Modeling realistic synaptic inputs of CA1 hippocampal pyramidal neurons and interneurons via Adaptive Generalized Leaky Integrate-and-Fire models.

Computational models of brain regions are crucial for understanding neuronal network dynamics and the emergence of cognitive functions. However, current supercomputing limitations hinder the implementation of large networks with millions of morphological and biophysical accurate neurons. Consequently, research has focused on simplified spiking neuron models, ranging from the computationally fast Leaky Integrate and Fire (LIF) linear models to more sophisticated non-linear implementations like Adaptive Exponential (AdEX) and Izhikevic models, through Generalized Leaky Integrate and Fire (GLIF) approaches. However, in almost all cases, these models are tuned (and can be validated) only under constant current injections and they may not, in general, also reproduce experimental findings under variable currents. This study introduces an Adaptive GLIF (A-GLIF) approach that addresses this limitation by incorporating a new set of update rules. The extended A-GLIF model successfully reproduces both constant and variable current inputs, and it was validated against the results obtained using a biophysical accurate model neuron. This enhancement provides researchers with a tool to optimize spiking neuron models using classic experimental traces under constant current injections, reliably predicting responses to synaptic inputs, which can be confidently used for large-scale network implementations.

Mathematical generation of data-driven hippocampal CA1 pyramidal neurons and interneurons copies via A-GLIF models for large-scale networks covering the experimental variability range.

Efficient and accurate large-scale networks are a fundamental tool in modeling brain areas, to advance our understanding of neuronal dynamics. However, their implementation faces two key issues: computational efficiency and heterogeneity. Computational efficiency is achieved using simplified neurons, whereas there are no practical solutions available to solve the problem of reproducing in a large-scale network the experimentally observed heterogeneity of the intrinsic properties of neurons. This is important, because the use of identical nodes in a network can generate artifacts which can hinder an adequate representation of the properties of a real network. To this aim, we introduce a mathematical procedure to generate an arbitrary large number of copies of simplified hippocampal CA1 pyramidal neurons and interneurons models, which exhibit the full range of firing dynamics observed in these cells - including adapting, non-adapting and bursting. For this purpose, we rely on a recently published adaptive generalized leaky integrate-and-fire (A-GLIF) modeling approach, leveraging on its ability to reproduce the rich set of electrophysiological behaviors of these types of neurons under a variety of different stimulation currents. The generation procedure is based on a perturbation of model's parameters related to the initial data, firing block, and internal dynamics, and suitably validated against experimental data to ensure that the firing dynamics of any given cell copy remains within the experimental range. A classification procedure confirmed that the firing behavior of most of the pyramidal/interneuron copies was consistent with the experimental data. This approach allows to obtain heterogeneous copies with mathematically controlled firing properties. A full set of heterogeneous neurons composing the CA1 region of a rat hippocampus (approximately 1.2 million neurons), are provided in a database freely available in the live paper section of the EBRAINS platform. By adapting the underlying A-GLIF framework, it will be possible to extend the numerical approach presented here to create, in a mathematically controlled manner, an arbitrarily large number of non-identical copies of cell populations with firing properties related to other brain areas.

The role of network connectivity on epileptiform activity.

A number of potentially important mechanisms have been identified as key players to generate epileptiform activity, such as genetic mutations, activity-dependent alteration of synaptic functions, and functional network reorganization at the macroscopic level. Here we study how network connectivity at cellular level can affect the onset of epileptiform activity, using computational model networks with different wiring properties. The model suggests that networks connected as in real brain circuits are more resistant to generate seizure-like activity. The results suggest new experimentally testable predictions on the cellular network connectivity in epileptic individuals, and highlight the importance of using the appropriate network connectivity to investigate epileptiform activity with computational models.

The REAL (REctal Anastomotic Leak) score for prediction of anastomotic leak after rectal cancer surgery.

