Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.

Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway.

The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show in mice that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.

The human brain contains billions of neurons working together to process the vast array of information we receive from our environment. These neurons communicate at junctions known as synapses, where chemical packages called vesicles released from one neuron stimulate a response in another. This synaptic communication is crucial for our ability to think, learn and remember. However, this activity depends on a complex interplay of proteins, whose balance and location within the neuron are tightly controlled. Any disruption to this delicate equilibrium can cause significant problems, including neurodevelopmental and neuropsychiatric disorders, such as schizophrenia and intellectual disability. One key regulator of activity at the synapse is a protein called Bcl11b, which has been linked to conditions affected by synaptic dysfunction. It plays a critical role in maintaining specific junctions known as mossy fibre synapses, which are important for learning and memory. One of the genes regulated by Bcl11b is C1ql2, which encodes for a synaptic protein. However, it is unclear what molecular mechanisms Bcl11b uses to carry out this role. To address this, Koumoundourou et al. explored the role of C1ql2 in mossy fibre synapses of adult mice. Experiments to manipulate the production of C1ql2 independently of Bcl11b revealed that C1ql2 is vital for recruiting vesicles to the synapse and strengthening synaptic connections between neurons. Further investigation showed that C1ql2's role in this process relies on interacting with another synaptic protein called neurexin-3. Disrupting this interaction reduced the amount of C1ql2 at the synapse and, consequently, impaired vesicle recruitment. These findings will help our understanding of how neurodevelopmental and neuropsychiatric disorders develop. Bcl11b, C1ql2 and neurexin-3 have been independently associated with these conditions, and the now-revealed interactions between these proteins offer new insights into the molecular basis of synaptic faults. This research opens the door to further study of how these proteins interact and their roles in brain health and disease.

Hippocampal-medial entorhinal circuit is differently organized along the dorsoventral axis in rodents.

The general understanding of hippocampal circuits is that the hippocampus and the entorhinal cortex (EC) are topographically connected through parallel identical circuits along the dorsoventral axis. Our anterograde tracing and in vitro electrophysiology data, however, show a markedly different dorsoventral organization of the hippocampal projection to the medial EC (MEC). While dorsal hippocampal projections are confined to the dorsal MEC, ventral hippocampal projections innervate both dorsal and ventral MEC. Further, whereas the dorsal hippocampus preferentially targets layer Vb (LVb) neurons, the ventral hippocampus mainly targets cells in layer Va (LVa). This connectivity scheme differs from hippocampal projections to the lateral EC, which are topographically organized along the dorsoventral axis. As LVa neurons project to telencephalic structures, our findings indicate that the ventral hippocampus regulates LVa-mediated entorhinal-neocortical output from both dorsal and ventral MEC. Overall, the marked dorsoventral differences in hippocampal-entorhinal connectivity impose important constraints on signal flow in hippocampal-neocortical circuits.

Apples and oranges in the basket of a clinical model for exercise addiction: Rebuttal to Brevers et al. (2022).

This note is a reply to Brevers et al.'s (2022) the commentary. We first explain that the commentary's title is in discord with the theoretical implications of the Expanded Interactional Model of Exercise Addiction (EIMEA; Dinardi et al., 2021). Subsequently, we argue that in contrast to Brevers et al.'s arguments, exercise volume or intensive physical exercise is not even mentioned in the revised EIMEA. Most importantly, we point out that the commentary's reference to assessment scales of exercise addiction is irrelevant, because the EIMEA is intended for idiographic clinical cases rather than nomothetic research. Furthermore, we discuss how the ELMEA cannot account for secondary exercise addiction and motivational incentives due to its individual-specific orientation. Finally, we conclude our reply by highlighting that Brevers et al.'s commentary seems to revolve around nomothetic research assessing a certain level of 'risk' of exercise addiction, while the EIMEA accounts for specific clinically dysfunctional cases presented in the limited number of case studies published in the literature.

The expanded interactional model of exercise addiction.

