediated through CYP3A5-induced generation of reactive oxygen species, inhibition of neocortical progenitor cell proliferation, induction of premature neuronal differentiation, and interruption of neural tissue development. Furthermore, knockdown of CYP3A5 reversed these cocaine-induced pathological phenotypes, suggesting CYP3A5 as a therapeutic target to mitigate the deleterious neurodevelopmental effects of prenatal cocaine exposure in humans. Moreover, 3D organoid methodology provides an innovative platform for identifying adverse effects of abused psychostimulants and pharmaceutical agents, and can be adapted for use in neurodevelopmental disorders with genetic etiologies.

Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells

PubMed Central

Kurabayashi, Nobuhiro; Sanada, Kamon

2013-01-01

Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS. PMID:24352425

Computational and Organotypic Modeling of Microcephaly ...

EPA Pesticide Factsheets

Microcephaly is associated with reduced cortical surface area and ventricular dilations. Many genetic and environmental factors precipitate this malformation, including prenatal alcohol exposure and maternal Zika infection. This complexity motivates the engineering of computational and experimental models to probe the underlying molecular targets, cellular consequences, and biological processes. We describe an Adverse Outcome Pathway (AOP) framework for microcephaly derived from literature on all gene-, chemical-, or viral- effects and brain development. Overlap with NTDs is likely, although the AOP connections identified here focused on microcephaly as the adverse outcome. A query of the Mammalian Phenotype Browser database for ‘microcephaly’ (MP:0000433) returned 85 gene associations; several function in microtubule assembly and centrosome cycle regulated by (microcephalin, MCPH1), a gene for primary microcephaly in humans. The developing ventricular zone is the likely target. In this zone, neuroprogenitor cells (NPCs) self-replicate during the 1st trimester setting brain size, followed by neural differentiation of the neocortex. Recent studies with human NPCs confirmed infectivity with Zika virions invoking critical cell loss (apoptosis) of precursor NPCs; similar findings have been shown with fetal alcohol or methylmercury exposure in rodent studies, leading to mathematical models of NPC dynamics in size determination of the ventricular zone. A key event

Near-instant automatic access to visually presented words in the human neocortex: neuromagnetic evidence.

PubMed

Shtyrov, Yury; MacGregor, Lucy J

2016-05-24

Rapid and efficient processing of external information by the brain is vital to survival in a highly dynamic environment. The key channel humans use to exchange information is language, but the neural underpinnings of its processing are still not fully understood. We investigated the spatio-temporal dynamics of neural access to word representations in the brain by scrutinising the brain's activity elicited in response to psycholinguistically, visually and phonologically matched groups of familiar words and meaningless pseudowords. Stimuli were briefly presented on the visual-field periphery to experimental participants whose attention was occupied with a non-linguistic visual feature-detection task. The neural activation elicited by these unattended orthographic stimuli was recorded using multi-channel whole-head magnetoencephalography, and the timecourse of lexically-specific neuromagnetic responses was assessed in sensor space as well as at the level of cortical sources, estimated using individual MR-based distributed source reconstruction. Our results demonstrate a neocortical signature of automatic near-instant access to word representations in the brain: activity in the perisylvian language network characterised by specific activation enhancement for familiar words, starting as early as ~70 ms after the onset of unattended word stimuli and underpinned by temporal and inferior-frontal cortices.

Auditory Spatial Attention Representations in the Human Cerebral Cortex

PubMed Central

Kong, Lingqiang; Michalka, Samantha W.; Rosen, Maya L.; Sheremata, Summer L.; Swisher, Jascha D.; Shinn-Cunningham, Barbara G.; Somers, David C.

2014-01-01

Auditory spatial attention serves important functions in auditory source separation and selection. Although auditory spatial attention mechanisms have been generally investigated, the neural substrates encoding spatial information acted on by attention have not been identified in the human neocortex. We performed functional magnetic resonance imaging experiments to identify cortical regions that support auditory spatial attention and to test 2 hypotheses regarding the coding of auditory spatial attention: 1) auditory spatial attention might recruit the visuospatial maps of the intraparietal sulcus (IPS) to create multimodal spatial attention maps; 2) auditory spatial information might be encoded without explicit cortical maps. We mapped visuotopic IPS regions in individual subjects and measured auditory spatial attention effects within these regions of interest. Contrary to the multimodal map hypothesis, we observed that auditory spatial attentional modulations spared the visuotopic maps of IPS; the parietal regions activated by auditory attention lacked map structure. However, multivoxel pattern analysis revealed that the superior temporal gyrus and the supramarginal gyrus contained significant information about the direction of spatial attention. These findings support the hypothesis that auditory spatial information is coded without a cortical map representation. Our findings suggest that audiospatial and visuospatial attention utilize distinctly different spatial coding schemes. PMID:23180753

True and False Memories, Parietal Cortex, and Confidence Judgments

ERIC Educational Resources Information Center

Urgolites, Zhisen J.; Smith, Christine N.; Squire, Larry R.

2015-01-01

Recent studies have asked whether activity in the medial temporal lobe (MTL) and the neocortex can distinguish true memory from false memory. A frequent complication has been that the confidence associated with correct memory judgments (true memory) is typically higher than the confidence associated with incorrect memory judgments (false memory).…

Acetylcholine, Histamine, and Cognition: Two Sides of the Same Coin

ERIC Educational Resources Information Center

Blandina, Patrizio; Efoudebe, Marcel; Cenni, Gabriele; Mannaioni, Pierfrancesco; Passani, Maria Beatrice

2004-01-01

The forebrain cholinergic neurons are localized in the nucleus basalis magnocellularis (NBM), the major source of cholinergic innervation to the neocortex and to the amygdala, and in the medium septum-banda diagonalis complex, which provides cholinergic inputs to the hippocampus (Mesulam et al. 1983; Woolf et al. 1984; Nicoll 1985). Basic and…

Kinase Activity in the Olfactory Bulb Is Required for Odor Memory Consolidation

ERIC Educational Resources Information Center

Tong, Michelle T.; Kim, Tae-Young P.; Cleland, Thomas A.

2018-01-01

Long-term fear memory formation in the hippocampus and neocortex depends upon brain-derived neurotrophic factor (BDNF) signaling after acquisition. Incremental, appetitive odor discrimination learning is thought to depend substantially on the differentiation of adult-born neurons within the olfactory bulb (OB)--a process that is closely associated…

Neocortical Maturation during Adolescence: Change in Neuronal Soma Dimension

ERIC Educational Resources Information Center

Rabinowicz, Theodore; Petetot, Jean MacDonald-Comber; Khoury, Jane C.; de Courten-Myers, Gabrielle M.

2009-01-01

During adolescence, cognitive abilities increase robustly. To search for possible related structural alterations of the cerebral cortex, we measured neuronal soma dimension (NSD = width times height), cortical thickness and neuronal densities in different types of neocortex in post-mortem brains of five 12-16 and five 17-24 year-olds (each 2F,…

Is the Mind Inherently Forward-Looking? Comparing Prediction and Retrodiction

ERIC Educational Resources Information Center

Jones, Jason; Pashler, Harold

2007-01-01

It has been suggested that prediction may be an organizing principle of the mind and/or the neocortex, with cognitive machinery specifically engineered to detect forward-looking temporal relationships, rather than merely associating temporally contiguous events. There is a remarkable absence of behavioral tests of this idea, however. To address…

Endocranial morphology of Palaeocene Plesiadapis tricuspidens and evolution of the early primate brain.

PubMed

Orliac, Maeva J; Ladevèze, Sandrine; Gingerich, Philip D; Lebrun, Renaud; Smith, Thierry

2014-04-22

Expansion of the brain is a key feature of primate evolution. The fossil record, although incomplete, allows a partial reconstruction of changes in primate brain size and morphology through time. Palaeogene plesiadapoids, closest relatives of Euprimates (or crown-group primates), are crucial for understanding early evolution of the primate brain. However, brain morphology of this group remains poorly documented, and major questions remain regarding the initial phase of euprimate brain evolution. Micro-CT investigation of the endocranial morphology of Plesiadapis tricuspidens from the Late Palaeocene of Europe--the most complete plesiadapoid cranium known--shows that plesiadapoids retained a very small and simple brain. Plesiadapis has midbrain exposure, and minimal encephalization and neocorticalization, making it comparable with that of stem rodents and lagomorphs. However, Plesiadapis shares a domed neocortex and downwardly shifted olfactory-bulb axis with Euprimates. If accepted phylogenetic relationships are correct, then this implies that the euprimate brain underwent drastic reorganization during the Palaeocene, and some changes in brain structure preceded brain size increase and neocortex expansion during evolution of the primate brain.

Effects of Different Modes of Hypobaric Hypoxia on the Content of Epigenetic Factors in the Rat in Neurons of Rat Neocortex.

PubMed

Samoilov, M O; Churilova, A V; Glushchenko, T S; Rybnikova, E A

2017-04-01

We studied the effects of different modes of hypobaric hypoxia on the content of epigenetic factors acH3K24, meH3K9, and meDNA modulating conformational characteristics of chromatin and gene expression in neurons of associative complex of rat parietal neocortex. Severe destructive hypoxia dramatically reduced the level of acH3K24 in 3 h after the end of exposure and increased meH3K9 and meDNA content. By contrast, 3-fold (but not single) adaptive exposure to moderate hypobaric hypoxia that produced a neuroprotective effect enhanced neuronal acH3K24 expression and decreased both meH3K9 and meDNA levels. Elevated acH3K24 content facilitates, while increased content of meH3K9 hampers binding of transcription factors to the target genes. At the same time, increased expression of meDNA suppresses transcription. The role of modification of epigenetic mechanisms in the regulation of proadaptive genes under the effects of hypoxic exposure according to various protocols is discussed.

Heat shock protein defenses in the neo- and allocortex of the telencephalon

PubMed Central

Posimo, Jessica M.; Weilnau, Justin N.; Gleixner, Amanda M.; Broeren, Matthew T.; Weiland, Nicole L.; Brodsky, Jeffrey L.; Wipf, Peter; Leak, Rehana K.

2015-01-01

The telencephalic allocortex develops protein inclusions before the neocortex in many age-related proteinopathies. One major defense mechanism against proteinopathic stress is the heat shock protein (Hsp) network. We therefore contrasted Hsp defenses in stressed primary neo- and allocortical cells. Neocortical neurons were more resistant to the proteasome inhibitor MG132 than neurons from three allocortical subregions: entorhinal cortex, piriform cortex, and hippocampus. However, allocortical neurons exhibited higher MG132-induced increases in Hsp70 and Hsc70. MG132-treated allocortical neurons also exhibited greater levels of protein ubiquitination. Inhibition of Hsp70/Hsc70 activity synergistically exacerbated MG132 toxicity in allocortical neurons more than neocortical neurons, suggesting that the allocortex is more reliant on these Hsp defenses. In contrast, astrocytes harvested from neo- or allocortex did not differ in their response to Hsp70/Hsc70 inhibition. Consistent with the idea that chaperones are maximally engaged in allocortical neurons, an increase in Hsp70/Hsc70 activity was protective only in neocortical neurons. Finally, the levels of select Hsps were altered in neocortex and allocortex in vivo with aging. PMID:25771395

A Neocortical Delta Rhythm Facilitates Reciprocal Interlaminar Interactions via Nested Theta Rhythms

PubMed Central

Carracedo, Lucy M.; Kjeldsen, Henrik; Cunnington, Leonie; Jenkins, Alastair; Schofield, Ian; Cunningham, Mark O.; Davies, Ceri H.; Traub, Roger D.

2013-01-01

Delta oscillations (1–4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta-frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a “Helmholtz machine”-like process to control synaptic rescaling during deep sleep. PMID:23804097

Distribution of messenger RNAs for D1 dopamine receptors and DARPP-32 in striatum and cerebral cortex of the cynomolgus monkey: relationship to D1 dopamine receptors.

PubMed

Brené, S; Hall, H; Lindefors, N; Karlsson, P; Halldin, C; Sedvall, G

1995-07-01

Messenger RNAs for the D1 dopamine receptor and dopamine- and cyclic AMP-regulated phosphoprotein of relative mass 32,000 (DARPP-32) were examined by in situ hybridization in the cynomolgus monkey brain. The messenger RNA distribution was compared to the distribution of D1 dopamine receptors using [3H]SCH 23390 autoradiography. In the caudate nucleus and putamen, D1 dopamine receptor messenger RNA-positive cells were unevenly distributed. Clusters of cells with an approximately three-fold higher intensity of labeling, as compared to surrounding regions, were found. Some of these D1 dopamine receptor messenger RNA intensive cell clusters in the caudate nucleus appeared to some extent to be matched to regions of higher intensity of [3H]SCH 23390 binding. The distribution of cells expressing DARPP-32 messenger RNA in the caudate nucleus and putamen was found to be non-clustered. In neocortical regions, cells of different sizes expressing D1 dopamine receptor messenger RNA were present in layers II-VI. D1 dopamine receptor messenger RNA-positive cells were most abundant in layer V. Unexpectedly, no DARPP-32 messenger RNA signal was detected in neocortex. Chronic SCH 23390 administration did not change the relative levels of messenger RNAs for the D1 dopamine receptor and DARPP-32 or [3H]SCH 23390 binding as measured by quantitative image analysis. The clustered distribution of D1 dopamine receptor messenger RNA is in contrast to that of DARPP-32 messenger RNA. This suggests that D1 dopamine receptors may play a more significant role in regulating DARPP-32 function in patch regions as compared to matrix regions. D1 dopamine receptor messenger RNA-expressing cells could also be visualized in several layers of the primate neocortex, implying that dopamine acts through D1 dopamine receptors within functionally different neuronal circuits of the neocortex.

Distinct perinatal features of the hyperpolarization-activated non-selective cation current Ih in the rat cortical plate

PubMed Central

2012-01-01

Background During neocortical development, multiple voltage- and ligand-gated ion channels are differentially expressed in neurons thereby shaping their intrinsic electrical properties. One of these voltage-gated ion channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and its current Ih, is an important regulator of neuronal excitability. Thus far, studies on an early Ih appearance in rodent neocortex are missing or conflicting. Therefore, we focused our study on perinatal neocortical Ih and its properties. Results In the perinatal rat neocortex we observed a rapid increase in the number of neurons exhibiting Ih. Perinatal Ih had unique properties: first, a pronounced cAMP sensitivity resulting in a marked shift of the voltage sufficient for half-maximum activation of the current towards depolarized voltages and second, an up to 10 times slower deactivation at physiological membrane potentials when compared to the one at postnatal day 30. The combination of these features was sufficient to suppress membrane resonance in our in silico and in vitro experiments. Although all four HCN subunits were present on the mRNA level we only detected HCN4, HCN3 and HCN1 on the protein level at P0. HCN1 protein at P0, however, appeared incompletely processed. At P30 glycosilated HCN1 and HCN2 dominated. By in silico simulations and heterologous co-expression experiments of a ‘slow’ and a ‘fast’ Ih conducting HCN channel subunit in HEK293 cells, we mimicked most characteristics of the native current, pointing to a functional combination of subunit homo- or heteromeres. Conclusion Taken together, these data indicate a HCN subunit shift initiated in the first 24 hours after birth and implicate a prominent perinatal role of the phylogenetically older HCN3 and/or HCN4 subunits in the developing neocortex. PMID:22694806

Monoaminergic control of cellular glucose utilization by glycogenolysis in neocortex and hippocampus

PubMed Central

DiNuzzo, Mauro; Giove, Federico; Maraviglia, Bruno; Mangia, Silvia

2016-01-01

Brainstem nuclei are the principal sites of monoamine (MA) innervation to major forebrain structures. In the cortical grey matter, increased secretion of MA neuromodulators occurs in response to a wealth of environmental and homeostatic challenges, whose onset is associated with rapid, preparatory changes in neural activity as well as with increases in energy metabolism. Blood-borne glucose is the main substrate for energy production in the brain. Once entered the tissue, interstitial glucose is equally accessible to neurons and astrocytes, the two cell types accounting for most of cellular volume and energy metabolism in neocortex and hippocampus. Astrocytes also store substantial amounts of glycogen, but non-stimulated glycogen turnover is very small. The rate of cellular glucose utilization in the brain is largely determined by hexokinase, which under basal conditions is more than 90% inhibited by its product glucose-6-phosphate (Glc-6-P). During rapid increases in energy demand, glycogen is a primary candidate in modulating the intracellular level of Glc-6-P, which can occur only in astrocytes. Glycogenolysis can produce Glc-6-P at a rate higher than uptake and phosphorylation of glucose. MA neurotransmitter are released extrasinaptically by brainstem neurons projecting to neocortex and hippocampus, thus activating MA receptors located on both neuronal and astrocytic plasma membrane. Importantly, MAs are glycogenolytic agents and thus they are exquisitely suitable for regulation of astrocytic Glc-6-P concentration, upstream substrate flow through hexokinase and hence cellular glucose uptake. Conforming to such mechanism, Gerald A. Dienel and Nancy F. Cruz recently suggested that activation of noradrenergic locus coeruleus might reversibly block astrocytic glucose uptake by stimulating glycogenolysis in these cells, thereby anticipating the rise in glucose need by active neurons. In this paper, we further develop the idea that the whole monoaminergic system modulates both function and metabolism of forebrain regions in a manner mediated by glycogen mobilization in astrocytes. PMID:26168779

Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro.

PubMed

Hassel, Bjørnar; Elsais, Ahmed; Frøland, Anne-Sofie; Taubøll, Erik; Gjerstad, Leif; Quan, Yi; Dingledine, Raymond; Rise, Frode

2015-05-01

Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose-labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of hexokinase 1, which channels fructose into glycolysis, and whose activity was similar with fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. We asked how the brain handles fructose, which may react spontaneously with proteins to form 'advanced glycation end products' and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was expressed too. Neocortical cells also took up and metabolized glyceraldehyde oxidatively. © 2015 International Society for Neurochemistry.

Monoaminergic Control of Cellular Glucose Utilization by Glycogenolysis in Neocortex and Hippocampus.

PubMed

DiNuzzo, Mauro; Giove, Federico; Maraviglia, Bruno; Mangia, Silvia

2015-12-01

Brainstem nuclei are the principal sites of monoamine (MA) innervation to major forebrain structures. In the cortical grey matter, increased secretion of MA neuromodulators occurs in response to a wealth of environmental and homeostatic challenges, whose onset is associated with rapid, preparatory changes in neural activity as well as with increases in energy metabolism. Blood-borne glucose is the main substrate for energy production in the brain. Once entered the tissue, interstitial glucose is equally accessible to neurons and astrocytes, the two cell types accounting for most of cellular volume and energy metabolism in neocortex and hippocampus. Astrocytes also store substantial amounts of glycogen, but non-stimulated glycogen turnover is very small. The rate of cellular glucose utilization in the brain is largely determined by hexokinase, which under basal conditions is more than 90 % inhibited by its product glucose-6-phosphate (Glc-6-P). During rapid increases in energy demand, glycogen is a primary candidate in modulating the intracellular level of Glc-6-P, which can occur only in astrocytes. Glycogenolysis can produce Glc-6-P at a rate higher than uptake and phosphorylation of glucose. MA neurotransmitter are released extrasinaptically by brainstem neurons projecting to neocortex and hippocampus, thus activating MA receptors located on both neuronal and astrocytic plasma membrane. Importantly, MAs are glycogenolytic agents and thus they are exquisitely suitable for regulation of astrocytic Glc-6-P concentration, upstream substrate flow through hexokinase and hence cellular glucose uptake. Conforming to such mechanism, Gerald A. Dienel and Nancy F. Cruz recently suggested that activation of noradrenergic locus coeruleus might reversibly block astrocytic glucose uptake by stimulating glycogenolysis in these cells, thereby anticipating the rise in glucose need by active neurons. In this paper, we further develop the idea that the whole monoaminergic system modulates both function and metabolism of forebrain regions in a manner mediated by glycogen mobilization in astrocytes.

Comparative Analysis of the Subventricular Zone in Rat, Ferret and Macaque: Evidence for an Outer Subventricular Zone in Rodents

PubMed Central

Camacho, Jasmin; Antczak, Jared L.; Prakash, Anish N.; Cziep, Matthew E.; Walker, Anita I.; Noctor, Stephen C.

2012-01-01

The mammalian cerebral cortex arises from precursor cells that reside in a proliferative region surrounding the lateral ventricles of the developing brain. Recent work has shown that precursor cells in the subventricular zone (SVZ) provide a major contribution to prenatal cortical neurogenesis, and that the SVZ is significantly thicker in gyrencephalic mammals such as primates than it is in lissencephalic mammals including rodents. Identifying characteristics that are shared by or that distinguish cortical precursor cells across mammalian species will shed light on factors that regulate cortical neurogenesis and may point toward mechanisms that underlie the evolutionary expansion of the neocortex in gyrencephalic mammals. We immunostained sections of the developing cerebral cortex from lissencephalic rats, and from gyrencephalic ferrets and macaques to compare the distribution of precursor cell types in each species. We also performed time-lapse imaging of precursor cells in the developing rat neocortex. We show that the distribution of Pax6+ and Tbr2+ precursor cells is similar in lissencephalic rat and gyrencephalic ferret, and different in the gyrencephalic cortex of macaque. We show that mitotic Pax6+ translocating radial glial cells (tRG) are present in the cerebral cortex of each species during and after neurogenesis, demonstrating that the function of Pax6+ tRG cells is not restricted to neurogenesis. Furthermore, we show that Olig2 expression distinguishes two distinct subtypes of Pax6+ tRG cells. Finally we present a novel method for discriminating the inner and outer SVZ across mammalian species and show that the key cytoarchitectural features and cell types that define the outer SVZ in developing primates are present in the developing rat neocortex. Our data demonstrate that the developing rat cerebral cortex possesses an outer subventricular zone during late stages of cortical neurogenesis and that the developing rodent cortex shares important features with that of primates. PMID:22272298

Comparative analysis of the subventricular zone in rat, ferret and macaque: evidence for an outer subventricular zone in rodents.

PubMed

Martínez-Cerdeño, Verónica; Cunningham, Christopher L; Camacho, Jasmin; Antczak, Jared L; Prakash, Anish N; Cziep, Matthew E; Walker, Anita I; Noctor, Stephen C

2012-01-01

The mammalian cerebral cortex arises from precursor cells that reside in a proliferative region surrounding the lateral ventricles of the developing brain. Recent work has shown that precursor cells in the subventricular zone (SVZ) provide a major contribution to prenatal cortical neurogenesis, and that the SVZ is significantly thicker in gyrencephalic mammals such as primates than it is in lissencephalic mammals including rodents. Identifying characteristics that are shared by or that distinguish cortical precursor cells across mammalian species will shed light on factors that regulate cortical neurogenesis and may point toward mechanisms that underlie the evolutionary expansion of the neocortex in gyrencephalic mammals. We immunostained sections of the developing cerebral cortex from lissencephalic rats, and from gyrencephalic ferrets and macaques to compare the distribution of precursor cell types in each species. We also performed time-lapse imaging of precursor cells in the developing rat neocortex. We show that the distribution of Pax6+ and Tbr2+ precursor cells is similar in lissencephalic rat and gyrencephalic ferret, and different in the gyrencephalic cortex of macaque. We show that mitotic Pax6+ translocating radial glial cells (tRG) are present in the cerebral cortex of each species during and after neurogenesis, demonstrating that the function of Pax6+ tRG cells is not restricted to neurogenesis. Furthermore, we show that Olig2 expression distinguishes two distinct subtypes of Pax6+ tRG cells. Finally we present a novel method for discriminating the inner and outer SVZ across mammalian species and show that the key cytoarchitectural features and cell types that define the outer SVZ in developing primates are present in the developing rat neocortex. Our data demonstrate that the developing rat cerebral cortex possesses an outer subventricular zone during late stages of cortical neurogenesis and that the developing rodent cortex shares important features with that of primates.

Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease.

PubMed

Davies, Danielle S; Ma, Jolande; Jegathees, Thuvarahan; Goldsbury, Claire

2017-11-01

Changes in microglia function are involved in Alzheimer's disease (AD) for which ageing is the major risk factor. We evaluated microglial cell process morphologies and their gray matter coverage (arborized area) during ageing and in the presence and absence of AD pathology in autopsied human neocortex. Microglial cell processes were reduced in length, showed less branching and reduced arborized area with aging (case range 52-98 years). This occurred during normal ageing and without microglia dystrophy or changes in cell density. There was a larger reduction in process length and arborized area in AD compared to aged-matched control microglia. In AD cases, on average, 49%-64% of microglia had discontinuous and/or punctate Iba1 labeled processes instead of continuous Iba1 distribution. Up to 16% of aged-matched control microglia displayed discontinuous or punctate features. There was no change in the density of microglial cell bodies in gray matter during ageing or AD. This demonstrates that human microglia show progressive cell process retraction without cell loss during ageing. Additional changes in microglia occur with AD including Iba1 protein puncta and discontinuity. We suggest that reduced microglial arborized area may be an aging-related correlate of AD in humans. These variations in microglial cells during ageing and in AD could reflect changes in neural-glial interactions which are emerging as key to mechanisms involved in ageing and neurodegenerative disease. © 2016 International Society of Neuropathology.

Natural and Artificial Intelligence, Language, Consciousness, Emotion, and Anticipation

NASA Astrophysics Data System (ADS)

Dubois, Daniel M.

2010-11-01

The classical paradigm of the neural brain as the seat of human natural intelligence is too restrictive. This paper defends the idea that the neural ectoderm is the actual brain, based on the development of the human embryo. Indeed, the neural ectoderm includes the neural crest, given by pigment cells in the skin and ganglia of the autonomic nervous system, and the neural tube, given by the brain, the spinal cord, and motor neurons. So the brain is completely integrated in the ectoderm, and cannot work alone. The paper presents fundamental properties of the brain as follows. Firstly, Paul D. MacLean proposed the triune human brain, which consists to three brains in one, following the species evolution, given by the reptilian complex, the limbic system, and the neo-cortex. Secondly, the consciousness and conscious awareness are analysed. Thirdly, the anticipatory unconscious free will and conscious free veto are described in agreement with the experiments of Benjamin Libet. Fourthly, the main section explains the development of the human embryo and shows that the neural ectoderm is the whole neural brain. Fifthly, a conjecture is proposed that the neural brain is completely programmed with scripts written in biological low-level and high-level languages, in a manner similar to the programmed cells by the genetic code. Finally, it is concluded that the proposition of the neural ectoderm as the whole neural brain is a breakthrough in the understanding of the natural intelligence, and also in the future design of robots with artificial intelligence.