BACKGROUND: Anastomotic leak after rectal cancer surgery is a severe complication associated with poorer oncologic outcome and quality of life. Preoperative assessment of the risk for anastomotic leak is a key component of surgical planning, including the opportunity to create a defunctioning stoma. OBJECTIVE: The purpose of this study was to identify and quantify the risk factors for anastomotic leak to minimize risk by either not restoring bowel continuity or protecting the anastomosis with a temporary diverting stoma. METHODS: Potentially relevant studies were identified from the following databases: PubMed, Embase and Cochrane Library. This meta-analysis included studies on transabdominal resection for rectal cancer that reported data about anastomotic leak. The risk for anastomotic leak after rectal cancer surgery was investigated. Preoperative, intraoperative, and postoperative factors were extracted and used to compare anastomotic leak rates. All variables demonstrating a p value < 0.1 in the univariate analysis were entered into a multivariate logistic regression model to determine the risk factors for anastomotic leak. RESULTS: Twenty-six centers provided individual data on 9735 patients. Selected preoperative covariates (time before surgery, age, gender, smoking, previous abdominal surgery, BMI, diabetes, ASA, hemoglobin level, TNM classification stage, anastomotic distance) were used as independent factors in a logistic regression model with anastomotic leak as dependent variable. With a threshold value of the receiver operating characteristics (ROC) curve corresponding to 0.0791 in the training set, the area under the ROC curve (AUC) was 0.585 (p < 0.0001). Sensitivity and specificity of the model's probability > 0.0791 to identify anastomotic leak were 79.1% and 32.9%, respectively. Accuracy of the threshold value was confirmed in the validation set with 77.8% sensitivity and 35.2% specificity. CONCLUSIONS: We trust that, with further refinement using prospective data, this nomogram based on preoperative risk factors may assist surgeons in decision making. The score is now available online ( http://www.real-score.org ).

Morphofunctional alterations in ventral tegmental area dopamine neurons in acute and prolonged opiates withdrawal. A computational perspective.

Dopamine (DA) neurons of the ventral tegmental area (VTA) play a key role in the neurobiological basis of goal-directed behaviors and addiction. Morphine (MOR) withdrawal induces acute and long-term changes in the morphology and physiology of VTA DA cells, but the mechanisms underlying these modifications are poorly understood. Because of their predictive value, computational models are a powerful tool in neurobiological research, and are often used to gain further insights and deeper understanding on the molecular and physiological mechanisms underlying the development of various psychiatric disorders. Here we present a biophysical model of a DA VTA neuron based on 3D morphological reconstruction and electrophysiological data, showing how opiates withdrawal-driven morphological and electrophysiological changes could affect the firing rate and discharge pattern. The model findings suggest how and to what extent a change in the balance of GABA/GLU inputs can take into account the experimentally observed hypofunction of VTA DA neurons during acute and prolonged withdrawal, whereas morphological changes may play a role in the increased excitability of VTA DA cell to opiate administration observed during opiate withdrawal.

Intranasal administration of glial-derived neurotrophic factor (GDNF) rapidly and significantly increases whole-brain GDNF level in rats.

Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) exerts significant neuroprotective effects on substantia nigra (SN) neurons in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this study we used enzyme-linked immunosorbent assay (ELISA) to determine GDNF brain levels and distribution to target regions (i.e. striatum and SN) following intranasal administration of GDNF at different time points after administration. Brain levels increased significantly within 1h following a single 50-µg dose of GDNF in a liposomal formulation, returning to baseline by 24h. In a second study, different doses of GDNF (10-150 µg) in phosphate-buffered saline (PBS) were studied at the 1-h time point. Dose-dependent increases in brain GDNF levels were observed with apparent saturation of uptake at doses above 100 µg. Liposomes delivered 10-fold more GDNF to brain than PBS despite yielding similar neuroprotective efficacy in the 6-OHDA model, suggesting incomplete release of GDNF from liposomes in tissue. In a third study, autoradiography was performed on brain sections taken 1h after intranasal (125)I-labeled GDNF. Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD.

Tracing the trajectory of behavioral impairments and oxidative stress in an animal model of neonatal inflammation.