BACKGROUND AND AIMS: Cited in over 100 articles, the interactional model of exercise addiction (Egorov & Szabo, 2013) forms the theoretical foundation of many studies on the risk of exercise addiction. Still, the inclusion of previously omitted determinants could make it more useful. Therefore, this review presents the expanded version of the original model. METHOD: We added 'self-concept' as another determinant in the 'personal factors' domain and 'attractive alternatives' to the 'situational factors' domain. Further, we doubled the reasons for exercise in the 'incentives for exercise domain.' Last, we added a new domain, the 'exercise-related stressors,' to illustrate that exercise itself might be a source of stress. RESULTS: The expanded model is more inclusive and accounts for a greater combination of interactions playing roles in exercise addiction. Overlooking the eventuality that stress resulting from exercise might also fuel the dysfunction was a significant omission from the original model, rectified in the current update. Finally, the new expansions make the model more applicable to competitive situations too. CONCLUSION: The expanded interactional model of exercise addiction is more comprehensive than its original version. It also accounts for the exercise or sport-related stress as possible fuel in addictive exercise behavior.

Endogenous Bufadienolide, Blood Pressure and Alcohol Withdrawal.

BACKGROUND AND OBJECTIVE: Previously, it was demonstrated that marinobufagenin (MBG) is implicated in the development of ethanol withdrawal in rats. It has been shown that ethanol withdrawal is associated with a pressor response in the alcoholics. We hypothesized that elevated levels of sodium pump ligand, MBG, would underline the increase in systolic blood pressure during alcohol withdrawal in humans. METHODS: The cohort included 9 patients with the diagnosis "alcohol dependence syndrome" (F10.(1-3) according to ICD-10). The blood samples for measurement of MBG concentration were collected from the subjects on the first day of withdrawal and after 7 days treatment of the abstinence. Arterial blood pressure was measured via plethysmography at the same time points. RESULTS: The beginning of the alcoholic abstinence was associated with the rise of arterial blood pressure with enhanced levels of plasma MBG. At day 7 following withdrawal, the systolic blood pressure and MBG levels were decreased to normal values. CONCLUSION: The development of alcohol withdrawal is accompanied by an increase in arterial blood pressure, which is associated with increased plasma MBG concentration.

Processing of Hippocampal Network Activity in the Receiver Network of the Medial Entorhinal Cortex Layer V.

The interplay between hippocampus and medial entorhinal cortex (mEC) is of key importance for forming spatial representations. Within the hippocampal-entorhinal loop, the hippocampus receives context-specific signals from layers II/III of the mEC and feeds memory-associated activity back into layer V (LV). The processing of this output signal within the mEC, however, is largely unknown. We characterized the activation of the receiving mEC network by evoked and naturally occurring output patterns in mouse hippocampal-entorhinal cortex slices. Both types of glutamatergic neurons (mEC LVa and LVb) as well as fast-spiking inhibitory interneurons receive direct excitatory input from the intermediate/ventral hippocampus. Connections between the two types of excitatory neurons are sparse, and local processing of hippocampal output signals within mEC LV is asymmetric, favoring excitation of far projecting LVa neurons over locally projecting LVb neurons. These findings suggest a new role for mEC LV as a bifurcation gate for feedforward (telencephalic) and feedback (entorhinal-hippocampal) signal propagation.SIGNIFICANCE STATEMENT Patterned network activity in hippocampal networks plays a key role in the formation and consolidation of spatial memories. It is, however, largely unclear how information is transferred to the neocortex for long-term engrams. Here, we elucidate the propagation of network activity from the hippocampus to the medial entorhinal cortex. We show that patterned output from the hippocampus reaches both major cell types of deep entorhinal layers. These cells are, however, only weakly connected, giving rise to two parallel streams of activity for local and remote signal propagation, respectively. The relative weight of both pathways is regulated by local inhibitory interneurons. Our data reveal important insights into the hippocampal-neocortical dialogue, which is of key importance for memory consolidation in the mammalian brain.

Clusters of cooperative ion channels enable a membrane-potential-based mechanism for short-term memory.