Cortical Hierarchies Perform Bayesian Causal Inference in Multisensory Perception

PubMed Central

Rohe, Tim; Noppeney, Uta

2015-01-01

To form a veridical percept of the environment, the brain needs to integrate sensory signals from a common source but segregate those from independent sources. Thus, perception inherently relies on solving the “causal inference problem.” Behaviorally, humans solve this problem optimally as predicted by Bayesian Causal Inference; yet, the underlying neural mechanisms are unexplored. Combining psychophysics, Bayesian modeling, functional magnetic resonance imaging (fMRI), and multivariate decoding in an audiovisual spatial localization task, we demonstrate that Bayesian Causal Inference is performed by a hierarchy of multisensory processes in the human brain. At the bottom of the hierarchy, in auditory and visual areas, location is represented on the basis that the two signals are generated by independent sources (= segregation). At the next stage, in posterior intraparietal sulcus, location is estimated under the assumption that the two signals are from a common source (= forced fusion). Only at the top of the hierarchy, in anterior intraparietal sulcus, the uncertainty about the causal structure of the world is taken into account and sensory signals are combined as predicted by Bayesian Causal Inference. Characterizing the computational operations of signal interactions reveals the hierarchical nature of multisensory perception in human neocortex. It unravels how the brain accomplishes Bayesian Causal Inference, a statistical computation fundamental for perception and cognition. Our results demonstrate how the brain combines information in the face of uncertainty about the underlying causal structure of the world. PMID:25710328

Early development of synchrony in cortical activations in the human.

PubMed

Koolen, N; Dereymaeker, A; Räsänen, O; Jansen, K; Vervisch, J; Matic, V; Naulaers, G; De Vos, M; Van Huffel, S; Vanhatalo, S

2016-05-13

Early intermittent cortical activity is thought to play a crucial role in the growth of neuronal network development, and large scale brain networks are known to provide the basis for higher brain functions. Yet, the early development of the large scale synchrony in cortical activations is unknown. Here, we tested the hypothesis that the early intermittent cortical activations seen in the human scalp EEG show a clear developmental course during the last trimester of pregnancy, the period of intensive growth of cortico-cortical connections. We recorded scalp EEG from altogether 22 premature infants at post-menstrual age between 30 and 44 weeks, and the early cortical synchrony was quantified using recently introduced activation synchrony index (ASI). The developmental correlations of ASI were computed for individual EEG signals as well as anatomically and mathematically defined spatial subgroups. We report two main findings. First, we observed a robust and statistically significant increase in ASI in all cortical areas. Second, there were significant spatial gradients in the synchrony in fronto-occipital and left-to-right directions. These findings provide evidence that early cortical activity is increasingly synchronized across the neocortex. The ASI-based metrics introduced in our work allow direct translational comparison to in vivo animal models, as well as hold promise for implementation as a functional developmental biomarker in future research on human neonates. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex.

PubMed

Hill, Matthew J; Killick, Richard; Navarrete, Katherinne; Maruszak, Aleksandra; McLaughlin, Gemma M; Williams, Brenda P; Bray, Nicholas J

2017-05-01

Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. To explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. We tested for genetic association between the set of differentially expressed genes and schizophrenia using genome-wide association study data from the Psychiatric Genomics Consortium and competitive gene set analysis (MAGMA). Effects on cell proliferation were assessed using high content imaging. Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. There was a nonsignificant trend for genetic association between the differentially expressed gene set and schizophrenia. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. A detailed mechanistic explanation of how TCF4 knockdown alters human neural progenitor cell proliferation is not provided by this study. Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in individuals with Pitt-Hopkins syndrome and risk for schizophrenia.

Overlapping regional distribution of CCK and TPPII mRNAs in Cynomolgus monkey brain and correlated levels in human cerebral cortex (BA 10).

PubMed

Radu, Diana; Tomkinson, Birgitta; Zachrisson, Olof; Weber, Günther; de Belleroche, Jacqueline; Hirsch, Steven; Lindefors, Nils

2006-08-09

Tripeptidyl peptidase II (TPPII) is a high molecular weight exopeptidase important in inactivating extracellular cholecystokinin (CCK). Our aims were to study the anatomical localization of TPPII and CCK mRNA in the Cynomolgus monkey brain as a basis for a possible functional anatomical connection between enzyme (TPPII) and substrate (CCK) and examine if indications of changes in substrate availability in the human brain might be reflected in changes of levels of TPPII mRNA. mRNA in situ hybridization on postmortem brain from patients having had a schizophrenia diagnosis as compared to controls and on monkey and rat brain slices. overlapping distribution patterns of mRNAs for TPPII and CCK in rat and monkey. High amounts of TPPII mRNA are seen in the neocortex, especially in the frontal region and the hippocampus. TPPII mRNA is also present in the basal ganglia and cerebellum where CCK immunoreactivity and/or CCK B receptors have been found in earlier studies, suggesting presence of CCK-ergic afferents from other brain regions. Levels of mRNAs for CCK and TPPII show a positive correlation in postmortem human cerebral cortex Brodmann area (BA) 10. TPPII mRNA might be affected following schizophrenia. overall TPPII and CCK mRNA show a similar distribution in rat and monkey brain, confirming and extending earlier studies in rodents. In addition, correlated levels of TPPII and CCK mRNA in human BA 10 corroborate a functional link between CCK and TPPII in the human brain.

Determination of the radioprotective effects of topical applications of MEA, WR-2721, and N-acetylcysteine on murine skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verhey, L.J.; Sedlacek, R.

1983-01-01

Topical applications of MEA (beta-mercaptoethylamine or cysteamine), WR-2721 (S-2-(3-aminopropylamino)-ethylphosphorothioic acid), and N-acetylcysteine (NAC) were tested for their ability to protect the normal skin of the hind legs of mice against acute and late damage from single doses of /sup 137/Cs radiation. No significant protection was observed with either WR-2721 or NAC. MEA was shown to offer significant protection against acute skin damage in both buffered and unbuffered forms, but no significant protection against late contraction. The use of topical MEA on unanesthetized animals breathing carbogen (95% O2, 5% CO2) appears to give an enhanced level of radioprotection over that shownmore » for anesthetized, air-breathing animals.« less

Reversible Information Flow across the Medial Temporal Lobe: The Hippocampus Links Cortical Modules during Memory Retrieval

PubMed Central

Cooper, Elisa; Henson, Richard N.

2013-01-01

A simple cue can be sufficient to elicit vivid recollection of a past episode. Theoretical models suggest that upon perceiving such a cue, disparate episodic elements held in neocortex are retrieved through hippocampal pattern completion. We tested this fundamental assumption by applying functional magnetic resonance imaging (fMRI) while objects or scenes were used to cue participants' recall of previously paired scenes or objects, respectively. We first demonstrate functional segregation within the medial temporal lobe (MTL), showing domain specificity in perirhinal and parahippocampal cortices (for object-processing vs scene-processing, respectively), but domain generality in the hippocampus (retrieval of both stimulus types). Critically, using fMRI latency analysis and dynamic causal modeling, we go on to demonstrate functional integration between these MTL regions during successful memory retrieval, with reversible signal flow from the cue region to the target region via the hippocampus. This supports the claim that the human hippocampus provides the vital associative link that integrates information held in different parts of cortex. PMID:23986252

Recent Advances on the Role of Neurogenesis in the Adult Brain: Therapeutic Potential in Parkinson's and Alzheimer's Diseases.

PubMed

Radad, Khaled; Moldzio, Rudolf; Al-Shraim, Mubarak; Kranner, Barbara; Krewenka, Christopher; Rausch, Wolf-Dieter

2017-01-01

Generation of nascent functional neurons from neural stem cells in the adult brain has recently become largely accepted by the neuroscience community. In adult mammals including humans, the process of neurogenesis has been well documented in two brain regions; the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. Some evidence has indicated neurogenesis in other regions of the adult mammalian brain such as the neocortex, cerebellum, striatum, amygdala and hypothalamus. These discoveries question a long standing dogma on nervous system regeneration and provide medical science with potential new strategies to harness the process of neurogenesis for treating neurological disabilities and neurodegenerative diseases. In this current review, we address the most recent advances on the role of neurogenesis in the adult brain and therapeutic potential in the two most common neurodegenerative disorders, Parkinson's and Alzheimer's diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The rate of transient beta frequency events predicts behavior across tasks and species

PubMed Central

Law, Robert; Tsutsui, Shawn; Moore, Christopher I; Jones, Stephanie R

2017-01-01

Beta oscillations (15-29Hz) are among the most prominent signatures of brain activity. Beta power is predictive of healthy and abnormal behaviors, including perception, attention and motor action. In non-averaged signals, beta can emerge as transient high-power 'events'. As such, functionally relevant differences in averaged power across time and trials can reflect changes in event number, power, duration, and/or frequency span. We show that functionally relevant differences in averaged beta power in primary somatosensory neocortex reflect a difference in the number of high-power beta events per trial, i.e. event rate. Further, beta events occurring close to the stimulus were more likely to impair perception. These results are consistent across detection and attention tasks in human magnetoencephalography, and in local field potentials from mice performing a detection task. These results imply that an increased propensity of beta events predicts the failure to effectively transmit information through specific neocortical representations. PMID:29106374

The HIV-1 viral protein Tat increases glutamate and decreases GABA exocytosis from human and mouse neocortical nerve endings.

PubMed

Musante, Veronica; Summa, Maria; Neri, Elisa; Puliti, Aldamaria; Godowicz, Tomasz T; Severi, Paolo; Battaglia, Giuseppe; Raiteri, Maurizio; Pittaluga, Anna

2010-08-01

Human immunodeficiency virus-1 (HIV-1)-encoded transactivator of transcription (Tat) potentiated the depolarization-evoked exocytosis of [(3)H]D-aspartate ([(3)H]D-ASP) from human neocortical terminals. The metabotropic glutamate (mGlu) 1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) prevented this effect, whereas the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) was ineffective. Western blot analysis showed that human neocortex synaptosomes possess mGlu1 and mGlu5 receptors. Tat potentiated the K(+)-evoked release of [(3)H]D-ASP or of endogenous glutamate from mouse neocortical synaptosomes in a CPCCOEt-sensitive and MPEP-insensitive manner. Deletion of mGlu1 receptors (crv4/crv4 mice) or mGlu5 receptors (mGlu5(-/-)mouse) silenced Tat effects. Tat enhanced inositol 1,4,5-trisphosphate production in human and mouse neocortical synaptosomes, consistent with the involvement of group I mGlu receptors. Tat inhibited the K(+)-evoked release of [(3)H]gamma-aminobutyric acid ([(3)H]GABA) from human synaptosomes and that of endogenous GABA or [(3)H]GABA from mouse nerve terminals; the inhibition was insensitive to CPCCOEt or MPEP. Tat-induced effects were retained by Tat(37-72) but not by Tat(48-85). In mouse neocortical slices, Tat facilitated the K(+)- and the veratridine-induced release of [(3)H]D-ASP in a CPCCOEt-sensitive manner and was ineffective in crv4/crv4 mouse slices. These observations are relevant to the comprehension of the pathophysiological effects of Tat in central nervous system and may suggest new potential therapeutic approaches to the cure of HIV-1-associated dementia.

Basal ganglia and cerebellar interconnectivity within the human thalamus.

PubMed

Pelzer, Esther A; Melzer, Corina; Timmermann, Lars; von Cramon, D Yves; Tittgemeyer, Marc

2017-01-01

Basal ganglia and the cerebellum are part of a densely interconnected network. While both subcortical structures process information in basically segregated loops that primarily interact in the neocortex, direct subcortical interaction has been recently confirmed by neuroanatomical studies using viral transneuronal tracers in non-human primate brains. The thalamus is thought to be the main relay station of both projection systems. Yet, our understanding of subcortical basal ganglia and cerebellar interconnectivity within the human thalamus is rather sparse, primarily due to limitation in the acquisition of in vivo tracing. Consequently, we strive to characterize projections of both systems and their potential overlap within the human thalamus by diffusion MRI and tractography. Our analysis revealed a decreasing anterior-to-posterior gradient for pallido-thalamic connections in: (1) the ventral-anterior thalamus, (2) the intralaminar nuclei, and (3) midline regions. Conversely, we found a decreasing posterior-to-anterior gradient for dentato-thalamic projections predominantly in: (1) the ventral-lateral and posterior nucleus; (2) dorsal parts of the intralaminar nuclei and the subparafascicular nucleus, and (3) the medioventral and lateral mediodorsal nucleus. A considerable overlap of connectivity pattern was apparent in intralaminar nuclei and midline regions. Notably, pallidal and cerebellar projections were both hemispherically lateralized to the left thalamus. While strikingly consistent with findings from transneuronal studies in non-human primates as well as with pre-existing anatomical studies on developmentally expressed markers or pathological human brains, our assessment provides distinctive connectional fingerprints that illustrate the anatomical substrate of integrated functional networks between basal ganglia and the cerebellum. Thereby, our findings furnish useful implications for cerebellar contributions to the clinical symptomatology of movement disorders.

Activity-Dependent Human Brain Coding/Noncoding Gene Regulatory Networks

PubMed Central

Lipovich, Leonard; Dachet, Fabien; Cai, Juan; Bagla, Shruti; Balan, Karina; Jia, Hui; Loeb, Jeffrey A.

2012-01-01

While most gene transcription yields RNA transcripts that code for proteins, a sizable proportion of the genome generates RNA transcripts that do not code for proteins, but may have important regulatory functions. The brain-derived neurotrophic factor (BDNF) gene, a key regulator of neuronal activity, is overlapped by a primate-specific, antisense long noncoding RNA (lncRNA) called BDNFOS. We demonstrate reciprocal patterns of BDNF and BDNFOS transcription in highly active regions of human neocortex removed as a treatment for intractable seizures. A genome-wide analysis of activity-dependent coding and noncoding human transcription using a custom lncRNA microarray identified 1288 differentially expressed lncRNAs, of which 26 had expression profiles that matched activity-dependent coding genes and an additional 8 were adjacent to or overlapping with differentially expressed protein-coding genes. The functions of most of these protein-coding partner genes, such as ARC, include long-term potentiation, synaptic activity, and memory. The nuclear lncRNAs NEAT1, MALAT1, and RPPH1, composing an RNAse P-dependent lncRNA-maturation pathway, were also upregulated. As a means to replicate human neuronal activity, repeated depolarization of SY5Y cells resulted in sustained CREB activation and produced an inverse pattern of BDNF-BDNFOS co-expression that was not achieved with a single depolarization. RNAi-mediated knockdown of BDNFOS in human SY5Y cells increased BDNF expression, suggesting that BDNFOS directly downregulates BDNF. Temporal expression patterns of other lncRNA-messenger RNA pairs validated the effect of chronic neuronal activity on the transcriptome and implied various lncRNA regulatory mechanisms. lncRNAs, some of which are unique to primates, thus appear to have potentially important regulatory roles in activity-dependent human brain plasticity. PMID:22960213

Effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia in the frequently sampled intravenous glucose tolerance test.

PubMed

Shin, Mi-Kyung; Han, Woobum; Joo, Hoon; Bevans-Fonti, Shannon; Shiota, Masakazu; Stefanovski, Darko; Polotsky, Vsevolod Y

2017-04-01

Obstructive sleep apnea is associated with type 2 diabetes. We have previously developed a mouse model of intermittent hypoxia (IH) mimicking oxyhemoglobin desaturations in patients with sleep apnea and have shown that IH increases fasting glucose, hepatic glucose output, and plasma catecholamines. We hypothesize that adrenal medulla modulates glucose responses to IH and that such responses can be prevented by adrenal medullectomy. We performed adrenal medullectomy or sham surgery in lean C57BL/6J mice, which were exposed to IH or intermittent air (control) for 4 wk followed by the frequently sampled intravenous glucose tolerance test (FSIVGTT) in unanesthetized unrestrained animals. IH was administered during the 12-h light phase (9 AM to 9 PM) by decreasing inspired oxygen from 21 to 6.5% 60 cycles/h. Insulin sensitivity (S I ), insulin independent glucose disposal [glucose effectiveness (S G )], and the insulin response to glucose (AIR G ) were determined using the minimal model method. In contrast to our previous data obtained in restrained mice, IH did not affect fasting blood glucose and plasma insulin levels in sham-operated mice. IH significantly decreased S G but did not affect S I and AIR G Adrenal medullectomy decreased fasting blood glucose and plasma insulin levels and increased glycogen synthesis in the liver in hypoxic mice but did not have a significant effect on the FSIVGTT metrics. We conclude that, in the absence of restraints, IH has no effect on glucose metabolism in lean mice with exception of decreased S G , whereas adrenal medullectomy decreases fasting glucose and insulin levels in the IH environment. NEW & NOTEWORTHY To our knowledge, this is the first study examining the role of adrenal catecholamines in glucose metabolism during intermittent hypoxia (IH) in unanesthetized unrestrained C57BL/6J mice. We report that IH did not affect fasting glucose and insulin levels nor insulin sensitivity and insulin secretion during, whereas glucose effectiveness was decreased. Adrenal medullectomy decreased fasting blood glucose and insulin levels in mice exposed to IH but had no effect on glucose metabolism, insulin secretion, and insulin sensitivity. Copyright © 2017 the American Physiological Society.

Effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia in the frequently sampled intravenous glucose tolerance test

PubMed Central

Shin, Mi-Kyung; Han, Woobum; Joo, Hoon; Bevans-Fonti, Shannon; Shiota, Masakazu; Stefanovski, Darko

2017-01-01

Obstructive sleep apnea is associated with type 2 diabetes. We have previously developed a mouse model of intermittent hypoxia (IH) mimicking oxyhemoglobin desaturations in patients with sleep apnea and have shown that IH increases fasting glucose, hepatic glucose output, and plasma catecholamines. We hypothesize that adrenal medulla modulates glucose responses to IH and that such responses can be prevented by adrenal medullectomy. We performed adrenal medullectomy or sham surgery in lean C57BL/6J mice, which were exposed to IH or intermittent air (control) for 4 wk followed by the frequently sampled intravenous glucose tolerance test (FSIVGTT) in unanesthetized unrestrained animals. IH was administered during the 12-h light phase (9 AM to 9 PM) by decreasing inspired oxygen from 21 to 6.5% 60 cycles/h. Insulin sensitivity (SI), insulin independent glucose disposal [glucose effectiveness (SG)], and the insulin response to glucose (AIRG) were determined using the minimal model method. In contrast to our previous data obtained in restrained mice, IH did not affect fasting blood glucose and plasma insulin levels in sham-operated mice. IH significantly decreased SG but did not affect SI and AIRG. Adrenal medullectomy decreased fasting blood glucose and plasma insulin levels and increased glycogen synthesis in the liver in hypoxic mice but did not have a significant effect on the FSIVGTT metrics. We conclude that, in the absence of restraints, IH has no effect on glucose metabolism in lean mice with exception of decreased SG, whereas adrenal medullectomy decreases fasting glucose and insulin levels in the IH environment. NEW & NOTEWORTHY To our knowledge, this is the first study examining the role of adrenal catecholamines in glucose metabolism during intermittent hypoxia (IH) in unanesthetized unrestrained C57BL/6J mice. We report that IH did not affect fasting glucose and insulin levels nor insulin sensitivity and insulin secretion during, whereas glucose effectiveness was decreased. Adrenal medullectomy decreased fasting blood glucose and insulin levels in mice exposed to IH but had no effect on glucose metabolism, insulin secretion, and insulin sensitivity. PMID:28104753

A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading

NASA Astrophysics Data System (ADS)

Walb, M. C.; Black, P. J.; Payne, V. S.; Munley, M. T.; Willey, J. S.

2015-07-01

Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm × 30.5 cm × 40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their dosimetry properties, this method may find great utility in the implementation of future ground-based studies that examine the combined spaceflight challenges of reduced loading and radiation while using the HLU rodent model.

Pattern Separation, Pattern Completion, and New Neuronal Codes within a Continuous CA3 Map

ERIC Educational Resources Information Center

Leutgeb, Stefan; Leutgeb, Jill K.

2007-01-01

The hippocampal CA3 subregion is critical for rapidly encoding new memories, which suggests that neuronal computations are implemented in its circuitry that cannot be performed elsewhere in the hippocampus or in the neocortex. Recording studies show that CA3 cells are bound to a large degree to a spatial coordinate system, while CA1 cells can…

Boundary Conditions for the Maintenance of Memory by PKM[zeta] in Neocortex

ERIC Educational Resources Information Center

Shema, Reul; Hazvi, Shoshi; Sacktor, Todd C.; Dudai, Yadin

2009-01-01

We report here that ZIP, a selective inhibitor of the atypical protein kinase C isoform PKM[zeta], abolishes very long-term conditioned taste aversion (CTA) associations in the insular cortex of the behaving rat, at least 3 mo after encoding. The effect of ZIP is not replicated by a general serine/threonine protein kinase inhibitor that is…

Rapid consolidation of new knowledge in adulthood via fast mapping.

PubMed

Coutanche, Marc N; Thompson-Schill, Sharon L

2015-09-01

Rapid word learning, where words are 'fast mapped' onto new concepts, may help build vocabulary during childhood. Recent evidence has suggested that fast mapping might help to rapidly integrate information into memory networks of the adult neocortex. The neural basis for this learning by fast mapping determines key properties of the learned information. Copyright © 2015 Elsevier Ltd. All rights reserved.

TERMINAL ARBORS OF AXONS PROJECTING TO THE SOMATOSENSORY CORTEX OF THE ADULT RAT. 2. THE ALTERED MORPHOLOGY OF THALAMOCORTICAL AFFERENTS FOLLOWING NEONATAL INFRAORBITAL NERVE CUT (JOURNAL VERSION)

EPA Science Inventory

The organization of the whisker representation within the neocortex of the rat is dependent on an intact periphery during development. To further investigate how alterations in the cortical map arise the authors examined the organization of thalamocortical afferents to the whiske...

The Molecular Pathway Regulating Bergmann Glia and Folia Generation in the Cerebellum.

PubMed

Leung, Alan W; Li, James Y H

2018-02-01

Evolution of complex behaviors in higher vertebrates and primates require the development of sophisticated neuronal circuitry and the expansion of brain surface area to accommodate the vast number of neuronal and glial populations. To achieve these goals, the neocortex in primates and the cerebellum in amniotes have developed specialized types of basal progenitors to aid the folding of their cortices. In the cerebellum, Bergmann glia constitute such a basal progenitor population, having a distinctive morphology and playing a critical role in cerebellar corticogenesis. Here, we review recent studies on the induction of Bergmann glia and their crucial role in mediating folding of the cerebellar cortex. These studies uncover a key function of FGF-ERK-ETV signaling cascade in the transformation of Bergmann glia from radial glia in the ventricular zone. Remarkably, in the neocortex, the same signaling axis operates to facilitate the transformation of ventricular radial glia into basal radial glia, a Bergmann glia-like basal progenitor population, which have been implicated in the establishment of neocortical gyri. These new findings draw a striking similarity in the function and ontogeny of the two basal progenitor populations born in distinct brain compartments.

Inferring cortical function in the mouse visual system through large-scale systems neuroscience.

PubMed

Hawrylycz, Michael; Anastassiou, Costas; Arkhipov, Anton; Berg, Jim; Buice, Michael; Cain, Nicholas; Gouwens, Nathan W; Gratiy, Sergey; Iyer, Ramakrishnan; Lee, Jung Hoon; Mihalas, Stefan; Mitelut, Catalin; Olsen, Shawn; Reid, R Clay; Teeter, Corinne; de Vries, Saskia; Waters, Jack; Zeng, Hongkui; Koch, Christof

2016-07-05

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

Physiological significance of multipolar cells generated from neural stem cells and progenitors for the establishment of neocortical cytoarchitecture.

PubMed

Mizutani, Ken-Ichi

2018-01-01

Neurogenesis encompasses an entire set of events that leads to the generation of newborn neurons from neural stem cells and more committed progenitor cells, including cell division, the production of migratory precursors and their progeny, differentiation and integration into circuits. In particular, the precise control of neuronal migration and morphological changes is essential for the development of the neocortex. Postmitotic cells within the intermediate zone have been found to transiently assume a characteristic "multipolar" morphology, after which a multipolar-to-bipolar transition occurs before the cells enter the cortical plate; however, the importance of this multipolar phase in the establishment of mature cortical cytoarchitecture and the precise genetic control of this phase remains largely unknown. Thus, this review article focuses on the multipolar phase in the developing neocortex. It begins by summarizing the molecular mechanism that underlies multipolar migration for the regulation of each step in multipolar phase in intermediate zone. The physiological significance of this multipolar phase in the establishment of mature cortical lamination and neurodevelopmental disorders associated with migration defects is then described. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory.

PubMed

Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

2016-01-15

Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor-dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace. Copyright © 2015 Elsevier B.V. All rights reserved.

Variable Anisotropic Brain Electrical Conductivities in Epileptogenic Foci

PubMed Central

Mandelkern, M.; Bui, D.; Salamon, N.; Vinters, H. V.; Mathern, G. W.

2010-01-01

Source localization models assume brain electrical conductivities are isotropic at about 0.33 S/m. These assumptions have not been confirmed ex vivo in humans. This study determined bidirectional electrical conductivities from pediatric epilepsy surgery patients. Electrical conductivities perpendicular and parallel to the pial surface of neocortex and subcortical white matter (n = 15) were measured using the 4-electrode technique and compared with clinical variables. Mean (±SD) electrical conductivities were 0.10 ± 0.01 S/m, and varied by 243% from patient to patient. Perpendicular and parallel conductivities differed by 45%, and the larger values were perpendicular to the pial surface in 47% and parallel in 40% of patients. A perpendicular principal axis was associated with normal, while isotropy and parallel principal axes were linked with epileptogenic lesions by MRI. Electrical conductivities were decreased in patients with cortical dysplasia compared with non-dysplasia etiologies. The electrical conductivity values of freshly excised human brain tissues were approximately 30% of assumed values, varied by over 200% from patient to patient, and had erratic anisotropic and isotropic shapes if the MRI showed a lesion. Understanding brain electrical conductivity and ways to non-invasively measure them are probably necessary to enhance the ability to localize EEG sources from epilepsy surgery patients. PMID:20440549

Electrical Stimulation Modulates High γ Activity and Human Memory Performance

PubMed Central

Berry, Brent M.; Miller, Laura R.; Khadjevand, Fatemeh; Ezzyat, Youssef; Wanda, Paul; Sperling, Michael R.; Lega, Bradley; Stead, S. Matt

2018-01-01

Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high γ (62–118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with “poor” memory encoding. The high γ modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high γ activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high γ activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation. PMID:29404403

Influence of sound source location on the behavior and physiology of the precedence effect in cats.

PubMed

Dent, Micheal L; Tollin, Daniel J; Yin, Tom C T

2009-08-01

Psychophysical experiments on the precedence effect (PE) in cats have shown that they localize pairs of auditory stimuli presented from different locations in space based on the spatial position of the stimuli and the interstimulus delay (ISD) between the stimuli in a manner similar to humans. Cats exhibit localization dominance for pairs of transient stimuli with |ISDs| from approximately 0.4 to 10 ms, summing localization for |ISDs| < 0.4 ms and breakdown of fusion for |ISDs| > 10 ms, which is the approximate echo threshold. The neural correlates to the PE have been described in both anesthetized and unanesthetized animals at many levels from auditory nerve to cortex. Single-unit recordings from the inferior colliculus (IC) and auditory cortex of cats demonstrate that neurons respond to both lead and lag sounds at ISDs above behavioral echo thresholds, but the response to the lag is reduced at shorter ISDs, consistent with localization dominance. Here the influence of the relative locations of the leading and lagging sources on the PE was measured behaviorally in a psychophysical task and physiologically in the IC of awake behaving cats. At all configurations of lead-lag stimulus locations, the cats behaviorally exhibited summing localization, localization dominance, and breakdown of fusion. Recordings from the IC of awake behaving cats show neural responses paralleling behavioral measurements. Both behavioral and physiological results suggest systematically shorter echo thresholds when stimuli are further apart in space.