Exposure to early-life inflammation results in time-of-challenge-dependent changes in both brain and behavior. The consequences of this neural and behavioral reprogramming are most often reported in adulthood. However, the trajectory for the expression of these various changes is not well delineated, particularly between the juvenile and adult phases of development. Moreover, interventions to protect against these neurodevelopmental disruptions are rarely evaluated. Here, female Sprague-Dawley rats were housed in either environmental enrichment (EE) or standard care (SC) and their male and female offspring were administered 50 µg/kg i.p. of lipopolysaccharide (LPS) or pyrogen-free saline in a dual-administration neonatal protocol. All animals maintained their respective housing assignments from breeding until the end of the study. LPS exposure on postnatal days (P) 3 and 5 of life resulted in differential expression of emotional and cognitive disruptions and evidence of oxidative stress across development. Specifically, social behavior was reduced in neonatal-treated (n)LPS animals at adolescence (P40), but not adulthood (P70). In contrast, male nLPS rats exhibited intact spatial memory as adolescents which was impaired in later life. Moreover, these males had decreased prefrontal cortex levels of glutathione at P40, which was normalized in adult animals. Notably, EE appeared to offer some protection against the consequences of inflammation on juvenile social behavior and fully prevented reduced glutathione levels in the juvenile prefrontal cortex. Combined, these time-dependent effects provide evidence that early-life inflammation interacts with other developmental variables, specifically puberty and EE, in the expression (and prevention) of select behavioral and molecular programs.

Environmental enrichment models a naturalistic form of maternal separation and shapes the anxiety response patterns of offspring.

Environmental enrichment (EE) mimics positive life experiences by providing enhanced social and physical stimulation. Placement into EE following weaning, or in later life, confers beneficial outcomes on both emotional and cognitive processes. However, anxiety-like behavior is also reported, particularly in rats exposed to enhanced housing during early development. Notably, the quality of maternal behavior affects stress regulation and emotional stability in offspring, yet the impact of environmental context on maternal care has not been thoroughly evaluated, or are the influences of EE on their offspring understood. To investigate the role of EE on these factors we analyzed the details of mother-neonate interactions, and juvenile offspring performance on several anxiety measures. Additionally, we evaluated neurochemical differences (i.e. serotonin, corticosterone, GABA, glutamate) in prefrontal cortex and hippocampus as a function of EE, Communal Nesting (CN) and Standard Care (SC). Although EE dams spent significantly less time on the nest and had lower nursing frequencies compared to SC dams, there were no differences in maternal licking/grooming. In offspring, EE increased GLUR1 level and GABA concentrations in the prefrontal cortex of both juvenile male and female rats. A similar pattern for glutamate was only observed in males. Although EE offspring spent less time on the open arms of the elevated plus maze and had faster escape latencies in a light-dark test, there were no other indications of anxiety-like behavior on these measures or when engaged in social interaction with a conspecific. In the wild, rats live in complicated and variable environments. Consequently dams must leave their nest to defend and forage, limiting their duration of direct contact. EE exposure in early development may mimic this naturalistic maternal separation, shaping parental behavior and offspring resiliency to stressors.

Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system.

Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100µg/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.

Anterior, extracanalar, cervical spine osteochondroma associated with DISH: description of a very rare tumor causing bilateral vocal cord paralysis, laryngeal compression and dysphagia. Case report and review of the literature.

INTRODUCTION: Osteochondromas are common benign bone tumors, rarely involving the spine. BACKGROUND: Osteochondroma account for about 35% of bone benign tumors and 9% of all bone tumors. Spinal involvement is described in 1%-4% of cases and their origin from the anterior surface of cervical vertebral bodies is exceedingly rare. AIM: We describe the rare case of an osteochondroma arising from the anterior surface of the C4 and C5 vertebral bodies, and not involving the spinal canal, in a 68-year-old male patient suffering from Diffuse Idiopathic Skeletal Hyperostosis (DISH). MATERIALS AND METHODS: The patient presented with acute onset of respiratory distress due to laryngeal compression exerted by the lesion, dysphagia and paralysis of left vocal cord. Imaging revealed the unusual lesion compressing and dislocating the air ways. An anterior approach to cervical spine was performed to remove the tumor. RESULTS: Postoperatively, the patient sustained a progressive improvement of respiratory function and recovery of the vocal cord paralysis. DISCUSSION: We believe that this case holds some interesting peculiarities: firstly, the anterior location of a cervical osteochondroma could be considered exceptional; yet, the resulting clinical picture should be remembered for differential diagnosis. Secondly, we hypothesized a possible correlation between the tumorigenesis of osteochondroma and the co-existence of DISH. Indeed, the abnormal bone turnover in cervical segments due to DISH could explain the unusual occurrence of osteochondromas in adult age. CONCLUSIONS: The occurrence of an osteochondroma should be considered in patients suffering from DISH and harbouring large osteophytes.

Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-µg GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 µg of GDNF in PBS or cationic liposomes 1h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-µg doses of GDNF in PBS, or 150-µg doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-µg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-µg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD.

Pharmacophore model of the quercetin binding site of the SIRT6 protein.

SIRT6 is a histone deacetylase that has been proposed as a potential therapeutic target for metabolic disorders and the prevention of age-associated diseases. We have previously reported on the identification of quercetin and vitexin as SIRT6 inhibitors, and studied structurally related flavonoids including luteolin, kaempferol, apigenin and naringenin. It was determined that the SIRT6 protein remained active after immobilization and that a single frontal displacement could correctly predict the functional activity of the immobilized enzyme. The previous study generated a preliminary pharmacophore for the quercetin binding site on SIRT6, containing 3 hydrogen bond donors and one hydrogen bond acceptor. In this study, we have generated a refined pharmacophore with an additional twelve quercetin analogs. The resulting model had a positive linear behavior between the experimental elution time verses the fit values obtained from the model with a correlation coefficient of 0.8456.

Redox regulation of cellular stress response in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies.

TRAIL, DR5 and caspase 3-dependent apoptosis in vessels of diseased human temporomandibular joint disc. An immunohistochemical study.

To evaluate the apoptosis involvement in the angiogenesis as a self-limiting process in patients with temporomandibular joint (TMJ) degenerated disc vessels, we assessed, by immunohistochemistry, the detection of TRAIL, its death receptor DR5 and caspase 3. TRAIL, its death receptor DR5 and caspase 3 expression were studied by immunohistochemistry in 15 TMJ discs displaced without reduction and in 4 unaffected discs. These apoptosis molecules were detected in the intima and media layers of newly formed vessels affected discs. In conclusion, vessels apoptosis activation in TMJ disc with ID could be regarded as a self-limiting process that try to leads to vessel regression; in this way an inhibition of angiogenic vessels may prove a key strategy in limiting pathological angiogenesis, by cutting off blood supply to tumors, or by reducing harmful inflammation.

The membrane response of hippocampal CA3b pyramidal neurons near rest: Heterogeneity of passive properties and the contribution of hyperpolarization-activated currents.

Pyramidal neurons in the CA3 region of the hippocampal formation integrate synaptic information arriving in the dendrites within discrete laminar regions. At potentials near or below the resting potential integration of synaptic signals is most affected by the passive properties of the cell and hyperpolarization-activated currents (I(h)). Here we focused specifically on a subset of neurons within the CA3b subregion of the rat hippocampus in order to better understand their membrane response within subthreshold voltage ranges. Using a combined experimental and computational approach we found that the passive properties of these neurons varied up to fivefold between cells. Likewise, there was a large variance in the expression of I(h) channels. However, the contribution of I(h) was minimal at resting potentials endowing the membrane with an apparent linear response to somatic current injection within +/-10 mV. Unlike in CA1 pyramidal neurons, however, I(h) activation was not potentiated in an activity-dependent manner. Computer modeling, based on a combination of voltage- and current-clamp data, suggested that an increasing density of these channels with distance from the soma, compared with a uniform distribution, would have no significant effect on the general properties of the cell because of their relatively lower expression. Nonetheless, temporal summation of excitatory inputs was affected by the presence of I(h) in the dendrites in a frequency- and distance-dependent fashion.

Preterm delivery and premature rupture of membranes after conization in 80 women. Preliminary data.