Across biological systems, cooperativity between proteins enables fast actions, supra-linear responses, and long-lasting molecular switches. In the nervous system, however, the function of cooperative interactions between voltage-dependent ionic channels remains largely unknown. Based on mathematical modeling, we here demonstrate that clusters of strongly cooperative ion channels can plausibly form bistable conductances. Consequently, clusters are permanently switched on by neuronal spiking, switched off by strong hyperpolarization, and remain in their state for seconds after stimulation. The resulting short-term memory of the membrane potential allows to generate persistent firing when clusters of cooperative channels are present together with non-cooperative spike-generating conductances. Dynamic clamp experiments in rodent cortical neurons confirm that channel cooperativity can robustly induce graded persistent activity - a single-cell based, multistable mnemonic firing mode experimentally observed in several brain regions. We therefore propose that ion channel cooperativity constitutes an efficient cell-intrinsic implementation for short-term memories at the voltage level.

Impact of Social Conformity on Ethanol Preference in Wistar Rats.

INTRODUCTION: Social conformity is considered a possible promoter of alcohol use disorder in humans. The goal of this study was to explore the impact of conformity as one of the social factors that might contribute to the alcohol preference in a rat model of ethanol intake. METHODS: To model social conformity, 105 Wistar rats were group housed (3 animals per cage) with a different number of rats drinking either 10% ethanol or water during daily drinking sessions. Ethanol preference tests were performed. RESULTS: Ethanol preference significantly increased if the majority of cage mates received ethanol during drinking sessions. The analysis also showed an increase in the number of approaches to the ethanol bottle versus the water bottle and an increased duration of a single ethanol approach during the 2 bottle preference test in such groups. CONCLUSION: These results demonstrate that social conditions promote the ethanol consumption in the novel conformity model used in this study.

TRPC channels are not required for graded persistent activity in entorhinal cortex neurons.

Adaptive behavior requires the transient storage of information beyond the physical presence of external stimuli. This short-lasting form of memory involves sustained ("persistent") neuronal firing which may be generated by cell-autonomous biophysical properties of neurons or/and neural circuit dynamics. A number of studies from brain slices reports intrinsically generated persistent firing in cortical excitatory neurons following suprathreshold depolarization by intracellular current injection. In layer V (LV) neurons of the medial entorhinal cortex (mEC) persistent firing depends on the activation of cholinergic muscarinic receptors and is mediated by a calcium-activated nonselective cation current (ICAN ). The molecular identity of this conductance remains, however, unknown. Recently, it has been suggested that the underlying ion channels belong to the canonical transient receptor potential (TRPC) channel family and include heterotetramers of TRPC1/5, TRPC1/4, and/or TRPC1/4/5 channels. While this suggestion was based on pharmacological experiments and on effects of TRP-interacting peptides, an unambiguous proof based on TRPC channel-depleted animals is pending. Here, we used two different lines of TRPC channel knockout mice, either lacking TRPC1-, TRPC4-, and TRPC5-containing channels or lacking all seven members of the TRPC family. We report unchanged persistent activity in mEC LV neurons in these animals, ruling out that muscarinic-dependent persistent activity depends on TRPC channels.

Synaptic entrainment of ectopic action potential generation in hippocampal pyramidal neurons.

KEY POINTS: Ectopic action potentials (EAPs) arise at distal locations in axonal fibres and are often associated with neuronal pathologies such as epilepsy or nerve injury, but they also occur during physiological network conditions. This study investigates whether initiation of such EAPs is modulated by subthreshold synaptic activity. Somatic subthreshold potentials invade the axonal compartment to considerable distances (>350 µm), whereas spread of axonal subthreshold potentials to the soma is inefficient. Ectopic spike generation is entrained by conventional synaptic signalling mechanisms. Excitatory synaptic potentials promote EAPs, whereas inhibitory synaptic potentials block EAPs. The modulation of ectopic excitability depends on propagation of somatic voltage deflections to the axonal EAP initiation site. Synaptic modulation of EAP initiation challenges the view of the distal axon being independent of synaptic activity and may contribute to mechanisms underlying fast network oscillations and pathological network activity. ABSTRACT: While most action potentials are generated at the axon initial segment, they can also be triggered at more distal sites along the axon. Such ectopic action potentials (EAPs) occur during several neuronal pathologies such as epilepsy, nerve injuries and inflammation but have also been observed during physiological network activity. EAPs propagate antidromically towards the somato-dendritic compartment where they modulate synaptic plasticity. Here we investigate the converse signal direction: do somato-dendritic synaptic potentials affect the generation of ectopic spikes? We measured anti- and orthodromic spikes in the soma and axon of mouse hippocampal CA1 pyramidal cells. We found that synaptic potentials propagate reliably through the axon, causing significant voltage transients at distances >350 µm. At these sites, excitatory input efficiently facilitated EAP initiation in distal axons and, conversely, inhibitory input suppressed EAP initiation. Our data reveal a new mechanism by which ectopically generated spikes can be entrained by conventional synaptic signalling during normal and pathological network activity.

Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons.

Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP ). Recent evidence indicates that action potentials can also be generated at remote locations along the axonal fiber, giving rise to ectopic action potentials during physiological states (e.g., fast network oscillations) or in pathological situations (e.g., following demyelination). Here, we investigated how ectopic axonal excitability of mouse hippocampal CA1 pyramidal neurons is regulated by INaP . Recordings of field potentials and intracellular voltage in brain slices revealed that electrically evoked antidromic spikes were readily suppressed by two different blockers of INaP , riluzole and phenytoin. The effect was mediated by a reduction of the probability of ectopic spike generation while latency was unaffected. Interestingly, the contribution of INaP to excitability was much more pronounced in axonal branches heading toward the entorhinal cortex compared with the opposite fiber direction toward fimbria. Thus, excitability of distal CA1 pyramidal cell axons is affected by persistent sodium currents in a direction-selective manner. This mechanism may be of importance for ectopic spike generation in oscillating network states as well as in pathological situations.

Stability and Function of Hippocampal Mossy Fiber Synapses Depend on Bcl11b/Ctip2.

Structural and functional plasticity of synapses are critical neuronal mechanisms underlying learning and memory. While activity-dependent regulation of synaptic strength has been extensively studied, much less is known about the transcriptional control of synapse maintenance and plasticity. Hippocampal mossy fiber (MF) synapses connect dentate granule cells to CA3 pyramidal neurons and are important for spatial memory formation and consolidation. The transcription factor Bcl11b/Ctip2 is expressed in dentate granule cells and required for postnatal hippocampal development. Ablation of Bcl11b/Ctip2 in the adult hippocampus results in impaired adult neurogenesis and spatial memory. The molecular mechanisms underlying the behavioral impairment remained unclear. Here we show that selective deletion of Bcl11b/Ctip2 in the adult mouse hippocampus leads to a rapid loss of excitatory synapses in CA3 as well as reduced ultrastructural complexity of remaining mossy fiber boutons (MFBs). Moreover, a dramatic decline of long-term potentiation (LTP) of the dentate gyrus-CA3 (DG-CA3) projection is caused by adult loss of Bcl11b/Ctip2. Differential transcriptomics revealed the deregulation of genes associated with synaptic transmission in mutants. Together, our data suggest Bcl11b/Ctip2 to regulate maintenance and function of MF synapses in the adult hippocampus.

Marinobufagenin in Urine: A Potential Marker of Predisposition to Ethanol and a Target for Spironolactone.