Influence of Sound Source Location on the Behavior and Physiology of the Precedence Effect in Cats

PubMed Central

Dent, Micheal L.; Tollin, Daniel J.; Yin, Tom C. T.

2009-01-01

Psychophysical experiments on the precedence effect (PE) in cats have shown that they localize pairs of auditory stimuli presented from different locations in space based on the spatial position of the stimuli and the interstimulus delay (ISD) between the stimuli in a manner similar to humans. Cats exhibit localization dominance for pairs of transient stimuli with |ISDs| from ∼0.4 to 10 ms, summing localization for |ISDs| < 0.4 ms and breakdown of fusion for |ISDs| > 10 ms, which is the approximate echo threshold. The neural correlates to the PE have been described in both anesthetized and unanesthetized animals at many levels from auditory nerve to cortex. Single-unit recordings from the inferior colliculus (IC) and auditory cortex of cats demonstrate that neurons respond to both lead and lag sounds at ISDs above behavioral echo thresholds, but the response to the lag is reduced at shorter ISDs, consistent with localization dominance. Here the influence of the relative locations of the leading and lagging sources on the PE was measured behaviorally in a psychophysical task and physiologically in the IC of awake behaving cats. At all configurations of lead-lag stimulus locations, the cats behaviorally exhibited summing localization, localization dominance, and breakdown of fusion. Recordings from the IC of awake behaving cats show neural responses paralleling behavioral measurements. Both behavioral and physiological results suggest systematically shorter echo thresholds when stimuli are further apart in space. PMID:19439668

Dual sensitivity of inferior colliculus neurons to ITD in the envelopes of high-frequency sounds: experimental and modeling study

PubMed Central

Wang, Le; Devore, Sasha; Delgutte, Bertrand

2013-01-01

Human listeners are sensitive to interaural time differences (ITDs) in the envelopes of sounds, which can serve as a cue for sound localization. Many high-frequency neurons in the mammalian inferior colliculus (IC) are sensitive to envelope-ITDs of sinusoidally amplitude-modulated (SAM) sounds. Typically, envelope-ITD-sensitive IC neurons exhibit either peak-type sensitivity, discharging maximally at the same delay across frequencies, or trough-type sensitivity, discharging minimally at the same delay across frequencies, consistent with responses observed at the primary site of binaural interaction in the medial and lateral superior olives (MSO and LSO), respectively. However, some high-frequency IC neurons exhibit dual types of envelope-ITD sensitivity in their responses to SAM tones, that is, they exhibit peak-type sensitivity at some modulation frequencies and trough-type sensitivity at other frequencies. Here we show that high-frequency IC neurons in the unanesthetized rabbit can also exhibit dual types of envelope-ITD sensitivity in their responses to SAM noise. Such complex responses to SAM stimuli could be achieved by convergent inputs from MSO and LSO onto single IC neurons. We test this hypothesis by implementing a physiologically explicit, computational model of the binaural pathway. Specifically, we examined envelope-ITD sensitivity of a simple model IC neuron that receives convergent inputs from MSO and LSO model neurons. We show that dual envelope-ITD sensitivity emerges in the IC when convergent MSO and LSO inputs are differentially tuned for modulation frequency. PMID:24155013

The chronically instrumental ewe: a model for studying vascular reactivity to angiotensin II in pregnancy.

PubMed Central

Rosenfeld, C R; Gant, N F

1981-01-01

Vascular refractoriness to the systemic pressor effects of angiotension II (AII) develops normally during human pregnancy. To ascertain if the ewe might provide a suitable animal model to study the mechanisms responsible for this response (unique to pregnancy) we studied this phenomenon in unanesthetized, chronically instrumented nonpregnant and pregnant sheep, 68-143 d gestation. In these studies dose-response curves were established for changes in both mean arterial pressure and uterine blood flow. The pressor response to continuous infusions of AII increases as a function of the dose of AII in both nonpregnant and pregnant animals (P less than 0.001), R = 0.943 and 0.879, respectively. However, the pregnant animals were refractory to the pressor effects of AII, requiring 0.016 microgram of AII/min per kg to elicit a 20 mm HG rise in mean arterial pressure, in contrast to 0.009 for nonpregnant animals. The slope and intercept for the regression lines are different at P less than 0.001. In pregnant animals the dose-response curve for uterine blood flow was also determined. Increases in uterine blood flow were observed at doses of AII less than 0.016 microgram/min per kg, while larger doses resulted in a progressively greater reduction in blood flow. It appears likely that the ewe may serve as an animal model suitable for the further study of the unique pregnancy-modified systemic and uteroplacental vascular responses elicited by AII. PMID:7462427

Circadian Rhythm Control: Neurophysiological Investigations

NASA Technical Reports Server (NTRS)

Glotzbach, S. F.

1985-01-01

The suprachiasmatic nucleus (SCN) was implicated as a primary component in central nervous system mechanisms governing circadian rhythms. Disruption of the normal synchronization of temperature, activity, and other rhythms is detrimental to health. Sleep wake disorders, decreases in vigilance and performance, and certain affective disorders may result from or be exacerbated by such desynchronization. To study the basic neurophysiological mechanisms involved in entrainment of circadian systems by the environment, Parylene-coated, etched microwire electrode bundles were used to record extracellular action potentials from the small somata of the SCN and neighboring hypothalamic nuclei in unanesthetized, behaving animals. Male Wistar rats were anesthetized and chronically prepared with EEG ane EMG electrodes in addition to a moveable microdrive assembly. The majority of cells had firing rates 10 Hz and distinct populations of cells which had either the highest firing rate or lowest firing rate during sleep were seen.

Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor

PubMed Central

O’Sullivan, Thomas D.; Heitz, Roxana T.; Parashurama, Natesh; Barkin, David B.; Wooley, Bruce A.; Gambhir, Sanjiv S.; Harris, James S.; Levi, Ofer

2013-01-01

Performance improvements in instrumentation for optical imaging have contributed greatly to molecular imaging in living subjects. In order to advance molecular imaging in freely moving, untethered subjects, we designed a miniature vertical-cavity surface-emitting laser (VCSEL)-based biosensor measuring 1cm3 and weighing 0.7g that accurately detects both fluorophore and tumor-targeted molecular probes in small animals. We integrated a critical enabling component, a complementary metal-oxide semiconductor (CMOS) read-out integrated circuit, which digitized the fluorescence signal to achieve autofluorescence-limited sensitivity. After surgical implantation of the lightweight sensor for two weeks, we obtained continuous and dynamic fluorophore measurements while the subject was un-anesthetized and mobile. The technology demonstrated here represents a critical step in the path toward untethered optical sensing using an integrated optoelectronic implant. PMID:24009996

Neuroimaging in human MDMA (Ecstasy) users: A cortical model

PubMed Central

Cowan, Ronald L; Roberts, Deanne M; Joers, James M

2009-01-01

MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. MDMA and Ecstasy are often used synonymously but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and non-human primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long-lasting reductions in markers of brain serotonin (5-HT) that appear specific to fine diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long-lasting or permanent 5-HT axon damage or loss, and the widespread role of 5-HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long-lasting changes in brain function consistent with 5-HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research. PMID:18991874

Statistical mechanics of neocortical interactions: Constraints on 40-Hz models of short-term memory

NASA Astrophysics Data System (ADS)

Ingber, Lester

1995-10-01

Calculations presented in L. Ingber and P.L. Nunez, Phys. Rev. E 51, 5074 (1995) detailed the evolution of short-term memory in the neocortex, supporting the empirical 7+/-2 rule of constraints on the capacity of neocortical processing. These results are given further support when other recent models of 40-Hz subcycles of low-frequency oscillations are considered.

Saturated Reconstruction of a Volume of Neocortex

DTIC Science & Technology

2015-07-30

Narayanan Kasthuri, Kenneth Jeffrey Hayworth, Daniel Raimund Berger, ..., Carey Eldin Priebe, Hanspeter Pfister, Jeff William Lichtman Correspondence...Sussman,4 Carey Eldin Priebe,5 Hanspeter Pfister,2 and Jeff William Lichtman1,* 1Department of Molecular and Cellular Biology and Center for Brain...redundancies in the synaptic connections andwanted to know if these were acci- dental . For all these reasons, we have attempted to analyze the connectivity

Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice.

PubMed

Sherman, Maxwell A; Lee, Shane; Law, Robert; Haegens, Saskia; Thorn, Catherine A; Hämäläinen, Matti S; Moore, Christopher I; Jones, Stephanie R

2016-08-16

Human neocortical 15-29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting <150 ms with a stereotypical waveform. Computational modeling uniquely designed to infer the electrical currents underlying these signals showed that beta events could emerge from the integration of nearly synchronous bursts of excitatory synaptic drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (∼50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function.

Structural and functional analyses of human cerebral cortex using a surface-based atlas

NASA Technical Reports Server (NTRS)

Van Essen, D. C.; Drury, H. A.

1997-01-01

We have analyzed the geometry, geography, and functional organization of human cerebral cortex using surface reconstructions and cortical flat maps of the left and right hemispheres generated from a digital atlas (the Visible Man). The total surface area of the reconstructed Visible Man neocortex is 1570 cm2 (both hemispheres), approximately 70% of which is buried in sulci. By linking the Visible Man cerebrum to the Talairach stereotaxic coordinate space, the locations of activation foci reported in neuroimaging studies can be readily visualized in relation to the cortical surface. The associated spatial uncertainty was empirically shown to have a radius in three dimensions of approximately 10 mm. Application of this approach to studies of visual cortex reveals the overall patterns of activation associated with different aspects of visual function and the relationship of these patterns to topographically organized visual areas. Our analysis supports a distinction between an anterior region in ventral occipito-temporal cortex that is selectively involved in form processing and a more posterior region (in or near areas VP and V4v) involved in both form and color processing. Foci associated with motion processing are mainly concentrated in a region along the occipito-temporal junction, the ventral portion of which overlaps with foci also implicated in form processing. Comparisons between flat maps of human and macaque monkey cerebral cortex indicate significant differences as well as many similarities in the relative sizes and positions of cortical regions known or suspected to be homologous in the two species.

[Effect of glutamate on the kinetics of sodium metabolism in slices of rat neocortex and hippocampus].

PubMed

Emel'ianov, N A; Bagaeva, T R; Kuznetsov, V L

1980-08-01

Three kinetic compartments (one extra--and two intracellular) of Na were distinguished in the rat neocortical and hippocampal cuts. Glutamate (Glu) caused the increase of intracellular Na compartments via two mechanisms: by the elevation of Na influx rate constant and by the decrease of Na efflux rate constant. The relationship between the phenomena observed and possible transmitter action of the Glu is discussed.

Regional homogeneity changes in prelingually deafened patients: a resting-state fMRI study

NASA Astrophysics Data System (ADS)

Li, Wenjing; He, Huiguang; Xian, Junfang; Lv, Bin; Li, Meng; Li, Yong; Liu, Zhaohui; Wang, Zhenchang

2010-03-01

Resting-state functional magnetic resonance imaging (fMRI) is a technique that measures the intrinsic function of brain and has some advantages over task-induced fMRI. Regional homogeneity (ReHo) assesses the similarity of the time series of a given voxel with its nearest neighbors on a voxel-by-voxel basis, which reflects the temporal homogeneity of the regional BOLD signal. In the present study, we used the resting state fMRI data to investigate the ReHo changes of the whole brain in the prelingually deafened patients relative to normal controls. 18 deaf patients and 22 healthy subjects were scanned. Kendall's coefficient of concordance (KCC) was calculated to measure the degree of regional coherence of fMRI time courses. We found that regional coherence significantly decreased in the left frontal lobe, bilateral temporal lobes and right thalamus, and increased in the postcentral gyrus, cingulate gyrus, left temporal lobe, left thalamus and cerebellum in deaf patients compared with controls. These results show that the prelingually deafened patients have higher degree of regional coherence in the paleocortex, and lower degree in neocortex. Since neocortex plays an important role in the development of auditory, these evidences may suggest that the deaf persons reorganize the paleocortex to offset the loss of auditory.

Epigenome profiling and editing of neocortical progenitor cells during development.

PubMed

Albert, Mareike; Kalebic, Nereo; Florio, Marta; Lakshmanaperumal, Naharajan; Haffner, Christiane; Brandl, Holger; Henry, Ian; Huttner, Wieland B

2017-09-01

The generation of neocortical neurons from neural progenitor cells (NPCs) is primarily controlled by transcription factors binding to DNA in the context of chromatin. To understand the complex layer of regulation that orchestrates different NPC types from the same DNA sequence, epigenome maps with cell type resolution are required. Here, we present genomewide histone methylation maps for distinct neural cell populations in the developing mouse neocortex. Using different chromatin features, we identify potential novel regulators of cortical NPCs. Moreover, we identify extensive H3K27me3 changes between NPC subtypes coinciding with major developmental and cell biological transitions. Interestingly, we detect dynamic H3K27me3 changes on promoters of several crucial transcription factors, including the basal progenitor regulator Eomes We use catalytically inactive Cas9 fused with the histone methyltransferase Ezh2 to edit H3K27me3 at the Eomes locus in vivo , which results in reduced Tbr2 expression and lower basal progenitor abundance, underscoring the relevance of dynamic H3K27me3 changes during neocortex development. Taken together, we provide a rich resource of neocortical histone methylation data and outline an approach to investigate its contribution to the regulation of selected genes during neocortical development. © 2017 The Authors.

Relationships between structure, in vivo function and long-range axonal target of cortical pyramidal tract neurons.

PubMed

Rojas-Piloni, Gerardo; Guest, Jason M; Egger, Robert; Johnson, Andrew S; Sakmann, Bert; Oberlaender, Marcel

2017-10-11

Pyramidal tract neurons (PTs) represent the major output cell type of the neocortex. To investigate principles of how the results of cortical processing are broadcasted to different downstream targets thus requires experimental approaches, which provide access to the in vivo electrophysiology of PTs, whose subcortical target regions are identified. On the example of rat barrel cortex (vS1), we illustrate that retrograde tracer injections into multiple subcortical structures allow identifying the long-range axonal targets of individual in vivo recorded PTs. Here we report that soma depth and dendritic path lengths within each cortical layer of vS1, as well as spiking patterns during both periods of ongoing activity and during sensory stimulation, reflect the respective subcortical target regions of PTs. We show that these cellular properties result in a structure-function parameter space that allows predicting a PT's subcortical target region, without the need to inject multiple retrograde tracers.The major output cell type of the neocortex - pyramidal tract neurons (PTs) - send axonal projections to various subcortical areas. Here the authors combined in vivo recordings, retrograde tracings, and reconstructions of PTs in rat somatosensory cortex to show that PT structure and activity can predict specific subcortical targets.

Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study.

PubMed

Wolf, D S; Gearing, M; Snowdon, D A; Mori, H; Markesbery, W R; Mirra, S S

1999-01-01

Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Brain surface temperature under a craniotomy

PubMed Central

Kalmbach, Abigail S.

2012-01-01

Many neuroscientists access surface brain structures via a small cranial window, opened in the bone above the brain region of interest. Unfortunately this methodology has the potential to perturb the structure and function of the underlying brain tissue. One potential perturbation is heat loss from the brain surface, which may result in local dysregulation of brain temperature. Here, we demonstrate that heat loss is a significant problem in a cranial window preparation in common use for electrical recording and imaging studies in mice. In the absence of corrective measures, the exposed surface of the neocortex was at ∼28°C, ∼10°C below core body temperature, and a standing temperature gradient existed, with tissue below the core temperature even several millimeters into the brain. Cooling affected cellular and network function in neocortex and resulted principally from increased heat loss due to convection and radiation through the skull and cranial window. We demonstrate that constant perfusion of solution, warmed to 37°C, over the brain surface readily corrects the brain temperature, resulting in a stable temperature of 36–38°C at all depths. Our results indicate that temperature dysregulation may be common in cranial window preparations that are in widespread use in neuroscience, underlining the need to take measures to maintain the brain temperature in many physiology experiments. PMID:22972953

The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

PubMed Central

2016-01-01

The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

Sensory Response of Transplanted Astrocytes in Adult Mammalian Cortex In Vivo

PubMed Central

Zhang, Kuan; Chen, Chunhai; Yang, Zhiqi; He, Wenjing; Liao, Xiang; Ma, Qinlong; Deng, Ping; Lu, Jian; Li, Jingcheng; Wang, Meng; Li, Mingli; Zheng, Lianghong; Zhou, Zhuan; Sun, Wei; Wang, Liting; Jia, Hongbo; Yu, Zhengping; Zhou, Zhou; Chen, Xiaowei

2016-01-01

Glial precursor transplantation provides a potential therapy for brain disorders. Before its clinical application, experimental evidence needs to indicate that engrafted glial cells are functionally incorporated into the existing circuits and become essential partners of neurons for executing fundamental brain functions. While previous experiments supporting for their functional integration have been obtained under in vitro conditions using slice preparations, in vivo evidence for such integration is still lacking. Here, we utilized in vivo two-photon Ca2+ imaging along with immunohistochemistry, fluorescent indicator labeling-based axon tracing and correlated light/electron microscopy to analyze the profiles and the functional status of glial precursor cell-derived astrocytes in adult mouse neocortex. We show that after being transplanted into somatosensory cortex, precursor-derived astrocytes are able to survive for more than a year and respond with Ca2+ signals to sensory stimulation. These sensory-evoked responses are mediated by functionally-expressed nicotinic receptors and newly-established synaptic contacts with the host cholinergic afferents. Our results provide in vivo evidence for a functional integration of transplanted astrocytes into adult mammalian neocortex, representing a proof-of-principle for sensory cortex remodeling through addition of essential neural elements. Moreover, we provide strong support for the use of glial precursor transplantation to understand glia-related neural development in vivo. PMID:27405333

Inhibitory dendrite dynamics as a general feature of the adult cortical microcircuit.

PubMed

Chen, Jerry L; Flanders, Genevieve H; Lee, Wei-Chung Allen; Lin, Walter C; Nedivi, Elly

2011-08-31

The mammalian neocortex is functionally subdivided into architectonically distinct regions that process various types of information based on their source of afferent input. Yet, the modularity of neocortical organization in terms of cell type and intrinsic circuitry allows afferent drive to continuously reassign cortical map space. New aspects of cortical map plasticity include dynamic turnover of dendritic spines on pyramidal neurons and remodeling of interneuron dendritic arbors. While spine remodeling occurs in multiple cortical regions, it is not yet known whether interneuron dendrite remodeling is common across primary sensory and higher-level cortices. It is also unknown whether, like pyramidal dendrites, inhibitory dendrites respect functional domain boundaries. Given the importance of the inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps, we sought to address these questions by using two-photon microscopy to monitor interneuron dendritic arbors of thy1-GFP-S transgenic mice expressing GFP in neurons sparsely distributed across the superficial layers of the neocortex. We find that interneuron dendritic branch tip remodeling is a general feature of the adult cortical microcircuit, and that remodeling rates are similar across primary sensory regions of different modalities, but may differ in magnitude between primary sensory versus higher cortical areas. We also show that branch tip remodeling occurs in bursts and respects functional domain boundaries.

Identity of sensory and motor systems that are critical to the immobility reflex ("animal hypnosis").

PubMed

Klemm, W R

1976-01-01

This review presents an analysis of the sensory and motor mechanisms as they are now understood that cause the immobility reflex (IR). Of the sensory systems that conceivably could trigger and sustain the IR, as commonly induced experimentally by inversion and manual restraint, evidence has been presented to eliminate some senses (vestibular, vision, sound, many visceral sensations, olfaction, taste, temperature), while incriminating tactile and proprioceptive influences. Of the motor systems which could cause the profound immobility during IR, neurosurgical and electrophysiological evidence identifies the locus of the inhibitory neurons in the brain stem and/or spinal cord. The evidence reviewed leads to a unified working hypothesis of IR mechanisms. IR is considered to be caused by a group of neurons in the brain stem which inhibit spinal motoneurons, either directly or indirectly, when those inhibitory neurons are activated by a specific pattern of tactile and proprioceptive input. Modulation of the IR control system appears to come from the limbic system, which under fear-producing conditions, potentiates the IR in part by release of epinephrine. Inhibition of the IR control system appears to come from the neocortex, as well as the brain stem reticulum, when it is activated by nonspecific, arousing somaesthetic sensations that produce generalized activation of the neocortex and skeletal muscle.

The cortical structure of consolidated memory: a hypothesis on the role of the cingulate-entorhinal cortical connection.

PubMed

Insel, Nathan; Takehara-Nishiuchi, Kaori

2013-11-01

Daily experiences are represented by networks of neurons distributed across the neocortex, bound together for rapid storage and later retrieval by the hippocampus. While the hippocampus is necessary for retrieving recent episode-based memory associations, over time, consolidation processes take place that enable many of these associations to be expressed independent of the hippocampus. It is generally thought that mechanisms of consolidation involve synaptic weight changes between cortical regions; or, in other words, the formation of "horizontal" cortico-cortical connections. Here, we review anatomical, behavioral, and physiological data which suggest that the connections in and between the entorhinal and cingulate cortices may be uniquely important for the long-term storage of memories that initially depend on the hippocampus. We propose that current theories of consolidation that divide memory into dual systems of hippocampus and neocortex might be improved by introducing a third, middle layer of entorhinal and cingulate allocortex, the synaptic weights within which are necessary and potentially sufficient for maintaining initially hippocampus-dependent associations over long time periods. This hypothesis makes a number of still untested predictions, and future experiments designed to address these will help to fill gaps in the current understanding of the cortical structure of consolidated memory. Copyright © 2013 Elsevier Inc. All rights reserved.

Intracranial evaluation and laser ablation for epilepsy with periventricular nodular heterotopia.

PubMed

Thompson, Stephen A; Kalamangalam, Giridhar P; Tandon, Nitin

2016-10-01

Surgical treatment of focal epilepsy in the presence of periventricular nodular heterotopia (PVNH) poses a challenge, as the relative roles of the nodular tissue and the overlying cortex in the generation of seizures can be complex and variable. Here, we review the literature on chronic invasive EEG recordings in humans with this substrate and present two illustrative cases from our practice. We found that while inter-ictal spiking from nodules is common, clinical seizures rarely arise solely from nodular tissue. More typically, ictal onset is simultaneous with overlying neocortex or mesial temporal structures. Surgical outcome is more favorable in cases with unilateral (as opposed to bilateral) PVNH, and when a substantial or complete ablation of PVNH is performed. In rare cases, nodular ablation alone may be sufficient, as may be completed by MRI-guided laser interstitial thermal therapy. The mechanism(s) by which PNVH interacts with overlying cortex are not fully understood, but we suggest that PVNH either orchestrates or amplifies local network epileptogenicity. At present, invasive recordings with penetrating depth electrodes are required prior to surgical therapy, as illustrated in our cases. Published by Elsevier Ltd.

Expression profile of Lgi1 gene in mouse brain during development.

PubMed

Ribeiro, Patrícia A O; Sbragia, Lourenço; Gilioli, Rovilson; Langone, Francesco; Conte, Fábio F; Lopes-Cendes, Iscia

2008-07-01

Mutations in LGI1 were described in patients with autosomal dominant partial epilepsy with auditory features (ADPEAF), and recent clinical findings have implicated LGI1 in human brain development. However, the precise role of LGI1 in epileptogenesis remains largely unknown. The objective of this study was to determine the expression pattern of Lgi1 in mice brain during development and in adult animals. Real-time polymerase chain reaction (PCR) quantification and Western blot experiments showed a relative low expression during intrauterine stages, increasing until adulthood. In addition, we did not find significant differences between left and right hemispheres. The hippocampus presented higher levels of Lgi1 expression when compared to the neocortex and the cerebellum of adult animals; however, these results did not reach statistical significance. This study was the first to determine a specific profile of Lgi1 gene expression during central nervous system development, which suggests a possible inhibitory function in latter stages of development. In addition, we did not find differences in hemispheric expression that could explain the predominance of left-sided abnormalities in patients with ADPEAF.

Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals.

PubMed

Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth; Miller, Elaine; Ariza, Jeanelle; Kienzle, Devon; Plank, Kaela; Noctor, Stephen C; Van de Water, Judy

2016-01-01

Autism spectrum disorders (ASDs) affect up to 1 in 68 children. Autism-specific autoantibodies directed against fetal brain proteins have been found exclusively in a subpopulation of mothers whose children were diagnosed with ASD or maternal autoantibody-related autism. We tested the impact of autoantibodies on brain development in mice by transferring human antigen-specific IgG directly into the cerebral ventricles of embryonic mice during cortical neurogenesis. We show that autoantibodies recognize radial glial cells during development. We also show that prenatal exposure to autism-specific maternal autoantibodies increased stem cell proliferation in the subventricular zone (SVZ) of the embryonic neocortex, increased adult brain size and weight, and increased the size of adult cortical neurons. We propose that prenatal exposure to autism-specific maternal autoantibodies directly affects radial glial cell development and presents a viable pathologic mechanism for the maternal autoantibody-related prenatal ASD risk factor. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Efficient post-exposure prophylaxis against rabies by applying a four-dose DNA vaccine intranasally.

PubMed

Tesoro Cruz, Emiliano; Feria Romero, Iris Angélica; López Mendoza, Juan Gabriel; Orozco Suárez, Sandra; Hernández González, Rafael; Favela, Francisco Blanco; Pérez Torres, Armando; José Alvaro Aguilar Setién

2008-12-09

We tested two post-exposure prophylaxes (PEPs) for rabies in laboratory animals; one was a traditional antirabies vaccine for humans via intramuscular route (IM), and the other was a DNA vaccine administered by intranasal route (IN). In contrast to The World Health Organization's recommended five-dose PEP, we gave only four doses without hyper-immune antirabies sera, making the PEP more rigorous. All animals were challenged with challenge virus strain (CVS); 16h later, PEP was applied. All animals that received the PEP with DNA/IN survived, and 87% of the rabbits and 80% of the mice that received the PEP with traditional antirabies vaccine/IM survived. Negative controls succumbed to infection. The expression of G protein was detected in the NALT, cerebellum, cerebral cortex (neocortex), cerebellum and hippocampus, mainly in the glial cells (microglia) and microvessels. On the other hand, plasmid construct was detected in brain and its mRNA expression in medium and posterior encephalon. The efficiency of this DNA/IN PEP is probably due to the early expression of the antigen in the brain stimulating the immune system locally.

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice.