AIM: Cervical intraepithelial neoplasia is most frequently in young women in reproductive age. Cold knife conization, laser ablation, laser conization and large loop excision are conservative methods of treatment to remove the transformation zone and preserve the cervical function. Previous studies have shown conflicting results on the outcomes of pregnancy following these therapies that might increase the risk of preterm delivery. The purpose of this study was to evaluate the outcome of pregnancy after conization and its role as predictive risk factor. METHODS: A retrospective study was performed. The study group comprised 80 women who had a conization and that had a subsequent singleton pregnancy. Variables considered includes maternal excision date, surgery procedure, previous surgery treatments, time interval between excisional procedure and subsequent pregnancy; duration and week of pregnancy, mode of delivery, histological grading (no cervical intraepithelial neoplasia [CIN], CIN 1, CIN 2-3) and cone excised depth. RESULTS: In group study 45 women underwent loop electrosurgical excision procedure (LEEP) conization, 32 cold knife conization and 3 laser CO2. The authors found 11 cases of cone tissue depth<1 cm, and remaining one>1 cm. Eight preterm delivery have been reported to data: 5 between 28 and 34 weeks, 2 lower than 28 weeks and 1 between 34 and 37 weeks. CONCLUSION: In these preliminary data the percentage of preterm birth appears as 10% and in range 6-15% evaluated for women not submitted to excisional procedures.

Realistic simulations of neuronal activity: a contribution to the debate on direct detection of neuronal currents by MRI.

Many efforts have been done in order to preview the properties of the magnetic resonance (MR) signals produced by the neuronal currents using simulations. In this paper, starting with a detailed calculation of the magnetic field produced by the neuronal currents propagating over single hippocampal CA1 pyramidal neurons placed inside a cubic MR voxel of length 1.2 mm, we proceeded on the estimation of the phase and magnitude MR signals. We then extended the results to layers of parallel and synchronous similar neurons and to ensembles of layers, considering different echo times, voxel volumes and neuronal densities. The descriptions of the neurons and of their electrical activity took into account the real neuronal morphologies and the physiology of the neuronal events. Our results concern: (a) the expected time course of the MR signals produced by the neuronal currents in the brain, based on physiological and anatomical properties; (b) the different contributions of post-synaptic potentials and of action potentials to the MR signals; (c) the estimation of the equivalent current dipole and the influence of its orientation with respect to the external magnetic field on the observable MR signal variations; (d) the size of the estimated neuronal current induced phase and magnitude MR signal changes with respect to the echo time, voxel-size and neuronal density. The inclusion of realistic neuronal properties into the simulation introduces new information that can be helpful for the design of MR sequences for the direct detection of neuronal current effects and the testing of bio-electromagnetic models.

Dendritic action potentials connect distributed dendrodendritic microcircuits.

Lateral inhibition of cells surrounding an excited area is a key property of sensory systems, sharpening the preferential tuning of individual cells in the presence of closely related input signals. In the olfactory pathway, a dendrodendritic synaptic microcircuit between mitral and granule cells in the olfactory bulb has been proposed to mediate this type of interaction through granule cell inhibition of surrounding mitral cells. However, it is becoming evident that odor inputs result in broad activation of the olfactory bulb with interactions that go beyond neighboring cells. Using a realistic modeling approach we show how backpropagating action potentials in the long lateral dendrites of mitral cells, together with granule cell actions on mitral cells within narrow columns forming glomerular units, can provide a mechanism to activate strong local inhibition between arbitrarily distant mitral cells. The simulations predict a new role for the dendrodendritic synapses in the multicolumnar organization of the granule cells. This new paradigm gives insight into the functional significance of the patterns of connectivity revealed by recent viral tracing studies. Together they suggest a functional wiring of the olfactory bulb that could greatly expand the computational roles of the mitral-granule cell network.

Learning mechanism for column formation in the olfactory bulb.

Sensory discrimination requires distributed arrays of processing units. In the olfactory bulb, the processing units for odor discrimination are believed to involve dendrodendritic synaptic interactions between mitral and granule cells. There is increasing anatomical evidence that these cells are organized in columns, and that the columns processing a given odor are arranged in widely distributed arrays. Experimental evidence is lacking on the underlying learning mechanisms for how these columns and arrays are formed. To gain insight into these mechanisms, we have used a simplified realistic circuit model to test the hypothesis that distributed connectivity can self-organize through an activity-dependent dendrodendritic synaptic mechanism. The results point to action potentials propagating in the mitral cell lateral dendrites as playing a critical role in this mechanism. The model predicts that columns emerge from the interaction between the local temporal dynamics of the action potentials and the synapses that they activate during dendritic propagation. The results suggest a novel and robust learning mechanism for the development of distributed processing units in a cortical structure.