BACKGROUND AND OBJECTIVE: Previously it was demonstrated that digitalis-like cardiotonic steroid, marinobufagenin (MBG), is implicated in the development of ethanol addiction in rats. We hypothesized that (i) levels of sodium pump ligand, MBG, would be negatively correlated with the amount of ethanol consumed by rats, and (ii) that spironolactone would oppose the MBG induced ethanol-seeking behavior and blood pressure in rats. METHODS: Voluntary consumption of 9% alcohol (vs. water) during 10 days period by 11 adult male Wistar rats was studied. Eight weeks after the beginning of the experiment, the animals were divided into two treatment subgroups: high alcohol drinkers (HAD, n=6, daily consumption of ethanol > 4 g/kg) and low alcohol drinkers (LAD, n=5, daily consumption of ethanol < 4 g/kg) rats. Spironolactone treatment (7 days) was started following 3-day habituation to intragastric vehicle administration. Consumption of ethanol and blood pressure were recorded daily. RESULTS: Urinary MBG excretion at baseline was 11.2±0.6 pmoles in HAD rats and 19.1±2.9 pmoles (p<0.05) in LAD rats, respectively. Seven days of spironolactone treatment was associated with reduction in ethanol intake (2.9 g/kg/24 hr), reduction in systolic blood pressure (5 mm Hg), and increase in sodium excretion (1 mmol/24 hr). CONCLUSION: Levels of MBG may be a predisposing factor to voluntary ethanol intake. Spironolactone, along with antihypertensive effect, decreases ethanol intake.

Downstream effects of hippocampal sharp wave ripple oscillations on medial entorhinal cortex layer V neurons in vitro.

The entorhinal cortex (EC) is a critical component of the medial temporal lobe (MTL) memory system. Local networks within the MTL express a variety of state-dependent network oscillations that are believed to organize neuronal activity during memory formation. The peculiar pattern of sharp wave-ripple complexes (SPW-R) entrains neurons by a very fast oscillation at ∼200 Hz in the hippocampal areas CA3 and CA1 and then propagates through the "output loop" into the EC. The precise mechanisms of SPW-R propagation and the resulting cellular input patterns in the mEC are, however, largely unknown. We therefore investigated the activity of layer V (LV) principal neurons of the medial EC (mEC) during SPW-R oscillations in horizontal mouse brain slices. Intracellular recordings in the mEC were combined with extracellular monitoring of propagating network activity. SPW-R in CA1 were regularly followed by negative field potential deflections in the mEC. Propagation of SPW-R activity from CA1 to the mEC was mostly monosynaptic and excitatory, such that synaptic input to mEC LV neurons directly reflected unit activity in CA1. Comparison with propagating network activity from CA3 to CA1 revealed a similar role of excitatory long-range connections for both regions. However, SPW-R-induced activity in CA1 involved strong recruitment of rhythmic synaptic inhibition and corresponding fast field oscillations, in contrast to the mEC. These differences between features of propagating SPW-R emphasize the differential processing of network activity by each local network of the hippocampal output loop. © 2016 Wiley Periodicals, Inc.

KATP channels modulate intrinsic firing activity of immature entorhinal cortex layer III neurons.

Medial temporal lobe structures are essential for memory formation which is associated with coherent network oscillations. During ontogenesis, these highly organized patterns develop from distinct, less synchronized forms of network activity. This maturation process goes along with marked changes in intrinsic firing patterns of individual neurons. One critical factor determining neuronal excitability is activity of ATP-sensitive K(+) channels (KATP channels) which coupled electrical activity to metabolic state. Here, we examined the role of KATP channels for intrinsic firing patterns and emerging network activity in the immature medial entorhinal cortex (mEC) of rats. Western blot analysis of Kir6.2 (a subunit of the KATP channel) confirmed expression of this protein in the immature entorhinal cortex. Neuronal activity was monitored by field potential (fp) and whole-cell recordings from layer III (LIII) of the mEC in horizontal brain slices obtained at postnatal day (P) 6-13. Spontaneous fp-bursts were suppressed by the KATP channel opener diazoxide and prolonged after blockade of KATP channels by glibenclamide. Immature mEC LIII principal neurons displayed two dominant intrinsic firing patterns, prolonged bursts or regular firing activity, respectively. Burst discharges were suppressed by the KATP channel openers diazoxide and NN414, and enhanced by the KATP channel blockers tolbutamide and glibenclamide. Activity of regularly firing neurons was modulated in a frequency-dependent manner: the diazoxide-mediated reduction of firing correlated negatively with basal frequency, while the tolbutamide-mediated increase of firing showed a positive correlation. These data are in line with an activity-dependent regulation of KATP channel activity. Together, KATP channels exert powerful modulation of intrinsic firing patterns and network activity in the immature mEC.