PubMed

Toia, Alyssa R; Cuoco, Joshua A; Esposito, Anthony W; Ahsan, Jawad; Joshi, Alok; Herron, Bruce J; Torres, German; Bolivar, Valerie J; Ramos, Raddy L

2017-01-18

Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1 A/J /NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Network-Level Structure-Function Relationships in Human Neocortex

PubMed Central

Mišić, Bratislav; Betzel, Richard F.; de Reus, Marcel A.; van den Heuvel, Martijn P.; Berman, Marc G.; McIntosh, Anthony R.; Sporns, Olaf

2016-01-01

The dynamics of spontaneous fluctuations in neural activity are shaped by underlying patterns of anatomical connectivity. While numerous studies have demonstrated edge-wise correspondence between structural and functional connections, much less is known about how large-scale coherent functional network patterns emerge from the topology of structural networks. In the present study, we deploy a multivariate statistical technique, partial least squares, to investigate the association between spatially extended structural networks and functional networks. We find multiple statistically robust patterns, reflecting reliable combinations of structural and functional subnetworks that are optimally associated with one another. Importantly, these patterns generally do not show a one-to-one correspondence between structural and functional edges, but are instead distributed and heterogeneous, with many functional relationships arising from nonoverlapping sets of anatomical connections. We also find that structural connections between high-degree hubs are disproportionately represented, suggesting that these connections are particularly important in establishing coherent functional networks. Altogether, these results demonstrate that the network organization of the cerebral cortex supports the emergence of diverse functional network configurations that often diverge from the underlying anatomical substrate. PMID:27102654

Brain evolution relating to family, play, and the separation call.

PubMed

MacLean, P D

1985-04-01

Mammals stem from the mammal-like reptiles (therapsids) that were widely prevalent in Pangaea 250 million years ago. In the evolutionary transition from reptiles to mammals, three key developments were (1) nursing, in conjunction with maternal care; (2) audiovocal communication for maintaining maternal-offspring contact; and (3) play. The separation call perhaps ranks as the earliest and most basic mammalian vocalization, while play may have functioned originally to promote harmony in the nest. How did such family related behavior develop? In its evolution, the forebrain of advanced mammals has expanded as a triune structure that anatomically and chemically reflects ancestral commonalities with reptiles, early mammals, and late mammals. Recent findings suggest that the development of the behavioral triad in question may have depended on the evolution of the thalamocingulate division of the limbic system, a derivative from early mammals. The thalamocingulate division (which has no distinctive counterpart in the reptilian brain) is, in turn, geared in with the prefrontal neocortex that, in human beings, may be inferred to play a key role in familial acculturation.

Brain Entropy Mapping Using fMRI

PubMed Central

Wang, Ze; Li, Yin; Childress, Anna Rose; Detre, John A.

2014-01-01

Entropy is an important trait for life as well as the human brain. Characterizing brain entropy (BEN) may provide an informative tool to assess brain states and brain functions. Yet little is known about the distribution and regional organization of BEN in normal brain. The purpose of this study was to examine the whole brain entropy patterns using a large cohort of normal subjects. A series of experiments were first performed to validate an approximate entropy measure regarding its sensitivity, specificity, and reliability using synthetic data and fMRI data. Resting state fMRI data from a large cohort of normal subjects (n = 1049) from multi-sites were then used to derive a 3-dimensional BEN map, showing a sharp low-high entropy contrast between the neocortex and the rest of brain. The spatial heterogeneity of resting BEN was further studied using a data-driven clustering method, and the entire brain was found to be organized into 7 hierarchical regional BEN networks that are consistent with known structural and functional brain parcellations. These findings suggest BEN mapping as a physiologically and functionally meaningful measure for studying brain functions. PMID:24657999

Multidimensional custom-made non-linear microscope: from ex-vivo to in-vivo imaging

NASA Astrophysics Data System (ADS)

Cicchi, R.; Sacconi, L.; Jasaitis, A.; O'Connor, R. P.; Massi, D.; Sestini, S.; de Giorgi, V.; Lotti, T.; Pavone, F. S.

2008-09-01

We have built a custom-made multidimensional non-linear microscope equipped with a combination of several non-linear laser imaging techniques involving fluorescence lifetime, multispectral two-photon and second-harmonic generation imaging. The optical system was mounted on a vertical honeycomb breadboard in an upright configuration, using two galvo-mirrors relayed by two spherical mirrors as scanners. A double detection system working in non-descanning mode has allowed both photon counting and a proportional regime. This experimental setup offering high spatial (micrometric) and temporal (sub-nanosecond) resolution has been used to image both ex-vivo and in-vivo biological samples, including cells, tissues, and living animals. Multidimensional imaging was used to spectroscopically characterize human skin lesions, as malignant melanoma and naevi. Moreover, two-color detection of two photon excited fluorescence was applied to in-vivo imaging of living mice intact neocortex, as well as to induce neuronal microlesions by femtosecond laser burning. The presented applications demonstrate the capability of the instrument to be used in a wide range of biological and biomedical studies.

The Metabolism of the Volatile Amines

PubMed Central

Tobe, Barry A.; Goldman, Bernard S.

1963-01-01

The effects of certain drugs on metabolism of ammonia by the liver and kidneys in dogs were investigated by a technique in which both hepatic inflow and outflow bloods could be repeatedly sampled in unanesthetized healthy animals. Specific representatives of the classes of the drugs studied included thiopental (barbiturates), morphine (opiates and analgesics), promazine (tranquillizers), and chlorothiazide (oral diuretics). The three drugs commonly used as sedatives were all found to impair the ability of the liver to metabolize ammonia. The diuretic, by contrast, increased the amount of ammonia put into the systemic system by the kidneys. Ethanol appeared to have little or no direct effect on ammonia metabolism. The possibility exists that the occurrence of acute hepatic encephalopathy in patients with severe liver disease may be avoided in many cases if these drugs are administered with proper care. Results also indicated that current concepts of the pharmacological action of sedatives, opiates and tranquillizers may require revision. ImagesFig. 2 PMID:14069611

Responses to the lowering of magnesium and calcium concentrations in the cerebrospinal fluid of unanesthetized sheep.

PubMed

Allsop, T F; Pauli, J V

1975-12-01

A technique for ventriculolumbar perfusion of the cerebrospinal fluid space has been used to study the neuromuscular effects of low concentrations of magnesium and calcium in the cerebrospinal fluid of conscious sheep. Perfusion with synthetic cerebrospinal fluid solutions containing less than 0-6 mg magnesium/100 ml produced episodes of tetany which were abolished by perfusion with a solution of normal magnesium concentration. This suggests that the low cerebrospinal fluid magnesium concentrations reported in cases of hypomagneseamic tetany may result in changes within the central nervous system that could produce the nervous signs. Perfusates with a calcium concentration below 2-0 mg/100 ml caused hyperpnoea and continuous muscle tremors. Magnesium (0-6 mg/100 ml) and calcium (2-0 mg/100 ml) perfused simultaneously acted synergistically to produce signs characteristic of low levels of each of the ions.

Pyrogenic renal hyperemia: the role of prostaglandins.

PubMed

Gagnon, J A; Ramwell, P W; Flamenbaum, W

1978-01-01

The intravenous administration of triple typhoid vaccine to anesthetized dogs resulted in a significant increase in renal blood flow accompanied by a modest decline in systemic blood pressure. This renal hyperemia was associated with elevated renal secretory rates of renin and prostaglandin E and F. Measurements of the intracortical distribution of radiolabeled microspheres revealed a progressive decrease in outer cortical blood flow rates and a progressive increase in inner cortical flow rates. When meclofenamate, an inhibitor of prostaglandin synthetase, was administered concomitantly with triple typhoid vaccine renal hyperemia did not develop. The renal renin secretory rate increased modestly and intracortical renal blood flow was not redistributed. The increased renal blood flow after triple typhoid vaccine administration to unanesthetized dogs was also reversed by meclofenamate. The marked increase in prostaglandin secretion by the kidney during renal hyperemia following triple typhoid vaccine administration (pyrogen), and the effect of meclofenamate, is consonant with a role for increased renal synthesis and release of prostaglandins.

Renal electrolyte circadian rhythms - Independence from feeding and activity patterns

NASA Technical Reports Server (NTRS)

Moore-Ede, M. C.; Herd, J. A.

1977-01-01

Experiments were conducted on six unanesthetized chair-acclimatized adult male squirrel monkeys (Saimiri sciureus) weighing 600-900 g to determine whether internal synchronization is the result of simple passive dependence of renal excretory rhythms on endogenous rhythms of those variable that influence electrolyte excretion such as dietary intake and muscular activity. Independence of the urinary rhythms from diurnal variations in feeding, drinking, and activity was secured by depriving the animals of food, water, and training them to perform a two-hourly schedule of feeding, drinking, and activity throughout day and night. Results indicate that the internal synchronization which is normally observed between the behavioral and urinary rhythms cannot be explained by any direct dependence of renal function on behavioral patterns. The most probable mechanism for circadian internal synchronization is that the various behavioral and renal rhythms are controlled by potentially independent separate oscillators which are normally kept in synchrony with one another.

Renal responses to central vascular expansion are suppressed at night in conscious primates

NASA Technical Reports Server (NTRS)

Kass, D. A.; Sulzman, F. M.; Fuller, C. A.; Moore-Ede, M. C.

1980-01-01

The renal and hemodynamic responses of squirrel monkeys to central vascular volume expansion induced by lower body positive pressure (LBPP) during the day and night are investigated. Twelve unanesthetized animals trained to sit in a metabolism chair in which they were restrained only at the waist by a partition separating upper and lower body chambers were subjected to 4 h of continuous LBPP during the day and night, and hemodynamic, urinary and drinking data were monitored. LBPP during day and night is found to induce similar increases in central venous pressure, rises in heart rate and elevations in mean arterial blood pressure. However, although daytime LBPP induced a significant increase in urine flow and sodium excretion, a marked nocturnal inhibition of the renal response to LBPP is observed. Analysis of the time course and circadian regulation patterns of the urinary responses suggests that several separate efferent control pathways are involved.

Control of abdominal muscles by brain stem respiratory neurons in the cat

NASA Technical Reports Server (NTRS)

Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

1985-01-01

The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

In vitro 3D regeneration-like growth of human patient brain tissue.

PubMed

Tang-Schomer, M D; Wu, W B; Kaplan, D L; Bookland, M J

2018-05-01

In vitro culture of primary neurons is widely adapted with embryonic but not mature brain tissue. Here, we extended a previously developed bioengineered three-dimensional (3D) embryonic brain tissue model to resected normal patient brain tissue in an attempt to regenerate human neurons in vitro. Single cells and small sized (diameter < 100 μm) spheroids from dissociated brain tissue were seeded into 3D silk fibroin-based scaffolds, with or without collagen or Matrigel, and compared with two-dimensional cultures and scaffold-free suspension cultures. Changes of cell phenotypes (neuronal, astroglial, neural progenitor, and neuroepithelial) were quantified with flow cytometry and analyzed with a new method of statistical analysis specifically designed for percentage comparison. Compared with a complete lack of viable cells in conventional neuronal cell culture condition, supplements of vascular endothelial growth factor-containing pro-endothelial cell condition led to regenerative growth of neurons and astroglial cells from "normal" human brain tissue of epilepsy surgical patients. This process involved delayed expansion of Nestin+ neural progenitor cells, emergence of TUJ1+ immature neurons, and Vimentin+ neuroepithelium-like cell sheet formation in prolonged cultures (14 weeks). Micro-tissue spheroids, but not single cells, supported the brain tissue growth, suggesting importance of preserving native cell-cell interactions. The presence of 3D scaffold, but not hydrogel, allowed for Vimentin+ cell expansion, indicating a different growth mechanism than pluripotent cell-based brain organoid formation. The slow and delayed process implied an origin of quiescent neural precursors in the neocortex tissue. Further optimization of the 3D tissue model with primary human brain cells could provide personalized brain disease models. Copyright © 2018 John Wiley & Sons, Ltd.

Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors.

PubMed

Hall, Hélène; Jewett, Michael; Landeck, Natalie; Nilsson, Nathalie; Schagerlöf, Ulrika; Leanza, Giampiero; Kirik, Deniz

2013-01-01

Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.

Neuroimaging in human MDMA (Ecstasy) users.

PubMed

Cowan, Ronald L; Roberts, Deanne M; Joers, James M

2008-10-01

MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. The terms "MDMA" and "Ecstasy" are often used synonymously, but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and nonhuman primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long-lasting reductions in markers of brain serotonin (5-HT) that appear specific to fine-diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long-lasting or permanent 5-HT axon damage or loss, and the widespread role of 5-HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long-lasting changes in brain function consistent with 5-HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA's effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide a context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data, but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research.

γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ.

PubMed

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R; Rose, Gregory M; Cai, Huaibin; Struble, Robert G; Cai, Yan; Yan, Xiao-Xin

2013-05-01

Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

γ-Secretase binding sites in aged and Alzheimer’s disease human cerebrum: The choroid plexus as a putative origin of CSF Aβ

PubMed Central

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R.; Rose, Gregory M.; Cai, Huaibin; Struble, Robert G.; Cai, Yan; Yan, Xiao-Xin

2013-01-01

Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD. PMID:23432732

The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease.

PubMed

Bertacchi, Michele; Parisot, Josephine; Studer, Michèle

2018-04-27

Transcription factors are expressed in a dynamic fashion both in time and space during brain development, and exert their roles by activating a cascade of multiple target genes. This implies that understanding the precise function of a transcription factor becomes a challenging task. In this review, we will focus on COUP-TFI (or NR2F1), a nuclear receptor belonging to the superfamily of the steroid/thyroid hormone receptors, and considered to be one of the major transcriptional regulators orchestrating cortical arealization, cell-type specification and maturation. Recent data have unraveled the multi-faceted functions of COUP-TFI in the development of several mouse brain structures, including the neocortex, hippocampus and ganglionic eminences. Despite NR2F1 mutations and deletions in humans have been linked to a complex neurodevelopmental disease mainly associated to optic atrophy and intellectual disability, its role during the formation of the retina and optic nerve remains unclear. In light of its major influence in cortical development, we predict that its haploinsufficiency might be the cause of other cognitive diseases, not identified so far. Mouse models offer a unique opportunity of dissecting COUP-TFI function in different regions during brain assembly; hence, the importance of comparing and discussing common points linking mouse models to human patients' symptoms. Copyright © 2018 Elsevier B.V. All rights reserved.

Dissociation of frontal-midline delta-theta and posterior alpha oscillations: A mobile EEG study.

PubMed

Liang, Mingli; Starrett, Michael J; Ekstrom, Arne D

2018-04-22

Numerous reports have demonstrated low-frequency oscillations during navigation using invasive recordings in the hippocampus of both rats and human patients. Given evidence, in some cases, of low-frequency synchronization between midline cortex and hippocampus, it is also possible that low-frequency movement-related oscillations manifest in healthy human neocortex. However, this possibility remains largely unexplored, in part due to the difficulties of coupling free ambulation and effective scalp EEG recordings. In the current study, participants freely ambulated on an omnidirectional treadmill and explored an immersive virtual reality city rendered on a head-mounted display while undergoing simultaneous wireless scalp EEG recordings. We found that frontal-midline (FM) delta-theta (2-7.21 Hz) oscillations increased during movement compared to standing still periods, consistent with a role in navigation. In contrast, posterior alpha (8.32-12.76 Hz) oscillations were suppressed in the presence of visual input, independent of movement. Our findings suggest that FM delta-theta and posterior alpha oscillations arise at independent frequencies, under complementary behavioral conditions, and, at least for FM delta-theta oscillations, at independent recordings sites. Together, our findings support a double dissociation between movement-related FM delta-theta and resting-related posterior alpha oscillations. Our study thus provides novel evidence that FM delta-theta oscillations arise, in part, from real-world ambulation, and are functionally independent from posterior alpha oscillations. © 2018 Society for Psychophysiological Research.

Robust hippocampal responsivity during retrieval of consolidated associative memory.

PubMed

Hattori, Shoai; Chen, Lillian; Weiss, Craig; Disterhoft, John F

2015-05-01

A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Photostimulation of Phox2b medullary neurons activates cardiorespiratory function in conscious rats.

PubMed

Kanbar, Roy; Stornetta, Ruth L; Cash, Devin R; Lewis, Stephen J; Guyenet, Patrice G

2010-11-01

Hypoventilation is typically treated with positive pressure ventilation or, in extreme cases, by phrenic nerve stimulation. This preclinical study explores whether direct stimulation of central chemoreceptors could be used as an alternative method to stimulate breathing. To determine whether activation of the retrotrapezoid nucleus (RTN), which is located in the rostral ventrolateral medulla (RVLM), stimulates breathing with appropriate selectivity. A lentivirus was used to induce expression of the photoactivatable cationic channel channelrhodopsin-2 (ChR2) by RVLM Phox2b-containing neurons, a population that consists of central chemoreceptors (the ccRTN neurons) and blood pressure (BP)-regulating neurons (the C1 cells). The transfected neurons were activated with pulses of laser light. Respiratory effects were measured by plethysmography or diaphragmatic EMG recording and cardiovascular effects by monitoring BP, renal sympathetic nerve discharge, and the baroreflex. The RVLM contained 600 to 900 ChR2-transfected neurons (63% C1, 37% ccRTN). RVLM photostimulation significantly increased breathing rate (+42%), tidal volume (21%), minute volume (68%), and peak expiratory flow (48%). Photostimulation increased diaphragm EMG amplitude (19%) and frequency (21%). Photostimulation increased BP (4 mmHg) and renal sympathetic nerve discharge (43%) while decreasing heart rate (15 bpm). Photostimulation of ChR2-transfected RVLM Phox2b neurons produces a vigorous stimulation of breathing accompanied by a small sympathetically mediated increase in BP. These results demonstrate that breathing can be relatively selectively activated in resting unanesthetized mammals via optogenetic manipulation of RVLM neurons presumed to be central chemoreceptors. This methodology could perhaps be used in the future to enhance respiration in humans.

Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome.

PubMed

Boland, Michael J; Nazor, Kristopher L; Tran, Ha T; Szücs, Attila; Lynch, Candace L; Paredes, Ryder; Tassone, Flora; Sanna, Pietro Paolo; Hagerman, Randi J; Loring, Jeanne F

2017-03-01

New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models. Differentiation of human pluripotent stem cells recapitulates development of the neocortex, an area affected in both fragile X syndrome and autism spectrum disorder. We have generated induced human pluripotent stem cells from several individuals clinically diagnosed with fragile X syndrome and autism spectrum disorder. When differentiated to dorsal forebrain cell fates, our fragile X syndrome human pluripotent stem cell lines exhibited reproducible aberrant neurogenic phenotypes. Using global gene expression and DNA methylation profiling, we have analysed the early stages of neurogenesis in fragile X syndrome human pluripotent stem cells. We discovered aberrant DNA methylation patterns at specific genomic regions in fragile X syndrome cells, and identified dysregulated gene- and network-level correlates of fragile X syndrome that are associated with developmental signalling, cell migration, and neuronal maturation. Integration of our gene expression and epigenetic analysis identified altered epigenetic-mediated transcriptional regulation of a distinct set of genes in fragile X syndrome. These fragile X syndrome-aberrant networks are significantly enriched for genes associated with autism spectrum disorder, giving support to the idea that underlying similarities exist among these neurodevelopmental diseases. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal-thalamus-hippocampus network.

PubMed

Thielen, Jan-Willem; Hong, Donghyun; Rohani Rankouhi, Seyedmorteza; Wiltfang, Jens; Fernández, Guillén; Norris, David G; Tendolkar, Indira

2018-06-01

The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long-term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC γ-aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face-name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory-related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory-related functional connectivity in a medial prefrontal-thalamus-hippocampus network. © 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Pre-stimulus thalamic theta power predicts human memory formation.

PubMed

Sweeney-Reed, Catherine M; Zaehle, Tino; Voges, Jürgen; Schmitt, Friedhelm C; Buentjen, Lars; Kopitzki, Klaus; Richardson-Klavehn, Alan; Hinrichs, Hermann; Heinze, Hans-Jochen; Knight, Robert T; Rugg, Michael D

2016-09-01

Pre-stimulus theta (4-8Hz) power in the hippocampus and neocortex predicts whether a memory for a subsequent event will be formed. Anatomical studies reveal thalamus-hippocampal connectivity, and lesion, neuroimaging, and electrophysiological studies show that memory processing involves the dorsomedial (DMTN) and anterior thalamic nuclei (ATN). The small size and deep location of these nuclei have limited real-time study of their activity, however, and it is unknown whether pre-stimulus theta power predictive of successful memory formation is also found in these subcortical structures. We recorded human electrophysiological data from the DMTN and ATN of 7 patients receiving deep brain stimulation for refractory epilepsy. We found that greater pre-stimulus theta power in the right DMTN was associated with successful memory encoding, predicting both behavioral outcome and post-stimulus correlates of successful memory formation. In particular, significant correlations were observed between right DMTN theta power and both frontal theta and right ATN gamma (32-50Hz) phase alignment, and frontal-ATN theta-gamma cross-frequency coupling. We draw the following primary conclusions. Our results provide direct electrophysiological evidence in humans of a role for the DMTN as well as the ATN in memory formation. Furthermore, prediction of subsequent memory performance by pre-stimulus thalamic oscillations provides evidence that post-stimulus differences in thalamic activity that index successful and unsuccessful encoding reflect brain processes specifically underpinning memory formation. Finally, the findings broaden the understanding of brain states that facilitate memory encoding to include subcortical as well as cortical structures. Copyright © 2016 Elsevier Inc. All rights reserved.

The Functioning of a Cortex without Layers.

PubMed

Guy, Julien; Staiger, Jochen F

2017-01-01

A major hallmark of cortical organization is the existence of a variable number of layers, i.e., sheets of neurons stacked on top of each other, in which neurons have certain commonalities. However, even for the neocortex, variable numbers of layers have been described and it is just a convention to distinguish six layers from each other. Whether cortical layers are a structural epiphenomenon caused by developmental dynamics or represent a functionally important modularization of cortical computation is still unknown. Here we present our insights from the reeler mutant mouse, a model for a developmental, "molecular lesion"-induced loss of cortical layering that could serve as ground truth of what an intact layering adds to the cortex in terms of functionality. We could demonstrate that the reeler neocortex shows no inversion of cortical layers but rather a severe disorganization that in the primary somatosensory cortex leads to the complete loss of layers. Nevertheless, the somatosensory system is well organized. When exploring an enriched environment with specific sets of whiskers, activity-dependent gene expression takes place in the corresponding modules. Precise whisker stimuli lead to the functional activation of somatotopically organized barrel columns as visualized by intrinsic signal optical imaging. Similar results were obtained in the reeler visual system. When analyzing pathways that could be responsible for preservation of tactile perception, lemniscal thalamic projections were found to be largely intact, despite the smearing of target neurons across the cortical mantle. However, with optogenetic experiments we found evidence for a mild dispersion of thalamic synapse targeting on layer IV-spiny stellate cells, together with a general weakening in thalamocortical input strength. This weakening of thalamic inputs was compensated by intracortical mechanisms involving increased recurrent excitation and/or reduced feedforward inhibition. In conclusion, a layer loss so far only led to the detection of subtle defects in sensory processing by reeler mice. This argues in favor of a view in which cortical layers are not an essential component for basic perception and cognition. A view also supported by recent studies in birds, which can have remarkable cognitive capacities despite the lack of a neocortex with multiple cortical layers. In conclusion, we suggest that future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location.

Mitochondrial Damage: A Diagnostic and Metabolic Approach in Traumatic Brain Injury and Post-Traumatic Disorder

DTIC Science & Technology

2013-01-29

Scanning Confocal Microscope (Zeiss- Pascal) using 20x obj. and edited using Zeiss Image Examiner Ver 5.0. The iso-cortical pyramidal layers 1 and 2 are...NeuN immunoreactivity is seen in the neuronal cytoplasm and especially apical dendrites of pyramidal neurons (white arrows), which facilitates the...identification of the pyramidal cell morphology in the outer pyramidal cell layer of neo-cortex (see picture A, depicted as py). Cortical Pyramidal

Long-Term Modulation of Electrical Synapses in the Mammalian Thalamus

NASA Astrophysics Data System (ADS)

Landisman, Carole E.; Connors, Barry W.

2005-12-01

Electrical synapses are common between inhibitory neurons in the mammalian thalamus and neocortex. Synaptic modulation, which allows flexibility of communication between neurons, has been studied extensively at chemical synapses, but modulation of electrical synapses in the mammalian brain has barely been examined. We found that the activation of metabotropic glutamate receptors, via endogenous neurotransmitter or by agonist, causes long-term reduction of electrical synapse strength between the inhibitory neurons of the rat thalamic reticular nucleus.

[The effect of atropine on the ultrastructural postsynaptic plasticity of the associative type in the rat neocortex].

PubMed

Khludova, G G; Gusev, P A

1998-01-01

The effect of muscarinic antagonist atropine on thickness of postsynaptic density of axodendritic synapses was studied in the sensorimotor region of the brain cortex of rats during paired repeated microapplication of glutamate and acetylcholine. In the applied conditioning paradigm atropine significantly decreased morphological dimensions of the postsynaptic density, however, the control values were not reached. This finding testifies to participation of both muscarinic and nicotinic cholinoreceptors in associative postsynaptic plasticity.

Interactions of Subsymptomatic Doses of Sarin with Pyridostigmine - Neurochemical, Behavioral, and Physiological Effects

DTIC Science & Technology

2005-03-01

electrocardiogram (ECG) by suturing one of them with 5-0 polyvinyl material to the subcutaneous tissue over the right scapula and the other one at the...bands (Pereira de Souza et al.,2001). Concentrations ofACh, Ch, their deuterated variants, and ACh turnover in brain tissue . Animals were anesthetized...mesencephalon, neocortex, piriform cortex, and striatum. These tissue fragments were homogenized in ice cold 15% IN formic acid, 85% acetone for analysis

Modulation of NMDA and AMPA-Mediated Synaptic Transmission by CB1 Receptors in Frontal Cortical Pyramidal Cells

PubMed Central

Li, Qiang; Yan, Haidun; Wilson, Wilkie A.; Swartzwelder, H. Scott

2010-01-01

Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutmatergic activity by CB1 receptors in the frontal neocortex is mediated by a pre-synaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function. PMID:20420813

The loss of the kinases SadA and SadB results in early neuronal apoptosis and a reduced number of progenitors.

PubMed

Dhumale, Pratibha; Menon, Sindhu; Chiang, Joanna; Püschel, Andreas W

2018-01-01

The neurons that form the mammalian neocortex originate from progenitor cells in the ventricular (VZ) and subventricular zone (SVZ). Newborn neurons are multipolar but become bipolar during their migration from the germinal layers to the cortical plate (CP) by forming a leading process and an axon that extends in the intermediate zone (IZ). Once they settle in the CP, neurons assume a highly polarized morphology with a single axon and multiple dendrites. The AMPK-related kinases SadA and SadB are intrinsic factors that are essential for axon formation during neuronal development downstream of Lkb1. The knockout of both genes encoding Sad kinases (Sada and Sadb) results not only in a loss of axons but also a decrease in the size of the cortical plate. The defect in axon formation has been linked to a function of Sad kinases in the regulation of microtubule binding proteins. However, the causes for the reduced size of the cortical plate in the Sada-/-;Sadb-/- knockout remain to be analyzed in detail. Here we show that neuronal cell death is increased and the number of neural progenitors is decreased in the Sada-/-;Sadb-/- CP. The reduced number of progenitors is a non-cell autonomous defect since they do not express Sad kinases. These defects are restricted to the neocortex while the hippocampus remains unaffected.

Quantification of mu and non-mu opiate receptors in temporal lobe epilepsy using positron emission tomography.

PubMed

Mayberg, H S; Sadzot, B; Meltzer, C C; Fisher, R S; Lesser, R P; Dannals, R F; Lever, J R; Wilson, A A; Ravert, H T; Wagner, H N

1991-07-01

Alterations in a variety of neurotransmitter systems have been identified in experimental models of epilepsy and in brain tissue from patients with intractable temporal lobe seizures. The availability of new high-affinity radioligands permits the study of some neuroreceptors in vivo with positron emission tomography (PET). We previously characterized the in vivo binding of 11C-carfentanil, a potent and selective mu opiate receptor agonist, and described increases in 11C-carfentanil binding in the temporal neocortex of patients with unilateral temporal lobe epilepsy. These studies have been extended to 11C-diprenorphine, which labels mu, kappa, and delta opiate receptor subtypes. Paired measurements of opiate receptor binding were performed with PET using 11C-carfentanil and 11C-diprenorphine in patients with unilateral temporal lobe seizures. Carfentanil binding, reflecting changes in mu opiate receptors, was increased in the temporal neocortex and decreased in the amygdala on the side of the epileptic focus. Diprenorphine binding, reflecting mu as well as non-mu opiate subtypes, was not significantly different among regions in the focus and nonfocus temporal lobes. Regional glucose metabolism, measured using 18F-2-fluoro-2-deoxyglucose, was decreased in the mesial and lateral aspects of the temporal lobe ipsilateral to the epileptogenic focus. The variation in pattern of carfentanil and diprenorphine binding supports a differential regulation of opiate subtypes in unilateral temporal lobe epilepsy.

Alterations of apoptosis and autophagy in developing brain of rats with epilepsy: Changes in LC3, P62, Beclin-1 and Bcl-2 levels.

PubMed

Li, Qinrui; Han, Ying; Du, Junbao; Jin, Hongfang; Zhang, Jing; Niu, Manman; Qin, Jiong

2018-05-01

Current studies have indicated that apoptotic and autophagic signaling pathways are triggered by epileptic seizures, but the precise roles of these processes in epilepsy-induced neuronal loss remain unclear. Identifying a concrete molecular mechanism may help researchers develop relevant epilepsy therapies that are more effective than existing treatments. Autophagy is a type of conserved degradation that contributes to cellular homeostasis. The involved signaling pathways allow us to observe alterations in autophagy and apoptosis during epileptic seizures over time. This study investigated the time-dependent changes in autophagy, apoptosis and neuronal morphology in developing brain of epilepsy model rats. At 48h after epileptic seizure onset, the number of neurons in neocortex decreased, and the number of apoptotic cells in neocortex increased. The ratio of microtubule-associated protein 1 light chain 3 (LC3) II to LC3 I and Beclin-1 protein levels increased from 12h to 48h after epileptic seizure onset. P62 protein and Bcl-2 protein levels decreased from 24h to 48h after epileptic seizure onset. The changes in the levels of these autophagy and apoptosis markers indicate that autophagy starts before apoptosis in rats with epilepsy, demonstrating a potential role of autophagy in epilepsy-induced neuronal loss in developing brain. Copyright © 2017. Published by Elsevier B.V.

Brain mechanisms of emotions.

PubMed

Simonov, P V

1997-01-01

At the 23rd International Congress of Physiology Sciences (Tokyo, 1965) the results of experiment led us to the conclusion that emotions were determined by the actual need and estimation of probability (possibility) of its satisfaction. Low probability of need satisfaction leads to negative emotions actively minimized by the subject. Increased probability of satisfaction, as compared to the earlier forecast, generates positive emotions which the subject tries to maximize, that is, to enhance, to prolong, to repeat. We named our concept the Need-Informational Theory of Emotions. According to this theory, motivation, emotion, and estimation of probability have different neuromorphological substrates. Activation through the hypothalamic motivatiogenic structures of the frontal parts of the neocortex orients the behavior to signals with a high probability of their reinforcement. At the same time the hippocampus is necessary for reactions to signals of low probability events, which are typical for the emotionally excited brain. By comparison of motivational excitation with available stimuli or their engrams, the amygdala selects a dominant motivation, destined to be satisfied in the first instance. In the cases of classical conditioning and escape reaction the reinforcement was related to involvement of the negative emotion's hypothalamic neurons, while in the course of avoidance reaction the positive emotion's neurons were involved. The role of the left and right frontal neocortex in the appearance or positive or negative emotions depends on these informational (cognitive) functions.

[The brain mechanisms of emotions].

PubMed

Simonov, P V

1997-01-01

At the 23rd International Congress of Physiological Sciences (Tokyo, 1965) the results of experiment brought us to a conclusion that emotions were determined by the actual need and estimation of probability (possibility) of its satisfaction. Low probability of need satisfaction leads to negative emotions actively minimized by the subject. Increased probability of satisfaction, as compared to the earlier forecast, generates positive emotions which the subject tries to maximize, that is to enhance, to prolong, to repeat. We named our concept the Need-Informational Theory of Emotions. According to this theory, motivation, emotion and estimation of probability have different neuromorphological substrate. Activating by motivatiogenic structures of the hypothalamus the frontal parts of neocortex orients the behavior to signals with a high probability of their reinforcement. At the same time the hippocampus is necessary for reactions to signals of low probability events, which is typical for emotionally excited brain. By comparison of motivational excitation with available stimuli or their engrams the amygdala selects a dominant motivation, destined to be satisfied in the first instance. In the cases of classical conditioning and escape reaction the reinforcement was related to involvement of the negative emotion's hypothalamic neurons while in the course of avoidance reaction the positive emotion's neurons being involved. The role of the left and right frontal neocortex in the appearance of positive or negative emotions depends on this informational (cognitive) functions.

Reduced Cerebrovascular Reactivity and Increased Resting Cerebral Perfusion in Rats Exposed to a Cafeteria Diet.

PubMed

Gomez-Smith, Mariana; Janik, Rafal; Adams, Conner; Lake, Evelyn M; Thomason, Lynsie A M; Jeffers, Matthew S; Stefanovic, Bojana; Corbett, Dale

2018-02-10

To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO 2 challenges in both the hippocampus and the neocortex. CAF rats switched to chow for one month (SWT) exhibited improved resting perfusion in the hippocampus as well as improved cerebrovascular reactivity in the neocortex. However, the diet switch did not correct cerebrovascular reactivity in the hippocampus. These changes were not accompanied by alterations in the structural integrity of the cerebral microvasculature, examined using rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) immunostaining. Also, the extent of tissue damage induced by endothelin-1 injection into sensorimotor cortex was not affected by the Cafeteria diet. These results demonstrate that short-term consumption of an ultra-processed diet reduces cerebrovascular reactivity. This effect persists after dietary normalization despite recovery of peripheral symptomatology. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Iron, zinc and copper in the Alzheimer’s disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion

PubMed Central

Schrag, Matthew; Mueller, Claudius; Oyoyo, Udochukwu; Kirsch, Wolff M.

2011-01-01

Dysfunctional homeostasis of transition metals is believed to play a role in the pathogenesis of Alzheimer’s disease (AD). Although questioned by some, brain copper, zinc, and particularly iron overload are widely accepted features of AD which have led to the hypothesis that oxidative stress generated from aberrant homeostasis of these transition metals might be a pathogenic mechanism behind AD. This meta-analysis compiled and critically assessed available quantitative data on brain iron, zinc and copper levels in AD patients compared to aged controls. The results were very heterogeneous. A series of heavily cited articles from one laboratory reported a large increase in iron in AD neocortex compared to age-matched controls (p<0.0001) while seven laboratories failed to reproduce these findings reporting no significant difference between the groups (p=0.76). A more than three-fold citation bias was found to favor outlier studies reporting increases in iron and this bias was particularly prominent among narrative review articles. Additionally, while zinc was not significantly changed in the neocortex (p=0.29), copper was significantly depleted in AD (p=0.0003). In light of these findings, it will be important to re-evaluate the hypothesis that transition metal overload accounts for oxidative injury noted in AD. PMID:21600264

Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to-isoleucine substitution at codon 180 on the prion protein gene.

PubMed

Ito, Yoko; Sanjo, Nobuo; Hizume, Masaki; Kobayashi, Atsushi; Ohgami, Tetsuya; Satoh, Katsuya; Hamaguchi, Tsuyoshi; Yamada, Masahito; Kitamoto, Tetsuyuki; Mizusawa, Hidehiro; Yokota, Takanori

2018-02-19

Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrP res at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrP res in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrP res were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Evolution of columns, modules, and domains in the neocortex of primates.

PubMed

Kaas, Jon H

2012-06-26

The specialized regions of neocortex of mammals, called areas, have been divided into smaller functional units called minicolumns, columns, modules, and domains. Here we describe some of these functional subdivisions of areas in primates and suggest when they emerged in mammalian evolution. We distinguish several types of these smaller subdivisions. Minicolumns, vertical arrays of neurons that are more densely interconnected with each other than with laterally neighboring neurons, are present in all cortical areas. Classic columns are defined by a repeating pattern of two or more types of cortex distinguished by having different inputs and neurons with different response properties. Sensory stimuli that continuously vary along a stimulus dimension may activate groups of neurons that vary continuously in location, producing "columns" without specific boundaries. Other groups or columns of cortical neurons are separated by narrow septa of fibers that reflect discontinuities in the receptor sheet. Larger regions of posterior parietal cortex and frontal motor cortex are parts of networks devoted to producing different sequences of movements. We distinguish these larger functionally distinct regions as domains. Columns of several types have evolved independently a number of times. Some of the columns found in primates likely emerged with the first primates, whereas others likely were present in earlier ancestors. The sizes and shapes of columns seem to depend on the balance of neuron activation patterns and molecular signals during development.

Distinct roles of hippocampus and medial prefrontal cortex in spatial and nonspatial memory.

PubMed

Sapiurka, Maya; Squire, Larry R; Clark, Robert E

2016-12-01

In earlier work, patients with hippocampal damage successfully path integrated, apparently by maintaining spatial information in working memory. In contrast, rats with hippocampal damage were unable to path integrate, even when the paths were simple and working memory might have been expected to support performance. We considered possible ways to understand these findings. We tested rats with either hippocampal lesions or lesions of medial prefrontal cortex (mPFC) on three tasks of spatial or nonspatial memory: path integration, spatial alternation, and a nonspatial alternation task. Rats with mPFC lesions were impaired on both spatial and nonspatial alternation but performed normally on path integration. By contrast, rats with hippocampal lesions were impaired on path integration and spatial alternation but performed normally on nonspatial alternation. We propose that rodent neocortex is limited in its ability to construct a coherent spatial working memory of complex environments. Accordingly, in tasks such as path integration and spatial alternation, working memory cannot depend on neocortex alone. Rats may accomplish many spatial memory tasks by relying on long-term memory. Alternatively, they may accomplish these tasks within working memory through sustained coordination between hippocampus and other cortical brain regions such as mPFC, in the case of spatial alternation, or parietal cortex in the case of path integration. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Differential Expression Patterns of occ1-Related Genes in Adult Monkey Visual Cortex

PubMed Central

Takahata, Toru; Komatsu, Yusuke; Watakabe, Akiya; Hashikawa, Tsutomu; Tochitani, Shiro

2009-01-01

We have previously revealed that occ1 is preferentially expressed in the primary visual area (V1) of the monkey neocortex. In our attempt to identify more area-selective genes in the macaque neocortex, we found that testican-1, an occ1-related gene, and its family members also exhibit characteristic expression patterns along the visual pathway. The expression levels of testican-1 and testican-2 mRNAs as well as that of occ1 mRNA start of high in V1, progressively decrease along the ventral visual pathway, and end of low in the temporal areas. Complementary to them, the neuronal expression of SPARC mRNA is abundant in the association areas and scarce in V1. Whereas occ1, testican-1, and testican-2 mRNAs are preferentially distributed in thalamorecipient layers including “blobs,” SPARC mRNA expression avoids these layers. Neither SC1 nor testican-3 mRNA expression is selective to particular areas, but SC1 mRNA is abundantly observed in blobs. The expressions of occ1, testican-1, testican-2, and SC1 mRNA were downregulated after monocular tetrodotoxin injection. These results resonate with previous works on chemical and functional gradients along the primate occipitotemporal visual pathway and raise the possibility that these gradients and functional architecture may be related to the visual activity–dependent expression of these extracellular matrix glycoproteins. PMID:19073625

Neuronal imprinting of human values.

PubMed

Delgado, J M

2000-03-01

In the 21st century, psychophysiology will face the challenge of establishing ethical principles and practical means for the genetic and social influencing of the development of human beings. Neuronal imprinting of beliefs and morality within infantile minds will be necessary for the peaceful coexistence of races and cultures. This process requires study and consideration, among others, of the following psychophysiological facts: (1) Genes do not transmit moral values. (2) Material support of physiological activities is necessary for the existence and development of mental functions. (3) Imprinting of human values is based on material changes within neuronal structures. (4) Early neuronal imprinting is performed without personal awareness or consent of the individual and depends on sensory inputs, mainly from the social structure of the group. (5) Biological structures lack values. Personal and social antagonisms do not depend on genes, but on cultural indoctrination. (6) Pleasure and punishment (positive and negative reinforcement) are the two main elements, which regulate animal and human behavior. (7) Values must be chosen by adults, who decide the questions 'why'? 'when'? 'which ones'?, 'who should teach'?, 'what?' and 'how'? (8) Many biological imperatives are shared by all animals and by all people. Human beings may be considered the 'crickets of the Universe', unable to understand the mysteries of nature because of our insufficient neuronal capacity. (9) Our emotional life is mainly related to the structure of the limbic system controlled by the neocortex. (10) New theories based on the integration of physics, chemistry, biology and other specific areas of knowledge, as proposed by the General Theory of Systems, will avoid 'opposites', favoring the acceptance of complementary aspects of reality. (11) Early education will promote preferential learning which depends on both genetic endowment and neuronal development influenced by experience. It is the responsibility of psychophysiology to establish the guidelines for better education, clarifying the material and psychological aspects of the mind.

The Summer Apprentice Program, 1992

DTIC Science & Technology

1992-01-01

AD-A266 726 LABORATORY NOTE NO. 81 The Summer Apprentice Program 1992 Katherine Ellen Renn D TL C Thornton Samuel Mu JLE E DDavid M. Dahle JUL 0 6...Webster mice at 15-17 days gestation. The neocortex was removed, minced, and placed in media containing 0.08% acetylated trypsin at 370 C for one hour...plated on pure glial cultures. The cells were plated in 15 mm multiwell plates (2.5 x 10 -5 cells/well). The cultures were maintained at 370 C in a 5

[Structural analysis of the functional status of the brain as affected by bemethyl using pattern recognition theory].

PubMed

Bobkov, Iu G; Machula, A I; Morozov, Iu I; Dvalishvili, E G

1987-11-01

Evoked visual potentials in associated, parietal and second somatosensory zones of the neocortex were analysed in trained cats using implanted electrodes. The influence of bemethyl on the structure of behavioral reactions was analysed using theoretical methods of perceptual images, particularly the method of cluster analysis. Bemethyl was shown to increase the level of interaction between the functional elements of the system, leading to a more stable resolution of problems facing the system, as compared to the initial state.

Unconscious relational encoding depends on hippocampus

PubMed Central

Duss, Simone B.; Reber, Thomas P.; Hänggi, Jürgen; Schwab, Simon; Wiest, Roland; Müri, René M.; Brugger, Peter; Gutbrod, Klemens

2014-01-01

Textbooks divide between human memory systems based on consciousness. Hippocampus is thought to support only conscious encoding, while neocortex supports both conscious and unconscious encoding. We tested whether processing modes, not consciousness, divide between memory systems in three neuroimaging experiments with 11 amnesic patients (mean age = 45.55 years, standard deviation = 8.74, range = 23–60) and 11 matched healthy control subjects. Examined processing modes were single item versus relational encoding with only relational encoding hypothesized to depend on hippocampus. Participants encoded and later retrieved either single words or new relations between words. Consciousness of encoding was excluded by subliminal (invisible) word presentation. Amnesic patients and controls performed equally well on the single item task activating prefrontal cortex. But only the controls succeeded on the relational task activating the hippocampus, while amnesic patients failed as a group. Hence, unconscious relational encoding, but not unconscious single item encoding, depended on hippocampus. Yet, three patients performed normally on unconscious relational encoding in spite of amnesia capitalizing on spared hippocampal tissue and connections to language cortex. This pattern of results suggests that processing modes divide between memory systems, while consciousness divides between levels of function within a memory system. PMID:25273998

Implicit aversive memory under anaesthesia in animal models: a narrative review.

PubMed

Samuel, N; Taub, A H; Paz, R; Raz, A

2018-07-01

Explicit memory after anaesthesia has gained considerable attention because of its negative implications, while implicit memory, which is more elusive and lacks patients' explicit recall, has received less attention and dedicated research. This is despite the likely impact of implicit memory on postoperative long-term well-being and behaviour. Given the scarcity of human data, fear conditioning in animals offers a reliable model of implicit learning, and importantly, one where we already have a good understanding of the underlying neural circuitry in awake conditions. Animal studies provide evidence that fear conditioning occurs under anaesthesia. The effects of different anaesthetics on memory are complex, with different drugs interacting at different stages of learning. Modulatory suppressive effects can be because of context, specific drugs, and dose dependency. In some cases, low doses of general anaesthetics can actually lead to a paradoxical opposite effect. The underlying mechanisms involve several neurotransmitter systems, acting mainly in the amygdala, hippocampus, and neocortex. Here, we review animal studies of aversive conditioning under anaesthesia, discuss the complex picture that arises, identify the gaps in knowledge that require further investigation, and highlight the potential translational relevance of the models. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Neocortical maturation during adolescence: change in neuronal soma dimension.

PubMed

Rabinowicz, Theodore; Petetot, Jean Macdonald-Comber; Khoury, Jane C; de Courten-Myers, Gabrielle M

2009-03-01

During adolescence, cognitive abilities increase robustly. To search for possible related structural alterations of the cerebral cortex, we measured neuronal soma dimension (NSD = width times height), cortical thickness and neuronal densities in different types of neocortex in post-mortem brains of five 12-16 and five 17-24 year-olds (each 2F, 3M). Using a generalized mixed model analysis, mean normalized NSD comparing the age groups shows layer-specific change for layer 2 (p < .0001) and age-related differences between categorized type of cortex: primary/primary association cortex (BA 1, 3, 4, and 44) shows a generalized increase; higher-order regions (BA 9, 21, 39, and 45) also show increase in layers 2 and 5 but decrease in layers 3, 4, and 6 while limbic/orbital cortex (BA 23, 24, and 47) undergoes minor decrease (BA 1, 3, 4, and 44 vs. BA 9, 21, 39, and 45: p = .036 and BA 1, 3, 4, and 44 vs. BA 23, 24, and 47: p = .004). These data imply the operation of cortical layer- and type-specific processes of growth and regression adding new evidence that the human brain matures during adolescence not only functionally but also structurally.

Elevated cortisol levels in Cushing's disease are associated with cognitive decrements.

PubMed

Starkman, M N; Giordani, B; Berent, S; Schork, M A; Schteingart, D E

2001-01-01

The objective of this study was to use Cushing's disease as a unique human model to elucidate the cognitive deficits resulting from exposure to chronic stress-level elevations of endogenous cortisol. Forty-eight patients with a first episode of acute, untreated Cushing's disease and 38 healthy control subjects were studied. Scores for four of five verbal IQ subtests were significantly lower in patients with Cushing's disease; their scores were significantly lower for only one nonverbal performance IQ subtest (block design). Verbal, but not visual, learning and delayed recall at 30 minutes were significantly decreased among patients with Cushing's disease. Although verbal delayed recall was significantly lower in these patients, the retention index (percentage), which compares the amount of initially learned material to that recalled after the delay, was not significantly decreased. There was no significant association between depression scores and cognitive performance. A higher degree of cortisol elevation was associated with poorer performance on several subtests of learning, delayed recall, and visual-spatial ability. Chronically elevated levels of glucocorticoids have deleterious effects on particular domains of cognition. Verbal learning and other verbal functions seem more vulnerable than nonverbal functions. The results suggest that both the neocortex and hippocampus are affected.

Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model

PubMed Central

Lozovaya, N.; Gataullina, S.; Tsintsadze, T.; Tsintsadze, V.; Pallesi-Pocachard, E.; Minlebaev, M.; Goriounova, N. A.; Buhler, E.; Watrin, F.; Shityakov, S.; Becker, A. J.; Bordey, A.; Milh, M.; Scavarda, D.; Bulteau, C.; Dorfmuller, G.; Delalande, O.; Represa, A.; Cardoso, C.; Dulac, O.; Ben-Ari, Y.; Burnashev, N.

2014-01-01

Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1+/− mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (

The role of sleep in declarative memory consolidation--direct evidence by intracranial EEG.

PubMed

Axmacher, Nikolai; Haupt, Sven; Fernández, Guillén; Elger, Christian E; Fell, Juergen

2008-03-01

Two step theories of memory formation assume that an initial learning phase is followed by a consolidation stage. Memory consolidation has been suggested to occur predominantly during sleep. Very recent findings, however, suggest that important steps in memory consolidation occur also during waking state but may become saturated after some time awake. Sleep, in this model, specifically favors restoration of synaptic plasticity and accelerated memory consolidation while asleep and briefly afterwards. To distinguish between these different views, we recorded intracranial electroencephalograms from the hippocampus and rhinal cortex of human subjects while they retrieved information acquired either before or after a "nap" in the afternoon or on a control day without nap. Reaction times, hippocampal event-related potentials, and oscillatory gamma activity indicated a temporal gradient of hippocampal involvement in information retrieval on the control day, suggesting hippocampal-neocortical information transfer during waking state. On the day with nap, retrieval of recent items that were encoded briefly after the nap did not involve the hippocampus to a higher degree than retrieval of items encoded before the nap. These results suggest that sleep facilitates rapid processing through the hippocampus but is not necessary for information transfer into the neocortex per se.

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

PubMed Central

Hong, Donghyun; Rohani Rankouhi, Seyedmorteza; Wiltfang, Jens; Fernández, Guillén; Norris, David G.; Tendolkar, Indira

2018-01-01

Abstract The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long‐term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC γ‐aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face–name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory‐related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory‐related functional connectivity in a medial prefrontal–thalamus–hippocampus network. PMID:29488277

Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor

PubMed Central

Manuel, Martine N.; Mi, Da; Mason, John O.; Price, David J.

2015-01-01

Understanding brain development remains a major challenge at the heart of understanding what makes us human. The neocortex, in evolutionary terms the newest part of the cerebral cortex, is the seat of higher cognitive functions. Its normal development requires the production, positioning, and appropriate interconnection of very large numbers of both excitatory and inhibitory neurons. Pax6 is one of a relatively small group of transcription factors that exert high-level control of cortical development, and whose mutation or deletion from developing embryos causes major brain defects and a wide range of neurodevelopmental disorders. Pax6 is very highly conserved between primate and non-primate species, is expressed in a gradient throughout the developing cortex and is essential for normal corticogenesis. Our understanding of Pax6’s functions and the cellular processes that it regulates during mammalian cortical development has significantly advanced in the last decade, owing to the combined application of genetic and biochemical analyses. Here, we review the functional importance of Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of cortical layers and highlight important differences between rodents and primates. We also review the pathological effects of PAX6 mutations in human neurodevelopmental disorders. We discuss some aspects of Pax6’s molecular actions including its own complex transcriptional regulation, the distinct molecular functions of its splice variants and some of Pax6’s known direct targets which mediate its actions during cortical development. PMID:25805971

Multiscale Aspects of Generation of High-Gamma Activity during Seizures in Human Neocortex123

PubMed Central

Marcuccilli, Charles J.; Ben-Mabrouk, Faiza; Lew, Sean M.; Goodman, Robert R.; McKhann, Guy M.; Frim, David M.; Kohrman, Michael H.; Schevon, Catherine A.; van Drongelen, Wim

2016-01-01

High-gamma (HG; 80-150 Hz) activity in macroscopic clinical records is considered a marker for critical brain regions involved in seizure initiation; it is correlated with pathological multiunit firing during neocortical seizures in the seizure core, an area identified by correlated multiunit spiking and low frequency seizure activity. However, the effects of the spatiotemporal dynamics of seizure on HG power generation are not well understood. Here, we studied HG generation and propagation, using a three-step, multiscale signal analysis and modeling approach. First, we analyzed concurrent neuronal and microscopic network HG activity in neocortical slices from seven intractable epilepsy patients. We found HG activity in these networks, especially when neurons displayed paroxysmal depolarization shifts and network activity was highly synchronized. Second, we examined HG activity acquired with microelectrode arrays recorded during human seizures (n = 8). We confirmed the presence of synchronized HG power across microelectrode records and the macroscale, both specifically associated with the core region of the seizure. Third, we used volume conduction-based modeling to relate HG activity and network synchrony at different network scales. We showed that local HG oscillations require high levels of synchrony to cross scales, and that this requirement is met at the microscopic scale, but not within macroscopic networks. Instead, we present evidence that HG power at the macroscale may result from harmonics of ongoing seizure activity. Ictal HG power marks the seizure core, but the generating mechanism can differ across spatial scales. PMID:27257623

Evoked effective connectivity of the human neocortex.

PubMed

Entz, László; Tóth, Emília; Keller, Corey J; Bickel, Stephan; Groppe, David M; Fabó, Dániel; Kozák, Lajos R; Erőss, Loránd; Ulbert, István; Mehta, Ashesh D

2014-12-01

The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an inverse relationship to distance between sites. Coregistration to Brodmann areas (BA) permitted group analysis. Connections were frequently directional with 43% of early responses and 50% of late responses of connections reflecting relative dominance of incoming or outgoing connections. The most consistent connections were seen as outgoing from motor cortex, BA6-BA9, somatosensory (SS) cortex, anterior cingulate cortex, and Broca's area. Network topology revealed motor, SS, and premotor cortices along with BA9 and BA10 and language areas to serve as hubs for cortical connections. BA20 and BA39 demonstrated the most consistent dominance of outdegree connections, while BA5, BA7, auditory cortex, and anterior cingulum demonstrated relatively greater indegree. This multicenter, large-scale, directional study of local and long-range cortical connectivity using direct recordings from awake, humans will aid the interpretation of noninvasive functional connectome studies. © 2014 Wiley Periodicals, Inc.

Effects of sulfate aerosols upon cardiopulmonary function in squirrel monkeys (final report). (Second year final report: effects of nitrate and /or sulfate aerosols upon cardiopulmonary function)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greenberg, H.L.; Avol, E.L.; Bailey, R.M.