Axon-carrying dendrites convey privileged synaptic input in hippocampal neurons.

Neuronal processing is classically conceptualized as dendritic input, somatic integration, and axonal output. The axon initial segment, the proposed site of action potential generation, usually emanates directly from the soma. However, we found that axons of hippocampal pyramidal cells frequently derive from a basal dendrite rather than from the soma. This morphology is particularly enriched in central CA1, the principal hippocampal output area. Multiphoton glutamate uncaging revealed that input onto the axon-carrying dendrites (AcDs) was more efficient in eliciting action potential output than input onto regular basal dendrites. First, synaptic input onto AcDs generates action potentials with lower activation thresholds compared with regular dendrites. Second, AcDs are intrinsically more excitable, generating dendritic spikes with higher probability and greater strength. Thus, axon-carrying dendrites constitute a privileged channel for excitatory synaptic input in a subset of cortical pyramidal cells.

Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro.

The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal networks.

Development of coherent neuronal activity patterns in mammalian cortical networks: common principles and local hetereogeneity.

Many mammals are born in a very immature state and develop their rich repertoire of behavioral and cognitive functions postnatally. This development goes in parallel with changes in the anatomical and functional organization of cortical structures which are involved in most complex activities. The emerging spatiotemporal activity patterns in multi-neuronal cortical networks may indeed form a direct neuronal correlate of systemic functions like perception, sensorimotor integration, decision making or memory formation. During recent years, several studies--mostly in rodents--have shed light on the ontogenesis of such highly organized patterns of network activity. While each local network has its own peculiar properties, some general rules can be derived. We therefore review and compare data from the developing hippocampus, neocortex and--as an intermediate region--entorhinal cortex. All cortices seem to follow a characteristic sequence starting with uncorrelated activity in uncoupled single neurons where transient activity seems to have mostly trophic effects. In rodents, before and shortly after birth, cortical networks develop weakly coordinated multineuronal discharges which have been termed synchronous plateau assemblies (SPAs). While these patterns rely mostly on electrical coupling by gap junctions, the subsequent increase in number and maturation of chemical synapses leads to the generation of large-scale coherent discharges. These patterns have been termed giant depolarizing potentials (GDPs) for predominantly GABA-induced events or early network oscillations (ENOs) for mostly glutamatergic bursts, respectively. During the third to fourth postnatal week, cortical areas reach their final activity patterns with distinct network oscillations and highly specific neuronal discharge sequences which support adult behavior. While some of the mechanisms underlying maturation of network activity have been elucidated much work remains to be done in order to fully understand the rules governing transition from immature to mature patterns of network activity.

The exercise paradox: An interactional model for a clearer conceptualization of exercise addiction.

BACKGROUND AND AIMS: Exercise addiction receives substantial attention in the field of behavioral addictions. It is a unique form of addiction because in contrast to other addictive disorders it is carried out with major physical-effort and high energy expenditure. METHODS: A critical literature review was performed. RESULTS: The literature evaluation shows that most published accounts report the levels of risk for exercise addiction rather than actual cases or morbidities. The inconsistent prevalence of exercise addiction, ranging from 0.3% to 77.0%, reported in the literature may be ascribed to incomplete conceptual models for the morbidity. Current explanations of exercise addiction may suggest that the disorder is progressive from healthy to unhealthy exercise pattern. This approach drives research into the wrong direction. DISCUSSION: An interactional model is offered accounting for the adoption, maintenance, and transformation of exercise behavior. The here proposed model has an idiosyncratic black-box containing the antecedents and characteristics that are unique to the individual, which cannot be researched via the nomothetic approach. Subjective aspects in the black-box interact with stressful life events that force the person to cope. The range of coping may be wide. Escape into exercise depends on personal (subjective) and situational (objective) factors, but the subjective components are inaccessible for a priori scholastic scrutiny. It is our view that currently only this dual interactional model may account for the fact that exercise addiction emerges suddenly and only in a few individuals from among those at high risk, estimated to be around 3.0% of the exercising population.