1977-06-24

Squirrel monkeys were exposed to nominal concentrations of 2.5 mg/cu m of the following generated aerosols: zinc ammonium sulfate at both low (40%) and high (85%) nominal relative humidities, histamine diphosphate at low relative humidity, and ammonium bisulfate at low relative humidity. There were few statistically significant changes in oscillatory resistance, however, several trends toward increased resistance were present. Additional studies were performed using two different aerosol nebulizers to produce histamine diphosphate particles in two distinct size distributions, an order of magnitude different in size. These results, supported by data collected during sulfur dioxide exposures of squirrel monkeys, are usedmore » to discuss the suitability of Saimiri sciureus as a sensitive indicator species and oscillatory resistance as a valuable measurement of proximal airway changes. Development of the esophageal balloon technique as a means of measuring compliance and resistance in the unanesthetized squirrel monkey is discussed.« less

Isoflurane and Ketamine Anesthesia have Different Effects on Ventilatory Pattern Variability in Rats

PubMed Central

Chung, Augustine; Fishman, Mikkel; Dasenbrook, Elliot C.; Loparo, Kenneth A.; Dick, Thomas E.; Jacono, Frank J.

2013-01-01

We hypothesize that isoflurane and ketamine impact ventilatory pattern variability (VPV) differently. Adult Sprague-Dawley rats were recorded in a whole-body plethysmograph before, during and after deep anesthesia. VPV was quantified from 60-s epochs using a complementary set of analytic techniques that included constructing surrogate data sets that preserved the linear structure but disrupted nonlinear deterministic properties of the original data. Even though isoflurane decreased and ketamine increased respiratory rate, VPV as quantified by the coefficient of variation decreased for both anesthetics. Further, mutual information increased and sample entropy decreased and the nonlinear complexity index (NLCI) increased during anesthesia despite qualitative differences in the shape and period of the waveform. Surprisingly mutual information and sample entropy did not change in the surrogate sets constructed from isoflurane data, but in those constructed from ketamine data, mutual information increased and sample entropy decreased significantly in the surrogate segments constructed from anesthetized relative to unanesthetized epochs. These data suggest that separate mechanisms modulate linear and nonlinear variability of breathing. PMID:23246800

Prostaglandin control of renal circulation in the unanesthetized dog and baboon

NASA Technical Reports Server (NTRS)

Swain, J. A.; Vatner, S. F.; Heyndrickx, G. R.; Boettcher, D. H.

1975-01-01

Effects of indomethacin and meclofenamate, inhibitors of prostaglandin synthesis, were evaluated in the regulation of renal blood flow in conscious and anesthetized dogs and in tranquilized baboons, instrumented with arterial pressure catheters and renal blood flow probes. Indomethacin, 10 mg/kg, did not alter renal blood flow or resistance significantly in the conscious dog. In the anesthetized dog, however, indomethacin caused a reduction in renal blood flow and an elevation of renal vascular resistance. Meclofenamate, 4 mg/kg, reduced renal flow and increased renal vascular resistance in conscious dogs. In conscious dogs and tranquilized primates, indomethacin and meclofenamate reduced the reactive hyperemia in the renal bed. Methoxamine and angiotensin II infused in graded doses induced significantly greater renal vasoconstriction in conscious dogs in the presence of indomethacin. Thus, in the conscious animal, prostaglandins appear to play only a minor part in the control of renal circulation at rest, but they are of greater importance in mediating the renal responses to reactive hyperemia and to vasoconstriction.

Correlation of hippocampal theta rhythm with changes in cutaneous temperature. [evoked neuron response in thermoregulation

NASA Technical Reports Server (NTRS)

Horowitz, J. M.; Saleh, M. A.; Karem, R. D.

1974-01-01

A possible role for the hippocampus in alerting an animal to changes in cutaneous temperature was examined. Following local warming or cooling of the ears of unanesthetized, loosely restrained rabbits, theta waves (4-7 Hz EEG waves) were recorded from electrodes straddling the hippocampus. The onset of the hippocampal theta rhythm was correlated with changes in cutaneous temperature, an observation consistent with studies indicating that the theta rhythm is a nonspecific response evoked by stimulation of several sensory modalities. Additional data from cats and rabbits were correlated with specific neurons within the hippocampus, namely pyramidal cells. Post stimulus time histograms obtained by excitation of the dorsal fornix were interpreted in terms of excitatory and inhibitory inputs to pyramidal cells. Thus, the theta rhythm, which appears to be evoked by changes in cutaneous temperature, can be related to a specific type of hippocampal neuron which is in turn connected with other areas of the brain involved in temperature regulation.

Behavioral characterization of cereblon forebrain-specific conditional null mice: A model for human non-syndromic intellectual disability

PubMed Central

Rajadhyaksha, Anjali M.; Ra, Stephen; Kishinevsky, Sarah; Lee, Anni S.; Romanienko, Peter; DuBoff, Mariel; Yang, Chingwen; Zupan, Bojana; Byrne, Maureen; Daruwalla, Zeeba R.; Mark, Willie; Kosofsky, Barry E.; Toth, Miklos; Higgins, Joseph J.

2018-01-01

A nonsense mutation in the human cereblon gene (CRBN) causes a mild type of autosomal recessive non-syndromic intellectual disability (ID). Animal studies show that crbn is a cytosolic protein with abundant expression in the hippocampus (HPC) and neocortex (CTX). Its diverse functions include the developmental regulation of ion channels at the neuronal synapse, the mediation of developmental programs by ubiquitination, and a target for herpes simplex type I virus in HPC neurons. To test the hypothesis that anomalous CRBN expression leads to HPC-mediated memory and learning deficits, we generated germ-line crbn knock-out mice (crbn−/−). We also inactivated crbn in forebrain neurons in conditional knock-out mice in which crbn exons 3 and 4 are deleted by cre recombinase under the direction of the Ca2+/calmodulin-dependent protein kinase II alpha promoter (CamKIIcre/+, crbn−/−). crbn mRNA levels were negligible in the HPC, CTX, and cerebellum (CRBM) of the crbn−/− mice. In contrast, crbn mRNA levels were reduced 3- to 4-fold in the HPC, CTX but not in the CRBM in CamKIIcre/+, crbn−/− mice as compared to wild type (CamKIIcre/+, crbn+/+). Contextual fear conditioning showed a significant decrease in the percentage of freezing time in CamKIIcre/+, crbn−/− and crbn−/− mice while motor function, exploratory motivation, and anxiety-related behaviors were normal. These findings suggest that CamKIIcre/+, crbn−/− mice exhibit selective HPC-dependent deficits in associative learning and supports the use of these mice as in vivo models to study the functional consequences of CRBN aberrations on memory and learning in humans. PMID:21995942

Comprehensive Morpho-Electrotonic Analysis Shows 2 Distinct Classes of L2 and L3 Pyramidal Neurons in Human Temporal Cortex

PubMed Central

Deitcher, Yair; Eyal, Guy; Kanari, Lida; Verhoog, Matthijs B; Atenekeng Kahou, Guy Antoine; Mansvelder, Huibert D; de Kock, Christiaan P J; Segev, Idan

2017-01-01

Abstract There have been few quantitative characterizations of the morphological, biophysical, and cable properties of neurons in the human neocortex. We employed feature-based statistical methods on a rare data set of 60 3D reconstructed pyramidal neurons from L2 and L3 in the human temporal cortex (HL2/L3 PCs) removed after brain surgery. Of these cells, 25 neurons were also characterized physiologically. Thirty-two morphological features were analyzed (e.g., dendritic surface area, 36 333 ± 18 157 μm2; number of basal trees, 5.55 ± 1.47; dendritic diameter, 0.76 ± 0.28 μm). Eighteen features showed a significant gradual increase with depth from the pia (e.g., dendritic length and soma radius). The other features showed weak or no correlation with depth (e.g., dendritic diameter). The basal dendritic terminals in HL2/L3 PCs are particularly elongated, enabling multiple nonlinear processing units in these dendrites. Unlike the morphological features, the active biophysical features (e.g., spike shapes and rates) and passive/cable features (e.g., somatic input resistance, 47.68 ± 15.26 MΩ, membrane time constant, 12.03 ± 1.79 ms, average dendritic cable length, 0.99 ± 0.24) were depth-independent. A novel descriptor for apical dendritic topology yielded 2 distinct classes, termed hereby as “slim-tufted” and “profuse-tufted” HL2/L3 PCs; the latter class tends to fire at higher rates. Thus, our morpho-electrotonic analysis shows 2 distinct classes of HL2/L3 PCs. PMID:28968789

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

PubMed

Lionel, Anath C; Tammimies, Kristiina; Vaags, Andrea K; Rosenfeld, Jill A; Ahn, Joo Wook; Merico, Daniele; Noor, Abdul; Runke, Cassandra K; Pillalamarri, Vamsee K; Carter, Melissa T; Gazzellone, Matthew J; Thiruvahindrapuram, Bhooma; Fagerberg, Christina; Laulund, Lone W; Pellecchia, Giovanna; Lamoureux, Sylvia; Deshpande, Charu; Clayton-Smith, Jill; White, Ann C; Leather, Susan; Trounce, John; Melanie Bedford, H; Hatchwell, Eli; Eis, Peggy S; Yuen, Ryan K C; Walker, Susan; Uddin, Mohammed; Geraghty, Michael T; Nikkel, Sarah M; Tomiak, Eva M; Fernandez, Bridget A; Soreni, Noam; Crosbie, Jennifer; Arnold, Paul D; Schachar, Russell J; Roberts, Wendy; Paterson, Andrew D; So, Joyce; Szatmari, Peter; Chrysler, Christina; Woodbury-Smith, Marc; Brian Lowry, R; Zwaigenbaum, Lonnie; Mandyam, Divya; Wei, John; Macdonald, Jeffrey R; Howe, Jennifer L; Nalpathamkalam, Thomas; Wang, Zhuozhi; Tolson, Daniel; Cobb, David S; Wilks, Timothy M; Sorensen, Mark J; Bader, Patricia I; An, Yu; Wu, Bai-Lin; Musumeci, Sebastiano Antonino; Romano, Corrado; Postorivo, Diana; Nardone, Anna M; Monica, Matteo Della; Scarano, Gioacchino; Zoccante, Leonardo; Novara, Francesca; Zuffardi, Orsetta; Ciccone, Roberto; Antona, Vincenzo; Carella, Massimo; Zelante, Leopoldo; Cavalli, Pietro; Poggiani, Carlo; Cavallari, Ugo; Argiropoulos, Bob; Chernos, Judy; Brasch-Andersen, Charlotte; Speevak, Marsha; Fichera, Marco; Ogilvie, Caroline Mackie; Shen, Yiping; Hodge, Jennelle C; Talkowski, Michael E; Stavropoulos, Dimitri J; Marshall, Christian R; Scherer, Stephen W

2014-05-15

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Photostimulation of Phox2b Medullary Neurons Activates Cardiorespiratory Function in Conscious Rats

PubMed Central

Kanbar, Roy; Stornetta, Ruth L.; Cash, Devin R.; Lewis, Stephen J.; Guyenet, Patrice G.

2010-01-01

Rationale: Hypoventilation is typically treated with positive pressure ventilation or, in extreme cases, by phrenic nerve stimulation. This preclinical study explores whether direct stimulation of central chemoreceptors could be used as an alternative method to stimulate breathing. Objectives: To determine whether activation of the retrotrapezoid nucleus (RTN), which is located in the rostral ventrolateral medulla (RVLM), stimulates breathing with appropriate selectivity. Methods: A lentivirus was used to induce expression of the photoactivatable cationic channel channelrhodopsin-2 (ChR2) by RVLM Phox2b-containing neurons, a population that consists of central chemoreceptors (the ccRTN neurons) and blood pressure (BP)-regulating neurons (the C1 cells). The transfected neurons were activated with pulses of laser light. Respiratory effects were measured by plethysmography or diaphragmatic EMG recording and cardiovascular effects by monitoring BP, renal sympathetic nerve discharge, and the baroreflex. Measurements and Main Results: The RVLM contained 600 to 900 ChR2-transfected neurons (63% C1, 37% ccRTN). RVLM photostimulation significantly increased breathing rate (+42%), tidal volume (21%), minute volume (68%), and peak expiratory flow (48%). Photostimulation increased diaphragm EMG amplitude (19%) and frequency (21%). Photostimulation increased BP (4 mmHg) and renal sympathetic nerve discharge (43%) while decreasing heart rate (15 bpm). Conclusions: Photostimulation of ChR2-transfected RVLM Phox2b neurons produces a vigorous stimulation of breathing accompanied by a small sympathetically mediated increase in BP. These results demonstrate that breathing can be relatively selectively activated in resting unanesthetized mammals via optogenetic manipulation of RVLM neurons presumed to be central chemoreceptors. This methodology could perhaps be used in the future to enhance respiration in humans. PMID:20622037

Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but α-LNA-containing n-3 PUFA adequate diet.

PubMed

Gao, Fei; Kim, Hyung-Wook; Igarashi, Miki; Kiesewetter, Dale; Chang, Lisa; Ma, Kaizong; Rapoport, Stanley I

2011-01-01

The long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6), are critical for health. These PUFAs can be synthesized in liver from their plant-derived precursors, α-linolenic acid (α-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6). Vegetarians and vegans may have suboptimal long-chain n-3 PUFA status, and the extent of the conversion of α-LNA to EPA and DHA by the liver is debatable. We quantified liver conversion of DHA and other n-3 PUFAs from α-LNA in rats fed a DHA-free but α-LNA (n-3 PUFA) adequate diet, and compared results to conversion of LA to AA. [U-(13)C]LA or [U-(13)C]α-LNA was infused intravenously for 2h at a constant rate into unanesthetized rats fed a DHA-free α-LNA adequate diet, and published equations were used to calculate kinetic parameters. The conversion coefficient k(⁎) of DHA from α-LNA was much higher than for AA from LA (97.2×10(-3) vs. 10.6×10(-3)min(-1)), suggesting that liver elongation-desaturation is more selective for n-3 PUFA biosynthesis on a per molecule basis. The net daily secretion rate of DHA, 20.3μmol/day, exceeded the reported brain DHA consumption rate by 50-fold, suggesting that the liver can maintain brain DHA metabolism with an adequate dietary supply solely of α-LNA. This infusion method could be used in vegetarians or vegans to determine minimal daily requirements of EPA and DHA in humans. Published by Elsevier B.V.

Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice.

PubMed

Ehrlichman, Richard S; Maxwell, Christina R; Majumdar, Sonalee; Siegel, Steven J

2008-08-01

People with schizophrenia exhibit reduced ability to detect change in the auditory environment, which has been linked to abnormalities in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotransmission. This ability to detect changes in stimulus qualities can be measured with electroencephalography using auditory event-related potentials (ERPs). For example, reductions in the N100 and mismatch negativity (MMN), in response to pitch deviance, have been proposed as endophenotypes of schizophrenia. This study examines a novel rodent model of impaired pitch deviance detection in mice using the NMDA receptor antagonist ketamine. ERPs were recorded from unanesthetized mice during a pitch deviance paradigm prior to and following ketamine administration. First, N40 amplitude was evaluated using stimuli between 4 and 10 kHz to assess the amplitude of responses across the frequency range used. The amplitude and latency of the N40 were analyzed following standard (7 kHz) and deviant (5-9 kHz) stimuli. Additionally, we examined which portions of the ERP are selectively altered by pitch deviance to define possible regions for the mouse MMN. Mice displayed increased N40 amplitude that was followed by a later negative component between 50 and 75 msec in response to deviant stimuli. Both the increased N40 and the late N40 negativity were attenuated by ketamine. Ketamine increased N40 latency for both standard and deviant stimuli alike. The mouse N40 and a subsequent temporal region have deviance response properties similar to the human N100 and, possibly, MMN. Deviance responses were abolished by ketamine, suggesting that ketamine-induced changes in mice mimic deviance detection deficits in schizophrenia.

The functional and anatomical organization of marsupial neocortex: Evidence for parallel evolution across mammals

PubMed Central

Karlen, Sarah J.; Krubitzer, Leah

2007-01-01

Marsupials are a diverse group of mammals that occupy a large range of habitats and have evolved a wide array of unique adaptations. Although they are as diverse as placental mammals, our understanding of marsupial brain organization is more limited. Like placental mammals, marsupials have striking similarities in neocortical organization, such as a constellation of cortical fields including S1, S2, V1, V2, and A1, that are functionally, architectonically, and connectionally distinct. In this review, we describe the general lifestyle and morphological characteristics of all marsupials and the organization of somatosensory, motor, visual, and auditory cortex. For each sensory system, we compare the functional organization and the corticocortical and thalamocortical connections of the neocortex across species. Differences between placental and marsupial species are discussed and the theories on neocortical evolution that have been derived from studying marsupials, particularly the idea of a sensorimotor amalgam, are evaluated. Overall, marsupials inhabit a variety of niches and assume many different lifestyles. For example, marsupials occupy terrestrial, arboreal, burrowing, and aquatic environments; some animals are highly social while others are solitary; and different species are carnivorous, herbivorous, or omnivorous. For each of these adaptations, marsupials have evolved an array of morphological, behavioral, and cortical specializations that are strikingly similar to those observed in placental mammals occupying similar habitats, which indicate that there are constraints imposed on evolving nervous systems that result in recurrent solutions to similar environmental challenges. PMID:17507143

Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy.

PubMed

Ouedraogo, David W; Lenck-Santini, Pierre-Pascal; Marti, Geoffrey; Robbe, David; Crépel, Valérie; Epsztein, Jérôme

2016-01-01

The dentate gyrus, a major entry point to the hippocampus, gates (or filters) incoming information from the cortex. During sleep or anesthesia, the slow-wave oscillation (SWO) orchestrates hippocampus-neocortex communication, which is important for memory formation. The dentate gate is altered in temporal lobe epilepsy (TLE) early during epileptogenesis, which favors the propagation of pathological activities. Yet, whether the gating of physiological SWO by dentate granule cells (DGCs) is altered in TLE has remained unexplored. We combined intracellular recordings of membrane potential (V m) of DGCs and local field potential recordings of the SWO in parietal cortex in anesthetized rats early during epileptogenesis [post-status epilepticus (SE) rats]. As expected, in control rats, the V m of DGCs weakly and rarely oscillated in the SWO frequency range. In contrast, in post-SE rats, the V m of DGCs displayed strong and long-lasting SWO. In these cells, clear UP and DOWN states, in phase with the neocortical SWO, led to a bimodal V m distribution. In post-SE rats, the firing of DGCs was increased and more temporally modulated by the neocortical SWO. We conclude that UP/DOWN state dynamics dominate the V m of DGCs and firing early during epileptogenesis. This abnormally strong neocortical influence on the dynamics of DGCs may profoundly modify the hippocampus-neocortex dialogue during sleep and associated cognitive functions.

The Y-Box Binding Protein 1 Suppresses Alzheimer’s Disease Progression in Two Animal Models

PubMed Central

Bobkova, N. V.; Lyabin, D. N.; Medvinskaya, N. I.; Samokhin, A. N.; Nekrasov, P. V.; Nesterova, I. V.; Aleksandrova, I. Y.; Tatarnikova, O. G.; Bobylev, A. G.; Vikhlyantsev, I. M.; Kukharsky, M. S.; Ustyugov, A. A.; Polyakov, D. N.; Eliseeva, I. A.; Kretov, D. A.; Guryanov, S. G.; Ovchinnikov, L. P.

2015-01-01

The Y-box binding protein 1 (YB-1) is a member of the family of DNA- and RNA binding proteins. It is involved in a wide variety of DNA/RNA-dependent events including cell proliferation and differentiation, stress response, and malignant cell transformation. Previously, YB-1 was detected in neurons of the neocortex and hippocampus, but its precise role in the brain remains undefined. Here we show that subchronic intranasal injections of recombinant YB-1, as well as its fragment YB-11−219, suppress impairment of spatial memory in olfactory bulbectomized (OBX) mice with Alzheimer’s type degeneration and improve learning in transgenic 5XFAD mice used as a model of cerebral amyloidosis. YB-1-treated OBX and 5XFAD mice showed a decreased level of brain β-amyloid. In OBX animals, an improved morphological state of neurons was revealed in the neocortex and hippocampus; in 5XFAD mice, a delay in amyloid plaque progression was observed. Intranasally administered YB-1 penetrated into the brain and could enter neurons. In vitro co-incubation of YB-1 with monomeric β-amyloid (1–42) inhibited formation of β-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with β-amyloid prevents formation of filaments that are responsible for neurotoxicity and neuronal death. Our data are the first evidence for a potential therapeutic benefit of YB-1 for treatment of Alzheimer’s disease. PMID:26394155

ApoER2 Controls Not Only Neuronal Migration in the Intermediate Zone But Also Termination of Migration in the Developing Cerebral Cortex.

PubMed

Hirota, Yuki; Kubo, Ken-Ichiro; Fujino, Takahiro; Yamamoto, Tokuo T; Nakajima, Kazunori

2018-01-01

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Intrinsic-Signal Optical Imaging Reveals Cryptic Ocular Dominance Columns in Primary Visual Cortex of New World Owl Monkeys

PubMed Central

Kaskan, Peter M.; Lu, Haidong D.; Dillenburger, Barbara C.; Roe, Anna W.; Kaas, Jon H.

2007-01-01

A significant concept in neuroscience is that sensory areas of the neocortex have evolved the remarkable ability to represent a number of stimulus features within the confines of a global map of the sensory periphery. Modularity, the term often used to describe the inhomogeneous nature of the neocortex, is without a doubt an important organizational principle of early sensory areas, such as the primary visual cortex (V1). Ocular dominance columns, one type of module in V1, are found in many primate species as well as in carnivores. Yet, their variable presence in some New World monkey species and complete absence in other species has been enigmatic. Here, we demonstrate that optical imaging reveals the presence of ocular dominance columns in the superficial layers of V1 of owl monkeys (Aotus trivirgatus), even though the geniculate inputs related to each eye are highly overlapping in layer 4. The ocular dominance columns in owl monkeys revealed by optical imaging are circular in appearance. The distance between left eye centers and right eye centers is approximately 650 μm. We find no relationship between ocular dominance centers and other modular organizational features such as orientation pinwheels or the centers of the cytochrome oxidase blobs. These results are significant because they suggest that functional columns may exist in the absence of obvious differences in the distributions of activating inputs and ocular dominance columns may be more widely distributed across mammalian taxa than commonly suggested. PMID:18974855

The neuroprotective effects of MK-801 on the induction of microgyria by freezing injury to the newborn rat neocortex.

PubMed

Rosen, G D; Sigel, E A; Sherman, G F; Galaburda, A M

1995-11-01

Four-layered microgyria is associated with many developmental disorders, including mental retardation, epilepsy, and developmental dyslexia. Freezing lesions to the newborn rodent neocortex result in the formation of four-layered microgyria. Previous research had suggested this type of injury acts as an hypoxic/ischemic event to the developing cortical plate. The current study examines the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) in protecting against freezing injury to the newborn rat cortical plate. Three groups of rats received freezing injury to the cortical plate on the first day of life (postnatal day 1). Two groups were treated with MK-801 (1 or 2 mg/kg) 0.5 h before the lesion and 6 and 14 h after, while one group received saline injections. A fourth group received MK-801 injections, but did not have a freezing lesion. The volume of neocortical abnormality was determined for all three groups in rats killed after postnatal day 7. Treatment with the higher dose of MK-801 (3 x 2 mg/kg) dramatically reduced the effects of freezing injury but also resulted in over 50% mortality in both lesioned and unlesioned groups. Animals in the lesioned group, however, had a decreased volume of abnormal cortex, and there were fewer animals with microsulci than in the untreated group. This is the first demonstration of a significant anatomical neuroprotective effect in newborns leading to a reduction of cortical malformation.

Neurobiology of Alzheimer’s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions

PubMed Central

Raskin, Joel; Cummings, Jeffrey; Hardy, John; Schuh, Kory; Dean, Robert A.

2015-01-01

Background: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms. PMID:26412218

Period Concatenation Underlies Interactions between Gamma and Beta Rhythms in Neocortex

PubMed Central

Roopun, Anita K.; Kramer, Mark A.; Carracedo, Lucy M.; Kaiser, Marcus; Davies, Ceri H.; Traub, Roger D.; Kopell, Nancy J.; Whittington, Miles A.

2008-01-01

The neocortex generates rhythmic electrical activity over a frequency range covering many decades. Specific cognitive and motor states are associated with oscillations in discrete frequency bands within this range, but it is not known whether interactions and transitions between distinct frequencies are of functional importance. When coexpressed rhythms have frequencies that differ by a factor of two or more interactions can be seen in terms of phase synchronization. Larger frequency differences can result in interactions in the form of nesting of faster frequencies within slower ones by a process of amplitude modulation. It is not known how coexpressed rhythms, whose frequencies differ by less than a factor of two may interact. Here we show that two frequencies (gamma – 40 Hz and beta2 – 25 Hz), coexpressed in superficial and deep cortical laminae with low temporal interaction, can combine to generate a third frequency (beta1 – 15 Hz) showing strong temporal interaction. The process occurs via period concatenation, with basic rhythm-generating microcircuits underlying gamma and beta2 rhythms forming the building blocks of the beta1 rhythm by a process of addition. The mean ratio of adjacent frequency components was a constant – approximately the golden mean – which served to both minimize temporal interactions, and permit multiple transitions, between frequencies. The resulting temporal landscape may provide a framework for multiplexing – parallel information processing on multiple temporal scales. PMID:18946516

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum.

PubMed

Mattsson, Anna; Olson, Lars; Svensson, Torgny H; Schilström, Björn

2007-11-01

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.

Genetic Elimination of GABAergic Neurotransmission Reveals Two Distinct Pacemakers for Spontaneous Waves of Activity in the Developing Mouse Cortex

PubMed Central

Easton, Curtis R.; Weir, Keiko; Scott, Adina; Moen, Samantha P.; Barger, Zeke; Folch, Albert; Hevner, Robert F.

2014-01-01

Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves. PMID:24623764

Parameters in fractional laser assisted delivery of topical anesthetics: Role of laser type and laser settings.

PubMed

Meesters, Arne A; Nieboer, Marilin J; Kezic, Sanja; de Rie, Menno A; Wolkerstorfer, Albert

2018-05-07

Efficacy of topical anesthetics can be enhanced by pretreatment of the skin with ablative fractional lasers. However, little is known about the role of parameters such as laser modality and laser density settings in this technique. Aims of this study were to compare the efficacy of pretreatment with two different ablative fractional laser modalities, a CO 2 laser and an Er:YAG laser, and to assess the role of laser density in ablative fractional laser assisted topical anesthesia. In each of 15 healthy subjects, four 10 × 10 mm test regions on the back were randomized to pretreatment (70-75 μm ablation depth) with CO 2 laser at 5% density, CO 2 laser at 15% density, Er:YAG laser at 5% density or Er:YAG laser at 15% density. Articaine hydrochloride 40 mg/ml + epinephrine 10 μg/ml solution was applied under occlusion to all four test regions. After 15 minutes, a pass with the CO 2 laser (1,500 μm ablation depth) was administered as pain stimulus to each test region. A reference pain stimulus was given on unanesthetized skin. The main outcome parameter, pain, was scored on a 0-10 visual analogue scale (VAS) after each pain stimulus. Median VAS scores were 1.50 [CO 2 5%], 0.50 [CO 2 15%], 1.50 [Er:YAG 5%], 0.43 [Er:YAG 15%], and 4.50 [unanesthetized reference]. VAS scores for all pretreated test regions were significantly lower compared to the untreated reference region (P < 0.01). We found no significant difference in VAS scores between the CO 2 and the Er:YAG laser pretreated regions. However, VAS scores were significantly lower at 15% density compared to 5% density for both for the CO 2 laser (P < 0.05) and the Er:YAG laser (P < 0.01). Pretreatment with the CO 2 laser was considered slightly more painful than pretreatment with Er:YAG laser by the subjects. Fractional laser assisted topical anesthesia is effective even with very low energy settings and an occlusion time of only 15 minutes. Both the CO 2 laser and the Er:YAG laser can be used to assist topical anesthesia although the CO 2 laser pretreatment is experienced as more painful. In our study settings, using articaine/epinephrine solution and an occlusion time of 15 minutes, a density of 15% was more effective than 5%. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Rapid Neocortical Dynamics: Cellular and Network Mechanisms

PubMed Central

Haider, Bilal; McCormick, David A.

2011-01-01

The highly interconnected local and large-scale networks of the neocortical sheet rapidly and dynamically modulate their functional connectivity according to behavioral demands. This basic operating principle of the neocortex is mediated by the continuously changing flow of excitatory and inhibitory synaptic barrages that not only control participation of neurons in networks but also define the networks themselves. The rapid control of neuronal responsiveness via synaptic bombardment is a fundamental property of cortical dynamics that may provide the basis of diverse behaviors, including sensory perception, motor integration, working memory, and attention. PMID:19409263

Molecules and mechanisms involved in the generation and migration of cortical interneurons

PubMed Central

Hernández-Miranda, Luis R; Parnavelas, John G; Chiara, Francesca

2010-01-01

The GABA (γ-aminobutyric acid)-containing interneurons of the neocortex are largely derived from the ganglionic eminences in the subpallium. Numerous studies have previously defined the migratory paths travelled by these neurons from their origins to their destinations in the cortex. We review here results of studies that have identified many of the genes expressed in the subpallium that are involved in the specification of the subtypes of cortical interneurons, and the numerous transcription factors, motogenic factors and guidance molecules that are involved in their migration. PMID:20360946

The Basal Ganglia and Adaptive Motor Control

NASA Astrophysics Data System (ADS)

Graybiel, Ann M.; Aosaki, Toshihiko; Flaherty, Alice W.; Kimura, Minoru

1994-09-01

The basal ganglia are neural structures within the motor and cognitive control circuits in the mammalian forebrain and are interconnected with the neocortex by multiple loops. Dysfunction in these parallel loops caused by damage to the striatum results in major defects in voluntary movement, exemplified in Parkinson's disease and Huntington's disease. These parallel loops have a distributed modular architecture resembling local expert architectures of computational learning models. During sensorimotor learning, such distributed networks may be coordinated by widely spaced striatal interneurons that acquire response properties on the basis of experienced reward.

Intravital imaging of dendritic spine plasticity

PubMed Central

Sau Wan Lai, Cora

2014-01-01

Abstract Dendritic spines are the postsynaptic part of most excitatory synapses in the mammalian brain. Recent works have suggested that the structural and functional plasticity of dendritic spines have been associated with information coding and memories. Advances in imaging and labeling techniques enable the study of dendritic spine dynamics in vivo. This perspective focuses on intravital imaging studies of dendritic spine plasticity in the neocortex. I will introduce imaging tools for studying spine dynamics and will further review current findings on spine structure and function under various physiological and pathological conditions. PMID:28243511

Multi-tissue analysis of co-expression networks by higher-order generalized singular value decomposition identifies functionally coherent transcriptional modules.

PubMed

Xiao, Xiaolin; Moreno-Moral, Aida; Rotival, Maxime; Bottolo, Leonardo; Petretto, Enrico

2014-01-01

Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks) that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted) networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based) and humans (mRNA-sequencing-based) and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi-tissue subnetwork of co-expressed heat shock protein (Hsp) and cardiomyopathy genes (Bag3, Cryab, Kras, Emd, Plec), which was significantly replicated using separate failing heart and liver gene expression datasets in humans, thus revealing a conserved functional role for Hsp genes in cardiovascular disease.

Interaction between synaptic inhibition and glial-potassium dynamics leads to diverse seizure transition modes in biophysical models of human focal seizures.

PubMed

Y Ho, E C; Truccolo, Wilson

2016-10-01

How focal seizures initiate and evolve in human neocortex remains a fundamental problem in neuroscience. Here, we use biophysical neuronal network models of neocortical patches to study how the interaction between inhibition and extracellular potassium ([K (+)] o ) dynamics may contribute to different types of focal seizures. Three main types of propagated focal seizures observed in recent intracortical microelectrode recordings in humans were modelled: seizures characterized by sustained (∼30-60 Hz) gamma local field potential (LFP) oscillations; seizures where the onset in the propagated site consisted of LFP spikes that later evolved into rhythmic (∼2-3 Hz) spike-wave complexes (SWCs); and seizures where a brief stage of low-amplitude fast-oscillation (∼10-20 Hz) LFPs preceded the SWC activity. Our findings are fourfold: (1) The interaction between elevated [K (+)] o (due to abnormal potassium buffering by glial cells) and the strength of synaptic inhibition plays a predominant role in shaping these three types of seizures. (2) Strengthening of inhibition leads to the onset of sustained narrowband gamma seizures. (3) Transition into SWC seizures is obtained either by the weakening of inhibitory synapses, or by a transient strengthening followed by an inhibitory breakdown (e.g. GABA depletion). This reduction or breakdown of inhibition among fast-spiking (FS) inhibitory interneurons increases their spiking activity and leads them eventually into depolarization block. Ictal spike-wave discharges in the model are then sustained solely by pyramidal neurons. (4) FS cell dynamics are also critical for seizures where the evolution into SWC activity is preceded by low-amplitude fast oscillations. Different levels of elevated [K (+)] o were important for transitions into and maintenance of sustained gamma oscillations and SWC discharges. Overall, our modelling study predicts that the interaction between inhibitory interneurons and [K (+)] o glial buffering under abnormal conditions may explain different types of ictal transitions and dynamics during propagated seizures in human focal epilepsy.

Olfactory discrimination ability and brain expression of c-fos, Gir and Glut1 mRNA are altered in n-3 fatty acid-depleted rats.

PubMed

Hichami, Aziz; Datiche, Frédérique; Ullah, Sana; Liénard, Fabienne; Chardigny, Jean-Michel; Cattarelli, Martine; Khan, Naim Akhtar

2007-11-22

The long-chain polyunsaturated n-3 fatty acids (n-3 PUFA), particularly docosahexaenoic acid (DHA), are abundantly present in the central nervous system and play an important role in cognitive functions such as learning and memory. We, therefore, investigated the effects of n-3 PUFA-depletion in rats (F2 generation) on the learning of an olfactory discrimination task, progressively acquired within a four-arm maze, and on the mRNA expression of some candidate genes, i.e., c-fos, Gir and glucose transporter (Glut1), which could reflect the level of cerebral activity. We observed that DHA contents were dramatically decreased in the olfactory bulb, the piriform cortex and the neocortex of n-3-depleted rats. Furthermore, the n-3 deficiency resulted in a mild olfactory learning impairment as these rats required more days to master the olfactory task compared to control rats. Real-time RT-PCR experiments revealed that the training induced the expression of c-fos mRNA in all the three regions of the brain whereas Gir and Glut1 mRNA were induced only in olfactory bulb and neocortex. However, such an increase was less marked in the n-3-deficient rats. Taken together, these results allow us to assume that the behavioural impairment in n-3-deficient rats is linked to the depletion of n-3 fatty acids in brain regions processing olfactory cues. Data are discussed in view of the possible role of some of these genes in learning-induced neuronal olfactory plasticity.

Sleep stage dynamics in neocortex and hippocampus.

PubMed

Durán, Ernesto; Oyanedel, Carlos N; Niethard, Niels; Inostroza, Marion; Born, Jan

2018-06-01

Mammalian sleep comprises the stages of slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Additionally, a transition state is often discriminated which in rodents is termed intermediate stage (IS). Although these sleep stages are thought of as unitary phenomena affecting the whole brain in a congruent fashion, recent findings have suggested that sleep stages can also appear locally restricted to specific networks and regions. Here, we compared in rats sleep stages and their transitions between neocortex and hippocampus. We simultaneously recorded the electroencephalogram (EEG) from skull electrodes over frontal and parietal cortex and the local field potential (LFP) from the medial prefrontal cortex and dorsal hippocampus. Results indicate a high congruence in the occurrence of sleep and SWS (>96.5%) at the different recording sites. Congruence was lower for REM sleep (>87%) and lowest for IS (<36.5%). Incongruences occurring at sleep stage transitions were most pronounced for REM sleep which in 36.6 per cent of all epochs started earlier in hippocampal LFP recordings than in the other recordings, with an average interval of 17.2 ± 1.1 s between REM onset in the hippocampal LFP and the parietal EEG (p < 0.001). Earlier REM onset in the hippocampus was paralleled by a decrease in muscle tone, another hallmark of REM sleep. These findings indicate a region-specific regulation of REM sleep which has clear implications not only for our understanding of the organization of sleep, but possibly also for the functions, e.g. in memory formation, that have been associated with REM sleep.

A Theory of How Columns in the Neocortex Enable Learning the Structure of the World

PubMed Central

Hawkins, Jeff; Ahmad, Subutai; Cui, Yuwei

2017-01-01

Neocortical regions are organized into columns and layers. Connections between layers run mostly perpendicular to the surface suggesting a columnar functional organization. Some layers have long-range excitatory lateral connections suggesting interactions between columns. Similar patterns of connectivity exist in all regions but their exact role remain a mystery. In this paper, we propose a network model composed of columns and layers that performs robust object learning and recognition. Each column integrates its changing input over time to learn complete predictive models of observed objects. Excitatory lateral connections across columns allow the network to more rapidly infer objects based on the partial knowledge of adjacent columns. Because columns integrate input over time and space, the network learns models of complex objects that extend well beyond the receptive field of individual cells. Our network model introduces a new feature to cortical columns. We propose that a representation of location relative to the object being sensed is calculated within the sub-granular layers of each column. The location signal is provided as an input to the network, where it is combined with sensory data. Our model contains two layers and one or more columns. Simulations show that using Hebbian-like learning rules small single-column networks can learn to recognize hundreds of objects, with each object containing tens of features. Multi-column networks recognize objects with significantly fewer movements of the sensory receptors. Given the ubiquity of columnar and laminar connectivity patterns throughout the neocortex, we propose that columns and regions have more powerful recognition and modeling capabilities than previously assumed. PMID:29118696

Phase Advance of the Light-Dark Cycle Perturbs Diurnal Rhythms of Brain-derived Neurotrophic Factor and Neurotrophin-3 Protein Levels, Which Reduces Synaptophysin-positive Presynaptic Terminals in the Cortex of Juvenile Rats

PubMed Central

Hamatake, Michiko; Miyazaki, Noriko; Sudo, Kaori; Matsuda, Motoko; Sadakata, Tetsushi; Furuya, Asako; Ichisaka, Satoshi; Hata, Yoshio; Nakagawa, Chiaki; Nagata, Koh-ichi; Furuichi, Teiichi; Katoh-Semba, Ritsuko

2011-01-01

In adult rat brains, brain-derived neurotrophic factor (BDNF) rhythmically oscillates according to the light-dark cycle and exhibits unique functions in particular brain regions. However, little is known of this subject in juvenile rats. Here, we examined diurnal variation in BDNF and neurotrophin-3 (NT-3) levels in 14-day-old rats. BDNF levels were high in the dark phase and low in the light phase in a majority of brain regions. In contrast, NT-3 levels demonstrated an inverse phase relationship that was limited to the cerebral neocortex, including the visual cortex, and was most prominent on postnatal day 14. An 8-h phase advance of the light-dark cycle and sleep deprivation induced an increase in BDNF levels and a decrease in NT-3 levels in the neocortex, and the former treatment reduced synaptophysin expression and the numbers of synaptophysin-positive presynaptic terminals in cortical layer IV and caused abnormal BDNF and NT-3 rhythms 1 week after treatment. A similar reduction of synaptophysin expression was observed in the cortices of Bdnf gene-deficient mice and Ca2+-dependent activator protein for secretion 2 gene-deficient mice with abnormal free-running rhythm and autistic-like phenotypes. In the latter mice, no diurnal variation in BDNF levels was observed. These results indicate that regular rhythms of BDNF and NT-3 are essential for correct cortical network formation in juvenile rodents. PMID:21527636

Phase advance of the light-dark cycle perturbs diurnal rhythms of brain-derived neurotrophic factor and neurotrophin-3 protein levels, which reduces synaptophysin-positive presynaptic terminals in the cortex of juvenile rats.

PubMed

Hamatake, Michiko; Miyazaki, Noriko; Sudo, Kaori; Matsuda, Motoko; Sadakata, Tetsushi; Furuya, Asako; Ichisaka, Satoshi; Hata, Yoshio; Nakagawa, Chiaki; Nagata, Koh-ichi; Furuichi, Teiichi; Katoh-Semba, Ritsuko

2011-06-17

In adult rat brains, brain-derived neurotrophic factor (BDNF) rhythmically oscillates according to the light-dark cycle and exhibits unique functions in particular brain regions. However, little is known of this subject in juvenile rats. Here, we examined diurnal variation in BDNF and neurotrophin-3 (NT-3) levels in 14-day-old rats. BDNF levels were high in the dark phase and low in the light phase in a majority of brain regions. In contrast, NT-3 levels demonstrated an inverse phase relationship that was limited to the cerebral neocortex, including the visual cortex, and was most prominent on postnatal day 14. An 8-h phase advance of the light-dark cycle and sleep deprivation induced an increase in BDNF levels and a decrease in NT-3 levels in the neocortex, and the former treatment reduced synaptophysin expression and the numbers of synaptophysin-positive presynaptic terminals in cortical layer IV and caused abnormal BDNF and NT-3 rhythms 1 week after treatment. A similar reduction of synaptophysin expression was observed in the cortices of Bdnf gene-deficient mice and Ca(2+)-dependent activator protein for secretion 2 gene-deficient mice with abnormal free-running rhythm and autistic-like phenotypes. In the latter mice, no diurnal variation in BDNF levels was observed. These results indicate that regular rhythms of BDNF and NT-3 are essential for correct cortical network formation in juvenile rodents.

Embedding of Cortical Representations by the Superficial Patch System

PubMed Central

Da Costa, Nuno M. A.; Girardin, Cyrille C.; Naaman, Shmuel; Omer, David B.; Ruesch, Elisha; Grinvald, Amiram; Douglas, Rodney J.

2011-01-01

Pyramidal cells in layers 2 and 3 of the neocortex of many species collectively form a clustered system of lateral axonal projections (the superficial patch system—Lund JS, Angelucci A, Bressloff PC. 2003. Anatomical substrates for functional columns in macaque monkey primary visual cortex. Cereb Cortex. 13:15–24. or daisy architecture—Douglas RJ, Martin KAC. 2004. Neuronal circuits of the neocortex. Annu Rev Neurosci. 27:419–451.), but the function performed by this general feature of the cortical architecture remains obscure. By comparing the spatial configuration of labeled patches with the configuration of responses to drifting grating stimuli, we found the spatial organizations both of the patch system and of the cortical response to be highly conserved between cat and monkey primary visual cortex. More importantly, the configuration of the superficial patch system is directly reflected in the arrangement of function across monkey primary visual cortex. Our results indicate a close relationship between the structure of the superficial patch system and cortical responses encoding a single value across the surface of visual cortex (self-consistent states). This relationship is consistent with the spontaneous emergence of orientation response–like activity patterns during ongoing cortical activity (Kenet T, Bibitchkov D, Tsodyks M, Grinvald A, Arieli A. 2003. Spontaneously emerging cortical representations of visual attributes. Nature. 425:954–956.). We conclude that the superficial patch system is the physical encoding of self-consistent cortical states, and that a set of concurrently labeled patches participate in a network of mutually consistent representations of cortical input. PMID:21383233

“End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?

PubMed Central

Abner, Erin L.; Kryscio, Richard J.; Schmitt, Frederick A.; SantaCruz, Karen S.; Jicha, Gregory A.; Lin, Yushun; Neltner, Janna M.; Smith, Charles D.; Van Eldik, Linda J.; Nelson, Peter T.

2011-01-01

Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores [MMSE] and clinical ‘dementia’ status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. PMID:21471646

Electrographic waveform structure predicts laminar focus location in a model of temporal lobe seizures in vitro.

PubMed

Adams, Christopher; Adams, Natalie E; Traub, Roger D; Whittington, Miles A

2015-01-01

Temporal lobe epilepsy is the most common form of partial-onset epilepsy and accounts for the majority of adult epilepsy cases in most countries. A critical role for the hippocampus (and to some extent amygdala) in the pathology of these epilepsies is clear, with selective removal of these regions almost as effective as temporal lobectomy in reducing subsequent seizure risk. However, there is debate about whether hippocampus is 'victim' or 'perpetrator': The structure is ideally placed to 'broadcast' epileptiform activity to a great many other brain regions, but removal often leaves epileptiform events still occurring in cortex, particularly in adjacent areas, and recruitment of the hippocampus into seizure-like activity has been shown to be difficult in clinically-relevant models. Using a very simple model of acute epileptiform activity with known, single primary pathology (GABAA Receptor partial blockade), we track the onset and propagation of epileptiform events in hippocampus, parahippocampal areas and neocortex. In this model the hippocampus acts as a potential seizure focus for the majority of observed events. Events with hippocampal focus were far more readily propagated throughout parahippocampal areas and into neocortex than vice versa. The electrographic signature of events of hippocampal origin was significantly different to those of primary neocortical origin - a consequence of differential laminar activation. These data confirm the critical role of the hippocampus in epileptiform activity generation in the temporal lobe and suggest the morphology of non-invasive electrical recording of neocortical interictal events may be useful in confirming this role.

Electrographic Waveform Structure Predicts Laminar Focus Location in a Model of Temporal Lobe Seizures In Vitro

PubMed Central

Adams, Christopher; Adams, Natalie E.; Traub, Roger D.; Whittington, Miles A.

2015-01-01

Temporal lobe epilepsy is the most common form of partial-onset epilepsy and accounts for the majority of adult epilepsy cases in most countries. A critical role for the hippocampus (and to some extent amygdala) in the pathology of these epilepsies is clear, with selective removal of these regions almost as effective as temporal lobectomy in reducing subsequent seizure risk. However, there is debate about whether hippocampus is ‘victim’ or ‘perpetrator’: The structure is ideally placed to ‘broadcast’ epileptiform activity to a great many other brain regions, but removal often leaves epileptiform events still occurring in cortex, particularly in adjacent areas, and recruitment of the hippocampus into seizure-like activity has been shown to be difficult in clinically-relevant models. Using a very simple model of acute epileptiform activity with known, single primary pathology (GABAA Receptor partial blockade), we track the onset and propagation of epileptiform events in hippocampus, parahippocampal areas and neocortex. In this model the hippocampus acts as a potential seizure focus for the majority of observed events. Events with hippocampal focus were far more readily propagated throughout parahippocampal areas and into neocortex than vice versa. The electrographic signature of events of hippocampal origin was significantly different to those of primary neocortical origin – a consequence of differential laminar activation. These data confirm the critical role of the hippocampus in epileptiform activity generation in the temporal lobe and suggest the morphology of non-invasive electrical recording of neocortical interictal events may be useful in confirming this role. PMID:25799020

Feedforward inhibition regulates perirhinal transmission of neocortical inputs to the entorhinal cortex: ultrastructural study in guinea pigs.

PubMed

Pinto, Aline; Fuentes, Cesar; Paré, Denis

2006-04-20

The rhinal cortices constitute the main route for impulse traffic to and from the hippocampus. Tracing studies have revealed that the perirhinal cortex forms strong reciprocal connections with the neo- and entorhinal cortex (EC). However, physiological investigations indicate that perirhinal transmission of neocortical and EC inputs occurs with a low probability. In search of an explanation for these contradictory findings, we have analyzed synaptic connections in this network by combining injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHAL) into the neocortex, area 36, or area 35 with gamma-aminobutyric acid (GABA) immunocytochemistry and electron microscopic observations. Within area 36, neocortical axon terminals formed only asymmetric synapses, usually with GABA-negative spines (87%), and less frequently with GABA-immunopositive (GABA+) dendrites (13%). A similar synaptic distribution was observed within area 35 except that asymmetric synapses onto GABA+ dendrites were more frequent (23% of synapses). Examination of the projections from area 36 to area 35 and from both regions to the EC revealed an even higher incidence of asymmetric synapses onto GABA+ dendrites (35 and 32%, respectively) than what was observed in the neocortical projection to areas 36 and 35. Furthermore, some of the neocortical and perirhinal terminals containing PHAL and GABA immunolabeling formed symmetric synapses onto GABA-negative dendrites in their projection sites (neocortex to area 35, 16%; area 36 to 35, 7%; areas 36-35 to EC, 12%). Taken together, these findings suggest that impulse transmission through the rhinal circuit is subjected to strong inhibitory influences, reconciling anatomical and physiological data about this network.

FEEDFORWARD INHIBITION REGULATES PERIRHINAL TRANSMISSION OF NEOCORTICAL INPUTS TO THE ENTORHINAL CORTEX: ULTRASTRUCTURAL STUDY IN GUINEA PIGS

PubMed Central

Pinto, Aline; Fuentes, Cesar; Paré, Denis

2008-01-01

The rhinal cortices constitute the main route for impulse traffic to and from the hippocampus. Tracing studies have revealed that the perirhinal cortex forms strong reciprocal connections with the neo- and entorhinal cortex (EC). Yet, physiological investigations indicate that perirhinal transmission of neocortical and EC inputs occurs with a low probability. In search of an explanation for these contradictory findings, we have analyzed synaptic connections in this network by combining injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHAL) into the neocortex, area 36, or area 35 with GABA immunocytochemistry and electron microscopic observations. Within area 36, neocortical axon terminals formed only asymmetric synapses, usually with GABA negative spines (87%), and less frequently with GABA immunopositive (GABA+) dendrites (13%). A similar synaptic distribution was observed within area 35 except that asymmetric synapses onto GABA+ dendrites were more frequent (23% of synapses). Examination of the projections from area 36 to area 35 and from both regions to the EC revealed an even higher incidence of asymmetric synapses onto GABA+ dendrites (35% and 32% respectively) than what was observed in the neocortical projection to areas 36 and 35. Furthermore, a proportion of neocortical and perirhinal terminals containing PHAL and GABA immunolabeling formed symmetric synapses onto GABA negative dendrites in their projection sites (neocortex to area 35, 16%; area 36 to 35, 7%; areas 36–35 to EC, 12%). Taken together, these findings suggest that impulse transmission through the rhinal circuit is subjected to strong inhibitory influences, reconciling anatomical and physiological data about this network. PMID:16506192

Zolpidem displays heterogeneity in its binding to the nonhuman primate benzodiazepine receptor in vivo.

PubMed

Schmid, L; Bottlaender, M; Fuseau, C; Fournier, D; Brouillet, E; Mazière, M

1995-10-01

The distinctive pharmacological activity of zolpidem in rats compared with classical benzodiazepines has been related to its differential affinity for benzodiazepine receptor (BZR) subtypes. By contrast, in nonhuman primates the pharmacological activity of zolpidem was found to be quite similar to that of classical BZR agonists. In an attempt to explain this discrepancy, we examined the ability of zolpidem to differentiate BZR subtypes in vivo in primate brain using positron emission tomography. The BZRs were specifically labeled with [11C]flumazenil. Radiotracer displacement by zolpidem was monophasic in cerebellum and neocortex, with in vivo Hill coefficients close to 1. Conversely, displacement of [11C]flumazenil was biphasic in hippocampus, amygdala, septum, insula, striatum, and pons, with Hill coefficients significantly smaller than 1, suggesting two different binding sites for zolpidem. In these cerebral regions, the half-maximal inhibitory doses for the high-affinity binding site were similar to those found in cerebellum and neocortex and approximately 100-fold higher for the low-affinity binding site. The low-affinity binding site accounted for < 32% of the specific [11C]-flumazenil binding. Such zolpidem binding characteristics contrast with those reported for rodents, where three different binding sites were found. Species differences in binding characteristics may explain why zolpidem has a distinctive pharmacological activity in rodents, whereas its pharmacological activity in primates is quite similar to that of classical BZR agonists, except for the absence of severe effects on memory functions, which may be due to the lack of substantial zolpidem affinity for a distinct BZR subtype in cerebral structures belonging to the limbic system.

In vivo characterization of a bigenic fluorescent mouse model of Alzheimer's disease with neurodegeneration.

PubMed

Crowe, Sarah E; Ellis-Davies, Graham C R

2013-07-01

The loss of cognitive function in Alzheimer's disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing "H-line" yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12-14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention. Copyright © 2013 Wiley Periodicals, Inc.

Properties of Contextual Memory Formed in the Absence of αCaMKII Autophosphorylation

PubMed Central

2011-01-01

The alpha-isoform of calcium/calmodulin-dependent kinase II (αCaMKII) is a major synaptic kinase that undergoes autophosphorylation after NMDA receptor activation, switching the kinase into a calcium-independent activity state. This αCaMKII autophosphorylation is essential for NMDA receptor-dependent long-term potentiation (LTP), induced by a single tetanus, in hippocampal area CA1 and in neocortex. Furthermore, the αCaMKII autophosphorylation is essential for contextual long-term memory (LTM) formation after a single training trial but not after a massed training session. Here, we show that in the absence of αCaMKII autophosphorylation contextual fear conditioning is hippocampus dependent and that multi-tetanus-dependent late-LTP cannot be induced in hippocampal area CA1. Furthermore, we show that in the absence of αCaMKII autophosphorylation contextual LTM persists for 30 days, the latest time point tested. Additionally, contextual, but not cued, LTM formation in the absence of αCaMKII autophosphorylation appears to be impaired in 18 month-old mice. Taken together, our findings suggest that αCaMKII autophosphorylation-independent plasticity in the hippocampus is sufficient for contextual LTM formation and that αCaMKII autophosphorylation may be important for delaying age-related impairments in hippocampal memory formation. Furthermore, they propose that NMDA receptor-dependent LTP in hippocampal area CA1 is essential for contextual LTM formation after a single trial but not after massed training. Finally, our results challenge the proposal that NMDA receptor-dependent LTP in neocortex is required for remote contextual LTM. PMID:21276220

Detection and description of non-linear interdependence in normal multichannel human EEG data.

PubMed

Breakspear, M; Terry, J R

2002-05-01

This study examines human scalp electroencephalographic (EEG) data for evidence of non-linear interdependence between posterior channels. The spectral and phase properties of those epochs of EEG exhibiting non-linear interdependence are studied. Scalp EEG data was collected from 40 healthy subjects. A technique for the detection of non-linear interdependence was applied to 2.048 s segments of posterior bipolar electrode data. Amplitude-adjusted phase-randomized surrogate data was used to statistically determine which EEG epochs exhibited non-linear interdependence. Statistically significant evidence of non-linear interactions were evident in 2.9% (eyes open) to 4.8% (eyes closed) of the epochs. In the eyes-open recordings, these epochs exhibited a peak in the spectral and cross-spectral density functions at about 10 Hz. Two types of EEG epochs are evident in the eyes-closed recordings; one type exhibits a peak in the spectral density and cross-spectrum at 8 Hz. The other type has increased spectral and cross-spectral power across faster frequencies. Epochs identified as exhibiting non-linear interdependence display a tendency towards phase interdependencies across and between a broad range of frequencies. Non-linear interdependence is detectable in a small number of multichannel EEG epochs, and makes a contribution to the alpha rhythm. Non-linear interdependence produces spatially distributed activity that exhibits phase synchronization between oscillations present at different frequencies. The possible physiological significance of these findings are discussed with reference to the dynamical properties of neural systems and the role of synchronous activity in the neocortex.

Cortical influences drive amyotrophic lateral sclerosis.

PubMed

Eisen, Andrew; Braak, Heiko; Del Tredici, Kelly; Lemon, Roger; Ludolph, Albert C; Kiernan, Matthew C

2017-11-01

The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Rapid language-related plasticity: microstructural changes in the cortex after a short session of new word learning.

PubMed

Hofstetter, Shir; Friedmann, Naama; Assaf, Yaniv

2017-04-01

Human brain imaging revealed that the brain can undergo structural plasticity following new learning experiences. Most magnetic resonance imaging (MRI) uncovered morphometric alternation in cortical density after the long-term training of weeks to months. A recent diffusion tensor imaging (DTI) study has found changes in diffusion indices after 2 h of training, primarily in the hippocampus. However, whether a short learning experience can induce microstructural changes in the neocortex is still unclear. Here, we used diffusion MRI, a method sensitive to tissue microstructure, to study cortical plasticity. To attain cortical involvement, we used a short language task (under 1 h) of introducing new lexical items (flower names) to the lexicon. We have found significant changes in diffusivity in cortical regions involved in language and reading (inferior frontal gyrus, middle temporal gyrus, and inferior parietal lobule). In addition, the difference in the values of diffusivity correlated with the lexical learning rate in the task. Moreover, significant changes were found in white matter tracts near the cortex, and the extent of change correlated with behavioral measures of lexical learning rate. These findings provide first evidence of short-term cortical plasticity in the human brain after a short language learning task. It seems that short training of less than an hour of high cognitive demand can induce microstructural changes in the cortex, suggesting a rapid time scale of neuroplasticity and providing additional evidence of the power of MRI to investigate the temporal and spatial progressions of this process.

Inflammation occurs early during the Abeta deposition process in TgCRND8 mice.

PubMed

Dudal, Sherri; Krzywkowski, Pascale; Paquette, Julie; Morissette, Céline; Lacombe, Diane; Tremblay, Patrick; Gervais, Francine

2004-08-01

Alzheimer's disease (AD) is characterized by a progressive cognitive decline leading to dementia and involves the deposition of amyloid-beta (Abeta) peptides into senile plaques. Other neuropathological features that accompany progression of the disease include a decrease in synaptic density, neurofibrillary tangles, dystrophic neurites, inflammation, and neuronal cell loss. In this study, we report the early kinetics of brain amyloid deposition and its associated inflammation in an early onset transgenic mouse model of AD (TgCRND8) harboring the human amyloid precursor protein gene with the Indiana and Swedish mutations. Both diffuse and compact plaques were detected as early as 9-10 weeks of age. Abeta-immunoreactive (Abeta-IR) plaques (4G8-positive) appeared first in the neocortex and amygdala, then in the hippocampal formation, and lastly in the thalamus. Compact plaques (ThioS-positive) with an amyloid core were observed as early as diffuse plaques were detected, but in lower numbers. Amyloid deposition increased progressively with age. The formation of plaques was concurrent with the appearance of activated microglial cells and shortly followed by the clustering of activated astrocytes around plaques at 13-14 weeks of age. This TgCRND8 mouse model allows for a rapid, time-dependent study of the relationship between the fibrillogenic process and the inflammatory response during the brain amyloidogenic process.

Impaired visual search in rats reveals cholinergic contributions to feature binding in visuospatial attention.

PubMed

Botly, Leigh C P; De Rosa, Eve

2012-10-01

The visual search task established the feature integration theory of attention in humans and measures visuospatial attentional contributions to feature binding. We recently demonstrated that the neuromodulator acetylcholine (ACh), from the nucleus basalis magnocellularis (NBM), supports the attentional processes required for feature binding using a rat digging-based task. Additional research has demonstrated cholinergic contributions from the NBM to visuospatial attention in rats. Here, we combined these lines of evidence and employed visual search in rats to examine whether cortical cholinergic input supports visuospatial attention specifically for feature binding. We trained 18 male Long-Evans rats to perform visual search using touch screen-equipped operant chambers. Sessions comprised Feature Search (no feature binding required) and Conjunctive Search (feature binding required) trials using multiple stimulus set sizes. Following acquisition of visual search, 8 rats received bilateral NBM lesions using 192 IgG-saporin to selectively reduce cholinergic afferentation of the neocortex, which we hypothesized would selectively disrupt the visuospatial attentional processes needed for efficient conjunctive visual search. As expected, relative to sham-lesioned rats, ACh-NBM-lesioned rats took significantly longer to locate the target stimulus on Conjunctive Search, but not Feature Search trials, thus demonstrating that cholinergic contributions to visuospatial attention are important for feature binding in rats.

Environmental Enrichment Reveals Effects of Genotype on Hippocampal Spine Morphologies in the Mouse Model of Fragile X Syndrome

PubMed Central

Lauterborn, Julie C.; Jafari, Matiar; Babayan, Alex H.; Gall, Christine M.

2015-01-01

Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS. PMID:24046080

A Critical Evaluation of the Gamma-Hydroxybutyrate (GHB) Model of Absence Seizures

PubMed Central

Venzi, Marcello; Di Giovanni, Giuseppe; Crunelli, Vincenzo

2015-01-01

Typical absence seizures (ASs) are nonconvulsive epileptic events which are commonly observed in pediatric and juvenile epilepsies and may be present in adults suffering from other idiopathic generalized epilepsies. Our understanding of the pathophysiological mechanisms of ASs has been greatly advanced by the availability of genetic and pharmacological models, in particular the γ-hydroxybutyrate (GHB) model which, in recent years, has been extensively used in studies in transgenic mice. GHB is an endogenous brain molecule that upon administration to various species, including humans, induces not only ASs but also a state of sedation/hypnosis. Analysis of the available data clearly indicates that only in the rat does there exist a set of GHB-elicited behavioral and EEG events that can be confidently classified as ASs. Other GHB activities, particularly in mice, appear to be mostly of a sedative/hypnotic nature: thus, their relevance to ASs requires further investigation. At the molecular level, GHB acts as a weak GABA-B agonist, while the existence of a GHB receptor remains elusive. The pre- and postsynaptic actions underlying GHB-elicited ASs have been thoroughly elucidated in thalamus, but little is known about the cellular/network effects of GHB in neocortex, the other brain region involved in the generation of ASs. PMID:25403866

Perspectives on fear generalization and its implications for emotional disorders.

PubMed

Jasnow, Aaron M; Lynch, Joseph F; Gilman, T Lee; Riccio, David C

2017-03-01

Although generalization to conditioned stimuli is not a new phenomenon, renewed interest in understanding its biological underpinning has stemmed from its association with a number of anxiety disorders. Generalization as it relates to fear processing is a temporally dynamic process in which animals, including humans, display fear in response to similar yet distinct cues or contexts as the time between training and testing increases. This Review surveys the literature on contextual fear generalization and its relation to several views of memory, including systems consolidation, forgetting, and transformation hypothesis, which differentially implicate roles of the hippocampus and neocortex in memory consolidation and retrieval. We discuss recent evidence on the neurobiological mechanisms contributing to the increase in fear generalization over time and how generalized responding may be modulated by acquisition, consolidation, and retrieval mechanisms. Whereas clinical perspectives of generalization emphasize a lack of fear inhibition to CS - cues or fear toward intermediate CS cues, the time-dependent nature of generalization and its relation to traditional views on memory consolidation and retrieval are often overlooked. Understanding the time-dependent increase in fear generalization has important implications not only for understanding how generalization contributes to anxiety disorders but also for understanding basic long-term memory function. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome

PubMed Central

Goodliffe, Joseph W.; Olmos-Serrano, Jose Luis; Aziz, Nadine M.; Pennings, Jeroen L.A.; Guedj, Faycal; Bianchi, Diana W.

2016-01-01

Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. SIGNIFICANCE STATEMENT Down syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral deficits after the first 2 postnatal weeks. These results uncover important differences in prenatal phenotype between Dp16 animals and humans with DS and other DS mouse models. PMID:26961948

High-throughput imaging of adult fluorescent zebrafish with an LED fluorescence macroscope

PubMed Central

Blackburn, Jessica S; Liu, Sali; Raimondi, Aubrey R; Ignatius, Myron S; Salthouse, Christopher D; Langenau, David M

2011-01-01

Zebrafish are a useful vertebrate model for the study of development, behavior, disease and cancer. A major advantage of zebrafish is that large numbers of animals can be economically used for experimentation; however, high-throughput methods for imaging live adult zebrafish had not been developed. Here, we describe protocols for building a light-emitting diode (LED) fluorescence macroscope and for using it to simultaneously image up to 30 adult animals that transgenically express a fluorescent protein, are transplanted with fluorescently labeled tumor cells or are tagged with fluorescent elastomers. These protocols show that the LED fluorescence macroscope is capable of distinguishing five fluorescent proteins and can image unanesthetized swimming adult zebrafish in multiple fluorescent channels simultaneously. The macroscope can be built and used for imaging within 1 day, whereas creating fluorescently labeled adult zebrafish requires 1 hour to several months, depending on the method chosen. The LED fluorescence macroscope provides a low-cost, high-throughput method to rapidly screen adult fluorescent zebrafish and it will be useful for imaging transgenic animals, screening for tumor engraftment, and tagging individual fish for long-term analysis. PMID:21293462

Pontine cholinergic reticular mechanisms cause state-dependent changes in the discharge of parabrachial neurons.

PubMed

Gilbert, K A; Lydic, R

1994-01-01

The present study examined the hypothesis that cholinoceptive reticular mechanisms in the gigantocellular tegmental field (FTG) of the medial pontine reticular formation cause state-dependent changes in the discharge of parabrachial neurons. In chronically implanted, unanesthetized cats, extracellular recordings were made from nonrespiratory and respiratory neurons in the parabrachial nuclear complex (PBNC) during the natural sleep-wake cycle and during the rapid eye movement (REM) sleeplike state caused by FTG microinjection of carbachol or neostigmine. PBNC cells that increased discharge during natural REM sleep (REM-on cells) revealed similar increased discharge during the carbachol-induced REM sleeplike state (DCarb). Cells that decreased discharge in natural REM sleep (REM-off cells) displayed decreased discharge during both DCarb and the neostigmine-induced REM sleeplike states. The limited sample of parabrachial respiratory neurons revealed significantly diminished discharge during the cholinergically induced REM sleeplike state. Thus cholinoceptive mechanisms localized to specific regions of the pontine reticular formation can cause state-dependent changes in the firing rates of respiratory and nonrespiratory neurons in the PBNC.

Multimodal sensory responses of nucleus reticularis gigantocellularis and the responses' relation to cortical and motor activation.

PubMed

Martin, Eugene M; Pavlides, Constantine; Pfaff, Donald

2010-05-01

The connectivity of large neurons of the nucleus reticularis gigantocellularis (NRGc) in the medullary reticular formation potentially allows both for the integration of stimuli, in several modalities, that would demand immediate action, and for coordinated activation of cortical and motoric activity. We have simultaneously recorded cortical local field potentials, neck muscle electromyograph (EMG), and the neural activity of medullary NRGc neurons in unrestrained, unanesthetized rats to determine whether the activity of the NRGc is consistent with the modulation of general arousal. We observed excitatory responses of individual NRGc neurons to all modalities tested: tactile, visual, auditory, vestibular, and olfactory. Excitation was directly linked to increases in neck muscle EMG amplitude and corresponded with increases in the power of fast oscillations (30 to 80 Hz) of cortical activity and decreases in the power of slow oscillations (2 to 8 Hz). Because these reticular formation neurons can respond to broad ranges of stimuli with increased firing rates associated with the initiation of behavioral responses, we infer that they are part of an elementary "first responder" CNS arousal mechanism.

Multimodal Sensory Responses of Nucleus Reticularis Gigantocellularis and the Responses' Relation to Cortical and Motor Activation

PubMed Central

Pavlides, Constantine; Pfaff, Donald

2010-01-01

The connectivity of large neurons of the nucleus reticularis gigantocellularis (NRGc) in the medullary reticular formation potentially allows both for the integration of stimuli, in several modalities, that would demand immediate action, and for coordinated activation of cortical and motoric activity. We have simultaneously recorded cortical local field potentials, neck muscle electromyograph (EMG), and the neural activity of medullary NRGc neurons in unrestrained, unanesthetized rats to determine whether the activity of the NRGc is consistent with the modulation of general arousal. We observed excitatory responses of individual NRGc neurons to all modalities tested: tactile, visual, auditory, vestibular, and olfactory. Excitation was directly linked to increases in neck muscle EMG amplitude and corresponded with increases in the power of fast oscillations (30 to 80 Hz) of cortical activity and decreases in the power of slow oscillations (2 to 8 Hz). Because these reticular formation neurons can respond to broad ranges of stimuli with increased firing rates associated with the initiation of behavioral responses, we infer that they are part of an elementary “first responder” CNS arousal mechanism. PMID:20181730

A restraint-free small animal SPECT imaging system with motion tracking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weisenberger, A.G.; Gleason, S.S.; Goddard, J.

2005-06-01

We report on an approach toward the development of a high-resolution single photon emission computed tomography (SPECT) system to image the biodistribution of radiolabeled tracers such as Tc-99m and I-125 in unrestrained/unanesthetized mice. An infrared (IR)-based position tracking apparatus has been developed and integrated into a SPECT gantry. The tracking system is designed to measure the spatial position of a mouse's head at a rate of 10-15 frames per second with submillimeter accuracy. The high-resolution, gamma imaging detectors are based on pixellated NaI(Tl) crystal scintillator arrays, position-sensitive photomultiplier tubes, and novel readout circuitry requiring fewer analog-digital converter (ADC) channels whilemore » retaining high spatial resolution. Two SPECT gamma camera detector heads based upon position-sensitive photomultiplier tubes have been built and installed onto the gantry. The IR landmark-based pose measurement and tracking system is under development to provide animal position data during a SPECT scan. The animal position and orientation data acquired by the tracking system will be used for motion correction during the tomographic image reconstruction.« less

Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep.

PubMed

Kuratomi, Y; Lefferts, P L; Christman, B W; Parker, R E; Smith, W G; Mueller, R A; Snapper, J R

1993-02-01

We studied the effects of a 5-lipoxygenase inhibitor, SC-45662, on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. Each sheep was studied with endotoxin alone, SC-45662 alone, and endotoxin after SC-45662 pretreatment. Endotoxin did not cause consistent increases in plasma or lung lymph concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood from sheep before and after treatment with SC-45662 demonstrated no inhibition of cyclooxygenase metabolism but an approximately 80% inhibition of LTB4 production. At drug concentrations obtained in vivo, SC-45662 did not significantly inhibit in vitro A23187-stimulated whole blood thromboxane B2 production but did inhibit LTB4 production from ionophore-stimulated sheep granulocytes. SC-45662 attenuated the early changes in lung mechanics and pulmonary hypertension but did not attenuate the later increase in lung fluid and solute exchange observed after endotoxemia. We conclude that 5-lipoxygenase products are not measurably involved in the later increase in lung fluid and solute exchange observed after endotoxemia in sheep.

[Evolution of superolateral surface of the cerebral hemisphere on 16-21 weeks fetus].

PubMed

Varlam, H; St Antohe, D

2002-01-01

Edification of neocortex is accompanied by the development and growth of the cerebral hemisphere, both processes being part of the more complex one, known under the name of telencephalization. The expression of this process is more acute on the superolateral surface of the cerebral hemisphere that expands laterally by growth of the frontal, temporal and parietal lobes. We describe the modifications of shape and deepness of the lateral cerebral fossa including the stages of its closure. We consider this event as the beginning of the appearance of gyri and sulci on the superolateral surface of the cerebral hemisphere.

ProBDNF Signaling Regulates Depression-Like Behaviors in Rodents under Chronic Stress.

PubMed

Bai, Yin-Yin; Ruan, Chun-Sheng; Yang, Chun-Rui; Li, Jia-Yi; Kang, Zhi-Long; Zhou, Li; Liu, Dennis; Zeng, Yue-Qing; Wang, Ting-Hua; Tian, Chang-Fu; Liao, Hong; Bobrovskaya, Larisa; Zhou, Xin-Fu

2016-11-01

Chronic exposure to stressful environment is a key risk factor contributing to the development of depression. However, the mechanisms involved in this process are still unclear. Brain-derived neurotropic factor (BDNF) has long been investigated for its positive role in regulation of mood, although the role of its precursor, proBDNF, in regulation of mood is not known. In this study, using an unpredictable chronic mild stress (UCMS) paradigm we found that the protein levels of proBDNF were increased in the neocortex and hippocampus of stressed mice and this UCMS-induced upregulation of proBDNF was abolished by chronic administration of fluoxetine. We then established a rat model of UCMS and found that the expression of proBDNF/p75 NTR /sortilin was upregulated, whereas the expression of mature BDNF and TrkB was downregulated in both neocortex and hippocampus of chronically stressed rats. Finally, we found that the injection of anti-proBDNF antibody via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) approaches into the UCMS rats significantly reversed the stress-induced depression-like behavior and restored the exploratory activity and spine growth. Although intramuscular injection of AAV-proBDNF did not exacerbate the UCMS-elicited rat mood-related behavioral or pathological abnormalities, i.c.v. injection of AAV-proBDNF increased the depression-like behavior in naive rats. Our findings suggest that proBDNF plays a role in the development of chronic stress-induced mood disturbances in rodents. Central (i.c.v.) or peripheral (i.p.) inhibition of proBDNF by injecting specific anti-proBDNF antibodies may provide a novel therapeutic approach for the treatment of stress-related mood disorders.

[Ornithine decarboxylase in mammalian organs and tissues at hibernation and artificial hypobiosis].

PubMed

Logvinovich, O S; Aksenova, G E

2013-01-01

Ornithine decarboxylase (ODC, EC 4.1.1.17.) is a short-lived and dynamically regulated enzyme of polyamines biosynthesis. Regulation of functional, metabolic and proliferative state of organs and tissues involves the modifications of the ODC enzymatic activity. The organ-specific changes in ODC activity were revealed in organs and tissues (liver, spleen, bone marrow, kidney, and intestinal mucosa) of hibernating mammals - squirrels Spermophilus undulates - during the hibernating season. At that, a positive correlation was detected between the decline and recovery of the specialized functions of organs and tissues and the respective modifications of ODC activity during hibernation bouts. Investigation of changes in ODC activity in organs and tissues of non-hibernating mammals under artificial hypobiosis showed that in Wistar rats immediately after exposure to hypothermia-hypoxia-hypercapnia (hypobiosis) the level of ODC activity was low in thymus, spleen, small intestine mucosa, neocortex, and liver. The most marked reduction in enzyme activity was observed in actively proliferating tissues: thymus, spleen, small intestine mucosa. In bone marrow of squirrels, while in a state of torpor, as well as in thymus of rats after exposure to hypothermia-hypoxia-hypercapnia, changes in the ODC activity correlated with changes in the rate of cell proliferation (by the criterion of cells distribution over cell cycle). The results obtained, along with the critical analysis of published data, indicate that the ODC enzyme is involved in biochemical adaptation of mammals to natural and artificial hypobiosis. A decline in the ODC enzymatic activity indicates a decline in proliferative, functional, and metabolic activity of organs and tissues of mammals (bone marrow, mucosa of small intestine, thymus, spleen, neocortex, liver, kidneys) when entering the state of hypobiosis.

Ornithine decarboxylase activity in rat organs and tissues under artificial hypobiosis.

PubMed

Aksyonova, G E; Logvinovich, O S; Fialkovskaya, L A; Afanasyev, V N; Ignat'ev, D A; Kolomiytseva, I K

2010-09-01

The influence of hypothermia-hypoxia-hypercapnia on ornithine decarboxylase (ODC, EC 4.1.1.17) activities in rat organs and tissues and also on the thymocyte distribution throughout the cell cycle stages was studied. The state of artificial hypobiosis in rats on decrease in the body temperature to 14.4-18.0°C during 3.0-3.5 h was accompanied by drops in the ODC activities in the neocortex and liver by 50-60% and in rapidly proliferating tissues (thymus, spleen, and small intestine mucosa) by 80% of the control value. In kidneys the ODC activity raised to 200% of the control level. Twenty-four hours after termination of the cooling and replacing the rats under the standard conditions, the ODC activities in the neocortex, liver, kidneys, spleen, and intestinal mucosa returned to the control values, but remained decreased in the thymus. Forty-eight hours later the ODC activities in the thymus and spleen exceeded the normal level. The distribution of thymocytes throughout the cell cycle stages did not change in rats in the state of hypothermia (hypobiosis); 24 and 48 h after termination of the cooling the fraction of thymocytes in the S stage was decreased and the fraction of the cells in the G(0)+G(1) stage was increased. The normal distribution of thymocytes throughout the cell cycle stages recovered in 72 h. Thus, in the thymus the diminution of the ODC activity preceded the suppression of the cell proliferation rate. The tissue-specific changes in the ODC activity are suggested to reflect adaptive changes in the functional and proliferative activities of organs and tissues during the development of hypobiosis under conditions of hypothermia-hypoxia-hypercapnia.

Molecular analysis of neocortical layer structure in the ferret

PubMed Central

Rowell, Joanna J.; Mallik, Atul K.; Dugas-Ford, Jennifer; Ragsdale, Clifton W.

2010-01-01

Molecular markers that distinguish specific layers of rodent neocortex are increasingly employed to study cortical development and the physiology of cortical circuits. The extent to which these markers represent general features of neocortical cell type identity across mammals is, however, unknown. To assess the conservation of layer markers more broadly, we isolated orthologs for fifteen layer-enriched genes in the ferret, a carnivore with a large, gyrencephalic brain, and analyzed their patterns of neocortical gene expression. Our major findings are: (1) Many but not all layer markers tested show similar patterns of layer-specific gene expression between mouse and ferret cortex, supporting the view that layer-specific cell type identity is conserved at a molecular level across mammalian superorders; (2) Our panel of deep layer markers (ER81/ETV1, SULF2, PCP4, FEZF2/ZNF312, CACNA1H, KCNN2/SK2, SYT6, FOXP2, CTGF) provides molecular evidence that the specific stratifications of layer 5 and 6 into 5a, 5b, 6a and 6b are also conserved between rodents and carnivores. (3) Variations in layer-specific gene expression are more pronounced across areas of ferret cortex than between homologous areas of mouse and ferret cortex; (4) This variation of area gene expression was clearest with the superficial layer markers studied (SERPINE2, MDGA1, CUX1, UNC5D, RORB/NR1F2, EAG2/KCNH5). Most dramatically, the layer 4 markers RORB and EAG2 disclosed a molecular sublamination to ferret visual cortex and demonstrated a molecular dissociation among the so-called agranular areas of the neocortex. Our findings establish molecular markers as a powerful complement to cytoarchitecture for neocortical layer and cell-type comparisons across mammals. PMID:20575059

The G1 restriction point as critical regulator of neocortical neuronogenesis

NASA Technical Reports Server (NTRS)

Caviness, V. S. Jr; Takahashi, T.; Nowakowski, R. S.

1999-01-01

Neuronogenesis in the pseudostratified ventricular epithelium is the initial process in a succession of histogenetic events which give rise to the laminate neocortex. Here we review experimental findings in mouse which support the thesis that the restriction point of the G1 phase of the cell cycle is the critical point of regulation of the overall neuronogenetic process. The neuronogenetic interval in mouse spans 6 days. In the course of these 6 days the founder population and its progeny execute 11 cell cycles. With each successive cycle there is an increase in the fraction of postmitotic cells which leaves the cycle (the Q fraction) and also an increase in the length of the cell cycle due to an increase in the length of the G1 phase of the cycle. Q corresponds to the probability that postmitotic cells will exit the cycle at the restriction point of the G1 phase of the cell cycle. Q increases non-linearly, but the rate of change of Q with cycle (i.e., the first derivative) over the course of the neuronogenetic interval is a constant, k, which appears to be set principally by cell internal mechanisms which are species specific. Q also seems to be modulated, but at low amplitude, by a balance of mitogenic and antimitogenic influences acting from without the cell. We suggest that intracellular signal transduction systems control a general advance of Q during development and thereby determine the general developmental plan (i.e., cell number and laminar composition) of the neocortex and that external mitogens and anti-mitogens modulate this advance regionally and temporally and thereby produce regional modifications of the general plan.

Increased Vulnerability of the Hippocampus in Transgenic Mice Overexpressing APP and Triple Repeat Tau.

PubMed

Arner, Andrew; Rockenstein, Edward; Mante, Michael; Florio, Jazmin; Masliah, Deborah; Salehi, Bahar; Adame, Anthony; Overk, Cassia; Masliah, Eliezer; Rissman, Robert A

2018-01-01

 Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions.

Characterization of cortical neuronal and glial alterations during culture of organotypic whole brain slices from neonatal and mature mice.

PubMed

Staal, Jerome A; Alexander, Samuel R; Liu, Yao; Dickson, Tracey D; Vickers, James C

2011-01-01

Organotypic brain slice culturing techniques are extensively used in a wide range of experimental procedures and are particularly useful in providing mechanistic insights into neurological disorders or injury. The cellular and morphological alterations associated with hippocampal brain slice cultures has been well established, however, the neuronal response of mouse cortical neurons to culture is not well documented. In the current study, we compared the cell viability, as well as phenotypic and protein expression changes in cortical neurons, in whole brain slice cultures from mouse neonates (P4-6), adolescent animals (P25-28) and mature adults (P50+). Cultures were prepared using the membrane interface method. Propidium iodide labeling of nuclei (due to compromised cell membrane) and AlamarBlue™ (cell respiration) analysis demonstrated that neonatal tissue was significantly less vulnerable to long-term culture in comparison to the more mature brain tissues. Cultures from P6 animals showed a significant increase in the expression of synaptic markers and a decrease in growth-associated proteins over the entire culture period. However, morphological analysis of organotypic brain slices cultured from neonatal tissue demonstrated that there were substantial changes to neuronal and glial organization within the neocortex, with a distinct loss of cytoarchitectural stratification and increased GFAP expression (p<0.05). Additionally, cultures from neonatal tissue had no glial limitans and, after 14 DIV, displayed substantial cellular protrusions from slice edges, including cells that expressed both glial and neuronal markers. In summary, we present a substantial evaluation of the viability and morphological changes that occur in the neocortex of whole brain tissue cultures, from different ages, over an extended period of culture.